Nonmelanoma Skin Cancer

TOPLINE:

A recent survey highlighted ethical concerns US oncologists have about using artificial intelligence (AI) to help make cancer treatment decisions and revealed some contradictory views about how best to integrate these tools into practice. Most respondents, for instance, said patients should not be expected to understand how AI tools work, but many also felt patients could make treatment decisions based on AI-generated recommendations. Most oncologists also felt responsible for protecting patients from biased AI, but few were confident that they could do so.

METHODOLOGY:

• The US Food and Drug Administration (FDA) has  for use in various medical specialties over the past few decades, and increasingly, AI tools are being integrated into cancer care.
• However, the uptake of these tools in oncology has raised ethical questions and concerns, including challenges with AI bias, error, or misuse, as well as issues explaining how an AI model reached a result.
• In the current study, researchers asked 204 oncologists from 37 states for their views on the ethical implications of using AI for cancer care.
• Among the survey respondents, 64% were men and 63% were non-Hispanic White; 29% were from academic practices, 47% had received some education on AI use in healthcare, and 45% were familiar with clinical decision models.
• The researchers assessed respondents’ answers to various questions, including whether to provide informed consent for AI use and how oncologists would approach a scenario where the AI model and the oncologist recommended a different treatment regimen.

TAKEAWAY:

• Overall, 81% of oncologists supported having patient consent to use an AI model during treatment decisions, and 85% felt that oncologists needed to be able to explain an AI-based clinical decision model to use it in the clinic; however, only 23% felt that patients also needed to be able to explain an AI model.
• When an AI decision model recommended a different treatment regimen than the treating oncologist, the most common response (36.8%) was to present both options to the patient and let the patient decide. Oncologists from academic settings were about 2.5 times more likely than those from other settings to let the patient decide. About 34% of respondents said they would present both options but recommend the oncologist’s regimen, whereas about 22% said they would present both but recommend the AI’s regimen. A small percentage would only present the oncologist’s regimen (5%) or the AI’s regimen (about 2.5%).
• About three of four respondents (76.5%) agreed that oncologists should protect patients from biased AI tools; however, only about one of four (27.9%) felt confident they could identify biased AI models.
• Most oncologists (91%) felt that AI developers were responsible for the medico-legal problems associated with AI use; less than half (47%) said oncologists or hospitals (43%) shared this responsibility.

IN PRACTICE:

“Together, these data characterize barriers that may impede the ethical adoption of AI into cancer care. The findings suggest that the implementation of AI in oncology must include rigorous assessments of its effect on care decisions, as well as decisional responsibility when problems related to AI use arise,” the authors concluded.

SOURCE:

The study, with first author Andrew Hantel, MD, from Dana-Farber Cancer Institute, Boston, was published last month in JAMA Network Open.

LIMITATIONS:

The study had a moderate sample size and response rate, although demographics of participating oncologists appear to be nationally representative. The cross-sectional study design limited the generalizability of the findings over time as AI is integrated into cancer care.

DISCLOSURES:

The study was funded by the National Cancer Institute, the Dana-Farber McGraw/Patterson Research Fund, and the Mark Foundation Emerging Leader Award. Dr. Hantel reported receiving personal fees from AbbVie, AstraZeneca, the American Journal of Managed Care, Genentech, and GSK.

A version of this article appeared on Medscape.com.

TOPLINE:

A recent survey highlighted ethical concerns US oncologists have about using artificial intelligence (AI) to help make cancer treatment decisions and revealed some contradictory views about how best to integrate these tools into practice. Most respondents, for instance, said patients should not be expected to understand how AI tools work, but many also felt patients could make treatment decisions based on AI-generated recommendations. Most oncologists also felt responsible for protecting patients from biased AI, but few were confident that they could do so.

METHODOLOGY:

• The US Food and Drug Administration (FDA) has  for use in various medical specialties over the past few decades, and increasingly, AI tools are being integrated into cancer care.
• However, the uptake of these tools in oncology has raised ethical questions and concerns, including challenges with AI bias, error, or misuse, as well as issues explaining how an AI model reached a result.
• In the current study, researchers asked 204 oncologists from 37 states for their views on the ethical implications of using AI for cancer care.
• Among the survey respondents, 64% were men and 63% were non-Hispanic White; 29% were from academic practices, 47% had received some education on AI use in healthcare, and 45% were familiar with clinical decision models.
• The researchers assessed respondents’ answers to various questions, including whether to provide informed consent for AI use and how oncologists would approach a scenario where the AI model and the oncologist recommended a different treatment regimen.

TAKEAWAY:

• Overall, 81% of oncologists supported having patient consent to use an AI model during treatment decisions, and 85% felt that oncologists needed to be able to explain an AI-based clinical decision model to use it in the clinic; however, only 23% felt that patients also needed to be able to explain an AI model.
• When an AI decision model recommended a different treatment regimen than the treating oncologist, the most common response (36.8%) was to present both options to the patient and let the patient decide. Oncologists from academic settings were about 2.5 times more likely than those from other settings to let the patient decide. About 34% of respondents said they would present both options but recommend the oncologist’s regimen, whereas about 22% said they would present both but recommend the AI’s regimen. A small percentage would only present the oncologist’s regimen (5%) or the AI’s regimen (about 2.5%).
• About three of four respondents (76.5%) agreed that oncologists should protect patients from biased AI tools; however, only about one of four (27.9%) felt confident they could identify biased AI models.
• Most oncologists (91%) felt that AI developers were responsible for the medico-legal problems associated with AI use; less than half (47%) said oncologists or hospitals (43%) shared this responsibility.

IN PRACTICE:

“Together, these data characterize barriers that may impede the ethical adoption of AI into cancer care. The findings suggest that the implementation of AI in oncology must include rigorous assessments of its effect on care decisions, as well as decisional responsibility when problems related to AI use arise,” the authors concluded.

SOURCE:

The study, with first author Andrew Hantel, MD, from Dana-Farber Cancer Institute, Boston, was published last month in JAMA Network Open.

LIMITATIONS:

The study had a moderate sample size and response rate, although demographics of participating oncologists appear to be nationally representative. The cross-sectional study design limited the generalizability of the findings over time as AI is integrated into cancer care.

DISCLOSURES:

The study was funded by the National Cancer Institute, the Dana-Farber McGraw/Patterson Research Fund, and the Mark Foundation Emerging Leader Award. Dr. Hantel reported receiving personal fees from AbbVie, AstraZeneca, the American Journal of Managed Care, Genentech, and GSK.

A version of this article appeared on Medscape.com.

TOPLINE:

A recent survey highlighted ethical concerns US oncologists have about using artificial intelligence (AI) to help make cancer treatment decisions and revealed some contradictory views about how best to integrate these tools into practice. Most respondents, for instance, said patients should not be expected to understand how AI tools work, but many also felt patients could make treatment decisions based on AI-generated recommendations. Most oncologists also felt responsible for protecting patients from biased AI, but few were confident that they could do so.

METHODOLOGY:

• The US Food and Drug Administration (FDA) has  for use in various medical specialties over the past few decades, and increasingly, AI tools are being integrated into cancer care.
• However, the uptake of these tools in oncology has raised ethical questions and concerns, including challenges with AI bias, error, or misuse, as well as issues explaining how an AI model reached a result.
• In the current study, researchers asked 204 oncologists from 37 states for their views on the ethical implications of using AI for cancer care.
• Among the survey respondents, 64% were men and 63% were non-Hispanic White; 29% were from academic practices, 47% had received some education on AI use in healthcare, and 45% were familiar with clinical decision models.
• The researchers assessed respondents’ answers to various questions, including whether to provide informed consent for AI use and how oncologists would approach a scenario where the AI model and the oncologist recommended a different treatment regimen.

TAKEAWAY:

• Overall, 81% of oncologists supported having patient consent to use an AI model during treatment decisions, and 85% felt that oncologists needed to be able to explain an AI-based clinical decision model to use it in the clinic; however, only 23% felt that patients also needed to be able to explain an AI model.
• When an AI decision model recommended a different treatment regimen than the treating oncologist, the most common response (36.8%) was to present both options to the patient and let the patient decide. Oncologists from academic settings were about 2.5 times more likely than those from other settings to let the patient decide. About 34% of respondents said they would present both options but recommend the oncologist’s regimen, whereas about 22% said they would present both but recommend the AI’s regimen. A small percentage would only present the oncologist’s regimen (5%) or the AI’s regimen (about 2.5%).
• About three of four respondents (76.5%) agreed that oncologists should protect patients from biased AI tools; however, only about one of four (27.9%) felt confident they could identify biased AI models.
• Most oncologists (91%) felt that AI developers were responsible for the medico-legal problems associated with AI use; less than half (47%) said oncologists or hospitals (43%) shared this responsibility.

IN PRACTICE:

“Together, these data characterize barriers that may impede the ethical adoption of AI into cancer care. The findings suggest that the implementation of AI in oncology must include rigorous assessments of its effect on care decisions, as well as decisional responsibility when problems related to AI use arise,” the authors concluded.

SOURCE:

The study, with first author Andrew Hantel, MD, from Dana-Farber Cancer Institute, Boston, was published last month in JAMA Network Open.

LIMITATIONS:

The study had a moderate sample size and response rate, although demographics of participating oncologists appear to be nationally representative. The cross-sectional study design limited the generalizability of the findings over time as AI is integrated into cancer care.

DISCLOSURES:

The study was funded by the National Cancer Institute, the Dana-Farber McGraw/Patterson Research Fund, and the Mark Foundation Emerging Leader Award. Dr. Hantel reported receiving personal fees from AbbVie, AstraZeneca, the American Journal of Managed Care, Genentech, and GSK.

A version of this article appeared on Medscape.com.

SAN DIEGO — The number of solid organ transplant survivors is on the rise, a dermatologist told colleagues, and they face unique challenges from higher risks for skin cancer and skin infections because of their suppressed immune systems.

“There are over 450,000 people with a solid organ transplant living in the United States. If you do the math, that works out to about 40 organ transplant recipients for every dermatologist, so there’s a lot of them out there for us to take care of,” Sean Christensen, MD, PhD, associate professor of dermatology, Yale University, New Haven, Connecticut, said at the annual meeting of the American Academy of Dermatology (AAD). “If we expand that umbrella to include all types of immunosuppression, that’s over 4 million adults in the US.”

Dr. Christensen encouraged dermatologists to be aware of the varying risks for immunosuppressive drugs and best screening practices for these patients, and to take advantage of a validated skin cancer risk assessment tool for transplant patients.

During his presentation, he highlighted five classes of immunosuppressive drugs and their associated skin cancer risks:

• Calcineurin inhibitors (tacrolimus or cyclosporine), which cause severe immune suppression and pose a severe skin cancer risk. They may also cause gingival hyperplasia and sebaceous hyperplasia.
• Antimetabolites (mycophenolate mofetil or azathioprine), which cause moderate to severe immune suppression and pose a severe skin cancer risk.
• Mammalian target of rapamycin inhibitors (sirolimus or everolimus), which cause severe immune suppression and pose a moderate skin cancer risk. They also impair wound healing.
• Corticosteroids (prednisone), which cause mild to severe immune suppression and pose a minimal skin cancer risk.
• A decoy receptor protein (belatacept), which causes severe immune suppression and poses a mild skin cancer risk.

“Most of our solid-organ transplant recipients will be on both a calcineurin inhibitor and an antimetabolite,” Dr. Christensen said. “In addition to the skin cancer risk associated with immunosuppression, there is an additive risk” that is a direct effect of these medications on the skin. “That means our transplant recipients have a severely and disproportionate increase in skin cancer,” he noted.

Up to half of solid-organ transplant recipients will develop skin cancer, Dr. Christensen said. These patients have a sixfold to 10-fold increased risk for basal cell carcinoma (BCC), a 35- to 65-fold increased risk for squamous cell carcinoma (SCC), a twofold to sevenfold increased risk for melanoma, and a 16- to 100-fold increased risk for Merkel cell carcinoma.

Transplant recipients with SCC, he said, have a twofold to threefold higher risk for metastasis (4%-8% nodal metastasis) and twofold to fivefold higher risk for death (2%-7% mortality) from SCC.

As for other kinds of immunosuppression, HIV positivity, treatment with 6-mercaptopurine or azathioprine (for inflammatory bowel disease and rheumatoid arthritis), and antitumor necrosis factor agents (for psoriasis, inflammatory bowel disease, and rheumatoid arthritis) have been linked in studies to a higher risk for nonmelanoma skin cancer.

Dr. Christensen also highlighted graft-versus-host disease (GVHD). “It does look like there is a disproportionate and increased risk of SCC of the oropharynx and of the skin in patients who have chronic GVHD. This is probably due to a combination of both the immunosuppressive medications that are required but also from chronic and ongoing inflammation in the skin.”

Chronic GVHD has been linked to a 5.3-fold increase in the risk for SCC and a twofold increase in the risk for BCC, he added.

Moreover, new medications for treating GVHD have been linked to an increased risk for SCC, including a 3.2-fold increased risk for SCC associated with ruxolitinib, a Janus kinase (JAK) 1 and JAK2 inhibitor, in a study of patients with polycythemia vera and myelofibrosis; and a case report of SCC in a patient treated with belumosudil, a rho-associated coiled-coil-containing protein kinase-2 kinase inhibitor, for chronic GVHD. Risk for SCC appears to increase based on duration of use with voriconazole, an antifungal, which, he said, is a potent photosynthesizer.

Dr. Christensen also noted the higher risk for infections in immunocompromised patients and added that these patients can develop inflammatory disease despite immunosuppression:

Staphylococcus, Streptococcus, and Dermatophytes are the most common skin pathogens in these patients. There’s a significantly increased risk for reactivation of herpes simplex, varicella-zoster viruses, and cytomegalovirus. Opportunistic and disseminated fungal infections, such as mycobacteria, Candida, histoplasma, cryptococcus, aspergillus, and mucormycosis, can also appear.

More than 80% of transplant recipients develop molluscum and verruca vulgaris/human papillomavirus infection. They may also develop noninfectious inflammatory dermatoses.

Risk Calculator

What can dermatologists do to help transplant patients? Dr. Christensen highlighted the Skin and UV Neoplasia Transplant Risk Assessment Calculator, which predicts skin cancer risk based on points given for race, gender, skin cancer history, age at transplant, and site of transplant.

The tool, validated in a 2023 study of transplant recipients in Europe, is available online and as an app. It makes recommendations to users about when patients should have initial skin screening exams. Those with the most risk — 45% at 5 years — should be screened within 6 months. “We can use [the tool] to triage these cases when we first meet them and get them plugged into the appropriate care,” Dr. Christensen said.

He recommended seeing high-risk patients at least annually. Patients with a prior SCC and a heavy burden of actinic keratosis should be followed more frequently, he said.

In regard to SCC, he highlighted a 2024 study of solid organ transplant recipients that found the risk for a second SCC after a first SCC was 74%, the risk for a third SCC after a second SCC was 83%, and the risk for another SCC after five SCCs was 92%.

Dr. Christensen disclosed relationships with Canfield Scientific Inc. (consulting), Inhibitor Therapeutics (advisory board), and Sol-Gel Technologies Ltd. (grants/research funding).

A version of this article first appeared on Medscape.com.

SAN DIEGO — The number of solid organ transplant survivors is on the rise, a dermatologist told colleagues, and they face unique challenges from higher risks for skin cancer and skin infections because of their suppressed immune systems.

“There are over 450,000 people with a solid organ transplant living in the United States. If you do the math, that works out to about 40 organ transplant recipients for every dermatologist, so there’s a lot of them out there for us to take care of,” Sean Christensen, MD, PhD, associate professor of dermatology, Yale University, New Haven, Connecticut, said at the annual meeting of the American Academy of Dermatology (AAD). “If we expand that umbrella to include all types of immunosuppression, that’s over 4 million adults in the US.”

Dr. Christensen encouraged dermatologists to be aware of the varying risks for immunosuppressive drugs and best screening practices for these patients, and to take advantage of a validated skin cancer risk assessment tool for transplant patients.

During his presentation, he highlighted five classes of immunosuppressive drugs and their associated skin cancer risks:

• Calcineurin inhibitors (tacrolimus or cyclosporine), which cause severe immune suppression and pose a severe skin cancer risk. They may also cause gingival hyperplasia and sebaceous hyperplasia.
• Antimetabolites (mycophenolate mofetil or azathioprine), which cause moderate to severe immune suppression and pose a severe skin cancer risk.
• Mammalian target of rapamycin inhibitors (sirolimus or everolimus), which cause severe immune suppression and pose a moderate skin cancer risk. They also impair wound healing.
• Corticosteroids (prednisone), which cause mild to severe immune suppression and pose a minimal skin cancer risk.
• A decoy receptor protein (belatacept), which causes severe immune suppression and poses a mild skin cancer risk.

“Most of our solid-organ transplant recipients will be on both a calcineurin inhibitor and an antimetabolite,” Dr. Christensen said. “In addition to the skin cancer risk associated with immunosuppression, there is an additive risk” that is a direct effect of these medications on the skin. “That means our transplant recipients have a severely and disproportionate increase in skin cancer,” he noted.

Up to half of solid-organ transplant recipients will develop skin cancer, Dr. Christensen said. These patients have a sixfold to 10-fold increased risk for basal cell carcinoma (BCC), a 35- to 65-fold increased risk for squamous cell carcinoma (SCC), a twofold to sevenfold increased risk for melanoma, and a 16- to 100-fold increased risk for Merkel cell carcinoma.

Transplant recipients with SCC, he said, have a twofold to threefold higher risk for metastasis (4%-8% nodal metastasis) and twofold to fivefold higher risk for death (2%-7% mortality) from SCC.

As for other kinds of immunosuppression, HIV positivity, treatment with 6-mercaptopurine or azathioprine (for inflammatory bowel disease and rheumatoid arthritis), and antitumor necrosis factor agents (for psoriasis, inflammatory bowel disease, and rheumatoid arthritis) have been linked in studies to a higher risk for nonmelanoma skin cancer.

Dr. Christensen also highlighted graft-versus-host disease (GVHD). “It does look like there is a disproportionate and increased risk of SCC of the oropharynx and of the skin in patients who have chronic GVHD. This is probably due to a combination of both the immunosuppressive medications that are required but also from chronic and ongoing inflammation in the skin.”

Chronic GVHD has been linked to a 5.3-fold increase in the risk for SCC and a twofold increase in the risk for BCC, he added.

