Part 2: CME # 115 — June 2003 Advances and
Challenges in Melanoma
June 2003
Unsuspected Drainage Patterns
With widespread use of lymphatic mapping and sentinel lymphadenectomy, more precise mapping of the drainage of a primary cutaneous melanoma has developed. With this precision, several previously held beliefs regarding lymphatic drainage have been dispelled.
The most notable flaw in our previous understanding of lymphatic mapping was the concept of “Sappey’s lines” around the trunk.80 Sappey believed lymphatic drainage never crossed midline and that there was an ambiguous zone within 5 cm of the umbilicus transversely. Clearly with the further delineation of lymphatic mapping, it’s clear that a patient’s lymphatic drainage pattern can cross midline and that zones of ambiguity extend much greater than just 5 cm within the umbilicus.87,82 Furthermore, areas that are not typically felt to be nodal-bearing regions have become very important in the accurate lymphatic mapping, including the intermuscular space83 just lateral to the scapula and the epitrochlear and popliteal nodes.84 These aberrant drainage patterns illustrate the complexity of the procedure as well as the importance of coordination between the nuclear medicine physicians and the surgeon.
Side Effects of LM/SL
The injections of the technetium-99m sulfur colloid, while uncomfortable to the patient, have no real side effects. The side effects of the injected mapping agents are predominantly due to the isosulfan blue dye. Following the intradermal injection of the isosulfan blue dye, some patients have a false drop in the oxygen saturation on the pulse oximeter. This doesn’t represent a true hypoxemia.
However, some patients can have anaphylactic-type reaction to the isosulfan blue dye. This can range from hypoxemia with bronchospasm to hypotension to blue urticaria.85 These anaphylactic-type reactions are usually easily supported with increasing FIO2, increasing positive and expiratory pressure, intravenous diphenhydramine and intravenous methylprednisolone. The Phase III trials for isosulfan blue dye only showed a 0.9% adverse effect incidence (5/543 patients) and all of these reactions were minor.86
Other complications associated with LM/SL involve local wound problems. These include cellulitis and/or infections that occur in 2% to 3% of patients. These are most commonly seen in the inguinal region lymph nodes.
About 5% to 7% of patients develop seromas at the SN excision site. Most seromas resolve with expectant management; however, some may require percutaneous aspiration.
Paraesthesias secondary to injury to one of the local cutaneous sensory nerves can occur. The true incidence of lymphedema following this procedure is not known. It’s being prospectively studied in a breast cancer trial by the American College of Surgeons Oncology Group Trial.
Lymphadenectomy Trial
Accrual to the Phase III randomized trial (Multicenter Selective Lymphadenectomy Trial, D.L. Morton, Principal Investigator) randomizing cutaneous melanoma patients to wide local excision with or without lymphatic mapping and sentinel lymphadenectomy is complete, and we await data analysis, but in the interim, a couple of things are clear. First, there is no role for elective lymph node dissection in patients with cutaneous melanoma. Second, lymphatic mapping and sentinel lymphadenectomy is a complex process that requires the coordination and expertise of three separate disciplines — nuclear medicine, surgery and pathology. All three disciplines are vital to ensure the high accuracy rates (99%) associated with this procedure.
Medical Treatment Options
• Adjuvant Therapy of High-risk Disease. Interferon alpha is the only approved therapy for patients with high-risk melanoma that has been surgically resected. However, the use of interferon in the adjuvant setting remains controversial. There have been several randomized trials that have reported significant improvements in disease-free survival when patients are treated with interferon compared to observation, but this hasn’t consistently translated into an improvement in survival.88-90
To date, there have been two randomized trials that have reported a significant beneficial impact on overall survival with interferon alfa after definitive surgery.91,92
The first trial, which led to the FDA approval of interferon, randomized patients with deep melanomas (greater than 4.0 mm) or with positive regional lymph nodes after surgery to 1 year of interferon or observation.91 In this trial, interferon was administered intravenously for 1 month, followed by subcutaneous administration three times every week for 48 weeks. The 5-year survival rate on the treatment arm was 46%, compared to 37% for observation (p = 0.0237).
In the second trial, this dose and schedule of interferon was compared to a melanoma vaccine.92 This trial was stopped early after an interim analysis indicated a significant survival benefit favoring the interferon arm.
