Questions? Mail them to us!
We subscribe to the HONcode
principlesof the Health On the Net Foundation
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of melanoma. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.
Information about the following is included in this summary:
This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.
This summary is available in a patient version, written in less technical language, and in Spanish.
Note: Separate PDQ summaries on Skin Cancer Treatment; Skin Cancer Prevention; and Skin Cancer Screening are also available.
Note: Estimated new cases and deaths from melanoma in the United States in 2009: [1]
Melanoma is a malignant tumor of melanocytes, which are the cells that make the pigment melanin and are derived from the neural crest. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate. Melanoma occurs predominantly in adults, and more than 50% of the cases arise in apparently normal areas of the skin. Early signs in a nevus that would suggest malignant change include darker or variable discoloration, itching, an increase in size, or the development of satellites. Ulceration or bleeding are later signs. Melanoma in women occurs more commonly on the extremities and in men on the trunk or head and neck, but it can arise from any site on the skin surface. A biopsy, preferably by local excision, should be performed for any suspicious lesions, and the specimens should be examined by an experienced pathologist to allow for microstaging. Suspicious lesions should never be shaved off or cauterized. Studies show that distinguishing between benign pigmented lesions and early melanomas can be difficult, and even experienced dermatopathologists can have differing opinions. To reduce the possibility of misdiagnosis for an individual patient, a second review by an independent qualified pathologist should be considered. [2]
Prognosis is affected by clinical and histological factors and by anatomic location of the lesion. Thickness and/or level of invasion of the melanoma, mitotic index, presence of tumor infiltrating lymphocytes, number of regional lymph nodes involved, and ulceration or bleeding at the primary site affect the prognosis. [3] [4] [5] [6] Microscopic satellites in stage I melanoma may be a poor prognostic histologic factor, but this is controversial. [7] Patients who are younger, female, and who have melanomas on the extremities generally have a better prognosis. [3] [4] [5] [6]
Clinical staging is based on whether the tumor has spread to regional lymph nodes or distant sites. For disease clinically confined to the primary site, the greater the thickness and depth of local invasion of the melanoma, the higher the chance of lymph node or systemic metastases and the worse the prognosis. Melanoma can spread by local extension (through lymphatics) and/or by hematogenous routes to distant sites. Any organ may be involved by metastases, but lungs and liver are common sites. The risk of relapse decreases substantially over time, though late relapses are not uncommon. [8] [9]
Following is a list of clinicopathologic cellular subtypes of malignant melanoma. These should be considered descriptive terms of historic interest only as they do not have independent prognostic or therapeutic significance.
Agreement between pathologists in the histologic diagnosis of melanomas and benign pigmented lesions has been studied and found to be considerably variable. One such study found that there was discordance on the diagnosis of melanoma versus benign lesions in 37 of 140 cases examined by a panel of experienced dermatopathologists. [1] For the histologic classification of cutaneous melanoma, the highest concordance was attained for Breslow thickness and presence of ulceration, while the agreement was poor for other histologic features such as Clark level of invasion, presence of regression, and lymphocytic infiltration. In another study, 38% of cases examined by a panel of expert pathologists had two or more discordant interpretations. These studies convincingly show that distinguishing between benign pigmented lesions and early melanoma can be difficult, and even experienced dermatopathologists can have differing opinions. To reduce the possibility of misdiagnosis for an individual patient, a second review by an independent qualified pathologist should be considered. [2]
The microstage of malignant melanoma is determined on histologic examination by the vertical thickness of the lesion in millimeters (Breslow classification) and/or the anatomic level of local invasion (Clark classification). The Breslow thickness is more reproducible and more accurately predicts subsequent behavior of malignant melanoma in lesions larger than 1.5 mm in thickness and should always be reported. Accurate microstaging of the primary tumor requires careful histologic evaluation of the entire specimen by an experienced pathologist. Estimates of prognosis should be modified by sex and anatomic site as well as by clinical and histologic evaluation.
The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define melanoma. [3]
Micrometastases are diagnosed after elective or sentinel lymphadenectomy; macrometastases are defined as clinically detectable lymph nodes metastases confirmed by therapeutic lymphadenectomy, or when any lymph node metastasis exhibits gross extracapsular extension.
