Melanoma

DESTIN, Fla. - When it comes to melanoma treatment, one of the most effective strategies - excision - is what dermatologists do best, Dr. Christopher J. Miller said.

"Getting the tumor out is the one thing we are good at [with melanoma]. And we have tools to be better at it," he emphasized.

Histostains, including melanoma antigen recognized by T cells 1 (MART-1), are one such tool. "These stains have revolutionized our ability to treat melanoma using frozen sections," said Dr. Miller, director of dermatologic surgery at the University of Pennsylvania in Philadelphia.

Dr. Miller said he hopes MART-1 staining will change a belief in dermatology that detection of residual disease is less accurate with use of frozen sections after Mohs surgery, compared with use of permanent sections after staged excision, also known as "slow Mohs."

"That is a dogma that is holding back the transition to using frozen sections," Dr. Miller noted at the annual meeting of the Alabama Dermatology Society.

There are data to indicate this is a safe practice, Dr. Miller said, including a large study of 625 patients with melanoma in the head and neck area, "an anatomic location with historically high recurrence and metastasis rates and poor survival rates." Mohs surgery using frozen sections resulted in complete melanoma removal in 97%, with 5-year local recurrence and metastasis rates, and disease-specific survival rates comparable to or better than those for historical controls (J. Am. Acad. Dermatol. 2005;52:92-100).

"And the proof is in the high cure rates all of us are getting with Mohs surgery using frozen sections and immunostains," he said.

"If you compare the frozen sections with MART-1 to the permanent sections with MART-1, we’re making the same calls," emphasized Dr. Miller.

Several studies support a finding that MART-1 imparts equivalence in terms of residual disease detection between frozen sections and permanent sections (Dermatol. Surg. 2009;35:207-13; J. Am. Acad. Dermatol. 2002;46:78-84).

With frozen sections, the Mohs surgeon (not a pathologist) checks for evidence of residual disease, results are immediate, and multiple stages of surgery can be performed on the same day. In contrast, slow Mohs requires that permanent sections processed in formalin be sent to a pathologist for evaluation. "And you have to coordinate a lot of logistics because you have to make sure the pathologist is ready to read these slides when they are available, and the patient is ready to come back right when you know your answer," Dr. Miller said. Typical turnaround time for pathology results is 24-48 hours.

Both Mohs with frozen sections and slow Mohs with permanent sections demonstrate excellent cure rates in studies, Dr. Miller said. Recurrences were in the range of 0%-2.6% in a review study (Cancer Control 2008;15:216-24).

"So they are both reliable methods in experienced hands," he noted. Importantly, both Mohs techniques permit examination of 100% of the excised margin for residual disease, Dr. Miller said. "That is what determines how certain you will be that the cancer is removed."

There are dermatologists who remain unconvinced about the benefits of frozen sections, Dr. Miller said. "I’d invite anybody to spend time with me treating these melanomas in my clinic. I’m sure I can convince them that with high-quality sections and attentive [histotechnicians] who are true experts in these stains, we can have stains that are of excellent quality that can give our patients the highest cure rates," he said in a follow-up interview.

Recognition that melanoma is a microscopic disease is important, Dr. Miller noted. "Let's accept we cannot see subclinical spread in every case. Twenty percent of the time we don’t get it all with what we think is an appropriate margin. Surgeons are having to go back for a second stage to remove tumor that wasn’t visible to them."

Dr. Miller's surgical approach to melanoma is Mohs with frozen sections. He supplements a standard hematoxylin and eosin (H&E) stain with a MART-1 immunostain for each patient. This strategy "has allowed me in multiple cases to detect melanocytes I probably would have missed had I used hematoxylin and eosin alone."

Dr. Miller also recommended an online tool that calculates the likelihood for survival from localized melanoma or regional metastatic disease based on clinical and patient characteristics. A blog posting on this easy-to-use tool is available.

For advice from Dr. Miller on the management of patients with thin melanomas, including why sentinel lymph node biopsies remain controversial in this population, watch a video interview.

Dr. Miller said he had no relevant financial disclosures.

DESTIN, Fla. - When it comes to melanoma treatment, one of the most effective strategies - excision - is what dermatologists do best, Dr. Christopher J. Miller said.

"Getting the tumor out is the one thing we are good at [with melanoma]. And we have tools to be better at it," he emphasized.

Histostains, including melanoma antigen recognized by T cells 1 (MART-1), are one such tool. "These stains have revolutionized our ability to treat melanoma using frozen sections," said Dr. Miller, director of dermatologic surgery at the University of Pennsylvania in Philadelphia.

Dr. Miller said he hopes MART-1 staining will change a belief in dermatology that detection of residual disease is less accurate with use of frozen sections after Mohs surgery, compared with use of permanent sections after staged excision, also known as "slow Mohs."

"That is a dogma that is holding back the transition to using frozen sections," Dr. Miller noted at the annual meeting of the Alabama Dermatology Society.

There are data to indicate this is a safe practice, Dr. Miller said, including a large study of 625 patients with melanoma in the head and neck area, "an anatomic location with historically high recurrence and metastasis rates and poor survival rates." Mohs surgery using frozen sections resulted in complete melanoma removal in 97%, with 5-year local recurrence and metastasis rates, and disease-specific survival rates comparable to or better than those for historical controls (J. Am. Acad. Dermatol. 2005;52:92-100).

"And the proof is in the high cure rates all of us are getting with Mohs surgery using frozen sections and immunostains," he said.

"If you compare the frozen sections with MART-1 to the permanent sections with MART-1, we’re making the same calls," emphasized Dr. Miller.

Several studies support a finding that MART-1 imparts equivalence in terms of residual disease detection between frozen sections and permanent sections (Dermatol. Surg. 2009;35:207-13; J. Am. Acad. Dermatol. 2002;46:78-84).

With frozen sections, the Mohs surgeon (not a pathologist) checks for evidence of residual disease, results are immediate, and multiple stages of surgery can be performed on the same day. In contrast, slow Mohs requires that permanent sections processed in formalin be sent to a pathologist for evaluation. "And you have to coordinate a lot of logistics because you have to make sure the pathologist is ready to read these slides when they are available, and the patient is ready to come back right when you know your answer," Dr. Miller said. Typical turnaround time for pathology results is 24-48 hours.

Both Mohs with frozen sections and slow Mohs with permanent sections demonstrate excellent cure rates in studies, Dr. Miller said. Recurrences were in the range of 0%-2.6% in a review study (Cancer Control 2008;15:216-24).

"So they are both reliable methods in experienced hands," he noted. Importantly, both Mohs techniques permit examination of 100% of the excised margin for residual disease, Dr. Miller said. "That is what determines how certain you will be that the cancer is removed."

There are dermatologists who remain unconvinced about the benefits of frozen sections, Dr. Miller said. "I’d invite anybody to spend time with me treating these melanomas in my clinic. I’m sure I can convince them that with high-quality sections and attentive [histotechnicians] who are true experts in these stains, we can have stains that are of excellent quality that can give our patients the highest cure rates," he said in a follow-up interview.

Recognition that melanoma is a microscopic disease is important, Dr. Miller noted. "Let's accept we cannot see subclinical spread in every case. Twenty percent of the time we don’t get it all with what we think is an appropriate margin. Surgeons are having to go back for a second stage to remove tumor that wasn’t visible to them."

Dr. Miller's surgical approach to melanoma is Mohs with frozen sections. He supplements a standard hematoxylin and eosin (H&E) stain with a MART-1 immunostain for each patient. This strategy "has allowed me in multiple cases to detect melanocytes I probably would have missed had I used hematoxylin and eosin alone."

Dr. Miller also recommended an online tool that calculates the likelihood for survival from localized melanoma or regional metastatic disease based on clinical and patient characteristics. A blog posting on this easy-to-use tool is available.

For advice from Dr. Miller on the management of patients with thin melanomas, including why sentinel lymph node biopsies remain controversial in this population, watch a video interview.

Dr. Miller said he had no relevant financial disclosures.

DESTIN, Fla. - When it comes to melanoma treatment, one of the most effective strategies - excision - is what dermatologists do best, Dr. Christopher J. Miller said.

"Getting the tumor out is the one thing we are good at [with melanoma]. And we have tools to be better at it," he emphasized.

Histostains, including melanoma antigen recognized by T cells 1 (MART-1), are one such tool. "These stains have revolutionized our ability to treat melanoma using frozen sections," said Dr. Miller, director of dermatologic surgery at the University of Pennsylvania in Philadelphia.

Dr. Miller said he hopes MART-1 staining will change a belief in dermatology that detection of residual disease is less accurate with use of frozen sections after Mohs surgery, compared with use of permanent sections after staged excision, also known as "slow Mohs."

"That is a dogma that is holding back the transition to using frozen sections," Dr. Miller noted at the annual meeting of the Alabama Dermatology Society.

There are data to indicate this is a safe practice, Dr. Miller said, including a large study of 625 patients with melanoma in the head and neck area, "an anatomic location with historically high recurrence and metastasis rates and poor survival rates." Mohs surgery using frozen sections resulted in complete melanoma removal in 97%, with 5-year local recurrence and metastasis rates, and disease-specific survival rates comparable to or better than those for historical controls (J. Am. Acad. Dermatol. 2005;52:92-100).

"And the proof is in the high cure rates all of us are getting with Mohs surgery using frozen sections and immunostains," he said.

"If you compare the frozen sections with MART-1 to the permanent sections with MART-1, we’re making the same calls," emphasized Dr. Miller.

Several studies support a finding that MART-1 imparts equivalence in terms of residual disease detection between frozen sections and permanent sections (Dermatol. Surg. 2009;35:207-13; J. Am. Acad. Dermatol. 2002;46:78-84).

With frozen sections, the Mohs surgeon (not a pathologist) checks for evidence of residual disease, results are immediate, and multiple stages of surgery can be performed on the same day. In contrast, slow Mohs requires that permanent sections processed in formalin be sent to a pathologist for evaluation. "And you have to coordinate a lot of logistics because you have to make sure the pathologist is ready to read these slides when they are available, and the patient is ready to come back right when you know your answer," Dr. Miller said. Typical turnaround time for pathology results is 24-48 hours.

