Biomarker Research Likely to Establish New Standards for Long-Suffering Melanoma Patients
Scientists Examine Both Genetic and Non-Genetic Markers
While oncologists are struggling to find ways to prolong the lives of otherwise difficult-to-treat stage III and IV melanoma patients, other medical research into the nature of melanoma is uncovering secrets of the disease that can translate into more accurate diagnostic tests now and, hopefully, much-needed medical therapies in the future. Some of the scientists who presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago were involved in molecular research with potential therapeutic implications. However, at least two of the posters and presentations dealt with biomarkers, which can be used now to determine those patients at increased risk for metastases and to mark those patients for earlier chemotherapy or more aggressive nodal surveillance.
Multi-Gene Assays Key to Development and Diagnosis
“Some melanoma patients have lymph nodes removed, and within a few months they’re dead,” said Tom John, M.D., a practicing oncologist and doctoral student at the Ludwig Institute for Cancer Research at Melbourne Center for Clinical Sciences in Australia. “I wanted to see if there was a gene expression profile that could predict which patients would do well, and which patients would do poorly,” he said.
Dr. John presented the results of his research at this year’s ASCO meeting in Chicago. “This is a procedure that patients can take now. We’ve developed an assay of five genes, which can be run in a standard laboratory,” he said, noting that younger patients and women in his study tended to do better than others.
Dr. John agreed with other researchers that new diagnostics and therapies are necessary because of the paucity of reliable treatments for advanced disease. While approximately 30% of stage III melanoma patients will do well, the only established treatment for the others, interferon, has been shown to delay the time to recurrence, but not to actually change the survival rate, he said.
“In the States, you use interferon all the time, but in Australia and the U.K., we don’t use it because it’s quite a toxic treatment and there’s no survival benefit. We don’t use anything, because nothing else been shown to have a benefit,” he said.
Starting off with an analysis of the lymph nodes of 29 patients, Dr. John and colleagues worked through a set of 30,000 genes and identified a set of 15 genes as prognostic indicators. Those 15 genes show about 90% effectiveness at distinguishing the 30% of patients who will achieve long-term survival from those who will relapse early, according to abstract number 8502, “Predicting Clinical Outcome Through Gene Expression Profiling in Stage III Melanoma.”
“I can actually get the list from 15 down to five genes that seem to perform quite well in segregating the two groups, although the actual biological relevance of each individual gene may not reflect the pathway that it’s involved in,” Dr. John said.
The research into biomarkers translates into new knowledge that affects the standard of care, or how melanoma patients should be treated now, according to Jeff Lee, M.D., Professor of Surgery at the University of Texas M.D. Anderson Cancer Center, who also coauthored a paper presented at ASCO this year.
“We don’t do a sentinel node biopsy on most patients with very thin tumors that aren’t ulcerated, because the chance that the sentinel node will contain tumor is so small. But our results suggest there may be a group of patients who can be identified at low cost,” he said, noting that the cost of the test might be around a couple of hundred dollars at most.
“Patients who are entered into clinical trials, particularly those involving immunotherapies, need to be routinely HLA typed for these genes in particular. It also might be reasonable to start typing early-stage melanoma patients and considering more intensive surveillance of lymph nodes in the group of patients who are at particularly high risk to develop lymph node recurrence.
Also, you might consider lowering the threshold for sentinel lymph node biopsy for the group of patients identified,” said Dr. Lee, who helped identify a cohort of about 35 important genes in melanoma patients in abstract 8503, “HLA Class II Alleles Predict Recurrence and Pattern of Failure in Early-Stage Melanoma Patients.”
The study examined more than 1,200 patients with grade I and II melanoma and found that about 11% of the population had the allele that was associated with a higher risk of recurrence; about 20% had the allele that correlated with the lower risk of recurrence. Generally, about 15% of stage I and II patients experience a recurrence of their disease, Dr. Lee said.
Although alleles each contain several nucleotide polymorphisms, there are two genes in particular that captured researchers’ interest, Dr. Lee maintained. “The gene, which we call HLA-DRB 1, is a single gene, but within that gene, there are two polymorphisms that are important,” he said.
“We actually know what the function of this gene is,” explained Dr. Lee. “The function is to bind short melanoma peptide antigens, and it’s that combination in a lock-and-key type of mechanism that either turns on or turns off the immune system,” he said.
“This is a critical control molecule in regulating immune responses. The melanoma proteins that bind to the 401 allele are different from the ones that bind to the 1101 allele. The 401 is a good prognostic indicator, and the 1101 is a bad prognostic indicator for patients, because the immune response is more effective when the peptides bind to the 401, and less effective when they bind to the 1101,” he said.
Another researcher into the genetic basis of melanoma has not only identified two major pathways associated with a poor prognosis, but has uncovered evidence that may revolutionize the 35-year-old classification of the disease.
“Just focusing on 60 genes in the signature, we identified two major pathways in which over-regulation was associated with a poor prognosis,” said Alan Spatz, M.D., Chair of the Immunohistochemistry Department and Pathologist at the Gustave Roussy Institute in France.
“The first pathway involved the replication origins firing genes; the second involved the DNA repair genes. These findings allowed us to identify key cascades in which deregulation is almost mandatory to progress to metastatic melanoma.”
Using high-density chips, Dr. Spatz and his colleagues examined 44,000 genes from 115 primary melanomas, and found that the mcm4 and mcm6 genes will allow drug developers to regulate tumor progression and clinical outcome.
“Another thing that has been told by this study is that we are probably facing another name for melanoma,” said Dr. Spatz, who is also Chairperson of the European Organization of Research and Treatment for Cancer.
