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In Reply

University of Texas at El Paso, El Paso, TX

First, let us say that we are pleased that members of the group whose important meta-analyses we cited prominently in the Introduction to our article have read our contribution, and were sufficiently motivated to respond to it. Let us also repeat what we stated in the article—that we could not prove whether both groups improved overall survival and disease-free survival compared with surgery alone, or that neither did, because we did not include a control group for the reasons cited in the Discussion section. Furthermore, we did not test low-dose interferon alfa (IFN ) and Melacine (Corixa-Montana Corp, Hamilton, MT) separately, so we cannot ascertain the contribution of each. In mice, we would have set up three additional groups: one with a placebo, one with low-dose IFN alone, and one with active specific immunotherapy alone, to decide whether there was a difference between treated patients and controls, and between treatments with one or both components of the combination. Because we studied humans, that was clearly impossible.

We chose to report point estimates of treatment effect as survival probabilities with CIs at 1, 3, and 5 years for ease of interpretation. We thank Wheatley et al for pointing out and calculating an alternative measurement, more accurately, the hazard rate rather than the hazard ratio, and corresponding CI for each group. The hazard ratio for Melacine + low-dose IFN relative to high-dose IFN , calculated from the proportional hazards model, is 0.92 (95% CI, 0.70 to 1.21).

We must, however, respectfully disagree with the gist of the comments of Wheatley et al, at least in their present communication. Whether it was the combination of Melacine (active specific immunotherapy, or "vaccine" as they refer to it) with low-dose IFN rather than simply the low-dose IFN that caused any beneficial effect, was a question that we raised specifically, concluding that it was in fact the combination, because of the lack of evidence in published reports for significant activity of various "low-dose" regimens. Of course, we did not have access to the unpublished data now cited by Wheatley et al, that low-dose IFN may be equally effective as a high-dose regimen, and their suggestion that both may be effective regimens. We find their new conclusions somewhat perplexing, because their previous conclusions from a clinical trial with extended low-dose IFN at a level somewhat lower than our dose level, and their meta-analysis of results with high-dose IFN were among the most telling arguments against any effect on survival by IFN .^1,2 To quote from the abstract of their 2004 article in this journal² "The results from this study...do not indicate that extended-duration low-dose interferon is significantly better than observation alone in the initial treatment of completely resected high-risk malignant melanoma." Wheatley et al now call these two studies "qualitative" analyses; we regret having failed to note their additional "quantitative" analysis in 2003. It is difficult to know, however, whether their new information should now be taken as definitive simply because it is newer, or whether we should await further confirmatory information from a meta-analysis by an independent group. Perhaps it may be useful here to point out the hazards of any meta-analysis. Regardless of the large numbers surveyed, a meta-analysis has its own limitations, such as having to rely on studies whose populations and methods of treatment often vary from each other in ways that are difficult to detect from published information, either subtly or more markedly. Some degree of homogeneity must be assumed to permit an analysis at all. When "high," "low," and "ultra-low" levels of IFN are all surveyed, with several different schedules, obvious problems with interpretation arise, even when seemingly reliable hazards ratios or CIs emerge.

In any event, we did not rely solely on reports from Wheatley et al. The data from a variety of reviews and meta-analyses that were available to us when we wrote our article—as well as others that we were obliged to omit because of limitations to the length of the manuscript—still lead us to believe that IFN at either a high- or low-dose has only a marginal, if any, effect on prolonging overall survival, even though disease-free survival may perhaps be increased. As clinicians, and therefore advocates for patients, we would be very pleased were low-dose IFN effective alone, as we believe it is as an adjunct to active specific immunotherapy in our combination. Either situation would reduce both the toxicity and the considerable financial cost of the regimen for resected stage III melanoma, compared with the current "standard" regimen.

There is substantial evidence from several sources that Melacine by itself, and therefore presumably in the combination, can cause prolongation of overall survival. In patients with the class I haplotypes human leukocyte antigen (HLA) -A2, -B44, and -C3, survival was improved (P < .001) compared with untreated controls in resected stage II melanoma.³ This study by the Southwest Oncology Group was not a retrospective "subgroup" analysis. Instead, HLA class I typing was designed into the large randomized trial from its inception. HLA typing was performed on all patients before treatment —although they were not stratified by the result—specifically to try to confirm our analysis of the importance of those class I alleles in the objective response to Melacine in stage IV melanoma patients.⁴ In that study, the association of the presence of the same class I haplotypes with a significantly higher percentage of partial and complete remissions than in their absence was found with a rigorous statistical analysis. Prolongation of time-to-progression, often without shrinkage of the tumor, with a consequent extension of survival, is a characteristic noted mainly with active specific immunotherapy,^5,6 though also with interleukin-2.

It would, in our opinion, be a mistake and a tragic error to ignore even the possible value of virtually nontoxic specific immunization to improve survival at an early stage of melanoma, which is incurable at later stages, instead utilizing only the cytotoxic effect of high-dose IFN or relying on nonspecific "activation of immunity" by low-dose IFN .⁷ Schlom and colleagues⁶ have recently reviewed active specific immunotherapy for various cancers, and concluded that among its effects may be to improve longevity even without objective remissions, and perhaps to improve the response to subsequent therapies, which is difficult to prove but which we have also noted. It was the personal experience of many physicians in our study that Melacine per se was a valuable single agent, which led them to participate in the ad hoc group. There was in fact a discussion about whether IFN need be added, but because of the striking experience with sequential Melacine and IFN ,⁸ both agents were included.