The toxicity of interferon can be significant. In the initial ECOG trial, a dose delay or reduction was required for toxicity at least once in 50% of the patients during the first month of intravenous interferon, and 48% of the patients during the 48 weeks of subcutaneous treatment.91 The most common toxicities included constitutional symptoms, myelosuppression, elevated liver enzymes and neurological toxicity. Most toxicities were reversible, and after 4 months of therapy, most patients remaining on study were able to complete therapy.
Patients with deep primary melanomas (>4.0 mm) or stage III disease should be considered for adjuvant therapy after definitive surgery. Other high-risk patients, including those with intermediate-thickness melanomas (1.0 mm to
4.0 mm) that are ulcerated or those patients who have had resection of distant metastases (stage IV), should be considered for adjuvant therapy.
Despite its limitations, Interferon alpha remains the only reasonable option outside the setting of a clinical trial for these high-risk patients. There are several additional strategies currently being investigated in the adjuvant setting, including vaccine and other immunotherapy-based approaches. Although these strategies remain experimental, consider patients at high risk for relapse for clinical trials.
• Systemic Therapy for Metastatic Disease. Once melanoma has spread beyond the regional nodal basin, the overall prognosis is quite poor and less than 5% of patients will be long-term survivors. Currently, cytotoxic chemotherapy has a limited role in the management of patients with disseminated melanoma. Dacarbazine (DTIC) is the most common chemotherapeutic agent that has been studied in this disease. Radiographic response rates range from 15% to 20% as a single agent.93 The majority of responses with any chemotherapeutic regimen is generally partial and lasts less than 3 to 4 months, with complete responses occurring in less than 5% of patients.94 Although DTIC-based combination regimens are associated with higher overall response rates, they have not improved survival when compared to single-agent DTIC in randomized trials.95
Like interferon, interleukin-2 (IL-2) is a biological agent with activity in advanced melanoma. IL-2 is a potent T-cell growth factor and immunomodulator. Based on activity in pre-clinical models, IL-2 was initially tested in patients in a high-dose schedule that required in-patient administration.96
In a recent update of the database generated from trials conducted by the National Cancer Institute and Cytokine Working Group, treatment with IL-2 resulted in an overall response rate of 16%, with 6% of patients achieving a complete remission.97
In contrast to the experience with chemotherapy, the responses were more prolonged, with median response duration of 5.9 months for the partial responders, and a median response duration that had not been reached for those patients who had achieved a complete response. There were no relapses in patients whose complete response lasted more than 30 months, suggesting that a small percentage of patients may be cured from their disease.
However, also like interferon, the toxicity with IL-2 is significant and only a limited number of patients will be candidates for this therapy. Combinations of chemotherapy and biologic agents, including interferon and IL-2, referred to as biochemotherapy, have shown promising results in initial testing, and randomized trials studying these regimens are ongoing.98
Still Work to be Done
Ultimately, there remains a need to develop novel treatment strategies for patients with metastatic melanoma, and most patients with metastatic melanoma should also be considered for clinical trials.
Unsuspected Drainage Patterns
With widespread use of lymphatic mapping and sentinel lymphadenectomy, more precise mapping of the drainage of a primary cutaneous melanoma has developed. With this precision, several previously held beliefs regarding lymphatic drainage have been dispelled.
The most notable flaw in our previous understanding of lymphatic mapping was the concept of “Sappey’s lines” around the trunk.80 Sappey believed lymphatic drainage never crossed midline and that there was an ambiguous zone within 5 cm of the umbilicus transversely. Clearly with the further delineation of lymphatic mapping, it’s clear that a patient’s lymphatic drainage pattern can cross midline and that zones of ambiguity extend much greater than just 5 cm within the umbilicus.87,82 Furthermore, areas that are not typically felt to be nodal-bearing regions have become very important in the accurate lymphatic mapping, including the intermuscular space83 just lateral to the scapula and the epitrochlear and popliteal nodes.84 These aberrant drainage patterns illustrate the complexity of the procedure as well as the importance of coordination between the nuclear medicine physicians and the surgeon.
Side Effects of LM/SL
The injections of the technetium-99m sulfur colloid, while uncomfortable to the patient, have no real side effects. The side effects of the injected mapping agents are predominantly due to the isosulfan blue dye. Following the intradermal injection of the isosulfan blue dye, some patients have a false drop in the oxygen saturation on the pulse oximeter. This doesn’t represent a true hypoxemia.