“We are probably looking at two different diseases — one associated with clinical UV exposure and fibrous fragmentation. Another disease, associated with intermittent or no UV exposure, uses another molecular pathway to progress, and has different prognostic characteristics. Probably within 1 year we’ll be able to increase our knowledge of the homogenous characteristics of both diseases,” he said.
Non-Genetic Biomarkers Also Important
Not all the important presentations on biomarkers at this year’s ASCO conference related to genetics. Also important was a presentation on a substance that may be related to embryonic stem cells, which plays a role in melanoma, according to Mary Hendrix, Ph.D., scientific director of Children’s Memorial Research Center in Chicago.
“We’re looking at an aggregate of different biomarkers, including an embryonic morphogen called Nodal I , to tell us about those patients who have susceptibility to melanoma, or those patients who are going to have an aggressive form of the disease, who should be treated more aggressively,” said Dr. Hendrix, who also spoke on the topic at this year’s ASCO conference.
Dr. Hendrix said that Nodal I, a member of the transforming growth factor beta super-family, is usually only found in embryonic tissues and related cells such as trophoblasts as they form the placenta. The protein normally disappears after birth.
“We discovered that it is highly and aberrantly expressed in aggressive and metastatic melanoma. Equally importantly, non-aggressive tumors do not express nodal. And when we down- regulate or turn off the expression of nodal, we see a remarkable decrease in the invasion potential of cells. We see an abrogation or remarkable decrease in the ability of tumor cells to form,” she said.
Dr. Hendrix said that her team has also been successful in using a molecular approach to turn off or turn down the expression of nodal in tumor cells. However, their current technology only turns down expression for about 2 weeks, she said.
“Our challenge is to keep it turned off indefinitely, and then when we place it into a target, we want to know whether we will also be able to target the metastases,” she added.
Dr. Hendrix said that her research had been published in part in Nature last year and in Nature Reviews-Cancer in April of 2007.
ASCO Presentations Established Updated Standard of Care for Melanoma Patients
While No Uniformly Effective Pharmacologic Therapies Exist, Adjuvant Procedures Were Highlighted
While researchers described scientific progress relating to the promise of biomarkers and genomic studies to result in improved treatments for melanoma (see previous ASCO meeting coverage), other posters and oral presentations explained that no consistently effective pharmacological treatments currently exist for certain classes of melanoma patients. Nonetheless, dermatologists and oncologists are advised to enroll advanced cancer patients in clinical trials and make use of proven adjuvant procedures to prolong their lives and increase the possibility of a cure.
Because the survival rate is high for stage I and II melanoma patients, many physicians do not order lymph node surveillance absent evidence of metastasis. Additionally, while immunotherapies such as interferon and interleukin are FDA approved for certain advanced melanoma cases, they are so toxic and often show so little benefit that they are not prescribed in certain countries. Furthermore, there are currently no FDA-approved drugs to treat stage IV metastatic melanoma. But that doesn’t mean that physicians should nothing, or that patients should despair.
As biomarker researchers presented new gene arrays that may help identify those early-stage patients who would benefit from more aggressive surveillance, other presentations introduced evidence that all melanoma patients should undergo sentinel lymph node biopsy, as opposed to only those patients with suspected metastatic disease as many advocate. For those patients with late-stage melanoma, clinical trials combining bio-chemotherapy with established immuno-therapies are encouraged, since there is no effective cure for stage IV melanoma today. For other patients with brain metastases, careful use of radiosurgery may greatly extend their lives.
When the Standard of Care is Experimental
“The optimal therapy for stage IV, metastatic melanoma has still proven elusive, because no treatment has been consistently proven to prolong overall survival in the context of a randomized clinical trial,” said Mohammed Kashani-Sabet, M.D., Director of the Melanoma Center and Associate Professor of Dermatology at the University of California at San Francisco.
While agents such as interferon, interleukin-2, and dacarbazine have been approved by the FDA for stage III melanoma, no agents are satisfactory for stage IV of the disease.
“This leaves a lot of room for investigative and experimental agents, because the standard agents are not very effective or come with considerable toxicity in these patients,” explained Dr. Kashani, who co-authored a poster studying survival in patients who received bio-chemotherapy, and who also commented on the presentations of other researchers at another session.
The poster, “Survival and Long-Term Toxicities of Biochemotherapy for Metastatic Melanoma,” described results from a follow-up study in which 38 patients received interferon, interleukin-2, temozolomid, platinol, and vinblastine for metastatic disease.
Twenty-one percent enjoyed a complete response, while 37% had partial responses, and 10 of the 38 patients are still alive more than 3 years later, according to the poster (abstract number 8553 from this year’s ASCO meeting). All drugs are approved for some forms of cancer, but only three for certain stages of melanoma.
Other findings presented at the ASCO conference included a study combining taxol with high-dose interleukin-2 in 13 patients, and a meta-analysis of clinical trials involving over 2,000 patients, which compared those treated with standard chemotherapy to those who received combined bio-chemotherapy.
Dr. Kashani also offered commentary on findings presented on melanoma at the ASCO conference. Perhaps the other important melanoma findings at the conference dealt with high-dose interferon. Poster “Long-Term Adjuvant Pegylated Interferon-alpha2b Compared to Observation in Resected Stage III Melanoma, Final Results of a Randomized Clinical Trial,” and “A Randomized Phase III Trial of 1 Month Versus 1 Year Adjuvant High-Dose Interferon alfa-2b in Patients with Resected High Risk Melanoma,” both found some clinical benefit to interferon use, but suggested no benefit to prolonging the treatment regimen over the course of 1 year, compared to 1 month.