Moreover, new medications for treating GVHD have been linked to an increased risk for SCC, including a 3.2-fold increased risk for SCC associated with ruxolitinib, a Janus kinase (JAK) 1 and JAK2 inhibitor, in a study of patients with polycythemia vera and myelofibrosis; and a case report of SCC in a patient treated with belumosudil, a rho-associated coiled-coil-containing protein kinase-2 kinase inhibitor, for chronic GVHD. Risk for SCC appears to increase based on duration of use with voriconazole, an antifungal, which, he said, is a potent photosynthesizer.

Dr. Christensen also noted the higher risk for infections in immunocompromised patients and added that these patients can develop inflammatory disease despite immunosuppression:

Staphylococcus, Streptococcus, and Dermatophytes are the most common skin pathogens in these patients. There’s a significantly increased risk for reactivation of herpes simplex, varicella-zoster viruses, and cytomegalovirus. Opportunistic and disseminated fungal infections, such as mycobacteria, Candida, histoplasma, cryptococcus, aspergillus, and mucormycosis, can also appear.

More than 80% of transplant recipients develop molluscum and verruca vulgaris/human papillomavirus infection. They may also develop noninfectious inflammatory dermatoses.

Risk Calculator

What can dermatologists do to help transplant patients? Dr. Christensen highlighted the Skin and UV Neoplasia Transplant Risk Assessment Calculator, which predicts skin cancer risk based on points given for race, gender, skin cancer history, age at transplant, and site of transplant.

The tool, validated in a 2023 study of transplant recipients in Europe, is available online and as an app. It makes recommendations to users about when patients should have initial skin screening exams. Those with the most risk — 45% at 5 years — should be screened within 6 months. “We can use [the tool] to triage these cases when we first meet them and get them plugged into the appropriate care,” Dr. Christensen said.

He recommended seeing high-risk patients at least annually. Patients with a prior SCC and a heavy burden of actinic keratosis should be followed more frequently, he said.

In regard to SCC, he highlighted a 2024 study of solid organ transplant recipients that found the risk for a second SCC after a first SCC was 74%, the risk for a third SCC after a second SCC was 83%, and the risk for another SCC after five SCCs was 92%.

Dr. Christensen disclosed relationships with Canfield Scientific Inc. (consulting), Inhibitor Therapeutics (advisory board), and Sol-Gel Technologies Ltd. (grants/research funding).

A version of this article first appeared on Medscape.com.

SAN DIEGO — The number of solid organ transplant survivors is on the rise, a dermatologist told colleagues, and they face unique challenges from higher risks for skin cancer and skin infections because of their suppressed immune systems.

“There are over 450,000 people with a solid organ transplant living in the United States. If you do the math, that works out to about 40 organ transplant recipients for every dermatologist, so there’s a lot of them out there for us to take care of,” Sean Christensen, MD, PhD, associate professor of dermatology, Yale University, New Haven, Connecticut, said at the annual meeting of the American Academy of Dermatology (AAD). “If we expand that umbrella to include all types of immunosuppression, that’s over 4 million adults in the US.”

Dr. Christensen encouraged dermatologists to be aware of the varying risks for immunosuppressive drugs and best screening practices for these patients, and to take advantage of a validated skin cancer risk assessment tool for transplant patients.

During his presentation, he highlighted five classes of immunosuppressive drugs and their associated skin cancer risks:

• Calcineurin inhibitors (tacrolimus or cyclosporine), which cause severe immune suppression and pose a severe skin cancer risk. They may also cause gingival hyperplasia and sebaceous hyperplasia.
• Antimetabolites (mycophenolate mofetil or azathioprine), which cause moderate to severe immune suppression and pose a severe skin cancer risk.
• Mammalian target of rapamycin inhibitors (sirolimus or everolimus), which cause severe immune suppression and pose a moderate skin cancer risk. They also impair wound healing.
• Corticosteroids (prednisone), which cause mild to severe immune suppression and pose a minimal skin cancer risk.
• A decoy receptor protein (belatacept), which causes severe immune suppression and poses a mild skin cancer risk.

“Most of our solid-organ transplant recipients will be on both a calcineurin inhibitor and an antimetabolite,” Dr. Christensen said. “In addition to the skin cancer risk associated with immunosuppression, there is an additive risk” that is a direct effect of these medications on the skin. “That means our transplant recipients have a severely and disproportionate increase in skin cancer,” he noted.

Up to half of solid-organ transplant recipients will develop skin cancer, Dr. Christensen said. These patients have a sixfold to 10-fold increased risk for basal cell carcinoma (BCC), a 35- to 65-fold increased risk for squamous cell carcinoma (SCC), a twofold to sevenfold increased risk for melanoma, and a 16- to 100-fold increased risk for Merkel cell carcinoma.

Transplant recipients with SCC, he said, have a twofold to threefold higher risk for metastasis (4%-8% nodal metastasis) and twofold to fivefold higher risk for death (2%-7% mortality) from SCC.

As for other kinds of immunosuppression, HIV positivity, treatment with 6-mercaptopurine or azathioprine (for inflammatory bowel disease and rheumatoid arthritis), and antitumor necrosis factor agents (for psoriasis, inflammatory bowel disease, and rheumatoid arthritis) have been linked in studies to a higher risk for nonmelanoma skin cancer.

Dr. Christensen also highlighted graft-versus-host disease (GVHD). “It does look like there is a disproportionate and increased risk of SCC of the oropharynx and of the skin in patients who have chronic GVHD. This is probably due to a combination of both the immunosuppressive medications that are required but also from chronic and ongoing inflammation in the skin.”

Chronic GVHD has been linked to a 5.3-fold increase in the risk for SCC and a twofold increase in the risk for BCC, he added.

Moreover, new medications for treating GVHD have been linked to an increased risk for SCC, including a 3.2-fold increased risk for SCC associated with ruxolitinib, a Janus kinase (JAK) 1 and JAK2 inhibitor, in a study of patients with polycythemia vera and myelofibrosis; and a case report of SCC in a patient treated with belumosudil, a rho-associated coiled-coil-containing protein kinase-2 kinase inhibitor, for chronic GVHD. Risk for SCC appears to increase based on duration of use with voriconazole, an antifungal, which, he said, is a potent photosynthesizer.

Dr. Christensen also noted the higher risk for infections in immunocompromised patients and added that these patients can develop inflammatory disease despite immunosuppression:

Staphylococcus, Streptococcus, and Dermatophytes are the most common skin pathogens in these patients. There’s a significantly increased risk for reactivation of herpes simplex, varicella-zoster viruses, and cytomegalovirus. Opportunistic and disseminated fungal infections, such as mycobacteria, Candida, histoplasma, cryptococcus, aspergillus, and mucormycosis, can also appear.

More than 80% of transplant recipients develop molluscum and verruca vulgaris/human papillomavirus infection. They may also develop noninfectious inflammatory dermatoses.

Risk Calculator

What can dermatologists do to help transplant patients? Dr. Christensen highlighted the Skin and UV Neoplasia Transplant Risk Assessment Calculator, which predicts skin cancer risk based on points given for race, gender, skin cancer history, age at transplant, and site of transplant.

The tool, validated in a 2023 study of transplant recipients in Europe, is available online and as an app. It makes recommendations to users about when patients should have initial skin screening exams. Those with the most risk — 45% at 5 years — should be screened within 6 months. “We can use [the tool] to triage these cases when we first meet them and get them plugged into the appropriate care,” Dr. Christensen said.

He recommended seeing high-risk patients at least annually. Patients with a prior SCC and a heavy burden of actinic keratosis should be followed more frequently, he said.

In regard to SCC, he highlighted a 2024 study of solid organ transplant recipients that found the risk for a second SCC after a first SCC was 74%, the risk for a third SCC after a second SCC was 83%, and the risk for another SCC after five SCCs was 92%.

Dr. Christensen disclosed relationships with Canfield Scientific Inc. (consulting), Inhibitor Therapeutics (advisory board), and Sol-Gel Technologies Ltd. (grants/research funding).

A version of this article first appeared on Medscape.com.

SAN DIEGO — Monitoring a patient’s circulating tumor DNA (ctDNA) can provide valuable insights on early response to targeted therapies among patients with HER2-positive cancers.

This was the main finding of new data presented by study author Razelle Kurzrock, MD, at the American Association for Cancer Research annual meeting.

“We found that on-treatment ctDNA can detect progression before standard-of-care response assessments. These data suggest that monitoring ctDNA can provide clinicians with important prognostic information that may guide treatment decisions,” Dr. Kurzrock, professor at the Medical College of Wisconsin, Milwaukee, said during her presentation.

Christos Evangelou/MDedge News

Commenting on the clinical implications of these findings during an interview, she said the results suggest that ctDNA dynamics provide an early window into predicting response to targeted therapies in patients with HER2-altered cancers, confirming previous findings of the predictive value of ctDNA in other cancer types.

“Such monitoring may be useful in clinical trials and eventually in practice,” she added.
 

Need for new methods to predict early tumor response

Limitations of standard radiographic tumor assessments present challenges in determining clinical response, particularly for patients receiving targeted therapies.

During her talk, Dr. Kurzrock explained that although targeted therapies are effective for patients with specific molecular alterations, standard imaging assessments fail to uncover molecular-level changes within tumors, limiting the ability of clinicians to accurately assess a patient’s response to targeted therapies.

“In addition to limitations with imaging, patients and physicians want to know as soon as possible whether or not the agents are effective, especially if there are side effects,” Dr. Kurzrock during an interview. She added that monitoring early response may be especially important across tumor types, as HER2 therapies are increasingly being considered in the pan-cancer setting.

Commenting on the potential use of this method in other cancer types with HER2 alterations, Pashtoon Murtaza Kasi, MD, MS, noted that since the study relied on a tumor-informed assay, it would be applicable across diverse tumor types.

“It is less about tissue type but more about that particular patient’s tumor at that instant in time for which a unique barcode is created,” said Dr. Kasi, a medical oncologist at Weill Cornell Medicine, New York, who was not involved in the study.

In an interview, he added that the shedding and biology would affect the assay’s performance for some tissue types.
 

Design of patient-specific ctDNA assays

In this retrospective study, the researchers examined ctDNA dynamics in 58 patients with various HER2-positive tumor types, including breast, colorectal, and other solid malignancies harboring HER2 alterations. All the patients received combination HER2-targeted therapy with trastuzumab and pertuzumab in the phase 2 basket trial My Pathway (NCT02091141).

By leveraging comprehensive genomic profiling of each patient’s tumor, the researchers designed personalized ctDNA assays, tracking 2-16 tumor-specific genetic variants in the patients’ blood samples. FoundationOne Tracker was used to detect and quantify ctDNA at baseline and the third cycle of therapy (cycle 3 day 1, or C3D1).

During an interview, Dr. Kurzrock explained that FoundationOne Tracker is a personalized ctDNA monitoring assay that allows for the detection of ctDNA in plasma, enabling ongoing liquid-based monitoring and highly sensitive quantification of ctDNA levels as mean tumor molecules per milliliter of plasma.

Among the 52 patients for whom personalized ctDNA assays were successfully designed, 48 (92.3%) had ctDNA data available at baseline, with a median of 100.7 tumor molecules per milliliter of plasma. Most patients (89.6%) were deemed ctDNA-positive, with a median of 119.5 tumor molecules per milliliter of plasma.
 

Changes in ctDNA levels predict patient survival

The researchers found that patients who experienced a greater than 90% decline in ctDNA levels by the third treatment cycle had significantly longer overall survival (OS) than those with less than 90% ctDNA decline or any increase. According to data presented by Dr. Kurzrock, the median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 9.4 months in the group with less than 90% decline or ctDNA increase (P = .007). These findings held true when the analysis was limited to the 14 patients with colorectal cancer, in which median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 10.2 months in the group with less than 90% decline or ctDNA increase (P = 0.04).

Notably, the prognostic significance of ctDNA changes remained even among patients exhibiting radiographic stable disease, underscoring the limitations of relying solely on anatomic tumor measurements and highlighting the potential for ctDNA monitoring to complement standard clinical assessments. In the subset of patients with radiographic stable disease, those with a greater than 90% ctDNA decline had significantly longer OS than those with less ctDNA reduction (not reached versus 9.4 months; P = .01).

“When used as a complement to imaging, tissue-informed ctDNA monitoring with FoundationOne Tracker can provide more accuracy than imaging alone,” Dr. Kurzrock noted in an interview.

Dr. Kasi echoed Dr. Kurzrock’s enthusiasm regarding the clinical usefulness of these findings, saying, “Not only can you see very early on in whom the ctDNA is going down and clearing, but you can also tell apart within the group who has ‘stable disease’ as to who is deriving more benefit.”

The researchers also observed that increases in on-treatment ctDNA levels often preceded radiographic evidence of disease progression by a median of 1.3 months. These findings highlight the potential for ctDNA monitoring to complement standard clinical assessments, allowing us to detect treatment response and disease progression earlier than what is possible with imaging alone, Dr. Kurzrock explained during her talk. “This early warning signal could allow clinicians to intervene and modify treatment strategies before overt clinical deterioration,” she said.

In an interview, Dr. Kasi highlighted that this high sensitivity and specificity and the short half-life of the tumor-informed ctDNA assay make this liquid biopsy of great clinical value. “The short half-life of a few hours means that if you do an intervention to treat cancer with HER2-directed therapy, you can very quickly assess response to therapy way earlier than traditional radiographic methods.”

Dr. Kasi cautioned, however, that this assay would not capture whether new mutations or HER2 loss occurred at the time of resistance. “A repeat tissue biopsy or a next-generation sequencing-based plasma-only assay would be required for that,” he said.
 

Implementation of ctDNA monitoring in clinical trials

Dr. Kurzrock acknowledged that further research is needed to validate these results in larger, prospective cohorts before FoundationOne Tracker is adopted in the clinic. She noted, however, that this retrospective analysis, along with results from previous studies, provides a rationale for the use of ctDNA monitoring in clinical trials.

“In some centers like ours, ctDNA monitoring is already part of our standard of care since not only does it help from a physician standpoint to have a more accurate and early assessment of response, but patients also appreciate the information gained from ctDNA dynamics,” Dr. Kasi said in an interview. He explained that when radiographic findings are equivocal, ctDNA monitoring is an additional tool in their toolbox to help guide care.

He noted, however, that the cost is a challenge for implementing ctDNA monitoring as a complementary tool for real-time treatment response monitoring. “For serial monitoring, helping to reduce costs would be important in the long run,” he said in an interview. He added that obtaining sufficient tissue for testing using a tumor-informed assay can present a logistical challenge, at least for the first test. “You need sufficient tissue to make the barcode that you then follow along,” he explained.

“Developing guidelines through systematic studies about testing cadence would also be important. This would help establish whether ctDNA monitoring is helpful,” Dr. Kasi said in an interview. He explained that in some situations, biological variables affect the shedding and detection of ctDNA beyond the assay — in those cases, ctDNA monitoring may not be helpful. “Like any test, it is not meant for every patient or clinical question,” Dr. Kasi concluded.

Dr. Kurzrock and Dr. Kasi reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

SAN DIEGO — Monitoring a patient’s circulating tumor DNA (ctDNA) can provide valuable insights on early response to targeted therapies among patients with HER2-positive cancers.

This was the main finding of new data presented by study author Razelle Kurzrock, MD, at the American Association for Cancer Research annual meeting.

“We found that on-treatment ctDNA can detect progression before standard-of-care response assessments. These data suggest that monitoring ctDNA can provide clinicians with important prognostic information that may guide treatment decisions,” Dr. Kurzrock, professor at the Medical College of Wisconsin, Milwaukee, said during her presentation.

Christos Evangelou/MDedge News

Commenting on the clinical implications of these findings during an interview, she said the results suggest that ctDNA dynamics provide an early window into predicting response to targeted therapies in patients with HER2-altered cancers, confirming previous findings of the predictive value of ctDNA in other cancer types.

“Such monitoring may be useful in clinical trials and eventually in practice,” she added.
 

Need for new methods to predict early tumor response

Limitations of standard radiographic tumor assessments present challenges in determining clinical response, particularly for patients receiving targeted therapies.

During her talk, Dr. Kurzrock explained that although targeted therapies are effective for patients with specific molecular alterations, standard imaging assessments fail to uncover molecular-level changes within tumors, limiting the ability of clinicians to accurately assess a patient’s response to targeted therapies.

“In addition to limitations with imaging, patients and physicians want to know as soon as possible whether or not the agents are effective, especially if there are side effects,” Dr. Kurzrock during an interview. She added that monitoring early response may be especially important across tumor types, as HER2 therapies are increasingly being considered in the pan-cancer setting.

Commenting on the potential use of this method in other cancer types with HER2 alterations, Pashtoon Murtaza Kasi, MD, MS, noted that since the study relied on a tumor-informed assay, it would be applicable across diverse tumor types.

“It is less about tissue type but more about that particular patient’s tumor at that instant in time for which a unique barcode is created,” said Dr. Kasi, a medical oncologist at Weill Cornell Medicine, New York, who was not involved in the study.

In an interview, he added that the shedding and biology would affect the assay’s performance for some tissue types.
 

Design of patient-specific ctDNA assays

In this retrospective study, the researchers examined ctDNA dynamics in 58 patients with various HER2-positive tumor types, including breast, colorectal, and other solid malignancies harboring HER2 alterations. All the patients received combination HER2-targeted therapy with trastuzumab and pertuzumab in the phase 2 basket trial My Pathway (NCT02091141).

By leveraging comprehensive genomic profiling of each patient’s tumor, the researchers designed personalized ctDNA assays, tracking 2-16 tumor-specific genetic variants in the patients’ blood samples. FoundationOne Tracker was used to detect and quantify ctDNA at baseline and the third cycle of therapy (cycle 3 day 1, or C3D1).

During an interview, Dr. Kurzrock explained that FoundationOne Tracker is a personalized ctDNA monitoring assay that allows for the detection of ctDNA in plasma, enabling ongoing liquid-based monitoring and highly sensitive quantification of ctDNA levels as mean tumor molecules per milliliter of plasma.

Among the 52 patients for whom personalized ctDNA assays were successfully designed, 48 (92.3%) had ctDNA data available at baseline, with a median of 100.7 tumor molecules per milliliter of plasma. Most patients (89.6%) were deemed ctDNA-positive, with a median of 119.5 tumor molecules per milliliter of plasma.
 

Changes in ctDNA levels predict patient survival

The researchers found that patients who experienced a greater than 90% decline in ctDNA levels by the third treatment cycle had significantly longer overall survival (OS) than those with less than 90% ctDNA decline or any increase. According to data presented by Dr. Kurzrock, the median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 9.4 months in the group with less than 90% decline or ctDNA increase (P = .007). These findings held true when the analysis was limited to the 14 patients with colorectal cancer, in which median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 10.2 months in the group with less than 90% decline or ctDNA increase (P = 0.04).