Both Mohs with frozen sections and slow Mohs with permanent sections demonstrate excellent cure rates in studies, Dr. Miller said. Recurrences were in the range of 0%-2.6% in a review study (Cancer Control 2008;15:216-24).

"So they are both reliable methods in experienced hands," he noted. Importantly, both Mohs techniques permit examination of 100% of the excised margin for residual disease, Dr. Miller said. "That is what determines how certain you will be that the cancer is removed."

There are dermatologists who remain unconvinced about the benefits of frozen sections, Dr. Miller said. "I’d invite anybody to spend time with me treating these melanomas in my clinic. I’m sure I can convince them that with high-quality sections and attentive [histotechnicians] who are true experts in these stains, we can have stains that are of excellent quality that can give our patients the highest cure rates," he said in a follow-up interview.

Recognition that melanoma is a microscopic disease is important, Dr. Miller noted. "Let's accept we cannot see subclinical spread in every case. Twenty percent of the time we don’t get it all with what we think is an appropriate margin. Surgeons are having to go back for a second stage to remove tumor that wasn’t visible to them."

Dr. Miller's surgical approach to melanoma is Mohs with frozen sections. He supplements a standard hematoxylin and eosin (H&E) stain with a MART-1 immunostain for each patient. This strategy "has allowed me in multiple cases to detect melanocytes I probably would have missed had I used hematoxylin and eosin alone."

Dr. Miller also recommended an online tool that calculates the likelihood for survival from localized melanoma or regional metastatic disease based on clinical and patient characteristics. A blog posting on this easy-to-use tool is available.

For advice from Dr. Miller on the management of patients with thin melanomas, including why sentinel lymph node biopsies remain controversial in this population, watch a video interview.

Dr. Miller said he had no relevant financial disclosures.

NEW YORK - Clean, nonsterile gloves are just as effective in preventing infection in Mohs surgery as their more expensive sterile counterparts.

These findings from two studies add to a growing body of data that support the use of clean technique and could translate into significant cost savings for Mohs surgeons - up to several thousand dollars a year, by one estimate.

In the first study presented at the annual meeting of the American College of Mohs Surgery, researchers led by Dr. Heather D. Rogers of the University of Washington, Seattle, sought to evaluate the rate of surgical site infection (SSI) in Mohs surgery patients using clean surgical technique versus sterile technique for "all steps of MMS [Mohs micrographic surgery], including wound reconstruction, in the absence of prophylactic antibiotics."

The researchers evaluated 1,000 patients undergoing MMS using clean technique, which included the use of clean (vs. sterile) gloves, clean (vs. sterile) towels, and a "single pack" of sterile instruments for the entire wound reconstruction.

Infection was classified according to the Centers for Disease Control and Prevention parameters: A site was considered infected if it expressed purulent discharge, if it displayed edema or erythema, and if the patient complained of pain or tenderness at the site.

"There were 11 infections in 1,000 patients with 1,204 tumors," said Dr. Rogers, for an infection rate of 0.91%. Three of the infections were complications of hematomas.

"Our SSI rate of 0.91% is extremely low," she said, "underscoring the overall safety of MMS and its performance in the outpatient setting without the use of antibiotic prophylaxis or sterile technique."

The second study was presented by Dr. Yang Xia of the division of Mohs surgery at the Scripps Clinic, La Jolla, Calif. Dr. Xia conducted a prospective, subject-blinded pilot study of 60 patients at the clinic to assess the difference in infection rate between clean, nonsterile gloves and sterile gloves for the repair of surgical defects in MMS.

"Clean gloves were used for all patients in the tumor removal phase," said Dr. Xia.

After tumors were removed, patients were randomized to repair with either clean or sterile gloves. A total of 30 patients were enrolled in each arm. Sterile paper and trays were used during all repairs. The mean age of the clean group was 69 years (26 men); the mean age of the sterile group was 74 years (28 men). Patients were excluded from the study if they were taking antibiotics at the time of the procedure or if they had any serious comorbidities, such as HIV.

After surgery, patients were followed up for 5-21 days, and the wounds were assessed by a nurse or assistant who was not affiliated with the study.
In the clean group, there was one SSI, in a 67-year-old man who cultured positive for methicillin-susceptible Staphylococcus aureus (MSSA). He was prescribed cephalexin.

In the sterile group, there were two SSIs: one case of MSSA, which was treated with cephalexin and resolved, and one case of methicillin-resistant Staphylococcus aureus (MRSA), which resolved with administration of Septra (trimethoprim and sulfamethoxazole) twice a day for 14 days.

Given the equally low rates of infection in the two study arms, the potential cost-savings of switching from sterile to clean gloves for these procedures could be tremendous, Dr. Xia said. One online search put the cost of a box of 100 clean gloves at $4-$9, although Dr. Xia gave a figure of $4-$29 for a box of 150 gloves. In contrast, a box of 100 sterile surgical gloves costs $74-$250, according to Dr. Xia. (A separate online search found a box of 100 sterile gloves available for $45-$275.)

Depending on the annual volume of a surgeon's cases, switching from sterile to clean gloves could save $6,000 to $20,000 a year, Dr. Xia estimated.

Dr. Rogers and Dr. Xia said they had no disclosures to make in relation to their presentations.

NEW YORK - Clean, nonsterile gloves are just as effective in preventing infection in Mohs surgery as their more expensive sterile counterparts.

These findings from two studies add to a growing body of data that support the use of clean technique and could translate into significant cost savings for Mohs surgeons - up to several thousand dollars a year, by one estimate.

In the first study presented at the annual meeting of the American College of Mohs Surgery, researchers led by Dr. Heather D. Rogers of the University of Washington, Seattle, sought to evaluate the rate of surgical site infection (SSI) in Mohs surgery patients using clean surgical technique versus sterile technique for "all steps of MMS [Mohs micrographic surgery], including wound reconstruction, in the absence of prophylactic antibiotics."

The researchers evaluated 1,000 patients undergoing MMS using clean technique, which included the use of clean (vs. sterile) gloves, clean (vs. sterile) towels, and a "single pack" of sterile instruments for the entire wound reconstruction.

Infection was classified according to the Centers for Disease Control and Prevention parameters: A site was considered infected if it expressed purulent discharge, if it displayed edema or erythema, and if the patient complained of pain or tenderness at the site.

"There were 11 infections in 1,000 patients with 1,204 tumors," said Dr. Rogers, for an infection rate of 0.91%. Three of the infections were complications of hematomas.

"Our SSI rate of 0.91% is extremely low," she said, "underscoring the overall safety of MMS and its performance in the outpatient setting without the use of antibiotic prophylaxis or sterile technique."

The second study was presented by Dr. Yang Xia of the division of Mohs surgery at the Scripps Clinic, La Jolla, Calif. Dr. Xia conducted a prospective, subject-blinded pilot study of 60 patients at the clinic to assess the difference in infection rate between clean, nonsterile gloves and sterile gloves for the repair of surgical defects in MMS.

"Clean gloves were used for all patients in the tumor removal phase," said Dr. Xia.

After tumors were removed, patients were randomized to repair with either clean or sterile gloves. A total of 30 patients were enrolled in each arm. Sterile paper and trays were used during all repairs. The mean age of the clean group was 69 years (26 men); the mean age of the sterile group was 74 years (28 men). Patients were excluded from the study if they were taking antibiotics at the time of the procedure or if they had any serious comorbidities, such as HIV.

After surgery, patients were followed up for 5-21 days, and the wounds were assessed by a nurse or assistant who was not affiliated with the study.
In the clean group, there was one SSI, in a 67-year-old man who cultured positive for methicillin-susceptible Staphylococcus aureus (MSSA). He was prescribed cephalexin.

In the sterile group, there were two SSIs: one case of MSSA, which was treated with cephalexin and resolved, and one case of methicillin-resistant Staphylococcus aureus (MRSA), which resolved with administration of Septra (trimethoprim and sulfamethoxazole) twice a day for 14 days.

Given the equally low rates of infection in the two study arms, the potential cost-savings of switching from sterile to clean gloves for these procedures could be tremendous, Dr. Xia said. One online search put the cost of a box of 100 clean gloves at $4-$9, although Dr. Xia gave a figure of $4-$29 for a box of 150 gloves. In contrast, a box of 100 sterile surgical gloves costs $74-$250, according to Dr. Xia. (A separate online search found a box of 100 sterile gloves available for $45-$275.)

Depending on the annual volume of a surgeon's cases, switching from sterile to clean gloves could save $6,000 to $20,000 a year, Dr. Xia estimated.

Dr. Rogers and Dr. Xia said they had no disclosures to make in relation to their presentations.

NEW YORK - Clean, nonsterile gloves are just as effective in preventing infection in Mohs surgery as their more expensive sterile counterparts.

These findings from two studies add to a growing body of data that support the use of clean technique and could translate into significant cost savings for Mohs surgeons - up to several thousand dollars a year, by one estimate.

In the first study presented at the annual meeting of the American College of Mohs Surgery, researchers led by Dr. Heather D. Rogers of the University of Washington, Seattle, sought to evaluate the rate of surgical site infection (SSI) in Mohs surgery patients using clean surgical technique versus sterile technique for "all steps of MMS [Mohs micrographic surgery], including wound reconstruction, in the absence of prophylactic antibiotics."

The researchers evaluated 1,000 patients undergoing MMS using clean technique, which included the use of clean (vs. sterile) gloves, clean (vs. sterile) towels, and a "single pack" of sterile instruments for the entire wound reconstruction.

Infection was classified according to the Centers for Disease Control and Prevention parameters: A site was considered infected if it expressed purulent discharge, if it displayed edema or erythema, and if the patient complained of pain or tenderness at the site.

