Cytotoxic chemotherapy may have a palliative benefit in some patients with metastatic melanoma, but it usually does not lead to durable responses and has not been proven to have a survival benefit. Preclinical and clinical data have revealed the susceptibility of melanoma to approaches designed to modulate the immune system. Some immunotherapeutic approaches have led to durable complete responses in a small subset of patients, although it has been challenging to predict which patients will respond to immunotherapy. The successes and failures of melanoma immunotherapy have contributed profoundly to our understanding of basic immunology.
IL-2 is a lymphokine that stimulates T-cell proliferation and function; augments natural killer cell proliferation and cytotoxic activity; and triggers the release by activated lymphocytes of cytokines such as interferon gamma(Drug information on interferon gamma), tumor necrosis factor, and others. High-dose bolus IL-2 (HD IL-2) was approved by the FDA in 1998 for the treatment of metastatic melanoma due to the potential for durable complete responses in a small number of patients.
In a pooled analysis of 270 patients treated with HD IL-2, the ORR was 16% (CR 6%, PR 10%).[32,33] Sixty percent of the complete responders had durable responses that were ongoing at the time of the report (duration > 42 months to > 122 months). Forty-four percent of responders were long-term survivors beyond 5 years (range, > 70 months to > 150 months). None of the responding patients experienced disease progression after 5 years. Also, some patients who had relapsed after having a complete response or were partial responders with minimal residual disease underwent surgical resection of the disease and achieved prolonged relapse-free survival, thus suggesting the potential for long-term control of micrometastatic disease by HD IL-2.
HD IL-2 is administered at a dose of 600,000 to 720,000 IU/kg by IV bolus every 8 hours on days 1 to 5 (cycle 1) and days 15 to 19 (cycle 2), with a maximum of 28 doses per each two-cycle course. Response evaluation is usually performed 4 weeks after the second cycle. Courses of HD IL-2 may be repeated in patients with evidence of tumor regression. The administration of HD IL-2 requires hospitalization with intensive monitoring and is mostly limited to specialized centers with personnel who are experienced in the management of this regimen.
Major toxicities associated with HD IL-2 include fever, chills, hypotension, increased capillary permeability, cardiac arrhythmias, oliguria, volume overload, delirium, and rash. Bacterial sepsis can also complicate HD IL-2 administration, and antibiotic prophylaxis is recommended. The risk of multiorgan complications usually limits HD IL-2 administration to younger patients with excellent performance status and organ function.
Due to the toxicities associated with HD IL-2, it would be helpful to limit its administration to patients who are more likely to respond. However, pretreatment prediction of responses to HD IL-2 has been an elusive goal so far. A large retrospective analysis of 305 patients who received HD IL-2 alone could not identify any pretreatment factors that were strongly associated with increased ORR or long-term survival. An analysis of 379 patients who received HD IL-2 in combination with vaccines identified those patients with cutaneous and/or subcutaneous metastases only as having a significantly higher chance of responding, as compared to patients with disease in other sites (46% vs 13%, respectively; P = .00005). However, responses with HD IL-2 have been noted in patients with visceral metastases and/or large tumor burdens.[33,34]
Interferon alfa-2b (IFN-a, Intron A), approved by the FDA for adjuvant therapy of resected high-risk melanoma, is associated with modest antitumor activity (ORR 22%, CR < 4%) in patients with metastatic melanoma. Responses, however, are limited to patients with low-volume disease in cutaneous or soft-tissue sites and are sometimes delayed, with onset many months after initiation. The common toxicities associated with IFN-a, such as fever, chills, fatigue, myalgias, psychocognitive impairment, and autoimmune events, adversely affect patient quality of life, especially with long-term administration. Pegylated IFN-a (PEG-Intron) permits more convenient administration with good tolerability and has been suggested to have similar efficacy in metastatic disease. Due to the low likelihood of response and the cumulative toxicities, IFN-a monotherapy has limited utility in the treatment of stage IV melanoma. However, the antitumor activity of IFN-a has led to extensive investigation of its use in combination with other therapies.
To summarize, HD IL-2 may lead to durable complete responses in a subset of patients and should be considered in patients who are likely to tolerate it. The success of HD IL-2 in inducing durable complete responses in some patients with metastatic melanoma has provided “proof of concept” for the field of immunotherapy, and has fuelled extensive investigation of novel immunotherapeutic approaches.
The term biochemotherapy refers to regimens that combine cytotoxic agents with IFN-a and/or IL-2. Early single-institution trials of biochemotherapy demonstrated promising antitumor activity. This led to the rapid development of many such regimens and subsequently to an extensive investigation comparing these regimens to chemotherapy alone. The pivotal randomized trials comparing combinations of chemotherapy with IL-2 and/or IFN-a to chemotherapy alone are listed in Table 2.
As is evident from the results of these trials, biochemotherapy is sometimes associated with a higher response rate, but this has not resulted in significant improvement in overall survival. These findings were further confirmed in a meta-analysis of 18 trials involving 2,621 patients. The results of this meta-analysis suggested a clear improvement in ORR with biochemotherapy (odds ratio = 0.59; 95% confidence interval [CI] = 0.49–0.72; P < .00001) but no benefit in OS (odds ratio = 0.99; 95% CI = 0.91–1.08; P = .9). The increased ORR with biochemotherapy comes at the cost of significantly increased toxicity compared to chemotherapy alone.
Biochemotherapy may provide a palliative benefit in patients who are symptomatic and/or have rapidly progressive disease. However, the lack of survival benefit with biochemotherapy suggests that alternative therapies such as HD IL-2 or investigational agents should be considered for such patients once their disease has been stabilized. Biochemotherapy requires a reduction in the IL-2 dose to combine it safely with chemotherapy, and hence, the possibility of a durable CR may be compromised. Indeed, preclinical and clinical evidence suggests the importance of dose-intensity of IL-2 for achieving durable responses. A recent report suggested that 16% of patients whose disease had progressed after receiving biochemotherapy had a complete remission with subsequent HD IL-2. Most responders to biochemotherapy eventually experience disease progression, often in the central nervous system. This has led to substitution of temozolomide(Drug information on temozolomide) for dacarbazine(Drug information on dacarbazine) in many biochemotherapy regimens. However, the recently reported results of a phase III trial comparing cisplatin(Drug information on cisplatin)/IL-2/temozolomide vs cisplatin/IL-2/dacarbazine did not show any benefit of temozolomide in preventing brain metastases.
To summarize, biochemotherapy may increase response rates compared to chemotherapy alone but is associated with increased toxicity without a definite survival benefit.