Melanoma

Using adjunctive reflectance confocal microscopy (RCM) for examining suspect skin lesions reduced the number of unnecessary skin excisions by 43%, results from a large randomized clinical trial showed.

“Skin cancer management exerts a sizable burden on health systems,” researchers led by Giovanni Pellacani, MD, wrote in an article published in JAMA Dermatology. “The systematic application of RCM in the triage of high-risk patients should improve diagnostic accuracy and reduce unnecessary excisions for histopathological diagnostic confirmation, thereby reducing costs, surgical waiting lists, and delayed diagnoses.”

However, they added, “the clinical application of RCM has mainly been limited to retrospective and prospective observational studies producing hypothetical estimates of clinical applicability without intention to affect clinical and therapeutic patient pathways.”

For the current study, Dr. Pellacani, who chairs the department of dermatology at Sapienza University, Rome, and colleagues hypothesized that RCM would reduce unnecessary excisions by more than 30% and would identify all melanoma lesions 0.5 mm or thinner at baseline. They enrolled 3,165 patients with suspect lesions from three dermatology referral centers between January 2017 and December 2019, with a mean follow-up of 9.6 months in the study. Participants were randomly assigned 1:1 to standard therapeutic care, which consisted of clinical and dermoscopy evaluation with or without adjunctive RCM, a novel noninvasive technology that provides in vivo imaging of the skin, with a high diagnostic accuracy.

Histopathologic examination of all excised lesions was performed at the pathology department of the referral center. Resulting information guided prospective clinical decision-making (excision or follow-up). The mean age of patients was 49 years, 49% were women, 21% had a personal history of melanoma, and 51% had Fitzpatrick phototype 2 skin.

When compared with standard therapeutic care only, adjunctive RCM was associated with a higher positive predictive value (18.9 vs. 33.3, respectively), lower benign to malignant ratio (3.7:1.0 vs. 1.8:1.0), and a reduction in the number needed to excise of 43.4% (5.3 vs. 3.0). In addition, all 15 lesions with delayed melanoma diagnoses were thinner than 0.5 mm. Of these, eight were diagnosed as melanoma in situ.

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., who was asked to comment on the study, said that a strength of the analysis was its follow-up and histopathologic evaluation, “which are both essentially forms of feedback. Good, relevant feedback is necessary for all of us to improve.”

She pointed out that, while RCM does appear to reduce the number of benign lesions unnecessarily removed and increase the number of skin cancers appropriately excised, the authors acknowledged that they had at least 4 years of experience with RCM. “The study also does not address the time factor (the procedure takes about 7 minutes per lesion) and the financial cost of reflectance confocal microscopy, as compared to the cost of standard follow-up alone with an increased number of excisions.”

She added that the findings “are not yet applicable to general dermatology across the world, as the authors comment, given that reflectance confocal microscopy is not yet widely available.”

The Italian Ministry of Health supported the study. Neither the researchers nor Dr. Ko reported having relevant financial conflicts.

Using adjunctive reflectance confocal microscopy (RCM) for examining suspect skin lesions reduced the number of unnecessary skin excisions by 43%, results from a large randomized clinical trial showed.

“Skin cancer management exerts a sizable burden on health systems,” researchers led by Giovanni Pellacani, MD, wrote in an article published in JAMA Dermatology. “The systematic application of RCM in the triage of high-risk patients should improve diagnostic accuracy and reduce unnecessary excisions for histopathological diagnostic confirmation, thereby reducing costs, surgical waiting lists, and delayed diagnoses.”

However, they added, “the clinical application of RCM has mainly been limited to retrospective and prospective observational studies producing hypothetical estimates of clinical applicability without intention to affect clinical and therapeutic patient pathways.”

For the current study, Dr. Pellacani, who chairs the department of dermatology at Sapienza University, Rome, and colleagues hypothesized that RCM would reduce unnecessary excisions by more than 30% and would identify all melanoma lesions 0.5 mm or thinner at baseline. They enrolled 3,165 patients with suspect lesions from three dermatology referral centers between January 2017 and December 2019, with a mean follow-up of 9.6 months in the study. Participants were randomly assigned 1:1 to standard therapeutic care, which consisted of clinical and dermoscopy evaluation with or without adjunctive RCM, a novel noninvasive technology that provides in vivo imaging of the skin, with a high diagnostic accuracy.

Histopathologic examination of all excised lesions was performed at the pathology department of the referral center. Resulting information guided prospective clinical decision-making (excision or follow-up). The mean age of patients was 49 years, 49% were women, 21% had a personal history of melanoma, and 51% had Fitzpatrick phototype 2 skin.

When compared with standard therapeutic care only, adjunctive RCM was associated with a higher positive predictive value (18.9 vs. 33.3, respectively), lower benign to malignant ratio (3.7:1.0 vs. 1.8:1.0), and a reduction in the number needed to excise of 43.4% (5.3 vs. 3.0). In addition, all 15 lesions with delayed melanoma diagnoses were thinner than 0.5 mm. Of these, eight were diagnosed as melanoma in situ.

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., who was asked to comment on the study, said that a strength of the analysis was its follow-up and histopathologic evaluation, “which are both essentially forms of feedback. Good, relevant feedback is necessary for all of us to improve.”

She pointed out that, while RCM does appear to reduce the number of benign lesions unnecessarily removed and increase the number of skin cancers appropriately excised, the authors acknowledged that they had at least 4 years of experience with RCM. “The study also does not address the time factor (the procedure takes about 7 minutes per lesion) and the financial cost of reflectance confocal microscopy, as compared to the cost of standard follow-up alone with an increased number of excisions.”

She added that the findings “are not yet applicable to general dermatology across the world, as the authors comment, given that reflectance confocal microscopy is not yet widely available.”

The Italian Ministry of Health supported the study. Neither the researchers nor Dr. Ko reported having relevant financial conflicts.

Using adjunctive reflectance confocal microscopy (RCM) for examining suspect skin lesions reduced the number of unnecessary skin excisions by 43%, results from a large randomized clinical trial showed.

“Skin cancer management exerts a sizable burden on health systems,” researchers led by Giovanni Pellacani, MD, wrote in an article published in JAMA Dermatology. “The systematic application of RCM in the triage of high-risk patients should improve diagnostic accuracy and reduce unnecessary excisions for histopathological diagnostic confirmation, thereby reducing costs, surgical waiting lists, and delayed diagnoses.”

However, they added, “the clinical application of RCM has mainly been limited to retrospective and prospective observational studies producing hypothetical estimates of clinical applicability without intention to affect clinical and therapeutic patient pathways.”

For the current study, Dr. Pellacani, who chairs the department of dermatology at Sapienza University, Rome, and colleagues hypothesized that RCM would reduce unnecessary excisions by more than 30% and would identify all melanoma lesions 0.5 mm or thinner at baseline. They enrolled 3,165 patients with suspect lesions from three dermatology referral centers between January 2017 and December 2019, with a mean follow-up of 9.6 months in the study. Participants were randomly assigned 1:1 to standard therapeutic care, which consisted of clinical and dermoscopy evaluation with or without adjunctive RCM, a novel noninvasive technology that provides in vivo imaging of the skin, with a high diagnostic accuracy.

Histopathologic examination of all excised lesions was performed at the pathology department of the referral center. Resulting information guided prospective clinical decision-making (excision or follow-up). The mean age of patients was 49 years, 49% were women, 21% had a personal history of melanoma, and 51% had Fitzpatrick phototype 2 skin.

When compared with standard therapeutic care only, adjunctive RCM was associated with a higher positive predictive value (18.9 vs. 33.3, respectively), lower benign to malignant ratio (3.7:1.0 vs. 1.8:1.0), and a reduction in the number needed to excise of 43.4% (5.3 vs. 3.0). In addition, all 15 lesions with delayed melanoma diagnoses were thinner than 0.5 mm. Of these, eight were diagnosed as melanoma in situ.

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., who was asked to comment on the study, said that a strength of the analysis was its follow-up and histopathologic evaluation, “which are both essentially forms of feedback. Good, relevant feedback is necessary for all of us to improve.”

She pointed out that, while RCM does appear to reduce the number of benign lesions unnecessarily removed and increase the number of skin cancers appropriately excised, the authors acknowledged that they had at least 4 years of experience with RCM. “The study also does not address the time factor (the procedure takes about 7 minutes per lesion) and the financial cost of reflectance confocal microscopy, as compared to the cost of standard follow-up alone with an increased number of excisions.”

She added that the findings “are not yet applicable to general dermatology across the world, as the authors comment, given that reflectance confocal microscopy is not yet widely available.”

The Italian Ministry of Health supported the study. Neither the researchers nor Dr. Ko reported having relevant financial conflicts.

Patients receiving treatment with ibrutinib for chronic lymphocytic leukemia (CLL) show significant increases in the risk for bleeding when undergoing Mohs micrographic surgery for skin cancer, indicating the need for temporary treatment interruptions, new research shows.

“Our cohort of CLL patients on ibrutinib had a two-times greater risk of bleeding complications relative to those on anticoagulants and a nearly 40-times greater risk of bleeding complications relative to those patients on no anticoagulants or CLL therapy,” Kelsey E. Hirotsu, MD, first author of one of two studies on the issue presented at the American College of Mohs Surgery annual meeting, told this news organization.

“It was definitely surprising to see this doubled risk with ibrutinib relative to anticoagulants, and certainly highlights the clinically relevant increased bleeding risk in patients on ibrutinib,” said Dr. Hirotsu, a Mohs micrographic surgery fellow in the department of dermatology, University of California, San Diego (UCSD).

With CLL associated with an increased risk for aggressive skin cancers, particularly squamous cell carcinoma, Mohs surgeons may commonly find themselves treating patients with these unique considerations. Surgical treatment of those cancers can be complicated not only because of potential underlying thrombocytopenia, which occurs in about 5% of untreated CLL patients, but also because of the increased risk for bleeding that is associated with the use of the Bruton tyrosine kinase inhibitor ibrutinib, commonly used for CLL.

While the nature of the increased bleeding-related complications among patients with CLL undergoing Mohs surgery has been documented in some case reports, evidence from larger studies has been lacking.

In one of the studies presented at the ACMS meeting, Dr. Hirotsu and her colleagues evaluated data on patients with CLL who underwent at least one Mohs surgery procedure at UCSD Dermatologic Surgery over 10 years. Of the 362 Mohs cases among 98 patients with CLL, 32 cases had at least one complication. Patients on anticoagulants, including antiplatelet agents, Coumadin, and direct oral anticoagulants (DOACs), not surprisingly, had higher rates of complications, particularly bleeding.

However, those treated with ibrutinib had the highest rates of complications among all of the patients (40.6%), with all of their complications involving bleeding-related events. In comparison, the complication rates, for instance, of patients treated with antiplatelets were 21.9%; Coumadin, 6.2%; and DOACs, 15.6%.

The incidence of bleeding-related complications among the cases in the ibrutinib-treated patients was 30.2% compared with 13.2% among those on blood thinners and no CLL therapy (relative risk [RR], 2.08; 95% confidence interval [CI], 0.85-5.11; P = .11). “Although not statistically significant, these results could trend toward significance with larger sample sizes,” Dr. Hirotsu said.

The risk for bleeding among patients on ibrutinib compared with patients on no medications, however, was significant, with a relative risk of 39.0 (95% CI, 2.35-646; P = .011).

Of note, among 12 patients on ibrutinib who experienced bleeding complications, 7 had previously undergone Mohs surgeries when they were not taking ibrutinib and no bleeding complications had occurred in those procedures. “This may further implicate ibrutinib as a cause of the bleeding-related complications,” Dr. Hirotsu said.

In investigating the role of thrombocytopenia at the time of Mohs surgery, the authors found that, among ibrutinib-treated patients who had no complications, 30% had thrombocytopenia, compared with 70% of those who did have bleeding while on ibrutinib at the time of surgery.

“It was interesting that thrombocytopenia is more common in ibrutinib patients with bleeding-related complications, but further research needs to be done to determine the clinical relevance and possible management implications,” Dr. Hirotsu said.

In a separate study presented at the meeting, 37 patients treated with ibrutinib for CLL while undergoing cutaneous surgery that included Mohs surgery and excisions had a significantly increased bleeding complication rate compared with a control group of 64 age- and sex-matched patients with CLL undergoing cutaneous surgery: 6 of 75 procedures (8%) versus 1 of 115 procedures (0.9%; P = .02).

Those with bleeding complications while on ibrutinib were all male, older (mean age, 82.7 vs. 73.0; P = .01), and had lower mean platelet counts (104 K/mcL vs. 150.5 K/mcL; P = .03).

There were no significant differences between the case and control groups in terms of anatomic site, type of procedure (Mohs versus excision), tumor diagnosis, lesion size, or type of reconstruction, while the control group was more likely to be on aspirin or other anticoagulants (P < .0001).

In an interview, senior author Nahid Y. Vidal, MD, a Mohs surgeon and dermatologic oncologist at the Mayo Clinic, Rochester, Minn., said that “the take-home message is that patients on ibrutinib should be considered higher risk for bleeding events, regardless of whether they are having a simpler surgery [excision] or more involved skin surgery procedure [Mohs with flap].”

Holding treatment

To offset the bleeding risk, Dr. Vidal notes that holding the treatment is considered safe and that the manufacturer recommends holding ibrutinib for at least 3-7 days pre- and post surgery, “depending on type of surgery and risk of bleeding.”

“In our institution, with the hematologist/oncologist’s input, we hold ibrutinib for 5 days preop and 3 days post op, and have not had bleed complications in these patients,” she said, noting that there were no bleeding events in the patients in the study when ibrutinib was held.

Likewise, Dr. Hirotsu noted that at her center at UCSD, patients on ibrutinib are asked during the preop call to hold treatment for 3 days before and after Mohs surgery – but are advised to discuss the decision with their hematologist/oncologist for approval.

The measure isn’t always successful in preventing bleeding, however, as seen in a case study describing two patients who experienced bleeding complications following Mohs surgery despite being taken off ibrutinib 3 days prior to the procedure.

The senior author of that study, Kira Minkis, MD, PhD, department of dermatology, Weill Cornell/New York Presbyterian, New York, told this news organization that her team concluded that in those cases ibrutinib perhaps should have been held longer than 3 days.

“In some cases, especially if the Mohs surgery is a large procedure with a more advanced reconstruction, such as a large flap, it might be more prudent to continue it longer than 3 days,” Dr. Minkis said. She noted that the high bleeding risk observed in the studies at ACMS was notable – but not unexpected.

“I’m not that surprised because if you look at the hematologic literature, the risk is indeed pretty significant, so it makes sense that it would also occur with Mohs surgeries,” she said.

She underscored that a 3-day hold of ibrutinib should be considered the minimum, “and in some cases, it should be held up to 7 days prior to surgery, depending on the specific surgery,” with the important caveat of consulting with the patient’s hematology team.

“Multidisciplinary decision-making is necessary for these cases, and the interruption of therapy should always be discussed with their hematology team,” she added. That said, Dr. Minkis noted that “I’ve never had a hematologist who had any concerns for withholding ibrutinib even for a week around the time of a surgery.”

Dr. Hirotsu, Dr. Vidal, and Dr. Minkis reported no relevant financial relationships.

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

Patients receiving treatment with ibrutinib for chronic lymphocytic leukemia (CLL) show significant increases in the risk for bleeding when undergoing Mohs micrographic surgery for skin cancer, indicating the need for temporary treatment interruptions, new research shows.

“Our cohort of CLL patients on ibrutinib had a two-times greater risk of bleeding complications relative to those on anticoagulants and a nearly 40-times greater risk of bleeding complications relative to those patients on no anticoagulants or CLL therapy,” Kelsey E. Hirotsu, MD, first author of one of two studies on the issue presented at the American College of Mohs Surgery annual meeting, told this news organization.

“It was definitely surprising to see this doubled risk with ibrutinib relative to anticoagulants, and certainly highlights the clinically relevant increased bleeding risk in patients on ibrutinib,” said Dr. Hirotsu, a Mohs micrographic surgery fellow in the department of dermatology, University of California, San Diego (UCSD).

With CLL associated with an increased risk for aggressive skin cancers, particularly squamous cell carcinoma, Mohs surgeons may commonly find themselves treating patients with these unique considerations. Surgical treatment of those cancers can be complicated not only because of potential underlying thrombocytopenia, which occurs in about 5% of untreated CLL patients, but also because of the increased risk for bleeding that is associated with the use of the Bruton tyrosine kinase inhibitor ibrutinib, commonly used for CLL.

While the nature of the increased bleeding-related complications among patients with CLL undergoing Mohs surgery has been documented in some case reports, evidence from larger studies has been lacking.

In one of the studies presented at the ACMS meeting, Dr. Hirotsu and her colleagues evaluated data on patients with CLL who underwent at least one Mohs surgery procedure at UCSD Dermatologic Surgery over 10 years. Of the 362 Mohs cases among 98 patients with CLL, 32 cases had at least one complication. Patients on anticoagulants, including antiplatelet agents, Coumadin, and direct oral anticoagulants (DOACs), not surprisingly, had higher rates of complications, particularly bleeding.

However, those treated with ibrutinib had the highest rates of complications among all of the patients (40.6%), with all of their complications involving bleeding-related events. In comparison, the complication rates, for instance, of patients treated with antiplatelets were 21.9%; Coumadin, 6.2%; and DOACs, 15.6%.