However, some patients can have anaphylactic-type reaction to the isosulfan blue dye. This can range from hypoxemia with bronchospasm to hypotension to blue urticaria.85 These anaphylactic-type reactions are usually easily supported with increasing FIO2, increasing positive and expiratory pressure, intravenous diphenhydramine and intravenous methylprednisolone. The Phase III trials for isosulfan blue dye only showed a 0.9% adverse effect incidence (5/543 patients) and all of these reactions were minor.86
Other complications associated with LM/SL involve local wound problems. These include cellulitis and/or infections that occur in 2% to 3% of patients. These are most commonly seen in the inguinal region lymph nodes.
About 5% to 7% of patients develop seromas at the SN excision site. Most seromas resolve with expectant management; however, some may require percutaneous aspiration.
Paraesthesias secondary to injury to one of the local cutaneous sensory nerves can occur. The true incidence of lymphedema following this procedure is not known. It’s being prospectively studied in a breast cancer trial by the American College of Surgeons Oncology Group Trial.
Lymphadenectomy Trial
Accrual to the Phase III randomized trial (Multicenter Selective Lymphadenectomy Trial, D.L. Morton, Principal Investigator) randomizing cutaneous melanoma patients to wide local excision with or without lymphatic mapping and sentinel lymphadenectomy is complete, and we await data analysis, but in the interim, a couple of things are clear. First, there is no role for elective lymph node dissection in patients with cutaneous melanoma. Second, lymphatic mapping and sentinel lymphadenectomy is a complex process that requires the coordination and expertise of three separate disciplines — nuclear medicine, surgery and pathology. All three disciplines are vital to ensure the high accuracy rates (99%) associated with this procedure.
Medical Treatment Options
• Adjuvant Therapy of High-risk Disease. Interferon alpha is the only approved therapy for patients with high-risk melanoma that has been surgically resected. However, the use of interferon in the adjuvant setting remains controversial. There have been several randomized trials that have reported significant improvements in disease-free survival when patients are treated with interferon compared to observation, but this hasn’t consistently translated into an improvement in survival.88-90
To date, there have been two randomized trials that have reported a significant beneficial impact on overall survival with interferon alfa after definitive surgery.91,92
The first trial, which led to the FDA approval of interferon, randomized patients with deep melanomas (greater than 4.0 mm) or with positive regional lymph nodes after surgery to 1 year of interferon or observation.91 In this trial, interferon was administered intravenously for 1 month, followed by subcutaneous administration three times every week for 48 weeks. The 5-year survival rate on the treatment arm was 46%, compared to 37% for observation (p = 0.0237).
In the second trial, this dose and schedule of interferon was compared to a melanoma vaccine.92 This trial was stopped early after an interim analysis indicated a significant survival benefit favoring the interferon arm.
The toxicity of interferon can be significant. In the initial ECOG trial, a dose delay or reduction was required for toxicity at least once in 50% of the patients during the first month of intravenous interferon, and 48% of the patients during the 48 weeks of subcutaneous treatment.91 The most common toxicities included constitutional symptoms, myelosuppression, elevated liver enzymes and neurological toxicity. Most toxicities were reversible, and after 4 months of therapy, most patients remaining on study were able to complete therapy.
Patients with deep primary melanomas (>4.0 mm) or stage III disease should be considered for adjuvant therapy after definitive surgery. Other high-risk patients, including those with intermediate-thickness melanomas (1.0 mm to
4.0 mm) that are ulcerated or those patients who have had resection of distant metastases (stage IV), should be considered for adjuvant therapy.
Despite its limitations, Interferon alpha remains the only reasonable option outside the setting of a clinical trial for these high-risk patients. There are several additional strategies currently being investigated in the adjuvant setting, including vaccine and other immunotherapy-based approaches. Although these strategies remain experimental, consider patients at high risk for relapse for clinical trials.
