BRIEF COMMUNICATIONS
Interferon a-2a and Dacarbazine in Melanoma
In May 1989, at the convention of the American Society of Clinical Oncology, a resurgence of interest in combinations of interferon (IFN) with dacarbazine (DTIC) for therapy of metastatic melanoma surfaced, with the presentation of several papers on the subject. Bajetta et al. (7) reported objective responses in 19 of 75 patients (25%), with 8% complete responses and 17% partial responses. Patients received IFN a-2aatdosesof3 x 106U/day to 9 x 106 U/day for 6 days per week for the first 10 weeks; and then three times per week; DTIC was given at a dose of 800 mg/m2 intravenously (IV) in a 2-hour infusion every 3 weeks. Kerr et al. (2) reported objective partial response in one of 19 patients. These 19 patients received the following protocol: 3 x 106 U/day of IFN a-2a subcutaneously (SC) for 14 days; DTIC was given at a dose of 800 mg/m2 IV on day 15 and repeated every 28 days; and IFN a-2a doses were escalated by 3 x 106 U/day every week to tolerance. Two patients were excluded from the study as a result of early toxic effects and intracerebral hemorrhage. Only one patient tolerated the full planned dose of IFN a-2a (9 x 106 U/day). Finally, Vorobiof et al. (3) carried out a randomized phase II trial of DTIC given at a dose of 250 mg/m2 IV every day for 5 days, repeated every 28 days, versus DTIC plus IFN a-2b given at a dose of 15 x 106 U/m2 IV per day for 5 days every week for 3 weeks, then given 1062
No compelling conclusions can be drawn about the lack of advantage for combined administration of DTIC with IFN a-2 in this trial. However, given that this trial is the only randomized comparison of the combined therapy versus each of its single component agents, and given that the numbers of patients entered in this study exceed the reported numbers in several publications of the recent Proceedings of the American Society of Clinical Oncology, it was felt that this experience should be factored into current considerations of combinedmodality therapy of melanoma. The published single agent activity of IFN a-2 at approximately 18% and that of DTIC at approximately 20%-23% require that any new comparative trials to test the possible permutations of dose and sequence of IFN a-2-DTIC administration must accrue hundreds of patients to establish potential differences in the range of 10%-15%, with any acceptable confidence level. Moreover, it will be extremely important for any comparative trials to ensure balanced randomization that recognizes the prognostic factors of age, gender, and site and size of metastases, which have been previously documented in the literature.
Received April 9, 1990; accepted April 10, 1990. J. M. Kirkwood, Department of Medicine, Division of Medical Oncology, Pittsburgh Cancer Institute, Pittsburgh, Pa. M. S. Ernstoff, University of Pittsburgh School of Medicine, Pa. A. Giuliano, University of California at Los Angeles, Calif. R. Gams, University of Alabama at Birmingham School of Medicine, Ala. W. A. Robinson, University of Colorado at Denver, Colo. J. Costanzi, Thompson Cancer Survival Center, Knoxville, Tenn. P. Pouillart, Institut Curie, Paris, France. J. Speyer, New York University, New York, NY. M. Grimm, Schering-Plough Corporation, Kenilworth, NJ. R. Spiegel, Schering Multi-Center Trial Group, Kenilworth, NJ. Correspondence to: John M. Kirkwood, M.D., Department of Medicine, Division of Medical Oncology, Pittsburgh Cancer Institute, 201 DeSotoat O'HaraSts., Rm. 1214, Pittsburgh, PA 15213.
Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at University of Birmingham on August 24, 2015
John M. Kirkwood,* M. S. Emstoff, A. Giuliano, R. Gams, W. A. Robinson, J. Costanzi, P. Pouillart, J. Speyer, M. Grimm, R. Spiegel
at a dose of 10 x 106 U/m2 SC three times per week. Of the 19 recipients of DTIC who were evaluated, three achieved objective responses. Of 18 recipients of DTIC plus IFN a-2b who were evaluated, seven achieved objective responses. In that comparative trial, significant imbalances in age and gender distribution were not accounted for in the randomization scheme or preliminary analysis, although the combined arm was suggested to be superior. Younger female patients predominated the combined therapy arm. In light of these results, which suggest that combined-modality therapy of metastatic melanoma may be more effective than the sequential use of the single component agents, we would like to note the results of the only randomized threearm trial that has compared DTIC, IFN a-2b, and the combination therapy (5). In this trial, the combination treatment was as follows: DTIC was given at a dose of 250 mg/m2 per day for 5 days every 3 weeks and IFN a-2b was given at a dose of 30 x 106 U/day for 5 days every week for 3 weeks, then given at a dose of 10 x 106 U/m2 SC three times per week versus the combination of the two foregoing treatment arms. This multicenter study, sponsored by Schering-Plough Corp. (Kenilworth, NJ), was initiated in 1984 and was terminated administratively in December of 1985, when 74 patients had been entered in the study. An analysis of the results available to the coordinating office in March 1986 revealed that, of 68 entrants, there were 24 in the DTIC arm, 23 in the IFN a-2b arm, and 21 in the combination therapy arm. Toxicity was slightly worse for the combination therapy arm than for either single agent. The three arms were balanced in regard to gender, distribution of metastatic disease to visceral or nonvisceral sites, equivalent time on treatment, and percentage of dose administered. Objective response was noted in five of 24 patients in the DTIC arm, in one of 23 receiving IFN a-2b alone, and in four of 21 receiving combination therapy. The response to IFN a-2b was lower than we have noted in many prior trials, and lower than the 18% from our previous review of the literature (4).
References (/) BAJETTA E, NEGRETTI E, GIANNOTTI B, ET AL:
Phase II study of interferon alpha-2a (rIFN alpha-2a) and dacarbazine (DTIC) in metastatic melanoma (MM). Proc ASCO 8:286, 1989 (2) KERR R, PIPPEN P, MENNEL R, ET AL: Treat-
ment of metastatic malignant melanoma with a combination of interferon alpha-2a (Ifn alpha2a; Roferon) and dacarbazine (DTIC). Proc ASCO 8:288, 1989 (3) VOROBIOF D, FALKSON G, VOCES CW: DTIC
versus DTIC and recombinant interferon alfa 2b (rIFNa 2b) in the treatment of patients (PTS) with advanced malignant melanoma (MM). Proc ASCO 8:284, 1989 (4) KIRKWOOD JM, ERNSTOFFMS: Potential appli-
cations of the interferons in oncology: Lessons drawn from studies of human melanoma. Semin Oncol 13:48-56, 1986 (5) KIRKWOOD JM, ERNSTOFF MS, GIULIANO A,
Ocular Toxic Effects of Fenretinide Manuel R. Modiano,* William S. Dalton, Scott M. Lippman, Leonard Joffe, Ann R. Booth, Frank L. Meyskens, Jr. Retinoids, the natural and synthetic analogues of vitamin A, inhibit growth and induce differentiation in many animal and human malignant cell types, and they show clinical promise as chemopreventive antineoplastic agents (1-3). Isotretinoin has been the most widely used synthetic retinoid in cancer treatment and cancer prevention trials. However, its toxic effects, primarily mucocutaneous and teratogenic, make it difficult to tolerate, since continued exposure to the retinoid is required to maintain its effect (1,2). We have recently completed a phase II trial of fenretinide in advanced malignancies (4). Fenretinide was administered in doses of 300-400 mg/day to 16 patients with advanced, metastatic, refractory breast cancer, 15 with melanoma, five with Kaposi's sarcoma, and one with mycosis fungoides. Although fenretinide was inactive in advanced dis-
Vol. 82, No. 12, June 20, 1990
Kaiser-Kupfer et al. (5) have also looked at the effect of fenretinide on the electroretinogram. They reported on electroretinograms for three offivepatients with basal cell carcinoma who were receiving fenretinide at a dose of 800 mg/day. In two of these patients, dark-adaptation thresholds were elevated and the electroretinogram shows that amplitude for rod-mediated vision was depressed. Both developed nyctalopia within 3 weeks of treatment. Costa et al. (6) also found reversible nyctalopia in one of 25 patients treated with 300 mg of fenretinide per day over 6 months. These comparisons suggest that
the ocular toxic effects of fenretinide may be dose related. The ocular side effects of fenretinide, which resemble those of other synthetic retinoids (7), may be-due to the interference of these agents with vitamin A metabolism. This hypothesis is supported by a recent pharmacokinetic evaluation of patients receiving this treatment (8), which revealed that fenretinide caused a reduction in serum retinol levels.