The incidence of bleeding-related complications among the cases in the ibrutinib-treated patients was 30.2% compared with 13.2% among those on blood thinners and no CLL therapy (relative risk [RR], 2.08; 95% confidence interval [CI], 0.85-5.11; P = .11). “Although not statistically significant, these results could trend toward significance with larger sample sizes,” Dr. Hirotsu said.

The risk for bleeding among patients on ibrutinib compared with patients on no medications, however, was significant, with a relative risk of 39.0 (95% CI, 2.35-646; P = .011).

Of note, among 12 patients on ibrutinib who experienced bleeding complications, 7 had previously undergone Mohs surgeries when they were not taking ibrutinib and no bleeding complications had occurred in those procedures. “This may further implicate ibrutinib as a cause of the bleeding-related complications,” Dr. Hirotsu said.

In investigating the role of thrombocytopenia at the time of Mohs surgery, the authors found that, among ibrutinib-treated patients who had no complications, 30% had thrombocytopenia, compared with 70% of those who did have bleeding while on ibrutinib at the time of surgery.

“It was interesting that thrombocytopenia is more common in ibrutinib patients with bleeding-related complications, but further research needs to be done to determine the clinical relevance and possible management implications,” Dr. Hirotsu said.

In a separate study presented at the meeting, 37 patients treated with ibrutinib for CLL while undergoing cutaneous surgery that included Mohs surgery and excisions had a significantly increased bleeding complication rate compared with a control group of 64 age- and sex-matched patients with CLL undergoing cutaneous surgery: 6 of 75 procedures (8%) versus 1 of 115 procedures (0.9%; P = .02).

Those with bleeding complications while on ibrutinib were all male, older (mean age, 82.7 vs. 73.0; P = .01), and had lower mean platelet counts (104 K/mcL vs. 150.5 K/mcL; P = .03).

There were no significant differences between the case and control groups in terms of anatomic site, type of procedure (Mohs versus excision), tumor diagnosis, lesion size, or type of reconstruction, while the control group was more likely to be on aspirin or other anticoagulants (P < .0001).

In an interview, senior author Nahid Y. Vidal, MD, a Mohs surgeon and dermatologic oncologist at the Mayo Clinic, Rochester, Minn., said that “the take-home message is that patients on ibrutinib should be considered higher risk for bleeding events, regardless of whether they are having a simpler surgery [excision] or more involved skin surgery procedure [Mohs with flap].”

Holding treatment

To offset the bleeding risk, Dr. Vidal notes that holding the treatment is considered safe and that the manufacturer recommends holding ibrutinib for at least 3-7 days pre- and post surgery, “depending on type of surgery and risk of bleeding.”

“In our institution, with the hematologist/oncologist’s input, we hold ibrutinib for 5 days preop and 3 days post op, and have not had bleed complications in these patients,” she said, noting that there were no bleeding events in the patients in the study when ibrutinib was held.

Likewise, Dr. Hirotsu noted that at her center at UCSD, patients on ibrutinib are asked during the preop call to hold treatment for 3 days before and after Mohs surgery – but are advised to discuss the decision with their hematologist/oncologist for approval.

The measure isn’t always successful in preventing bleeding, however, as seen in a case study describing two patients who experienced bleeding complications following Mohs surgery despite being taken off ibrutinib 3 days prior to the procedure.

The senior author of that study, Kira Minkis, MD, PhD, department of dermatology, Weill Cornell/New York Presbyterian, New York, told this news organization that her team concluded that in those cases ibrutinib perhaps should have been held longer than 3 days.

“In some cases, especially if the Mohs surgery is a large procedure with a more advanced reconstruction, such as a large flap, it might be more prudent to continue it longer than 3 days,” Dr. Minkis said. She noted that the high bleeding risk observed in the studies at ACMS was notable – but not unexpected.

“I’m not that surprised because if you look at the hematologic literature, the risk is indeed pretty significant, so it makes sense that it would also occur with Mohs surgeries,” she said.

She underscored that a 3-day hold of ibrutinib should be considered the minimum, “and in some cases, it should be held up to 7 days prior to surgery, depending on the specific surgery,” with the important caveat of consulting with the patient’s hematology team.

“Multidisciplinary decision-making is necessary for these cases, and the interruption of therapy should always be discussed with their hematology team,” she added. That said, Dr. Minkis noted that “I’ve never had a hematologist who had any concerns for withholding ibrutinib even for a week around the time of a surgery.”

Dr. Hirotsu, Dr. Vidal, and Dr. Minkis reported no relevant financial relationships.

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

Patients receiving treatment with ibrutinib for chronic lymphocytic leukemia (CLL) show significant increases in the risk for bleeding when undergoing Mohs micrographic surgery for skin cancer, indicating the need for temporary treatment interruptions, new research shows.

“Our cohort of CLL patients on ibrutinib had a two-times greater risk of bleeding complications relative to those on anticoagulants and a nearly 40-times greater risk of bleeding complications relative to those patients on no anticoagulants or CLL therapy,” Kelsey E. Hirotsu, MD, first author of one of two studies on the issue presented at the American College of Mohs Surgery annual meeting, told this news organization.

“It was definitely surprising to see this doubled risk with ibrutinib relative to anticoagulants, and certainly highlights the clinically relevant increased bleeding risk in patients on ibrutinib,” said Dr. Hirotsu, a Mohs micrographic surgery fellow in the department of dermatology, University of California, San Diego (UCSD).

With CLL associated with an increased risk for aggressive skin cancers, particularly squamous cell carcinoma, Mohs surgeons may commonly find themselves treating patients with these unique considerations. Surgical treatment of those cancers can be complicated not only because of potential underlying thrombocytopenia, which occurs in about 5% of untreated CLL patients, but also because of the increased risk for bleeding that is associated with the use of the Bruton tyrosine kinase inhibitor ibrutinib, commonly used for CLL.

While the nature of the increased bleeding-related complications among patients with CLL undergoing Mohs surgery has been documented in some case reports, evidence from larger studies has been lacking.

In one of the studies presented at the ACMS meeting, Dr. Hirotsu and her colleagues evaluated data on patients with CLL who underwent at least one Mohs surgery procedure at UCSD Dermatologic Surgery over 10 years. Of the 362 Mohs cases among 98 patients with CLL, 32 cases had at least one complication. Patients on anticoagulants, including antiplatelet agents, Coumadin, and direct oral anticoagulants (DOACs), not surprisingly, had higher rates of complications, particularly bleeding.

However, those treated with ibrutinib had the highest rates of complications among all of the patients (40.6%), with all of their complications involving bleeding-related events. In comparison, the complication rates, for instance, of patients treated with antiplatelets were 21.9%; Coumadin, 6.2%; and DOACs, 15.6%.

The incidence of bleeding-related complications among the cases in the ibrutinib-treated patients was 30.2% compared with 13.2% among those on blood thinners and no CLL therapy (relative risk [RR], 2.08; 95% confidence interval [CI], 0.85-5.11; P = .11). “Although not statistically significant, these results could trend toward significance with larger sample sizes,” Dr. Hirotsu said.

The risk for bleeding among patients on ibrutinib compared with patients on no medications, however, was significant, with a relative risk of 39.0 (95% CI, 2.35-646; P = .011).

Of note, among 12 patients on ibrutinib who experienced bleeding complications, 7 had previously undergone Mohs surgeries when they were not taking ibrutinib and no bleeding complications had occurred in those procedures. “This may further implicate ibrutinib as a cause of the bleeding-related complications,” Dr. Hirotsu said.

In investigating the role of thrombocytopenia at the time of Mohs surgery, the authors found that, among ibrutinib-treated patients who had no complications, 30% had thrombocytopenia, compared with 70% of those who did have bleeding while on ibrutinib at the time of surgery.

“It was interesting that thrombocytopenia is more common in ibrutinib patients with bleeding-related complications, but further research needs to be done to determine the clinical relevance and possible management implications,” Dr. Hirotsu said.

In a separate study presented at the meeting, 37 patients treated with ibrutinib for CLL while undergoing cutaneous surgery that included Mohs surgery and excisions had a significantly increased bleeding complication rate compared with a control group of 64 age- and sex-matched patients with CLL undergoing cutaneous surgery: 6 of 75 procedures (8%) versus 1 of 115 procedures (0.9%; P = .02).

Those with bleeding complications while on ibrutinib were all male, older (mean age, 82.7 vs. 73.0; P = .01), and had lower mean platelet counts (104 K/mcL vs. 150.5 K/mcL; P = .03).

There were no significant differences between the case and control groups in terms of anatomic site, type of procedure (Mohs versus excision), tumor diagnosis, lesion size, or type of reconstruction, while the control group was more likely to be on aspirin or other anticoagulants (P < .0001).

In an interview, senior author Nahid Y. Vidal, MD, a Mohs surgeon and dermatologic oncologist at the Mayo Clinic, Rochester, Minn., said that “the take-home message is that patients on ibrutinib should be considered higher risk for bleeding events, regardless of whether they are having a simpler surgery [excision] or more involved skin surgery procedure [Mohs with flap].”

Holding treatment

To offset the bleeding risk, Dr. Vidal notes that holding the treatment is considered safe and that the manufacturer recommends holding ibrutinib for at least 3-7 days pre- and post surgery, “depending on type of surgery and risk of bleeding.”

“In our institution, with the hematologist/oncologist’s input, we hold ibrutinib for 5 days preop and 3 days post op, and have not had bleed complications in these patients,” she said, noting that there were no bleeding events in the patients in the study when ibrutinib was held.

Likewise, Dr. Hirotsu noted that at her center at UCSD, patients on ibrutinib are asked during the preop call to hold treatment for 3 days before and after Mohs surgery – but are advised to discuss the decision with their hematologist/oncologist for approval.

The measure isn’t always successful in preventing bleeding, however, as seen in a case study describing two patients who experienced bleeding complications following Mohs surgery despite being taken off ibrutinib 3 days prior to the procedure.

The senior author of that study, Kira Minkis, MD, PhD, department of dermatology, Weill Cornell/New York Presbyterian, New York, told this news organization that her team concluded that in those cases ibrutinib perhaps should have been held longer than 3 days.

“In some cases, especially if the Mohs surgery is a large procedure with a more advanced reconstruction, such as a large flap, it might be more prudent to continue it longer than 3 days,” Dr. Minkis said. She noted that the high bleeding risk observed in the studies at ACMS was notable – but not unexpected.

“I’m not that surprised because if you look at the hematologic literature, the risk is indeed pretty significant, so it makes sense that it would also occur with Mohs surgeries,” she said.

She underscored that a 3-day hold of ibrutinib should be considered the minimum, “and in some cases, it should be held up to 7 days prior to surgery, depending on the specific surgery,” with the important caveat of consulting with the patient’s hematology team.

“Multidisciplinary decision-making is necessary for these cases, and the interruption of therapy should always be discussed with their hematology team,” she added. That said, Dr. Minkis noted that “I’ve never had a hematologist who had any concerns for withholding ibrutinib even for a week around the time of a surgery.”

Dr. Hirotsu, Dr. Vidal, and Dr. Minkis reported no relevant financial relationships.

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

The use of adjunctive topical tranexamic acid (TXA) showed benefits in significantly reducing postoperative bleeding with second intention healing, or allowing wounds to heal naturally without sutures, following Mohs micrographic surgery, in a double-blind, randomized, controlled trial.

The findings suggest that “topical TXA application is an inexpensive and easy topical preventative measure to consider adding to the wound care of granulating defects in the setting of Mohs micrographic surgery,” first author Brianna Castillo, MD, chief dermatology resident at the University of Missouri, Columbia, told this news organization.

The study results were presented at the annual meeting of the American College of Mohs Surgery.

In wound healing by second intent after Mohs micrographic surgery, postoperative bleeding is common and can lead to patient distress, as well as return visits or emergency care, resulting in additional health care costs, Dr. Castillo said.

Topical TXA, an antifibrinolytic, synthetic lysine analogue that prevents blood clots from breaking down, is commonly used in surgical settings including cardiothoracic, orthopedic, gynecologic, oral, and trauma surgery, showing no increased risk of thrombotic events. However, its use is relatively new in dermatology.

TXA is approved by the Food and Drug Administration only as an oral formulation for menorrhagia in women and as a short-term preventative measure for hemophilia; however, other formulations are available for topical and subcutaneous uses, Dr. Castillo noted.

To evaluate the potential benefits of the treatment in postsurgical Mohs microsurgery bleeding, Dr. Castillo and colleagues enrolled 124 patients undergoing the surgery between October 2020 and December 2021 who had surgical defects deemed appropriate for second intention healing.

The patients were randomized to groups of 62 patients each to receive normal saline-soaked Telfa pads applied to the wound bed upon completion of surgery or TXA 25 mg/mL at a volume of 1 mL/cm²-soaked Telfa pads to the wound bed upon completion of the surgery.

In both groups, a standard pressure dressing was placed on top of the Telfa pads.

Most participants were men (90 vs. 34 patients), 45 were taking antiplatelet therapy, and 20 were taking anticoagulants, and in all cases, patients were similarly randomized in the two groups. Most of the surgical defects were on the head and neck or an extremity, and most (74) were under 2 cm.

All patients were provided with instructions to apply pressure to their wounds and to report bleeding complications. They were interviewed by phone 3 days following their surgeries regarding postoperative bleeding and any potential issues relating to the TXA treatment.

In follow-up interviews, six patients in the placebo group (9.7%) reported active bleeding from their wounds within 48 hours of surgery, with one patient requiring an intervention, while there were no reports of bleeding in the TXA group (P = .028). No side effects were reported in either group.

In the setting of Mohs micrographic surgery, subcutaneous TXA has previously been studied as an intraoperative hemostatic agent, with bleeding measured prior to the second layer or closure, Dr. Castillo explained. However, “no studies have evaluated topical TXA with the aim to reduce postoperative bleeding in the setting of Mohs micrographic surgery,” she said. 

Dr. Castillo noted that topical TXA is relatively inexpensive and typically available in hospital pharmacies. “It’s only about $7 per vial of 10 ccs and we do dilute it,” she noted during the session. “It has a pretty good shelf-life and does not have to be refrigerated.”

“We have implemented this into our practice at the University of Missouri,” she added.

Commenting on the study, M. Laurin Council, MD, associate professor of dermatology in the division of dermatology, department of internal medicine, Washington University, St. Louis, noted that second intention healing is “an excellent option for certain patients after skin cancer removal.

“One problem with this method, however, is that postsurgical wounds may bleed in the hours after a procedure, [and] this can be incredibly distressing to patients and their families,” she told this news organization.

“The study presented here shows great promise for the drug TXA for preventing postsurgical bleeding in this subset of patients,” said Dr. Council, director of dermatologic surgery and director of micrographic surgery and the dermatologic oncology fellowship at Washington University.

Commenting that “the results are impressive,” she noted the study had some limitations. “This is a small pilot study, and we don’t know about confounding factors in each group, such as the proportion of patients who are on blood thinners or who have low platelets, and therefore trouble clotting, for example.”

The authors have reported no relevant financial relationships. Dr. Council has consulted for AbbVie, Castle Biosciences, and Sanofi-Genzyme/Regeneron; however, the consulting was not relevant to the current study.

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

The use of adjunctive topical tranexamic acid (TXA) showed benefits in significantly reducing postoperative bleeding with second intention healing, or allowing wounds to heal naturally without sutures, following Mohs micrographic surgery, in a double-blind, randomized, controlled trial.

The findings suggest that “topical TXA application is an inexpensive and easy topical preventative measure to consider adding to the wound care of granulating defects in the setting of Mohs micrographic surgery,” first author Brianna Castillo, MD, chief dermatology resident at the University of Missouri, Columbia, told this news organization.

The study results were presented at the annual meeting of the American College of Mohs Surgery.

In wound healing by second intent after Mohs micrographic surgery, postoperative bleeding is common and can lead to patient distress, as well as return visits or emergency care, resulting in additional health care costs, Dr. Castillo said.

Topical TXA, an antifibrinolytic, synthetic lysine analogue that prevents blood clots from breaking down, is commonly used in surgical settings including cardiothoracic, orthopedic, gynecologic, oral, and trauma surgery, showing no increased risk of thrombotic events. However, its use is relatively new in dermatology.

TXA is approved by the Food and Drug Administration only as an oral formulation for menorrhagia in women and as a short-term preventative measure for hemophilia; however, other formulations are available for topical and subcutaneous uses, Dr. Castillo noted.

To evaluate the potential benefits of the treatment in postsurgical Mohs microsurgery bleeding, Dr. Castillo and colleagues enrolled 124 patients undergoing the surgery between October 2020 and December 2021 who had surgical defects deemed appropriate for second intention healing.

The patients were randomized to groups of 62 patients each to receive normal saline-soaked Telfa pads applied to the wound bed upon completion of surgery or TXA 25 mg/mL at a volume of 1 mL/cm²-soaked Telfa pads to the wound bed upon completion of the surgery.

In both groups, a standard pressure dressing was placed on top of the Telfa pads.

Most participants were men (90 vs. 34 patients), 45 were taking antiplatelet therapy, and 20 were taking anticoagulants, and in all cases, patients were similarly randomized in the two groups. Most of the surgical defects were on the head and neck or an extremity, and most (74) were under 2 cm.