Notably, the prognostic significance of ctDNA changes remained even among patients exhibiting radiographic stable disease, underscoring the limitations of relying solely on anatomic tumor measurements and highlighting the potential for ctDNA monitoring to complement standard clinical assessments. In the subset of patients with radiographic stable disease, those with a greater than 90% ctDNA decline had significantly longer OS than those with less ctDNA reduction (not reached versus 9.4 months; P = .01).

“When used as a complement to imaging, tissue-informed ctDNA monitoring with FoundationOne Tracker can provide more accuracy than imaging alone,” Dr. Kurzrock noted in an interview.

Dr. Kasi echoed Dr. Kurzrock’s enthusiasm regarding the clinical usefulness of these findings, saying, “Not only can you see very early on in whom the ctDNA is going down and clearing, but you can also tell apart within the group who has ‘stable disease’ as to who is deriving more benefit.”

The researchers also observed that increases in on-treatment ctDNA levels often preceded radiographic evidence of disease progression by a median of 1.3 months. These findings highlight the potential for ctDNA monitoring to complement standard clinical assessments, allowing us to detect treatment response and disease progression earlier than what is possible with imaging alone, Dr. Kurzrock explained during her talk. “This early warning signal could allow clinicians to intervene and modify treatment strategies before overt clinical deterioration,” she said.

In an interview, Dr. Kasi highlighted that this high sensitivity and specificity and the short half-life of the tumor-informed ctDNA assay make this liquid biopsy of great clinical value. “The short half-life of a few hours means that if you do an intervention to treat cancer with HER2-directed therapy, you can very quickly assess response to therapy way earlier than traditional radiographic methods.”

Dr. Kasi cautioned, however, that this assay would not capture whether new mutations or HER2 loss occurred at the time of resistance. “A repeat tissue biopsy or a next-generation sequencing-based plasma-only assay would be required for that,” he said.
 

Implementation of ctDNA monitoring in clinical trials

Dr. Kurzrock acknowledged that further research is needed to validate these results in larger, prospective cohorts before FoundationOne Tracker is adopted in the clinic. She noted, however, that this retrospective analysis, along with results from previous studies, provides a rationale for the use of ctDNA monitoring in clinical trials.

“In some centers like ours, ctDNA monitoring is already part of our standard of care since not only does it help from a physician standpoint to have a more accurate and early assessment of response, but patients also appreciate the information gained from ctDNA dynamics,” Dr. Kasi said in an interview. He explained that when radiographic findings are equivocal, ctDNA monitoring is an additional tool in their toolbox to help guide care.

He noted, however, that the cost is a challenge for implementing ctDNA monitoring as a complementary tool for real-time treatment response monitoring. “For serial monitoring, helping to reduce costs would be important in the long run,” he said in an interview. He added that obtaining sufficient tissue for testing using a tumor-informed assay can present a logistical challenge, at least for the first test. “You need sufficient tissue to make the barcode that you then follow along,” he explained.

“Developing guidelines through systematic studies about testing cadence would also be important. This would help establish whether ctDNA monitoring is helpful,” Dr. Kasi said in an interview. He explained that in some situations, biological variables affect the shedding and detection of ctDNA beyond the assay — in those cases, ctDNA monitoring may not be helpful. “Like any test, it is not meant for every patient or clinical question,” Dr. Kasi concluded.

Dr. Kurzrock and Dr. Kasi reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

SAN DIEGO — Monitoring a patient’s circulating tumor DNA (ctDNA) can provide valuable insights on early response to targeted therapies among patients with HER2-positive cancers.

This was the main finding of new data presented by study author Razelle Kurzrock, MD, at the American Association for Cancer Research annual meeting.

“We found that on-treatment ctDNA can detect progression before standard-of-care response assessments. These data suggest that monitoring ctDNA can provide clinicians with important prognostic information that may guide treatment decisions,” Dr. Kurzrock, professor at the Medical College of Wisconsin, Milwaukee, said during her presentation.

Christos Evangelou/MDedge News

Commenting on the clinical implications of these findings during an interview, she said the results suggest that ctDNA dynamics provide an early window into predicting response to targeted therapies in patients with HER2-altered cancers, confirming previous findings of the predictive value of ctDNA in other cancer types.

“Such monitoring may be useful in clinical trials and eventually in practice,” she added.
 

Need for new methods to predict early tumor response

Limitations of standard radiographic tumor assessments present challenges in determining clinical response, particularly for patients receiving targeted therapies.

During her talk, Dr. Kurzrock explained that although targeted therapies are effective for patients with specific molecular alterations, standard imaging assessments fail to uncover molecular-level changes within tumors, limiting the ability of clinicians to accurately assess a patient’s response to targeted therapies.

“In addition to limitations with imaging, patients and physicians want to know as soon as possible whether or not the agents are effective, especially if there are side effects,” Dr. Kurzrock during an interview. She added that monitoring early response may be especially important across tumor types, as HER2 therapies are increasingly being considered in the pan-cancer setting.

Commenting on the potential use of this method in other cancer types with HER2 alterations, Pashtoon Murtaza Kasi, MD, MS, noted that since the study relied on a tumor-informed assay, it would be applicable across diverse tumor types.

“It is less about tissue type but more about that particular patient’s tumor at that instant in time for which a unique barcode is created,” said Dr. Kasi, a medical oncologist at Weill Cornell Medicine, New York, who was not involved in the study.

In an interview, he added that the shedding and biology would affect the assay’s performance for some tissue types.
 

Design of patient-specific ctDNA assays

In this retrospective study, the researchers examined ctDNA dynamics in 58 patients with various HER2-positive tumor types, including breast, colorectal, and other solid malignancies harboring HER2 alterations. All the patients received combination HER2-targeted therapy with trastuzumab and pertuzumab in the phase 2 basket trial My Pathway (NCT02091141).

By leveraging comprehensive genomic profiling of each patient’s tumor, the researchers designed personalized ctDNA assays, tracking 2-16 tumor-specific genetic variants in the patients’ blood samples. FoundationOne Tracker was used to detect and quantify ctDNA at baseline and the third cycle of therapy (cycle 3 day 1, or C3D1).

During an interview, Dr. Kurzrock explained that FoundationOne Tracker is a personalized ctDNA monitoring assay that allows for the detection of ctDNA in plasma, enabling ongoing liquid-based monitoring and highly sensitive quantification of ctDNA levels as mean tumor molecules per milliliter of plasma.

Among the 52 patients for whom personalized ctDNA assays were successfully designed, 48 (92.3%) had ctDNA data available at baseline, with a median of 100.7 tumor molecules per milliliter of plasma. Most patients (89.6%) were deemed ctDNA-positive, with a median of 119.5 tumor molecules per milliliter of plasma.
 

Changes in ctDNA levels predict patient survival

The researchers found that patients who experienced a greater than 90% decline in ctDNA levels by the third treatment cycle had significantly longer overall survival (OS) than those with less than 90% ctDNA decline or any increase. According to data presented by Dr. Kurzrock, the median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 9.4 months in the group with less than 90% decline or ctDNA increase (P = .007). These findings held true when the analysis was limited to the 14 patients with colorectal cancer, in which median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 10.2 months in the group with less than 90% decline or ctDNA increase (P = 0.04).

Notably, the prognostic significance of ctDNA changes remained even among patients exhibiting radiographic stable disease, underscoring the limitations of relying solely on anatomic tumor measurements and highlighting the potential for ctDNA monitoring to complement standard clinical assessments. In the subset of patients with radiographic stable disease, those with a greater than 90% ctDNA decline had significantly longer OS than those with less ctDNA reduction (not reached versus 9.4 months; P = .01).

“When used as a complement to imaging, tissue-informed ctDNA monitoring with FoundationOne Tracker can provide more accuracy than imaging alone,” Dr. Kurzrock noted in an interview.

Dr. Kasi echoed Dr. Kurzrock’s enthusiasm regarding the clinical usefulness of these findings, saying, “Not only can you see very early on in whom the ctDNA is going down and clearing, but you can also tell apart within the group who has ‘stable disease’ as to who is deriving more benefit.”

The researchers also observed that increases in on-treatment ctDNA levels often preceded radiographic evidence of disease progression by a median of 1.3 months. These findings highlight the potential for ctDNA monitoring to complement standard clinical assessments, allowing us to detect treatment response and disease progression earlier than what is possible with imaging alone, Dr. Kurzrock explained during her talk. “This early warning signal could allow clinicians to intervene and modify treatment strategies before overt clinical deterioration,” she said.

In an interview, Dr. Kasi highlighted that this high sensitivity and specificity and the short half-life of the tumor-informed ctDNA assay make this liquid biopsy of great clinical value. “The short half-life of a few hours means that if you do an intervention to treat cancer with HER2-directed therapy, you can very quickly assess response to therapy way earlier than traditional radiographic methods.”

Dr. Kasi cautioned, however, that this assay would not capture whether new mutations or HER2 loss occurred at the time of resistance. “A repeat tissue biopsy or a next-generation sequencing-based plasma-only assay would be required for that,” he said.
 

Implementation of ctDNA monitoring in clinical trials

Dr. Kurzrock acknowledged that further research is needed to validate these results in larger, prospective cohorts before FoundationOne Tracker is adopted in the clinic. She noted, however, that this retrospective analysis, along with results from previous studies, provides a rationale for the use of ctDNA monitoring in clinical trials.

“In some centers like ours, ctDNA monitoring is already part of our standard of care since not only does it help from a physician standpoint to have a more accurate and early assessment of response, but patients also appreciate the information gained from ctDNA dynamics,” Dr. Kasi said in an interview. He explained that when radiographic findings are equivocal, ctDNA monitoring is an additional tool in their toolbox to help guide care.

He noted, however, that the cost is a challenge for implementing ctDNA monitoring as a complementary tool for real-time treatment response monitoring. “For serial monitoring, helping to reduce costs would be important in the long run,” he said in an interview. He added that obtaining sufficient tissue for testing using a tumor-informed assay can present a logistical challenge, at least for the first test. “You need sufficient tissue to make the barcode that you then follow along,” he explained.

“Developing guidelines through systematic studies about testing cadence would also be important. This would help establish whether ctDNA monitoring is helpful,” Dr. Kasi said in an interview. He explained that in some situations, biological variables affect the shedding and detection of ctDNA beyond the assay — in those cases, ctDNA monitoring may not be helpful. “Like any test, it is not meant for every patient or clinical question,” Dr. Kasi concluded.

Dr. Kurzrock and Dr. Kasi reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

SAN DIEGO — A novel multicancer early detection (MCED) blood test has demonstrated promising real-world results in detecting new cancers, including several cases of early-stage disease.

This was the conclusion of recent data presented by Ora Karp Gordon, MD, MS, during a session at the American Association for Cancer Research annual meeting.

The MCED test, known as Galleri, was made clinically available in the United States in April 2021. Developed by GRAIL LLC, the test analyzes cell-free DNA in the blood using targeted methylation analysis and machine learning to detect the presence of a cancer signal and determine its organ of origin or cancer signal origin. The initial screening of over 53,000 individuals with the Galleri test detected a cancer signal in 1.1% of participants.

The new real-world analysis examines the outcomes of repeat MCED testing in 5,794 individuals.

The study looked at individuals who initially received a ‘no cancer signal detected’ result and then underwent a second Galleri test. Over 80% of participants received their follow-up test 10-18 months after the first, with a median interval between blood draws of 12.9 months.

“The repeat tests detect those cancer cases that have reached the detection threshold since their last MCED test, which should be less than one year of incidence,” Dr. Gordon, professor at Saint John’s Cancer Institute, Santa Monica, California, said in an interview. “We are just now starting to see results from patients who get their second and even third round of screening.”

“Galleri is recommended to be used annually in addition to USPSTF [US Preventive Services Task Force]–recommended cancer screening tests, like mammography and colonoscopy,” she said.

This recommendation is based on a modeling study suggesting that annual screening would improve stage shift, diagnostic yield, and potentially mortality when compared to biennial screening, although biennial screening was still favorable compared with no screening, she explained.
 

Early Real-World Evidence of Repeat Testing

Among the cohort of 5,794 individuals who received repeat testing, 26 received a positive cancer signal on their second test, yielding a cancer signal detection rate of 0.45% (95% CI: 0.31%-0.66%). The cancer signal detection rate was slightly higher in men. The rate was 0.50% (95% CI: 0.32%-0.81%; 17 of 3367) in men versus 0.37% (95% CI: 0.2%-0.7%; 9 of 2427) in women.

During her presentation, Dr. Gordon highlighted that the repeat testing signal detection rate was lower than the initial 0.95% rate (95% CI: 0.87-1.0; 510 of 53,744) seen in the previous larger cohort of patients who were retested at 1 year.

She acknowledged that the lower cancer signal detection rate of repeat testing may indicate some degree of ‘early adopter’ bias, where those who return for a second test are systematically different from the general screening population. This could suggest that broader population-level screening may yield different results, she continued.
 

Shift Toward Unscreened Cancers

The top cancer types identified in the second round of testing were lymphoid, head and neck, bladder/urothelial, colorectal, and anal cancers. Clinicians were able to confirm clinical outcomes in 12 of 26 cases, in which cancer signals were detected. Of those 12 cases, 8 individuals received a cancer diagnosis and 4 did not have cancer. The remaining 14 of 26 cases in which cancer signals were detected are still under investigation.

“We found a shift away from USPSTF screen-detected cancers, like breast, lung, and prostate, and relative increase in unscreened urinary, head and neck, and lymphoid cancers, with 75% of cancers being those without any screening guidelines,” Dr. Gordon said in an interview.

She added that patients who choose to retest may have different cancer rates for several reasons, including bias toward a population that is health conscious and adhered to all recommended cancer screening.

“So the shift toward unscreened cancers is not unexpected and highlights the value of Galleri,” she said, but also acknowledged that “continued monitoring is needed to see if this translates in a persistent finding over time and tests.”
 

Shift Toward Early-Stage Cancers

Staging information was available for five cases, and Dr. Gordon highlighted in her talk that four of these confirmed cancers were stage I, including cancers of the anus, head and neck, bladder, and lymphoma. The fifth confirmed cancer with staging information was stage IV ovarian cancer.

“It is still early, and the numbers are very small, but the detection of early-stage cancers with second annual testing is very encouraging as these are the cases where MCED testing could have the greatest impact in improving outcomes through earlier treatment,” Dr. Gordon told this publication.

During an interview after the talk, Kenneth L. Kehl, MD, MPH, echoed that data must be confirmed in larger cohorts.

“The shift toward earlier stage cancers that are less detectable by standard screening methods is an interesting result, but we need to be cautious since the numbers were relatively small, and we do not have data on cancers that were diagnosed among patients whose second MCED test was also negative,” said Dr. Kehl, a medical oncologist at Dana-Farber Cancer Institute, Boston.
 

MCED Results Could Help Direct Diagnostic Workup

The test’s ability to predict the organ of origin was highly accurate, correctly identifying the cancer type in all eight confirmed cases. Among the eight cases with a confirmed cancer diagnosis, the accuracy of the first prediction was 100%, and diagnoses included invasive cancers across multiple tissues and organs, including anus, colon, head and neck, urothelial tract, ovary, and the lymphatic system.

“The fact that the site of origin for 100% of confirmed cancers was accurately predicted with GRAIL’s CSO by Galleri test confirms the promise that this can guide workup when a cancer signal is detected,” Dr. Gordon noted in the interview.
 

Looking Ahead

Dr. Kehl, who was not involved in the MCED study, noted in an interview that “further data on test characteristics beyond positive predictive value, including the sensitivity, specificity, and negative predictive value, as well as demonstration of clinical benefit — ideally in a randomized trial — will likely be required for MCED testing to become a standard public health recommendation.”

He added that challenges associated with implementing annual screening with MCED tests include the risks of both false positives and false negatives as testing becomes more widely available.

“False positives cause anxiety and lead to additional testing that may carry its own risks, and we need to understand if potentially false negative tests will be associated with less uptake of established screening strategies,” Dr. Kehl said in an interview. However, he noted that serial testing could lead to more frequent diagnoses of early-stage cancers that may be less detectable by standard methods.

Dr. Gordon reported financial relationships with GRAIL LLC and Genetic Technologies Corporation. Dr. Kehl reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

SAN DIEGO — A novel multicancer early detection (MCED) blood test has demonstrated promising real-world results in detecting new cancers, including several cases of early-stage disease.

This was the conclusion of recent data presented by Ora Karp Gordon, MD, MS, during a session at the American Association for Cancer Research annual meeting.

The MCED test, known as Galleri, was made clinically available in the United States in April 2021. Developed by GRAIL LLC, the test analyzes cell-free DNA in the blood using targeted methylation analysis and machine learning to detect the presence of a cancer signal and determine its organ of origin or cancer signal origin. The initial screening of over 53,000 individuals with the Galleri test detected a cancer signal in 1.1% of participants.

The new real-world analysis examines the outcomes of repeat MCED testing in 5,794 individuals.

The study looked at individuals who initially received a ‘no cancer signal detected’ result and then underwent a second Galleri test. Over 80% of participants received their follow-up test 10-18 months after the first, with a median interval between blood draws of 12.9 months.

“The repeat tests detect those cancer cases that have reached the detection threshold since their last MCED test, which should be less than one year of incidence,” Dr. Gordon, professor at Saint John’s Cancer Institute, Santa Monica, California, said in an interview. “We are just now starting to see results from patients who get their second and even third round of screening.”

“Galleri is recommended to be used annually in addition to USPSTF [US Preventive Services Task Force]–recommended cancer screening tests, like mammography and colonoscopy,” she said.

This recommendation is based on a modeling study suggesting that annual screening would improve stage shift, diagnostic yield, and potentially mortality when compared to biennial screening, although biennial screening was still favorable compared with no screening, she explained.
 

Early Real-World Evidence of Repeat Testing

Among the cohort of 5,794 individuals who received repeat testing, 26 received a positive cancer signal on their second test, yielding a cancer signal detection rate of 0.45% (95% CI: 0.31%-0.66%). The cancer signal detection rate was slightly higher in men. The rate was 0.50% (95% CI: 0.32%-0.81%; 17 of 3367) in men versus 0.37% (95% CI: 0.2%-0.7%; 9 of 2427) in women.

During her presentation, Dr. Gordon highlighted that the repeat testing signal detection rate was lower than the initial 0.95% rate (95% CI: 0.87-1.0; 510 of 53,744) seen in the previous larger cohort of patients who were retested at 1 year.

