Correspondence
Cytokine Therapy in Metastatic Renal Cancer
N Engl J Med 1998; 339:849-851September 17, 1998
- Article
To the Editor:
We have three questions about the article by Gleave et al. (April 30 issue)1 on cytokine therapy in patients with metastatic renal cancer. First, the incidence of “spontaneous” remissions was higher than that previously reported. Was there any histologic confirmation of metastatic disease in the patients who had responses? Second, are there any data on second-line therapy? It is possible that treatment with interferon alfa or interleukin-2 in a large proportion of patients may have skewed the final survival curves. Finally, survival at two years appears to have been 5 percent in the placebo group, whereas it was 25 percent in the interferon group. How many patients were followed for the full two years, and is this apparent difference significant?
1 ReferencesWalter M. Stadler, M.D.
Nicholas J. Vogelzang, M.D.
University of Chicago, Chicago, IL 606371
Gleave ME ,Elhilali M ,Fradet Y , et al. Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. N Engl J Med 1998;338:1265-1271
Full Text | Web of Science | Medline
To the Editor:
Negrier et al. (April 30 issue)1 compared the effects of interleukin-2, interferon alfa-2a, and a combination of the two agents. They state that in the intention-to-treat analysis, the rate of response to combination therapy (18.6 percent) exceeded that to interleukin-2 alone (6.5 percent) or interferon alfa-2a alone (7.5 percent); however, there was no significant difference in survival. It is important to note that the interleukin-2 regimen used in this study was a continuous-infusion regimen that is “widely used in Europe,” but the U.S. labeling for interleukin-2 specifies a 15-minute infusion every 8 hours. Although the initial application to the Food and Drug Administration contained limited data in support of both regimens, additional data requested and received by the agency led to the conclusion that, although the toxicity of the two regimens was similar, the regimen of doses given every eight hours was associated with a markedly higher response rate (15 percent).2
2 ReferencesSusan Jerian, M.D.
Patricia Keegan, M.D.
Jay Siegel, M.D.
Food and Drug Administration, Rockville, MD 208521
Negrier S ,Escudier B ,Lasset C , et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. N Engl J Med 1998;338:1272-1278
Full Text | Web of Science | Medline2
Transcript of proceedings, Department of Health and Human Services, Public Health Service, Food and Drug Administration, Biological Response Modifiers Advisory Committee, January 17, 1992:4-216.
To the Editor:
Gleave et al. are to be commended for their study of interferon gamma in patients with renal-cell carcinoma. This study had important negative results, including the demonstration that renal-cell carcinoma may regress spontaneously, and it shows that controlled trials are essential for this disease. However, the study design may have resulted in a lost opportunity to observe responses because of the use of conventional response criteria.
Interferon gamma was discontinued if there was disease progression, which was determined according to the standard criteria of more than a 25 percent increase in the size of at least one lesion or the appearance of any new lesions. This definition is appropriate for cytotoxic regimens; however, the kinetics of immunologically mediated responses may be slower, and there may be an initial increase in the size of the tumor before it regresses. For example, in a study of MAGE-3 HLA-A1–associated peptides in patients with metastatic melanoma,1 one patient had disease progression, with an increase in the size of three pulmonary metastases plus the appearance of two new lesions after three months of peptide vaccination. Two months later, there was substantial improvement in the disease, and further vaccination was given, with a good response. In the study by Gleave et al., most patients had progressive disease by two months, and interferon gamma was withdrawn. Some of these patients might have had a subsequent response. The number of patients who continued to receive interferon gamma was too small to determine whether continued treatment was effective.
In the article by Negrier et al., it is not possible to determine whether the patients with stable disease or responses at 25 weeks were the same as those at the 10-week evaluation. Is this information available?
New criteria for a clinical response may need to be established for patients undergoing biologic therapy. It would be appropriate to design future studies in such a way as to identify responses in patients who might initially appear to have progressive disease. Such a study design would allow continued therapy in the face of clinically unimportant progression, so long as symptoms or toxicity did not dictate alternative treatment; examples might include new or progressive asymptomatic pulmonary or cutaneous metastases. We are now including such criteria in our own immunotherapy studies.
Finally, I would like to point out that although I have the same name as one of Gleave's coauthors, our only relationship is that we confound each other's Medline searches.
1 ReferencesIan D. Davis, M.B., B.S., Ph.D.
Austin and Repatriation Medical Centre, Heidelberg, Victoria 3084, Australia1
Marchand M ,Weynants P ,Rankin E , et al. Tumor regression responses in melanoma patients treated with a peptide encoded by gene MAGE-3. Int J Cancer 1995;63:883-885
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: The results of the Canadian Urologic-Oncology Group study comparing placebo with interferon gamma for the treatment of metastatic renal-cell carcinoma are provocative because they undermine confidence in reported phase 2 data on this disease.1 Had a placebo group not been included in the study, we might have erroneously concluded that interferon gamma produced a small but definite benefit, which might have led to its addition to our therapeutic armamentarium. The placebo-controlled design permitted evaluation of more than just conventional response rates; it also permitted evaluation of the effects of interferon gamma on the time to disease progression, which is a critical end point in assessing the efficacy of biologic agents. Ethical approval was facilitated by ensuring that all patients had the opportunity to receive interferon gamma; unblinding with the option of crossover to treatment with interferon gamma was therefore necessary if there was radiologic evidence of disease progression.
