|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2002 American Society for Clinical Oncology Prolonged Survival After Complete Resection of Disseminated Melanoma and Active Immunotherapy With a Therapeutic Cancer VaccineByFrom the Sonya Valley Ghidossi Vaccine Laboratory, Roy E. Coats Research Laboratories, John Wayne Cancer Institute, Saint John’s Health Center, Santa Monica, CA. Address reprint requests to Donald L. Morton, MD, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404; email: mortond{at}jwci.org
PURPOSE: The curative effect of surgery in certain patients with metastatic melanoma suggests the presence of endogenous antitumor responses. Because melanoma is immunogenic, we investigated whether a therapeutic cancer vaccine called Canvaxin (CancerVax Corporation, Carlsbad, CA) could enhance antitumor immune responses and thereby prolong survival. PATIENTS AND METHODS: Of 263 patients who underwent complete resection of American Joint Committee on Cancer stage IV melanoma, 150 received postoperative adjuvant vaccine therapy and 113 did not. The overall survival (OS) for the two groups was compared by Cox regression. Further survival analysis was performed by matched-pair analysis according to three prognostic variables: sex, metastatic site, and number of tumor-involved organ sites. RESULTS: Five-year OS rates were 39% for vaccine and 19% for nonvaccine patients. On multivariate analysis, vaccine therapy was the most significant prognostic variable in this cohort (P = .0001). Analysis of 107 matched pairs of vaccine and nonvaccine patients revealed a significant OS advantage for vaccine therapy (P = .0009): 5-year OS was 39% for vaccine patients versus 20% for nonvaccine patients. There was a significant delayed-type hypersensitivity (DTH) response to adjuvant vaccine therapy (P = .0001), and OS was significantly correlated with DTH to vaccine (P = .0001) but not with DTH to purified protein derivative (PPD), a control antigen. CONCLUSION: Prolonged survival was observed in patients who received postoperative active immunotherapy with Canvaxin therapeutic cancer vaccine. The correlation of survival with vaccine-DTH responses but not PPD-DTH indicates a treatment-specific effect. These findings suggest that adjuvant active specific immunotherapy should be considered after cytoreductive surgery for advanced melanoma.
PROGNOSIS FOR PATIENTS with metastatic melanoma is grim: median survival is 6 to 8 months and the 5-year survival rate is less than 6%.1 Because the presence of distant metastases reflects systemic dissemination of tumor cells, conventional logic suggests that surgical resection of clinically apparent tumor should not have a significant impact on survival. However, reports from several independent investigators suggest otherwise. In 20% to 30% of patients with American Joint Committee on Cancer (AJCC) stage IV melanoma,2 complete surgical resection can yield a median survival of 15 to 20 months and a 5-year survival rate as high as 20%.3-11 This is in sharp contrast to an overall survival of 6 to 8 months for the average patient with metastatic melanoma managed by conventional chemotherapy.1 This discrepancy in survival strongly suggests protective host antitumor response(s). Because surgical resection reduces tumor burden and thereby eliminates a source of immunosuppression, we have suggested that surgery is a form of immunotherapy.12,13 The presence of specific antitumor immune responses in the postoperative period has been correlated with survival after surgery for metastatic melanoma.14 In addition, the elevation of these specific immune responses has been associated with improved survival in metastatic melanoma patients receiving active specific immunotherapy.15,16 Because of the resistance of metastatic melanoma to conventional chemotherapy and radiation therapy, surgical debulking followed by immunotherapy merits investigation as a possible therapeutic paradigm for prolonging survival of patients with disseminated melanoma. Since 1984, we have performed phase I/II trials of a therapeutic cancer vaccine called Canvaxin (CancerVax Corporation, Carlsbad, CA) in patients with AJCC stage IV melanoma.17,18 Canvaxin vaccine is an irradiated preparation of whole melanoma cells from three allogeneic melanoma cell lines. It stimulates the patient’s immune system by presenting highly immunogenic tumor-associated antigens.19 During the first 12 weeks of vaccine therapy, more than 80% of patients develop a significant increase in delayed-type hypersensitivity (DTH) to the vaccine and a significant increase in specific humoral responses to important tumor antigens expressed by vaccine cells.15 These cellular and humoral responses are associated with improved survival.15,16 This study reports prospectively collected data on immunologic response and survival for patients enrolled onto phase II protocols of adjuvant Canvaxin vaccine immunotherapy after complete resection of AJCC stage IV melanoma. We compared the survival of this group with that of computer-matched stage IV melanoma patients who did not receive postoperative adjuvant vaccine immunotherapy. To our knowledge, the data are the first evidence of a clinical benefit for postoperative adjuvant active immunotherapy in this subgroup of melanoma patients for whom there are few other therapeutic options.