She acknowledged that the lower cancer signal detection rate of repeat testing may indicate some degree of ‘early adopter’ bias, where those who return for a second test are systematically different from the general screening population. This could suggest that broader population-level screening may yield different results, she continued.
 

Shift Toward Unscreened Cancers

The top cancer types identified in the second round of testing were lymphoid, head and neck, bladder/urothelial, colorectal, and anal cancers. Clinicians were able to confirm clinical outcomes in 12 of 26 cases, in which cancer signals were detected. Of those 12 cases, 8 individuals received a cancer diagnosis and 4 did not have cancer. The remaining 14 of 26 cases in which cancer signals were detected are still under investigation.

“We found a shift away from USPSTF screen-detected cancers, like breast, lung, and prostate, and relative increase in unscreened urinary, head and neck, and lymphoid cancers, with 75% of cancers being those without any screening guidelines,” Dr. Gordon said in an interview.

She added that patients who choose to retest may have different cancer rates for several reasons, including bias toward a population that is health conscious and adhered to all recommended cancer screening.

“So the shift toward unscreened cancers is not unexpected and highlights the value of Galleri,” she said, but also acknowledged that “continued monitoring is needed to see if this translates in a persistent finding over time and tests.”
 

Shift Toward Early-Stage Cancers

Staging information was available for five cases, and Dr. Gordon highlighted in her talk that four of these confirmed cancers were stage I, including cancers of the anus, head and neck, bladder, and lymphoma. The fifth confirmed cancer with staging information was stage IV ovarian cancer.

“It is still early, and the numbers are very small, but the detection of early-stage cancers with second annual testing is very encouraging as these are the cases where MCED testing could have the greatest impact in improving outcomes through earlier treatment,” Dr. Gordon told this publication.

During an interview after the talk, Kenneth L. Kehl, MD, MPH, echoed that data must be confirmed in larger cohorts.

“The shift toward earlier stage cancers that are less detectable by standard screening methods is an interesting result, but we need to be cautious since the numbers were relatively small, and we do not have data on cancers that were diagnosed among patients whose second MCED test was also negative,” said Dr. Kehl, a medical oncologist at Dana-Farber Cancer Institute, Boston.
 

MCED Results Could Help Direct Diagnostic Workup

The test’s ability to predict the organ of origin was highly accurate, correctly identifying the cancer type in all eight confirmed cases. Among the eight cases with a confirmed cancer diagnosis, the accuracy of the first prediction was 100%, and diagnoses included invasive cancers across multiple tissues and organs, including anus, colon, head and neck, urothelial tract, ovary, and the lymphatic system.

“The fact that the site of origin for 100% of confirmed cancers was accurately predicted with GRAIL’s CSO by Galleri test confirms the promise that this can guide workup when a cancer signal is detected,” Dr. Gordon noted in the interview.
 

Looking Ahead

Dr. Kehl, who was not involved in the MCED study, noted in an interview that “further data on test characteristics beyond positive predictive value, including the sensitivity, specificity, and negative predictive value, as well as demonstration of clinical benefit — ideally in a randomized trial — will likely be required for MCED testing to become a standard public health recommendation.”

He added that challenges associated with implementing annual screening with MCED tests include the risks of both false positives and false negatives as testing becomes more widely available.

“False positives cause anxiety and lead to additional testing that may carry its own risks, and we need to understand if potentially false negative tests will be associated with less uptake of established screening strategies,” Dr. Kehl said in an interview. However, he noted that serial testing could lead to more frequent diagnoses of early-stage cancers that may be less detectable by standard methods.

Dr. Gordon reported financial relationships with GRAIL LLC and Genetic Technologies Corporation. Dr. Kehl reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

SAN DIEGO — A novel multicancer early detection (MCED) blood test has demonstrated promising real-world results in detecting new cancers, including several cases of early-stage disease.

This was the conclusion of recent data presented by Ora Karp Gordon, MD, MS, during a session at the American Association for Cancer Research annual meeting.

The MCED test, known as Galleri, was made clinically available in the United States in April 2021. Developed by GRAIL LLC, the test analyzes cell-free DNA in the blood using targeted methylation analysis and machine learning to detect the presence of a cancer signal and determine its organ of origin or cancer signal origin. The initial screening of over 53,000 individuals with the Galleri test detected a cancer signal in 1.1% of participants.

The new real-world analysis examines the outcomes of repeat MCED testing in 5,794 individuals.

The study looked at individuals who initially received a ‘no cancer signal detected’ result and then underwent a second Galleri test. Over 80% of participants received their follow-up test 10-18 months after the first, with a median interval between blood draws of 12.9 months.

“The repeat tests detect those cancer cases that have reached the detection threshold since their last MCED test, which should be less than one year of incidence,” Dr. Gordon, professor at Saint John’s Cancer Institute, Santa Monica, California, said in an interview. “We are just now starting to see results from patients who get their second and even third round of screening.”

“Galleri is recommended to be used annually in addition to USPSTF [US Preventive Services Task Force]–recommended cancer screening tests, like mammography and colonoscopy,” she said.

This recommendation is based on a modeling study suggesting that annual screening would improve stage shift, diagnostic yield, and potentially mortality when compared to biennial screening, although biennial screening was still favorable compared with no screening, she explained.
 

Early Real-World Evidence of Repeat Testing

Among the cohort of 5,794 individuals who received repeat testing, 26 received a positive cancer signal on their second test, yielding a cancer signal detection rate of 0.45% (95% CI: 0.31%-0.66%). The cancer signal detection rate was slightly higher in men. The rate was 0.50% (95% CI: 0.32%-0.81%; 17 of 3367) in men versus 0.37% (95% CI: 0.2%-0.7%; 9 of 2427) in women.

During her presentation, Dr. Gordon highlighted that the repeat testing signal detection rate was lower than the initial 0.95% rate (95% CI: 0.87-1.0; 510 of 53,744) seen in the previous larger cohort of patients who were retested at 1 year.

She acknowledged that the lower cancer signal detection rate of repeat testing may indicate some degree of ‘early adopter’ bias, where those who return for a second test are systematically different from the general screening population. This could suggest that broader population-level screening may yield different results, she continued.
 

Shift Toward Unscreened Cancers

The top cancer types identified in the second round of testing were lymphoid, head and neck, bladder/urothelial, colorectal, and anal cancers. Clinicians were able to confirm clinical outcomes in 12 of 26 cases, in which cancer signals were detected. Of those 12 cases, 8 individuals received a cancer diagnosis and 4 did not have cancer. The remaining 14 of 26 cases in which cancer signals were detected are still under investigation.

“We found a shift away from USPSTF screen-detected cancers, like breast, lung, and prostate, and relative increase in unscreened urinary, head and neck, and lymphoid cancers, with 75% of cancers being those without any screening guidelines,” Dr. Gordon said in an interview.

She added that patients who choose to retest may have different cancer rates for several reasons, including bias toward a population that is health conscious and adhered to all recommended cancer screening.

“So the shift toward unscreened cancers is not unexpected and highlights the value of Galleri,” she said, but also acknowledged that “continued monitoring is needed to see if this translates in a persistent finding over time and tests.”
 

Shift Toward Early-Stage Cancers

Staging information was available for five cases, and Dr. Gordon highlighted in her talk that four of these confirmed cancers were stage I, including cancers of the anus, head and neck, bladder, and lymphoma. The fifth confirmed cancer with staging information was stage IV ovarian cancer.

“It is still early, and the numbers are very small, but the detection of early-stage cancers with second annual testing is very encouraging as these are the cases where MCED testing could have the greatest impact in improving outcomes through earlier treatment,” Dr. Gordon told this publication.

During an interview after the talk, Kenneth L. Kehl, MD, MPH, echoed that data must be confirmed in larger cohorts.

“The shift toward earlier stage cancers that are less detectable by standard screening methods is an interesting result, but we need to be cautious since the numbers were relatively small, and we do not have data on cancers that were diagnosed among patients whose second MCED test was also negative,” said Dr. Kehl, a medical oncologist at Dana-Farber Cancer Institute, Boston.
 

MCED Results Could Help Direct Diagnostic Workup

The test’s ability to predict the organ of origin was highly accurate, correctly identifying the cancer type in all eight confirmed cases. Among the eight cases with a confirmed cancer diagnosis, the accuracy of the first prediction was 100%, and diagnoses included invasive cancers across multiple tissues and organs, including anus, colon, head and neck, urothelial tract, ovary, and the lymphatic system.

“The fact that the site of origin for 100% of confirmed cancers was accurately predicted with GRAIL’s CSO by Galleri test confirms the promise that this can guide workup when a cancer signal is detected,” Dr. Gordon noted in the interview.
 

Looking Ahead

Dr. Kehl, who was not involved in the MCED study, noted in an interview that “further data on test characteristics beyond positive predictive value, including the sensitivity, specificity, and negative predictive value, as well as demonstration of clinical benefit — ideally in a randomized trial — will likely be required for MCED testing to become a standard public health recommendation.”

He added that challenges associated with implementing annual screening with MCED tests include the risks of both false positives and false negatives as testing becomes more widely available.

“False positives cause anxiety and lead to additional testing that may carry its own risks, and we need to understand if potentially false negative tests will be associated with less uptake of established screening strategies,” Dr. Kehl said in an interview. However, he noted that serial testing could lead to more frequent diagnoses of early-stage cancers that may be less detectable by standard methods.

Dr. Gordon reported financial relationships with GRAIL LLC and Genetic Technologies Corporation. Dr. Kehl reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

The Diagnosis: Lymphoepithelioma-like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) is a rare, poorly differentiated, primary cutaneous neoplasm that occurs on sun-exposed skin, particularly on the head and neck of elderly individuals. It often manifests as an asymptomatic, slow-growing, flesh-colored or erythematous dermal nodule, though ulceration and tenderness have been reported.¹ Histopathologically, these neoplasms often are poorly circumscribed and can infiltrate surrounding subcutaneous and soft tissue. As a biphasic tumor, LELC is characterized by islands, nests, or trabeculae of epithelioid cells within the mid dermis surrounded by a dense lymphocytic infiltrate with plasma cells (Figure 1).¹ The epithelial component rarely communicates with the overlying epidermis and is composed of atypical polygonal cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and frequent mitosis.² These epithelial nests can be highlighted by pancytokeratin AE1/AE3 or other epithelial differentiation markers (eg, CAM 5.2, CK5/6, epithelial membrane antigen, high-molecular-weight cytokeratin), while the surrounding lymphocytic infiltrate consists of an admixture of T cells and B cells. Lymphoepithelioma-like carcinomas also can demonstrate sebaceous, eccrine, or follicular differentiations.³ The epithelial nests of LELC also are positive for p63 and epithelial membrane antigen.²

The usual treatment of LELC is wide local excision or Mohs micrographic surgery.¹ Despite the poorly differentiated morphology of the tumor, LELC has a generally good prognosis with low metastatic potential and few reports of local recurrence after incomplete excision.³ Patients who are not candidates for surgery as well as recalcitrant cases are managed with radiotherapy.¹

Cutaneous lymphadenoma (CL) is a benign adnexal neoplasm that manifests as a small, solitary, fleshcolored nodule usually in the head and neck region.⁴ Histologically, CL consists of well-circumscribed epithelial nests within the dermis that are peripherally outlined by palisading basaloid cells and filled with clear to eosinophilic epithelioid cells (Figure 2).5 The fibrotic tumor stroma often is infiltrated by numerous intralobular dendritic cells and lymphocytes that occasionally can be arranged in germinal center–like nodules.⁴ The lymphoepithelial nature of CL can be challenging to distinguish morphologically from LELC, and immunohistochemistry stains may be required. In CL, both the basaloid and epithelioid cells stain positive for pancytokeratin AE1/ AE3, but the peripheral palisaded basaloid cells also stain positive for BerEP4. Additionally, the fibrotic stroma can be highlighted by CD34 and the intralobular dendritic cells by S-100.⁴

Nasopharyngeal carcinoma (NPC), formerly known as lymphoepithelioma, refers to carcinoma arising within the epithelium of the nasopharynx.⁶ Endemic to China, NPC manifests as an enlarging nasopharyngeal mass, causing clinical symptoms such as nasal obstruction and epistaxis.⁷ Histologically, nonkeratinizing NPC exhibits a biphasic morphology consisting of epithelioid neoplastic cells and background lymphocytic infiltrates (Figure 3). The epithelial component consists of round to oval neoplastic cells with amphophilic to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli.⁶ Nasopharyngeal carcinoma is associated strongly with the Epstein-Barr virus while LELC is not; thus, Epstein- Barr encoding region in situ hybridization can reliably distinguish these entities. Metastatic NPC is rare but has been reported; therefore, it is highly recommended to perform an otolaryngologic examination in addition to testing for Epstein-Barr virus reactivity as part of a complete evaluation.⁸

Cutaneous squamous cell carcinoma (SCC) is a common epidermal malignancy with multiple subtypes and variable morphology. The clinical presentation of SCC is similar to LELC—an enlarging hyperkeratotic papule or nodule on sun-exposed skin that often is ulcerated and tender.⁹ Histologically, poorly differentiated nonkeratinizing SCC can form nests and trabeculae of epithelioid cells that are stained by epithelial differentiation markers, resembling the epithelioid nests of LELC. Distinguishing between LELC and poorly differentiated SCC with robust inflammatory infiltrate can be challenging (Figure 4). In fact, some experts support LELC as an SCC variant rather than a separate entity.9 However, in contrast to LELC, the dermal nests of SCC usually maintain an epidermal connection and often are associated with an overlying area of SCC in situ or welldifferentiated SCC.³

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma. It is the most common type of cutaneous lymphoma, accounting for almost 50% of all reported cases.¹⁰ Classic MF has an indolent course and progresses through several clinical stages. Patches and plaques characterize early stages; lymphadenopathy indicates progression to later stages in which erythroderma may develop with coalescence of patches, plaques, and tumors; and MF present in blood or lymph nodes characterizes the late stage. Each stage of MF is different histologically—from a superficial lichenoid infiltrate with exocytosis of malignant T cells in the patch stage, to more robust epidermotropism and dermal infiltrate in the plaque stage, and finally a dense dermal infiltrate in the late stage.¹¹ The rare syringotropic variant of MF clinically manifests as solitary or multiple erythematous lesions, often with overlying alopecia. Syringotropic MF uniquely exhibits folliculotropism and syringotropism along with syringometaplasia on histologic evaluation (Figure 5).¹² The syringometaplasia can be difficult to distinguish from the epithelial nests of LELC, particularly with the lymphocytic background. Immunohistochemical panels for T-cell markers can highlight aberrant T cells in syringotropic MF through their usual loss of CD5 and CD7, in comparison to normal T cells in LELC.¹¹ An elevated CD4:CD8 ratio of 4:1 and molecular analysis for T-cell receptor gene clonal rearrangements also can support the diagnosis of MF.¹²

The Diagnosis: Lymphoepithelioma-like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) is a rare, poorly differentiated, primary cutaneous neoplasm that occurs on sun-exposed skin, particularly on the head and neck of elderly individuals. It often manifests as an asymptomatic, slow-growing, flesh-colored or erythematous dermal nodule, though ulceration and tenderness have been reported.¹ Histopathologically, these neoplasms often are poorly circumscribed and can infiltrate surrounding subcutaneous and soft tissue. As a biphasic tumor, LELC is characterized by islands, nests, or trabeculae of epithelioid cells within the mid dermis surrounded by a dense lymphocytic infiltrate with plasma cells (Figure 1).¹ The epithelial component rarely communicates with the overlying epidermis and is composed of atypical polygonal cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and frequent mitosis.² These epithelial nests can be highlighted by pancytokeratin AE1/AE3 or other epithelial differentiation markers (eg, CAM 5.2, CK5/6, epithelial membrane antigen, high-molecular-weight cytokeratin), while the surrounding lymphocytic infiltrate consists of an admixture of T cells and B cells. Lymphoepithelioma-like carcinomas also can demonstrate sebaceous, eccrine, or follicular differentiations.³ The epithelial nests of LELC also are positive for p63 and epithelial membrane antigen.²

The usual treatment of LELC is wide local excision or Mohs micrographic surgery.¹ Despite the poorly differentiated morphology of the tumor, LELC has a generally good prognosis with low metastatic potential and few reports of local recurrence after incomplete excision.³ Patients who are not candidates for surgery as well as recalcitrant cases are managed with radiotherapy.¹

Cutaneous lymphadenoma (CL) is a benign adnexal neoplasm that manifests as a small, solitary, fleshcolored nodule usually in the head and neck region.⁴ Histologically, CL consists of well-circumscribed epithelial nests within the dermis that are peripherally outlined by palisading basaloid cells and filled with clear to eosinophilic epithelioid cells (Figure 2).5 The fibrotic tumor stroma often is infiltrated by numerous intralobular dendritic cells and lymphocytes that occasionally can be arranged in germinal center–like nodules.⁴ The lymphoepithelial nature of CL can be challenging to distinguish morphologically from LELC, and immunohistochemistry stains may be required. In CL, both the basaloid and epithelioid cells stain positive for pancytokeratin AE1/ AE3, but the peripheral palisaded basaloid cells also stain positive for BerEP4. Additionally, the fibrotic stroma can be highlighted by CD34 and the intralobular dendritic cells by S-100.⁴

Nasopharyngeal carcinoma (NPC), formerly known as lymphoepithelioma, refers to carcinoma arising within the epithelium of the nasopharynx.⁶ Endemic to China, NPC manifests as an enlarging nasopharyngeal mass, causing clinical symptoms such as nasal obstruction and epistaxis.⁷ Histologically, nonkeratinizing NPC exhibits a biphasic morphology consisting of epithelioid neoplastic cells and background lymphocytic infiltrates (Figure 3). The epithelial component consists of round to oval neoplastic cells with amphophilic to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli.⁶ Nasopharyngeal carcinoma is associated strongly with the Epstein-Barr virus while LELC is not; thus, Epstein- Barr encoding region in situ hybridization can reliably distinguish these entities. Metastatic NPC is rare but has been reported; therefore, it is highly recommended to perform an otolaryngologic examination in addition to testing for Epstein-Barr virus reactivity as part of a complete evaluation.⁸

Cutaneous squamous cell carcinoma (SCC) is a common epidermal malignancy with multiple subtypes and variable morphology. The clinical presentation of SCC is similar to LELC—an enlarging hyperkeratotic papule or nodule on sun-exposed skin that often is ulcerated and tender.⁹ Histologically, poorly differentiated nonkeratinizing SCC can form nests and trabeculae of epithelioid cells that are stained by epithelial differentiation markers, resembling the epithelioid nests of LELC. Distinguishing between LELC and poorly differentiated SCC with robust inflammatory infiltrate can be challenging (Figure 4). In fact, some experts support LELC as an SCC variant rather than a separate entity.9 However, in contrast to LELC, the dermal nests of SCC usually maintain an epidermal connection and often are associated with an overlying area of SCC in situ or welldifferentiated SCC.³

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma. It is the most common type of cutaneous lymphoma, accounting for almost 50% of all reported cases.¹⁰ Classic MF has an indolent course and progresses through several clinical stages. Patches and plaques characterize early stages; lymphadenopathy indicates progression to later stages in which erythroderma may develop with coalescence of patches, plaques, and tumors; and MF present in blood or lymph nodes characterizes the late stage. Each stage of MF is different histologically—from a superficial lichenoid infiltrate with exocytosis of malignant T cells in the patch stage, to more robust epidermotropism and dermal infiltrate in the plaque stage, and finally a dense dermal infiltrate in the late stage.¹¹ The rare syringotropic variant of MF clinically manifests as solitary or multiple erythematous lesions, often with overlying alopecia. Syringotropic MF uniquely exhibits folliculotropism and syringotropism along with syringometaplasia on histologic evaluation (Figure 5).¹² The syringometaplasia can be difficult to distinguish from the epithelial nests of LELC, particularly with the lymphocytic background. Immunohistochemical panels for T-cell markers can highlight aberrant T cells in syringotropic MF through their usual loss of CD5 and CD7, in comparison to normal T cells in LELC.¹¹ An elevated CD4:CD8 ratio of 4:1 and molecular analysis for T-cell receptor gene clonal rearrangements also can support the diagnosis of MF.¹²

The Diagnosis: Lymphoepithelioma-like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) is a rare, poorly differentiated, primary cutaneous neoplasm that occurs on sun-exposed skin, particularly on the head and neck of elderly individuals. It often manifests as an asymptomatic, slow-growing, flesh-colored or erythematous dermal nodule, though ulceration and tenderness have been reported.¹ Histopathologically, these neoplasms often are poorly circumscribed and can infiltrate surrounding subcutaneous and soft tissue. As a biphasic tumor, LELC is characterized by islands, nests, or trabeculae of epithelioid cells within the mid dermis surrounded by a dense lymphocytic infiltrate with plasma cells (Figure 1).¹ The epithelial component rarely communicates with the overlying epidermis and is composed of atypical polygonal cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and frequent mitosis.² These epithelial nests can be highlighted by pancytokeratin AE1/AE3 or other epithelial differentiation markers (eg, CAM 5.2, CK5/6, epithelial membrane antigen, high-molecular-weight cytokeratin), while the surrounding lymphocytic infiltrate consists of an admixture of T cells and B cells. Lymphoepithelioma-like carcinomas also can demonstrate sebaceous, eccrine, or follicular differentiations.³ The epithelial nests of LELC also are positive for p63 and epithelial membrane antigen.²

The usual treatment of LELC is wide local excision or Mohs micrographic surgery.¹ Despite the poorly differentiated morphology of the tumor, LELC has a generally good prognosis with low metastatic potential and few reports of local recurrence after incomplete excision.³ Patients who are not candidates for surgery as well as recalcitrant cases are managed with radiotherapy.¹

Cutaneous lymphadenoma (CL) is a benign adnexal neoplasm that manifests as a small, solitary, fleshcolored nodule usually in the head and neck region.⁴ Histologically, CL consists of well-circumscribed epithelial nests within the dermis that are peripherally outlined by palisading basaloid cells and filled with clear to eosinophilic epithelioid cells (Figure 2).5 The fibrotic tumor stroma often is infiltrated by numerous intralobular dendritic cells and lymphocytes that occasionally can be arranged in germinal center–like nodules.⁴ The lymphoepithelial nature of CL can be challenging to distinguish morphologically from LELC, and immunohistochemistry stains may be required. In CL, both the basaloid and epithelioid cells stain positive for pancytokeratin AE1/ AE3, but the peripheral palisaded basaloid cells also stain positive for BerEP4. Additionally, the fibrotic stroma can be highlighted by CD34 and the intralobular dendritic cells by S-100.⁴

Nasopharyngeal carcinoma (NPC), formerly known as lymphoepithelioma, refers to carcinoma arising within the epithelium of the nasopharynx.⁶ Endemic to China, NPC manifests as an enlarging nasopharyngeal mass, causing clinical symptoms such as nasal obstruction and epistaxis.⁷ Histologically, nonkeratinizing NPC exhibits a biphasic morphology consisting of epithelioid neoplastic cells and background lymphocytic infiltrates (Figure 3). The epithelial component consists of round to oval neoplastic cells with amphophilic to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli.⁶ Nasopharyngeal carcinoma is associated strongly with the Epstein-Barr virus while LELC is not; thus, Epstein- Barr encoding region in situ hybridization can reliably distinguish these entities. Metastatic NPC is rare but has been reported; therefore, it is highly recommended to perform an otolaryngologic examination in addition to testing for Epstein-Barr virus reactivity as part of a complete evaluation.⁸

Cutaneous squamous cell carcinoma (SCC) is a common epidermal malignancy with multiple subtypes and variable morphology. The clinical presentation of SCC is similar to LELC—an enlarging hyperkeratotic papule or nodule on sun-exposed skin that often is ulcerated and tender.⁹ Histologically, poorly differentiated nonkeratinizing SCC can form nests and trabeculae of epithelioid cells that are stained by epithelial differentiation markers, resembling the epithelioid nests of LELC. Distinguishing between LELC and poorly differentiated SCC with robust inflammatory infiltrate can be challenging (Figure 4). In fact, some experts support LELC as an SCC variant rather than a separate entity.9 However, in contrast to LELC, the dermal nests of SCC usually maintain an epidermal connection and often are associated with an overlying area of SCC in situ or welldifferentiated SCC.³

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma. It is the most common type of cutaneous lymphoma, accounting for almost 50% of all reported cases.¹⁰ Classic MF has an indolent course and progresses through several clinical stages. Patches and plaques characterize early stages; lymphadenopathy indicates progression to later stages in which erythroderma may develop with coalescence of patches, plaques, and tumors; and MF present in blood or lymph nodes characterizes the late stage. Each stage of MF is different histologically—from a superficial lichenoid infiltrate with exocytosis of malignant T cells in the patch stage, to more robust epidermotropism and dermal infiltrate in the plaque stage, and finally a dense dermal infiltrate in the late stage.¹¹ The rare syringotropic variant of MF clinically manifests as solitary or multiple erythematous lesions, often with overlying alopecia. Syringotropic MF uniquely exhibits folliculotropism and syringotropism along with syringometaplasia on histologic evaluation (Figure 5).¹² The syringometaplasia can be difficult to distinguish from the epithelial nests of LELC, particularly with the lymphocytic background. Immunohistochemical panels for T-cell markers can highlight aberrant T cells in syringotropic MF through their usual loss of CD5 and CD7, in comparison to normal T cells in LELC.¹¹ An elevated CD4:CD8 ratio of 4:1 and molecular analysis for T-cell receptor gene clonal rearrangements also can support the diagnosis of MF.¹²

Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma (CTCL), is characterized by clonal proliferation of predominantly CD4⁺ T cells with localization to the skin.¹ Mycosis fungoides typically affects older adults with a male to female ratio of 2:1 but also can occur in children and younger adults.^2,3 Known as the great imitator, the manifestations of MF can be variable with considerable clinical and pathologic overlap with benign inflammatory skin diseases, rendering definitive diagnosis challenging.^4-7 The early stages of classic MF manifest as pruritic erythematous patches and plaques with variable scaling that can progress in later stages to ulceration and tumors.⁸ Histopathologically, classic MF is characterized by epidermotropic proliferation of small- to intermediate-sized pleomorphic lymphocytes with cerebriform nuclei and a haloed appearance; intraepidermal nests of atypical lymphocytes known as Pautrier microabscesses occasionally are observed.⁵ Mycosis fungoides typically follows an indolent clinical course, with advanced-stage MF portending a poor prognosis.^9,10 Current treatment is focused on halting disease progression, with topical therapies, phototherapy, and radiation therapy as the standard therapies for early-stage MF.^11-13 For advanced-stage MF, treatment may include systemic therapies such as interferon alfa and oral retinoids along with chemotherapies for more refractive cases.¹⁴ Allogenic hematopoietic cell transplantation is the only curative treatment.¹¹

Current staging guidelines for MF do not address anatomic location as there is little known about its impact on patient outcomes.^11,15 Due to the indolent nature of MF leading to diagnostic challenges, the exact frequency of each primary disease site for MF also remains unclear, though the suggested incidence of MF of the head and neck ranges from 30% to 70%.^16,17 Involvement of the head and neck^16,18 or external ear and external auditory canal¹⁹ is associated with worse prognosis. The purpose of this study was to examine the impact of anatomic location of primary disease site on survival in MF.

Methods

The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database includes patient records from 18 registries and encompasses approximately 48% of the US population.²⁰ Using SEER*STAT software (version 8.4.0.1), we conducted a search of patients diagnosed with MF (International Classification of Diseases for Oncology, Third Edition [ICD-O-3] histologic code 9700/3 [mycosis fungoides]) between 2000 and 2019. For inclusion in the study, patients were required to have a known age, specified primary site, and a known cause of death (if applicable). Patients with known Sézary syndrome (SS)—an aggressive form of CTCL that is characterized by the presence of clonally related neoplastic T cells in the skin, lymph nodes, and peripheral blood—were not included because the World Health Organization/European Organisation for Research and Treatment of Cancer considers SS and MF to be separate entities^1,15; SS does not necessarily arise from preexisting MF and is associated with markedly poorer survival. This study was exempt from institutional review board approval because the data were publicly available and anonymized.

Data Collection—For age at diagnosis, patients were divided into the following categories: younger than 40 years, 40 to 59 years, 60 to 79 years, and 80 years and older. Demographics, tumor characteristics, and surgical management (if applicable) were obtained for each patient. The designations of chemotherapy and radiation treatment in the SEER database are not reliable and prone to false negatives. As such, these were excluded from analysis.

The primary outcomes of interest were overall survival (OS) and disease-specific survival (DSS), which were calculated as time from MF diagnosis to death. Although OS included all patients who died of any cause, DSS only included patients who died of MF.

Statistical Analysis—Demographics (age, sex, race, ethnicity), tumor characteristics (tumor size, primary site, T stage, lymph node involvement, metastasis), and surgical management (if applicable) were summarized. Overall survival and DSS were calculated using Kaplan-Meier analysis. Univariate and multivariable Cox proportional hazards regression models were generated to determine which prognostic factors for MF were associated with poorer OS and DSS. Only statistically significant variables in the univariate analysis were used to construct the multivariable analysis. Hazard ratios (HRs) and their associated 95% CIs were reported. Incidence rates were calculated and age adjusted to the 2000 US standard population. The SEER JoinPoint Regression program was used to determine the annual percent change (APC)—change in incidence rate over time. P<.05 was considered statistically significant. All statistical analyses were conducted with R version 4.0.2.

Patient Demographics and Tumor Characteristics—There were 4265 patients diagnosed with MF from 2000 to 2019. The overall incidence of MF was 2.55 per million (95% CI, 2.48-2.63) when age adjusted to the 2000 US standard population, which increased with time (mean APC, 0.97% per year; P=.01). The mean age at diagnosis was 56.4 years with a male to female ratio of 1.2:1. Males (3.07 per million; 95% CI, 2.94-3.20) had a higher incidence of MF than females (2.16 per million; 95% CI, 2.06-2.26), with incidence in females increasing over time (mean APC, 1.52% per year; P=.02) while incidence in males remained stable (mean APC, 1.09%; P=.37). Patients predominantly self-identified as White (73.08%). Patients with MF of the head and neck were more likely to have smaller tumors (P=.02), a more advanced T stage (P<.001), and lymph node involvement (P=.01) at the time of diagnosis. Additional demographics and tumor characteristics are summarized in eTable 1.

Survival Outcomes—The mean follow-up time was 86.9 months. The 5- and 10-year OS rates were 85.4% (95% CI, 84.2%-86.6%) and 75.0% (95% CI, 73.4%-76.7%), respectively (Figure 1)(Table). The 5- and 10-year DSS rates were 93.3% (95% CI, 92.4%-94.1%) and 89.5% (95% CI, 88.3%-90.6%), respectively. For OS, univariate analysis indicated that significant prognostic factors included increasing age (P<.001), female sex (P<.001), self-identifying as Asian or Pacific Islander (P<.001), self-identifying as Hispanic Latino (P<.001), primary tumor sites of either the head and neck or upper limb (P<.001), T3 or T4 staging (P=.001), lymph node involvement at the time of diagnosis (P<.001), and metastasis (P<.001).

For DSS, univariate analysis had similar risk factors with self-identifying as Black being an additional risk factor (P=.02), though self-identifying as Asian/Pacific Islander or Hispanic Latino were not significant nor was location on the lower limb. For recorded tumor size, the HR increased by 1.001 per each 1-mm increase in size (eTable 2).

Multivariate analysis showed age at diagnosis (60–79 years: HR, 23.11 [95% CI, 3.03-176.32]; P=.002; ≥80 years: HR, 92.41 [95% CI, 11.78-724.75]; P<.001), T3 staging (HR, 2.37 [95% CI, 1.32-4.27]; P=.004), and metastasis (HR, 40.14 [95% CI, 4.14-389.50]; P=.001) significantly influenced OS. For DSS, multivariate analysis indicated the significant prognostic factors were age at diagnosis (60–79 years: HR, 8.94 [95% CI, 1.16-69.23]; P=.04];≥80 years: HR, 26.71; [95% CI, 3.26-218.99]; P=.002), tumor size (HR, 1.001 [95% CI, 1.000-1.002]; P=.04), T3 staging (HR, 3.71 [95% CI, 1.58-8.67]; P=.003), lymph node involvement (HR, 3.87 [95% CI, 1.11-13.50]; P=.03) and metastasis (HR, 49.76 [95% CI, 4.03-615.00]; P=.002)(Figure 2). When controlling for the aforementioned factors, the primary disease site was not significant (eTable 3).

Comment

Although the prognostic significance of primary disease sites on various types of CTCLs has been examined, limited research exists on MF due to its rarity. For the 4265 patients with MF included in our study, statistically significant prognostic factors on multivariate analysis for DSS included age at diagnosis, tumor size, T staging, lymph node involvement, and presence of metastasis. For OS, only age at diagnosis, T staging, and presence of metastasis were statistically significant predictors. Although initially statistically significant on univariate analysis for both OS and DSS, tumor location was not significant when controlling for confounders.

Our population-based analysis found that 5- and 10-year OS for patients with head and neck MF were 85.4% and 75.0%, respectively, and 5- and 10-year DSS were 93.3% and 89.5%, respectively. Our 10-year OS survival rate of 75.0% was slightly worse than the 81.6% reported by Jung et al¹⁶ in a study of 39 cases of MF of the head and neck from the Asan Medical Center database. The difference in survival rate may not only be due to differences in sample size but also because the Asan Medical Center database had a higher proportion of Asian patients as a Korean registry. In our univariate analysis, Asian/Pacific Islander race was shown to be a statistically significant predictor of worse prognosis for OS (P<.001). When comparing survival in patients with head and neck MF vs all primary tumor sites, our OS rate for head and neck MF was more favorable than the 5-year OS of 75% reported by Agar et al²¹ in their analysis of 1502 patients with MF of all locations, though their cohort also included patients with SS, which is known to have a poorer prognosis. Additionally, our 10-year OS rate of 75.0% for patients with MF with a primary tumor site of the head and neck was slightly less favorable than the 81.0% reported by a prior analysis of the SEER database for MF of all locations,²² which initially may be suggestive of worse outcomes associated with MF originating from the head and neck.

Although MF originating in the head and neck region was found to be a statistically significant prognostic factor under univariate analysis (P<.001), tumor location was not significant upon adjusting for confounders in the multivariate analysis. These results are consistent with those reported in a multivariable analysis conducted by Jung et al,¹⁶ which compared 39 cases of head and neck MF to 85 cases without head and neck involvement. The investigators found that the head and neck as the primary site was a significant prognostic factor associated with worsened rates of OS when patients had stages IA to IIA (P=.009) and T2 stage tumors (P=.012) but not in either T1 stage or advanced stage IIB to IVB tumors.¹⁶ In contrast, a study by Su et al¹⁸ evaluating patients with MF from the National Cancer Database found that patients with MF originating in the head and neck region had similar survival compared with MF originating in the lower limbs after pairwise propensity matching. It previously has been postulated that primary MF lesions originating in the head and neck region have relatively higher frequencies of biological markers believed to be associated with more aggressive tumor behavior and poorer prognosis, such as histopathologic folliculotropism, T-cell receptor gene rearrangements, and large-cell transformations.¹⁶ However, MF typically is an indolent disease with advanced-stage MF following an aggressive disease course that often is refractory to treatment. A review from a single academic center noted that 5-year DSS was 97.3% for T1a but only 37.5% for T4.²³ Similarly, a meta-analysis evaluating survival in patients with MF noted the 5-year OS for stage IB was 85.8% while for stage IVB it was only 23.3%.²⁴ As such, having advanced-stage MF influences survival to a far greater extent than the presence of head and neck involvement alone. Accordingly, the significantly higher prevalence of advanced T stage disease and increased likelihood of lymph node involvement in MF lesions originating in the head and neck region (both P<.001) may explain why previous studies noted a poorer survival rate with head and neck involvement, as they did not have the sample size to adjust for these factors. Controlling for the above factors likely explains the nonsignificance of this region as a prognostic indicator in our multivariate analysis of OS and DSS.

Similar to MF originating in the head and neck region, the upper limb as a primary tumor site initially was found to be a significant predictor of both OS and DSS on univariate analysis but not on multivariate analysis. By contrast, Su et al¹⁸ found survival outcomes were worse for patients diagnosed with MF with the upper limb as the primary tumor site compared with the lower limb on multivariate Cox proportional hazards analysis but not on pairwise propensity score matching. The difference in our results compared with Su et al¹⁸ may be because the National Cancer Database only reports OS, while DSS may be more useful in determining prognostic factors associated with poorer survival, especially in an older patient population with greater comorbidities. Furthermore, the nonsignificance of the upper limb as a primary tumor site on further multivariate analysis may be due to similar reasonings as for the head and neck, including more advanced T staging and an anatomic location close to lymph nodes.

Study Limitations—The SEER database is a national registry, which lends itself to potential data heterogeneity in recording and miscoding. Additionally, there may be higher rates of unconfirmed or missing information given the retrospective nature of the SEER database; the database also does not delineate facility type, insurance status, or Charlson/Deyo comorbidity index as demographic factors, which could influence the multivariable analysis. Finally, the SEER database does not further demarcate subtypes of MF, such as the aggressive folliculotropic variant commonly seen in head and neck MF lesions, which precludes independent analysis of disease course by subtype.