All patients were provided with instructions to apply pressure to their wounds and to report bleeding complications. They were interviewed by phone 3 days following their surgeries regarding postoperative bleeding and any potential issues relating to the TXA treatment.

In follow-up interviews, six patients in the placebo group (9.7%) reported active bleeding from their wounds within 48 hours of surgery, with one patient requiring an intervention, while there were no reports of bleeding in the TXA group (P = .028). No side effects were reported in either group.

In the setting of Mohs micrographic surgery, subcutaneous TXA has previously been studied as an intraoperative hemostatic agent, with bleeding measured prior to the second layer or closure, Dr. Castillo explained. However, “no studies have evaluated topical TXA with the aim to reduce postoperative bleeding in the setting of Mohs micrographic surgery,” she said. 

Dr. Castillo noted that topical TXA is relatively inexpensive and typically available in hospital pharmacies. “It’s only about $7 per vial of 10 ccs and we do dilute it,” she noted during the session. “It has a pretty good shelf-life and does not have to be refrigerated.”

“We have implemented this into our practice at the University of Missouri,” she added.

Commenting on the study, M. Laurin Council, MD, associate professor of dermatology in the division of dermatology, department of internal medicine, Washington University, St. Louis, noted that second intention healing is “an excellent option for certain patients after skin cancer removal.

“One problem with this method, however, is that postsurgical wounds may bleed in the hours after a procedure, [and] this can be incredibly distressing to patients and their families,” she told this news organization.

“The study presented here shows great promise for the drug TXA for preventing postsurgical bleeding in this subset of patients,” said Dr. Council, director of dermatologic surgery and director of micrographic surgery and the dermatologic oncology fellowship at Washington University.

Commenting that “the results are impressive,” she noted the study had some limitations. “This is a small pilot study, and we don’t know about confounding factors in each group, such as the proportion of patients who are on blood thinners or who have low platelets, and therefore trouble clotting, for example.”

The authors have reported no relevant financial relationships. Dr. Council has consulted for AbbVie, Castle Biosciences, and Sanofi-Genzyme/Regeneron; however, the consulting was not relevant to the current study.

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

The use of adjunctive topical tranexamic acid (TXA) showed benefits in significantly reducing postoperative bleeding with second intention healing, or allowing wounds to heal naturally without sutures, following Mohs micrographic surgery, in a double-blind, randomized, controlled trial.

The findings suggest that “topical TXA application is an inexpensive and easy topical preventative measure to consider adding to the wound care of granulating defects in the setting of Mohs micrographic surgery,” first author Brianna Castillo, MD, chief dermatology resident at the University of Missouri, Columbia, told this news organization.

The study results were presented at the annual meeting of the American College of Mohs Surgery.

In wound healing by second intent after Mohs micrographic surgery, postoperative bleeding is common and can lead to patient distress, as well as return visits or emergency care, resulting in additional health care costs, Dr. Castillo said.

Topical TXA, an antifibrinolytic, synthetic lysine analogue that prevents blood clots from breaking down, is commonly used in surgical settings including cardiothoracic, orthopedic, gynecologic, oral, and trauma surgery, showing no increased risk of thrombotic events. However, its use is relatively new in dermatology.

TXA is approved by the Food and Drug Administration only as an oral formulation for menorrhagia in women and as a short-term preventative measure for hemophilia; however, other formulations are available for topical and subcutaneous uses, Dr. Castillo noted.

To evaluate the potential benefits of the treatment in postsurgical Mohs microsurgery bleeding, Dr. Castillo and colleagues enrolled 124 patients undergoing the surgery between October 2020 and December 2021 who had surgical defects deemed appropriate for second intention healing.

The patients were randomized to groups of 62 patients each to receive normal saline-soaked Telfa pads applied to the wound bed upon completion of surgery or TXA 25 mg/mL at a volume of 1 mL/cm²-soaked Telfa pads to the wound bed upon completion of the surgery.

In both groups, a standard pressure dressing was placed on top of the Telfa pads.

Most participants were men (90 vs. 34 patients), 45 were taking antiplatelet therapy, and 20 were taking anticoagulants, and in all cases, patients were similarly randomized in the two groups. Most of the surgical defects were on the head and neck or an extremity, and most (74) were under 2 cm.

All patients were provided with instructions to apply pressure to their wounds and to report bleeding complications. They were interviewed by phone 3 days following their surgeries regarding postoperative bleeding and any potential issues relating to the TXA treatment.

In follow-up interviews, six patients in the placebo group (9.7%) reported active bleeding from their wounds within 48 hours of surgery, with one patient requiring an intervention, while there were no reports of bleeding in the TXA group (P = .028). No side effects were reported in either group.

In the setting of Mohs micrographic surgery, subcutaneous TXA has previously been studied as an intraoperative hemostatic agent, with bleeding measured prior to the second layer or closure, Dr. Castillo explained. However, “no studies have evaluated topical TXA with the aim to reduce postoperative bleeding in the setting of Mohs micrographic surgery,” she said. 

Dr. Castillo noted that topical TXA is relatively inexpensive and typically available in hospital pharmacies. “It’s only about $7 per vial of 10 ccs and we do dilute it,” she noted during the session. “It has a pretty good shelf-life and does not have to be refrigerated.”

“We have implemented this into our practice at the University of Missouri,” she added.

Commenting on the study, M. Laurin Council, MD, associate professor of dermatology in the division of dermatology, department of internal medicine, Washington University, St. Louis, noted that second intention healing is “an excellent option for certain patients after skin cancer removal.

“One problem with this method, however, is that postsurgical wounds may bleed in the hours after a procedure, [and] this can be incredibly distressing to patients and their families,” she told this news organization.

“The study presented here shows great promise for the drug TXA for preventing postsurgical bleeding in this subset of patients,” said Dr. Council, director of dermatologic surgery and director of micrographic surgery and the dermatologic oncology fellowship at Washington University.

Commenting that “the results are impressive,” she noted the study had some limitations. “This is a small pilot study, and we don’t know about confounding factors in each group, such as the proportion of patients who are on blood thinners or who have low platelets, and therefore trouble clotting, for example.”

The authors have reported no relevant financial relationships. Dr. Council has consulted for AbbVie, Castle Biosciences, and Sanofi-Genzyme/Regeneron; however, the consulting was not relevant to the current study.

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

To the Editor:

A 58-year-old man with a pigmented lesion on the left lower eyelid was referred to the oculoplastic clinic by an outside ophthalmologist. The patient had noticed the lesion growing over the course of the last 4 to 5 months. He reported scant amounts of blood and discharge coming from the nose and left eye the week prior, which persisted for 3 days. He had no associated pain or discomfort. A slit-lamp examination revealed a pigmented left lower eyelid lesion measuring 20×15 mm with telangiectasia and an eyelid margin abnormality with no palpable lymphadenopathy. The patient was diagnosed with clinical stage T3N0M0 malignant conjunctival melanoma of the left eyelid based on the American Joint Committee on Cancer classification. It is thought to have originated from conjunctival primary acquired melanosis (PAM). The T3 stage is defined as malignant melanoma with local invasion; the lesion involved the eyelid and puncta as well as canalicular portions of the lacrimal drainage system.¹ The bloody discharge was attributed to the involvement of the canalicular system, which drains tears from the eye to the nose. Melanomas can bleed, so any bloody discharge from the eye also will come through the ipsilateral nasal passage. Oncology evaluated the lesion to help determine the stage, and they found no lymph node involvement or brain, neck, chest, abdominal, or pelvic metastasis by computed tomography and magnetic resonance imaging. Sentinel lymph node biopsy was discussed with head and neck oncology specialists and was ultimately not performed per the recommendation from the Head and Neck Oncology Board; it is not a common modality for managing conjunctival melanoma because it has not been shown to alter morbidity and mortality.

The entire eyelid from the medial canthus to the lateral canthus was removed without touching the pigmented mass to ensure a “no-touch” technique removal of the mass. The no-touch technique primarily is utilized to decrease the likelihood of instrumental seeding of healthy tissues or the vascular system.² This technique focuses on preventing any direct manipulation of the tumor and avoiding an incisional biopsy as well as removal of the tumor en bloc. The margins were cutaneous—3 mm lateral to the lateral canthus, 5 mm below the lid margin, and 3 mm medial to the medial canthus—with dissection of the medial tissue from the orbital rim and lacrimal sac fossa. The lacrimal sac and lower canaliculus were then resected. The conjunctiva 5 mm inferior to the pigmented mass and the entire palpebral conjunctiva was resected to the inferior fornix across the entire palpebral conjunctiva of the lower eyelid (Figure). The eyelid and lacrimal portions were removed as a unit. Essentially, the entire lower eyelid (full thickness), including the lateral canthus, medial canthus, canaliculus, and lacrimal sac, were removed en bloc. The final tumor staging after tissue evaluation by pathology and systemic evaluation by oncology was pT3N0bM0.

A tarsoconjunctival (Hughes) flap from the upper eyelid was used to reconstruct the posterior lamella (tarsus/conjunctiva) of the lower eyelid, and a full-thickness skin graft harvested from the ipsilateral upper eyelid was used to reconstruct the anterior lamella (skin) of the lower eyelid. The reconstruction site was allowed to heal for 4 weeks before severing the tarsoconjunctival graft to allow the separation of the upper and lower eyelids. Adjunctive topical ophthalmic chemotherapy (mitomycin C 0.04%) was started 4 weeks after the last surgery. The medication was applied 4 times daily for 1 week and restarted after the conjunctival erythema and injection subsided, which was approximately 2.5 weeks, on average. The regimen of applying the medication (1 week on and 2.5 weeks off) was completed for 4 cycles. At 1 year follow-up after his diagnosis, the patient was without local recurrence or evidence of systemic metastasis. We plan to have him continue ophthalmic and oncologic evaluation every 3 to 4 months for the next 24 months, and then every 6 months for years 2 through 5.

Ocular melanoma can be further divided into uveal and conjunctival types, both arising from the respective tissue. Melanoma of the conjunctiva commonly arises from PAM with atypia, which is an acquired conjunctival pigmented lesion similar to a skin nevus that has the potential to become dysplastic. In a genetic analysis of 78 conjunctival melanomas, BRAF mutations were identified in 29% (23/78) of tumors, and NRAS mutations were detected in 18% (14/78) of tumors³; however, in our case, there were no BRAF or NRAS mutations detected. In a study of 84,836 cases that included a diagnosis of melanoma, ocular melanoma comprised 5.2% of melanomas, with cutaneous, mucosal, and unknown primary sites totaling the remaining percentage of melanomas. Of 4522 patients with ocular melanomas, 85% had uveal melanomas; 4.8% had conjunctival melanoma; and 10.2% were classified as other—comprised of cornea, not otherwise specified (NOS); retina; lacrimal gland; orbit, NOS; overlapping lesion of the eye; and eye, NOS.⁴ Melanomas of the uvea, including the ciliary body, choroid, and iris, result from a notably different pathogenesis than conjunctival melanoma, with the former being primarily associated with GNAQ and GNA mutations.³ Ciliary body and choroidal melanomas each have a different pathogenesis for occurrence, with choroidal melanoma being mostly from metastasis and ciliary body melanoma from mutations or metastasis.

Pigmented lesions on the conjunctiva or sclera arise from either melanocytes or nonmelanocytes and have a diverse differential diagnosis, including congenital melanosis, conjunctival nevi, PAM or secondary acquired melanosis, or conjunctival melanoma. The diagnosis of uveal melanoma should be based on fundoscopic examination by an experienced clinician. Uveal melanoma is unlike most other cancers in that diagnosis can be by clinical fundoscopic examination alone. Imaging studies such as ultrasound and fluorescein angiography can be performed for prognostication and characterization. Fine needle aspiration biopsy for molecular analysis is becoming more routine, but the results rarely affect the plan of care. Primary treatment of uveal melanoma should strive to preserve vision and prevent metastasis; however, a primary modality has yet to show notable results in decreasing distant disease spread or overall survival. Treatment of the primary tumor should involve consideration of tumor size, location, health of the patient, and patient preference.^1,5

For patients with melanoma arising from the conjunctiva, initial management should focus on local disease control, including wide local excision to avoid seeding, supplemented with cryotherapy and alcohol epitheliectomy to the cornea to ensure local tumor extinction.^2,6 Techniques including enucleation and orbital exenteration historically have been used for treatment of extensive disease, but this approach has not been associated with improvement in mortality and is a cause of notable morbidity.^7,8 Sentinel lymph node biopsy has an established role in the management of cutaneous melanoma, but its use in the setting of conjunctival melanoma is controversial, with studies showing that up to 50% of patients with local recurrence can develop distant metastasis with no evidence of regional lymph node involvement.^9,10 When the tumor is present at the surgical margins or in the case that lesions cannot be fully excised, adjuvant therapy may improve long-term control and prevent recurrence following surgical intervention. Mitomycin C 0.04% is the most commonly used topical chemotherapy agent because it has an established role in the treatment of PAM, but it remains adjuvant therapy for conjunctival melanoma due to the relatively poor outcomes when it is used for primary therapy.¹¹

In one study, recurrence rates for conjunctival melanoma were 26%, 51%, and 65% at 5, 10, and 15 years, respectively.¹² Risk factors for recurrence include increased tumor thickness, incomplete excision, positive margins, surgical excision without adjuvant therapy, and nonlimbal location.¹³ A multivariate analysis of 150 patients showed that the melanoma location not touching the limbus (P=.01) and pathologic evidence of tumor to the lateral margin (P=.02) were related to tumor recurrence, with relative risks (IQR) of 2.3 (1.2-4.6) and 2.9 (1.2-7.1), respectively. Careful surgical planning using wide microsurgical excisional biopsy emphasizing a no-touch technique as well as supplemental alcohol therapy for the cornea and conjunctiva is advised.¹²

To the Editor:

A 58-year-old man with a pigmented lesion on the left lower eyelid was referred to the oculoplastic clinic by an outside ophthalmologist. The patient had noticed the lesion growing over the course of the last 4 to 5 months. He reported scant amounts of blood and discharge coming from the nose and left eye the week prior, which persisted for 3 days. He had no associated pain or discomfort. A slit-lamp examination revealed a pigmented left lower eyelid lesion measuring 20×15 mm with telangiectasia and an eyelid margin abnormality with no palpable lymphadenopathy. The patient was diagnosed with clinical stage T3N0M0 malignant conjunctival melanoma of the left eyelid based on the American Joint Committee on Cancer classification. It is thought to have originated from conjunctival primary acquired melanosis (PAM). The T3 stage is defined as malignant melanoma with local invasion; the lesion involved the eyelid and puncta as well as canalicular portions of the lacrimal drainage system.¹ The bloody discharge was attributed to the involvement of the canalicular system, which drains tears from the eye to the nose. Melanomas can bleed, so any bloody discharge from the eye also will come through the ipsilateral nasal passage. Oncology evaluated the lesion to help determine the stage, and they found no lymph node involvement or brain, neck, chest, abdominal, or pelvic metastasis by computed tomography and magnetic resonance imaging. Sentinel lymph node biopsy was discussed with head and neck oncology specialists and was ultimately not performed per the recommendation from the Head and Neck Oncology Board; it is not a common modality for managing conjunctival melanoma because it has not been shown to alter morbidity and mortality.

The entire eyelid from the medial canthus to the lateral canthus was removed without touching the pigmented mass to ensure a “no-touch” technique removal of the mass. The no-touch technique primarily is utilized to decrease the likelihood of instrumental seeding of healthy tissues or the vascular system.² This technique focuses on preventing any direct manipulation of the tumor and avoiding an incisional biopsy as well as removal of the tumor en bloc. The margins were cutaneous—3 mm lateral to the lateral canthus, 5 mm below the lid margin, and 3 mm medial to the medial canthus—with dissection of the medial tissue from the orbital rim and lacrimal sac fossa. The lacrimal sac and lower canaliculus were then resected. The conjunctiva 5 mm inferior to the pigmented mass and the entire palpebral conjunctiva was resected to the inferior fornix across the entire palpebral conjunctiva of the lower eyelid (Figure). The eyelid and lacrimal portions were removed as a unit. Essentially, the entire lower eyelid (full thickness), including the lateral canthus, medial canthus, canaliculus, and lacrimal sac, were removed en bloc. The final tumor staging after tissue evaluation by pathology and systemic evaluation by oncology was pT3N0bM0.

A tarsoconjunctival (Hughes) flap from the upper eyelid was used to reconstruct the posterior lamella (tarsus/conjunctiva) of the lower eyelid, and a full-thickness skin graft harvested from the ipsilateral upper eyelid was used to reconstruct the anterior lamella (skin) of the lower eyelid. The reconstruction site was allowed to heal for 4 weeks before severing the tarsoconjunctival graft to allow the separation of the upper and lower eyelids. Adjunctive topical ophthalmic chemotherapy (mitomycin C 0.04%) was started 4 weeks after the last surgery. The medication was applied 4 times daily for 1 week and restarted after the conjunctival erythema and injection subsided, which was approximately 2.5 weeks, on average. The regimen of applying the medication (1 week on and 2.5 weeks off) was completed for 4 cycles. At 1 year follow-up after his diagnosis, the patient was without local recurrence or evidence of systemic metastasis. We plan to have him continue ophthalmic and oncologic evaluation every 3 to 4 months for the next 24 months, and then every 6 months for years 2 through 5.

