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Chemotherapy Compared With Biochemotherapy for the Treatment of Metastatic Melanoma: A Meta-Analysis of 18 Trials Involving 2,621 Patients

Natalie J. Ives, Rebecca L. Stowe, Paul Lorigan, Keith Wheatley

From the Birmingham Clinical Trials Unit, Division of Medical Sciences, Robert Aitken Institute, University of Birmingham, Edgbaston, Birmingham; and the CRUK Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom

Address reprint requests to Natalie Ives, MSc, Birmingham Clinical Trials Unit, Division of Medical Sciences, Robert Aitken Institute, University of Birmingham, Edgbaston, Birmingham B15 2TT; e-mail: n.j.ives{at}bham.ac.uk

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose To assess the effect of adding interferon- (IFN) ± interleukin-2 (IL-2) to chemotherapy in patients with metastatic melanoma.

Methods A published data meta-analysis of trials of biochemotherapy versus chemotherapy in patients with metastatic melanoma was undertaken. End points evaluated were rates of partial response (PR), complete response (CR) and overall (partial + complete) response (OR); response duration; progression-free survival; overall survival (OS); and toxicity. The only subgroup analysis performed was by type of immunotherapy, with trials divided according to whether IFN only or IFN and IL-2 were administered in the biochemotherapy arm.

Results Eighteen randomized trials were identified: 11 trials of chemotherapy ± IFN and seven trials of chemotherapy ± IFN and IL-2. More than 2,600 patients were entered onto the trials, with 555 responses and 2,039 deaths. There was a clear benefit for biochemotherapy for PR (odds ratio = 0.66; 95% CI, 0.53 to 0.82; P = .0001), CR (odds ratio = 0.50; 95% CI, 0.35 to 0.73; P = .0003) and OR (odds ratio = 0.59; 95% CI, 0.49 to 0.72; P < .00001). For OR, these benefits were significant for both the IFN (odds ratio = 0.60; 95% CI, 0.46 to 0.79; P = .0002) and IFN + IL-2 (odds ratio = 0.58; 95% CI, 0.44 to 0.77; P = .0001) subgroups. In contrast, there was no benefit overall in OS (odds ratio = 0.99; 95% CI, 0.91 to 1.08; P = .9), but there was evidence of heterogeneity of treatment effect between the individual trials (P = .006).

Conclusion This meta-analysis provides a comprehensive summary of all the data currently available, and shows that although biochemotherapy clearly improves response rates, this does not appear to translate into a survival benefit.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Malignant melanoma represents less than 10% of skin cancer cases, but accounts for 80% of skin cancer deaths.¹ The primary treatment for locoregional disease is surgical excision. Prognosis is related to disease stage at presentation, with Breslow thickness, tumor ulceration and lymph node involvement being independent prognostic factors.² The prognosis for patients with metastatic melanoma is poor. Single-agent dacarbazine (DTIC) has been the standard of care for many years, with response rates of 7.5% to 12.1% and a median survival of 6.4 to 7.8 months having been reported in recent large phase III trials.^3,4 The pattern of metastatic disease may influence response to therapy and survival, with patients with cutaneous or soft tissue disease faring better than those with visceral metastases.^2,4 Both interferon- (IFN) and interleukin-2 (IL-2) are active in malignant melanoma. Response rates of approximately 20% have been reported for low-dose IFN in earlier phase II studies,^5,6 and a clinical response rate of 55%, with a 15% complete pathologic response rate was reported in patients receiving high-dose IFN administered as neoadjuvant therapy for stage III disease.⁷ In contrast, reported response rates for low-dose IL-2 are 2% to 3%,⁸ though high-dose IL-2 has a reported response rate of 16% in selected patients, with 6% of patients achieving a complete response (CR) and more than half of these alive and disease free 2 years later.⁹ However, toxicity with high-dose IL-2 is considerable, and thus has limited its use to highly selected patients being treated in specialist centers with experience in this area. Studies of combination immunotherapy suggest that the combination of IFN and IL-2 is superior to IL-2 alone.¹⁰ In an attempt to improve both response rates and overall survival (OS), there have been several randomized trials comparing chemotherapy with chemotherapy combined with immunotherapy (IFN ± IL-2; ie, biochemotherapy). Although the results of these studies have not been consistent, many suggested that biochemotherapy is associated with an increased response rate, but has the disadvantage of increased toxicity.

To obtain an unbiased and reliable assessment of the true benefit of biochemotherapy in metastatic melanoma, a published data meta-analysis of all randomized trials comparing biochemotherapy and chemotherapy was performed.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Trial Identification
A systematic search for randomized controlled trials (between 1966 and September 2006) of combination chemotherapy and immunotherapy with IFN and/or IL-2 (ie, biochemotherapy) compared with (the same) chemotherapy regimen alone in metastatic melanoma was undertaken using an extension of the Cochrane search strategy.¹¹ This involved searching electronic databases including the Cochrane Library, MEDLINE, Embase, LILACS, PubMed, and Web of Science. This search was supplemented by hand-searching of general medical journals (eg, New England Journal of Medicine, British Journal of Medicine, The Lancet, and JAMA: The Journal of the American Medical Association) and journals in the cancer field (eg, Journal of Clinical Oncology, Journal of the National Cancer Institute, Annals of Oncology, Cancer Research, Cancer, European Journal of Cancer, British Journal of Cancer, Cancer Treatment Reviews, and Melanoma Research). Abstract books of conference proceedings from the main society meetings such as American Society of Clinical Oncology and World Melanoma Congress were also searched. Further information was sought from scanning reference lists of already retrieved papers, in particular review papers and from searches of the Cochrane Skin Group Ongoing Trials Register.

Sources of Data
Trial design and outcome data were extracted from either the full paper, meeting abstracts and/or conference presentations published on the Internet. If more than one report was found for a trial, the most recent was used where possible unless the results were similar between the two, but reported more accurately (eg, with hazard ratio, CI, and/or P value) in the earlier report.

End Points
Data on response rates (partial response [PR], CR, and overall response [PR + CR; OR]), duration of response, progression-free survival, OS, and toxicity were independently abstracted by two reviewers (R.L.S. and N.J.I.), with any discrepancies resolved by consensus (and if necessary with a third reviewer [K.W.]). These end points were analyzed for all trials for which data were available. The only subgroup analysis performed was by type of immunotherapy, with trials divided according to the type of immunotherapy administered in the biochemotherapy arm (IFN or IFN + IL-2).

Statistical Analysis
The results of each trial were combined using standard meta-analytic methods to estimate an overall effect for biochemotherapy versus chemotherapy-treated patients. To summarize these methods, for response rates and toxicity data, estimates of the treatment effects were obtained from the number of events reported in each arm and combined using the methods of Mantel and Haenszel.^12,13 This involved comparing the number of events observed (O) with the number of events that would have been expected (E), if the probability of that event was unrelated to treatment. For each trial the "observed minus expected" (O–E) difference and its variance was calculated for the biochemotherapy arm, and then used to calculate odds ratios with 95% CIs.¹⁴ For mortality, the methods described by Parmar et al for survival end points were used.¹⁵ Summing the statistics for each trial provides the overall statistics, which were then used to calculate reductions in the odds of each event. Differences in treatment effects between trials and subgroups of trials were assessed using standard tests of heterogeneity.¹⁴

For continuous variables (eg, duration of response), weighted mean difference methods were used.¹⁶ For each trial, the difference between the outcome measure means for each treatment group was calculated, along with its variance. These values were combined to give the overall weighted mean difference and its SE, with 95% CI for this pooled estimate of the mean difference.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Trials
Eighteen trials involving more than 2,600 patients were identified as eligible for inclusion in the meta-analysis (Fig 1). There were 11 trials (1,395 patients) of chemotherapy ± IFN ^17-27 and seven trials (1,226 patients) of chemotherapy ± IFN and IL-2.^28-36 Tables 1 and A1 (online only) give details of the trial designs, patient populations, treatment schedules and duration, patient accrual and study end points. In the 11 trials of chemotherapy ± IFN, most trials (n = 10) used a single-agent chemotherapy regimen, with seven trials using DTIC, 2 trials using temozolomide (TMZ), and one trial using vindesine. The other trial used combination chemotherapy (aranoza and cisplatin).²⁴ In contrast, all seven trials of chemotherapy ± IFN and IL-2 used a combination chemotherapy regimen of DTIC and cisplatin (with five trials using a triple chemotherapy regimen of DTIC and cisplatin combined with carmustine, vinblastine, or vindesine). There was one three-arm trial that compared DTIC and DTIC combined with two different doses of IFN (low-dose = 3 mU or intermediate dose = 9 mU).²⁰ Although this trial was not powered to compare the two IFN dose arms, there were no differences in activity between the two doses (though patients in the lower IFN dose group required less frequent dose reductions), so for the purpose of this analysis, the results from the two IFN dose groups were combined.

View larger version (40K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Improving the quality of reports of meta-analyses of randomised controlled trials (RCTs); the QUality Of Reporting Of Meta-analyses (QUOROM) statement flow diagram.

View larger version (29K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Partial response in trials of biochemotherapy (BCT) versus chemotherapy (CT) for metastatic melanoma. O–E, observed minus expected; var, variance; OR, odds ratio; DTIC, dacarbazine; TMZ, temozolomide.

View larger version (28K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Complete response in trials of biochemotherapy (BCT) versus chemotherapy (CT) for metastatic melanoma. O–E, observed minus expected; var, variance; OR, odds ratio; DTIC, dacarbazine; TMZ, temozolomide.

View larger version (30K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Overall response in trials of biochemotherapy (BCT) versus chemotherapy (CT) for metastatic melanoma. O–E, observed minus expected; var, variance; OR, odds ratio; DTIC, dacarbazine; TMZ, temozolomide.

Progression-Free Survival
Data on progression-free survival (assessed on all patients entered into the trials) was limited to seven trials (two chemotherapy ± IFN and five chemotherapy ± IFN and IL-2 trials). Time to disease progression was measured as the time between random assignment and disease progression, which was defined as either the appearance of new lesions or an increase in disease of more than 25%. Biochemotherapy delayed the time to disease progression (odds ratio = 0.80; 95% CI, 0.71 to 0.89; P = .0001), with no evidence of heterogeneity between individual trials (P = .4) or between the type of immunotherapy used (P = .5; Figure A2). Progression-free survival was correlated with response rate, which is expected because the two end points are related.

OS
Mortality data were reported at various time points (minimum, 1.5 years; maximum, 7 years) and were available in 15 trials (for three trials,^17,18,24 only response data were reported). The analysis was based on 2,466 patients (94%), with 2,039 deaths observed. In contrast to response rates, there was no benefit for biochemotherapy on OS (odds ratio = 0.99; 95% CI, 0.91 to 1.08; P = .9; Fig 5). In terms of absolute risk, this CI is compatible with a 3% to 4% benefit or harm for biochemotherapy. There was however, evidence of heterogeneity of the treatment effect between the individual trials (test for heterogeneity; P = .006), but not between the two immunotherapy subgroups (P = 1.0). Investigation into possible sources of this heterogeneity found that most of the heterogeneity was among the trials comparing chemotherapy ± IFN (test for heterogeneity; P = .002), and specifically the two small trials that reported a significant survival benefit with biochemotherapy (Fig 5).^21,22 When these two trials were removed from the analysis, the test for heterogeneity was no longer significant (P = .2; data not shown). Further investigation found no obvious reason why these two trials gave results that were inconsistent with the other trials. The two trials were of similar design and recruited similar patients to the other trials included in the meta-analysis, and there were no reported significant differences at baseline in the patient characteristics for the two studies (though in the Falkson study,²² patients randomly assigned to DTIC were 10 years older than DTIC and IFN patients; median age = 57.5 v 49 years).

View larger version (25K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5. Overall survival in trials of biochemotherapy (BCT) versus chemotherapy (CT) for metastatic melonoma. O–E, observed minus expected; var, variance; OR, odds ratio. () Data estimated from survival curve.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
This meta-analysis brings together all currently available data from randomized trials comparing a combination of chemotherapy and immunotherapy with the same chemotherapy regimen alone in patients with metastatic melanoma, thereby providing a reliable assessment of the role of biochemotherapy in advanced disease. Meta-analysis assesses the totality of the available evidence, thus avoiding selective emphasis on the most positive or negative trials. Furthermore, many randomized controlled trials are too small to reliably detect meaningful differences in important end points such as survival. Combining data from a number of trials gives greater statistical reliability, given that a much larger number of events are included in a meta-analysis than in any individual trial. This means that the risk of random errors, caused by the play of chance, is reduced.³⁸

The results of this meta-analysis show that response rates were higher in patients treated with biochemotherapy compared with those receiving chemotherapy alone. However, the increased response rate was associated with an increase in hematologic toxicity and no significant improvement in survival. Further, 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. In certain clinical situations, an increased response rate may be an important therapeutic outcome, perhaps leading to better symptom control or rendering a tumor mass operable. However, this needs to be balanced against the increased toxicity associated with the approach.

Although, overall, there was no survival benefit for biochemotherapy, there was heterogeneity of treatment effect across the trials. This was mainly explained by two small trials that showed reductions of more than 40% in the odds of death.^21,22 There was no obvious reason for this discrepancy, and chance may be a factor. The positive results of the study by Falkson (n = 73) published in 1995²² was of a similar design to a subsequent larger study (n = 271) by the same group that yielded negative results.²³ Similarly, the other trial reporting a large treatment effect was a small trial (n = 40) with just 25 deaths.²¹ It is of interest, though, that most of the variability comes from the single-center studies (test for heterogeneity across trials, P = .001), whereas the multicenter studies are much more consistent with one another (test for heterogeneity, P = .5).

The overall response rate was significantly higher in the biochemotherapy arm, with similar improvements across the two biochemotherapy regimens (IFN and IFN + IL-2). Indirect comparison of the two immunotherapy regimens showed no difference, suggesting that the addition of low-dose IL-2 to IFN has no advantage in this situation, a finding in keeping with a recent study from the European Organisation for Research and Treatment of Cancer.³⁹ In this meta-analysis, all but one of the chemotherapy ± IFN trials used a single-agent chemotherapy regimen compared with multi-agent regimens in the trials of chemotherapy ± IFN and IL-2. A number of studies have shown no benefit for combination chemotherapy over single-agent regimens.^40-42 Although such indirect comparisons require cautious interpretation, the lack of difference in the overall response rate across the two biochemotherapy regimens (IFN and IFN + IL-2) supports this hypothesis and 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.

Although the results for overall response were similar for both biochemotherapy regimens, when the responses were split into either a PR or CR, there were significant differences between the two immunotherapy subgroups. Patients receiving IFN and IL-2 were significantly more likely to achieve a PR (odds ratio = 0.55; P < .0001), than those patients who received just IFN (odds ratio = 0.81; P = .2). In contrast, a CR was more likely in those patients receiving just IFN. So although, the direction of the treatment effect was the same for both immunotherapy subgroups (ie, favored biochemotherapy), the size of the benefit appeared to differ. Investigation into possible reasons for this (eg, differences in trial design such as dose or total dose of treatment or the types of patients entered) revealed no obvious explanation for these differences. Possible clinical explanations include differences in pattern of disease (eg, M1a v M1c).

A recent Cochrane review addressed the same question as this meta-analysis, but included a study that was excluded from our review because the results were confounded (the trial compared DTIC, cisplatin, carmustine, and tamoxifen v DTIC and IFN⁴²).⁴³ Furthermore, this meta-analysis includes response data from an additional study,¹⁸ includes updates of data for two trials,^22,27 expands the discussion on the two biochemotherapy regimens assessed, and includes an analysis of OS that includes all trials, whereas the Cochrane review reported OS data for just eight of the 18 trials.

The main purpose of the meta-analysis was to present all available evidence in a systematic, quantitative, and unbiased fashion. Clinicians can then make treatment decisions based on this evidence and discussion with the patient on what they hope to achieve. 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.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Natalie J. Ives, Rebecca L. Stowe, Keith Wheatley

Collection and assembly of data: Natalie J. Ives, Rebecca L. Stowe

Data analysis and interpretation: Natalie J. Ives, Rebecca L. Stowe, Paul Lorigan, Keith Wheatley

Manuscript writing: Natalie J. Ives, Rebecca L. Stowe, Paul Lorigan, Keith Wheatley

Final approval of manuscript: Natalie J. Ives, Rebecca L. Stowe, Paul Lorigan, Keith Wheatley

	Appendix

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Duration of response (months) in trials of biochemotherapy (BCT) versus chemotherapy (CT) in metastatic melanoma. PR, partial response; CR, complete response.

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A2. Progression-free survival (PFS) in trials of biochemotherapy (BCT) versus chemotherapy (CT) for metastatic melanoma. O–E, observed minus expected; var, variance; OR, odds ratio. () Data estimated from survival curve.

View larger version (22K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A3. Hematologic toxicity (grade 3) in trials of biochemotherapy (BCT) versus chemotherapy (CT) for metastatic melanoma. O–E, observed minus expected; var, variance; OR, odds ratio.

	ACKNOWLEDGMENTS

 
We thank the original trial teams and the individuals who performed the trials that contributed to this meta-analysis, and the patients who agreed to help improve the treatment of malignant melanoma treatment by taking part in these trials.

	NOTES

 
Supported by the National Co-ordinating Centre for Research Capacity Development.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted May 15, 2007; accepted September 7, 2007.

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