Study Population Since 1971, we have maintained a prospective database for all melanoma patients seen by physicians of the John Wayne Cancer Institute. This database now contains records for more than 10,000 patients. The database was searched within a 25-year interval (January 1, 1971, to December 31, 1996) to identify all patients who were clinically disease-free after complete surgical resection of AJCC stage IV melanoma. Complete resection was defined as the resection of all clinically detectable disease with negative margins. One hundred fifty patients identified during the database search were enrolled onto phase II protocols for postoperative adjuvant therapy with Canvaxin therapeutic cancer vaccine. These protocols all required an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The patients had no clinical or radiographic evidence of disease before vaccine initiation. Excluded were patients receiving chemotherapy, radiation therapy, biologic therapy, or other immunologic therapy within 30 days of vaccine initiation. Also excluded were patients who received vaccine before development or complete resection of distant metastases. In all cases, informed consent for participation in a vaccine protocol was obtained after appropriate discussion and before enrollment. One hundred thirteen patients identified during the database search did not receive Canvaxin vaccine after complete resection of distant melanoma metastases or at any point during their treatment at our cancer institute. Demographic data were similar between the 150 vaccine patients and the 113 nonvaccine patients (Table 1). Both groups had a preponderance of male patients and patients with only one tumor-involved anatomic site. Thirty-one nonvaccine patients (27%) did not receive any adjuvant treatment. Fifty-four patients (48%) received bacille Calmette-Guérin (BCG) by means of various administering modalities, 33 (29%) received chemotherapy, and 16 (14%) received radiation therapy postoperatively. There was a higher proportion of vaccine than nonvaccine patients with more than one tumor-involved organ site (29% v 12%).
Vaccine Preparation Canvaxin therapeutic cancer vaccine is an allogeneic whole-cell vaccine composed of cells from three melanoma cell lines that together express at least 20 immunogenic tumor antigens.19 Its preparation is described elsewhere.18 Briefly, cells from M10-V, M24-V, and M101-V melanoma lines are grown in tissue culture medium, harvested, washed, and pooled (8 x 106 cells/line, 24 x 106 total cells) under sterile conditions. The cells are then irradiated with 150 Gy and cryopreserved in liquid nitrogen. Before April 30, 1996, 10% dimethyl sulfoxide used in cryopreservation was washed out of all three lines after thawing, and the cells were reconstituted in RPMI 1640 before injection; each line was kept in a separate vial. After April 30, 1996, cells from the three lines were cryopreserved together in a smaller volume (0.5 mL) and reconstituted with the addition of 0.5 mL of saline. The vaccine contains 10% dimethyl sulfoxide. It is administered immediately after thawing.
Vaccine Protocols One milliliter of vaccine was injected intradermally into two sites in each of following four areas: left and right hypogastrium, and left and right upper lateral truncal regions. The vaccine was given every 2 weeks for 5 weeks, and then monthly for 10 months for the first year of treatment. After 1 year, the vaccination interval was every 3 months during the second year, and then every 6 months for the next 3 years for a total of 5 years. For the first two treatments, vaccine was mixed with the Tice strain of BCG. In the first injection, BCG was given in a dose of 2.7 to 10.8 x 106 colony-forming units in PPD-negative patients and half that dose in PPD-positive patients. The second dose of BCG (given with the second dose of vaccine) was half of the initial BCG dose. All patients enrolled on a vaccine protocol after April 30, 1996, also received a dose of vaccine on day 42. Follow-up clinical and laboratory evaluations were repeated monthly, with chest radiography at least every 3 months for the first 2 years.