Clinical staging includes microstaging of the primary melanoma and clinical and/or radiologic evaluation for metastases. By convention, it should be assigned after complete excision of the primary melanoma with clinical assessment for regional and distant metastases. [3]
With the exception of clinical stage 0 or stage IA patients (who have a low risk of lymphatic involvement and do not require pathologic evaluation of their lymph nodes), pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after sentinel node biopsy and, if indicated, complete lymphadenectomy. [3]
Melanomas that have not spread beyond the site at which they developed are highly curable. Most of these are thin lesions that have not invaded beyond the papillary dermis (Clark level I–II; Breslow thickness ≤1 mm). The treatment of localized melanoma is surgical excision with margins proportional to the microstage of the primary lesion; for most lesions 2 mm or less in thickness, this means 1 cm radial re-excision margins. [1] [2]
Melanomas with a Breslow thickness of 2 mm or more are still curable in a significant proportion of patients, but the risk of lymph node and/or systemic metastasis increases with increasing thickness of the primary lesion. The local treatment for these melanomas is surgical excision with margins based on Breslow thickness and anatomic location. For most melanomas more than 2 mm to 4 mm in thickness, this means 2 cm to 3 cm radial excision margins. These patients should also be considered for sentinel lymph node biopsy followed by complete lymph node dissection if the sentinel node(s) are microscopically or macroscopically positive. Sentinel node biopsy should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping. Patients with melanomas that have a Breslow thickness more than 4 mm should be considered for adjuvant therapy with high-dose interferon.
Some melanomas that have spread to regional lymph nodes may be curable with wide local excision of the primary tumor and removal of the involved regional lymph nodes. [3] [4] [5] [6] In a prospective randomized controlled trial (EST-1684), adjuvant high-dose interferon was shown to increase relapse-free survival and overall survival (OS) when compared to observation. [7] A subsequent randomized trial (EST-1690) conducted by the same group of investigators using the same high-dose interferon regimen confirmed the relapse-free survival but not the OS advantage. [8] A third randomized trial (E-2696) again demonstrated both a disease-free survival and OS advantage to high-dose interferon when compared to a ganglioside vaccine. [9] Clinicians should be aware that high-dose interferon regimens have substantial side effects, and patients should be monitored closely. Adjuvant therapy with lower doses of interferon have not been consistently shown to have an impact on either relapse-free survival or OS. [10] Adjuvant chemotherapy does not improve survival. A multicenter phase III randomized trial (EORTC-18832) of patients with high-risk primary limb melanoma did not show a benefit from isolated limb perfusion with melphalan in regard to disease-free survival or OS when compared to surgery alone. [11]
Melanoma that has spread to distant sites is rarely curable with standard therapy, though high-dose interleukin-2 (IL-2) has been reported to produce durable responses in a small number of patients. [12] [13] In patients with systemic metastasis confined to one anatomic site, long-term survival is occasionally achieved by complete resection of all metastatic disease. [14] [15] [16] [17] All patients with distant metastasis are appropriately considered candidates for clinical trials exploring new forms of treatment, including combination chemotherapy, biological response modifiers (such as specific monoclonal antibodies, interferons, IL-2, or tumor necrosis factor-alpha), vaccine immunotherapy, or biochemotherapy (chemoimmunotherapy).
Malignant melanoma has been reported to spontaneously regress; however, the incidence of spontaneous complete regressions is less than 1%. [18]
Patients with all stages of melanoma may be considered candidates for ongoing clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Patients with stage 0 disease may be treated by excision with minimal, but microscopically free, margins.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage 0 melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Standard treatment options:
Elective regional lymph node dissection is of no proven benefit for patients with stage I melanoma. Lymphatic mapping and sentinel lymph node biopsy for patients who have tumors of intermediate thickness and/or ulcerated tumors, however, may allow the identification of individuals with occult nodal disease who might benefit from regional lymphadenectomy and adjuvant therapy. [6] [7] [8] [9]
The International Multicenter Selective Lymphadenectomy Trial (MSLT-1) included 1,269 patients with intermediate-thickness (defined as 1.2 mm-3.5 mm in this study) primary melanomas. [10] There was no melanoma-specific survival advantage (the primary endpoint) for those patients randomly assigned to wide excision plus sentinel lymph node biopsy followed by immediate completion lymphadenectomy for node positivity versus patients randomly assigned to nodal observation and delayed lymphadenectomy for subsequent nodal recurrence at a median of 59.8 months. [10][Level of evidence: 1iiB]
This trial was not designed to detect a difference in the impact of lymphadenectomy in patients with microscopic lymph node involvement. [10]
Treatment options under clinical evaluation:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Standard treatment options:
Lymphatic mapping and sentinel lymph node biopsy have been used to assess the presence of occult metastasis in the regional lymph nodes of patients with stage II disease, potentially identifying individuals who may be spared the morbidity of regional lymph node dissection and individuals who may benefit from adjuvant therapy. [7] [8] [9] [10] [11] The diagnostic accuracy of sentinel lymph node biopsy has been demonstrated in several studies with a false-negative rate of 0% to 2%. [7] [12] [13] [14] [15] [16] Using a vital blue dye and a radiopharmaceutical agent, which are injected at the site of the primary tumor, the first lymph node in the lymphatic basin that drains the lesion can be identified, removed, and examined microscopically. If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure. To ensure accurate identification of the sentinel lymph node, lymphatic mapping and removal of the sentinel lymph node should be performed prior to wide excision of the primary melanoma.
To date, no published data from prospective trials are available on the clinical significance of micrometastatic melanoma in regional lymph nodes, but some evidence suggests that for patients with tumors of intermediate thickness and occult metastasis, survival is better among those patients who undergo immediate regional lymphadenectomy than it is among those who delay lymphadenectomy until the clinical appearance of nodal metastasis. [6] Because this finding arose from a posthoc subset analysis of data from a randomized trial, it should be viewed with caution.
The International Multicenter Selective Lymphadenectomy Trial (MSLT-1) included 1,269 patients with intermediate-thickness (defined as 1.2 mm–3.5 mm in this study) primary melanomas. [17] There was no melanoma-specific survival advantage (the primary endpoint) for those patients randomly assigned to wide excision plus sentinel lymph node biopsy followed by immediate completion lymphadenectomy for node positivity versus patients randomly assigned to nodal observation and delayed lymphadenectomy for subsequent nodal recurrence at a median of 59.8 months. [17][Level of evidence: 1iiB]
This trial was not designed to detect a difference in the impact of lymphadenectomy in patients with microscopic lymph node involvement. [17]
Adjuvant therapy:
The median OS for patients who received the high-dose regimen of interferon-alpha-2b was 3.8 years compared with 2.8 years for those in the observation group. [18][Level of evidence: 1iiA] A subset analysis of the stage II patients failed to show any benefit from high-dose interferon in terms of relapse-free survival or OS. Because the number of stage II patients was small in this subset analysis, it is difficult to draw meaningful conclusions from this study for this specific group.
A subsequent multicenter randomized controlled study (EST-1690) by the same investigators compared the same high-dose regimen of interferon-alpha to either a lower dose regimen (3 mU/m2 of body surface per day given subcutaneously 3 times a week every week for 104 weeks) or observation. [19] The stage entry criteria for this trial were the same as for the initial study. This 3-arm trial entered 642 patients. At a median follow-up of 52 months, a statistically significant relapse-free survival advantage was shown for all patients who received high-dose interferon (including the clinical stage II patients) when compared with the observation group (P = .03); however, no statistically significant relapse-free survival advantage for low-dose interferon was seen when compared with the observation group. The 5-year estimated relapse-free survival rates for the high-dose interferon, low-dose interferon, and observation groups were 44%, 40%, and 35%, respectively. Neither high-dose nor low-dose interferon yielded an OS benefit when compared with observation (HR = 1.0; P = .995). [19][Level of evidence: 1iiA]
Another multicenter prospective trial (E-1694) randomized patients with resected stage IIB or III melanoma to receive either the same high-dose interferon-alpha-2b regimen or a vaccine of conjugated GM2 melanoma antigen (GM2-KLH/QS-21)(GMK). [20] Of the 880 patients who were randomly assigned, 774 patients were eligible for efficacy analysis. This trial was closed after an interim evaluation indicated the inferiority of the GMK vaccine compared to treatment with interferon. A statistically significant relapse-free survival was found for high-dose interferon (HR = 1.47; P = .0015), as was a statistically significant OS benefit (HR = 1.52, P = .009). (In the intent-to-treat analysis, relapse-free survival [HR = 1.49]; OS [HR = 1.38].) For the population eligible for efficacy analysis, the greatest benefit was seen in the node-negative (stage IIB) subset (relapse-free survival [HR = 2.07]; OS [HR = 2.71]). [20][Level of evidence: 1iiA]
Clinicians should be aware that the high-dose regimens have substantial side effects and patients must be monitored closely.
Several randomized trials using lower doses of interferon have been conducted in the adjuvant setting. To date, no consistent evidence is available that intermediate or low doses of interferon improve relapse-free survival or OS. [21]
Treatment options under clinical evaluation:
An ongoing phase III trial (ECOG-1697) is evaluating the effect of 1 month of high-dose adjuvant interferon-alpha-2b versus observation on relapse-free survival and OS in patients with melanomas more than 1.5 mm in thickness and with or without a single microscopically positive lymph node. Results are pending from another phase III study (EORTC-18952) that randomized patients with stage II or stage III disease to adjuvant intermediate high-dose interferon-alpha-2b versus intermediate low-dose interferon-alpha-2b versus observation.
Autologous bone marrow transplantation with high-dose chemotherapy has not been shown to improve survival. [22]
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Standard treatment options:
A multicenter, randomized controlled study (EST-1684) has compared a high-dose regimen of interferon-alpha-2b (20 mU/m2 of body surface per day given intravenously for 5 days a week every week for 4 weeks, then 10 mU/m2 of body surface per day given subcutaneously 3 times a week every week for 48 weeks) to observation. [8] This study included 287 patients at high risk for recurrence after potentially curative surgery for melanoma (patients with melanoma >4 mm thick without involved lymph nodes or patients with melanomas of any thickness with positive lymph nodes). Patients who had recurrent melanoma involving only the regional lymph nodes were also eligible. At a median follow-up of 7 years, this trial demonstrated a significant prolongation of relapse-free survival (P = .002) and overall survival (OS) (P = .024) for patients receiving high-dose interferon.
The median OS for patients who received the high-dose regimen of interferon-alpha-2b was 3.8 years compared with 2.8 years for those in the observation group. [8][Level of evidence: 1iiA] A subset analysis of the stage II patients, however, failed to show any benefit from high-dose interferon in terms of relapse-free survival or OS. Because the number of stage II patients was small in this subset analysis, it is difficult to draw meaningful conclusions from this study for this specific group.
A subsequent multicenter randomized controlled study (EST-1690) by the same investigators compared the same high-dose regimen of interferon-alpha to either a lower dose regimen (3 mU/m2 of body surface per day given subcutaneously 3 times a week every week for 104 weeks) or observation. [9] The stage entry criteria for this trial were the same as for the initial study. This 3-arm trial entered 642 patients. At a median follow-up of 52 months, a statistically significant relapse-free survival advantage was shown for all patients who received high-dose interferon (including the clinical stage II patients) when compared with the observation group (P = .03); however, no statistically significant relapse-free survival advantage was seen for low-dose interferon when compared to the observation group. The 5-year estimated relapse-free survival rates for the high-dose interferon, low-dose interferon, and observation groups were 44%, 40%, and 35%, respectively. Neither high-dose nor low-dose interferon yielded an OS benefit when compared with observation (hazard ratio [HR] = 1.0; P = .995). [9][Level of evidence: 1iiA]
Pooled analyses of the two high-dose arms versus the two observation arms from both studies suggest that treatment confers a significant relapse-free survival advantage but not a significant benefit for survival. [9][Level of evidence: 1iiA]
Another multicenter prospective trial randomized patients with resected stage IIB or III melanoma to receive either the same high-dose interferon-alpha-2b regimen or a vaccine of conjugated GM2 melanoma antigen (GM2-KLH/QS-21)(GMK). [10] Of the 880 randomly assigned patients, 774 patients were eligible for efficacy analysis. This trial was closed after an interim evaluation indicated the inferiority of the GMK vaccine compared to treatment with interferon. A statistically significant relapse-free survival was found for high-dose interferon (HR = 1.47; P = .0015), as was a statistically significant OS benefit (HR = 1.52; P = .009). (In the intent-to-treat analysis, relapse-free survival [HR = 1.49]; OS [HR = 1.38].)
Clinicians should be aware that the high-dose regimens have significant toxic effects.
Several randomized trials using lower doses of interferon have been conducted in the adjuvant setting. To date, no consistent evidence is available that intermediate or low doses of interferon improve relapse-free survival or OS. [11]
Autologous bone marrow transplantation with high-dose chemotherapy has not been shown to improve survival. [12]
Treatment options under clinical evaluation:
An ongoing phase III trial (ECOG-1697) is evaluating the effect of 1 month of high-dose adjuvant interferon-alpha-2b versus observation on relapse-free survival and OS in patients with melanomas more than 1.5 mm in thickness, with or without a single microscopically positive lymph node. Another ongoing phase III trial (EORTC-18991) is evaluating adjuvant phenylated interferon-alpha-2b versus observation. Results are pending from a phase III study (EORTC-18952) that randomly assigned patients with stage II or stage III disease to adjuvant intermediate high-dose interferon-alpha-2b versus intermediate low-dose interferon-alpha-2b versus observation.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Standard treatment options:
Advanced melanoma is refractory to most standard systemic therapy, and all newly diagnosed patients should be considered candidates for clinical trials. Although advanced melanoma is relatively resistant to therapy, several biologic response modifiers and cytotoxic agents have been reported to produce objective responses.
The objective response rate to dacarbazine (DTIC) and the nitrosoureas, carmustine (BCNU) and lomustine, is approximately 10% to 20%. [4] [5] [6] [7] Responses are usually short-lived, ranging from 3 to 6 months, though long-term remissions can occur in a limited number of patients who attain a complete response. [4] [7] Other agents with modest single-agent activity include vinca alkaloids, platinum compounds, and taxanes. [4] [5] [8]
Phase II studies of three-drug combinations showed higher response rates (ranging from 22% to 45%) than were seen with single agents. [4] [5] Randomized trials comparing two-drug or three-drug combination regimens with DTIC alone have not consistently demonstrated any advantage for the combination, though these trials had limited sample sizes and insufficient power to detect small but clinically relevant differences in response or survival. [4]
The addition of tamoxifen to the three-drug combination regimen of cisplatin, BCNU, and DTIC (i.e., the Dartmouth regimen) showed high response rates in phase II studies, with a 20% complete response rate in several trials. [4] A phase III trial testing the three drugs with and without tamoxifen showed no benefit for the addition of tamoxifen, and the response rates in both study arms were once again in the 20% to 30% range. [9]
One trial directly compared DTIC alone to the three-drug regimen plus tamoxifen. [6] Results from this trial indicated no difference in tumor response or overall survival (OS) between the two treatment groups. The tumor response rate to DTIC was 10.2% compared with 18.5% for the three-drug combination plus tamoxifen (P = .09). Pending the outcome of further randomized, controlled trials, no combination regimen has yet been proven to be superior to DTIC alone.
The two biologic therapies that appear most active against melanoma are interferon-alpha and interleukin-2 (IL-2). Response rates for interferon range from 8% to 22%, and long-term administration on a daily or a three-times-per-week basis appears superior to once per week or more intermittent schedules. [10] Response to IL-2 regimens is similar and is in the 10% to 20% range. [11] [12] [13] Attempts to improve on this with the addition of lymphokine-activated killer cells (autologous lymphocytes activated by IL-2 ex vivo) and by tumor-infiltrating lymphocytes (lymphocytes derived from tumor isolates cultured in the presence of IL-2) have not improved response rates or durable remissions sufficiently to merit the expense and complexity of this therapy. Phase II studies testing combinations of interferon and IL-2 have demonstrated high response rates, but a phase III comparison of interferon and IL-2 compared with IL-2 alone in 85 patients did not show any benefit for the combination. [8]
Combinations of chemotherapy and biologics (chemoimmunotherapy or biochemotherapy) have been tested against chemotherapy alone. Four small phase III studies comparing DTIC and interferon with DTIC alone yielded conflicting results. [4] In a larger randomized trial involving 271 patients, 258 eligible patients received either DTIC alone; DTIC plus interferon; DTIC plus tamoxifen; or DTIC, interferon, and tamoxifen (2 × 2 factorial design). [14] No statistically significant differences were found in response rates, time-to-treatment failure, or survival among the different groups. Toxic effects were increased in the groups who received interferon. [14][Level of evidence: 1iiA] IL-2 has also been combined with cisplatin in several phase II trials [15] [16] [17] with encouraging response rates, but data supporting an improvement in survival are lacking. One prospective trial randomly assigned 102 patients to either chemotherapy (DTIC, cisplatin, and tamoxifen) alone or chemotherapy plus IL-2 and interferon-alpha-2b. [18] No statistically significant differences were found in objective response rate or OS between the treatment groups, and toxic side effects were increased in the group that received biochemotherapy.
A meta-analysis of 20 randomized trials (involving 3,273 patients) that compared single-agent DTIC to combination chemotherapy with or without immunotherapy found that the combination of DTIC and interferon-alpha produced a tumor response rate 53% greater (95% confidence interval, 1.10–2.13) than that seen with DTIC alone; [19] however, no difference in OS was found.
Ongoing phase II and III trials such as the EORTC-18951, UCCRC-9372, SFMH-BB-IND-5301, and E-E3695 trials, for example, are comparing complex biochemotherapy regimens (interferon, IL-2, and chemotherapy) to chemotherapy alone. Pending the results of these and future trials, no proof exists that biochemotherapy is superior to chemotherapy.
Treatment options under clinical evaluation:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Recurrent melanoma is resistant to most standard systemic therapy, and all newly diagnosed patients should be considered candidates for clinical trials. Deciding on further treatment depends on many factors, including prior treatment and site of recurrence, as well as individual patient considerations. Surgery is the most efficacious therapy for isolated recurrence in sites where it can be accomplished (including lymph node, skin, brain, lung, liver, and gastrointestinal sites). [1] [2] [3] Although advanced melanoma is relatively resistant to therapy, several biologic response modifiers and cytotoxic agents have been reported to produce objective responses.
The objective response rate to dacarbazine (DTIC) and the nitrosoureas, carmustine (BCNU) and lomustine, is approximately 10% to 20%. [2] [4] [5] [6] Responses are usually short-lived, ranging from 3 to 6 months, though long-term remissions can occur in a limited number of patients who attain a complete response. [4] [6] Other agents with modest single-agent activity include vinca alkaloids, platinum compounds, and taxanes. [2] [4]
Phase II studies of three-drug combinations showed higher response rates (ranging from 22%–45%) than were seen with single agents. [2] [4] Randomized trials comparing two-drug or three-drug combination regimens with DTIC alone have not consistently demonstrated any advantage for the combination, though these trials had limited sample sizes and insufficient power to detect small but clinically relevant differences in response or survival. [4]
The addition of tamoxifen to the three-drug combination regimen of cisplatin, BCNU, and DTIC (i.e., the Dartmouth regimen) showed high response rates in phase II studies with a 20% complete response rate in several trials. [4] A phase III trial testing the three drugs with and without tamoxifen showed no benefit for the addition of tamoxifen, and the response rates for both study arms were once again in the 20% to 30% range. [7]
One trial directly compared DTIC alone with the three-drug regimen plus tamoxifen. [5] Results from this trial indicated no difference in tumor response or overall survival (OS) between the two treatment groups. The tumor response rate to DTIC was 10.2% compared with 18.5% for the three-drug combination plus tamoxifen (P = .09). Pending the outcome of further randomized controlled trials, no combination regimen has yet been proven to be superior to DTIC alone.
The two biologic therapies that appear most active against melanoma are interferon-alpha and interleukin-2 (IL-2). Response rates for interferon range from 8% to 22% and long-term administration on a daily or a three-times-per-week basis appears superior to once per week or more intermittent schedules. [8] Response to IL-2 regimens is similar and is in the 10% to 20% range. [9] [10] [11] Attempts to improve on this with the addition of lymphokine-activated killer cells (autologous lymphocytes activated by IL-2 ex vivo) and by tumor-infiltrating lymphocytes (lymphocytes derived from tumor isolates cultured in the presence of IL-2) have not improved response rates or durable remissions sufficiently to merit the expense and complexity of these therapies. Phase II studies testing combinations of interferon and IL-2 have demonstrated high response rates, but a phase III comparison of interferon and IL-2 compared with IL-2 alone in 85 patients did not show any benefit for the combination. [12]
Combinations of chemotherapy and biologics (chemoimmunotherapy or biochemotherapy) have been tested against chemotherapy alone. Four small phase III studies comparing DTIC and interferon with DTIC alone yielded conflicting results. [4] In a larger randomized trial involving 271 patients, 258 eligible patients received either DTIC alone; DTIC plus interferon; DTIC plus tamoxifen; or DTIC, interferon, and tamoxifen (2 × 2 factorial design). [13] No statistically significant differences were found in response rates, time-to-treatment failure, or survival among the different groups. Toxic side effects were increased in the groups that received interferon. [13][Level of evidence: 1iiA]
IL-2 has also been combined with cisplatin in several phase II trials [14] [15] [16] with encouraging response rates, but data supporting an improvement in survival are lacking. One prospective trial randomly assigned 102 patients to either chemotherapy (DTIC, cisplatin, and tamoxifen) alone or chemotherapy plus IL-2 and interferon-alpha-2b. [17] No statistically significant differences were found in objective response rate or OS between the treatment groups, and toxic side effects were increased in the group that received biochemotherapy.
A meta-analysis of 20 randomized trials (involving 3,273 patients) that compared single-agent DTIC to combination chemotherapy with or without immunotherapy found that the combination of DTIC and interferon-alpha produced a tumor response rate 53% greater (95% confidence interval, 1.10–2.13) than that seen with DTIC alone. [18] No difference in OS was found, however.
Two ongoing phase III trials (E-E3695 and SWOG-S0008) are comparing complex biochemotherapy regimens (interferon, IL-2, and chemotherapy) to chemotherapy alone. Pending the results of these and future trials, no proof exists that biochemotherapy is superior to chemotherapy.
For patients with recurrent melanoma presenting in the extremities as in-transit or satellite metastases, surgical resection remains standard treatment for limited-volume disease. For multiple in-transit and/or satellite lesions, hyperthermic isolated limb perfusion (ILP) with melphalan has been associated with overall tumor response rates of approximately 80% to 90%, with complete response rates ranging from 7% to 82%. [19] [20] Small, single-institution studies have suggested that the addition of tumor necrosis factor-alpha (TNF-alpha) to melphalan-based ILP may further increase complete response rates (54%–90%). [20] [21] [22] [23] [24] A prospective, randomized multicenter study (ACSOG-Z0020) comparing hyperthermic ILP with melphalan alone to ILP with melphalan plus TNF demonstrated no statistically significant difference in 3-month complete response rates (25% melphalan vs. 26% melphalan plus TNF) or overall response (64% melphalan vs. 69% in melphalan plus TNF). [25][Level of evidence: 1iiDiv] Furthermore, ILP with melphalan plus TNF was associated with increased adverse events, including musculoskeletal complications of the perfused extremity resulting in two toxicity-related amputations.
Although melanoma is a relatively radiation-resistant tumor, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that patients with multiple brain metastases, bone metastases, and spinal cord compression may achieve symptom relief and some shrinkage of the tumor with radiation therapy. [26] [27] The most effective dose-fractionation schedule for palliation of melanoma metastatic to the bone or spinal cord is unclear, but high-dose-per-fraction schedules are sometimes used to overcome tumor resistance. A recently completed phase I and II clinical trial (MCC-11543) evaluated adjuvant radiation therapy plus interferon in patients with recurrent melanoma, and results are pending.
Treatment options:
(For more information on symptom relief, refer to the Pain summary.)
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Call 1-800-4-CANCER
For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. A trained Cancer Information Specialist is available to answer your questions.
Chat online
The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 9:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.
Write to us
For more information from the NCI, please write to this address:
Search the NCI Web site
The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.
There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.
Find Publications
The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Updated statistics with estimated new cases and deaths for 2009 (cited American Cancer Society as reference 1).
About PDQ
Additional PDQ Summaries
Important:
This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
Date last modified: 2009-07-01Sponsors:
The following organisations have financed parts of our PhD research project on
improving the quality of online cancer information.
| Back to the Cancer.gov
contents overview Questions? Mail them to us! |
We subscribe to the HONcode
principles of the Health On the Net Foundation
|