Conclusion

Our study evaluated primary disease site as a prognostic factor for OS and DSS in patients with MF. Although head and neck and upper limb as primary disease sites were found to be significant on univariate analysis, they were found to be an insignificant prognostic variable for OS or DSS in our multivariable analysis, potentially due to the aggressive nature of advanced-stage MF and localization close to lymph nodes. Further research including a deeper dive into MF of all stages and subtypes is needed to fully investigate primary disease site as a prognostic indicator. Older age, larger tumor size, a higher T stage, lymph node involvement, and presence of metastasis were associated with worse DSS, and patients with these attributes should be counseled regarding expected disease course and prognosis.

Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma (CTCL), is characterized by clonal proliferation of predominantly CD4⁺ T cells with localization to the skin.¹ Mycosis fungoides typically affects older adults with a male to female ratio of 2:1 but also can occur in children and younger adults.^2,3 Known as the great imitator, the manifestations of MF can be variable with considerable clinical and pathologic overlap with benign inflammatory skin diseases, rendering definitive diagnosis challenging.^4-7 The early stages of classic MF manifest as pruritic erythematous patches and plaques with variable scaling that can progress in later stages to ulceration and tumors.⁸ Histopathologically, classic MF is characterized by epidermotropic proliferation of small- to intermediate-sized pleomorphic lymphocytes with cerebriform nuclei and a haloed appearance; intraepidermal nests of atypical lymphocytes known as Pautrier microabscesses occasionally are observed.⁵ Mycosis fungoides typically follows an indolent clinical course, with advanced-stage MF portending a poor prognosis.^9,10 Current treatment is focused on halting disease progression, with topical therapies, phototherapy, and radiation therapy as the standard therapies for early-stage MF.^11-13 For advanced-stage MF, treatment may include systemic therapies such as interferon alfa and oral retinoids along with chemotherapies for more refractive cases.¹⁴ Allogenic hematopoietic cell transplantation is the only curative treatment.¹¹

Current staging guidelines for MF do not address anatomic location as there is little known about its impact on patient outcomes.^11,15 Due to the indolent nature of MF leading to diagnostic challenges, the exact frequency of each primary disease site for MF also remains unclear, though the suggested incidence of MF of the head and neck ranges from 30% to 70%.^16,17 Involvement of the head and neck^16,18 or external ear and external auditory canal¹⁹ is associated with worse prognosis. The purpose of this study was to examine the impact of anatomic location of primary disease site on survival in MF.

Methods

The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database includes patient records from 18 registries and encompasses approximately 48% of the US population.²⁰ Using SEER*STAT software (version 8.4.0.1), we conducted a search of patients diagnosed with MF (International Classification of Diseases for Oncology, Third Edition [ICD-O-3] histologic code 9700/3 [mycosis fungoides]) between 2000 and 2019. For inclusion in the study, patients were required to have a known age, specified primary site, and a known cause of death (if applicable). Patients with known Sézary syndrome (SS)—an aggressive form of CTCL that is characterized by the presence of clonally related neoplastic T cells in the skin, lymph nodes, and peripheral blood—were not included because the World Health Organization/European Organisation for Research and Treatment of Cancer considers SS and MF to be separate entities^1,15; SS does not necessarily arise from preexisting MF and is associated with markedly poorer survival. This study was exempt from institutional review board approval because the data were publicly available and anonymized.

Data Collection—For age at diagnosis, patients were divided into the following categories: younger than 40 years, 40 to 59 years, 60 to 79 years, and 80 years and older. Demographics, tumor characteristics, and surgical management (if applicable) were obtained for each patient. The designations of chemotherapy and radiation treatment in the SEER database are not reliable and prone to false negatives. As such, these were excluded from analysis.

The primary outcomes of interest were overall survival (OS) and disease-specific survival (DSS), which were calculated as time from MF diagnosis to death. Although OS included all patients who died of any cause, DSS only included patients who died of MF.

Statistical Analysis—Demographics (age, sex, race, ethnicity), tumor characteristics (tumor size, primary site, T stage, lymph node involvement, metastasis), and surgical management (if applicable) were summarized. Overall survival and DSS were calculated using Kaplan-Meier analysis. Univariate and multivariable Cox proportional hazards regression models were generated to determine which prognostic factors for MF were associated with poorer OS and DSS. Only statistically significant variables in the univariate analysis were used to construct the multivariable analysis. Hazard ratios (HRs) and their associated 95% CIs were reported. Incidence rates were calculated and age adjusted to the 2000 US standard population. The SEER JoinPoint Regression program was used to determine the annual percent change (APC)—change in incidence rate over time. P<.05 was considered statistically significant. All statistical analyses were conducted with R version 4.0.2.

Patient Demographics and Tumor Characteristics—There were 4265 patients diagnosed with MF from 2000 to 2019. The overall incidence of MF was 2.55 per million (95% CI, 2.48-2.63) when age adjusted to the 2000 US standard population, which increased with time (mean APC, 0.97% per year; P=.01). The mean age at diagnosis was 56.4 years with a male to female ratio of 1.2:1. Males (3.07 per million; 95% CI, 2.94-3.20) had a higher incidence of MF than females (2.16 per million; 95% CI, 2.06-2.26), with incidence in females increasing over time (mean APC, 1.52% per year; P=.02) while incidence in males remained stable (mean APC, 1.09%; P=.37). Patients predominantly self-identified as White (73.08%). Patients with MF of the head and neck were more likely to have smaller tumors (P=.02), a more advanced T stage (P<.001), and lymph node involvement (P=.01) at the time of diagnosis. Additional demographics and tumor characteristics are summarized in eTable 1.

Survival Outcomes—The mean follow-up time was 86.9 months. The 5- and 10-year OS rates were 85.4% (95% CI, 84.2%-86.6%) and 75.0% (95% CI, 73.4%-76.7%), respectively (Figure 1)(Table). The 5- and 10-year DSS rates were 93.3% (95% CI, 92.4%-94.1%) and 89.5% (95% CI, 88.3%-90.6%), respectively. For OS, univariate analysis indicated that significant prognostic factors included increasing age (P<.001), female sex (P<.001), self-identifying as Asian or Pacific Islander (P<.001), self-identifying as Hispanic Latino (P<.001), primary tumor sites of either the head and neck or upper limb (P<.001), T3 or T4 staging (P=.001), lymph node involvement at the time of diagnosis (P<.001), and metastasis (P<.001).

For DSS, univariate analysis had similar risk factors with self-identifying as Black being an additional risk factor (P=.02), though self-identifying as Asian/Pacific Islander or Hispanic Latino were not significant nor was location on the lower limb. For recorded tumor size, the HR increased by 1.001 per each 1-mm increase in size (eTable 2).

Multivariate analysis showed age at diagnosis (60–79 years: HR, 23.11 [95% CI, 3.03-176.32]; P=.002; ≥80 years: HR, 92.41 [95% CI, 11.78-724.75]; P<.001), T3 staging (HR, 2.37 [95% CI, 1.32-4.27]; P=.004), and metastasis (HR, 40.14 [95% CI, 4.14-389.50]; P=.001) significantly influenced OS. For DSS, multivariate analysis indicated the significant prognostic factors were age at diagnosis (60–79 years: HR, 8.94 [95% CI, 1.16-69.23]; P=.04];≥80 years: HR, 26.71; [95% CI, 3.26-218.99]; P=.002), tumor size (HR, 1.001 [95% CI, 1.000-1.002]; P=.04), T3 staging (HR, 3.71 [95% CI, 1.58-8.67]; P=.003), lymph node involvement (HR, 3.87 [95% CI, 1.11-13.50]; P=.03) and metastasis (HR, 49.76 [95% CI, 4.03-615.00]; P=.002)(Figure 2). When controlling for the aforementioned factors, the primary disease site was not significant (eTable 3).

Comment

Although the prognostic significance of primary disease sites on various types of CTCLs has been examined, limited research exists on MF due to its rarity. For the 4265 patients with MF included in our study, statistically significant prognostic factors on multivariate analysis for DSS included age at diagnosis, tumor size, T staging, lymph node involvement, and presence of metastasis. For OS, only age at diagnosis, T staging, and presence of metastasis were statistically significant predictors. Although initially statistically significant on univariate analysis for both OS and DSS, tumor location was not significant when controlling for confounders.

Our population-based analysis found that 5- and 10-year OS for patients with head and neck MF were 85.4% and 75.0%, respectively, and 5- and 10-year DSS were 93.3% and 89.5%, respectively. Our 10-year OS survival rate of 75.0% was slightly worse than the 81.6% reported by Jung et al¹⁶ in a study of 39 cases of MF of the head and neck from the Asan Medical Center database. The difference in survival rate may not only be due to differences in sample size but also because the Asan Medical Center database had a higher proportion of Asian patients as a Korean registry. In our univariate analysis, Asian/Pacific Islander race was shown to be a statistically significant predictor of worse prognosis for OS (P<.001). When comparing survival in patients with head and neck MF vs all primary tumor sites, our OS rate for head and neck MF was more favorable than the 5-year OS of 75% reported by Agar et al²¹ in their analysis of 1502 patients with MF of all locations, though their cohort also included patients with SS, which is known to have a poorer prognosis. Additionally, our 10-year OS rate of 75.0% for patients with MF with a primary tumor site of the head and neck was slightly less favorable than the 81.0% reported by a prior analysis of the SEER database for MF of all locations,²² which initially may be suggestive of worse outcomes associated with MF originating from the head and neck.

Although MF originating in the head and neck region was found to be a statistically significant prognostic factor under univariate analysis (P<.001), tumor location was not significant upon adjusting for confounders in the multivariate analysis. These results are consistent with those reported in a multivariable analysis conducted by Jung et al,¹⁶ which compared 39 cases of head and neck MF to 85 cases without head and neck involvement. The investigators found that the head and neck as the primary site was a significant prognostic factor associated with worsened rates of OS when patients had stages IA to IIA (P=.009) and T2 stage tumors (P=.012) but not in either T1 stage or advanced stage IIB to IVB tumors.¹⁶ In contrast, a study by Su et al¹⁸ evaluating patients with MF from the National Cancer Database found that patients with MF originating in the head and neck region had similar survival compared with MF originating in the lower limbs after pairwise propensity matching. It previously has been postulated that primary MF lesions originating in the head and neck region have relatively higher frequencies of biological markers believed to be associated with more aggressive tumor behavior and poorer prognosis, such as histopathologic folliculotropism, T-cell receptor gene rearrangements, and large-cell transformations.¹⁶ However, MF typically is an indolent disease with advanced-stage MF following an aggressive disease course that often is refractory to treatment. A review from a single academic center noted that 5-year DSS was 97.3% for T1a but only 37.5% for T4.²³ Similarly, a meta-analysis evaluating survival in patients with MF noted the 5-year OS for stage IB was 85.8% while for stage IVB it was only 23.3%.²⁴ As such, having advanced-stage MF influences survival to a far greater extent than the presence of head and neck involvement alone. Accordingly, the significantly higher prevalence of advanced T stage disease and increased likelihood of lymph node involvement in MF lesions originating in the head and neck region (both P<.001) may explain why previous studies noted a poorer survival rate with head and neck involvement, as they did not have the sample size to adjust for these factors. Controlling for the above factors likely explains the nonsignificance of this region as a prognostic indicator in our multivariate analysis of OS and DSS.

Similar to MF originating in the head and neck region, the upper limb as a primary tumor site initially was found to be a significant predictor of both OS and DSS on univariate analysis but not on multivariate analysis. By contrast, Su et al¹⁸ found survival outcomes were worse for patients diagnosed with MF with the upper limb as the primary tumor site compared with the lower limb on multivariate Cox proportional hazards analysis but not on pairwise propensity score matching. The difference in our results compared with Su et al¹⁸ may be because the National Cancer Database only reports OS, while DSS may be more useful in determining prognostic factors associated with poorer survival, especially in an older patient population with greater comorbidities. Furthermore, the nonsignificance of the upper limb as a primary tumor site on further multivariate analysis may be due to similar reasonings as for the head and neck, including more advanced T staging and an anatomic location close to lymph nodes.

Study Limitations—The SEER database is a national registry, which lends itself to potential data heterogeneity in recording and miscoding. Additionally, there may be higher rates of unconfirmed or missing information given the retrospective nature of the SEER database; the database also does not delineate facility type, insurance status, or Charlson/Deyo comorbidity index as demographic factors, which could influence the multivariable analysis. Finally, the SEER database does not further demarcate subtypes of MF, such as the aggressive folliculotropic variant commonly seen in head and neck MF lesions, which precludes independent analysis of disease course by subtype.

Conclusion

Our study evaluated primary disease site as a prognostic factor for OS and DSS in patients with MF. Although head and neck and upper limb as primary disease sites were found to be significant on univariate analysis, they were found to be an insignificant prognostic variable for OS or DSS in our multivariable analysis, potentially due to the aggressive nature of advanced-stage MF and localization close to lymph nodes. Further research including a deeper dive into MF of all stages and subtypes is needed to fully investigate primary disease site as a prognostic indicator. Older age, larger tumor size, a higher T stage, lymph node involvement, and presence of metastasis were associated with worse DSS, and patients with these attributes should be counseled regarding expected disease course and prognosis.

Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma (CTCL), is characterized by clonal proliferation of predominantly CD4⁺ T cells with localization to the skin.¹ Mycosis fungoides typically affects older adults with a male to female ratio of 2:1 but also can occur in children and younger adults.^2,3 Known as the great imitator, the manifestations of MF can be variable with considerable clinical and pathologic overlap with benign inflammatory skin diseases, rendering definitive diagnosis challenging.^4-7 The early stages of classic MF manifest as pruritic erythematous patches and plaques with variable scaling that can progress in later stages to ulceration and tumors.⁸ Histopathologically, classic MF is characterized by epidermotropic proliferation of small- to intermediate-sized pleomorphic lymphocytes with cerebriform nuclei and a haloed appearance; intraepidermal nests of atypical lymphocytes known as Pautrier microabscesses occasionally are observed.⁵ Mycosis fungoides typically follows an indolent clinical course, with advanced-stage MF portending a poor prognosis.^9,10 Current treatment is focused on halting disease progression, with topical therapies, phototherapy, and radiation therapy as the standard therapies for early-stage MF.^11-13 For advanced-stage MF, treatment may include systemic therapies such as interferon alfa and oral retinoids along with chemotherapies for more refractive cases.¹⁴ Allogenic hematopoietic cell transplantation is the only curative treatment.¹¹

Current staging guidelines for MF do not address anatomic location as there is little known about its impact on patient outcomes.^11,15 Due to the indolent nature of MF leading to diagnostic challenges, the exact frequency of each primary disease site for MF also remains unclear, though the suggested incidence of MF of the head and neck ranges from 30% to 70%.^16,17 Involvement of the head and neck^16,18 or external ear and external auditory canal¹⁹ is associated with worse prognosis. The purpose of this study was to examine the impact of anatomic location of primary disease site on survival in MF.

Methods

The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database includes patient records from 18 registries and encompasses approximately 48% of the US population.²⁰ Using SEER*STAT software (version 8.4.0.1), we conducted a search of patients diagnosed with MF (International Classification of Diseases for Oncology, Third Edition [ICD-O-3] histologic code 9700/3 [mycosis fungoides]) between 2000 and 2019. For inclusion in the study, patients were required to have a known age, specified primary site, and a known cause of death (if applicable). Patients with known Sézary syndrome (SS)—an aggressive form of CTCL that is characterized by the presence of clonally related neoplastic T cells in the skin, lymph nodes, and peripheral blood—were not included because the World Health Organization/European Organisation for Research and Treatment of Cancer considers SS and MF to be separate entities^1,15; SS does not necessarily arise from preexisting MF and is associated with markedly poorer survival. This study was exempt from institutional review board approval because the data were publicly available and anonymized.

Data Collection—For age at diagnosis, patients were divided into the following categories: younger than 40 years, 40 to 59 years, 60 to 79 years, and 80 years and older. Demographics, tumor characteristics, and surgical management (if applicable) were obtained for each patient. The designations of chemotherapy and radiation treatment in the SEER database are not reliable and prone to false negatives. As such, these were excluded from analysis.

The primary outcomes of interest were overall survival (OS) and disease-specific survival (DSS), which were calculated as time from MF diagnosis to death. Although OS included all patients who died of any cause, DSS only included patients who died of MF.

Statistical Analysis—Demographics (age, sex, race, ethnicity), tumor characteristics (tumor size, primary site, T stage, lymph node involvement, metastasis), and surgical management (if applicable) were summarized. Overall survival and DSS were calculated using Kaplan-Meier analysis. Univariate and multivariable Cox proportional hazards regression models were generated to determine which prognostic factors for MF were associated with poorer OS and DSS. Only statistically significant variables in the univariate analysis were used to construct the multivariable analysis. Hazard ratios (HRs) and their associated 95% CIs were reported. Incidence rates were calculated and age adjusted to the 2000 US standard population. The SEER JoinPoint Regression program was used to determine the annual percent change (APC)—change in incidence rate over time. P<.05 was considered statistically significant. All statistical analyses were conducted with R version 4.0.2.

Patient Demographics and Tumor Characteristics—There were 4265 patients diagnosed with MF from 2000 to 2019. The overall incidence of MF was 2.55 per million (95% CI, 2.48-2.63) when age adjusted to the 2000 US standard population, which increased with time (mean APC, 0.97% per year; P=.01). The mean age at diagnosis was 56.4 years with a male to female ratio of 1.2:1. Males (3.07 per million; 95% CI, 2.94-3.20) had a higher incidence of MF than females (2.16 per million; 95% CI, 2.06-2.26), with incidence in females increasing over time (mean APC, 1.52% per year; P=.02) while incidence in males remained stable (mean APC, 1.09%; P=.37). Patients predominantly self-identified as White (73.08%). Patients with MF of the head and neck were more likely to have smaller tumors (P=.02), a more advanced T stage (P<.001), and lymph node involvement (P=.01) at the time of diagnosis. Additional demographics and tumor characteristics are summarized in eTable 1.