Of his comments relating to other presenters at the meeting, Dr. Kashani said, “I’m not saying that bio-chemotherapy is the standard of care, but it is an option to consider for patients with stage IV melanoma because we have the potential to get durable complete responses. If we get patients into clinical trials, the hope is that as we identify the molecular aberrations and the genetic underpinning of melanoma, we will identify along with that better targets for therapy over the next several years,” Dr. Kashani added.
Sentinel Node Procedure Should Be More Widely Employed in Early-Stage Patients
“There is limited medical therapy for melanoma; most of it is investigational,” said Randy Scheri, M.D., a Surgical Oncology Fellow at the John Wayne Cancer Institute, Santa Monica, CA, who also presented at the conference.
“All patients with no evidence of metastatic disease should have their melanoma removed and a sentinel node procedure performed on them,” said Dr. Scheri, the lead author of “Improved Long-Term Survival in Patients with Intermediate Thickness Primary Melanoma Managed by Sentinel Node Biopsy.”
The study helps establish a standard of care for the disease. “There are two schools of thought when comers to melanoma,” said Dr. Scheri.
“Either the patient’s melanoma is removed and you just observe them to see if they develop in the lymph nodes, or you perform the sentinel node biopsy. According to the other school of thought, it used to be that the only way they would do this would be to remove all the lymph nodes in the area. But the vast majority of patients had no melanoma in the lymph nodes, so patients got no benefit from procedure. It went along with some problems, too,” he added.
In about 20% of patients, the melanoma has spread to the lymph nodes, Dr. Scheri said.
Dr. Scheri presented follow-up findings of a clinical study of about 3,800 melanoma patients, comparing the group of patients who underwent immediate completion lymphadenectomy with the group of patients undergoing lymph node observation. Projected 10-year survival was 76% in the group that underwent biopsies, compared to 63% in the observation group, the poster reported.
“We feel that all patients should have the sentinel node procedure performed for two reasons,” Dr. Scheri claimed. “It provides the best staging information possible, and patients who have lymph node disease have better survival if they have the sentinel node procedure performed,” Dr. Scheri explained.
While late-stage melanoma is difficult to treat, about 93% of patients with no lymph node cancer survive,” he added.
Radiosurgery Recommended for Patients with Brain Metastases
While stage IV melanoma is difficult to treat, metastases that result when the disease reaches the brain are especially non-responsive to chemotherapy, often resulting in a patient’s death within a few months. But a radiotherapy advocated by one presenter at this year’s ASCO conference may be able to extend the lives of stage IV patients by even more than a year.
“When the disease goes to the brain, there are no effective chemotherapeutic medications that cross the blood-brain barrier,” said Augustine Fregene, M.D., Ph.D., Associate Professor of Radiation Oncology at Wayne State University in Detroit. “The most effective chemotherapy agents in the brain have only about a 7% benefit, and then you have to deal with toxicity. So usually we use external beam radiation therapy, just like a chest X-ray, but at a higher dose,” he said.
But problems with standard radiation techniques often prove ineffective, too, said Dr. Fregene. “The standard dose is low, about 3,000 centigray, and it will control the METs for about 4 months at best. You want to make sure the tumor you’re treating gets all the dose you want. And you want to make sure your margin dose is good, because most of the spread is in the margin,” said Dr. Fregene, who presented “Gamma Knife Radiosurgery for Melanoma/Renal Cell Carcinoma Brain Metastases 1-10 Lesions With Optimized Margin Dose: Improved Tumor Control and Survival.”
Dr. Fregene and colleagues reported the use of a new model of the gamma knife device, the Perfection, manufactured by Electa. “We focus on the tumor about 201 different tiny beams, and in this way can control the growth of a tumor for a much longer period of time,” said Dr. Fregene, adding that the 24 patients in the study enjoyed a mean survival of 14.5 months.
Biomarker Research Likely to Establish New Standards for Long-Suffering Melanoma Patients
Scientists Examine Both Genetic and Non-Genetic Markers
While oncologists are struggling to find ways to prolong the lives of otherwise difficult-to-treat stage III and IV melanoma patients, other medical research into the nature of melanoma is uncovering secrets of the disease that can translate into more accurate diagnostic tests now and, hopefully, much-needed medical therapies in the future. Some of the scientists who presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago were involved in molecular research with potential therapeutic implications. However, at least two of the posters and presentations dealt with biomarkers, which can be used now to determine those patients at increased risk for metastases and to mark those patients for earlier chemotherapy or more aggressive nodal surveillance.
Multi-Gene Assays Key to Development and Diagnosis
“Some melanoma patients have lymph nodes removed, and within a few months they’re dead,” said Tom John, M.D., a practicing oncologist and doctoral student at the Ludwig Institute for Cancer Research at Melbourne Center for Clinical Sciences in Australia. “I wanted to see if there was a gene expression profile that could predict which patients would do well, and which patients would do poorly,” he said.
Dr. John presented the results of his research at this year’s ASCO meeting in Chicago. “This is a procedure that patients can take now. We’ve developed an assay of five genes, which can be run in a standard laboratory,” he said, noting that younger patients and women in his study tended to do better than others.
Dr. John agreed with other researchers that new diagnostics and therapies are necessary because of the paucity of reliable treatments for advanced disease. While approximately 30% of stage III melanoma patients will do well, the only established treatment for the others, interferon, has been shown to delay the time to recurrence, but not to actually change the survival rate, he said.
“In the States, you use interferon all the time, but in Australia and the U.K., we don’t use it because it’s quite a toxic treatment and there’s no survival benefit. We don’t use anything, because nothing else been shown to have a benefit,” he said.