"There were 11 infections in 1,000 patients with 1,204 tumors," said Dr. Rogers, for an infection rate of 0.91%. Three of the infections were complications of hematomas.

"Our SSI rate of 0.91% is extremely low," she said, "underscoring the overall safety of MMS and its performance in the outpatient setting without the use of antibiotic prophylaxis or sterile technique."

The second study was presented by Dr. Yang Xia of the division of Mohs surgery at the Scripps Clinic, La Jolla, Calif. Dr. Xia conducted a prospective, subject-blinded pilot study of 60 patients at the clinic to assess the difference in infection rate between clean, nonsterile gloves and sterile gloves for the repair of surgical defects in MMS.

"Clean gloves were used for all patients in the tumor removal phase," said Dr. Xia.

After tumors were removed, patients were randomized to repair with either clean or sterile gloves. A total of 30 patients were enrolled in each arm. Sterile paper and trays were used during all repairs. The mean age of the clean group was 69 years (26 men); the mean age of the sterile group was 74 years (28 men). Patients were excluded from the study if they were taking antibiotics at the time of the procedure or if they had any serious comorbidities, such as HIV.

After surgery, patients were followed up for 5-21 days, and the wounds were assessed by a nurse or assistant who was not affiliated with the study.
In the clean group, there was one SSI, in a 67-year-old man who cultured positive for methicillin-susceptible Staphylococcus aureus (MSSA). He was prescribed cephalexin.

In the sterile group, there were two SSIs: one case of MSSA, which was treated with cephalexin and resolved, and one case of methicillin-resistant Staphylococcus aureus (MRSA), which resolved with administration of Septra (trimethoprim and sulfamethoxazole) twice a day for 14 days.

Given the equally low rates of infection in the two study arms, the potential cost-savings of switching from sterile to clean gloves for these procedures could be tremendous, Dr. Xia said. One online search put the cost of a box of 100 clean gloves at $4-$9, although Dr. Xia gave a figure of $4-$29 for a box of 150 gloves. In contrast, a box of 100 sterile surgical gloves costs $74-$250, according to Dr. Xia. (A separate online search found a box of 100 sterile gloves available for $45-$275.)

Depending on the annual volume of a surgeon's cases, switching from sterile to clean gloves could save $6,000 to $20,000 a year, Dr. Xia estimated.

Dr. Rogers and Dr. Xia said they had no disclosures to make in relation to their presentations.

CHICAGO — A high degree of concordance of oral human papilloma virus infection between HPV-positive patients with oropharynx cancer and their sexual partners suggests that partners are at high risk for HPV-related disease, according to a study from the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators reported that HPV was transmitted between HPV+ patients with oropharynx cancer and their sexual partners at a rate approaching 70%. Almost 60% of these cases involved HPV 16, a causative agent in head and neck squamous cell carcinoma, specifically tonsil cancer, as well as in most cervical malignant and premalignant conditions.

"There was a high rate of human papilloma virus transmission between oropharynx cancer (OPC) patients with HPV+ mouth swabs and their spouses or partners," commented first author Dr. Vassiliki Papadimitrakopoulou, a professor in the department of thoracic/head and neck medical oncology at M.D. Anderson. The study was presented as a poster at the annual meeting of the American Society of Clinical Oncology.

Human papilloma virus transmission between sexual partners is well documented in cervical cancer, but not in head and neck squamous cell carcinoma. Investigators thought that information on transmission could help define a population that would benefit from heightened cancer screening and vaccination.

"HPV-related OPC occurs in a younger group of patients than does the tobacco-related squamous cell cancer of the head and neck," noted Dr. Anne Tsao, the study's principal investigator from the same department at M.D. Anderson.

The authors used mouth swabs to gather DNA from 454 individuals, comprising 227 pairs of oropharynx cancer patients and their partners. Samples from 200 patient-partner pairs yielded adequate DNA for analysis, and this was the minimum required to meet the study’s planned accrual.

In situ hybridization and/or p16 immunohistochemistry detected HPV in 84 (86%) of 98 patients, for whom complete information on HPV status in tumor tissue was available at the time of the presentation. Not all of these cases resulted in positive mouth swabs, however.

Of the 200 patient-partner pairs, only 39 pairs (20%) had one or both members with a mouth swab testing positive for HPV. In 28 of these 39 pairs (72%), the mouth swab was positive in patients, and in 19 of these 28 (68%) the partners also had positive mouth swabs. The investigators reported 100% concordance for at least one human papilloma virus genotype in these 19 pairs, confirming that the virus had been exchanged between the partners; 58% of transmission cases involved HPV-16.

In 11 of the 39 pairs, the patient with oropharynx cancer tested negative for HPV, whereas the partner tested positive.

Regardless of HPV status as determined by mouth swabs, 30% of female partners but none of the men in the study reported a history of HPV-related disease. The investigators observed that this generates a hypothesis "that HPV affects the cervix at an earlier age than it does the oropharynx, and that gender may have a role in oncogenic susceptibility and/or chronic transmission of the virus." The data "encourage" screening of female partners and HPV+ female patients for cervical abnormalities, they advised.

"We recommend increased screening of partners of human papilloma virus positive patients in general," said Dr. Papadimitrakopoulou. She cautioned, however: "We don't know that the mouth swab is an adequate screening method."

In a discussion of the study, Anil Chaturvedi, D.V.M., Ph.D, an investigator at the National Cancer Institute, observed, "We know that oral HPV infection is a strong cause of a subset of head and neck cancers [but] very little is currently known about the molecular epidemiology of human papilloma virus infections ... [this study] showed that oral human papilloma virus infection was highly concordant among human papilloma virus-positive patients and their partners. The study underscores the partner population as an ideal high-risk population to perhaps investigate the presence of a premalignant lesion."

Dr. Chaturvedi also expressed concern about the low sensitivity of mouth swabs as a test for HPV, however. "I'd like to note a potential limitation of this particular study, which relates to the low sensitivity of mouth swabs in detecting oral HPV infection, as evidenced by the low percent positive agreement between tumor HPV status and the presence of HPV in oral swabs," he said.

The investigators and the discussant disclosed no relevant relationships. The National Cancer Institute funded the study.

CHICAGO — A high degree of concordance of oral human papilloma virus infection between HPV-positive patients with oropharynx cancer and their sexual partners suggests that partners are at high risk for HPV-related disease, according to a study from the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators reported that HPV was transmitted between HPV+ patients with oropharynx cancer and their sexual partners at a rate approaching 70%. Almost 60% of these cases involved HPV 16, a causative agent in head and neck squamous cell carcinoma, specifically tonsil cancer, as well as in most cervical malignant and premalignant conditions.

"There was a high rate of human papilloma virus transmission between oropharynx cancer (OPC) patients with HPV+ mouth swabs and their spouses or partners," commented first author Dr. Vassiliki Papadimitrakopoulou, a professor in the department of thoracic/head and neck medical oncology at M.D. Anderson. The study was presented as a poster at the annual meeting of the American Society of Clinical Oncology.

Human papilloma virus transmission between sexual partners is well documented in cervical cancer, but not in head and neck squamous cell carcinoma. Investigators thought that information on transmission could help define a population that would benefit from heightened cancer screening and vaccination.

"HPV-related OPC occurs in a younger group of patients than does the tobacco-related squamous cell cancer of the head and neck," noted Dr. Anne Tsao, the study's principal investigator from the same department at M.D. Anderson.

The authors used mouth swabs to gather DNA from 454 individuals, comprising 227 pairs of oropharynx cancer patients and their partners. Samples from 200 patient-partner pairs yielded adequate DNA for analysis, and this was the minimum required to meet the study’s planned accrual.

In situ hybridization and/or p16 immunohistochemistry detected HPV in 84 (86%) of 98 patients, for whom complete information on HPV status in tumor tissue was available at the time of the presentation. Not all of these cases resulted in positive mouth swabs, however.

Of the 200 patient-partner pairs, only 39 pairs (20%) had one or both members with a mouth swab testing positive for HPV. In 28 of these 39 pairs (72%), the mouth swab was positive in patients, and in 19 of these 28 (68%) the partners also had positive mouth swabs. The investigators reported 100% concordance for at least one human papilloma virus genotype in these 19 pairs, confirming that the virus had been exchanged between the partners; 58% of transmission cases involved HPV-16.

In 11 of the 39 pairs, the patient with oropharynx cancer tested negative for HPV, whereas the partner tested positive.

Regardless of HPV status as determined by mouth swabs, 30% of female partners but none of the men in the study reported a history of HPV-related disease. The investigators observed that this generates a hypothesis "that HPV affects the cervix at an earlier age than it does the oropharynx, and that gender may have a role in oncogenic susceptibility and/or chronic transmission of the virus." The data "encourage" screening of female partners and HPV+ female patients for cervical abnormalities, they advised.

"We recommend increased screening of partners of human papilloma virus positive patients in general," said Dr. Papadimitrakopoulou. She cautioned, however: "We don't know that the mouth swab is an adequate screening method."

In a discussion of the study, Anil Chaturvedi, D.V.M., Ph.D, an investigator at the National Cancer Institute, observed, "We know that oral HPV infection is a strong cause of a subset of head and neck cancers [but] very little is currently known about the molecular epidemiology of human papilloma virus infections ... [this study] showed that oral human papilloma virus infection was highly concordant among human papilloma virus-positive patients and their partners. The study underscores the partner population as an ideal high-risk population to perhaps investigate the presence of a premalignant lesion."

Dr. Chaturvedi also expressed concern about the low sensitivity of mouth swabs as a test for HPV, however. "I'd like to note a potential limitation of this particular study, which relates to the low sensitivity of mouth swabs in detecting oral HPV infection, as evidenced by the low percent positive agreement between tumor HPV status and the presence of HPV in oral swabs," he said.

The investigators and the discussant disclosed no relevant relationships. The National Cancer Institute funded the study.