Survival Outcomes—The mean follow-up time was 86.9 months. The 5- and 10-year OS rates were 85.4% (95% CI, 84.2%-86.6%) and 75.0% (95% CI, 73.4%-76.7%), respectively (Figure 1)(Table). The 5- and 10-year DSS rates were 93.3% (95% CI, 92.4%-94.1%) and 89.5% (95% CI, 88.3%-90.6%), respectively. For OS, univariate analysis indicated that significant prognostic factors included increasing age (P<.001), female sex (P<.001), self-identifying as Asian or Pacific Islander (P<.001), self-identifying as Hispanic Latino (P<.001), primary tumor sites of either the head and neck or upper limb (P<.001), T3 or T4 staging (P=.001), lymph node involvement at the time of diagnosis (P<.001), and metastasis (P<.001).

For DSS, univariate analysis had similar risk factors with self-identifying as Black being an additional risk factor (P=.02), though self-identifying as Asian/Pacific Islander or Hispanic Latino were not significant nor was location on the lower limb. For recorded tumor size, the HR increased by 1.001 per each 1-mm increase in size (eTable 2).

Multivariate analysis showed age at diagnosis (60–79 years: HR, 23.11 [95% CI, 3.03-176.32]; P=.002; ≥80 years: HR, 92.41 [95% CI, 11.78-724.75]; P<.001), T3 staging (HR, 2.37 [95% CI, 1.32-4.27]; P=.004), and metastasis (HR, 40.14 [95% CI, 4.14-389.50]; P=.001) significantly influenced OS. For DSS, multivariate analysis indicated the significant prognostic factors were age at diagnosis (60–79 years: HR, 8.94 [95% CI, 1.16-69.23]; P=.04];≥80 years: HR, 26.71; [95% CI, 3.26-218.99]; P=.002), tumor size (HR, 1.001 [95% CI, 1.000-1.002]; P=.04), T3 staging (HR, 3.71 [95% CI, 1.58-8.67]; P=.003), lymph node involvement (HR, 3.87 [95% CI, 1.11-13.50]; P=.03) and metastasis (HR, 49.76 [95% CI, 4.03-615.00]; P=.002)(Figure 2). When controlling for the aforementioned factors, the primary disease site was not significant (eTable 3).

Comment

Although the prognostic significance of primary disease sites on various types of CTCLs has been examined, limited research exists on MF due to its rarity. For the 4265 patients with MF included in our study, statistically significant prognostic factors on multivariate analysis for DSS included age at diagnosis, tumor size, T staging, lymph node involvement, and presence of metastasis. For OS, only age at diagnosis, T staging, and presence of metastasis were statistically significant predictors. Although initially statistically significant on univariate analysis for both OS and DSS, tumor location was not significant when controlling for confounders.

Our population-based analysis found that 5- and 10-year OS for patients with head and neck MF were 85.4% and 75.0%, respectively, and 5- and 10-year DSS were 93.3% and 89.5%, respectively. Our 10-year OS survival rate of 75.0% was slightly worse than the 81.6% reported by Jung et al¹⁶ in a study of 39 cases of MF of the head and neck from the Asan Medical Center database. The difference in survival rate may not only be due to differences in sample size but also because the Asan Medical Center database had a higher proportion of Asian patients as a Korean registry. In our univariate analysis, Asian/Pacific Islander race was shown to be a statistically significant predictor of worse prognosis for OS (P<.001). When comparing survival in patients with head and neck MF vs all primary tumor sites, our OS rate for head and neck MF was more favorable than the 5-year OS of 75% reported by Agar et al²¹ in their analysis of 1502 patients with MF of all locations, though their cohort also included patients with SS, which is known to have a poorer prognosis. Additionally, our 10-year OS rate of 75.0% for patients with MF with a primary tumor site of the head and neck was slightly less favorable than the 81.0% reported by a prior analysis of the SEER database for MF of all locations,²² which initially may be suggestive of worse outcomes associated with MF originating from the head and neck.

Although MF originating in the head and neck region was found to be a statistically significant prognostic factor under univariate analysis (P<.001), tumor location was not significant upon adjusting for confounders in the multivariate analysis. These results are consistent with those reported in a multivariable analysis conducted by Jung et al,¹⁶ which compared 39 cases of head and neck MF to 85 cases without head and neck involvement. The investigators found that the head and neck as the primary site was a significant prognostic factor associated with worsened rates of OS when patients had stages IA to IIA (P=.009) and T2 stage tumors (P=.012) but not in either T1 stage or advanced stage IIB to IVB tumors.¹⁶ In contrast, a study by Su et al¹⁸ evaluating patients with MF from the National Cancer Database found that patients with MF originating in the head and neck region had similar survival compared with MF originating in the lower limbs after pairwise propensity matching. It previously has been postulated that primary MF lesions originating in the head and neck region have relatively higher frequencies of biological markers believed to be associated with more aggressive tumor behavior and poorer prognosis, such as histopathologic folliculotropism, T-cell receptor gene rearrangements, and large-cell transformations.¹⁶ However, MF typically is an indolent disease with advanced-stage MF following an aggressive disease course that often is refractory to treatment. A review from a single academic center noted that 5-year DSS was 97.3% for T1a but only 37.5% for T4.²³ Similarly, a meta-analysis evaluating survival in patients with MF noted the 5-year OS for stage IB was 85.8% while for stage IVB it was only 23.3%.²⁴ As such, having advanced-stage MF influences survival to a far greater extent than the presence of head and neck involvement alone. Accordingly, the significantly higher prevalence of advanced T stage disease and increased likelihood of lymph node involvement in MF lesions originating in the head and neck region (both P<.001) may explain why previous studies noted a poorer survival rate with head and neck involvement, as they did not have the sample size to adjust for these factors. Controlling for the above factors likely explains the nonsignificance of this region as a prognostic indicator in our multivariate analysis of OS and DSS.

Similar to MF originating in the head and neck region, the upper limb as a primary tumor site initially was found to be a significant predictor of both OS and DSS on univariate analysis but not on multivariate analysis. By contrast, Su et al¹⁸ found survival outcomes were worse for patients diagnosed with MF with the upper limb as the primary tumor site compared with the lower limb on multivariate Cox proportional hazards analysis but not on pairwise propensity score matching. The difference in our results compared with Su et al¹⁸ may be because the National Cancer Database only reports OS, while DSS may be more useful in determining prognostic factors associated with poorer survival, especially in an older patient population with greater comorbidities. Furthermore, the nonsignificance of the upper limb as a primary tumor site on further multivariate analysis may be due to similar reasonings as for the head and neck, including more advanced T staging and an anatomic location close to lymph nodes.

Study Limitations—The SEER database is a national registry, which lends itself to potential data heterogeneity in recording and miscoding. Additionally, there may be higher rates of unconfirmed or missing information given the retrospective nature of the SEER database; the database also does not delineate facility type, insurance status, or Charlson/Deyo comorbidity index as demographic factors, which could influence the multivariable analysis. Finally, the SEER database does not further demarcate subtypes of MF, such as the aggressive folliculotropic variant commonly seen in head and neck MF lesions, which precludes independent analysis of disease course by subtype.

Conclusion

Our study evaluated primary disease site as a prognostic factor for OS and DSS in patients with MF. Although head and neck and upper limb as primary disease sites were found to be significant on univariate analysis, they were found to be an insignificant prognostic variable for OS or DSS in our multivariable analysis, potentially due to the aggressive nature of advanced-stage MF and localization close to lymph nodes. Further research including a deeper dive into MF of all stages and subtypes is needed to fully investigate primary disease site as a prognostic indicator. Older age, larger tumor size, a higher T stage, lymph node involvement, and presence of metastasis were associated with worse DSS, and patients with these attributes should be counseled regarding expected disease course and prognosis.

Immersive virtual reality (VR) distraction therapy may be more effective at controlling pain in hospitalized patients with cancer than a two-dimensional guided imagery experience, suggests a new randomized controlled trial.

While both interventions brought some pain relief, VR therapy yielded greater, longer-lasting comfort, reported lead author Hunter Groninger, MD, of MedStar Health Research Institute, Hyattsville, Maryland, and colleagues.

MedStar Health

“Investigators have explored immersive VR interventions in cancer populations for a variety of indications including anxiety, depression, fatigue, and procedure‐associated pain, particularly among patients with pediatric cancer and adult breast cancer,” the investigators wrote in Cancer. “Nevertheless, despite growing evidence supporting the efficacy of VR‐delivered interventions for analgesia, few data address its role to mitigate cancer‐related pain specifically.”

To address this knowledge gap, Dr. Groninger and colleagues enrolled 128 adult hospitalized patients with cancer of any kind, all of whom had moderate to severe pain (self-reported score at least 4 out of 10) within the past 24 hours.
 

Study Methods and Results

Patients were randomized to receive either 10 minutes of immersive VR distraction therapy or 10 minutes of two-dimensional guided imagery distraction therapy.

“[The VR therapy] provides noncompetitive experiences in which the user can move around and explore natural environments (e.g., beachscape, forest) from standing, seated, or fixed positions, including within a hospital bed or chair,” the investigators wrote. “We provided over‐the‐ear headphones to assure high sound quality for the experience in the virtual natural environment.”

The two-dimensional intervention, delivered via electronic tablet, featured a meditation with images of natural landscapes and instrumental background music.

“We chose this active control because it is readily available and reflects content similar to relaxation‐focused television channels that are increasingly common in hospital settings,” the investigators noted.

Compared with this more common approach, patients who received VR therapy had significantly greater immediate reduction in pain (mean change in pain score, –1.4 vs –0.7; P = .03). Twenty-four hours later, improvements in the VR group generally persisted, while pain level in the two-dimensional group returned almost to baseline (P = .004). In addition, patients in the VR group reported significantly greater improvements in general distress and pain bothersomeness.

“VR therapies may modulate the pain experience by reducing the level of attention paid to noxious stimuli, thereby suppressing transmission of painful sensations via pain processing pathways to the cerebral cortex, particularly with more active VR experiences compared to passive experiences,” the investigators wrote.
 

Downsides to Using VR

Although VR brought more benefit, participants in the VR group more often reported difficulty using the intervention compared with those who interacted with an electronic tablet.

Plus, one VR user described mild dizziness that resolved with pharmacologic intervention. Still, approximately 9 out of 10 participants in each group reported willingness to try the intervention again.
 

Future VR Research

“Virtual reality is a rapidly evolving technology with a wealth of potential patient‐facing applications,” the investigators wrote. “Future studies should explore repeated use, optimal dosing, and impact on VR therapy on opioid analgesic requirements as well as usability testing, VR content preferences and facilitators of analgesia, and barriers and facilitators to use in acute care settings.”

This study was supported by the American Cancer Society. The investigators disclosed no conflicts of interest.

Immersive virtual reality (VR) distraction therapy may be more effective at controlling pain in hospitalized patients with cancer than a two-dimensional guided imagery experience, suggests a new randomized controlled trial.

While both interventions brought some pain relief, VR therapy yielded greater, longer-lasting comfort, reported lead author Hunter Groninger, MD, of MedStar Health Research Institute, Hyattsville, Maryland, and colleagues.

MedStar Health

“Investigators have explored immersive VR interventions in cancer populations for a variety of indications including anxiety, depression, fatigue, and procedure‐associated pain, particularly among patients with pediatric cancer and adult breast cancer,” the investigators wrote in Cancer. “Nevertheless, despite growing evidence supporting the efficacy of VR‐delivered interventions for analgesia, few data address its role to mitigate cancer‐related pain specifically.”

To address this knowledge gap, Dr. Groninger and colleagues enrolled 128 adult hospitalized patients with cancer of any kind, all of whom had moderate to severe pain (self-reported score at least 4 out of 10) within the past 24 hours.
 

Study Methods and Results

Patients were randomized to receive either 10 minutes of immersive VR distraction therapy or 10 minutes of two-dimensional guided imagery distraction therapy.

“[The VR therapy] provides noncompetitive experiences in which the user can move around and explore natural environments (e.g., beachscape, forest) from standing, seated, or fixed positions, including within a hospital bed or chair,” the investigators wrote. “We provided over‐the‐ear headphones to assure high sound quality for the experience in the virtual natural environment.”

The two-dimensional intervention, delivered via electronic tablet, featured a meditation with images of natural landscapes and instrumental background music.

“We chose this active control because it is readily available and reflects content similar to relaxation‐focused television channels that are increasingly common in hospital settings,” the investigators noted.

Compared with this more common approach, patients who received VR therapy had significantly greater immediate reduction in pain (mean change in pain score, –1.4 vs –0.7; P = .03). Twenty-four hours later, improvements in the VR group generally persisted, while pain level in the two-dimensional group returned almost to baseline (P = .004). In addition, patients in the VR group reported significantly greater improvements in general distress and pain bothersomeness.

“VR therapies may modulate the pain experience by reducing the level of attention paid to noxious stimuli, thereby suppressing transmission of painful sensations via pain processing pathways to the cerebral cortex, particularly with more active VR experiences compared to passive experiences,” the investigators wrote.
 

Downsides to Using VR

Although VR brought more benefit, participants in the VR group more often reported difficulty using the intervention compared with those who interacted with an electronic tablet.

Plus, one VR user described mild dizziness that resolved with pharmacologic intervention. Still, approximately 9 out of 10 participants in each group reported willingness to try the intervention again.
 

Future VR Research

“Virtual reality is a rapidly evolving technology with a wealth of potential patient‐facing applications,” the investigators wrote. “Future studies should explore repeated use, optimal dosing, and impact on VR therapy on opioid analgesic requirements as well as usability testing, VR content preferences and facilitators of analgesia, and barriers and facilitators to use in acute care settings.”

This study was supported by the American Cancer Society. The investigators disclosed no conflicts of interest.

Immersive virtual reality (VR) distraction therapy may be more effective at controlling pain in hospitalized patients with cancer than a two-dimensional guided imagery experience, suggests a new randomized controlled trial.

While both interventions brought some pain relief, VR therapy yielded greater, longer-lasting comfort, reported lead author Hunter Groninger, MD, of MedStar Health Research Institute, Hyattsville, Maryland, and colleagues.

MedStar Health

“Investigators have explored immersive VR interventions in cancer populations for a variety of indications including anxiety, depression, fatigue, and procedure‐associated pain, particularly among patients with pediatric cancer and adult breast cancer,” the investigators wrote in Cancer. “Nevertheless, despite growing evidence supporting the efficacy of VR‐delivered interventions for analgesia, few data address its role to mitigate cancer‐related pain specifically.”

To address this knowledge gap, Dr. Groninger and colleagues enrolled 128 adult hospitalized patients with cancer of any kind, all of whom had moderate to severe pain (self-reported score at least 4 out of 10) within the past 24 hours.
 

Study Methods and Results

Patients were randomized to receive either 10 minutes of immersive VR distraction therapy or 10 minutes of two-dimensional guided imagery distraction therapy.

“[The VR therapy] provides noncompetitive experiences in which the user can move around and explore natural environments (e.g., beachscape, forest) from standing, seated, or fixed positions, including within a hospital bed or chair,” the investigators wrote. “We provided over‐the‐ear headphones to assure high sound quality for the experience in the virtual natural environment.”

The two-dimensional intervention, delivered via electronic tablet, featured a meditation with images of natural landscapes and instrumental background music.

“We chose this active control because it is readily available and reflects content similar to relaxation‐focused television channels that are increasingly common in hospital settings,” the investigators noted.

Compared with this more common approach, patients who received VR therapy had significantly greater immediate reduction in pain (mean change in pain score, –1.4 vs –0.7; P = .03). Twenty-four hours later, improvements in the VR group generally persisted, while pain level in the two-dimensional group returned almost to baseline (P = .004). In addition, patients in the VR group reported significantly greater improvements in general distress and pain bothersomeness.

“VR therapies may modulate the pain experience by reducing the level of attention paid to noxious stimuli, thereby suppressing transmission of painful sensations via pain processing pathways to the cerebral cortex, particularly with more active VR experiences compared to passive experiences,” the investigators wrote.
 

Downsides to Using VR

Although VR brought more benefit, participants in the VR group more often reported difficulty using the intervention compared with those who interacted with an electronic tablet.

Plus, one VR user described mild dizziness that resolved with pharmacologic intervention. Still, approximately 9 out of 10 participants in each group reported willingness to try the intervention again.
 

Future VR Research

“Virtual reality is a rapidly evolving technology with a wealth of potential patient‐facing applications,” the investigators wrote. “Future studies should explore repeated use, optimal dosing, and impact on VR therapy on opioid analgesic requirements as well as usability testing, VR content preferences and facilitators of analgesia, and barriers and facilitators to use in acute care settings.”

This study was supported by the American Cancer Society. The investigators disclosed no conflicts of interest.

Healthcare providers hold wide-ranging opinions about prescribing opioids for chronic cancer pain, and many are haunted by the conflicting factors driving their views, from legal concerns to threats of violence, say the authors of new research.

These findings suggest that evidence-based, systematic guidance is needed to steer opioid usage in cancer survivorship, wrote lead author Hailey W. Bulls, PhD, of the University of Pittsburgh, and colleagues.

“Prescription opioids are considered the standard of care to treat moderate to severe cancer pain during active treatment, yet guidance in the posttreatment survivorship phase is much less clear,” the investigators wrote. “Existing clinical resources recognize that opioid prescribing in survivorship is complex and nuanced and that the relative benefits and risks in this population are not fully understood.”
 

Who Should Manage Chronic Cancer Pain?

Despite the knowledge gap, survivors are typically excluded from long-term opioid use studies, leaving providers in a largely data-free zone. Simultaneously, patients who had been receiving focused care during their cancer treatment find themselves with an ill-defined health care team.

“Without a clear transition of care, survivors may seek pain management services from a variety of specialties, including oncologists, palliative care clinicians, primary care clinicians, and pain management specialists,” the investigators wrote. “However, many clinicians may view pain management to be outside of their skill set and may not be well equipped to handle opioid continuation or deprescribing [or] to manage the potential consequences of long‐term opioid use like side effects, misuse, and/or opioid use disorder.”
 

What Factors Guide Opioid Prescribing Practices for Chronic Cancer Pain?

To learn more about prescribing practices in this setting, Dr. Bulls and colleagues conducted qualitative interviews with 20 providers representing four specialties: oncology (n = 5), palliative care (n = 8), primary care (n = 5), and pain management (n = 2). Eighteen of these participants were physicians and two were advanced practice providers. Average time in clinical practice was about 16 years.

These interviews yielded three themes.

First, no “medical home” exists for chronic pain management in cancer survivors.

“Although clinicians generally agreed that minimizing the role of opioids in chronic pain management in cancer survivors was desirable, they described a lack of common treatment protocols to guide pain management in survivorship,” the investigators wrote.

Second, the interviews revealed that prescribing strategies are partly driven by peer pressure, sometimes leading to tension between providers and feelings of self-doubt.