Starting off with an analysis of the lymph nodes of 29 patients, Dr. John and colleagues worked through a set of 30,000 genes and identified a set of 15 genes as prognostic indicators. Those 15 genes show about 90% effectiveness at distinguishing the 30% of patients who will achieve long-term survival from those who will relapse early, according to abstract number 8502, “Predicting Clinical Outcome Through Gene Expression Profiling in Stage III Melanoma.”
“I can actually get the list from 15 down to five genes that seem to perform quite well in segregating the two groups, although the actual biological relevance of each individual gene may not reflect the pathway that it’s involved in,” Dr. John said.
The research into biomarkers translates into new knowledge that affects the standard of care, or how melanoma patients should be treated now, according to Jeff Lee, M.D., Professor of Surgery at the University of Texas M.D. Anderson Cancer Center, who also coauthored a paper presented at ASCO this year.
“We don’t do a sentinel node biopsy on most patients with very thin tumors that aren’t ulcerated, because the chance that the sentinel node will contain tumor is so small. But our results suggest there may be a group of patients who can be identified at low cost,” he said, noting that the cost of the test might be around a couple of hundred dollars at most.
“Patients who are entered into clinical trials, particularly those involving immunotherapies, need to be routinely HLA typed for these genes in particular. It also might be reasonable to start typing early-stage melanoma patients and considering more intensive surveillance of lymph nodes in the group of patients who are at particularly high risk to develop lymph node recurrence.
Also, you might consider lowering the threshold for sentinel lymph node biopsy for the group of patients identified,” said Dr. Lee, who helped identify a cohort of about 35 important genes in melanoma patients in abstract 8503, “HLA Class II Alleles Predict Recurrence and Pattern of Failure in Early-Stage Melanoma Patients.”
The study examined more than 1,200 patients with grade I and II melanoma and found that about 11% of the population had the allele that was associated with a higher risk of recurrence; about 20% had the allele that correlated with the lower risk of recurrence. Generally, about 15% of stage I and II patients experience a recurrence of their disease, Dr. Lee said.
Although alleles each contain several nucleotide polymorphisms, there are two genes in particular that captured researchers’ interest, Dr. Lee maintained. “The gene, which we call HLA-DRB 1, is a single gene, but within that gene, there are two polymorphisms that are important,” he said.
“We actually know what the function of this gene is,” explained Dr. Lee. “The function is to bind short melanoma peptide antigens, and it’s that combination in a lock-and-key type of mechanism that either turns on or turns off the immune system,” he said.
“This is a critical control molecule in regulating immune responses. The melanoma proteins that bind to the 401 allele are different from the ones that bind to the 1101 allele. The 401 is a good prognostic indicator, and the 1101 is a bad prognostic indicator for patients, because the immune response is more effective when the peptides bind to the 401, and less effective when they bind to the 1101,” he said.
Another researcher into the genetic basis of melanoma has not only identified two major pathways associated with a poor prognosis, but has uncovered evidence that may revolutionize the 35-year-old classification of the disease.
“Just focusing on 60 genes in the signature, we identified two major pathways in which over-regulation was associated with a poor prognosis,” said Alan Spatz, M.D., Chair of the Immunohistochemistry Department and Pathologist at the Gustave Roussy Institute in France.
“The first pathway involved the replication origins firing genes; the second involved the DNA repair genes. These findings allowed us to identify key cascades in which deregulation is almost mandatory to progress to metastatic melanoma.”
Using high-density chips, Dr. Spatz and his colleagues examined 44,000 genes from 115 primary melanomas, and found that the mcm4 and mcm6 genes will allow drug developers to regulate tumor progression and clinical outcome.
“Another thing that has been told by this study is that we are probably facing another name for melanoma,” said Dr. Spatz, who is also Chairperson of the European Organization of Research and Treatment for Cancer.
“We are probably looking at two different diseases — one associated with clinical UV exposure and fibrous fragmentation. Another disease, associated with intermittent or no UV exposure, uses another molecular pathway to progress, and has different prognostic characteristics. Probably within 1 year we’ll be able to increase our knowledge of the homogenous characteristics of both diseases,” he said.
Non-Genetic Biomarkers Also Important
Not all the important presentations on biomarkers at this year’s ASCO conference related to genetics. Also important was a presentation on a substance that may be related to embryonic stem cells, which plays a role in melanoma, according to Mary Hendrix, Ph.D., scientific director of Children’s Memorial Research Center in Chicago.
“We’re looking at an aggregate of different biomarkers, including an embryonic morphogen called Nodal I , to tell us about those patients who have susceptibility to melanoma, or those patients who are going to have an aggressive form of the disease, who should be treated more aggressively,” said Dr. Hendrix, who also spoke on the topic at this year’s ASCO conference.
Dr. Hendrix said that Nodal I, a member of the transforming growth factor beta super-family, is usually only found in embryonic tissues and related cells such as trophoblasts as they form the placenta. The protein normally disappears after birth.
“We discovered that it is highly and aberrantly expressed in aggressive and metastatic melanoma. Equally importantly, non-aggressive tumors do not express nodal. And when we down- regulate or turn off the expression of nodal, we see a remarkable decrease in the invasion potential of cells. We see an abrogation or remarkable decrease in the ability of tumor cells to form,” she said.
Dr. Hendrix said that her team has also been successful in using a molecular approach to turn off or turn down the expression of nodal in tumor cells. However, their current technology only turns down expression for about 2 weeks, she said.
“Our challenge is to keep it turned off indefinitely, and then when we place it into a target, we want to know whether we will also be able to target the metastases,” she added.
Dr. Hendrix said that her research had been published in part in Nature last year and in Nature Reviews-Cancer in April of 2007.