Stadler and Vogelzang express concern about the apparently high spontaneous response rate (7 percent) and wonder whether this resulted from the inclusion of patients in whom metastases were not histologically confirmed. The true incidence of spontaneous remission is unclear because of the lack of placebo-controlled studies, but in uncontrolled trials, the reported incidence has ranged from 0 to 7 percent.2-4 All the patients in the placebo group who had responses (except one with obvious bilateral lung metastases) had histologic documentation of metastatic renal-cell carcinoma, and all had subsequent disease progression during the course of the study.
It is difficult to rule out an effect of second-line therapy in any clinical trial. It was possible to perform this placebo-controlled study in Canada because interleukin-2 and interferon alfa were not approved for metastatic renal-cell carcinoma in Canada and were rarely used there. Although used sporadically, second-line therapy was not recorded on case-report forms, because patients with radiologic documentation of disease progression were withdrawn from the study and treated at the discretion of the local physicians. Either way, the crossover design ensured that both groups were exposed to interferon gamma, and the two groups were equally likely to receive second-line therapy after progression with interferon gamma (although there was a bias in favor of the interferon gamma group because of the earlier opportunity to receive additional treatments). Finally, although there was apparently improved survival at two years in the interferon gamma group, this difference was not statistically significant because of the small numbers of patients. Responses were more durable and survival was prolonged in the 4 percent of patients who had responses while receiving interferon gamma, but these differences were not statistically significant because of the small sample.
4 ReferencesMartin Gleave, M.D.
University of British Columbia, Vancouver, BC V5Z 4E3, CanadaMostafa Elhilali, M.D.
McGill University, Montreal, QC H3G 1Y6, Canada1
Gleave ME ,Elhilali M ,Fradet Y , et al. Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. N Engl J Med 1998;338:1265-1271
Full Text | Web of Science | Medline2
Davis SD ,Koizumi JH ,Pitts WR . Spontaneous regression of pulmonary metastases from renal cell carcinoma. Urology 1989;33:141-144
CrossRef | Web of Science | Medline3
Vogelzang NJ ,Priest ER ,Borden L . Spontaneous regression of histologically proved pulmonary metastases from renal cell carcinoma: a case with 5-year followup. J Urol 1992;148:1247-1248
Web of Science | Medline4
de Riese W ,Goldenberg K ,Allhoff E , et al. Metastatic renal cell carcinoma (RCC): spontaneous regression, long-term survival and late recurrence. Int Urol Nephrol 1991;23:13-25
CrossRef | Medline
Author/Editor Response
Davis raises the question of a possible delay in the occurrence of an immunologically mediated tumor response in patients receiving immunotherapy and asks whether the patients in our trial who had responses at week 10 were the same as those who had responses at week 25. Of the 46 patients with responses at week 10, 28 continued to have responses, 12 had disease progression, and 6 were not evaluated at week 25. In addition, two patients who initially had minor tumor regression (less than 50 percent) had objective responses at week 25, according to the criteria of the World Health Organization (WHO)1 (more than 50 percent regression). In addition, two patients considered to have progressive disease at week 10 had objective responses at week 25. Each of these two patients initially had a mixed response to treatment: several metastases regressed, whereas another increased by more than 25 percent. These cases were classified as progressive disease by the review committee,2 which applied the WHO criteria strictly.
Of the 107 patients with disease stabilization at week 10, 31 continued to have stable disease, 74 had disease progression, and 2 had objective responses (the 2 patients with initially minor tumor regression who are mentioned above).
There was no evidence of a delayed response in the patients treated with interleukin-2, interferon alpha-2a, or both. The two cases in which an initially mixed response was followed by an objective response may represent an example of such an immunologic mechanism, but if so, this situation is obviously exceptional, since it occurred in only 2 of 425 patients.
2 ReferencesSylvie Negrier, M.D.
Christine Lasset, M.D.
Centre Léon Bérard, 69008 Lyons, FranceBernard Escudier, M.D.
Institut Gustave Roussy, 94805 Villejuif, Francefor the Groupe Français d'Immunothérapie
1
Miller AB ,Hoogstraten B ,Staquet M ,Winkler A . Reporting results of cancer treatment. Cancer 1981;47:207-214
CrossRef | Web of Science | Medline2
Thiesse P ,Ollivier L ,Di Stefano-Louineau D , et al. Response rate accuracy in oncology trials: reasons for interobserver variability. J Clin Oncol 1997;15:3507-3514
Web of Science | Medline
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