Ocular melanoma can be further divided into uveal and conjunctival types, both arising from the respective tissue. Melanoma of the conjunctiva commonly arises from PAM with atypia, which is an acquired conjunctival pigmented lesion similar to a skin nevus that has the potential to become dysplastic. In a genetic analysis of 78 conjunctival melanomas, BRAF mutations were identified in 29% (23/78) of tumors, and NRAS mutations were detected in 18% (14/78) of tumors³; however, in our case, there were no BRAF or NRAS mutations detected. In a study of 84,836 cases that included a diagnosis of melanoma, ocular melanoma comprised 5.2% of melanomas, with cutaneous, mucosal, and unknown primary sites totaling the remaining percentage of melanomas. Of 4522 patients with ocular melanomas, 85% had uveal melanomas; 4.8% had conjunctival melanoma; and 10.2% were classified as other—comprised of cornea, not otherwise specified (NOS); retina; lacrimal gland; orbit, NOS; overlapping lesion of the eye; and eye, NOS.⁴ Melanomas of the uvea, including the ciliary body, choroid, and iris, result from a notably different pathogenesis than conjunctival melanoma, with the former being primarily associated with GNAQ and GNA mutations.³ Ciliary body and choroidal melanomas each have a different pathogenesis for occurrence, with choroidal melanoma being mostly from metastasis and ciliary body melanoma from mutations or metastasis.

Pigmented lesions on the conjunctiva or sclera arise from either melanocytes or nonmelanocytes and have a diverse differential diagnosis, including congenital melanosis, conjunctival nevi, PAM or secondary acquired melanosis, or conjunctival melanoma. The diagnosis of uveal melanoma should be based on fundoscopic examination by an experienced clinician. Uveal melanoma is unlike most other cancers in that diagnosis can be by clinical fundoscopic examination alone. Imaging studies such as ultrasound and fluorescein angiography can be performed for prognostication and characterization. Fine needle aspiration biopsy for molecular analysis is becoming more routine, but the results rarely affect the plan of care. Primary treatment of uveal melanoma should strive to preserve vision and prevent metastasis; however, a primary modality has yet to show notable results in decreasing distant disease spread or overall survival. Treatment of the primary tumor should involve consideration of tumor size, location, health of the patient, and patient preference.^1,5

For patients with melanoma arising from the conjunctiva, initial management should focus on local disease control, including wide local excision to avoid seeding, supplemented with cryotherapy and alcohol epitheliectomy to the cornea to ensure local tumor extinction.^2,6 Techniques including enucleation and orbital exenteration historically have been used for treatment of extensive disease, but this approach has not been associated with improvement in mortality and is a cause of notable morbidity.^7,8 Sentinel lymph node biopsy has an established role in the management of cutaneous melanoma, but its use in the setting of conjunctival melanoma is controversial, with studies showing that up to 50% of patients with local recurrence can develop distant metastasis with no evidence of regional lymph node involvement.^9,10 When the tumor is present at the surgical margins or in the case that lesions cannot be fully excised, adjuvant therapy may improve long-term control and prevent recurrence following surgical intervention. Mitomycin C 0.04% is the most commonly used topical chemotherapy agent because it has an established role in the treatment of PAM, but it remains adjuvant therapy for conjunctival melanoma due to the relatively poor outcomes when it is used for primary therapy.¹¹

In one study, recurrence rates for conjunctival melanoma were 26%, 51%, and 65% at 5, 10, and 15 years, respectively.¹² Risk factors for recurrence include increased tumor thickness, incomplete excision, positive margins, surgical excision without adjuvant therapy, and nonlimbal location.¹³ A multivariate analysis of 150 patients showed that the melanoma location not touching the limbus (P=.01) and pathologic evidence of tumor to the lateral margin (P=.02) were related to tumor recurrence, with relative risks (IQR) of 2.3 (1.2-4.6) and 2.9 (1.2-7.1), respectively. Careful surgical planning using wide microsurgical excisional biopsy emphasizing a no-touch technique as well as supplemental alcohol therapy for the cornea and conjunctiva is advised.¹²

To the Editor:

A 58-year-old man with a pigmented lesion on the left lower eyelid was referred to the oculoplastic clinic by an outside ophthalmologist. The patient had noticed the lesion growing over the course of the last 4 to 5 months. He reported scant amounts of blood and discharge coming from the nose and left eye the week prior, which persisted for 3 days. He had no associated pain or discomfort. A slit-lamp examination revealed a pigmented left lower eyelid lesion measuring 20×15 mm with telangiectasia and an eyelid margin abnormality with no palpable lymphadenopathy. The patient was diagnosed with clinical stage T3N0M0 malignant conjunctival melanoma of the left eyelid based on the American Joint Committee on Cancer classification. It is thought to have originated from conjunctival primary acquired melanosis (PAM). The T3 stage is defined as malignant melanoma with local invasion; the lesion involved the eyelid and puncta as well as canalicular portions of the lacrimal drainage system.¹ The bloody discharge was attributed to the involvement of the canalicular system, which drains tears from the eye to the nose. Melanomas can bleed, so any bloody discharge from the eye also will come through the ipsilateral nasal passage. Oncology evaluated the lesion to help determine the stage, and they found no lymph node involvement or brain, neck, chest, abdominal, or pelvic metastasis by computed tomography and magnetic resonance imaging. Sentinel lymph node biopsy was discussed with head and neck oncology specialists and was ultimately not performed per the recommendation from the Head and Neck Oncology Board; it is not a common modality for managing conjunctival melanoma because it has not been shown to alter morbidity and mortality.

The entire eyelid from the medial canthus to the lateral canthus was removed without touching the pigmented mass to ensure a “no-touch” technique removal of the mass. The no-touch technique primarily is utilized to decrease the likelihood of instrumental seeding of healthy tissues or the vascular system.² This technique focuses on preventing any direct manipulation of the tumor and avoiding an incisional biopsy as well as removal of the tumor en bloc. The margins were cutaneous—3 mm lateral to the lateral canthus, 5 mm below the lid margin, and 3 mm medial to the medial canthus—with dissection of the medial tissue from the orbital rim and lacrimal sac fossa. The lacrimal sac and lower canaliculus were then resected. The conjunctiva 5 mm inferior to the pigmented mass and the entire palpebral conjunctiva was resected to the inferior fornix across the entire palpebral conjunctiva of the lower eyelid (Figure). The eyelid and lacrimal portions were removed as a unit. Essentially, the entire lower eyelid (full thickness), including the lateral canthus, medial canthus, canaliculus, and lacrimal sac, were removed en bloc. The final tumor staging after tissue evaluation by pathology and systemic evaluation by oncology was pT3N0bM0.

A tarsoconjunctival (Hughes) flap from the upper eyelid was used to reconstruct the posterior lamella (tarsus/conjunctiva) of the lower eyelid, and a full-thickness skin graft harvested from the ipsilateral upper eyelid was used to reconstruct the anterior lamella (skin) of the lower eyelid. The reconstruction site was allowed to heal for 4 weeks before severing the tarsoconjunctival graft to allow the separation of the upper and lower eyelids. Adjunctive topical ophthalmic chemotherapy (mitomycin C 0.04%) was started 4 weeks after the last surgery. The medication was applied 4 times daily for 1 week and restarted after the conjunctival erythema and injection subsided, which was approximately 2.5 weeks, on average. The regimen of applying the medication (1 week on and 2.5 weeks off) was completed for 4 cycles. At 1 year follow-up after his diagnosis, the patient was without local recurrence or evidence of systemic metastasis. We plan to have him continue ophthalmic and oncologic evaluation every 3 to 4 months for the next 24 months, and then every 6 months for years 2 through 5.

Ocular melanoma can be further divided into uveal and conjunctival types, both arising from the respective tissue. Melanoma of the conjunctiva commonly arises from PAM with atypia, which is an acquired conjunctival pigmented lesion similar to a skin nevus that has the potential to become dysplastic. In a genetic analysis of 78 conjunctival melanomas, BRAF mutations were identified in 29% (23/78) of tumors, and NRAS mutations were detected in 18% (14/78) of tumors³; however, in our case, there were no BRAF or NRAS mutations detected. In a study of 84,836 cases that included a diagnosis of melanoma, ocular melanoma comprised 5.2% of melanomas, with cutaneous, mucosal, and unknown primary sites totaling the remaining percentage of melanomas. Of 4522 patients with ocular melanomas, 85% had uveal melanomas; 4.8% had conjunctival melanoma; and 10.2% were classified as other—comprised of cornea, not otherwise specified (NOS); retina; lacrimal gland; orbit, NOS; overlapping lesion of the eye; and eye, NOS.⁴ Melanomas of the uvea, including the ciliary body, choroid, and iris, result from a notably different pathogenesis than conjunctival melanoma, with the former being primarily associated with GNAQ and GNA mutations.³ Ciliary body and choroidal melanomas each have a different pathogenesis for occurrence, with choroidal melanoma being mostly from metastasis and ciliary body melanoma from mutations or metastasis.

Pigmented lesions on the conjunctiva or sclera arise from either melanocytes or nonmelanocytes and have a diverse differential diagnosis, including congenital melanosis, conjunctival nevi, PAM or secondary acquired melanosis, or conjunctival melanoma. The diagnosis of uveal melanoma should be based on fundoscopic examination by an experienced clinician. Uveal melanoma is unlike most other cancers in that diagnosis can be by clinical fundoscopic examination alone. Imaging studies such as ultrasound and fluorescein angiography can be performed for prognostication and characterization. Fine needle aspiration biopsy for molecular analysis is becoming more routine, but the results rarely affect the plan of care. Primary treatment of uveal melanoma should strive to preserve vision and prevent metastasis; however, a primary modality has yet to show notable results in decreasing distant disease spread or overall survival. Treatment of the primary tumor should involve consideration of tumor size, location, health of the patient, and patient preference.^1,5

For patients with melanoma arising from the conjunctiva, initial management should focus on local disease control, including wide local excision to avoid seeding, supplemented with cryotherapy and alcohol epitheliectomy to the cornea to ensure local tumor extinction.^2,6 Techniques including enucleation and orbital exenteration historically have been used for treatment of extensive disease, but this approach has not been associated with improvement in mortality and is a cause of notable morbidity.^7,8 Sentinel lymph node biopsy has an established role in the management of cutaneous melanoma, but its use in the setting of conjunctival melanoma is controversial, with studies showing that up to 50% of patients with local recurrence can develop distant metastasis with no evidence of regional lymph node involvement.^9,10 When the tumor is present at the surgical margins or in the case that lesions cannot be fully excised, adjuvant therapy may improve long-term control and prevent recurrence following surgical intervention. Mitomycin C 0.04% is the most commonly used topical chemotherapy agent because it has an established role in the treatment of PAM, but it remains adjuvant therapy for conjunctival melanoma due to the relatively poor outcomes when it is used for primary therapy.¹¹

In one study, recurrence rates for conjunctival melanoma were 26%, 51%, and 65% at 5, 10, and 15 years, respectively.¹² Risk factors for recurrence include increased tumor thickness, incomplete excision, positive margins, surgical excision without adjuvant therapy, and nonlimbal location.¹³ A multivariate analysis of 150 patients showed that the melanoma location not touching the limbus (P=.01) and pathologic evidence of tumor to the lateral margin (P=.02) were related to tumor recurrence, with relative risks (IQR) of 2.3 (1.2-4.6) and 2.9 (1.2-7.1), respectively. Careful surgical planning using wide microsurgical excisional biopsy emphasizing a no-touch technique as well as supplemental alcohol therapy for the cornea and conjunctiva is advised.¹²

An injection of bupivacaine following Mohs micrographic surgery procedures that have notable postsurgical pain significantly reduces pain scores and, importantly, use of postsurgical narcotics, a randomized trial shows.

“Single-dose, in-office bupivacaine administration immediately following reconstructions known to be high risk for pain reduces postoperative narcotic use and acute pain during the time period when our patients have the highest levels of pain,” said first author Vanessa B. Voss, MD, of the University of Missouri–Columbia, who presented the findings at the annual meeting of the American College of Mohs Surgery.

Dr. Vanessa Voss

“It was well tolerated, there were no adverse effects, and we recommend the consideration of using this in Mohs micrographic surgery reconstructions that are at the highest risk for pain,” she said.

Recent research has shown that Mohs micrographic surgeons have the highest rates of opioid prescribing of all dermatologists, with about 11% of patients undergoing a Mohs procedure prescribed the drugs for postoperative use, Dr. Voss explained.

Yet, with the ongoing opioid epidemic and even short courses of postoperative opioids placing patients at risk for addiction, the pressure is on to find alternative, nonaddictive strategies for the treatment of acute postoperative pain.

Bupivacaine is commonly used intraoperatively with other types of surgeries to reduce postoperative pain, with a favorable duration of action lasting up to 7 hours, compared with just 2-3 hours with lidocaine. And while its use in Mohs surgery is typically also intraoperative, along with lidocaine, the unique postoperative treatment approach in Mohs surgery has not been well studied, Dr. Voss noted.

To investigate, Dr. Voss and colleagues conducted the prospective, multicenter randomized trial, enrolling 174 patients undergoing Mohs micrographic surgery for skin cancer.

Patients were receiving complex flap reconstructions that have been specifically designated in an American Academy of Dermatology position statement to be high risk for pain following Mohs surgeries, and hence, more likely to involve prescriptions for opioids. These include reconstruction flaps of the scalp, ear, nose or lip, a wedge repair of the ear or lip, or a Mustarde cheek rotation flap.

The mean age of the patients was about 69 years, and about 65% were male. The two groups had no significant differences in demographics, tumor types, or repairs. They were randomized to receive either local injections of bupivacaine 0.5% (with no epinephrine) or placebo with sterile saline injection immediately following the procedure, with the total amount of injection standardized and dependent upon the flap surface area, ranging from 2.5 to 5 cm³.

For postoperative pain, all patients were prescribed acetaminophen 1,000 mg alternating with ibuprofen 400 mg, and tramadol, with instructions to only use tramadol as needed for breakthrough pain.

The reported use of narcotic analgesics by participants was significantly higher among those receiving placebo versus bupivacaine in the first 24 hours following surgery (odds ratio, 2.18; P = .03), as well as in the second 24 hours (OR, 2.18; P = .08) and at 48 hours combined (OR, 2.58; P < .01).

Those in the bupivacaine group also reported lower average pain scores, on a scale of 0-10, during the first 8-hour interval (mean difference, 1.6; P < .001). Importantly, overall, reports of pain medication use and the percentage of patients reporting pain under control were similar between groups, despite lower opioid use in the bupivacaine group.

“The percentage of patients reporting their pain to be under control was similar at all time intervals in both groups, so this means the bupivacaine group had their pain well-controlled despite fewer narcotics, with significant reductions in opioid use,” Dr. Voss noted.

Bupivacaine, though generally regarded as safe, has a reputation for being the most cardiotoxic of the local anesthetic agents; however, there were no such side effects reported in the study. Dr. Voss said the likely explanation is the use of low doses.

“In our study, we had no cardiotoxic effects when using up to 5 cc of 0.5%, which equates to 25 mg per patient,” she explained. This is considered a “very low dose,” since the maximum in the Food and Drug Administration pamphlet for local infiltration is 175 mg per patient every 3 hours, “yet is sufficient for reducing pain/narcotic use.”

She added that “surgeons must be careful to avoid accidental intravascular injection, which could increase risks of systemic toxicity, but this is very rare in the reconstruction settings described.”

Overall, the study suggests a potentially beneficial and unique nonopioid approach that is currently lacking for Mohs procedures associated with a high level of pain. “These findings offer a very effective intervention to reduce postoperative opioid use in this subset of patients,” Dr. Voss told this news organization. “There is not any other intervention that I am aware of to address this, although further study into other long-acting anesthetics may demonstrate similar effects.”

Dr. Justin J. Leitenberger

Commenting on the study, Justin J. Leitenberger, MD, session moderator, said that these “data could be impactful for reducing pain as well as the need for opioid medication after dermatologic surgery, both of which would be significant for our patients and public health outcomes.”

Among the challenges in treating pain following Mohs surgeries is that “every patient has a different pain threshold and expectation after surgery,” said Dr. Leitenberger, assistant professor of medicine and dermatology and codirector of dermatologic surgery, Mohs micrographic surgery, and laser and cosmetic surgery at Oregon Health & Science University, Portland.

“Patients undergoing larger repairs in tense areas of skin can experience increased pain and require prescription pain medication,” he said. “Bupivacaine, in this study, shows promise to provide longer lasting pain control from the surgical appointment and easier bridging to nonopioid pain control.”

Regarding the potential cardiotoxicities associated with the drug, Dr. Leitenberger agreed that the risks are low, and added that many surgeons have, in fact, switched to full use of bupivacaine, as opposed to combination with lidocaine, apparently without problems. “This is a small dose locally to the area after a procedure and I agree that the risks are minuscule,” he said.

“Of note, during national lidocaine shortages over the past few years, many practices transitioned to exclusive use of bupivacaine for the entire Mohs procedure, and [anecdotally], this transition did not result in toxicities that were reported,” Dr. Leitenberger said.

GW Medical Faculty Associates

Commenting further, Vishal Patel, MD, assistant professor of dermatology and hematology/oncology at George Washington University and director of cutaneous oncology at the GW Cancer Center, both in Washington, also agreed that the benefits appear important. “The benefit from using bupivacaine is encouraging on multiple levels,” he said in an interview.