ASCO Presentations Established Updated Standard of Care for Melanoma Patients
While No Uniformly Effective Pharmacologic Therapies Exist, Adjuvant Procedures Were Highlighted
While researchers described scientific progress relating to the promise of biomarkers and genomic studies to result in improved treatments for melanoma (see previous ASCO meeting coverage), other posters and oral presentations explained that no consistently effective pharmacological treatments currently exist for certain classes of melanoma patients. Nonetheless, dermatologists and oncologists are advised to enroll advanced cancer patients in clinical trials and make use of proven adjuvant procedures to prolong their lives and increase the possibility of a cure.
Because the survival rate is high for stage I and II melanoma patients, many physicians do not order lymph node surveillance absent evidence of metastasis. Additionally, while immunotherapies such as interferon and interleukin are FDA approved for certain advanced melanoma cases, they are so toxic and often show so little benefit that they are not prescribed in certain countries. Furthermore, there are currently no FDA-approved drugs to treat stage IV metastatic melanoma. But that doesn’t mean that physicians should nothing, or that patients should despair.
As biomarker researchers presented new gene arrays that may help identify those early-stage patients who would benefit from more aggressive surveillance, other presentations introduced evidence that all melanoma patients should undergo sentinel lymph node biopsy, as opposed to only those patients with suspected metastatic disease as many advocate. For those patients with late-stage melanoma, clinical trials combining bio-chemotherapy with established immuno-therapies are encouraged, since there is no effective cure for stage IV melanoma today. For other patients with brain metastases, careful use of radiosurgery may greatly extend their lives.
When the Standard of Care is Experimental
“The optimal therapy for stage IV, metastatic melanoma has still proven elusive, because no treatment has been consistently proven to prolong overall survival in the context of a randomized clinical trial,” said Mohammed Kashani-Sabet, M.D., Director of the Melanoma Center and Associate Professor of Dermatology at the University of California at San Francisco.
While agents such as interferon, interleukin-2, and dacarbazine have been approved by the FDA for stage III melanoma, no agents are satisfactory for stage IV of the disease.
“This leaves a lot of room for investigative and experimental agents, because the standard agents are not very effective or come with considerable toxicity in these patients,” explained Dr. Kashani, who co-authored a poster studying survival in patients who received bio-chemotherapy, and who also commented on the presentations of other researchers at another session.
The poster, “Survival and Long-Term Toxicities of Biochemotherapy for Metastatic Melanoma,” described results from a follow-up study in which 38 patients received interferon, interleukin-2, temozolomid, platinol, and vinblastine for metastatic disease.
Twenty-one percent enjoyed a complete response, while 37% had partial responses, and 10 of the 38 patients are still alive more than 3 years later, according to the poster (abstract number 8553 from this year’s ASCO meeting). All drugs are approved for some forms of cancer, but only three for certain stages of melanoma.
Other findings presented at the ASCO conference included a study combining taxol with high-dose interleukin-2 in 13 patients, and a meta-analysis of clinical trials involving over 2,000 patients, which compared those treated with standard chemotherapy to those who received combined bio-chemotherapy.
Dr. Kashani also offered commentary on findings presented on melanoma at the ASCO conference. Perhaps the other important melanoma findings at the conference dealt with high-dose interferon. Poster “Long-Term Adjuvant Pegylated Interferon-alpha2b Compared to Observation in Resected Stage III Melanoma, Final Results of a Randomized Clinical Trial,” and “A Randomized Phase III Trial of 1 Month Versus 1 Year Adjuvant High-Dose Interferon alfa-2b in Patients with Resected High Risk Melanoma,” both found some clinical benefit to interferon use, but suggested no benefit to prolonging the treatment regimen over the course of 1 year, compared to 1 month.
Of his comments relating to other presenters at the meeting, Dr. Kashani said, “I’m not saying that bio-chemotherapy is the standard of care, but it is an option to consider for patients with stage IV melanoma because we have the potential to get durable complete responses. If we get patients into clinical trials, the hope is that as we identify the molecular aberrations and the genetic underpinning of melanoma, we will identify along with that better targets for therapy over the next several years,” Dr. Kashani added.
Sentinel Node Procedure Should Be More Widely Employed in Early-Stage Patients
“There is limited medical therapy for melanoma; most of it is investigational,” said Randy Scheri, M.D., a Surgical Oncology Fellow at the John Wayne Cancer Institute, Santa Monica, CA, who also presented at the conference.
“All patients with no evidence of metastatic disease should have their melanoma removed and a sentinel node procedure performed on them,” said Dr. Scheri, the lead author of “Improved Long-Term Survival in Patients with Intermediate Thickness Primary Melanoma Managed by Sentinel Node Biopsy.”
The study helps establish a standard of care for the disease. “There are two schools of thought when comers to melanoma,” said Dr. Scheri.
“Either the patient’s melanoma is removed and you just observe them to see if they develop in the lymph nodes, or you perform the sentinel node biopsy. According to the other school of thought, it used to be that the only way they would do this would be to remove all the lymph nodes in the area. But the vast majority of patients had no melanoma in the lymph nodes, so patients got no benefit from procedure. It went along with some problems, too,” he added.
In about 20% of patients, the melanoma has spread to the lymph nodes, Dr. Scheri said.
Dr. Scheri presented follow-up findings of a clinical study of about 3,800 melanoma patients, comparing the group of patients who underwent immediate completion lymphadenectomy with the group of patients undergoing lymph node observation. Projected 10-year survival was 76% in the group that underwent biopsies, compared to 63% in the observation group, the poster reported.