“I feel like there’s been this weird judgment thing that’s happened [to] the prescribers,” one primary care provider said during the interview. “Because, when I trained … pain was a vital sign, and we were supposed to treat pain, and now I feel like we’re all being judged for that.”

The third theme revolved around fear of consequences resulting from prescribing practices, including fears of violent repercussions.

“You may not know, but pain specialists have been shot in this country for [refusing to prescribe opioids],” one pain management specialist said during the interview. “There’s been a number of shootings of pain specialists who would not prescribe opioids. So, I mean, there’s real issues of violence.”

Meanwhile, a palliative care provider described legal pressure from the opposite direction:

“I think there’s a lot of fear of litigiousness … and loss of licenses. That sort of makes them pressure us into not prescribing opioids or sticking with a certain number per day that might not be therapeutic for a patient.”

Reflecting on these themes, the investigators identified “a fundamental uncertainty in survivorship pain management.”
 

What Strategies Might Improve Opioid Prescribing Practices for Chronic Cancer Pain?

After sharing their attitudes about prescribing opioids for chronic cancer pain, the clinicians were asked for suggestions to improve the situation.

They offered four main suggestions: create relevant guidelines, increase education and access to pain management options for clinicians, increase interdisciplinary communication across medical subspecialties, and promote multidisciplinary care in the survivorship setting.

Dr. Bulls and colleagues supported these strategies in their concluding remarks and called for more research.

This study was supported by the National Institute of Drug Abuse, the National Institutes of Health, the National Center for Advancing Translational Sciences, and the National Cancer Institute. The investigators disclosed relationships with Arcadia Health Solutions and Biomotivate.

Healthcare providers hold wide-ranging opinions about prescribing opioids for chronic cancer pain, and many are haunted by the conflicting factors driving their views, from legal concerns to threats of violence, say the authors of new research.

These findings suggest that evidence-based, systematic guidance is needed to steer opioid usage in cancer survivorship, wrote lead author Hailey W. Bulls, PhD, of the University of Pittsburgh, and colleagues.

“Prescription opioids are considered the standard of care to treat moderate to severe cancer pain during active treatment, yet guidance in the posttreatment survivorship phase is much less clear,” the investigators wrote. “Existing clinical resources recognize that opioid prescribing in survivorship is complex and nuanced and that the relative benefits and risks in this population are not fully understood.”
 

Who Should Manage Chronic Cancer Pain?

Despite the knowledge gap, survivors are typically excluded from long-term opioid use studies, leaving providers in a largely data-free zone. Simultaneously, patients who had been receiving focused care during their cancer treatment find themselves with an ill-defined health care team.

“Without a clear transition of care, survivors may seek pain management services from a variety of specialties, including oncologists, palliative care clinicians, primary care clinicians, and pain management specialists,” the investigators wrote. “However, many clinicians may view pain management to be outside of their skill set and may not be well equipped to handle opioid continuation or deprescribing [or] to manage the potential consequences of long‐term opioid use like side effects, misuse, and/or opioid use disorder.”
 

What Factors Guide Opioid Prescribing Practices for Chronic Cancer Pain?

To learn more about prescribing practices in this setting, Dr. Bulls and colleagues conducted qualitative interviews with 20 providers representing four specialties: oncology (n = 5), palliative care (n = 8), primary care (n = 5), and pain management (n = 2). Eighteen of these participants were physicians and two were advanced practice providers. Average time in clinical practice was about 16 years.

These interviews yielded three themes.

First, no “medical home” exists for chronic pain management in cancer survivors.

“Although clinicians generally agreed that minimizing the role of opioids in chronic pain management in cancer survivors was desirable, they described a lack of common treatment protocols to guide pain management in survivorship,” the investigators wrote.

Second, the interviews revealed that prescribing strategies are partly driven by peer pressure, sometimes leading to tension between providers and feelings of self-doubt.

“I feel like there’s been this weird judgment thing that’s happened [to] the prescribers,” one primary care provider said during the interview. “Because, when I trained … pain was a vital sign, and we were supposed to treat pain, and now I feel like we’re all being judged for that.”

The third theme revolved around fear of consequences resulting from prescribing practices, including fears of violent repercussions.

“You may not know, but pain specialists have been shot in this country for [refusing to prescribe opioids],” one pain management specialist said during the interview. “There’s been a number of shootings of pain specialists who would not prescribe opioids. So, I mean, there’s real issues of violence.”

Meanwhile, a palliative care provider described legal pressure from the opposite direction:

“I think there’s a lot of fear of litigiousness … and loss of licenses. That sort of makes them pressure us into not prescribing opioids or sticking with a certain number per day that might not be therapeutic for a patient.”

Reflecting on these themes, the investigators identified “a fundamental uncertainty in survivorship pain management.”
 

What Strategies Might Improve Opioid Prescribing Practices for Chronic Cancer Pain?

After sharing their attitudes about prescribing opioids for chronic cancer pain, the clinicians were asked for suggestions to improve the situation.

They offered four main suggestions: create relevant guidelines, increase education and access to pain management options for clinicians, increase interdisciplinary communication across medical subspecialties, and promote multidisciplinary care in the survivorship setting.

Dr. Bulls and colleagues supported these strategies in their concluding remarks and called for more research.

This study was supported by the National Institute of Drug Abuse, the National Institutes of Health, the National Center for Advancing Translational Sciences, and the National Cancer Institute. The investigators disclosed relationships with Arcadia Health Solutions and Biomotivate.

Healthcare providers hold wide-ranging opinions about prescribing opioids for chronic cancer pain, and many are haunted by the conflicting factors driving their views, from legal concerns to threats of violence, say the authors of new research.

These findings suggest that evidence-based, systematic guidance is needed to steer opioid usage in cancer survivorship, wrote lead author Hailey W. Bulls, PhD, of the University of Pittsburgh, and colleagues.

“Prescription opioids are considered the standard of care to treat moderate to severe cancer pain during active treatment, yet guidance in the posttreatment survivorship phase is much less clear,” the investigators wrote. “Existing clinical resources recognize that opioid prescribing in survivorship is complex and nuanced and that the relative benefits and risks in this population are not fully understood.”
 

Who Should Manage Chronic Cancer Pain?

Despite the knowledge gap, survivors are typically excluded from long-term opioid use studies, leaving providers in a largely data-free zone. Simultaneously, patients who had been receiving focused care during their cancer treatment find themselves with an ill-defined health care team.

“Without a clear transition of care, survivors may seek pain management services from a variety of specialties, including oncologists, palliative care clinicians, primary care clinicians, and pain management specialists,” the investigators wrote. “However, many clinicians may view pain management to be outside of their skill set and may not be well equipped to handle opioid continuation or deprescribing [or] to manage the potential consequences of long‐term opioid use like side effects, misuse, and/or opioid use disorder.”
 

What Factors Guide Opioid Prescribing Practices for Chronic Cancer Pain?

To learn more about prescribing practices in this setting, Dr. Bulls and colleagues conducted qualitative interviews with 20 providers representing four specialties: oncology (n = 5), palliative care (n = 8), primary care (n = 5), and pain management (n = 2). Eighteen of these participants were physicians and two were advanced practice providers. Average time in clinical practice was about 16 years.

These interviews yielded three themes.

First, no “medical home” exists for chronic pain management in cancer survivors.

“Although clinicians generally agreed that minimizing the role of opioids in chronic pain management in cancer survivors was desirable, they described a lack of common treatment protocols to guide pain management in survivorship,” the investigators wrote.

Second, the interviews revealed that prescribing strategies are partly driven by peer pressure, sometimes leading to tension between providers and feelings of self-doubt.

“I feel like there’s been this weird judgment thing that’s happened [to] the prescribers,” one primary care provider said during the interview. “Because, when I trained … pain was a vital sign, and we were supposed to treat pain, and now I feel like we’re all being judged for that.”

The third theme revolved around fear of consequences resulting from prescribing practices, including fears of violent repercussions.

“You may not know, but pain specialists have been shot in this country for [refusing to prescribe opioids],” one pain management specialist said during the interview. “There’s been a number of shootings of pain specialists who would not prescribe opioids. So, I mean, there’s real issues of violence.”

Meanwhile, a palliative care provider described legal pressure from the opposite direction:

“I think there’s a lot of fear of litigiousness … and loss of licenses. That sort of makes them pressure us into not prescribing opioids or sticking with a certain number per day that might not be therapeutic for a patient.”

Reflecting on these themes, the investigators identified “a fundamental uncertainty in survivorship pain management.”
 

What Strategies Might Improve Opioid Prescribing Practices for Chronic Cancer Pain?

After sharing their attitudes about prescribing opioids for chronic cancer pain, the clinicians were asked for suggestions to improve the situation.

They offered four main suggestions: create relevant guidelines, increase education and access to pain management options for clinicians, increase interdisciplinary communication across medical subspecialties, and promote multidisciplinary care in the survivorship setting.

Dr. Bulls and colleagues supported these strategies in their concluding remarks and called for more research.

This study was supported by the National Institute of Drug Abuse, the National Institutes of Health, the National Center for Advancing Translational Sciences, and the National Cancer Institute. The investigators disclosed relationships with Arcadia Health Solutions and Biomotivate.

This transcript has been edited for clarity.

I’m going to tell you about a chemical that might cause cancer — one I suspect you haven’t heard of before.

These types of stories usually end with a call for regulation — to ban said chemical or substance, or to regulate it — but in this case, that has already happened. This new carcinogen I’m telling you about is actually an old chemical. And it has not been manufactured or legally imported in the US since 2013.

So, why bother? Because in this case, the chemical — or, really, a group of chemicals called polybrominated diphenyl ethers (PBDEs) — are still around: in our soil, in our food, and in our blood.

PBDEs are a group of compounds that confer flame-retardant properties to plastics, and they were used extensively in the latter part of the 20th century in electronic enclosures, business equipment, and foam cushioning in upholstery.

But there was a problem. They don’t chemically bond to plastics; they are just sort of mixed in, which means they can leach out. They are hydrophobic, meaning they don’t get washed out of soil, and, when ingested or inhaled by humans, they dissolve in our fat stores, making it difficult for our normal excretory systems to excrete them.

PBDEs biomagnify. Small animals can take them up from contaminated soil or water, and those animals are eaten by larger animals, which accumulate higher concentrations of the chemicals. This bioaccumulation increases as you move up the food web until you get to an apex predator — like you and me.

This is true of lots of chemicals, of course. The concern arises when these chemicals are toxic. To date, the toxicity data for PBDEs were pretty limited. There were some animal studies where rats were exposed to extremely high doses and they developed liver lesions — but I am always very wary of extrapolating high-dose rat toxicity studies to humans. There was also some suggestion that the chemicals could be endocrine disruptors, affecting breast and thyroid tissue.

What about cancer? In 2016, the International Agency for Research on Cancer concluded there was “inadequate evidence in humans for the carcinogencity of” PBDEs.

In the same report, though, they suggested PBDEs are “probably carcinogenic to humans” based on mechanistic studies.

In other words, we can’t prove they’re cancerous — but come on, they probably are.

Finally, we have some evidence that really pushes us toward the carcinogenic conclusion, in the form of this study, appearing in JAMA Network Open. It’s a nice bit of epidemiology leveraging the population-based National Health and Nutrition Examination Survey (NHANES).

Researchers measured PBDE levels in blood samples from 1100 people enrolled in NHANES in 2003 and 2004 and linked them to death records collected over the next 20 years or so.

The first thing to note is that the researchers were able to measure PBDEs in the blood samples. They were in there. They were detectable. And they were variable. Dividing the 1100 participants into low, medium, and high PBDE tertiles, you can see a nearly 10-fold difference across the population.

Importantly, not many baseline variables correlated with PBDE levels. People in the highest group were a bit younger but had a fairly similar sex distribution, race, ethnicity, education, income, physical activity, smoking status, and body mass index.

This is not a randomized trial, of course — but at least based on these data, exposure levels do seem fairly random, which is what you would expect from an environmental toxin that percolates up through the food chain. They are often somewhat indiscriminate.

This similarity in baseline characteristics between people with low or high blood levels of PBDE also allows us to make some stronger inferences about the observed outcomes. Let’s take a look at them.

After adjustment for baseline factors, individuals in the highest PBDE group had a 43% higher rate of death from any cause over the follow-up period. This was not enough to achieve statistical significance, but it was close.

Dr. Wilson

Dr. F. Perry Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

I’m going to tell you about a chemical that might cause cancer — one I suspect you haven’t heard of before.

These types of stories usually end with a call for regulation — to ban said chemical or substance, or to regulate it — but in this case, that has already happened. This new carcinogen I’m telling you about is actually an old chemical. And it has not been manufactured or legally imported in the US since 2013.

So, why bother? Because in this case, the chemical — or, really, a group of chemicals called polybrominated diphenyl ethers (PBDEs) — are still around: in our soil, in our food, and in our blood.

PBDEs are a group of compounds that confer flame-retardant properties to plastics, and they were used extensively in the latter part of the 20th century in electronic enclosures, business equipment, and foam cushioning in upholstery.

But there was a problem. They don’t chemically bond to plastics; they are just sort of mixed in, which means they can leach out. They are hydrophobic, meaning they don’t get washed out of soil, and, when ingested or inhaled by humans, they dissolve in our fat stores, making it difficult for our normal excretory systems to excrete them.

PBDEs biomagnify. Small animals can take them up from contaminated soil or water, and those animals are eaten by larger animals, which accumulate higher concentrations of the chemicals. This bioaccumulation increases as you move up the food web until you get to an apex predator — like you and me.

This is true of lots of chemicals, of course. The concern arises when these chemicals are toxic. To date, the toxicity data for PBDEs were pretty limited. There were some animal studies where rats were exposed to extremely high doses and they developed liver lesions — but I am always very wary of extrapolating high-dose rat toxicity studies to humans. There was also some suggestion that the chemicals could be endocrine disruptors, affecting breast and thyroid tissue.

What about cancer? In 2016, the International Agency for Research on Cancer concluded there was “inadequate evidence in humans for the carcinogencity of” PBDEs.

In the same report, though, they suggested PBDEs are “probably carcinogenic to humans” based on mechanistic studies.

In other words, we can’t prove they’re cancerous — but come on, they probably are.

Finally, we have some evidence that really pushes us toward the carcinogenic conclusion, in the form of this study, appearing in JAMA Network Open. It’s a nice bit of epidemiology leveraging the population-based National Health and Nutrition Examination Survey (NHANES).

Researchers measured PBDE levels in blood samples from 1100 people enrolled in NHANES in 2003 and 2004 and linked them to death records collected over the next 20 years or so.

The first thing to note is that the researchers were able to measure PBDEs in the blood samples. They were in there. They were detectable. And they were variable. Dividing the 1100 participants into low, medium, and high PBDE tertiles, you can see a nearly 10-fold difference across the population.

Importantly, not many baseline variables correlated with PBDE levels. People in the highest group were a bit younger but had a fairly similar sex distribution, race, ethnicity, education, income, physical activity, smoking status, and body mass index.

This is not a randomized trial, of course — but at least based on these data, exposure levels do seem fairly random, which is what you would expect from an environmental toxin that percolates up through the food chain. They are often somewhat indiscriminate.

This similarity in baseline characteristics between people with low or high blood levels of PBDE also allows us to make some stronger inferences about the observed outcomes. Let’s take a look at them.

After adjustment for baseline factors, individuals in the highest PBDE group had a 43% higher rate of death from any cause over the follow-up period. This was not enough to achieve statistical significance, but it was close.

Dr. Wilson

Dr. F. Perry Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

I’m going to tell you about a chemical that might cause cancer — one I suspect you haven’t heard of before.

These types of stories usually end with a call for regulation — to ban said chemical or substance, or to regulate it — but in this case, that has already happened. This new carcinogen I’m telling you about is actually an old chemical. And it has not been manufactured or legally imported in the US since 2013.

So, why bother? Because in this case, the chemical — or, really, a group of chemicals called polybrominated diphenyl ethers (PBDEs) — are still around: in our soil, in our food, and in our blood.

PBDEs are a group of compounds that confer flame-retardant properties to plastics, and they were used extensively in the latter part of the 20th century in electronic enclosures, business equipment, and foam cushioning in upholstery.

But there was a problem. They don’t chemically bond to plastics; they are just sort of mixed in, which means they can leach out. They are hydrophobic, meaning they don’t get washed out of soil, and, when ingested or inhaled by humans, they dissolve in our fat stores, making it difficult for our normal excretory systems to excrete them.

PBDEs biomagnify. Small animals can take them up from contaminated soil or water, and those animals are eaten by larger animals, which accumulate higher concentrations of the chemicals. This bioaccumulation increases as you move up the food web until you get to an apex predator — like you and me.

This is true of lots of chemicals, of course. The concern arises when these chemicals are toxic. To date, the toxicity data for PBDEs were pretty limited. There were some animal studies where rats were exposed to extremely high doses and they developed liver lesions — but I am always very wary of extrapolating high-dose rat toxicity studies to humans. There was also some suggestion that the chemicals could be endocrine disruptors, affecting breast and thyroid tissue.

What about cancer? In 2016, the International Agency for Research on Cancer concluded there was “inadequate evidence in humans for the carcinogencity of” PBDEs.

In the same report, though, they suggested PBDEs are “probably carcinogenic to humans” based on mechanistic studies.

In other words, we can’t prove they’re cancerous — but come on, they probably are.

Finally, we have some evidence that really pushes us toward the carcinogenic conclusion, in the form of this study, appearing in JAMA Network Open. It’s a nice bit of epidemiology leveraging the population-based National Health and Nutrition Examination Survey (NHANES).

Researchers measured PBDE levels in blood samples from 1100 people enrolled in NHANES in 2003 and 2004 and linked them to death records collected over the next 20 years or so.

The first thing to note is that the researchers were able to measure PBDEs in the blood samples. They were in there. They were detectable. And they were variable. Dividing the 1100 participants into low, medium, and high PBDE tertiles, you can see a nearly 10-fold difference across the population.

Importantly, not many baseline variables correlated with PBDE levels. People in the highest group were a bit younger but had a fairly similar sex distribution, race, ethnicity, education, income, physical activity, smoking status, and body mass index.

This is not a randomized trial, of course — but at least based on these data, exposure levels do seem fairly random, which is what you would expect from an environmental toxin that percolates up through the food chain. They are often somewhat indiscriminate.

This similarity in baseline characteristics between people with low or high blood levels of PBDE also allows us to make some stronger inferences about the observed outcomes. Let’s take a look at them.

After adjustment for baseline factors, individuals in the highest PBDE group had a 43% higher rate of death from any cause over the follow-up period. This was not enough to achieve statistical significance, but it was close.

Dr. Wilson

Dr. F. Perry Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.