“Given all that we know about opioids and their negative side effect profile as well as their limited help in cutaneous surgery pain control, the use of long-acting anesthetics is an innovative and reasonable approach to provide pain control in the immediate postoperative window when patients tend to have the most pain,” said Dr. Patel, who is also director of dermatologic surgery at George Washington University.

“After this window, acetaminophen and ibuprofen, which have been shown when used in tandem in an alternating schedule to be superior to opioids, provides an effective pain regimen,” he said. “For larger and more pain-sensitive patients, this appears to be a promising combination.”

Dr. Voss, Dr. Leitenberger, and Dr. Patel have reported no relevant financial relationships.

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

An injection of bupivacaine following Mohs micrographic surgery procedures that have notable postsurgical pain significantly reduces pain scores and, importantly, use of postsurgical narcotics, a randomized trial shows.

“Single-dose, in-office bupivacaine administration immediately following reconstructions known to be high risk for pain reduces postoperative narcotic use and acute pain during the time period when our patients have the highest levels of pain,” said first author Vanessa B. Voss, MD, of the University of Missouri–Columbia, who presented the findings at the annual meeting of the American College of Mohs Surgery.

Dr. Vanessa Voss

“It was well tolerated, there were no adverse effects, and we recommend the consideration of using this in Mohs micrographic surgery reconstructions that are at the highest risk for pain,” she said.

Recent research has shown that Mohs micrographic surgeons have the highest rates of opioid prescribing of all dermatologists, with about 11% of patients undergoing a Mohs procedure prescribed the drugs for postoperative use, Dr. Voss explained.

Yet, with the ongoing opioid epidemic and even short courses of postoperative opioids placing patients at risk for addiction, the pressure is on to find alternative, nonaddictive strategies for the treatment of acute postoperative pain.

Bupivacaine is commonly used intraoperatively with other types of surgeries to reduce postoperative pain, with a favorable duration of action lasting up to 7 hours, compared with just 2-3 hours with lidocaine. And while its use in Mohs surgery is typically also intraoperative, along with lidocaine, the unique postoperative treatment approach in Mohs surgery has not been well studied, Dr. Voss noted.

To investigate, Dr. Voss and colleagues conducted the prospective, multicenter randomized trial, enrolling 174 patients undergoing Mohs micrographic surgery for skin cancer.

Patients were receiving complex flap reconstructions that have been specifically designated in an American Academy of Dermatology position statement to be high risk for pain following Mohs surgeries, and hence, more likely to involve prescriptions for opioids. These include reconstruction flaps of the scalp, ear, nose or lip, a wedge repair of the ear or lip, or a Mustarde cheek rotation flap.

The mean age of the patients was about 69 years, and about 65% were male. The two groups had no significant differences in demographics, tumor types, or repairs. They were randomized to receive either local injections of bupivacaine 0.5% (with no epinephrine) or placebo with sterile saline injection immediately following the procedure, with the total amount of injection standardized and dependent upon the flap surface area, ranging from 2.5 to 5 cm³.

For postoperative pain, all patients were prescribed acetaminophen 1,000 mg alternating with ibuprofen 400 mg, and tramadol, with instructions to only use tramadol as needed for breakthrough pain.

The reported use of narcotic analgesics by participants was significantly higher among those receiving placebo versus bupivacaine in the first 24 hours following surgery (odds ratio, 2.18; P = .03), as well as in the second 24 hours (OR, 2.18; P = .08) and at 48 hours combined (OR, 2.58; P < .01).

Those in the bupivacaine group also reported lower average pain scores, on a scale of 0-10, during the first 8-hour interval (mean difference, 1.6; P < .001). Importantly, overall, reports of pain medication use and the percentage of patients reporting pain under control were similar between groups, despite lower opioid use in the bupivacaine group.

“The percentage of patients reporting their pain to be under control was similar at all time intervals in both groups, so this means the bupivacaine group had their pain well-controlled despite fewer narcotics, with significant reductions in opioid use,” Dr. Voss noted.

Bupivacaine, though generally regarded as safe, has a reputation for being the most cardiotoxic of the local anesthetic agents; however, there were no such side effects reported in the study. Dr. Voss said the likely explanation is the use of low doses.

“In our study, we had no cardiotoxic effects when using up to 5 cc of 0.5%, which equates to 25 mg per patient,” she explained. This is considered a “very low dose,” since the maximum in the Food and Drug Administration pamphlet for local infiltration is 175 mg per patient every 3 hours, “yet is sufficient for reducing pain/narcotic use.”

She added that “surgeons must be careful to avoid accidental intravascular injection, which could increase risks of systemic toxicity, but this is very rare in the reconstruction settings described.”

Overall, the study suggests a potentially beneficial and unique nonopioid approach that is currently lacking for Mohs procedures associated with a high level of pain. “These findings offer a very effective intervention to reduce postoperative opioid use in this subset of patients,” Dr. Voss told this news organization. “There is not any other intervention that I am aware of to address this, although further study into other long-acting anesthetics may demonstrate similar effects.”

Dr. Justin J. Leitenberger

Commenting on the study, Justin J. Leitenberger, MD, session moderator, said that these “data could be impactful for reducing pain as well as the need for opioid medication after dermatologic surgery, both of which would be significant for our patients and public health outcomes.”

Among the challenges in treating pain following Mohs surgeries is that “every patient has a different pain threshold and expectation after surgery,” said Dr. Leitenberger, assistant professor of medicine and dermatology and codirector of dermatologic surgery, Mohs micrographic surgery, and laser and cosmetic surgery at Oregon Health & Science University, Portland.

“Patients undergoing larger repairs in tense areas of skin can experience increased pain and require prescription pain medication,” he said. “Bupivacaine, in this study, shows promise to provide longer lasting pain control from the surgical appointment and easier bridging to nonopioid pain control.”

Regarding the potential cardiotoxicities associated with the drug, Dr. Leitenberger agreed that the risks are low, and added that many surgeons have, in fact, switched to full use of bupivacaine, as opposed to combination with lidocaine, apparently without problems. “This is a small dose locally to the area after a procedure and I agree that the risks are minuscule,” he said.

“Of note, during national lidocaine shortages over the past few years, many practices transitioned to exclusive use of bupivacaine for the entire Mohs procedure, and [anecdotally], this transition did not result in toxicities that were reported,” Dr. Leitenberger said.

GW Medical Faculty Associates

Commenting further, Vishal Patel, MD, assistant professor of dermatology and hematology/oncology at George Washington University and director of cutaneous oncology at the GW Cancer Center, both in Washington, also agreed that the benefits appear important. “The benefit from using bupivacaine is encouraging on multiple levels,” he said in an interview.

“Given all that we know about opioids and their negative side effect profile as well as their limited help in cutaneous surgery pain control, the use of long-acting anesthetics is an innovative and reasonable approach to provide pain control in the immediate postoperative window when patients tend to have the most pain,” said Dr. Patel, who is also director of dermatologic surgery at George Washington University.

“After this window, acetaminophen and ibuprofen, which have been shown when used in tandem in an alternating schedule to be superior to opioids, provides an effective pain regimen,” he said. “For larger and more pain-sensitive patients, this appears to be a promising combination.”

Dr. Voss, Dr. Leitenberger, and Dr. Patel have reported no relevant financial relationships.

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

An injection of bupivacaine following Mohs micrographic surgery procedures that have notable postsurgical pain significantly reduces pain scores and, importantly, use of postsurgical narcotics, a randomized trial shows.

“Single-dose, in-office bupivacaine administration immediately following reconstructions known to be high risk for pain reduces postoperative narcotic use and acute pain during the time period when our patients have the highest levels of pain,” said first author Vanessa B. Voss, MD, of the University of Missouri–Columbia, who presented the findings at the annual meeting of the American College of Mohs Surgery.

Dr. Vanessa Voss

“It was well tolerated, there were no adverse effects, and we recommend the consideration of using this in Mohs micrographic surgery reconstructions that are at the highest risk for pain,” she said.

Recent research has shown that Mohs micrographic surgeons have the highest rates of opioid prescribing of all dermatologists, with about 11% of patients undergoing a Mohs procedure prescribed the drugs for postoperative use, Dr. Voss explained.

Yet, with the ongoing opioid epidemic and even short courses of postoperative opioids placing patients at risk for addiction, the pressure is on to find alternative, nonaddictive strategies for the treatment of acute postoperative pain.

Bupivacaine is commonly used intraoperatively with other types of surgeries to reduce postoperative pain, with a favorable duration of action lasting up to 7 hours, compared with just 2-3 hours with lidocaine. And while its use in Mohs surgery is typically also intraoperative, along with lidocaine, the unique postoperative treatment approach in Mohs surgery has not been well studied, Dr. Voss noted.

To investigate, Dr. Voss and colleagues conducted the prospective, multicenter randomized trial, enrolling 174 patients undergoing Mohs micrographic surgery for skin cancer.

Patients were receiving complex flap reconstructions that have been specifically designated in an American Academy of Dermatology position statement to be high risk for pain following Mohs surgeries, and hence, more likely to involve prescriptions for opioids. These include reconstruction flaps of the scalp, ear, nose or lip, a wedge repair of the ear or lip, or a Mustarde cheek rotation flap.

The mean age of the patients was about 69 years, and about 65% were male. The two groups had no significant differences in demographics, tumor types, or repairs. They were randomized to receive either local injections of bupivacaine 0.5% (with no epinephrine) or placebo with sterile saline injection immediately following the procedure, with the total amount of injection standardized and dependent upon the flap surface area, ranging from 2.5 to 5 cm³.

For postoperative pain, all patients were prescribed acetaminophen 1,000 mg alternating with ibuprofen 400 mg, and tramadol, with instructions to only use tramadol as needed for breakthrough pain.

The reported use of narcotic analgesics by participants was significantly higher among those receiving placebo versus bupivacaine in the first 24 hours following surgery (odds ratio, 2.18; P = .03), as well as in the second 24 hours (OR, 2.18; P = .08) and at 48 hours combined (OR, 2.58; P < .01).

Those in the bupivacaine group also reported lower average pain scores, on a scale of 0-10, during the first 8-hour interval (mean difference, 1.6; P < .001). Importantly, overall, reports of pain medication use and the percentage of patients reporting pain under control were similar between groups, despite lower opioid use in the bupivacaine group.

“The percentage of patients reporting their pain to be under control was similar at all time intervals in both groups, so this means the bupivacaine group had their pain well-controlled despite fewer narcotics, with significant reductions in opioid use,” Dr. Voss noted.

Bupivacaine, though generally regarded as safe, has a reputation for being the most cardiotoxic of the local anesthetic agents; however, there were no such side effects reported in the study. Dr. Voss said the likely explanation is the use of low doses.

“In our study, we had no cardiotoxic effects when using up to 5 cc of 0.5%, which equates to 25 mg per patient,” she explained. This is considered a “very low dose,” since the maximum in the Food and Drug Administration pamphlet for local infiltration is 175 mg per patient every 3 hours, “yet is sufficient for reducing pain/narcotic use.”

She added that “surgeons must be careful to avoid accidental intravascular injection, which could increase risks of systemic toxicity, but this is very rare in the reconstruction settings described.”

Overall, the study suggests a potentially beneficial and unique nonopioid approach that is currently lacking for Mohs procedures associated with a high level of pain. “These findings offer a very effective intervention to reduce postoperative opioid use in this subset of patients,” Dr. Voss told this news organization. “There is not any other intervention that I am aware of to address this, although further study into other long-acting anesthetics may demonstrate similar effects.”

Dr. Justin J. Leitenberger

Commenting on the study, Justin J. Leitenberger, MD, session moderator, said that these “data could be impactful for reducing pain as well as the need for opioid medication after dermatologic surgery, both of which would be significant for our patients and public health outcomes.”

Among the challenges in treating pain following Mohs surgeries is that “every patient has a different pain threshold and expectation after surgery,” said Dr. Leitenberger, assistant professor of medicine and dermatology and codirector of dermatologic surgery, Mohs micrographic surgery, and laser and cosmetic surgery at Oregon Health & Science University, Portland.

“Patients undergoing larger repairs in tense areas of skin can experience increased pain and require prescription pain medication,” he said. “Bupivacaine, in this study, shows promise to provide longer lasting pain control from the surgical appointment and easier bridging to nonopioid pain control.”

Regarding the potential cardiotoxicities associated with the drug, Dr. Leitenberger agreed that the risks are low, and added that many surgeons have, in fact, switched to full use of bupivacaine, as opposed to combination with lidocaine, apparently without problems. “This is a small dose locally to the area after a procedure and I agree that the risks are minuscule,” he said.

“Of note, during national lidocaine shortages over the past few years, many practices transitioned to exclusive use of bupivacaine for the entire Mohs procedure, and [anecdotally], this transition did not result in toxicities that were reported,” Dr. Leitenberger said.

GW Medical Faculty Associates

Commenting further, Vishal Patel, MD, assistant professor of dermatology and hematology/oncology at George Washington University and director of cutaneous oncology at the GW Cancer Center, both in Washington, also agreed that the benefits appear important. “The benefit from using bupivacaine is encouraging on multiple levels,” he said in an interview.

“Given all that we know about opioids and their negative side effect profile as well as their limited help in cutaneous surgery pain control, the use of long-acting anesthetics is an innovative and reasonable approach to provide pain control in the immediate postoperative window when patients tend to have the most pain,” said Dr. Patel, who is also director of dermatologic surgery at George Washington University.

“After this window, acetaminophen and ibuprofen, which have been shown when used in tandem in an alternating schedule to be superior to opioids, provides an effective pain regimen,” he said. “For larger and more pain-sensitive patients, this appears to be a promising combination.”

Dr. Voss, Dr. Leitenberger, and Dr. Patel have reported no relevant financial relationships.

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

To the Editor:

Skin cancer represents a notable health care burden of rising incidence.^1-3 Nondermatologist health care providers play a key role in skin cancer screening through the use of skin cancer examination (SCE)^1,4; however, several factors including poor diagnostic accuracy, low confidence, and lack of training have contributed to limited use of the SCE by these providers.^4,5 Therefore, it is important to identify and implement changes in the medical school curriculum that can facilitate improved use of SCE in clinical practice. We sought to examine factors in the medical school curriculum that influence skin cancer education.

A voluntary electronic survey was distributed through class email and social media to all medical student classes at 4 medical schools (Figure). Responses were collected between March 2 and April 20, 2020. Survey items assessed demographics and curricular factors that influence skin cancer education. Our study was approved by the Institutional Review Board for Human Research of the Medical University of South Carolina (Charleston, South Carolina).

Knowledge of the clinical features of melanoma was assessed by asking participants to correctly identify at least 5 of 6 pigmented lesions as concerning or not concerning for melanoma. Confidence in performing the SCE—the primary outcome—was measured by dichotomizing a 4-point Likert-type scale (“very confident” and “moderately confident” against “slightly confident” and “not at all confident”).

Logistic regression was used to examine curricular factors associated with confidence; descriptive statistics were used for remaining analyses. Analyses were performed using SAS 9.4 statistical software. Prior to analysis, responses from the University of South Carolina School of Medicine Greenville were excluded because the response rate was less than 20%.

The survey was distributed to 1524 students; 619 (40.6%) answered at least 1 question, with a variable response rate to each item (eTable 1). Most respondents were female (351 [56.7%]); 438 (70.8%) were White.

Most respondents said that they received 3 hours or less of general skin cancer (74.9%) or SCE-specific (93.0%) education by the end of their fourth year of medical training. Lecture was the most common method of instruction. Education was provided most often by dermatologists (48.6%), followed by general practice physicians (21.2%). Numerous (26.9%) fourth-year respondents reported that they had never observed SCE; even more (47.6%) had never performed SCE. Almost half of second- and third-year students (43.2% and 44.8%, respectively) considered themselves knowledgeable about the clinical features of melanoma, but only 31.9% of fourth-year students considered themselves knowledgeable.

Only 24.1% of fourth-year students reported confidence performing SCE (eTable 1). Students who received most of their instruction through real clinical encounters were 4.14 times more likely to be confident performing SCE than students who had been given lecture-based learning. Students who performed 1 to 3 SCE or 4 or more SCE were 3.02 and 32.25 times, respectively, more likely to be confident than students who had never performed SCE (eTable 2).

Consistent with a recent study,⁶ our results reflect the discrepancy between the burden and education of skin cancer. This is especially demonstrated by our cohort’s low confidence in performing SCE, a metric associated with both intention to perform and actual performance of SCE in practice.^4,5 We also observed a downward trend in knowledge among students who were about to enter residency, potentially indicating the need for longitudinal training.

Given curricular time constraints, it is essential that medical schools implement changes in learning that will have the greatest impact. Although our results strongly support the efficacy of hands-on clinical training, exposure to dermatology in the second half of medical school training is limited nationwide.⁶ Concentrated efforts to increase clinical exposure might help prepare future physicians in all specialties to combat the burden of this disease.

Limitations of our study include the potential for selection and recall biases. Although our survey spanned multiple institutions in different regions of the United States, results might not be universally representative.