“We feel that all patients should have the sentinel node procedure performed for two reasons,” Dr. Scheri claimed. “It provides the best staging information possible, and patients who have lymph node disease have better survival if they have the sentinel node procedure performed,” Dr. Scheri explained.
While late-stage melanoma is difficult to treat, about 93% of patients with no lymph node cancer survive,” he added.
Radiosurgery Recommended for Patients with Brain Metastases
While stage IV melanoma is difficult to treat, metastases that result when the disease reaches the brain are especially non-responsive to chemotherapy, often resulting in a patient’s death within a few months. But a radiotherapy advocated by one presenter at this year’s ASCO conference may be able to extend the lives of stage IV patients by even more than a year.
“When the disease goes to the brain, there are no effective chemotherapeutic medications that cross the blood-brain barrier,” said Augustine Fregene, M.D., Ph.D., Associate Professor of Radiation Oncology at Wayne State University in Detroit. “The most effective chemotherapy agents in the brain have only about a 7% benefit, and then you have to deal with toxicity. So usually we use external beam radiation therapy, just like a chest X-ray, but at a higher dose,” he said.
But problems with standard radiation techniques often prove ineffective, too, said Dr. Fregene. “The standard dose is low, about 3,000 centigray, and it will control the METs for about 4 months at best. You want to make sure the tumor you’re treating gets all the dose you want. And you want to make sure your margin dose is good, because most of the spread is in the margin,” said Dr. Fregene, who presented “Gamma Knife Radiosurgery for Melanoma/Renal Cell Carcinoma Brain Metastases 1-10 Lesions With Optimized Margin Dose: Improved Tumor Control and Survival.”
Dr. Fregene and colleagues reported the use of a new model of the gamma knife device, the Perfection, manufactured by Electa. “We focus on the tumor about 201 different tiny beams, and in this way can control the growth of a tumor for a much longer period of time,” said Dr. Fregene, adding that the 24 patients in the study enjoyed a mean survival of 14.5 months.
Biomarker Research Likely to Establish New Standards for Long-Suffering Melanoma Patients
Scientists Examine Both Genetic and Non-Genetic Markers
While oncologists are struggling to find ways to prolong the lives of otherwise difficult-to-treat stage III and IV melanoma patients, other medical research into the nature of melanoma is uncovering secrets of the disease that can translate into more accurate diagnostic tests now and, hopefully, much-needed medical therapies in the future. Some of the scientists who presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago were involved in molecular research with potential therapeutic implications. However, at least two of the posters and presentations dealt with biomarkers, which can be used now to determine those patients at increased risk for metastases and to mark those patients for earlier chemotherapy or more aggressive nodal surveillance.
Multi-Gene Assays Key to Development and Diagnosis
“Some melanoma patients have lymph nodes removed, and within a few months they’re dead,” said Tom John, M.D., a practicing oncologist and doctoral student at the Ludwig Institute for Cancer Research at Melbourne Center for Clinical Sciences in Australia. “I wanted to see if there was a gene expression profile that could predict which patients would do well, and which patients would do poorly,” he said.
Dr. John presented the results of his research at this year’s ASCO meeting in Chicago. “This is a procedure that patients can take now. We’ve developed an assay of five genes, which can be run in a standard laboratory,” he said, noting that younger patients and women in his study tended to do better than others.
Dr. John agreed with other researchers that new diagnostics and therapies are necessary because of the paucity of reliable treatments for advanced disease. While approximately 30% of stage III melanoma patients will do well, the only established treatment for the others, interferon, has been shown to delay the time to recurrence, but not to actually change the survival rate, he said.
“In the States, you use interferon all the time, but in Australia and the U.K., we don’t use it because it’s quite a toxic treatment and there’s no survival benefit. We don’t use anything, because nothing else been shown to have a benefit,” he said.
Starting off with an analysis of the lymph nodes of 29 patients, Dr. John and colleagues worked through a set of 30,000 genes and identified a set of 15 genes as prognostic indicators. Those 15 genes show about 90% effectiveness at distinguishing the 30% of patients who will achieve long-term survival from those who will relapse early, according to abstract number 8502, “Predicting Clinical Outcome Through Gene Expression Profiling in Stage III Melanoma.”
“I can actually get the list from 15 down to five genes that seem to perform quite well in segregating the two groups, although the actual biological relevance of each individual gene may not reflect the pathway that it’s involved in,” Dr. John said.
The research into biomarkers translates into new knowledge that affects the standard of care, or how melanoma patients should be treated now, according to Jeff Lee, M.D., Professor of Surgery at the University of Texas M.D. Anderson Cancer Center, who also coauthored a paper presented at ASCO this year.
“We don’t do a sentinel node biopsy on most patients with very thin tumors that aren’t ulcerated, because the chance that the sentinel node will contain tumor is so small. But our results suggest there may be a group of patients who can be identified at low cost,” he said, noting that the cost of the test might be around a couple of hundred dollars at most.
“Patients who are entered into clinical trials, particularly those involving immunotherapies, need to be routinely HLA typed for these genes in particular. It also might be reasonable to start typing early-stage melanoma patients and considering more intensive surveillance of lymph nodes in the group of patients who are at particularly high risk to develop lymph node recurrence.
Also, you might consider lowering the threshold for sentinel lymph node biopsy for the group of patients identified,” said Dr. Lee, who helped identify a cohort of about 35 important genes in melanoma patients in abstract 8503, “HLA Class II Alleles Predict Recurrence and Pattern of Failure in Early-Stage Melanoma Patients.”
The study examined more than 1,200 patients with grade I and II melanoma and found that about 11% of the population had the allele that was associated with a higher risk of recurrence; about 20% had the allele that correlated with the lower risk of recurrence. Generally, about 15% of stage I and II patients experience a recurrence of their disease, Dr. Lee said.