• Systemic Therapy for Metastatic Disease. Once melanoma has spread beyond the regional nodal basin, the overall prognosis is quite poor and less than 5% of patients will be long-term survivors. Currently, cytotoxic chemotherapy has a limited role in the management of patients with disseminated melanoma. Dacarbazine (DTIC) is the most common chemotherapeutic agent that has been studied in this disease. Radiographic response rates range from 15% to 20% as a single agent.93 The majority of responses with any chemotherapeutic regimen is generally partial and lasts less than 3 to 4 months, with complete responses occurring in less than 5% of patients.94 Although DTIC-based combination regimens are associated with higher overall response rates, they have not improved survival when compared to single-agent DTIC in randomized trials.95
Like interferon, interleukin-2 (IL-2) is a biological agent with activity in advanced melanoma. IL-2 is a potent T-cell growth factor and immunomodulator. Based on activity in pre-clinical models, IL-2 was initially tested in patients in a high-dose schedule that required in-patient administration.96
In a recent update of the database generated from trials conducted by the National Cancer Institute and Cytokine Working Group, treatment with IL-2 resulted in an overall response rate of 16%, with 6% of patients achieving a complete remission.97
In contrast to the experience with chemotherapy, the responses were more prolonged, with median response duration of 5.9 months for the partial responders, and a median response duration that had not been reached for those patients who had achieved a complete response. There were no relapses in patients whose complete response lasted more than 30 months, suggesting that a small percentage of patients may be cured from their disease.
However, also like interferon, the toxicity with IL-2 is significant and only a limited number of patients will be candidates for this therapy. Combinations of chemotherapy and biologic agents, including interferon and IL-2, referred to as biochemotherapy, have shown promising results in initial testing, and randomized trials studying these regimens are ongoing.98
Still Work to be Done
Ultimately, there remains a need to develop novel treatment strategies for patients with metastatic melanoma, and most patients with metastatic melanoma should also be considered for clinical trials.
Unsuspected Drainage Patterns
With widespread use of lymphatic mapping and sentinel lymphadenectomy, more precise mapping of the drainage of a primary cutaneous melanoma has developed. With this precision, several previously held beliefs regarding lymphatic drainage have been dispelled.
The most notable flaw in our previous understanding of lymphatic mapping was the concept of “Sappey’s lines” around the trunk.80 Sappey believed lymphatic drainage never crossed midline and that there was an ambiguous zone within 5 cm of the umbilicus transversely. Clearly with the further delineation of lymphatic mapping, it’s clear that a patient’s lymphatic drainage pattern can cross midline and that zones of ambiguity extend much greater than just 5 cm within the umbilicus.87,82 Furthermore, areas that are not typically felt to be nodal-bearing regions have become very important in the accurate lymphatic mapping, including the intermuscular space83 just lateral to the scapula and the epitrochlear and popliteal nodes.84 These aberrant drainage patterns illustrate the complexity of the procedure as well as the importance of coordination between the nuclear medicine physicians and the surgeon.
Side Effects of LM/SL
The injections of the technetium-99m sulfur colloid, while uncomfortable to the patient, have no real side effects. The side effects of the injected mapping agents are predominantly due to the isosulfan blue dye. Following the intradermal injection of the isosulfan blue dye, some patients have a false drop in the oxygen saturation on the pulse oximeter. This doesn’t represent a true hypoxemia.
However, some patients can have anaphylactic-type reaction to the isosulfan blue dye. This can range from hypoxemia with bronchospasm to hypotension to blue urticaria.85 These anaphylactic-type reactions are usually easily supported with increasing FIO2, increasing positive and expiratory pressure, intravenous diphenhydramine and intravenous methylprednisolone. The Phase III trials for isosulfan blue dye only showed a 0.9% adverse effect incidence (5/543 patients) and all of these reactions were minor.86
Other complications associated with LM/SL involve local wound problems. These include cellulitis and/or infections that occur in 2% to 3% of patients. These are most commonly seen in the inguinal region lymph nodes.
About 5% to 7% of patients develop seromas at the SN excision site. Most seromas resolve with expectant management; however, some may require percutaneous aspiration.
Paraesthesias secondary to injury to one of the local cutaneous sensory nerves can occur. The true incidence of lymphedema following this procedure is not known. It’s being prospectively studied in a breast cancer trial by the American College of Surgeons Oncology Group Trial.
Lymphadenectomy Trial
Accrual to the Phase III randomized trial (Multicenter Selective Lymphadenectomy Trial, D.L. Morton, Principal Investigator) randomizing cutaneous melanoma patients to wide local excision with or without lymphatic mapping and sentinel lymphadenectomy is complete, and we await data analysis, but in the interim, a couple of things are clear. First, there is no role for elective lymph node dissection in patients with cutaneous melanoma. Second, lymphatic mapping and sentinel lymphadenectomy is a complex process that requires the coordination and expertise of three separate disciplines — nuclear medicine, surgery and pathology. All three disciplines are vital to ensure the high accuracy rates (99%) associated with this procedure.