Acknowledgments—We thank Dirk Elston, MD, and Amy Wahlquist, MS (both from Charleston, South Carolina), who helped facilitate the survey on which our research is based. We also acknowledge the assistance of Philip Carmon, MD (Columbia, South Carolina); Julie Flugel (Columbia, South Carolina); Algimantas Simpson, MD (Columbia, South Carolina); Nathan Jasperse, MD (Irvine, California); Jeremy Teruel, MD (Charleston, South Carolina); Alan Snyder, MD, MSCR (Charleston, South Carolina); John Bosland (Charleston, South Carolina); and Daniel Spangler (Greenville, South Carolina).

To the Editor:

Skin cancer represents a notable health care burden of rising incidence.^1-3 Nondermatologist health care providers play a key role in skin cancer screening through the use of skin cancer examination (SCE)^1,4; however, several factors including poor diagnostic accuracy, low confidence, and lack of training have contributed to limited use of the SCE by these providers.^4,5 Therefore, it is important to identify and implement changes in the medical school curriculum that can facilitate improved use of SCE in clinical practice. We sought to examine factors in the medical school curriculum that influence skin cancer education.

A voluntary electronic survey was distributed through class email and social media to all medical student classes at 4 medical schools (Figure). Responses were collected between March 2 and April 20, 2020. Survey items assessed demographics and curricular factors that influence skin cancer education. Our study was approved by the Institutional Review Board for Human Research of the Medical University of South Carolina (Charleston, South Carolina).

Knowledge of the clinical features of melanoma was assessed by asking participants to correctly identify at least 5 of 6 pigmented lesions as concerning or not concerning for melanoma. Confidence in performing the SCE—the primary outcome—was measured by dichotomizing a 4-point Likert-type scale (“very confident” and “moderately confident” against “slightly confident” and “not at all confident”).

Logistic regression was used to examine curricular factors associated with confidence; descriptive statistics were used for remaining analyses. Analyses were performed using SAS 9.4 statistical software. Prior to analysis, responses from the University of South Carolina School of Medicine Greenville were excluded because the response rate was less than 20%.

The survey was distributed to 1524 students; 619 (40.6%) answered at least 1 question, with a variable response rate to each item (eTable 1). Most respondents were female (351 [56.7%]); 438 (70.8%) were White.

Most respondents said that they received 3 hours or less of general skin cancer (74.9%) or SCE-specific (93.0%) education by the end of their fourth year of medical training. Lecture was the most common method of instruction. Education was provided most often by dermatologists (48.6%), followed by general practice physicians (21.2%). Numerous (26.9%) fourth-year respondents reported that they had never observed SCE; even more (47.6%) had never performed SCE. Almost half of second- and third-year students (43.2% and 44.8%, respectively) considered themselves knowledgeable about the clinical features of melanoma, but only 31.9% of fourth-year students considered themselves knowledgeable.

Only 24.1% of fourth-year students reported confidence performing SCE (eTable 1). Students who received most of their instruction through real clinical encounters were 4.14 times more likely to be confident performing SCE than students who had been given lecture-based learning. Students who performed 1 to 3 SCE or 4 or more SCE were 3.02 and 32.25 times, respectively, more likely to be confident than students who had never performed SCE (eTable 2).

Consistent with a recent study,⁶ our results reflect the discrepancy between the burden and education of skin cancer. This is especially demonstrated by our cohort’s low confidence in performing SCE, a metric associated with both intention to perform and actual performance of SCE in practice.^4,5 We also observed a downward trend in knowledge among students who were about to enter residency, potentially indicating the need for longitudinal training.

Given curricular time constraints, it is essential that medical schools implement changes in learning that will have the greatest impact. Although our results strongly support the efficacy of hands-on clinical training, exposure to dermatology in the second half of medical school training is limited nationwide.⁶ Concentrated efforts to increase clinical exposure might help prepare future physicians in all specialties to combat the burden of this disease.

Limitations of our study include the potential for selection and recall biases. Although our survey spanned multiple institutions in different regions of the United States, results might not be universally representative.

Acknowledgments—We thank Dirk Elston, MD, and Amy Wahlquist, MS (both from Charleston, South Carolina), who helped facilitate the survey on which our research is based. We also acknowledge the assistance of Philip Carmon, MD (Columbia, South Carolina); Julie Flugel (Columbia, South Carolina); Algimantas Simpson, MD (Columbia, South Carolina); Nathan Jasperse, MD (Irvine, California); Jeremy Teruel, MD (Charleston, South Carolina); Alan Snyder, MD, MSCR (Charleston, South Carolina); John Bosland (Charleston, South Carolina); and Daniel Spangler (Greenville, South Carolina).

To the Editor:

Skin cancer represents a notable health care burden of rising incidence.^1-3 Nondermatologist health care providers play a key role in skin cancer screening through the use of skin cancer examination (SCE)^1,4; however, several factors including poor diagnostic accuracy, low confidence, and lack of training have contributed to limited use of the SCE by these providers.^4,5 Therefore, it is important to identify and implement changes in the medical school curriculum that can facilitate improved use of SCE in clinical practice. We sought to examine factors in the medical school curriculum that influence skin cancer education.

A voluntary electronic survey was distributed through class email and social media to all medical student classes at 4 medical schools (Figure). Responses were collected between March 2 and April 20, 2020. Survey items assessed demographics and curricular factors that influence skin cancer education. Our study was approved by the Institutional Review Board for Human Research of the Medical University of South Carolina (Charleston, South Carolina).

Knowledge of the clinical features of melanoma was assessed by asking participants to correctly identify at least 5 of 6 pigmented lesions as concerning or not concerning for melanoma. Confidence in performing the SCE—the primary outcome—was measured by dichotomizing a 4-point Likert-type scale (“very confident” and “moderately confident” against “slightly confident” and “not at all confident”).

Logistic regression was used to examine curricular factors associated with confidence; descriptive statistics were used for remaining analyses. Analyses were performed using SAS 9.4 statistical software. Prior to analysis, responses from the University of South Carolina School of Medicine Greenville were excluded because the response rate was less than 20%.

The survey was distributed to 1524 students; 619 (40.6%) answered at least 1 question, with a variable response rate to each item (eTable 1). Most respondents were female (351 [56.7%]); 438 (70.8%) were White.

Most respondents said that they received 3 hours or less of general skin cancer (74.9%) or SCE-specific (93.0%) education by the end of their fourth year of medical training. Lecture was the most common method of instruction. Education was provided most often by dermatologists (48.6%), followed by general practice physicians (21.2%). Numerous (26.9%) fourth-year respondents reported that they had never observed SCE; even more (47.6%) had never performed SCE. Almost half of second- and third-year students (43.2% and 44.8%, respectively) considered themselves knowledgeable about the clinical features of melanoma, but only 31.9% of fourth-year students considered themselves knowledgeable.

Only 24.1% of fourth-year students reported confidence performing SCE (eTable 1). Students who received most of their instruction through real clinical encounters were 4.14 times more likely to be confident performing SCE than students who had been given lecture-based learning. Students who performed 1 to 3 SCE or 4 or more SCE were 3.02 and 32.25 times, respectively, more likely to be confident than students who had never performed SCE (eTable 2).

Consistent with a recent study,⁶ our results reflect the discrepancy between the burden and education of skin cancer. This is especially demonstrated by our cohort’s low confidence in performing SCE, a metric associated with both intention to perform and actual performance of SCE in practice.^4,5 We also observed a downward trend in knowledge among students who were about to enter residency, potentially indicating the need for longitudinal training.

Given curricular time constraints, it is essential that medical schools implement changes in learning that will have the greatest impact. Although our results strongly support the efficacy of hands-on clinical training, exposure to dermatology in the second half of medical school training is limited nationwide.⁶ Concentrated efforts to increase clinical exposure might help prepare future physicians in all specialties to combat the burden of this disease.

Limitations of our study include the potential for selection and recall biases. Although our survey spanned multiple institutions in different regions of the United States, results might not be universally representative.

Acknowledgments—We thank Dirk Elston, MD, and Amy Wahlquist, MS (both from Charleston, South Carolina), who helped facilitate the survey on which our research is based. We also acknowledge the assistance of Philip Carmon, MD (Columbia, South Carolina); Julie Flugel (Columbia, South Carolina); Algimantas Simpson, MD (Columbia, South Carolina); Nathan Jasperse, MD (Irvine, California); Jeremy Teruel, MD (Charleston, South Carolina); Alan Snyder, MD, MSCR (Charleston, South Carolina); John Bosland (Charleston, South Carolina); and Daniel Spangler (Greenville, South Carolina).

New results from a phase 3 clinical trial may shut the door on the addition of progressive death–1 or PD–ligand 1 inhibitors to the combination of BRAF and MEK inhibitors for the treatment of BRAF V600–mutated melanoma.

The approach seemed promising, given the efficacy of PD-1 and PD-L1 inhibitors in metastatic melanoma, and the relatively short response times to BRAF and MEK inhibitors could potentially be supplemented by longer response times associated with PD-1 and PD-L1 inhibitors. The two categories also have different mechanisms of action and nonoverlapping toxicities, which led to an expectation that the combination would be well tolerated.

But the new study joins two previous randomized, controlled trials that also failed to show much clinical benefit. IMspire150 assigned BRAF V600–mutated melanoma patients to vemurafenib and cobimetinib plus the anti–PD-L1 antibody atezolizumab or placebo. The treatment arm had a small benefit in progression-free survival (hazard ratio, 0.78), which led to Food and Drug Administration approval of the combination, though there was no significant difference when the two cohorts were assessed by an independent review committee. The KEYNOTE-022 trial examined dabrafenib plus trametinib with or without the anti–PD-1 antibody pembrolizumab, and found no difference in investigator-assessed progression free survival.

The new study was published in the Journal of Clinical Oncology. In an accompanying editorial, Margaret K. Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center, and Paul B. Chapman, MD, of Weill Cornell Medicine, both in New York, speculated that the toxicity of the triplet combination might explain the latest failure, since patients in the triplet arm had more treatment interruptions and dose reductions than the doublet arm (32% received full-dose dabrafenib vs. 54% in the doublet arm), which may have undermined efficacy.

Citing the fact that there are now three randomized, controlled trials with discouraging results, “we believe that there are sufficient data now to be confident that the addition of anti–PD-1 or anti–PD-L1 antibodies to combination RAFi [RAF inhibitors] plus MEKi [MEK inhibitors] is not associated with a significant clinical benefit and should not be studied further in melanoma.

Moreover, “there is some evidence of harm,” the editorial authors wrote. “As the additional toxicity of triplet combination limited the delivery of combination RAFi plus MEKi therapy in COMBI-I. Focus should turn instead to optimizing doses and schedules of combination RAFi plus MEKi and checkpoint inhibitors, developing treatment strategies to overcome resistance to these therapies, and determining how best to sequence combination RAFi plus MEKi therapy and checkpoint inhibitors. Regarding the latter point, there are several sequential therapy trials currently underway in previously untreated patients with BRAF V600–mutated melanoma.”

In the study, patients were randomized to receive dabrafenib and trametinib plus the anti–PD receptor–1 antibody spartalizumab or placebo. After a median follow-up of 27.2 months, mean progression-free survival was 16.2 months in the spartalizumab arm and 12.0 months in the placebo arm (HR, 0.82; P = .042). The spartalizumab group had a 69% objective response rate versus 64% in the placebo group. 55% of the spartalizumab group experienced grade 3 or higher treatment-related adverse events, compared with 33% in the placebo group.

“These results do not support broad use of first-line immunotherapy plus targeted therapy combination, but they provide additional data toward understanding the optimal application of these therapeutic classes in patients with BRAF V600–mutant metastatic melanoma,” the authors of the study wrote.

The study was funded by F Hoffmann–La Roche and Genentech. Dr. Callahan has been employed at Bristol-Myers Squibb, Celgene, and Kleo Pharmaceuticals. Dr. Callahan has consulted for or advised AstraZeneca, Moderna Therapeutics, Merck, and Immunocore. Dr. Chapman has stock or ownership interest in Rgenix; has consulted for or advised Merck, Pfizer, and Black Diamond Therapeutics; and has received research funding from Genentech.

New results from a phase 3 clinical trial may shut the door on the addition of progressive death–1 or PD–ligand 1 inhibitors to the combination of BRAF and MEK inhibitors for the treatment of BRAF V600–mutated melanoma.

The approach seemed promising, given the efficacy of PD-1 and PD-L1 inhibitors in metastatic melanoma, and the relatively short response times to BRAF and MEK inhibitors could potentially be supplemented by longer response times associated with PD-1 and PD-L1 inhibitors. The two categories also have different mechanisms of action and nonoverlapping toxicities, which led to an expectation that the combination would be well tolerated.

But the new study joins two previous randomized, controlled trials that also failed to show much clinical benefit. IMspire150 assigned BRAF V600–mutated melanoma patients to vemurafenib and cobimetinib plus the anti–PD-L1 antibody atezolizumab or placebo. The treatment arm had a small benefit in progression-free survival (hazard ratio, 0.78), which led to Food and Drug Administration approval of the combination, though there was no significant difference when the two cohorts were assessed by an independent review committee. The KEYNOTE-022 trial examined dabrafenib plus trametinib with or without the anti–PD-1 antibody pembrolizumab, and found no difference in investigator-assessed progression free survival.

The new study was published in the Journal of Clinical Oncology. In an accompanying editorial, Margaret K. Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center, and Paul B. Chapman, MD, of Weill Cornell Medicine, both in New York, speculated that the toxicity of the triplet combination might explain the latest failure, since patients in the triplet arm had more treatment interruptions and dose reductions than the doublet arm (32% received full-dose dabrafenib vs. 54% in the doublet arm), which may have undermined efficacy.

Citing the fact that there are now three randomized, controlled trials with discouraging results, “we believe that there are sufficient data now to be confident that the addition of anti–PD-1 or anti–PD-L1 antibodies to combination RAFi [RAF inhibitors] plus MEKi [MEK inhibitors] is not associated with a significant clinical benefit and should not be studied further in melanoma.

Moreover, “there is some evidence of harm,” the editorial authors wrote. “As the additional toxicity of triplet combination limited the delivery of combination RAFi plus MEKi therapy in COMBI-I. Focus should turn instead to optimizing doses and schedules of combination RAFi plus MEKi and checkpoint inhibitors, developing treatment strategies to overcome resistance to these therapies, and determining how best to sequence combination RAFi plus MEKi therapy and checkpoint inhibitors. Regarding the latter point, there are several sequential therapy trials currently underway in previously untreated patients with BRAF V600–mutated melanoma.”

In the study, patients were randomized to receive dabrafenib and trametinib plus the anti–PD receptor–1 antibody spartalizumab or placebo. After a median follow-up of 27.2 months, mean progression-free survival was 16.2 months in the spartalizumab arm and 12.0 months in the placebo arm (HR, 0.82; P = .042). The spartalizumab group had a 69% objective response rate versus 64% in the placebo group. 55% of the spartalizumab group experienced grade 3 or higher treatment-related adverse events, compared with 33% in the placebo group.

“These results do not support broad use of first-line immunotherapy plus targeted therapy combination, but they provide additional data toward understanding the optimal application of these therapeutic classes in patients with BRAF V600–mutant metastatic melanoma,” the authors of the study wrote.

The study was funded by F Hoffmann–La Roche and Genentech. Dr. Callahan has been employed at Bristol-Myers Squibb, Celgene, and Kleo Pharmaceuticals. Dr. Callahan has consulted for or advised AstraZeneca, Moderna Therapeutics, Merck, and Immunocore. Dr. Chapman has stock or ownership interest in Rgenix; has consulted for or advised Merck, Pfizer, and Black Diamond Therapeutics; and has received research funding from Genentech.

New results from a phase 3 clinical trial may shut the door on the addition of progressive death–1 or PD–ligand 1 inhibitors to the combination of BRAF and MEK inhibitors for the treatment of BRAF V600–mutated melanoma.

The approach seemed promising, given the efficacy of PD-1 and PD-L1 inhibitors in metastatic melanoma, and the relatively short response times to BRAF and MEK inhibitors could potentially be supplemented by longer response times associated with PD-1 and PD-L1 inhibitors. The two categories also have different mechanisms of action and nonoverlapping toxicities, which led to an expectation that the combination would be well tolerated.

But the new study joins two previous randomized, controlled trials that also failed to show much clinical benefit. IMspire150 assigned BRAF V600–mutated melanoma patients to vemurafenib and cobimetinib plus the anti–PD-L1 antibody atezolizumab or placebo. The treatment arm had a small benefit in progression-free survival (hazard ratio, 0.78), which led to Food and Drug Administration approval of the combination, though there was no significant difference when the two cohorts were assessed by an independent review committee. The KEYNOTE-022 trial examined dabrafenib plus trametinib with or without the anti–PD-1 antibody pembrolizumab, and found no difference in investigator-assessed progression free survival.

The new study was published in the Journal of Clinical Oncology. In an accompanying editorial, Margaret K. Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center, and Paul B. Chapman, MD, of Weill Cornell Medicine, both in New York, speculated that the toxicity of the triplet combination might explain the latest failure, since patients in the triplet arm had more treatment interruptions and dose reductions than the doublet arm (32% received full-dose dabrafenib vs. 54% in the doublet arm), which may have undermined efficacy.

Citing the fact that there are now three randomized, controlled trials with discouraging results, “we believe that there are sufficient data now to be confident that the addition of anti–PD-1 or anti–PD-L1 antibodies to combination RAFi [RAF inhibitors] plus MEKi [MEK inhibitors] is not associated with a significant clinical benefit and should not be studied further in melanoma.