Although alleles each contain several nucleotide polymorphisms, there are two genes in particular that captured researchers’ interest, Dr. Lee maintained. “The gene, which we call HLA-DRB 1, is a single gene, but within that gene, there are two polymorphisms that are important,” he said.
“We actually know what the function of this gene is,” explained Dr. Lee. “The function is to bind short melanoma peptide antigens, and it’s that combination in a lock-and-key type of mechanism that either turns on or turns off the immune system,” he said.
“This is a critical control molecule in regulating immune responses. The melanoma proteins that bind to the 401 allele are different from the ones that bind to the 1101 allele. The 401 is a good prognostic indicator, and the 1101 is a bad prognostic indicator for patients, because the immune response is more effective when the peptides bind to the 401, and less effective when they bind to the 1101,” he said.
Another researcher into the genetic basis of melanoma has not only identified two major pathways associated with a poor prognosis, but has uncovered evidence that may revolutionize the 35-year-old classification of the disease.
“Just focusing on 60 genes in the signature, we identified two major pathways in which over-regulation was associated with a poor prognosis,” said Alan Spatz, M.D., Chair of the Immunohistochemistry Department and Pathologist at the Gustave Roussy Institute in France.
“The first pathway involved the replication origins firing genes; the second involved the DNA repair genes. These findings allowed us to identify key cascades in which deregulation is almost mandatory to progress to metastatic melanoma.”
Using high-density chips, Dr. Spatz and his colleagues examined 44,000 genes from 115 primary melanomas, and found that the mcm4 and mcm6 genes will allow drug developers to regulate tumor progression and clinical outcome.
“Another thing that has been told by this study is that we are probably facing another name for melanoma,” said Dr. Spatz, who is also Chairperson of the European Organization of Research and Treatment for Cancer.
“We are probably looking at two different diseases — one associated with clinical UV exposure and fibrous fragmentation. Another disease, associated with intermittent or no UV exposure, uses another molecular pathway to progress, and has different prognostic characteristics. Probably within 1 year we’ll be able to increase our knowledge of the homogenous characteristics of both diseases,” he said.
Non-Genetic Biomarkers Also Important
Not all the important presentations on biomarkers at this year’s ASCO conference related to genetics. Also important was a presentation on a substance that may be related to embryonic stem cells, which plays a role in melanoma, according to Mary Hendrix, Ph.D., scientific director of Children’s Memorial Research Center in Chicago.
“We’re looking at an aggregate of different biomarkers, including an embryonic morphogen called Nodal I , to tell us about those patients who have susceptibility to melanoma, or those patients who are going to have an aggressive form of the disease, who should be treated more aggressively,” said Dr. Hendrix, who also spoke on the topic at this year’s ASCO conference.
Dr. Hendrix said that Nodal I, a member of the transforming growth factor beta super-family, is usually only found in embryonic tissues and related cells such as trophoblasts as they form the placenta. The protein normally disappears after birth.
“We discovered that it is highly and aberrantly expressed in aggressive and metastatic melanoma. Equally importantly, non-aggressive tumors do not express nodal. And when we down- regulate or turn off the expression of nodal, we see a remarkable decrease in the invasion potential of cells. We see an abrogation or remarkable decrease in the ability of tumor cells to form,” she said.
Dr. Hendrix said that her team has also been successful in using a molecular approach to turn off or turn down the expression of nodal in tumor cells. However, their current technology only turns down expression for about 2 weeks, she said.
“Our challenge is to keep it turned off indefinitely, and then when we place it into a target, we want to know whether we will also be able to target the metastases,” she added.
Dr. Hendrix said that her research had been published in part in Nature last year and in Nature Reviews-Cancer in April of 2007.
ASCO Presentations Established Updated Standard of Care for Melanoma Patients
While No Uniformly Effective Pharmacologic Therapies Exist, Adjuvant Procedures Were Highlighted
While researchers described scientific progress relating to the promise of biomarkers and genomic studies to result in improved treatments for melanoma (see previous ASCO meeting coverage), other posters and oral presentations explained that no consistently effective pharmacological treatments currently exist for certain classes of melanoma patients. Nonetheless, dermatologists and oncologists are advised to enroll advanced cancer patients in clinical trials and make use of proven adjuvant procedures to prolong their lives and increase the possibility of a cure.
Because the survival rate is high for stage I and II melanoma patients, many physicians do not order lymph node surveillance absent evidence of metastasis. Additionally, while immunotherapies such as interferon and interleukin are FDA approved for certain advanced melanoma cases, they are so toxic and often show so little benefit that they are not prescribed in certain countries. Furthermore, there are currently no FDA-approved drugs to treat stage IV metastatic melanoma. But that doesn’t mean that physicians should nothing, or that patients should despair.
As biomarker researchers presented new gene arrays that may help identify those early-stage patients who would benefit from more aggressive surveillance, other presentations introduced evidence that all melanoma patients should undergo sentinel lymph node biopsy, as opposed to only those patients with suspected metastatic disease as many advocate. For those patients with late-stage melanoma, clinical trials combining bio-chemotherapy with established immuno-therapies are encouraged, since there is no effective cure for stage IV melanoma today. For other patients with brain metastases, careful use of radiosurgery may greatly extend their lives.
When the Standard of Care is Experimental
“The optimal therapy for stage IV, metastatic melanoma has still proven elusive, because no treatment has been consistently proven to prolong overall survival in the context of a randomized clinical trial,” said Mohammed Kashani-Sabet, M.D., Director of the Melanoma Center and Associate Professor of Dermatology at the University of California at San Francisco.
