Recurrent Melanoma
Current Clinical Trials
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).[1-3] 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%.[2,4-6]
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.[9-11] 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 [14-16]
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%).[20-24] 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:
- Resection of isolated single or localized metastases from skin, visceral, or
brain sites in selected patients is sometimes associated with prolonged
survival.
- Hyperthermic isolated limb perfusion for in-transit and/or satellite extremity recurrences.[25] Isolated limb infusion is being studied as a minimally invasive regional chemotherapy technique for extremity recurrences.[28,29]
- Palliative radiation therapy for bone, spinal cord, or brain metastases.
- Palliative biologic therapy and/or chemotherapy in phase I and II clinical
trials.
- Palliative treatment with interleukin-2 or interferon can occasionally
result in prolonged survival.
(For more information on symptom relief, refer to the Pain summary.)
Current Clinical Trials
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.
References
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Rosenberg SA, Yang JC, Schwartzentruber DJ, et al.: Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol 17 (3): 968-75, 1999.
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Huncharek M, Caubet JF, McGarry R: Single-agent DTIC versus combination chemotherapy with or without immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients from 20 randomized trials. Melanoma Res 11 (1): 75-81, 2001.
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Skene AI, Bulman AS, Williams TR, et al.: Hyperthermic isolated perfusion with melphalan in the treatment of advanced malignant melanoma of the lower limb. Br J Surg 77 (7): 765-7, 1990.
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