Moreover, “there is some evidence of harm,” the editorial authors wrote. “As the additional toxicity of triplet combination limited the delivery of combination RAFi plus MEKi therapy in COMBI-I. Focus should turn instead to optimizing doses and schedules of combination RAFi plus MEKi and checkpoint inhibitors, developing treatment strategies to overcome resistance to these therapies, and determining how best to sequence combination RAFi plus MEKi therapy and checkpoint inhibitors. Regarding the latter point, there are several sequential therapy trials currently underway in previously untreated patients with BRAF V600–mutated melanoma.”

In the study, patients were randomized to receive dabrafenib and trametinib plus the anti–PD receptor–1 antibody spartalizumab or placebo. After a median follow-up of 27.2 months, mean progression-free survival was 16.2 months in the spartalizumab arm and 12.0 months in the placebo arm (HR, 0.82; P = .042). The spartalizumab group had a 69% objective response rate versus 64% in the placebo group. 55% of the spartalizumab group experienced grade 3 or higher treatment-related adverse events, compared with 33% in the placebo group.

“These results do not support broad use of first-line immunotherapy plus targeted therapy combination, but they provide additional data toward understanding the optimal application of these therapeutic classes in patients with BRAF V600–mutant metastatic melanoma,” the authors of the study wrote.

The study was funded by F Hoffmann–La Roche and Genentech. Dr. Callahan has been employed at Bristol-Myers Squibb, Celgene, and Kleo Pharmaceuticals. Dr. Callahan has consulted for or advised AstraZeneca, Moderna Therapeutics, Merck, and Immunocore. Dr. Chapman has stock or ownership interest in Rgenix; has consulted for or advised Merck, Pfizer, and Black Diamond Therapeutics; and has received research funding from Genentech.

A mutation in a gene involved in chromatin remodeling is associated with aggressive melanoma, according to a new study that combined in vitro and animal model data.

The gene, ARID2, is a part of the switch/sucrose nonfermentable (SWI/SNF) complex, which maneuvers cellular structures called nucleosomes to make cellular DNA accessible. About 20% of human cancers have a mutation within the SWI/SNF complex.

In the new study, published in Cell Reports, researchers reported that the ARID2 subunit was mutated in about 13% of melanoma patients identified through the Cancer Genome Atlas.

ARID2 mutations have been found in early melanoma lesions, which the authors suggested may play a role in early cancer cell dissemination. Other studies have shown SWI/SNF mutations, including ARID2 mutations, in melanoma metastases, especially the brain.

The researchers also found an up-regulation of synaptic pathways in melanoma cells as well as the Cancer Genome Atlas, which also suggests a potential role of ARID2 loss in metastasis or targeting the brain, since synaptic activation in cancer cells has been shown elsewhere to influence cell migration and survival in the brain.

“We look forward to future studies that investigate the role of the PBAF complex ... in order to better tailor treatments for melanoma patients,” wrote the study authors, who were led by Emily Bernstein, PhD, a professor in oncological sciences with the Icahn School of Medicine at Mount Sinai, New York.

The SWI/SNF complex includes a subcomplex that targets specific DNA sequences or chromatin reader domains. There are multiple versions of the targeting subcomplex, but two of the most frequently occurring are BAF and PBAF. The most commonly mutated subunit in melanoma is ARID2, which is part of PBAF, and contains an AT-rich region responsible for non–sequence-specific DNA interactions. There is evidence that it plays a role in tumor suppression. In mouse tumors, depletion of ARID2 is associated with increased sensitivity to immune checkpoint inhibition and destruction by T cells.

To better understand the role of ARID2 in tumor suppression, the researchers used CRISPR-Cas9 to create ARID2 deficiency in a known human metastatic melanoma cell line. They found there was reduced chromatin accessibility and accompanying gene expression among some PBAF and shared BAF-PBAF–occupied regions. There was also increased chromatin accessibility and gene expression in BAF-occupied regions, and these changes were associated with tumor aggression. In mice, they led to metastasis of distal organs.

This mechanism appears to be conserved between different melanoma cell lines, but deregulated transcriptional targets were different depending on the dominant transcription factors in the cell line. That suggests that the effect of ARID2 mutation or loss may be different depending on the stage of melanoma progression or level of invasiveness. “As melanoma comprises transcriptionally distinct, heterogeneous cell populations, we envision future studies utilizing single-cell methodologies to better understand the nuanced effects of ARID2 loss within subpopulations of cells in human melanoma tumors,” the authors wrote.

The study is limited by the fact that not all ARID2 mutations lead to complete loss of protein, and may lead instead to aberrant complexes.

The study was funded by the National Institutes of Health.

A mutation in a gene involved in chromatin remodeling is associated with aggressive melanoma, according to a new study that combined in vitro and animal model data.

The gene, ARID2, is a part of the switch/sucrose nonfermentable (SWI/SNF) complex, which maneuvers cellular structures called nucleosomes to make cellular DNA accessible. About 20% of human cancers have a mutation within the SWI/SNF complex.

In the new study, published in Cell Reports, researchers reported that the ARID2 subunit was mutated in about 13% of melanoma patients identified through the Cancer Genome Atlas.

ARID2 mutations have been found in early melanoma lesions, which the authors suggested may play a role in early cancer cell dissemination. Other studies have shown SWI/SNF mutations, including ARID2 mutations, in melanoma metastases, especially the brain.

The researchers also found an up-regulation of synaptic pathways in melanoma cells as well as the Cancer Genome Atlas, which also suggests a potential role of ARID2 loss in metastasis or targeting the brain, since synaptic activation in cancer cells has been shown elsewhere to influence cell migration and survival in the brain.

“We look forward to future studies that investigate the role of the PBAF complex ... in order to better tailor treatments for melanoma patients,” wrote the study authors, who were led by Emily Bernstein, PhD, a professor in oncological sciences with the Icahn School of Medicine at Mount Sinai, New York.

The SWI/SNF complex includes a subcomplex that targets specific DNA sequences or chromatin reader domains. There are multiple versions of the targeting subcomplex, but two of the most frequently occurring are BAF and PBAF. The most commonly mutated subunit in melanoma is ARID2, which is part of PBAF, and contains an AT-rich region responsible for non–sequence-specific DNA interactions. There is evidence that it plays a role in tumor suppression. In mouse tumors, depletion of ARID2 is associated with increased sensitivity to immune checkpoint inhibition and destruction by T cells.

To better understand the role of ARID2 in tumor suppression, the researchers used CRISPR-Cas9 to create ARID2 deficiency in a known human metastatic melanoma cell line. They found there was reduced chromatin accessibility and accompanying gene expression among some PBAF and shared BAF-PBAF–occupied regions. There was also increased chromatin accessibility and gene expression in BAF-occupied regions, and these changes were associated with tumor aggression. In mice, they led to metastasis of distal organs.

This mechanism appears to be conserved between different melanoma cell lines, but deregulated transcriptional targets were different depending on the dominant transcription factors in the cell line. That suggests that the effect of ARID2 mutation or loss may be different depending on the stage of melanoma progression or level of invasiveness. “As melanoma comprises transcriptionally distinct, heterogeneous cell populations, we envision future studies utilizing single-cell methodologies to better understand the nuanced effects of ARID2 loss within subpopulations of cells in human melanoma tumors,” the authors wrote.

The study is limited by the fact that not all ARID2 mutations lead to complete loss of protein, and may lead instead to aberrant complexes.

The study was funded by the National Institutes of Health.

A mutation in a gene involved in chromatin remodeling is associated with aggressive melanoma, according to a new study that combined in vitro and animal model data.

The gene, ARID2, is a part of the switch/sucrose nonfermentable (SWI/SNF) complex, which maneuvers cellular structures called nucleosomes to make cellular DNA accessible. About 20% of human cancers have a mutation within the SWI/SNF complex.

In the new study, published in Cell Reports, researchers reported that the ARID2 subunit was mutated in about 13% of melanoma patients identified through the Cancer Genome Atlas.

ARID2 mutations have been found in early melanoma lesions, which the authors suggested may play a role in early cancer cell dissemination. Other studies have shown SWI/SNF mutations, including ARID2 mutations, in melanoma metastases, especially the brain.

The researchers also found an up-regulation of synaptic pathways in melanoma cells as well as the Cancer Genome Atlas, which also suggests a potential role of ARID2 loss in metastasis or targeting the brain, since synaptic activation in cancer cells has been shown elsewhere to influence cell migration and survival in the brain.

“We look forward to future studies that investigate the role of the PBAF complex ... in order to better tailor treatments for melanoma patients,” wrote the study authors, who were led by Emily Bernstein, PhD, a professor in oncological sciences with the Icahn School of Medicine at Mount Sinai, New York.

The SWI/SNF complex includes a subcomplex that targets specific DNA sequences or chromatin reader domains. There are multiple versions of the targeting subcomplex, but two of the most frequently occurring are BAF and PBAF. The most commonly mutated subunit in melanoma is ARID2, which is part of PBAF, and contains an AT-rich region responsible for non–sequence-specific DNA interactions. There is evidence that it plays a role in tumor suppression. In mouse tumors, depletion of ARID2 is associated with increased sensitivity to immune checkpoint inhibition and destruction by T cells.

To better understand the role of ARID2 in tumor suppression, the researchers used CRISPR-Cas9 to create ARID2 deficiency in a known human metastatic melanoma cell line. They found there was reduced chromatin accessibility and accompanying gene expression among some PBAF and shared BAF-PBAF–occupied regions. There was also increased chromatin accessibility and gene expression in BAF-occupied regions, and these changes were associated with tumor aggression. In mice, they led to metastasis of distal organs.

This mechanism appears to be conserved between different melanoma cell lines, but deregulated transcriptional targets were different depending on the dominant transcription factors in the cell line. That suggests that the effect of ARID2 mutation or loss may be different depending on the stage of melanoma progression or level of invasiveness. “As melanoma comprises transcriptionally distinct, heterogeneous cell populations, we envision future studies utilizing single-cell methodologies to better understand the nuanced effects of ARID2 loss within subpopulations of cells in human melanoma tumors,” the authors wrote.

The study is limited by the fact that not all ARID2 mutations lead to complete loss of protein, and may lead instead to aberrant complexes.

The study was funded by the National Institutes of Health.

There has been increasing awareness of field cancerization in dermatology and how it relates to actinic damage, actinic keratoses (AKs), and the development of cutaneous squamous cell carcinomas (SCCs). The concept of field cancerization, which was first described in the context of oropharyngeal SCCs, attempted to explain the repeated observation of local recurrences that were instead multiple primary oropharyngeal SCCs occurring within a specific region of tissue. It was hypothesized that the tissue surrounding a malignancy also harbors irreversible oncogenic damage and therefore predisposes the surrounding tissue to developing further malignancy.¹ The development of additional malignant lesions would be considered distinct from a true recurrence of the original malignancy.

Field cancerization may be partially explained by a genetic basis, as mutations in the tumor suppressor gene, TP53—the most frequently observed mutation in cutaneous SCCs—also is found in sun-exposed but clinically normal skin.^2,3 The finding of oncogenic mutations in nonlesional skin supports the theory of field cancerization, in which a region contains multiple genetically altered populations, some of which may progress to cancer. Because there currently is no widely accepted clinical definition or validated clinical measurement of field cancerization in dermatology, it may be difficult for dermatologists to recognize which patients may be at risk for developing further malignancy in a potential area of field cancerization. Willenbrink et al⁴ updated the definition of field cancerization in dermatology as “multifocal clinical atypia characterized by AKs or SCCs in situ with or without invasive disease occurring in a field exposed to chronic UV radiation.” Managing patients with field cancerization can be challenging. Herein, we discuss updates to nonsurgical field-directed and lesion-directed therapies as well as other emerging therapies.

Field-Directed Therapies

Topical 5-fluorouracil (5-FU) and imiquimod cream 5% used as field-directed therapies help reduce the extent of AKs and actinic damage in areas of possible field cancerization.⁵ The addition of calcipotriol to topical 5-FU, which theoretically augments the skin’s T-cell antitumor response via the cytokine thymic stromal lymphopoietin, recently has been studied using short treatment courses resulting in an 87.8% reduction in AKs compared to a 26.3% reduction with topical 5-FU alone (when used twice daily for 4 days) and conferred a reduced risk of cutaneous SCCs 3 years after treatment (hazard ratio, 0.215 [95% CI, 0.048-0.972]; P=.032).^6,7 Chemowraps using topical 5-FU may be considered in more difficult-to-treat areas of field cancerization with multiple AKs or keratinocyte carcinomas of the lower extremities.⁸ The routine use of chemowraps—weekly application of 5-FU covered with an occlusive dressing—may be limited by the inability to control the extent of epidermal damage and subsequent systemic absorption. Ingenol mebutate, which was approved for treatment of AKs in 2012, was removed from both the European and US markets in 2020 because the medication may paradoxically increase the long-term incidence of skin cancer.⁹

Meta-analysis has shown that photodynamic therapy (PDT) with aminolevulinic acid demonstrated complete AK clearance in 75.8% of patients (N=156)(95% CI, 55.4%-96.2%).¹⁰ A more recent method of PDT using natural sunlight as the activation source demonstrated AK clearance of 95.5%, and it appeared to be a less painful alternative to traditional PDT.¹¹ Tacalcitol, another form of vitamin D, also has been shown to enhance the efficacy of PDT for AKs.¹²

Field-directed treatment with erbium:YAG and CO₂ lasers, which physically remove the actinically damaged epidermis, have been shown to possibly be as efficacious as topical 5-FU and 30% trichloroacetic acid (TCA) but possibly inferior to PDT.¹³ There has been growing interest in laser-assisted therapy, in which an ablative fractional laser is used to generate microscopic channels to theoretically enhance the absorption of a topical medication. A meta-analysis of the use of laser-assisted therapy for photosensitizing agents in PDT demonstrated a 33% increased chance of AK clearance compared to PDT alone (P<.01).¹⁴

Lesion-Directed Therapies

Multiple KAs or cutaneous SCCs may develop in an area of field cancerization, and surgically treating these multiple lesions in a concentrated area may be challenging. Intralesional agents, including methotrexate, 5-FU, bleomycin, and interferon, are known treatments for KAs.¹⁵ Intralesional 5-FU (25 mg once weekly for 3–4 weeks) in particular produced complete resolution in 92% of cutaneous SCCs and may be optimal for multiple or rapidly growing lesions, especially on the extremities.¹⁶

Oral Therapies

Oral therapies are considered in high-risk patients with multiple or recurrent cutaneous SCCs or in those who are immunosuppressed. Two trials demonstrated that nicotinamide 500 mg twice daily for 4 and 12 months decreased AKs by 29% to 35% and 13% (average of 3–5 fewer AKs as compared to baseline), respectively.^17,18 A meta-analysis found a reduction of cutaneous SCCs (rate ratio, 0.48 [95% CI, 0.26-0.88]; I²=67%; 552 patients, 5 trials), and given the favorable safety profile, nicotinamide can be considered for chemoprevention.¹⁹

Acitretin, shown to reduce AKs by 13.4% to 50%, is the primary oral chemoprevention recommended in transplant recipients.²⁰ Interestingly, a recent meta-analysis failed to find significant differences between the efficacy of acitretin and nicotinamide.²¹ The tolerability of acitretin requires serious consideration, as 52.2% of patients withdrew due to adverse effects in one trial.²²

Capecitabine (250–1150 mg twice daily), the oral form of 5-FU, decreased the incidence of AKs and cutaneous SCCs in 53% and 72% of transplant recipients, respectively.²³ Although several reports observed paradoxical eruptions of AKs following capecitabine for other malignancies, this actually underscores the efficacy of capecitabine, as the newly emerged AKs resolved thereafter.²⁴ Still, the evidence supporting capecitabine does not include any controlled studies.

Novel Therapies

In 2021, tirbanibulin ointment 1%, a Src tyrosine kinase inhibitor of tubulin polymerization that induces p53 expression and subsequent cell death, was approved by the US Food and Drug Administration for the treatment of AKs.²⁵ Two trials reported AK clearance rates of 44% and 54% with application of tirbanibulin once daily for 5 days (vs 5% and 13%, respectively, with placebo, each with P<.001) at 2 months and a sustained clearance rate of 27% at 1 year. The predominant adverse effects were local skin reactions, including application-site pain, pruritus, mild erythema, or scaling. Unlike in other treatments such as 5-FU or cryotherapy, erosions, dyspigmentation, or scarring were not notably observed.

Intralesional talimogene laherparepvec (T-VEC), an oncolytic, genetically modified herpes simplex virus type 1 that incites antitumor immune responses, received US Food and Drug Administration approval in 2015 for the treatment of cutaneous and lymph node metastases of melanoma that are unable to be surgically resected. More recently, T-VEC has been investigated for oropharyngeal SCC. A phase 1 and phase 2 trial of 17 stage III/IV SCC patients receiving T-VEC and cisplatin demonstrated pathologic remission in 14 of 15 (93%) patients, with 82.4% survival at 29 months.²⁶ A multicenter phase 1b trial of 36 patients with recurrent or metastatic head and neck SCCs treated with T-VEC and pembrolizumab exhibited a tolerable safety profile, and 5 cases had a partial response.²⁷ However, phase 3 trials of T-VEC have yet to be pursued. Regarding its potential use for cutaneous SCCs, it has been reportedly used in a liver transplant recipient with metastatic cutaneous SCCs who received 2 doses of T-VEC (1 month apart) and attained remission of disease.²⁸ There currently is a phase 2 trial examining the effectiveness of T-VEC in patients with cutaneous SCCs (ClinicalTrials.gov identifier NCT03714828).