While agents such as interferon, interleukin-2, and dacarbazine have been approved by the FDA for stage III melanoma, no agents are satisfactory for stage IV of the disease.
“This leaves a lot of room for investigative and experimental agents, because the standard agents are not very effective or come with considerable toxicity in these patients,” explained Dr. Kashani, who co-authored a poster studying survival in patients who received bio-chemotherapy, and who also commented on the presentations of other researchers at another session.
The poster, “Survival and Long-Term Toxicities of Biochemotherapy for Metastatic Melanoma,” described results from a follow-up study in which 38 patients received interferon, interleukin-2, temozolomid, platinol, and vinblastine for metastatic disease.
Twenty-one percent enjoyed a complete response, while 37% had partial responses, and 10 of the 38 patients are still alive more than 3 years later, according to the poster (abstract number 8553 from this year’s ASCO meeting). All drugs are approved for some forms of cancer, but only three for certain stages of melanoma.
Other findings presented at the ASCO conference included a study combining taxol with high-dose interleukin-2 in 13 patients, and a meta-analysis of clinical trials involving over 2,000 patients, which compared those treated with standard chemotherapy to those who received combined bio-chemotherapy.
Dr. Kashani also offered commentary on findings presented on melanoma at the ASCO conference. Perhaps the other important melanoma findings at the conference dealt with high-dose interferon. Poster “Long-Term Adjuvant Pegylated Interferon-alpha2b Compared to Observation in Resected Stage III Melanoma, Final Results of a Randomized Clinical Trial,” and “A Randomized Phase III Trial of 1 Month Versus 1 Year Adjuvant High-Dose Interferon alfa-2b in Patients with Resected High Risk Melanoma,” both found some clinical benefit to interferon use, but suggested no benefit to prolonging the treatment regimen over the course of 1 year, compared to 1 month.
Of his comments relating to other presenters at the meeting, Dr. Kashani said, “I’m not saying that bio-chemotherapy is the standard of care, but it is an option to consider for patients with stage IV melanoma because we have the potential to get durable complete responses. If we get patients into clinical trials, the hope is that as we identify the molecular aberrations and the genetic underpinning of melanoma, we will identify along with that better targets for therapy over the next several years,” Dr. Kashani added.
Sentinel Node Procedure Should Be More Widely Employed in Early-Stage Patients
“There is limited medical therapy for melanoma; most of it is investigational,” said Randy Scheri, M.D., a Surgical Oncology Fellow at the John Wayne Cancer Institute, Santa Monica, CA, who also presented at the conference.
“All patients with no evidence of metastatic disease should have their melanoma removed and a sentinel node procedure performed on them,” said Dr. Scheri, the lead author of “Improved Long-Term Survival in Patients with Intermediate Thickness Primary Melanoma Managed by Sentinel Node Biopsy.”
The study helps establish a standard of care for the disease. “There are two schools of thought when comers to melanoma,” said Dr. Scheri.
“Either the patient’s melanoma is removed and you just observe them to see if they develop in the lymph nodes, or you perform the sentinel node biopsy. According to the other school of thought, it used to be that the only way they would do this would be to remove all the lymph nodes in the area. But the vast majority of patients had no melanoma in the lymph nodes, so patients got no benefit from procedure. It went along with some problems, too,” he added.
In about 20% of patients, the melanoma has spread to the lymph nodes, Dr. Scheri said.
Dr. Scheri presented follow-up findings of a clinical study of about 3,800 melanoma patients, comparing the group of patients who underwent immediate completion lymphadenectomy with the group of patients undergoing lymph node observation. Projected 10-year survival was 76% in the group that underwent biopsies, compared to 63% in the observation group, the poster reported.
“We feel that all patients should have the sentinel node procedure performed for two reasons,” Dr. Scheri claimed. “It provides the best staging information possible, and patients who have lymph node disease have better survival if they have the sentinel node procedure performed,” Dr. Scheri explained.
While late-stage melanoma is difficult to treat, about 93% of patients with no lymph node cancer survive,” he added.
Radiosurgery Recommended for Patients with Brain Metastases
While stage IV melanoma is difficult to treat, metastases that result when the disease reaches the brain are especially non-responsive to chemotherapy, often resulting in a patient’s death within a few months. But a radiotherapy advocated by one presenter at this year’s ASCO conference may be able to extend the lives of stage IV patients by even more than a year.
“When the disease goes to the brain, there are no effective chemotherapeutic medications that cross the blood-brain barrier,” said Augustine Fregene, M.D., Ph.D., Associate Professor of Radiation Oncology at Wayne State University in Detroit. “The most effective chemotherapy agents in the brain have only about a 7% benefit, and then you have to deal with toxicity. So usually we use external beam radiation therapy, just like a chest X-ray, but at a higher dose,” he said.
But problems with standard radiation techniques often prove ineffective, too, said Dr. Fregene. “The standard dose is low, about 3,000 centigray, and it will control the METs for about 4 months at best. You want to make sure the tumor you’re treating gets all the dose you want. And you want to make sure your margin dose is good, because most of the spread is in the margin,” said Dr. Fregene, who presented “Gamma Knife Radiosurgery for Melanoma/Renal Cell Carcinoma Brain Metastases 1-10 Lesions With Optimized Margin Dose: Improved Tumor Control and Survival.”
Dr. Fregene and colleagues reported the use of a new model of the gamma knife device, the Perfection, manufactured by Electa. “We focus on the tumor about 201 different tiny beams, and in this way can control the growth of a tumor for a much longer period of time,” said Dr. Fregene, adding that the 24 patients in the study enjoyed a mean survival of 14.5 months.