Assessment of Immunologic Response
Statistical Analysis
To control for inadvertent selection bias, a computer program was written for matched-pair analysis on the basis of sex, site of initial distant metastases (soft tissue/distant lymph nodes, liver/brain/bone, or lung/gastrointestinal/other), and number of tumor-involved anatomic sites (one or Vaccine and nonvaccine patients in each pair were compared with respect to OS. If both patients died, a survival benefit was attributed to the treatment received by the patient with the longer survival. If one patient died, a survival benefit was attributed to the treatment received by the surviving patient only if that patient survived longer than the patient who died; otherwise the survival benefit of treatment was considered indeterminate. If both patients were alive at the end of the study, the survival benefit of treatment also was considered indeterminate. The log-rank score test was used to estimate the treatment effect on the basis of the number of pairs favoring vaccine versus nonvaccine adjuvant therapy. A value of P < .05 was considered significant. All statistical analyses were two-tailed and performed using SAS software (SAS Institute, Inc, Cary, NC).
Survival Median follow-up time was 22 months (range, 2 to 182 months; > 60 months for survivors). Univariate analysis of prognostic factors in vaccine and nonvaccine patients showed that vaccine therapy was the only variable significantly associated with OS (P = .0001) (Table 2). Median OS and 5-year rate of OS for the 150 vaccine patients were 36 months and 39%, respectively. In contrast, the median OS and 5-year rate of OS were 18 months and 19%, respectively, for the 113 nonvaccine patients (Fig 1). OS was determined from the date of vaccine initiation in the vaccine group and from the date of surgery in the nonvaccine group. The significance of vaccine therapy as an independent prognostic variable for OS was further demonstrated on multivariate analysis (P = .0001). There was a consistent difference in survival between vaccine and nonvaccine patients when patients were grouped by nonvisceral versus visceral metastases and by one versus more than one tumor-involved organ sites. Among patients with M1a metastases, the median OS and 5-year rate of OS were 39 months and 40%, respectively, with vaccine, and 20 months and 15%, respectively, without vaccine (Fig 2). Among patients with M1b metastases, median OS and 5-year rate of OS were 38 months and 41%, respectively, with vaccine, and 19 months and 21%, respectively, without vaccine (Fig 2).
Matched-Pair Analysis To further control for selection bias when comparing the vaccine group with the nonvaccine (historical) group, we performed a matched-pair analysis of the two groups. Computerized matching of the 263 patients yielded 107 vaccine/nonvaccine pairs matched by the criteria described in Patients and Methods, under Statistical Analysis. Demographic data for each treatment group were similar after matching (Table 3); mean age at the time of complete surgical resection was 49 years for vaccine patients and 48 years for matched nonvaccine patients. Of the 107 nonvaccine patients, 27 received no postoperative adjuvant therapy, 24 received adjuvant BCG therapy, 11 received adjuvant systemic chemotherapy, 12 received adjuvant BCG plus chemotherapy, six received postoperative radiation therapy, and 27 received nonspecific immunotherapy with or without chemotherapy and/or radiation therapy.
Overall survival analysis of the 107 matched pairs showed that 66 pairs favored vaccine therapy, 33 pairs favored nonvaccine therapy, and eight pairs were indeterminate (Z = 3.32, P = .0009). Median OS and 5-year rate of OS were 38 months and 39%, respectively, for the vaccine group, compared with 19 months and 20%, respectively, for the nonvaccine group (Fig 3). The incidence of recurrence was 69% (n = 74) in vaccine patients and 88% (n = 94) in matched nonvaccine patients. Not surprisingly, vaccine patients who developed a recurrence of stage IV melanoma were more likely to receive immunotherapy than were matched nonvaccine patients (Table 4). To identify any inadvertent selection bias, survival between matched and unmatched cohorts was compared. There was no difference in OS between the 107 matched and the 43 unmatched vaccine patients (P = .6660). There was also no difference in OS between the 107 matched and six unmatched nonvaccine patients (P = .5238). A survival benefit favoring vaccine was noted in matched subgroups of patients with exclusively visceral metastases and with exclusively nonvisceral metastases (Fig 4). Of the 107 matched pairs, 39 had metastases confined to soft tissue or nonregional lymph nodes (M1a). Of these, 23 pairs favored vaccine therapy, 14 pairs favored nonvaccine therapies, and two pairs were indeterminate (Z = 1.48, P = .13). Median OS and 5-year rate of OS were 41 months and 41%, respectively, for M1a vaccine patients, versus 20 months and 15%, respectively, for M1a nonvaccine patients. Sixty matched pairs had metastases confined to visceral organs (M1b): 40 pairs favored vaccine therapy, 15 favored nonvaccine therapies, and five were indeterminate (Z = 3.37, P = .0007). Median OS and 5-year rate of OS were 40 months and 41%, respectively, for matched M1b vaccine patients, compared with 18 months and 20%, respectively, for matched M1b nonvaccine patients.