Medical Treatment Options
• Adjuvant Therapy of High-risk Disease. Interferon alpha is the only approved therapy for patients with high-risk melanoma that has been surgically resected. However, the use of interferon in the adjuvant setting remains controversial. There have been several randomized trials that have reported significant improvements in disease-free survival when patients are treated with interferon compared to observation, but this hasn’t consistently translated into an improvement in survival.88-90
To date, there have been two randomized trials that have reported a significant beneficial impact on overall survival with interferon alfa after definitive surgery.91,92
The first trial, which led to the FDA approval of interferon, randomized patients with deep melanomas (greater than 4.0 mm) or with positive regional lymph nodes after surgery to 1 year of interferon or observation.91 In this trial, interferon was administered intravenously for 1 month, followed by subcutaneous administration three times every week for 48 weeks. The 5-year survival rate on the treatment arm was 46%, compared to 37% for observation (p = 0.0237).
In the second trial, this dose and schedule of interferon was compared to a melanoma vaccine.92 This trial was stopped early after an interim analysis indicated a significant survival benefit favoring the interferon arm.
The toxicity of interferon can be significant. In the initial ECOG trial, a dose delay or reduction was required for toxicity at least once in 50% of the patients during the first month of intravenous interferon, and 48% of the patients during the 48 weeks of subcutaneous treatment.91 The most common toxicities included constitutional symptoms, myelosuppression, elevated liver enzymes and neurological toxicity. Most toxicities were reversible, and after 4 months of therapy, most patients remaining on study were able to complete therapy.
Patients with deep primary melanomas (>4.0 mm) or stage III disease should be considered for adjuvant therapy after definitive surgery. Other high-risk patients, including those with intermediate-thickness melanomas (1.0 mm to
4.0 mm) that are ulcerated or those patients who have had resection of distant metastases (stage IV), should be considered for adjuvant therapy.
Despite its limitations, Interferon alpha remains the only reasonable option outside the setting of a clinical trial for these high-risk patients. There are several additional strategies currently being investigated in the adjuvant setting, including vaccine and other immunotherapy-based approaches. Although these strategies remain experimental, consider patients at high risk for relapse for clinical trials.
• Systemic Therapy for Metastatic Disease. Once melanoma has spread beyond the regional nodal basin, the overall prognosis is quite poor and less than 5% of patients will be long-term survivors. Currently, cytotoxic chemotherapy has a limited role in the management of patients with disseminated melanoma. Dacarbazine (DTIC) is the most common chemotherapeutic agent that has been studied in this disease. Radiographic response rates range from 15% to 20% as a single agent.93 The majority of responses with any chemotherapeutic regimen is generally partial and lasts less than 3 to 4 months, with complete responses occurring in less than 5% of patients.94 Although DTIC-based combination regimens are associated with higher overall response rates, they have not improved survival when compared to single-agent DTIC in randomized trials.95
Like interferon, interleukin-2 (IL-2) is a biological agent with activity in advanced melanoma. IL-2 is a potent T-cell growth factor and immunomodulator. Based on activity in pre-clinical models, IL-2 was initially tested in patients in a high-dose schedule that required in-patient administration.96
In a recent update of the database generated from trials conducted by the National Cancer Institute and Cytokine Working Group, treatment with IL-2 resulted in an overall response rate of 16%, with 6% of patients achieving a complete remission.97
In contrast to the experience with chemotherapy, the responses were more prolonged, with median response duration of 5.9 months for the partial responders, and a median response duration that had not been reached for those patients who had achieved a complete response. There were no relapses in patients whose complete response lasted more than 30 months, suggesting that a small percentage of patients may be cured from their disease.
However, also like interferon, the toxicity with IL-2 is significant and only a limited number of patients will be candidates for this therapy. Combinations of chemotherapy and biologic agents, including interferon and IL-2, referred to as biochemotherapy, have shown promising results in initial testing, and randomized trials studying these regimens are ongoing.98
Still Work to be Done
Ultimately, there remains a need to develop novel treatment strategies for patients with metastatic melanoma, and most patients with metastatic melanoma should also be considered for clinical trials.
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