References (/) LIPPMAN SM, KESSLER JF, MEYSKENS FL JR:
Retinoids as preventive and therapeutic anticancer agents (part I). Cancer Treat Rep 71:391-405, 1987 (2) LIPPMAN SM, KESSLER JF, MEYSKENS FL JR:
Retinoids as preventive and therapeutic anticancer agents (part II). Cancer Treat Rep 71:493-515, 1987 (3) LIPPMAN SM, MEYSKENS FL JR: Retinoids for
the prevention of cancer. In Nutrition and Cancer Prevention: The Role of Micronutrients (MoonTE, Micozzi E, eds). New York: Marcel Dekker, 1987, pp 243-271 (4) MODIANO MR, DALTON WS, LIPPMAN SM,
ET AL: Phase II study of fenretinide (N-[Ahydroxyphenyl]retinamide) in advanced breast cancer and melanoma. Invest New Drugs. In press (5) KAISER-KUPFER MI, PECK GL, CARUSO RC,
ET AL: Abnormal retinal function associated with fenretinide, a synthetic retinoid. Arch Opthalmol 104:69-70, 1986 (6) COSTA A, MALONE W, PERLOFF M, ET AL:
Tolerability of the synthetic retinoid fenretinide (HPR). Eur J Cancer Clin Oncol 25:805-808, 1989 (7) EDWARDS L, ALBERTS DS, LEVINE N: Clinical
toxicity of low-dose isotretinoin. Cancer Treat Rep 70:663-664, 1986 (8) PENG Y-M, DALTON WS, ALBERTS DS, ET AL:
Pharmacokinetics of /V-4-hydroxyphenyl-retinamide and the effect of its oral administration on plasma retinol concentrations in cancer patients [published erratum appears in Int J Cancer 44:567, 1989]. Int J Cancer 43:22-26, 1989
Downloaded from http://jnci.oxfordjournals.org/ at University of Birmingham on August 24, 2015
ET AL: Clinical trials of interferon alfa-2B (Intron A, alpha IFN) in melanoma: Review of phase I, II, and III studies. Presented at the Fourteenth International Cancer Congress, Budapest, August 1986
ease, its toxic effects were mild and reversible. Toxic effects included a 45% elevation over baseline of serum triglycerides in 6% of the patients, a 13% elevation of serum cholesterol in 20% of patients, and mild mucocutaneous toxic effects in 52%. In addition, 10% suffered from nyctalopia (decreased night vision), which resolved when treatment was discontinued. One of these patients had reversible electroretinographic changes consisting of a significant decrease in the amplitude for scotopic (dark-adapted, or rod-mediated) vision on electroretinogram, which did not occur until after 1 month of treatment. This decrease was observed predominantly in the B-wave for rods on the electroretinogram and developed while the patient was receiving the higher dose of fenretinide (400 mg/day). Amplitude decreases for this patient's right eye were as follows: the pretherapy A-wave amplitude (normal, 150-250 (JLV) was 190 |xV, decreasing to 160 LIV after 2 months of treatment, and the B-wave amplitude (normal, 365-550 (JLV) dropped from 430 to 290 [iM after 2 months of therapy. No changes in the A-wave amplitude were recorded for the left eye, but the B-wave amplitude dropped from 430 to 340 (JLV after 2 months on fenretinide. These changes reversed after fenretinide was discontinued. Patients were given fenretinide for 15-300 days (mean, 52).
Received April 16, 1990; accepted April 17, 1990. M. R. Modiano, W. S. Dalton, L. Joffe, A. R. Booth, University of Arizona, Arizona Cancer Center, Tucson, AZ. S. M. Lippman, The University of Texas M. D. Anderson Cancer Center, Houston, TX. F. L. Meyskens, Jr., University of California, Irvine Clinical Cancer Center, Irvine, CA. *Correspondence to: Manuel R. Modiano, M.D., Department of Cancer Prevention and Control, Arizona Cancer Center, 1515 N. Campbell Ave., Rm. 1995, Tucson, AZ 85724.