Final Thoughts

It is important for dermatologists to bear in mind the possible role of field cancerization in their comprehensive care of patients at risk for multiple skin cancers. Management of areas of field cancerization can be challenging, particularly in patients who develop multiple KAs or cutaneous SCCs in a concentrated area and may need to involve different levels of treatment options, including field-directed therapies and lesion-directed therapies, as well as systemic chemoprevention.

There has been increasing awareness of field cancerization in dermatology and how it relates to actinic damage, actinic keratoses (AKs), and the development of cutaneous squamous cell carcinomas (SCCs). The concept of field cancerization, which was first described in the context of oropharyngeal SCCs, attempted to explain the repeated observation of local recurrences that were instead multiple primary oropharyngeal SCCs occurring within a specific region of tissue. It was hypothesized that the tissue surrounding a malignancy also harbors irreversible oncogenic damage and therefore predisposes the surrounding tissue to developing further malignancy.¹ The development of additional malignant lesions would be considered distinct from a true recurrence of the original malignancy.

Field cancerization may be partially explained by a genetic basis, as mutations in the tumor suppressor gene, TP53—the most frequently observed mutation in cutaneous SCCs—also is found in sun-exposed but clinically normal skin.^2,3 The finding of oncogenic mutations in nonlesional skin supports the theory of field cancerization, in which a region contains multiple genetically altered populations, some of which may progress to cancer. Because there currently is no widely accepted clinical definition or validated clinical measurement of field cancerization in dermatology, it may be difficult for dermatologists to recognize which patients may be at risk for developing further malignancy in a potential area of field cancerization. Willenbrink et al⁴ updated the definition of field cancerization in dermatology as “multifocal clinical atypia characterized by AKs or SCCs in situ with or without invasive disease occurring in a field exposed to chronic UV radiation.” Managing patients with field cancerization can be challenging. Herein, we discuss updates to nonsurgical field-directed and lesion-directed therapies as well as other emerging therapies.

Field-Directed Therapies

Topical 5-fluorouracil (5-FU) and imiquimod cream 5% used as field-directed therapies help reduce the extent of AKs and actinic damage in areas of possible field cancerization.⁵ The addition of calcipotriol to topical 5-FU, which theoretically augments the skin’s T-cell antitumor response via the cytokine thymic stromal lymphopoietin, recently has been studied using short treatment courses resulting in an 87.8% reduction in AKs compared to a 26.3% reduction with topical 5-FU alone (when used twice daily for 4 days) and conferred a reduced risk of cutaneous SCCs 3 years after treatment (hazard ratio, 0.215 [95% CI, 0.048-0.972]; P=.032).^6,7 Chemowraps using topical 5-FU may be considered in more difficult-to-treat areas of field cancerization with multiple AKs or keratinocyte carcinomas of the lower extremities.⁸ The routine use of chemowraps—weekly application of 5-FU covered with an occlusive dressing—may be limited by the inability to control the extent of epidermal damage and subsequent systemic absorption. Ingenol mebutate, which was approved for treatment of AKs in 2012, was removed from both the European and US markets in 2020 because the medication may paradoxically increase the long-term incidence of skin cancer.⁹

Meta-analysis has shown that photodynamic therapy (PDT) with aminolevulinic acid demonstrated complete AK clearance in 75.8% of patients (N=156)(95% CI, 55.4%-96.2%).¹⁰ A more recent method of PDT using natural sunlight as the activation source demonstrated AK clearance of 95.5%, and it appeared to be a less painful alternative to traditional PDT.¹¹ Tacalcitol, another form of vitamin D, also has been shown to enhance the efficacy of PDT for AKs.¹²

Field-directed treatment with erbium:YAG and CO₂ lasers, which physically remove the actinically damaged epidermis, have been shown to possibly be as efficacious as topical 5-FU and 30% trichloroacetic acid (TCA) but possibly inferior to PDT.¹³ There has been growing interest in laser-assisted therapy, in which an ablative fractional laser is used to generate microscopic channels to theoretically enhance the absorption of a topical medication. A meta-analysis of the use of laser-assisted therapy for photosensitizing agents in PDT demonstrated a 33% increased chance of AK clearance compared to PDT alone (P<.01).¹⁴

Lesion-Directed Therapies

Multiple KAs or cutaneous SCCs may develop in an area of field cancerization, and surgically treating these multiple lesions in a concentrated area may be challenging. Intralesional agents, including methotrexate, 5-FU, bleomycin, and interferon, are known treatments for KAs.¹⁵ Intralesional 5-FU (25 mg once weekly for 3–4 weeks) in particular produced complete resolution in 92% of cutaneous SCCs and may be optimal for multiple or rapidly growing lesions, especially on the extremities.¹⁶

Oral Therapies

Oral therapies are considered in high-risk patients with multiple or recurrent cutaneous SCCs or in those who are immunosuppressed. Two trials demonstrated that nicotinamide 500 mg twice daily for 4 and 12 months decreased AKs by 29% to 35% and 13% (average of 3–5 fewer AKs as compared to baseline), respectively.^17,18 A meta-analysis found a reduction of cutaneous SCCs (rate ratio, 0.48 [95% CI, 0.26-0.88]; I²=67%; 552 patients, 5 trials), and given the favorable safety profile, nicotinamide can be considered for chemoprevention.¹⁹

Acitretin, shown to reduce AKs by 13.4% to 50%, is the primary oral chemoprevention recommended in transplant recipients.²⁰ Interestingly, a recent meta-analysis failed to find significant differences between the efficacy of acitretin and nicotinamide.²¹ The tolerability of acitretin requires serious consideration, as 52.2% of patients withdrew due to adverse effects in one trial.²²

Capecitabine (250–1150 mg twice daily), the oral form of 5-FU, decreased the incidence of AKs and cutaneous SCCs in 53% and 72% of transplant recipients, respectively.²³ Although several reports observed paradoxical eruptions of AKs following capecitabine for other malignancies, this actually underscores the efficacy of capecitabine, as the newly emerged AKs resolved thereafter.²⁴ Still, the evidence supporting capecitabine does not include any controlled studies.

Novel Therapies

In 2021, tirbanibulin ointment 1%, a Src tyrosine kinase inhibitor of tubulin polymerization that induces p53 expression and subsequent cell death, was approved by the US Food and Drug Administration for the treatment of AKs.²⁵ Two trials reported AK clearance rates of 44% and 54% with application of tirbanibulin once daily for 5 days (vs 5% and 13%, respectively, with placebo, each with P<.001) at 2 months and a sustained clearance rate of 27% at 1 year. The predominant adverse effects were local skin reactions, including application-site pain, pruritus, mild erythema, or scaling. Unlike in other treatments such as 5-FU or cryotherapy, erosions, dyspigmentation, or scarring were not notably observed.

Intralesional talimogene laherparepvec (T-VEC), an oncolytic, genetically modified herpes simplex virus type 1 that incites antitumor immune responses, received US Food and Drug Administration approval in 2015 for the treatment of cutaneous and lymph node metastases of melanoma that are unable to be surgically resected. More recently, T-VEC has been investigated for oropharyngeal SCC. A phase 1 and phase 2 trial of 17 stage III/IV SCC patients receiving T-VEC and cisplatin demonstrated pathologic remission in 14 of 15 (93%) patients, with 82.4% survival at 29 months.²⁶ A multicenter phase 1b trial of 36 patients with recurrent or metastatic head and neck SCCs treated with T-VEC and pembrolizumab exhibited a tolerable safety profile, and 5 cases had a partial response.²⁷ However, phase 3 trials of T-VEC have yet to be pursued. Regarding its potential use for cutaneous SCCs, it has been reportedly used in a liver transplant recipient with metastatic cutaneous SCCs who received 2 doses of T-VEC (1 month apart) and attained remission of disease.²⁸ There currently is a phase 2 trial examining the effectiveness of T-VEC in patients with cutaneous SCCs (ClinicalTrials.gov identifier NCT03714828).

Final Thoughts

It is important for dermatologists to bear in mind the possible role of field cancerization in their comprehensive care of patients at risk for multiple skin cancers. Management of areas of field cancerization can be challenging, particularly in patients who develop multiple KAs or cutaneous SCCs in a concentrated area and may need to involve different levels of treatment options, including field-directed therapies and lesion-directed therapies, as well as systemic chemoprevention.

There has been increasing awareness of field cancerization in dermatology and how it relates to actinic damage, actinic keratoses (AKs), and the development of cutaneous squamous cell carcinomas (SCCs). The concept of field cancerization, which was first described in the context of oropharyngeal SCCs, attempted to explain the repeated observation of local recurrences that were instead multiple primary oropharyngeal SCCs occurring within a specific region of tissue. It was hypothesized that the tissue surrounding a malignancy also harbors irreversible oncogenic damage and therefore predisposes the surrounding tissue to developing further malignancy.¹ The development of additional malignant lesions would be considered distinct from a true recurrence of the original malignancy.

Field cancerization may be partially explained by a genetic basis, as mutations in the tumor suppressor gene, TP53—the most frequently observed mutation in cutaneous SCCs—also is found in sun-exposed but clinically normal skin.^2,3 The finding of oncogenic mutations in nonlesional skin supports the theory of field cancerization, in which a region contains multiple genetically altered populations, some of which may progress to cancer. Because there currently is no widely accepted clinical definition or validated clinical measurement of field cancerization in dermatology, it may be difficult for dermatologists to recognize which patients may be at risk for developing further malignancy in a potential area of field cancerization. Willenbrink et al⁴ updated the definition of field cancerization in dermatology as “multifocal clinical atypia characterized by AKs or SCCs in situ with or without invasive disease occurring in a field exposed to chronic UV radiation.” Managing patients with field cancerization can be challenging. Herein, we discuss updates to nonsurgical field-directed and lesion-directed therapies as well as other emerging therapies.

Field-Directed Therapies

Topical 5-fluorouracil (5-FU) and imiquimod cream 5% used as field-directed therapies help reduce the extent of AKs and actinic damage in areas of possible field cancerization.⁵ The addition of calcipotriol to topical 5-FU, which theoretically augments the skin’s T-cell antitumor response via the cytokine thymic stromal lymphopoietin, recently has been studied using short treatment courses resulting in an 87.8% reduction in AKs compared to a 26.3% reduction with topical 5-FU alone (when used twice daily for 4 days) and conferred a reduced risk of cutaneous SCCs 3 years after treatment (hazard ratio, 0.215 [95% CI, 0.048-0.972]; P=.032).^6,7 Chemowraps using topical 5-FU may be considered in more difficult-to-treat areas of field cancerization with multiple AKs or keratinocyte carcinomas of the lower extremities.⁸ The routine use of chemowraps—weekly application of 5-FU covered with an occlusive dressing—may be limited by the inability to control the extent of epidermal damage and subsequent systemic absorption. Ingenol mebutate, which was approved for treatment of AKs in 2012, was removed from both the European and US markets in 2020 because the medication may paradoxically increase the long-term incidence of skin cancer.⁹

Meta-analysis has shown that photodynamic therapy (PDT) with aminolevulinic acid demonstrated complete AK clearance in 75.8% of patients (N=156)(95% CI, 55.4%-96.2%).¹⁰ A more recent method of PDT using natural sunlight as the activation source demonstrated AK clearance of 95.5%, and it appeared to be a less painful alternative to traditional PDT.¹¹ Tacalcitol, another form of vitamin D, also has been shown to enhance the efficacy of PDT for AKs.¹²

Field-directed treatment with erbium:YAG and CO₂ lasers, which physically remove the actinically damaged epidermis, have been shown to possibly be as efficacious as topical 5-FU and 30% trichloroacetic acid (TCA) but possibly inferior to PDT.¹³ There has been growing interest in laser-assisted therapy, in which an ablative fractional laser is used to generate microscopic channels to theoretically enhance the absorption of a topical medication. A meta-analysis of the use of laser-assisted therapy for photosensitizing agents in PDT demonstrated a 33% increased chance of AK clearance compared to PDT alone (P<.01).¹⁴

Lesion-Directed Therapies

Multiple KAs or cutaneous SCCs may develop in an area of field cancerization, and surgically treating these multiple lesions in a concentrated area may be challenging. Intralesional agents, including methotrexate, 5-FU, bleomycin, and interferon, are known treatments for KAs.¹⁵ Intralesional 5-FU (25 mg once weekly for 3–4 weeks) in particular produced complete resolution in 92% of cutaneous SCCs and may be optimal for multiple or rapidly growing lesions, especially on the extremities.¹⁶

Oral Therapies

Oral therapies are considered in high-risk patients with multiple or recurrent cutaneous SCCs or in those who are immunosuppressed. Two trials demonstrated that nicotinamide 500 mg twice daily for 4 and 12 months decreased AKs by 29% to 35% and 13% (average of 3–5 fewer AKs as compared to baseline), respectively.^17,18 A meta-analysis found a reduction of cutaneous SCCs (rate ratio, 0.48 [95% CI, 0.26-0.88]; I²=67%; 552 patients, 5 trials), and given the favorable safety profile, nicotinamide can be considered for chemoprevention.¹⁹

Acitretin, shown to reduce AKs by 13.4% to 50%, is the primary oral chemoprevention recommended in transplant recipients.²⁰ Interestingly, a recent meta-analysis failed to find significant differences between the efficacy of acitretin and nicotinamide.²¹ The tolerability of acitretin requires serious consideration, as 52.2% of patients withdrew due to adverse effects in one trial.²²

Capecitabine (250–1150 mg twice daily), the oral form of 5-FU, decreased the incidence of AKs and cutaneous SCCs in 53% and 72% of transplant recipients, respectively.²³ Although several reports observed paradoxical eruptions of AKs following capecitabine for other malignancies, this actually underscores the efficacy of capecitabine, as the newly emerged AKs resolved thereafter.²⁴ Still, the evidence supporting capecitabine does not include any controlled studies.

Novel Therapies

In 2021, tirbanibulin ointment 1%, a Src tyrosine kinase inhibitor of tubulin polymerization that induces p53 expression and subsequent cell death, was approved by the US Food and Drug Administration for the treatment of AKs.²⁵ Two trials reported AK clearance rates of 44% and 54% with application of tirbanibulin once daily for 5 days (vs 5% and 13%, respectively, with placebo, each with P<.001) at 2 months and a sustained clearance rate of 27% at 1 year. The predominant adverse effects were local skin reactions, including application-site pain, pruritus, mild erythema, or scaling. Unlike in other treatments such as 5-FU or cryotherapy, erosions, dyspigmentation, or scarring were not notably observed.

Intralesional talimogene laherparepvec (T-VEC), an oncolytic, genetically modified herpes simplex virus type 1 that incites antitumor immune responses, received US Food and Drug Administration approval in 2015 for the treatment of cutaneous and lymph node metastases of melanoma that are unable to be surgically resected. More recently, T-VEC has been investigated for oropharyngeal SCC. A phase 1 and phase 2 trial of 17 stage III/IV SCC patients receiving T-VEC and cisplatin demonstrated pathologic remission in 14 of 15 (93%) patients, with 82.4% survival at 29 months.²⁶ A multicenter phase 1b trial of 36 patients with recurrent or metastatic head and neck SCCs treated with T-VEC and pembrolizumab exhibited a tolerable safety profile, and 5 cases had a partial response.²⁷ However, phase 3 trials of T-VEC have yet to be pursued. Regarding its potential use for cutaneous SCCs, it has been reportedly used in a liver transplant recipient with metastatic cutaneous SCCs who received 2 doses of T-VEC (1 month apart) and attained remission of disease.²⁸ There currently is a phase 2 trial examining the effectiveness of T-VEC in patients with cutaneous SCCs (ClinicalTrials.gov identifier NCT03714828).

Final Thoughts

It is important for dermatologists to bear in mind the possible role of field cancerization in their comprehensive care of patients at risk for multiple skin cancers. Management of areas of field cancerization can be challenging, particularly in patients who develop multiple KAs or cutaneous SCCs in a concentrated area and may need to involve different levels of treatment options, including field-directed therapies and lesion-directed therapies, as well as systemic chemoprevention.

I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.

Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.

Transitioning from active therapy to symptom management

Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.

The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones. Hospice transitions seem to reside in an area of clinical practice that is overlooked or, in my experience they are considered an afterthought by many oncologists.

When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.

In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.

A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
 

‘Don’t just put in the hospice order and walk away’

Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.

First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.

Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.

If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.

These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.

As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.

Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.

Transitioning from active therapy to symptom management

Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.

The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones. Hospice transitions seem to reside in an area of clinical practice that is overlooked or, in my experience they are considered an afterthought by many oncologists.

When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.

In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.

A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
 

‘Don’t just put in the hospice order and walk away’

Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.

First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.

Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.

If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.

These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.

As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.

Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.

Transitioning from active therapy to symptom management

Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.

The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones. Hospice transitions seem to reside in an area of clinical practice that is overlooked or, in my experience they are considered an afterthought by many oncologists.

When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.

In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.

A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
 

‘Don’t just put in the hospice order and walk away’

Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.

First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.

Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.

If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.

These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.

As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.