Immunologic Response The prospectively collected DTH data for the vaccine patients were analyzed for immunologic response to vaccine. Four patients had only baseline DTH data available and were censored from further analysis. The mean baseline DTH response to vaccine was 3.8 ± 4.2 mm (± SD). The mean maximum DTH response to vaccine after immunization was 12.8 ± 7.8 mm. This difference represented a significant increase by the signed rank sum test (P = .0001). The mean increase in DTH response to vaccine was 9.0 ± 7.2 mm. Cox proportional hazards regression identified a significant correlation between OS and DTH response to vaccine as a continuous variable (P = .0001). OS tended to increase with the strength of the DTH response to vaccine. When DTH was examined as a categorical variable using a previously defined cutoff level,15 there was a significant difference in OS for those patients with vaccine-DTH  8 mm versus less than 8 mm (P = .0324) (Fig 5).
Of the 150 vaccine-treated patients, 121 had a negative PPD skin test at the start of vaccine therapy. Eighty-five patients (70%) converted to PPD-positive after the second dose of vaccine. There was no significant correlation between DTH response to vaccine and PPD conversion after initiation of vaccine therapy (P = .1228). There was also no correlation between DTH to PPD and OS in this cohort (P = .1888).
This study demonstrated that complete surgical resection may allow long-term survival of a subset of patients with AJCC stage IV melanoma. Thus, patients with stage IV melanoma should be considered for cytoreductive surgery if all clinically evident disease can be safely resected with tumor-negative margins. In addition, survival was significantly improved in patients receiving adjuvant immunotherapy with Canvaxin therapeutic cancer vaccine after complete resection of stage IV melanoma. Survival after vaccine immunotherapy was significantly correlated with the DTH immune response to vaccine but not to a control antigen, as previously reported.15 Distressingly, most patients with AJCC stage IV melanoma will not live more than a year after diagnosis.1 Their poor prognosis reflects the lack of effective treatment for this disease. Responses to systemic chemotherapy are neither consistent nor durable. As yet, no chemotherapeutic agent(s) has proved superior to dacarbazine in prospective randomized trials. Although the combination of interleukin-2, interferon, and chemotherapeutic agents reportedly can produce a response rate as high as 64%, with a durable response rate of 9%,21,22 biochemotherapy has significant toxicity22; multicenter randomized trials are ongoing to evaluate its efficacy. Alternative therapeutic interventions are needed to improve the outcome of patients with metastatic melanoma. The combination of surgery and immunotherapy is a novel approach to treat patients with stage IV melanoma. Although surgery is usually regarded as a local therapy, our group and other investigators have noted long-term survival with the use of this therapy alone.3-13 The rationale for investigating immunotherapy in postsurgical melanoma patients is derived from laboratory and clinical data suggesting the potential value of treatment that modulates specific antimelanoma immune responses. Cytotoxic antibodies and lymphocytes have been detected in the peripheral blood of melanoma patients who have not received systemic therapy.23-26 Spontaneous regression of melanoma, albeit rare, has been observed in patients with metastatic disease, suggesting the presence of an endogenous antimelanoma immune response. Our group has also observed a direct correlation between specific endogenous antitumor antibody immune responses and postsurgical survival of patients with stage IV melanoma.14 Therefore, enhancing specific immune responses in these patients might be expected to improve their postsurgical survival. Although the percentage of stage IV melanomas amenable to complete surgical resection is relatively small, the combination of surgery and postsurgical immunotherapy might prove therapeutically useful in all candidates for cytoreductive surgery. Surgical reduction of tumor burden would allow time for the induction of maximal antitumor immune responses to active specific immunotherapy, a process that usually requires several weeks.13 In our study, the increase in OS associated with postsurgical vaccine therapy appeared to be more than double the increase reported for other postsurgical adjuvant therapies in patients with stage IV melanoma.3-11 This increase in survival was not associated with clinical variables such as organ site of involvement or number of metastases. There was no significant difference in OS associated with metastasis of melanoma to visceral versus nonvisceral sites. On the basis of our prior observation of prolonged survival for patients who underwent reinduction with vaccine after complete resection of recurrent melanoma,27 we speculate that adjuvant vaccine immunotherapy might have a cytostatic effect that limits the size and extent of recurrent lesions. In the present study, the approximate doubling of survival associated with adjuvant vaccine immunotherapy after complete resection of stage IV melanoma is similar to our recently reported observations in stage III melanoma.28 In summary, adjuvant immunotherapy with Canvaxin therapeutic cancer vaccine after complete resection of distant melanoma metastases was associated with prolonged survival when vaccine patients were compared with computer-matched historical controls. The data presented herein provided the rationale for a prospective, randomized, multicenter trial that is currently underway at 40 cancer centers in the United States, Europe, and Australia.
Supported in part by National Cancer Institute grant nos. CA87071, CA12582, and CA76489 and by funding from the Wayne and Gladys Valley Foundation (Oakland, CA) and the Harold McAlister Charitable Foundation (Los Angeles, CA). E.C.H.’s clinical research in melanoma immunotherapy is funded in part by a Career Development Award from the American Society of Clinical Oncology.
Canvaxin and CancerVax are trademarks of CancerVax Corporation, Carlsbad, CA.
1. Barth A, Wanek LA, Morton DL: Prognostic factors in 1,521 melanoma patients with distant metastasis. J Am Coll Surg 181: 193-201, 1995[Medline] 2. Fleming ID, Cooper JS, Henson DE, et al (eds): AJCC Cancer Staging Manual (ed 5). Philadelphia, PA, Lippincott-Raven, 1997 3. Feun LG, Gutterman J, Burgess MA, et al: The natural history of resect-able metastatic melanoma (stage IVA melanoma). Cancer 50: 1656-1663, 1982[CrossRef][Medline] 4. Wornom IL III, Soong S-J, Urist MM, et al: Surgery as palliative treatment for distant metastases of melanoma. Ann Surg 204: 181-185, 1986[Medline] 5. Karp NS, Boyd A, DePan HJ, et al: Thoracotomy for metastatic malignant melanoma of the lung. Surgery 107: 256-261, 1990[Medline] 6. Branum GD, Seigler HF: Role of surgical intervention in the management of intestinal metastases from malignant melanoma. Am J Surg 162: 428-431, 1991[CrossRef][Medline] 7. Gorenstein LA, Putnam JB, Natarajan G, et al: Improved survival after resection of pulmonary metastases from malignant melanoma. Ann Thorac Surg 52: 204-210, 1991[Abstract] 8. Harpole DH Jr, Johnson CM, Wolfe WG, et al: Analysis of 945 cases of pulmonary metastatic melanoma. J Thorac Cardiovasc Surg 103: 743-748, 1992[Abstract] 9. Karakousis CP, Velez A, Driscoll BA: Metastasectomy in malignant melanoma. Surgery 115: 295-302, 1994[Medline] 10. Skibber JM, Soong SJ, Austin L, et al: Cranial irradiation after surgical excision of brain metastases in melanoma patients. Ann Surg Oncol 3: 118-123, 1996[CrossRef][Medline] 11. Fletcher WS, Pommier RF, Lum S, et al: Surgical treatment of metastatic melanoma. Am J Surg 175: 413-417, 1998[CrossRef][Medline] 12. Morton DL: Changing concepts of cancer surgery: Surgery as immunotherapy. Am J Surg 135: 367-371, 1978[CrossRef][Medline] 13. Morton DL, Ollila DW, Hsueh EC, et al: Cytoreductive surgery and adjuvant immunotherapy: A new management paradigm for metastatic melanoma. CA Cancer J Clin 49: 101-116, 1999[Abstract] 14. Hsueh EC, Gupta RK, Yee R, et al: Does endogenous immune response determine the outcome of surgical therapy for metastatic melanoma? Ann Surg Oncol 7: 232-238, 2000[CrossRef][Medline]
15. Hsueh EC, Gupta RK, Qi K, et al: Correlation of specific immune responses with survival in patients receiving melanoma cell vaccine. J Clin Oncol 16: 2913-2920, 1998 16. Jones RC, Kelley M, Gupta RK, et al: Immune response to polyvalent melanoma cell vaccine in AJCC stage III melanoma: An immunologic survival model. Ann Surg Oncol 3: 437-445, 1996[CrossRef][Medline] 17. Morton DL, Barth A: Vaccine therapy for malignant melanoma. CA Cancer J Clin 46: 225-244, 1996[Medline] 18. Morton DL, