Single-Agent Chemotherapy Still Preferred To Biological Therapies For Treatment Of Metastatic Melanoma

Main Category: Cancer / Oncology
Article Date: 15 Jan 2008 - 14:00 PDT

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There is no evidence to suggest that clinicians should choose a combination of biological therapies---treatments that boost or restore the ability of the body's defense system to fight disease---and chemotherapy over the commonly used single-agent chemotherapy regimen for patients with metastatic melanoma, according to the results of a meta-analysis published in the Journal of Clinical Oncology.

Single-agent dacarbazine has been the standard of care for patients with metastatic melanoma for many years and results in median survival times of 6.4 to 7.8 months, according to the results of phase III trials. Although patients whose disease is localized have the option of a surgical excision, which produces far better survival rates, if the disease has spread then prognosis is poor and related to several prognostic factors including the stage of disease, Breslow thickness (the actual depth of the melanoma lesion), whether or not the tumour is ulcerated, and lymph node involvement.

To improve survival rates in patients whose disease has spread, several biological treatments have also been tested for patients with this cancer. Interferon-alpha (IFN) and interleukin-2 (IL-2) have anti-melanoma activity and have been tested in both low and high doses combined together or with chemotherapy in various studies. Although the results of clinical trials have been inconsistent, overall the evidence suggests that combining biological therapies with chemotherapy is associated with an increased response rate, but this treatment strategy has the disadvantage of increased toxicity.

To obtain an unbiased and reliable assessment of the true benefit of biochemotherapy in metastatic melanoma, Natalie Ives and colleagues from Birmingham and Manchester in the UK did a meta-analysis of all randomised trials comparing biochemotherapy and chemotherapy. They identified the studies for their analysis through a systematic search of trials published between 1966 and September 2006 in electronic databases. Any publications describing trials of combination chemotherapy and immunotherapy with IFN or IL-2 compared with chemotherapy alone in metastatic melanoma were included. The results of each trial were subsequently combined to estimate an overall effect for biochemotherapy versus chemotherapy-treated patients reflecting all the evidence.

Database searching identified 18 trials involving more than 2600 patients for the analysis. 11 of these compared chemotherapy plus IFN and 7 tested chemotherapy, IFN, and IL-2. Response data were available for 91% of the patients (n=2381) and when all this information was combined, there was a clear benefit for biochemotherapy in terms of partial, complete and overall responses. For overall response, the benefits were significant for whether IFN was administered alone or with IL-2.

In terms of duration of response, there was no difference between the two types of treatment, with duration of response being just 0.6 days longer in the biochemotherapy arm compared with chemotherapy alone. Mortality data, which were reported at various time points among the trials, up to a maximum of 7 years, were available in 15 trials covering 94% of the patient population. There were 2039 deaths observed among this group and, in contrast to the trend observed for response rates, there was no benefit for biochemotherapy on overall survival.

There were 11 trials for which toxicity data were useable, and these results show that the numbers of patients experiencing grade 3 or worse haematological toxicity (thrombocytopenia, neutropenia, or leukopenia) were greater in the biochemotherapy arm than in chemotherapy alone.

Ives and colleagues write of their analysis that it shows response rates were higher in patients treated with biochemotherapy than in those receiving chemotherapy alone. However, the increased response rate was associated with an increase in haematological toxicity and no significant improvement in survival. Furthermore, despite a better response rate in those patients receiving biochemotherapy, there was no difference between the two arms with regard to the median duration of response, though the data on duration of response was poorly reported and thus should be interpreted with caution.

Consistent with recent findings, the researchers found that indirect comparison of the two immunotherapy regimens showed no difference, suggesting that the addition of low-dose IL-2 to IFN confers no advantage. What is more, write the authors the similarity of overall response rates between the two biochemotherapy regimens further "suggests that it is unnecessary to subject patients to combination chemotherapy regimens that yield similar response results, but have greater toxicity, to that of single-agent chemotherapy."

"In the absence of a survival benefit with biochemotherapy, single-agent chemotherapy is currently considered the standard of care for the majority of patients receiving treatment for advanced melanoma outside the realm of a clinical trial, and the results of this meta-analysis provide no reason to change this," conclude the authors.

Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2621 patients.
Ives NJ, Stowe RL, Lorigan P, Wheatley K. J Clin Oncol December 1, 2007; 25: 5426-34.

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