CHICAGO — A high degree of concordance of oral human papilloma virus infection between HPV-positive patients with oropharynx cancer and their sexual partners suggests that partners are at high risk for HPV-related disease, according to a study from the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators reported that HPV was transmitted between HPV+ patients with oropharynx cancer and their sexual partners at a rate approaching 70%. Almost 60% of these cases involved HPV 16, a causative agent in head and neck squamous cell carcinoma, specifically tonsil cancer, as well as in most cervical malignant and premalignant conditions.

"There was a high rate of human papilloma virus transmission between oropharynx cancer (OPC) patients with HPV+ mouth swabs and their spouses or partners," commented first author Dr. Vassiliki Papadimitrakopoulou, a professor in the department of thoracic/head and neck medical oncology at M.D. Anderson. The study was presented as a poster at the annual meeting of the American Society of Clinical Oncology.

Human papilloma virus transmission between sexual partners is well documented in cervical cancer, but not in head and neck squamous cell carcinoma. Investigators thought that information on transmission could help define a population that would benefit from heightened cancer screening and vaccination.

"HPV-related OPC occurs in a younger group of patients than does the tobacco-related squamous cell cancer of the head and neck," noted Dr. Anne Tsao, the study's principal investigator from the same department at M.D. Anderson.

The authors used mouth swabs to gather DNA from 454 individuals, comprising 227 pairs of oropharynx cancer patients and their partners. Samples from 200 patient-partner pairs yielded adequate DNA for analysis, and this was the minimum required to meet the study’s planned accrual.

In situ hybridization and/or p16 immunohistochemistry detected HPV in 84 (86%) of 98 patients, for whom complete information on HPV status in tumor tissue was available at the time of the presentation. Not all of these cases resulted in positive mouth swabs, however.

Of the 200 patient-partner pairs, only 39 pairs (20%) had one or both members with a mouth swab testing positive for HPV. In 28 of these 39 pairs (72%), the mouth swab was positive in patients, and in 19 of these 28 (68%) the partners also had positive mouth swabs. The investigators reported 100% concordance for at least one human papilloma virus genotype in these 19 pairs, confirming that the virus had been exchanged between the partners; 58% of transmission cases involved HPV-16.

In 11 of the 39 pairs, the patient with oropharynx cancer tested negative for HPV, whereas the partner tested positive.

Regardless of HPV status as determined by mouth swabs, 30% of female partners but none of the men in the study reported a history of HPV-related disease. The investigators observed that this generates a hypothesis "that HPV affects the cervix at an earlier age than it does the oropharynx, and that gender may have a role in oncogenic susceptibility and/or chronic transmission of the virus." The data "encourage" screening of female partners and HPV+ female patients for cervical abnormalities, they advised.

"We recommend increased screening of partners of human papilloma virus positive patients in general," said Dr. Papadimitrakopoulou. She cautioned, however: "We don't know that the mouth swab is an adequate screening method."

In a discussion of the study, Anil Chaturvedi, D.V.M., Ph.D, an investigator at the National Cancer Institute, observed, "We know that oral HPV infection is a strong cause of a subset of head and neck cancers [but] very little is currently known about the molecular epidemiology of human papilloma virus infections ... [this study] showed that oral human papilloma virus infection was highly concordant among human papilloma virus-positive patients and their partners. The study underscores the partner population as an ideal high-risk population to perhaps investigate the presence of a premalignant lesion."

Dr. Chaturvedi also expressed concern about the low sensitivity of mouth swabs as a test for HPV, however. "I'd like to note a potential limitation of this particular study, which relates to the low sensitivity of mouth swabs in detecting oral HPV infection, as evidenced by the low percent positive agreement between tumor HPV status and the presence of HPV in oral swabs," he said.

The investigators and the discussant disclosed no relevant relationships. The National Cancer Institute funded the study.

MONTEREY, Calif. — Stainless steel embedding wells may be the best of several mechanisms available to flatten or “conform” tissue specimens for sectioning in Mohs surgery, in one expert’s opinion.

Sectioning of the peripheral/epidermal margin of the lesion is essential for Mohs surgery to ensure complete margin assessment. Most Mohs surgeons require that 90% or more of the epidermis be present to feel that they’re assessing an adequate epidermal margin, Dr. David F. Butler explained at a meeting of the American Society for Mohs Surgery.

Photo courtesy Dr. David F. Butler

Only two mechanisms can flatten multiple tissue specimens at once: the $20,000 CryoHist machine, or the $529 stainless steel embedding wells, said Dr. Butler, chair of dermatology at the Scott and White Hospital and Clinic and professor of medicine at Texas A&M University, both in Temple, Tex.

Lower cost, convenience, and quality results make him a fan of the stainless steel embedding wells, which consist of 1-inch steel bars with wells cut out in different sizes and depths. The bars reside within a cryostat, which provides a heat sink for the rapid freezing of the specimen.

The surgeon or other operator places a specimen facedown on the smooth surface of a well and presses down on the peripheral edge of the specimen with a gloved finger. “Like putting your tongue to a cold flagpole in Wisconsin in winter, it sticks,” he said.

Optimal cutting temperature (OCT) compound—a cryopreservation medium—is then applied over the specimen, and a metal chuck with a cross-grid pattern to better hold onto frozen OCT is applied to the OCT. A freezing block that’s been kept cold within the cryostat can be placed over the stem of the chuck to freeze the specimen more quickly.

As Dr. Butler described it, one of the sets includes one freezing bar with a 24-mm well, a 36-mm chuck, and the overchuck freezing block. He described the complete set as three bars with different well sizes, six small chucks, four large chucks, four overchuck freezing blocks, a chuck bin, an elevated embedding block, and angled freezing forceps.

The stainless steel embedding wells are available from Dr. Stephen R. Peters, the pathologist who designed them, Dr. Butler said. Dr. Peters is at Hackensack (N.J.) University Medical Center and can be reached through his Web site or via e-mail.

In using the stainless steel embedding wells for seven consecutive specimens, Dr. Butler found that five of the seven specimens (71%) met the goal of having more than 90% of the epidermis present by the sixth retained section.

He compared the time needed to freeze a specimen and mount the block using several mechanisms. It took 105 seconds with the embedding wells, 56 seconds with the CryoHist, 68 seconds with the Miami Special, and 91 seconds with the Cryocup. Only the embedding wells and CryoHist could freeze and mount multiple specimens at the same time “so the overall process doesn’t take very long,” he said.

The CryoHist is a large machine, plumbed for liquid nitrogen that flattens specimens via a vacuum suction. Compared with embedding wells, its disadvantages include the high cost and the need for greater space, external power and liquid nitrogen, and consumables such as a plastic film that is used in the process, Dr. Butler said.

The Miami Special is a long-handled clamp with flat metal plates at the end on which partially frozen OCT and a chuck are placed. The specimen is placed on the OCT and the clamp is closed and dipped in liquid nitrogen to freeze. “The problem is that it’s very cumbersome and can only do one at a time,” he said.

The Davidson Cryocup is a metal device with a long handle and a cup at one end in which tissue is placed facedown and covered with OCT and a chuck. The cup is lowered into liquid nitrogen to freeze. “It has the same problem as the Miami Special: You can only process one specimen at a time,” he said.

Other mechanisms include the inexpensive cryomold, small plastic trays of different sizes and depths on which specimens are placed facedown and covered with OCT and a chuck before placement in a cryostat. The plastic cryomold is peeled back before sectioning, one specimen at a time.

An older technique employs a heat extractor that resides within some cryostats and remains cold. A chuck is placed on the rack within the cryostat, OCT is applied, and the specimen is placed “deep side up” on the OCT, he said. A cold round bar of the heat extractor is pressed down on the specimen and OCT until frozen.

Dr. Butler said he has no pertinent conflicts of interest.

MONTEREY, Calif. — Stainless steel embedding wells may be the best of several mechanisms available to flatten or “conform” tissue specimens for sectioning in Mohs surgery, in one expert’s opinion.

Sectioning of the peripheral/epidermal margin of the lesion is essential for Mohs surgery to ensure complete margin assessment. Most Mohs surgeons require that 90% or more of the epidermis be present to feel that they’re assessing an adequate epidermal margin, Dr. David F. Butler explained at a meeting of the American Society for Mohs Surgery.

Photo courtesy Dr. David F. Butler

Only two mechanisms can flatten multiple tissue specimens at once: the $20,000 CryoHist machine, or the $529 stainless steel embedding wells, said Dr. Butler, chair of dermatology at the Scott and White Hospital and Clinic and professor of medicine at Texas A&M University, both in Temple, Tex.

Lower cost, convenience, and quality results make him a fan of the stainless steel embedding wells, which consist of 1-inch steel bars with wells cut out in different sizes and depths. The bars reside within a cryostat, which provides a heat sink for the rapid freezing of the specimen.

The surgeon or other operator places a specimen facedown on the smooth surface of a well and presses down on the peripheral edge of the specimen with a gloved finger. “Like putting your tongue to a cold flagpole in Wisconsin in winter, it sticks,” he said.

Optimal cutting temperature (OCT) compound—a cryopreservation medium—is then applied over the specimen, and a metal chuck with a cross-grid pattern to better hold onto frozen OCT is applied to the OCT. A freezing block that’s been kept cold within the cryostat can be placed over the stem of the chuck to freeze the specimen more quickly.

As Dr. Butler described it, one of the sets includes one freezing bar with a 24-mm well, a 36-mm chuck, and the overchuck freezing block. He described the complete set as three bars with different well sizes, six small chucks, four large chucks, four overchuck freezing blocks, a chuck bin, an elevated embedding block, and angled freezing forceps.

The stainless steel embedding wells are available from Dr. Stephen R. Peters, the pathologist who designed them, Dr. Butler said. Dr. Peters is at Hackensack (N.J.) University Medical Center and can be reached through his Web site or via e-mail.

In using the stainless steel embedding wells for seven consecutive specimens, Dr. Butler found that five of the seven specimens (71%) met the goal of having more than 90% of the epidermis present by the sixth retained section.

He compared the time needed to freeze a specimen and mount the block using several mechanisms. It took 105 seconds with the embedding wells, 56 seconds with the CryoHist, 68 seconds with the Miami Special, and 91 seconds with the Cryocup. Only the embedding wells and CryoHist could freeze and mount multiple specimens at the same time “so the overall process doesn’t take very long,” he said.

The CryoHist is a large machine, plumbed for liquid nitrogen that flattens specimens via a vacuum suction. Compared with embedding wells, its disadvantages include the high cost and the need for greater space, external power and liquid nitrogen, and consumables such as a plastic film that is used in the process, Dr. Butler said.

The Miami Special is a long-handled clamp with flat metal plates at the end on which partially frozen OCT and a chuck are placed. The specimen is placed on the OCT and the clamp is closed and dipped in liquid nitrogen to freeze. “The problem is that it’s very cumbersome and can only do one at a time,” he said.

The Davidson Cryocup is a metal device with a long handle and a cup at one end in which tissue is placed facedown and covered with OCT and a chuck. The cup is lowered into liquid nitrogen to freeze. “It has the same problem as the Miami Special: You can only process one specimen at a time,” he said.

Other mechanisms include the inexpensive cryomold, small plastic trays of different sizes and depths on which specimens are placed facedown and covered with OCT and a chuck before placement in a cryostat. The plastic cryomold is peeled back before sectioning, one specimen at a time.

An older technique employs a heat extractor that resides within some cryostats and remains cold. A chuck is placed on the rack within the cryostat, OCT is applied, and the specimen is placed “deep side up” on the OCT, he said. A cold round bar of the heat extractor is pressed down on the specimen and OCT until frozen.

Dr. Butler said he has no pertinent conflicts of interest.

MONTEREY, Calif. — Stainless steel embedding wells may be the best of several mechanisms available to flatten or “conform” tissue specimens for sectioning in Mohs surgery, in one expert’s opinion.

Sectioning of the peripheral/epidermal margin of the lesion is essential for Mohs surgery to ensure complete margin assessment. Most Mohs surgeons require that 90% or more of the epidermis be present to feel that they’re assessing an adequate epidermal margin, Dr. David F. Butler explained at a meeting of the American Society for Mohs Surgery.

Photo courtesy Dr. David F. Butler

Only two mechanisms can flatten multiple tissue specimens at once: the $20,000 CryoHist machine, or the $529 stainless steel embedding wells, said Dr. Butler, chair of dermatology at the Scott and White Hospital and Clinic and professor of medicine at Texas A&M University, both in Temple, Tex.

Lower cost, convenience, and quality results make him a fan of the stainless steel embedding wells, which consist of 1-inch steel bars with wells cut out in different sizes and depths. The bars reside within a cryostat, which provides a heat sink for the rapid freezing of the specimen.

The surgeon or other operator places a specimen facedown on the smooth surface of a well and presses down on the peripheral edge of the specimen with a gloved finger. “Like putting your tongue to a cold flagpole in Wisconsin in winter, it sticks,” he said.

Optimal cutting temperature (OCT) compound—a cryopreservation medium—is then applied over the specimen, and a metal chuck with a cross-grid pattern to better hold onto frozen OCT is applied to the OCT. A freezing block that’s been kept cold within the cryostat can be placed over the stem of the chuck to freeze the specimen more quickly.

As Dr. Butler described it, one of the sets includes one freezing bar with a 24-mm well, a 36-mm chuck, and the overchuck freezing block. He described the complete set as three bars with different well sizes, six small chucks, four large chucks, four overchuck freezing blocks, a chuck bin, an elevated embedding block, and angled freezing forceps.

The stainless steel embedding wells are available from Dr. Stephen R. Peters, the pathologist who designed them, Dr. Butler said. Dr. Peters is at Hackensack (N.J.) University Medical Center and can be reached through his Web site or via e-mail.

In using the stainless steel embedding wells for seven consecutive specimens, Dr. Butler found that five of the seven specimens (71%) met the goal of having more than 90% of the epidermis present by the sixth retained section.

He compared the time needed to freeze a specimen and mount the block using several mechanisms. It took 105 seconds with the embedding wells, 56 seconds with the CryoHist, 68 seconds with the Miami Special, and 91 seconds with the Cryocup. Only the embedding wells and CryoHist could freeze and mount multiple specimens at the same time “so the overall process doesn’t take very long,” he said.

The CryoHist is a large machine, plumbed for liquid nitrogen that flattens specimens via a vacuum suction. Compared with embedding wells, its disadvantages include the high cost and the need for greater space, external power and liquid nitrogen, and consumables such as a plastic film that is used in the process, Dr. Butler said.

The Miami Special is a long-handled clamp with flat metal plates at the end on which partially frozen OCT and a chuck are placed. The specimen is placed on the OCT and the clamp is closed and dipped in liquid nitrogen to freeze. “The problem is that it’s very cumbersome and can only do one at a time,” he said.

The Davidson Cryocup is a metal device with a long handle and a cup at one end in which tissue is placed facedown and covered with OCT and a chuck. The cup is lowered into liquid nitrogen to freeze. “It has the same problem as the Miami Special: You can only process one specimen at a time,” he said.

Other mechanisms include the inexpensive cryomold, small plastic trays of different sizes and depths on which specimens are placed facedown and covered with OCT and a chuck before placement in a cryostat. The plastic cryomold is peeled back before sectioning, one specimen at a time.

An older technique employs a heat extractor that resides within some cryostats and remains cold. A chuck is placed on the rack within the cryostat, OCT is applied, and the specimen is placed “deep side up” on the OCT, he said. A cold round bar of the heat extractor is pressed down on the specimen and OCT until frozen.

Dr. Butler said he has no pertinent conflicts of interest.

CHICAGO – The novel cytokine interleukin-21 has shown itself to be biologically active with an overall response rate of 22% in first-line metastatic melanoma patients.

Median progression-free survival reached 4.32 months in the phase II, multicenter IND 189 trial involving 40 patients, Dr. Teresa Petrella reported on behalf of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG).

This finding held up well when it was benchmarked against the widely cited Korn meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma (J. Clin. Oncol. 2008;26:527-34) and 68 historical NCIC CTG melanoma patients who matched the IND 189 study entry criteria. Median progression-free survival was 1.31 months in the Korn analysis and 1.58 months for the NCIC CTG patients, said Dr. Petrella of the Odette Cancer Centre in Toronto.

Age, performance status, and interleukin-21 (IL-21) treatment were significant predictors of progression-free survival in a multivariate analysis among IL-21–treated patients and historical controls that adjusted for prognostic factors.

Based on the findings, study sponsor ZymoGenetics Inc. is planning a phase IIB randomized trial with the NCIC CTG to validate the results, Dr. Petrella said.

Invited discussant Dr. Antoni Ribas of the University of California, Los Angeles, said the response rate was very respectable for a single-agent cytokine in previously untreated metastatic melanoma. The caveat is that the responses seem to be of limited duration.

Nine patients had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors) and CT for the objective response rate of 22.5% and median duration of 5.0 months. In all, 16 patients (40%) had stable disease for a median duration of 5.3 months.

“Two patients had a tail of 1.5 years of progression-free survival, but there was no clear evidence that most of the responses were durable, which questions if this is a memory T-cell response or maybe more of an innate response,” said Dr. Ribas. “I hope that further clinical investigation will address this question.”

IL-21 is a novel cytokine that has multiple immunomodulatory effects including beneficial effects on B cells, natural killer cells, and T cells, in particular CD4 and CD8 T cells. In two phase I, dose-escalation studies of IL-21 in metastatic melanoma, there was evidence of tumor response and immune activation with an eightfold increase in soluble CD25, reflecting lymphocyte activation (J. Clin. Oncol. 2008;26:2034-9; Clin. Cancer Res. 2007;13:3630-6).

The majority of patients in the IND 189 trial received IL-21 30 mcg/kg per day for 5 days on the first, third, and fifth weeks of an 8-week schedule, after dose-limiting toxicities were observed at higher, more frequent dosing.

Overall, IL-21 was well tolerated, with most adverse events being grade 1/2, Dr. Petrella said. The most common of these were fatigue, rash, fever, myalgia, anorexia, chills, and nausea, which were very similar to what was seen in the phase I studies. Seven patients experienced grade 3 rash.

Nine serious adverse events were reported, of which four were possibly, probably, or definitely treatment related. They included one infection with grade 4 neutropenia, two grade 4 liver enzyme elevations, and one second malignancy (acute myeloid leukemia) that occurred 11 months after the patient received only 5 days of interleukin-21 and thus was most likely not related to the treatment, she said.

Most patients had an Eastern Cooperative Oncology Group performance status of 0, 17 had received prior adjuvant immunotherapy with interferon, and 32 had metastases to the lung. Their median age was 56 years. Responses were seen in all sites of disease, and patients continue to be followed.

ZymoGenetics Inc. provided research funds and employs one of the researchers. Dr. Ribas reports honoraria from Amgen Inc. and Roche.

CHICAGO – The novel cytokine interleukin-21 has shown itself to be biologically active with an overall response rate of 22% in first-line metastatic melanoma patients.

Median progression-free survival reached 4.32 months in the phase II, multicenter IND 189 trial involving 40 patients, Dr. Teresa Petrella reported on behalf of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG).

This finding held up well when it was benchmarked against the widely cited Korn meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma (J. Clin. Oncol. 2008;26:527-34) and 68 historical NCIC CTG melanoma patients who matched the IND 189 study entry criteria. Median progression-free survival was 1.31 months in the Korn analysis and 1.58 months for the NCIC CTG patients, said Dr. Petrella of the Odette Cancer Centre in Toronto.

Age, performance status, and interleukin-21 (IL-21) treatment were significant predictors of progression-free survival in a multivariate analysis among IL-21–treated patients and historical controls that adjusted for prognostic factors.

Based on the findings, study sponsor ZymoGenetics Inc. is planning a phase IIB randomized trial with the NCIC CTG to validate the results, Dr. Petrella said.

Invited discussant Dr. Antoni Ribas of the University of California, Los Angeles, said the response rate was very respectable for a single-agent cytokine in previously untreated metastatic melanoma. The caveat is that the responses seem to be of limited duration.

Nine patients had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors) and CT for the objective response rate of 22.5% and median duration of 5.0 months. In all, 16 patients (40%) had stable disease for a median duration of 5.3 months.

“Two patients had a tail of 1.5 years of progression-free survival, but there was no clear evidence that most of the responses were durable, which questions if this is a memory T-cell response or maybe more of an innate response,” said Dr. Ribas. “I hope that further clinical investigation will address this question.”

IL-21 is a novel cytokine that has multiple immunomodulatory effects including beneficial effects on B cells, natural killer cells, and T cells, in particular CD4 and CD8 T cells. In two phase I, dose-escalation studies of IL-21 in metastatic melanoma, there was evidence of tumor response and immune activation with an eightfold increase in soluble CD25, reflecting lymphocyte activation (J. Clin. Oncol. 2008;26:2034-9; Clin. Cancer Res. 2007;13:3630-6).

The majority of patients in the IND 189 trial received IL-21 30 mcg/kg per day for 5 days on the first, third, and fifth weeks of an 8-week schedule, after dose-limiting toxicities were observed at higher, more frequent dosing.

Overall, IL-21 was well tolerated, with most adverse events being grade 1/2, Dr. Petrella said. The most common of these were fatigue, rash, fever, myalgia, anorexia, chills, and nausea, which were very similar to what was seen in the phase I studies. Seven patients experienced grade 3 rash.

Nine serious adverse events were reported, of which four were possibly, probably, or definitely treatment related. They included one infection with grade 4 neutropenia, two grade 4 liver enzyme elevations, and one second malignancy (acute myeloid leukemia) that occurred 11 months after the patient received only 5 days of interleukin-21 and thus was most likely not related to the treatment, she said.

Most patients had an Eastern Cooperative Oncology Group performance status of 0, 17 had received prior adjuvant immunotherapy with interferon, and 32 had metastases to the lung. Their median age was 56 years. Responses were seen in all sites of disease, and patients continue to be followed.

ZymoGenetics Inc. provided research funds and employs one of the researchers. Dr. Ribas reports honoraria from Amgen Inc. and Roche.

CHICAGO – The novel cytokine interleukin-21 has shown itself to be biologically active with an overall response rate of 22% in first-line metastatic melanoma patients.

Median progression-free survival reached 4.32 months in the phase II, multicenter IND 189 trial involving 40 patients, Dr. Teresa Petrella reported on behalf of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG).

This finding held up well when it was benchmarked against the widely cited Korn meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma (J. Clin. Oncol. 2008;26:527-34) and 68 historical NCIC CTG melanoma patients who matched the IND 189 study entry criteria. Median progression-free survival was 1.31 months in the Korn analysis and 1.58 months for the NCIC CTG patients, said Dr. Petrella of the Odette Cancer Centre in Toronto.

Age, performance status, and interleukin-21 (IL-21) treatment were significant predictors of progression-free survival in a multivariate analysis among IL-21–treated patients and historical controls that adjusted for prognostic factors.

Based on the findings, study sponsor ZymoGenetics Inc. is planning a phase IIB randomized trial with the NCIC CTG to validate the results, Dr. Petrella said.

Invited discussant Dr. Antoni Ribas of the University of California, Los Angeles, said the response rate was very respectable for a single-agent cytokine in previously untreated metastatic melanoma. The caveat is that the responses seem to be of limited duration.

Nine patients had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors) and CT for the objective response rate of 22.5% and median duration of 5.0 months. In all, 16 patients (40%) had stable disease for a median duration of 5.3 months.

“Two patients had a tail of 1.5 years of progression-free survival, but there was no clear evidence that most of the responses were durable, which questions if this is a memory T-cell response or maybe more of an innate response,” said Dr. Ribas. “I hope that further clinical investigation will address this question.”

IL-21 is a novel cytokine that has multiple immunomodulatory effects including beneficial effects on B cells, natural killer cells, and T cells, in particular CD4 and CD8 T cells. In two phase I, dose-escalation studies of IL-21 in metastatic melanoma, there was evidence of tumor response and immune activation with an eightfold increase in soluble CD25, reflecting lymphocyte activation (J. Clin. Oncol. 2008;26:2034-9; Clin. Cancer Res. 2007;13:3630-6).

The majority of patients in the IND 189 trial received IL-21 30 mcg/kg per day for 5 days on the first, third, and fifth weeks of an 8-week schedule, after dose-limiting toxicities were observed at higher, more frequent dosing.

Overall, IL-21 was well tolerated, with most adverse events being grade 1/2, Dr. Petrella said. The most common of these were fatigue, rash, fever, myalgia, anorexia, chills, and nausea, which were very similar to what was seen in the phase I studies. Seven patients experienced grade 3 rash.

Nine serious adverse events were reported, of which four were possibly, probably, or definitely treatment related. They included one infection with grade 4 neutropenia, two grade 4 liver enzyme elevations, and one second malignancy (acute myeloid leukemia) that occurred 11 months after the patient received only 5 days of interleukin-21 and thus was most likely not related to the treatment, she said.

Most patients had an Eastern Cooperative Oncology Group performance status of 0, 17 had received prior adjuvant immunotherapy with interferon, and 32 had metastases to the lung. Their median age was 56 years. Responses were seen in all sites of disease, and patients continue to be followed.

ZymoGenetics Inc. provided research funds and employs one of the researchers. Dr. Ribas reports honoraria from Amgen Inc. and Roche.

CHICAGO – A string of disappointing melanoma trials from the Eastern Cooperative Oncology Group left some seeing the proverbial glass as half empty, others as half full in an oral abstract session at the annual meeting of the American Society for Clinical Oncology.

No Benefit from GM-CSF
Updated data from the E4697 phase III cooperative trial in resected stage III and IV melanoma show only a hint of benefit for granulocyte-macrophage colony-stimulating factor (GM-CSF) in the adjuvant setting. The study was unblinded in April 2009, and an analysis reported later that year showed a significant improvement in disease-free survival for GM-CSF vs. placebo (P = .03), but no difference in overall survival.

In the updated analysis, with 86% of full data reported, the difference in disease-free survival at 9.2 months in 375 patients who were given placebo and 11.5 months in 368 patients who received GM-CSF was no longer significant (P = .14), Dr. David Lawson said. Again, there was no difference in overall survival.

GM-CSF also had no significant effect on either survival outcome in HLA A2–positive patients who also received peptide vaccination, said Dr. Lawson of Emory University in Atlanta.

A subset analysis that was stratified by disease stage, however, showed that GM-CSF did significantly improve disease-free survival in 258 patients with stage IV disease (hazard ratio 0.74, P = .04) but not overall survival (HR 0.72, P = .07).

Dr. Lawson said the data are worthy of further investigation and discussion. Invited discussant Dr. Michael S. Sabel of the University of Michigan in Ann Arbor said he is more skeptical, and would only go so far as to say that “you can’t take away the fact that there is some sort of immunologic effect potentially to these cytokines.”

Outcome Unchanged by Helper Peptides
Adding melanoma helper peptides to a multiepitope melanoma vaccination stimulated CD4+ and CD8+ T-cell responses, but did little to improve clinical outcome in the four-arm, phase II E1602 trial.

Patients with stage IV melanoma were vaccinated with 12 class I restricted melanoma peptides (arm A), plus either a tetanus peptide (arm B) or a mixture of six class II melanoma helper peptides (arm C), or with six class II melanoma helper peptides alone. Arm C was stopped early because of a lack of clinical response or disease stabilization.

The best overall response was partial response in 4% of 136 evaluable patients, said Dr. Craig L. Slingluff Jr., head of the surgical oncology division at the University of Virginia in Charlottesville. After a median follow-up of 21.4 months, median overall survival was 11.4 months, with no statistical differences between groups.

The trial can be viewed in two ways: as a success because it met the primary end point of stimulating T cells, but also as a requiem for peptide vaccines because “despite creating this army of antigen-specific T cells, the tumor continues to progress in the great majority of patients,” said invited discussant Dr. Antoni Ribas of the University of California, Los Angeles.

Adding Sorafenib Disappoints
There was little interpretation over the seventh and final analysis of the phase III E2603 trial of sorafenib (Nexavar) in combination with chemotherapy. Sorafenib does not improve overall survival, progression-free survival, or response rate when combined with carboplatin and paclitaxel in metastatic melanoma, reported Dr. Kevin Flaherty of Massachusetts General Hospital in Boston, who just 4 years ago set tongues wagging over sorafenib when he reported an 85% disease control rate in 105 melanoma patients.

Overall survival was 11.3 months, progression-free survival was 4.1 months, and the response rate was 16% with carboplatin/paclitaxel chemotherapy alone, compared with 11.1 months, 4.9 months, and 18%, respectively, for carboplatin/paclitaxel plus sorafenib. None of the differences was significantly different.

“There seem to be no additive effects, at least in melanoma,” said invited discussant Dr. Dirk Schadendorf, director of dermatology at University Hospital Essen (Germany). “What we have learned from the combination with chemotherapy, especially with carboplatin and paclitaxel, is that the progression-free survival time is around 4-5 months, which is interesting in patients who have rapid tumor progression and where you need a regimen to stop disease progression.”

Dr. Lawson reported a consultant/advisory role with Genzyme Corp. Dr. Slingluff reported a consultant/advisory role with and honoraria from Immatics Biotechnologies GmbH, research funding from Berlex Inc./Genzyme and GlaxoSmithKline, and other remuneration from the University of Virginia Patent Foundation. Dr. Ribas reported honoraria from Amgen Inc. and Roche. Dr. Flaherty disclosed no conflicts. Dr. Sabel reported a consultant/advisory role, honoraria, and research funding from Schering-Plough/Merck. Dr. Schadendorf disclosed consultant or advisory roles with AstraZeneca, Bristol-Myers Squibb Co., Plexxikon Inc., Roche, and Schering-Plough Corp., and research funding from Schering-Plough and Bayer-Schering.

CHICAGO – A string of disappointing melanoma trials from the Eastern Cooperative Oncology Group left some seeing the proverbial glass as half empty, others as half full in an oral abstract session at the annual meeting of the American Society for Clinical Oncology.

No Benefit from GM-CSF
Updated data from the E4697 phase III cooperative trial in resected stage III and IV melanoma show only a hint of benefit for granulocyte-macrophage colony-stimulating factor (GM-CSF) in the adjuvant setting. The study was unblinded in April 2009, and an analysis reported later that year showed a significant improvement in disease-free survival for GM-CSF vs. placebo (P = .03), but no difference in overall survival.

In the updated analysis, with 86% of full data reported, the difference in disease-free survival at 9.2 months in 375 patients who were given placebo and 11.5 months in 368 patients who received GM-CSF was no longer significant (P = .14), Dr. David Lawson said. Again, there was no difference in overall survival.

GM-CSF also had no significant effect on either survival outcome in HLA A2–positive patients who also received peptide vaccination, said Dr. Lawson of Emory University in Atlanta.

A subset analysis that was stratified by disease stage, however, showed that GM-CSF did significantly improve disease-free survival in 258 patients with stage IV disease (hazard ratio 0.74, P = .04) but not overall survival (HR 0.72, P = .07).

Dr. Lawson said the data are worthy of further investigation and discussion. Invited discussant Dr. Michael S. Sabel of the University of Michigan in Ann Arbor said he is more skeptical, and would only go so far as to say that “you can’t take away the fact that there is some sort of immunologic effect potentially to these cytokines.”

Outcome Unchanged by Helper Peptides
Adding melanoma helper peptides to a multiepitope melanoma vaccination stimulated CD4+ and CD8+ T-cell responses, but did little to improve clinical outcome in the four-arm, phase II E1602 trial.

Patients with stage IV melanoma were vaccinated with 12 class I restricted melanoma peptides (arm A), plus either a tetanus peptide (arm B) or a mixture of six class II melanoma helper peptides (arm C), or with six class II melanoma helper peptides alone. Arm C was stopped early because of a lack of clinical response or disease stabilization.

The best overall response was partial response in 4% of 136 evaluable patients, said Dr. Craig L. Slingluff Jr., head of the surgical oncology division at the University of Virginia in Charlottesville. After a median follow-up of 21.4 months, median overall survival was 11.4 months, with no statistical differences between groups.

The trial can be viewed in two ways: as a success because it met the primary end point of stimulating T cells, but also as a requiem for peptide vaccines because “despite creating this army of antigen-specific T cells, the tumor continues to progress in the great majority of patients,” said invited discussant Dr. Antoni Ribas of the University of California, Los Angeles.

Adding Sorafenib Disappoints
There was little interpretation over the seventh and final analysis of the phase III E2603 trial of sorafenib (Nexavar) in combination with chemotherapy. Sorafenib does not improve overall survival, progression-free survival, or response rate when combined with carboplatin and paclitaxel in metastatic melanoma, reported Dr. Kevin Flaherty of Massachusetts General Hospital in Boston, who just 4 years ago set tongues wagging over sorafenib when he reported an 85% disease control rate in 105 melanoma patients.

Overall survival was 11.3 months, progression-free survival was 4.1 months, and the response rate was 16% with carboplatin/paclitaxel chemotherapy alone, compared with 11.1 months, 4.9 months, and 18%, respectively, for carboplatin/paclitaxel plus sorafenib. None of the differences was significantly different.

“There seem to be no additive effects, at least in melanoma,” said invited discussant Dr. Dirk Schadendorf, director of dermatology at University Hospital Essen (Germany). “What we have learned from the combination with chemotherapy, especially with carboplatin and paclitaxel, is that the progression-free survival time is around 4-5 months, which is interesting in patients who have rapid tumor progression and where you need a regimen to stop disease progression.”

Dr. Lawson reported a consultant/advisory role with Genzyme Corp. Dr. Slingluff reported a consultant/advisory role with and honoraria from Immatics Biotechnologies GmbH, research funding from Berlex Inc./Genzyme and GlaxoSmithKline, and other remuneration from the University of Virginia Patent Foundation. Dr. Ribas reported honoraria from Amgen Inc. and Roche. Dr. Flaherty disclosed no conflicts. Dr. Sabel reported a consultant/advisory role, honoraria, and research funding from Schering-Plough/Merck. Dr. Schadendorf disclosed consultant or advisory roles with AstraZeneca, Bristol-Myers Squibb Co., Plexxikon Inc., Roche, and Schering-Plough Corp., and research funding from Schering-Plough and Bayer-Schering.

CHICAGO – A string of disappointing melanoma trials from the Eastern Cooperative Oncology Group left some seeing the proverbial glass as half empty, others as half full in an oral abstract session at the annual meeting of the American Society for Clinical Oncology.

No Benefit from GM-CSF
Updated data from the E4697 phase III cooperative trial in resected stage III and IV melanoma show only a hint of benefit for granulocyte-macrophage colony-stimulating factor (GM-CSF) in the adjuvant setting. The study was unblinded in April 2009, and an analysis reported later that year showed a significant improvement in disease-free survival for GM-CSF vs. placebo (P = .03), but no difference in overall survival.

In the updated analysis, with 86% of full data reported, the difference in disease-free survival at 9.2 months in 375 patients who were given placebo and 11.5 months in 368 patients who received GM-CSF was no longer significant (P = .14), Dr. David Lawson said. Again, there was no difference in overall survival.

GM-CSF also had no significant effect on either survival outcome in HLA A2–positive patients who also received peptide vaccination, said Dr. Lawson of Emory University in Atlanta.

A subset analysis that was stratified by disease stage, however, showed that GM-CSF did significantly improve disease-free survival in 258 patients with stage IV disease (hazard ratio 0.74, P = .04) but not overall survival (HR 0.72, P = .07).

Dr. Lawson said the data are worthy of further investigation and discussion. Invited discussant Dr. Michael S. Sabel of the University of Michigan in Ann Arbor said he is more skeptical, and would only go so far as to say that “you can’t take away the fact that there is some sort of immunologic effect potentially to these cytokines.”

Outcome Unchanged by Helper Peptides
Adding melanoma helper peptides to a multiepitope melanoma vaccination stimulated CD4+ and CD8+ T-cell responses, but did little to improve clinical outcome in the four-arm, phase II E1602 trial.

Patients with stage IV melanoma were vaccinated with 12 class I restricted melanoma peptides (arm A), plus either a tetanus peptide (arm B) or a mixture of six class II melanoma helper peptides (arm C), or with six class II melanoma helper peptides alone. Arm C was stopped early because of a lack of clinical response or disease stabilization.

The best overall response was partial response in 4% of 136 evaluable patients, said Dr. Craig L. Slingluff Jr., head of the surgical oncology division at the University of Virginia in Charlottesville. After a median follow-up of 21.4 months, median overall survival was 11.4 months, with no statistical differences between groups.

The trial can be viewed in two ways: as a success because it met the primary end point of stimulating T cells, but also as a requiem for peptide vaccines because “despite creating this army of antigen-specific T cells, the tumor continues to progress in the great majority of patients,” said invited discussant Dr. Antoni Ribas of the University of California, Los Angeles.

Adding Sorafenib Disappoints
There was little interpretation over the seventh and final analysis of the phase III E2603 trial of sorafenib (Nexavar) in combination with chemotherapy. Sorafenib does not improve overall survival, progression-free survival, or response rate when combined with carboplatin and paclitaxel in metastatic melanoma, reported Dr. Kevin Flaherty of Massachusetts General Hospital in Boston, who just 4 years ago set tongues wagging over sorafenib when he reported an 85% disease control rate in 105 melanoma patients.

Overall survival was 11.3 months, progression-free survival was 4.1 months, and the response rate was 16% with carboplatin/paclitaxel chemotherapy alone, compared with 11.1 months, 4.9 months, and 18%, respectively, for carboplatin/paclitaxel plus sorafenib. None of the differences was significantly different.

“There seem to be no additive effects, at least in melanoma,” said invited discussant Dr. Dirk Schadendorf, director of dermatology at University Hospital Essen (Germany). “What we have learned from the combination with chemotherapy, especially with carboplatin and paclitaxel, is that the progression-free survival time is around 4-5 months, which is interesting in patients who have rapid tumor progression and where you need a regimen to stop disease progression.”

Dr. Lawson reported a consultant/advisory role with Genzyme Corp. Dr. Slingluff reported a consultant/advisory role with and honoraria from Immatics Biotechnologies GmbH, research funding from Berlex Inc./Genzyme and GlaxoSmithKline, and other remuneration from the University of Virginia Patent Foundation. Dr. Ribas reported honoraria from Amgen Inc. and Roche. Dr. Flaherty disclosed no conflicts. Dr. Sabel reported a consultant/advisory role, honoraria, and research funding from Schering-Plough/Merck. Dr. Schadendorf disclosed consultant or advisory roles with AstraZeneca, Bristol-Myers Squibb Co., Plexxikon Inc., Roche, and Schering-Plough Corp., and research funding from Schering-Plough and Bayer-Schering.

CHICAGO — Percutaneous hepatic perfusion with melphalan improved local disease control, but not overall survival when compared with best available care in patients with ocular or cutaneous melanoma that had metastasized to the liver.

Chemoembolization is the standard of care in patients with hepatic metastases from ocular melanoma, a group that made up about 88% of the trial population. Systemic chemotherapy or immunotherapies do not appear to alter the natural history of the disease, which has a one-year survival of about 10%.

“Increased drug delivery achieved through novel regional therapeutic approaches may increase efficacy for a given agent (versus systemic administration) by overcoming a low therapeutic index,” said Dr. James Pingpank, Jr. who presented the late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

Forty-four patients were randomized to hepatic perfusion and 49 to best available care by the treating physician. More than half, 55%, of the control arm, crossed over to receive hepatic perfusion after hepatic progression.

High-dose melphalan at 3.0 mg/kg was infused into the hepatic artery via a percutaneously placed catheter with hepatic venous hemofiltration using a retrohepatic, double-balloon catheter and hemofiltration cartridges. Patients underwent 4 to 6 procedures at 28- to 35-day intervals.

The device and drug combination is under consideration by the Food and Drug Administration.

When compared with best available care, percutaneous hepatic perfusion increased median hepatic progression-free survival from 49 days to 245 days (hazard ratio 0.30, logrank P less than .0001), and overall progression-free survival from 46 days to 186 days (HR. 0.40, logrank P less than .0001).

No patients progressed while on hepatic perfusion with melphalan, and there were no differences in progression-free survival of ocular vs. cutaneous melanoma, said Dr. Pingpank of the University of Pittsburgh Hillman Cancer Center in Pittsburgh.

Median overall survival was similar at 301 days for best available care and 298 days for hepatic perfusion (HR 0.92, logrank P = .77). This was likely due to the high crossover rate, he said. When overall survival was examined in the control arm alone, it reached 398 days in patients who crossed over vs. 124 days for those who did not (logrank P = .0117).

Invited discussant Dr. Dirk Schadendorf, director of dermatology at University Hospital Essen in Essen, Germany, took issue with the high crossover rate and said a previous German trial (Br. J. Cancer 2002;87:840-5 also failed to show a significant survival advantage for intraarterial or IV fotemustine plus interferon-alpha and interleukin 2 in metastatic ocular melanoma.

“The clinical benefit besides local control is open and has not been answered by this trial,” he said. “The crossover in my view is a clear sign of bias and is not proving this treatment is of any benefit to the patient.”

Dr. Schadendorf said that additional relevant information is missing, such as the number of patients with liver-only metastases compared with other sites of metastasis, thus making it difficult to determine whether there is any potential patient imbalance between arms.

The most common therapy of the primary tumor was radiation in 52% of the experimental arm and 49% of the control arm, roughly 85% of patients had an ECOG performance status of 0, and their mean age was 55 years.

Expansion of the single-institution study to multiple centers proved safe and effective, Dr. Pingpank said. The most common grade 3/4 treatment-related toxicities in 40 evaluable patients receiving 116 perfusion treatments were thrombocytopenia (74%), neutropenia (61%), and anemia (47%). Three treatment-related deaths occurred, two due to neutropenic sepsis and one to hepatic failure.

Study sponsor Delcath Systems, Inc. provided melphalan and double-balloon catheters for the trial. The researchers disclosed serving on the scientific advisory board for and receiving research support from Delcath. Dr. Schadendorf disclosed honoraria or an advisory/consultancy role with AZD, Bristol-Myers Squibb, Plexxikon, Roche, Schering-Plough, and Bayer Schering Pharma.

CHICAGO — Percutaneous hepatic perfusion with melphalan improved local disease control, but not overall survival when compared with best available care in patients with ocular or cutaneous melanoma that had metastasized to the liver.

Chemoembolization is the standard of care in patients with hepatic metastases from ocular melanoma, a group that made up about 88% of the trial population. Systemic chemotherapy or immunotherapies do not appear to alter the natural history of the disease, which has a one-year survival of about 10%.

“Increased drug delivery achieved through novel regional therapeutic approaches may increase efficacy for a given agent (versus systemic administration) by overcoming a low therapeutic index,” said Dr. James Pingpank, Jr. who presented the late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

Forty-four patients were randomized to hepatic perfusion and 49 to best available care by the treating physician. More than half, 55%, of the control arm, crossed over to receive hepatic perfusion after hepatic progression.

High-dose melphalan at 3.0 mg/kg was infused into the hepatic artery via a percutaneously placed catheter with hepatic venous hemofiltration using a retrohepatic, double-balloon catheter and hemofiltration cartridges. Patients underwent 4 to 6 procedures at 28- to 35-day intervals.

The device and drug combination is under consideration by the Food and Drug Administration.

When compared with best available care, percutaneous hepatic perfusion increased median hepatic progression-free survival from 49 days to 245 days (hazard ratio 0.30, logrank P less than .0001), and overall progression-free survival from 46 days to 186 days (HR. 0.40, logrank P less than .0001).

No patients progressed while on hepatic perfusion with melphalan, and there were no differences in progression-free survival of ocular vs. cutaneous melanoma, said Dr. Pingpank of the University of Pittsburgh Hillman Cancer Center in Pittsburgh.

Median overall survival was similar at 301 days for best available care and 298 days for hepatic perfusion (HR 0.92, logrank P = .77). This was likely due to the high crossover rate, he said. When overall survival was examined in the control arm alone, it reached 398 days in patients who crossed over vs. 124 days for those who did not (logrank P = .0117).

Invited discussant Dr. Dirk Schadendorf, director of dermatology at University Hospital Essen in Essen, Germany, took issue with the high crossover rate and said a previous German trial (Br. J. Cancer 2002;87:840-5 also failed to show a significant survival advantage for intraarterial or IV fotemustine plus interferon-alpha and interleukin 2 in metastatic ocular melanoma.

“The clinical benefit besides local control is open and has not been answered by this trial,” he said. “The crossover in my view is a clear sign of bias and is not proving this treatment is of any benefit to the patient.”

Dr. Schadendorf said that additional relevant information is missing, such as the number of patients with liver-only metastases compared with other sites of metastasis, thus making it difficult to determine whether there is any potential patient imbalance between arms.

The most common therapy of the primary tumor was radiation in 52% of the experimental arm and 49% of the control arm, roughly 85% of patients had an ECOG performance status of 0, and their mean age was 55 years.

Expansion of the single-institution study to multiple centers proved safe and effective, Dr. Pingpank said. The most common grade 3/4 treatment-related toxicities in 40 evaluable patients receiving 116 perfusion treatments were thrombocytopenia (74%), neutropenia (61%), and anemia (47%). Three treatment-related deaths occurred, two due to neutropenic sepsis and one to hepatic failure.

Study sponsor Delcath Systems, Inc. provided melphalan and double-balloon catheters for the trial. The researchers disclosed serving on the scientific advisory board for and receiving research support from Delcath. Dr. Schadendorf disclosed honoraria or an advisory/consultancy role with AZD, Bristol-Myers Squibb, Plexxikon, Roche, Schering-Plough, and Bayer Schering Pharma.

CHICAGO — Percutaneous hepatic perfusion with melphalan improved local disease control, but not overall survival when compared with best available care in patients with ocular or cutaneous melanoma that had metastasized to the liver.

Chemoembolization is the standard of care in patients with hepatic metastases from ocular melanoma, a group that made up about 88% of the trial population. Systemic chemotherapy or immunotherapies do not appear to alter the natural history of the disease, which has a one-year survival of about 10%.

“Increased drug delivery achieved through novel regional therapeutic approaches may increase efficacy for a given agent (versus systemic administration) by overcoming a low therapeutic index,” said Dr. James Pingpank, Jr. who presented the late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

Forty-four patients were randomized to hepatic perfusion and 49 to best available care by the treating physician. More than half, 55%, of the control arm, crossed over to receive hepatic perfusion after hepatic progression.

High-dose melphalan at 3.0 mg/kg was infused into the hepatic artery via a percutaneously placed catheter with hepatic venous hemofiltration using a retrohepatic, double-balloon catheter and hemofiltration cartridges. Patients underwent 4 to 6 procedures at 28- to 35-day intervals.

The device and drug combination is under consideration by the Food and Drug Administration.

When compared with best available care, percutaneous hepatic perfusion increased median hepatic progression-free survival from 49 days to 245 days (hazard ratio 0.30, logrank P less than .0001), and overall progression-free survival from 46 days to 186 days (HR. 0.40, logrank P less than .0001).

No patients progressed while on hepatic perfusion with melphalan, and there were no differences in progression-free survival of ocular vs. cutaneous melanoma, said Dr. Pingpank of the University of Pittsburgh Hillman Cancer Center in Pittsburgh.

Median overall survival was similar at 301 days for best available care and 298 days for hepatic perfusion (HR 0.92, logrank P = .77). This was likely due to the high crossover rate, he said. When overall survival was examined in the control arm alone, it reached 398 days in patients who crossed over vs. 124 days for those who did not (logrank P = .0117).

Invited discussant Dr. Dirk Schadendorf, director of dermatology at University Hospital Essen in Essen, Germany, took issue with the high crossover rate and said a previous German trial (Br. J. Cancer 2002;87:840-5 also failed to show a significant survival advantage for intraarterial or IV fotemustine plus interferon-alpha and interleukin 2 in metastatic ocular melanoma.

“The clinical benefit besides local control is open and has not been answered by this trial,” he said. “The crossover in my view is a clear sign of bias and is not proving this treatment is of any benefit to the patient.”

Dr. Schadendorf said that additional relevant information is missing, such as the number of patients with liver-only metastases compared with other sites of metastasis, thus making it difficult to determine whether there is any potential patient imbalance between arms.

The most common therapy of the primary tumor was radiation in 52% of the experimental arm and 49% of the control arm, roughly 85% of patients had an ECOG performance status of 0, and their mean age was 55 years.

Expansion of the single-institution study to multiple centers proved safe and effective, Dr. Pingpank said. The most common grade 3/4 treatment-related toxicities in 40 evaluable patients receiving 116 perfusion treatments were thrombocytopenia (74%), neutropenia (61%), and anemia (47%). Three treatment-related deaths occurred, two due to neutropenic sepsis and one to hepatic failure.

Study sponsor Delcath Systems, Inc. provided melphalan and double-balloon catheters for the trial. The researchers disclosed serving on the scientific advisory board for and receiving research support from Delcath. Dr. Schadendorf disclosed honoraria or an advisory/consultancy role with AZD, Bristol-Myers Squibb, Plexxikon, Roche, Schering-Plough, and Bayer Schering Pharma.