We must finally caution that it is erroneous to assume, as Wheatley et al implicitly do, that the term "vaccine" can be applied generically to the wide variety of specific immunogens used in melanoma. The word does not have the precision of "interferon-alfa-2b," in referring to a specific molecule, nor does it denote even the general composition of the immunizing material. The article cited as reference 4 by Wheatley et al contains data on the testing of a whole melanoma cell preparation of Morton et al, which has never been directly compared with Melacine in a clinical trial, even though there are some similarities. Among the significant differences are that our adjuvant has always been the multivalent Detox (v the bacterium Bacille Calmette-Guérin), our melanoma cells are mechanically disrupted "lysates" derived from two cell lines (v a mixture of three irradiated "viable" cell lines), and our two schedules of injections are very different. Certainly we hope that Wheatley et al would agree at least that it would be incorrect to equate "vaccines" containing peptides or gangliosides, which despite their defined composition have thus far lacked clinical efficacy, with whole cell-derived preparations, such as vaccinia viral oncolysates⁹ and mechanical lysates such as Melacine (reviewed in Mitchell et al¹⁰), both of which have shown evidence of effectiveness. To quote from our paper, echoing Hersey's own interpretation of his trial with viral oncolysates in resected stage III melanoma, "[overall survival time] was 151 months in the vaccine-treated arm and 88 months in the control arm (95% CI, 0.64 to 1.02; P = .068). This CI, which barely included unity, did not rule out important gains from treatment." Although Melacine treatment was not associated with improved survival in a large randomized SWOG trial of resected stage II melanoma,¹¹ the authors stressed that a small but significant gain in survival could not be ruled out from their data, because of insufficient numbers of subjects. As we have already noted, those patients in the study who had the predicted "optimal" HLA Class I haplotypes showed significantly improved survival (P < .001).³

We therefore maintain our interpretation that active specific immunotherapy contributed to the longevity we observed, as part of a useful combination regimen.

At the outset, we realized that using a combination of agents might cause some confusion, especially if that combination proved effective, but we had only one opportunity to mount a clinical trial of this magnitude, requiring consensus among more than 25 investigators. We were obliged to use what seemed to be the best treatment available to us to compare with the "standard."

We thank Professor Wheatley and colleagues for sharing their new information and their current interpretations, and are pleased that our article moved them to do so.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

ACKNOWLEDGMENTS

We thank Dr Judith Abrams for her helpful comments on biostatistical issues.

REFERENCES

1. Hancock BW, Wheatley K, Harris S, et al: Adjuvant interferon in high-risk melanoma: The AIM HIGH Study—United Kingdom Coordinating Committee on Cancer Res randomized study of adjuvant low-dose extended-duration interferon alfa-2a in high-risk resected malignant melanoma. J Clin Oncol 22:53-61, 2004[Abstract/Free Full Text]

2. Wheatley K, Ives N, Hancock B, et al: Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials. Cancer Treat Rev 29:241-252, 2003[CrossRef][Medline]

3. Sosman JA, Unger JM, Liu PY, et al: Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: Impact of HLA class I antigen expression on outcome. J Clin Oncol 20:2067-2075, 2002[Abstract/Free Full Text]

4. Mitchell MS, Harel W, Groshen S: Association of HLA phenotype with response to active specific immunotherapy of melanoma. J Clin Oncol 10:1158-1164, 1992[Abstract]

5. Vaishampayan U, Abrams J, Darrah D, et al: Active immunotherapy of metastatic melanoma with allogeneic melanoma lysates and interferon . Clin Cancer Res 8:3696-3701, 2002[Abstract/Free Full Text]

6. Schlom J, Arlen PM, Gulley JL: Cancer vaccines: Moving beyond current paradigms. Clin Cancer Res 13:3776-3782, 2007[Abstract/Free Full Text]

7. Hengst JCD, Kempf RA, Kan-Mitchell J, et al: Immunological effects of recombinant interferon-alpha 2 in cancer patients. J Biol Resp Modif 2:516-527, 1983

8. Mitchell MS, Jakowatz J, Harel W, et al: Increased effectiveness of interferon alfa-2b following active specific immunotherapy for melanoma. J Clin Oncol 12:402-411, 1994[Abstract]

9. Hersey P, Coates AS, McCarthy WH, et al: Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: Results of a randomized trial. J Clin Oncol 20:4181-4190, 2002[Abstract/Free Full Text]

10. Mitchell MS, Darrah D, Stevenson L: Therapy of melanoma with allogeneic melanoma lysates alone or with interferon-alfa. Cancer Invest 20:759-768, 2002[CrossRef][Medline]

11. Sondak VK, Liu PY, Tuthill RJ, et al: Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: Overall results of a randomized trial of the Southwest Oncology Group. J Clin Oncol 20:2058-2066, 2002[Abstract/Free Full Text]

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