BRIEF COMMUNICATIONS
1063
Interferon a-2a and Dacarbazine in Melanoma
In May 1989, at the convention of the American Society of Clinical Oncology, a resurgence of interest in combinations of interferon (IFN) with dacarbazine (DTIC) for therapy of metastatic melanoma surfaced, with the presentation of several papers on the subject. Bajetta et al. (7) reported objective responses in 19 of 75 patients (25%), with 8% complete responses and 17% partial responses. Patients received IFN a-2aatdosesof3 x 106U/day to 9 x 106 U/day for 6 days per week for the first 10 weeks; and then three times per week; DTIC was given at a dose of 800 mg/m2 intravenously (IV) in a 2-hour infusion every 3 weeks. Kerr et al. (2) reported objective partial response in one of 19 patients. These 19 patients received the following protocol: 3 x 106 U/day of IFN a-2a subcutaneously (SC) for 14 days; DTIC was given at a dose of 800 mg/m2 IV on day 15 and repeated every 28 days; and IFN a-2a doses were escalated by 3 x 106 U/day every week to tolerance. Two patients were excluded from the study as a result of early toxic effects and intracerebral hemorrhage. Only one patient tolerated the full planned dose of IFN a-2a (9 x 106 U/day). Finally, Vorobiof et al. (3) carried out a randomized phase II trial of DTIC given at a dose of 250 mg/m2 IV every day for 5 days, repeated every 28 days, versus DTIC plus IFN a-2b given at a dose of 15 x 106 U/m2 IV per day for 5 days every week for 3 weeks, then given 1062
No compelling conclusions can be drawn about the lack of advantage for combined administration of DTIC with IFN a-2 in this trial. However, given that this trial is the only randomized comparison of the combined therapy versus each of its single component agents, and given that the numbers of patients entered in this study exceed the reported numbers in several publications of the recent Proceedings of the American Society of Clinical Oncology, it was felt that this experience should be factored into current considerations of combinedmodality therapy of melanoma. The published single agent activity of IFN a-2 at approximately 18% and that of DTIC at approximately 20%-23% require that any new comparative trials to test the possible permutations of dose and sequence of IFN a-2-DTIC administration must accrue hundreds of patients to establish potential differences in the range of 10%-15%, with any acceptable confidence level. Moreover, it will be extremely important for any comparative trials to ensure balanced randomization that recognizes the prognostic factors of age, gender, and site and size of metastases, which have been previously documented in the literature.
Received April 9, 1990; accepted April 10, 1990. J. M. Kirkwood, Department of Medicine, Division of Medical Oncology, Pittsburgh Cancer Institute, Pittsburgh, Pa. M. S. Ernstoff, University of Pittsburgh School of Medicine, Pa. A. Giuliano, University of California at Los Angeles, Calif. R. Gams, University of Alabama at Birmingham School of Medicine, Ala. W. A. Robinson, University of Colorado at Denver, Colo. J. Costanzi, Thompson Cancer Survival Center, Knoxville, Tenn. P. Pouillart, Institut Curie, Paris, France. J. Speyer, New York University, New York, NY. M. Grimm, Schering-Plough Corporation, Kenilworth, NJ. R. Spiegel, Schering Multi-Center Trial Group, Kenilworth, NJ. Correspondence to: John M. Kirkwood, M.D., Department of Medicine, Division of Medical Oncology, Pittsburgh Cancer Institute, 201 DeSotoat O'HaraSts., Rm. 1214, Pittsburgh, PA 15213.
Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at University of Birmingham on August 24, 2015
John M. Kirkwood,* M. S. Emstoff, A. Giuliano, R. Gams, W. A. Robinson, J. Costanzi, P. Pouillart, J. Speyer, M. Grimm, R. Spiegel
at a dose of 10 x 106 U/m2 SC three times per week. Of the 19 recipients of DTIC who were evaluated, three achieved objective responses. Of 18 recipients of DTIC plus IFN a-2b who were evaluated, seven achieved objective responses. In that comparative trial, significant imbalances in age and gender distribution were not accounted for in the randomization scheme or preliminary analysis, although the combined arm was suggested to be superior. Younger female patients predominated the combined therapy arm. In light of these results, which suggest that combined-modality therapy of metastatic melanoma may be more effective than the sequential use of the single component agents, we would like to note the results of the only randomized threearm trial that has compared DTIC, IFN a-2b, and the combination therapy (5). In this trial, the combination treatment was as follows: DTIC was given at a dose of 250 mg/m2 per day for 5 days every 3 weeks and IFN a-2b was given at a dose of 30 x 106 U/day for 5 days every week for 3 weeks, then given at a dose of 10 x 106 U/m2 SC three times per week versus the combination of the two foregoing treatment arms. This multicenter study, sponsored by Schering-Plough Corp. (Kenilworth, NJ), was initiated in 1984 and was terminated administratively in December of 1985, when 74 patients had been entered in the study. An analysis of the results available to the coordinating office in March 1986 revealed that, of 68 entrants, there were 24 in the DTIC arm, 23 in the IFN a-2b arm, and 21 in the combination therapy arm. Toxicity was slightly worse for the combination therapy arm than for either single agent. The three arms were balanced in regard to gender, distribution of metastatic disease to visceral or nonvisceral sites, equivalent time on treatment, and percentage of dose administered. Objective response was noted in five of 24 patients in the DTIC arm, in one of 23 receiving IFN a-2b alone, and in four of 21 receiving combination therapy. The response to IFN a-2b was lower than we have noted in many prior trials, and lower than the 18% from our previous review of the literature (4).
References (/) BAJETTA E, NEGRETTI E, GIANNOTTI B, ET AL:
Phase II study of interferon alpha-2a (rIFN alpha-2a) and dacarbazine (DTIC) in metastatic melanoma (MM). Proc ASCO 8:286, 1989 (2) KERR R, PIPPEN P, MENNEL R, ET AL: Treat-
ment of metastatic malignant melanoma with a combination of interferon alpha-2a (Ifn alpha2a; Roferon) and dacarbazine (DTIC). Proc ASCO 8:288, 1989 (3) VOROBIOF D, FALKSON G, VOCES CW: DTIC
versus DTIC and recombinant interferon alfa 2b (rIFNa 2b) in the treatment of patients (PTS) with advanced malignant melanoma (MM). Proc ASCO 8:284, 1989 (4) KIRKWOOD JM, ERNSTOFFMS: Potential appli-
cations of the interferons in oncology: Lessons drawn from studies of human melanoma. Semin Oncol 13:48-56, 1986 (5) KIRKWOOD JM, ERNSTOFF MS, GIULIANO A,
Ocular Toxic Effects of Fenretinide Manuel R. Modiano,* William S. Dalton, Scott M. Lippman, Leonard Joffe, Ann R. Booth, Frank L. Meyskens, Jr. Retinoids, the natural and synthetic analogues of vitamin A, inhibit growth and induce differentiation in many animal and human malignant cell types, and they show clinical promise as chemopreventive antineoplastic agents (1-3). Isotretinoin has been the most widely used synthetic retinoid in cancer treatment and cancer prevention trials. However, its toxic effects, primarily mucocutaneous and teratogenic, make it difficult to tolerate, since continued exposure to the retinoid is required to maintain its effect (1,2). We have recently completed a phase II trial of fenretinide in advanced malignancies (4). Fenretinide was administered in doses of 300-400 mg/day to 16 patients with advanced, metastatic, refractory breast cancer, 15 with melanoma, five with Kaposi's sarcoma, and one with mycosis fungoides. Although fenretinide was inactive in advanced dis-
Vol. 82, No. 12, June 20, 1990
Kaiser-Kupfer et al. (5) have also looked at the effect of fenretinide on the electroretinogram. They reported on electroretinograms for three offivepatients with basal cell carcinoma who were receiving fenretinide at a dose of 800 mg/day. In two of these patients, dark-adaptation thresholds were elevated and the electroretinogram shows that amplitude for rod-mediated vision was depressed. Both developed nyctalopia within 3 weeks of treatment. Costa et al. (6) also found reversible nyctalopia in one of 25 patients treated with 300 mg of fenretinide per day over 6 months. These comparisons suggest that
the ocular toxic effects of fenretinide may be dose related. The ocular side effects of fenretinide, which resemble those of other synthetic retinoids (7), may be-due to the interference of these agents with vitamin A metabolism. This hypothesis is supported by a recent pharmacokinetic evaluation of patients receiving this treatment (8), which revealed that fenretinide caused a reduction in serum retinol levels.
References (/) LIPPMAN SM, KESSLER JF, MEYSKENS FL JR:
Retinoids as preventive and therapeutic anticancer agents (part I). Cancer Treat Rep 71:391-405, 1987 (2) LIPPMAN SM, KESSLER JF, MEYSKENS FL JR:
Retinoids as preventive and therapeutic anticancer agents (part II). Cancer Treat Rep 71:493-515, 1987 (3) LIPPMAN SM, MEYSKENS FL JR: Retinoids for
the prevention of cancer. In Nutrition and Cancer Prevention: The Role of Micronutrients (MoonTE, Micozzi E, eds). New York: Marcel Dekker, 1987, pp 243-271 (4) MODIANO MR, DALTON WS, LIPPMAN SM,
ET AL: Phase II study of fenretinide (N-[Ahydroxyphenyl]retinamide) in advanced breast cancer and melanoma. Invest New Drugs. In press (5) KAISER-KUPFER MI, PECK GL, CARUSO RC,
ET AL: Abnormal retinal function associated with fenretinide, a synthetic retinoid. Arch Opthalmol 104:69-70, 1986 (6) COSTA A, MALONE W, PERLOFF M, ET AL:
Tolerability of the synthetic retinoid fenretinide (HPR). Eur J Cancer Clin Oncol 25:805-808, 1989 (7) EDWARDS L, ALBERTS DS, LEVINE N: Clinical
toxicity of low-dose isotretinoin. Cancer Treat Rep 70:663-664, 1986 (8) PENG Y-M, DALTON WS, ALBERTS DS, ET AL:
Pharmacokinetics of /V-4-hydroxyphenyl-retinamide and the effect of its oral administration on plasma retinol concentrations in cancer patients [published erratum appears in Int J Cancer 44:567, 1989]. Int J Cancer 43:22-26, 1989
Downloaded from http://jnci.oxfordjournals.org/ at University of Birmingham on August 24, 2015
ET AL: Clinical trials of interferon alfa-2B (Intron A, alpha IFN) in melanoma: Review of phase I, II, and III studies. Presented at the Fourteenth International Cancer Congress, Budapest, August 1986
ease, its toxic effects were mild and reversible. Toxic effects included a 45% elevation over baseline of serum triglycerides in 6% of the patients, a 13% elevation of serum cholesterol in 20% of patients, and mild mucocutaneous toxic effects in 52%. In addition, 10% suffered from nyctalopia (decreased night vision), which resolved when treatment was discontinued. One of these patients had reversible electroretinographic changes consisting of a significant decrease in the amplitude for scotopic (dark-adapted, or rod-mediated) vision on electroretinogram, which did not occur until after 1 month of treatment. This decrease was observed predominantly in the B-wave for rods on the electroretinogram and developed while the patient was receiving the higher dose of fenretinide (400 mg/day). Amplitude decreases for this patient's right eye were as follows: the pretherapy A-wave amplitude (normal, 150-250 (JLV) was 190 |xV, decreasing to 160 LIV after 2 months of treatment, and the B-wave amplitude (normal, 365-550 (JLV) dropped from 430 to 290 [iM after 2 months of therapy. No changes in the A-wave amplitude were recorded for the left eye, but the B-wave amplitude dropped from 430 to 340 (JLV after 2 months on fenretinide. These changes reversed after fenretinide was discontinued. Patients were given fenretinide for 15-300 days (mean, 52).
Received April 16, 1990; accepted April 17, 1990. M. R. Modiano, W. S. Dalton, L. Joffe, A. R. Booth, University of Arizona, Arizona Cancer Center, Tucson, AZ. S. M. Lippman, The University of Texas M. D. Anderson Cancer Center, Houston, TX. F. L. Meyskens, Jr., University of California, Irvine Clinical Cancer Center, Irvine, CA. *Correspondence to: Manuel R. Modiano, M.D., Department of Cancer Prevention and Control, Arizona Cancer Center, 1515 N. Campbell Ave., Rm. 1995, Tucson, AZ 85724.
BRIEF COMMUNICATIONS
1063
