The Adjuvant Treatment Of
Malignant Melanomas With Interferons

Alvaro Moreno, M.D. and William J. Maples, M.D.
Alvaro Moreno, M.D. is a Fellow, Hematology/Oncology Fellowship Program, Mayo Graduate School of Medicine, Mayo Clinic Jacksonville. William J. Maples, M.D. is Assistant Professor of Oncology, Mayo Medical School and Consultant in Medical Oncology, Mayo Clinic Jacksonville.

Introduction

The interferons (IFNs) are a complex group of proteins with virus replication inhibition capabilities first isolated by leukocytes in 1957 by Isaacs and Lindemann.1 Further studies demonstrated their ability to interfere with tumor cell proliferation and to modulate the host immune response (enhance cell surface antigen expression of both major histocompatibility complex antigens and some tumor antigens), although the exact mechanism(s) of actions are not clearly understood.2-4 These observed characteristics, along with the fact that these agents are species-restricted, made the interferons appealing for trials in a variety of malignancies. These trials began under the auspices of the American Cancer Society in 1979.5 However, significant clinical experience with these agents was not possible until recombinant DNA technology allowed production of large quantities of interferons. The human interferons are classified in two groups: Type I which includes interferon alpha (IFN-a), interferon beta (IFN-b), interferon tau (IFN-t) and interferon omega (IFN-w) and Type II which includes interferon gamma (IFN-g).6 The type I IFN genes are closely related and are in chromosome 9. They interact with the same cellular receptor. The IFN-g gene is in chromosome 12 and interacts with a different receptor. The two IFNs that had been most extensively studied against human malignancies are IFN-a and IFN-g.

The observation that malignancies can undergo significant regression following bacterial infections led to the hypothesis that the immune system was capable of an anti-tumor effect. More significant understanding of the immune system over the last 50 years has led to important advances in the field of anti-tumoral immunotherapy. The largest clinical experience with immunotherapy has been with the use of cytokines and monoclonal antibodies; melanoma has been the most common malignancy studied.

Interferon Alpha In Melanoma

There are currently several commercially available recombinant interferon alpha preparations with demonstrated efficacy in melanomas, IFN-a2a (Roferon-A®, Hoffman-La Roche), IFN-a2b (Intron-A®, Schering-Plough), and IFN-a2c (Boehringer Ingelheim). The administration includes the subcutaneous (SQ), intramuscular (IM) and intravenous (IV) routes. Responses in melanoma are frequently observed in a dose dependent manner, with the highest response rates seen when doses ³ 10 million U/m²/dose are used daily or three times a week. IFN-a has no demonstrable activity against central nervous system metastases given its inability to cross the blood-brain barrier.

Phase I-II single center trials demonstrated that IFN-a has an overall response rate of 10-20% in patients with metastatic melanoma.6-12 Almost 33% of the responders had a complete response to therapy, and some of them were reported to have sustained complete remissions of several years. The median duration of partial responses was 4 months. These observations stimulated researchers to test the newly available recombinant IFN-a in larger clinical trials as adjuvant therapy for patients considered to be at high-risk for relapse after they underwent complete surgical excision of their malignant melanoma.

Adjuvant Therapy Of Melanomas With IFN-a

Two of the most important prognostic factors for survival for patients with newly diagnosed melanoma are the Breslow tumor thickness (5-year survival rates for tumors thickness < 0.75 mm, between 0.76 mm and < 1.5 mm, > 1.5 mm but < 4.0 mm and > 4.0 mm are 96%, 89%, 72% and 56% respectively) and the presence of regional lymph node involvement (10-year survival rates for one, two to four, or more than four positive lymph nodes are 40%, 26% and 15% respectively).13 These two factors allow the identification of patients who are at high risk for developing recurrent disease. High-risk patients include those with tumor thickness > 4.0 mm, those with lymph node metastases and those with "in-transit metastases".

Approximately 10 different large clinical trials were conducted or are ongoing in North America and Europe addressing the benefit of adjuvant interferon therapy after total surgical excision of tumors with a depth of 1.5-4.0 mm (T3, stage IIA), >4.0 mm (T4, stage IIB) or with involvement of regional lymph nodes (N1, stage III) (Table 1).

Randomized Trials Of IFN-a Versus Observation For Patients With Stage IIA Only

Almost one-third of newly diagnosed melanomas will fall into the category of stage IIA. Most large adjuvant trials conducted in the 1980's and early 1990's did not include patients from this stage group. The Eastern Cooperative Oncology Group (ECOG) and the National Cancer Institute of Canada (NCIC) are currently running the E1697 trial for patients with stage IIA only. Patients receive induction therapy with interferon alpha at a dose of 20 million U/m²/Monday through Friday x 4 weeks versus observation only. This study was initiated in 1996 and a total of 1444 patients are expected to be accrued.

Randomized Trials Of IFN-a Versus Observation For Patients With Stage IIA Or IIB

The French Cooperative Group on Melanoma ran a prospective randomized trial targeted to stage IIA and IIB patients.19 Patients were either observed or treated with adjuvant IFN-a2a [3 million units (MU) subcutaneous (SQ) three times a week (TIW) for 18 months]. With a median follow-up of 3 years this study failed to show a benefit in overall survival although there was a reduction in recurrence from 44.7% for observation to 32.6% for the treatment arm. Another Austrian group has recently reported their results of their trial comparing low dose interferon-alpha for 1 year versus observation.20 A statistically significant improvement in the disease free survival (DFS) of the treated group (p=0.02) compared to the observation group was noted, although longer follow-up is still needed (median follow-up of 41 months at the time of report).

Randomized Trials Of IFN-a Versus Observation For Patients With Stage IIB Or III Disease Only

These stages are the most extensively studied by the different cooperative groups.

ECOG trial E 1684 — This study was conducted between 1984 and 1990 and evaluated 287 patients with stage IIB (11%) and stage III melanomas (89%).14 Patients were randomized to either observation or induction treatment with IFN-a2b (20 million U/m²/IV/d/five days a week x 4 weeks) followed by a maintenance phase of IFN-a2b (10 million U/m²/SQ/TIW) for the next 48 weeks (total 1 year of treatment). At a median follow up of 7 years, a significant improvement in median survival (from 2.8 to 3.8 years, p=0.02) and relapse-free interval (from 1.0 to 1.7 years, p=0.002) was noted. The greatest benefit was seen in patients having positive lymph node metastases (stage III) with no definitive benefits seen in the other group (stage IIB). This trial became the pivotal study leading to the Food and Drug Administration (FDA) approval of IFN-a as adjuvant to surgical treatment in patients 18 years of age or older with malignant melanoma who are free of disease but at high risk for systemic recurrence.

Although there were substantial treatment-related toxicities, a retrospective quality of life study and an economic analysis study were both favorable to the interferon treated group.21-22

ECOG trial E 1690/Intergroup trial 2055 — Initiated in 1990 and completed in 1995, this trial randomized 642 patients with stage IIB or III melanoma to either the same high dose interferon regimen as above in E 1684 for 48 weeks versus a low dose maintenance arm (same induction therapy as E 1684 but maintenance interferon dose was only 3 million/SQ/TIW and lasting for 2 years), versus observation only. A preliminary analysis in September 1998 (median follow up of 5 years) showed a significant impact in relapse-free survival for the high dose interferon arm over observation alone.15 However, no difference was observed for overall survival. Some investigators argue that the results were not mature enough to be analyzed; others suspect that the lack of difference for overall survival may be due that patients in the observation arm who relapsed with systemic disease were treated with high dose immunotherapy (i.e. IFN-a and IL-2), chemotherapy or chemo-immunotherapy that were not available for patients in the observation arm of the E 1684 study. The low dose interferon arm was not associated with significant benefits at this time. Further analysis of this trial is expected in 2000.

World Health Organization (WHO) Melanoma Program Trial #16 — Ran between 1990 and 1993, this trial randomized 444 patients with recurrent regional nodal metastases to receive low dose IFN-a2a (3 million U/SQ/TIW/x 3 years) or observation alone after surgical nodal excision. A preliminary report at 2 years suggested a benefit in relapse-free survival for the interferon group (46% vs 27%) but a more mature analysis (median follow-up ³ 39 months) showed no statistically significant benefit for relapse-free survival or overall survival.16, 23 Contrary to the E 1684 trial, the WHO trial included a large number of patients that had extracapsular nodal involvement.

North Central Cancer Treatment Group (NCCTG) study 83-7052 — Two-hundred sixty two patients with stage II and III were randomized to 12 weeks of IFN-a (20 million U/m²/IM/TIW) versus observation. Although there was a trend towards improved overall survival and disease-free survival for the stage III patients treated with IFN-a2a, there was no statistically significant improvement in DFS or OS for the whole population.17

European Organization for Research and Treatment of Cancer (EORTC) trial 18-952 — The EORTC 18-952 is a randomized study comparing observation alone versus two arms of intermediate-dose IFN-a2a (induction with IFN 10 million U/SQ/5 days a week for 4 weeks followed by a maintenance phase of either 10 million U/SQ/TIW for 1 year or 5 million U/SQ/TIW for 2 years). This trial is currently open and expects to accrue a total of 1,000 patients.

Randomized Trials Of IFN-a With Other Biologic Therapies

The E 1694 trial is expected to finish accrual of a total of 851 patients sometime this year. It is testing the benefit of high dose IFN-a2b versus an anti-ganglioside vaccine for patients with T4 lesions (depth > 4.0 mm; stage IIB) or patients with any tumor size with the presence of regional lymph node metastases (Stage III). The EORTC 18-871 is another large ongoing European trial that tests very low dose IFN-a2a (1million/SQ/TIW for 1 year) versus IFN-g (0.2 mg/SQ/TIW/1 year) versus observation.

IFN Gamma

Despite the preclinical evidence that interferon gamma is a potent immunomodulator for the natural killer cells, monocytes and T-lymphocytes, the use of this agent for the treatment of metastatic melanoma or in the adjuvant setting has been quiet disappointing. Based on the laboratory data of their interaction with different receptors it was hypothesized that their combination with interferon alpha may achieve a synergistic immunomodulatory effect. However, four published clinical trials using IFN-g alone or combining it with interferon-alpha failed to demonstrate an increased response rate over single agent IFN-a.18,24-26 This combination was also associated with increased toxicity.27 There is currently no role for the use of IFN-g for malignant melanoma outside the setting of a clinical trial.

Conclusions

Immunotherapy of melanomas has been extensively studied over the last two decades. The optimal dose and schedule of IFN-a in the treatment of melanoma has not been well established. The use of interferon alpha-2b in the adjuvant setting was approved by the FDA after the positive results of a single study, the E 1684 trial. The preliminary analysis of the more recent trial (E1690/INT2055) raises questions regarding IFN-a2b overall benefits, especially given its significant costs and toxicities. At this time, it is reasonable to discuss with patients at high risk the potential benefits of adjuvant IFN-a2b, especially for patients with node positive disease. The role of adjuvant therapy for the sub-group of node negative patients is much more controversial. Given our increasing knowledge of the immune system and the biology of tumors, the future will likely be full of newer and novel approaches for the treatment of malignant melanoma. Patients should be encouraged to participate in well-designed clinical trials.

REFERENCES

  1. Isaacs A, Lindemann, JJ. Virus Interference: The interferon. Proc R Soc Lond. 1957; 147:258-267.
  2. Greiner JW, Fisher PB, Pestka S, et al. Differential effects of recombinant human leukocyte interferons on cell surface antigen expresion. Cancer Res. 1986; 46: 4984.
  3. Borden EC. Augmented tumor-associated antigen expression by interferons. J Natl Cancer Inst. 1988; 80: 148.
  4. Murray JL, Stuckey SE, Pillow JK, et al. Differential in vitro effects of recombinant a-interferon and recombinant g-interferon alone or in combination on the expression of melanoma-associated surface antigens. J Biol Response Mod. 1988; 7:152.
  5. Krown SE, Burk MW, Kirkwood JM, et al. Human leukocyte (alpha) interferon in metastatic malignant melanoma: The American Cancer Society phase II trial. Cancer Treat Rep. 1984; 68:723.
  6. Kirkwood JM. Biologic therapy with interferon a and b: Clinical applications in Melanoma. In DeVita VT Jr, Hellman S, Rosenberg SA, eds. Biologic Therapy of Cancer: Principles and Practice. Philadelphia: JB Lippincott. 1995: 388-411.
  7. Retsas S, Priestman TJ, Newton KS, et al. Evaluation of human lymphoblastoid interferon in advanced malignant melanoma. Cancer. 1983; 51:273.
  8. Creagan ET, Ahmann DL, Green SJ, et al. Phase II study of recombinant leukocyte a interferon (RIFNaA) in disseminated malignant melanoma. Cancer. 1984; 54: 2844.
  9. Creagan ET, Ahmann DL, Frytak S, et al. Phase II trials of recombinant leukocyte a interferon  in disseminated malignant melanoma: results in 96 patients. Cancer Treat Rep. 1986; 70(suppl 5): 619-624.
  10. Robinson WA, Mughal TI, Thomas MR, et al. Treatment of metastatic malignant melanoma with recombinant interferon alpha-2. Immunobiology. 1986; 172: 275.
  11. Legha SS, Papadopoulos NEJ, Plager C, et al. Clinical evaluation of recombinant interferon a-2a (Roferon-a) in metastatic melanoma using two different schedules. J Clin Oncol. 1987; 5: 1240.
  12. Coates A, Ralling M, Hersey P, et al. Phase II study of recombinant alpha 2-interferon in advanced malignant melanoma. J Interferon Res. 1986; 6:1.
  13. Stadelmann WK, Rapaport DP, Soong SJ, Reintgen DS, Buzaid AC, Balch CM. Prognostic clinical and pathologic features. In: Balch CM, et al, eds. Cutaneous Melanoma, 3rd ed. Philadelphia: JB Lippincott. 1998; 11-35.
  14. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alpha-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996; 14:7-17.
  15. Agarwala SS. Update of the treatment of malignant melanoma. Ninth annual Hematology and Oncology reviews. July 30-August 1, 1999. (9): 281-288.
  16. Cascinelli N, BufalinoR, Morabito A, et al. Results of adjuvant interferon study in WHO melanoma programme. Lancet. 1994; 343: 913-914.
  17. Creagan ET, Dalton RJ, Ahmann DL, et al. Randomized, surgical adjuvant clinical trial of recombinat interferon alfa-2a in selected patients with malignant melanoma. J Clin Oncol. 1995; 13: 2776-2783.
  18. Meyskens FL, Kopecky KJ, Taylor CW, et al. Randomized trial of adjuvant human interferon gamma versus observation in high-risk cutaneous melanoma: A Southwest Oncology Group Study. J Natl Cancer Inst. 1995; 87: 1710-1713.
  19. Grob JJ, Dreno B, Delauney M, et al. Long term results of an adjucant therapy with low doses IFN-a2A in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. Melanoma Res. 1997; 7(suppl): S33 (abstract).
  20. Pehamberger H, Soyer P, Steiner A, et al. Adjuvant interferon alpha-2a treatment in resected primary cutaneous melanoma. Melanoma Res. 1997; 7(suppl): S31 (abstract).
  21. Cole BF, Gelber RD, Kirkwood JM, et al. A quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment for high-risk resected cutaneous melanoma: An Eastern Cooperative Oncology Group Study (E1684). J Clin Oncol. 1997; 15: 2351-8.
  22. Hillner BE, Kirkwood JM, Atkins MB, et al. Economic analysis of adjuvant interferon alfa-2b in high-risk melanoma based on projections from ECOG 1684. J Clin Oncol. 1995; 15: 2351-8.
  23. Cascinelli N. Evaluation of efficacy of adjuvant rIFNa2a in melanoma patients with regional node metastases. Proc Am Soc Clin Oncol. 1995; 14: 410 (abstract).
  24. Ernstoff MS, Trautman T, Davis CA, Reich SD, et al. A randomized phase I/II study of continuos versus intermittent intravenous interferon gamma in patients with metastatic melanoma. J Clin Oncol. 1987, 5 (suppl 11): 1804-1810.
  25. Creagan, ET, Loprinzi CL, Ahmann DL, et al. A phase I-II of the combination of recombinant leukocyte A interferon and recombinant interferon-gamma in patients with metastatic malignant melanoma. Cancer. 1988; 62: 2472-2474.
  26. Creagan ET, Ahmann DL, Long HJ, et al. Phase II study of recombinant interferon-gamma in patients with disseminated malignant melanoma. Cancer Treat Rep. 1987; 71: 843-844.
  27. Meyskens FL, Kopecky K, Samson M, et al. Recombinant human interferon gamma: Adverse effects in high-risk stage I and II cutaneous malignant melanoma. J Natl Cancer Inst. 1990; 82 (suppl 12): 1071.
October, 1999/ Jacksonville Medicine

 

What's New · Northeast Florida Medicine Journal · Know Your Physician · Legal & Legislative
· DCMS Alliance · DCMS Foundation · Member Websites · Community Health
About the DCMS · Meetings Calendar · Member Benefits · Employment Connection · Home

Duval County Medical Society   ·   555 Bishopgate Lane  ·   Jacksonville, FL  32204
Phone: (904) 355-6561   ·     FAX:  (904) 353-5848   
General Email: dcms@dcmsonline.org    ·   Webmaster's Email: mdoran@dcmsonline.org
Privacy Policy and Disclaimers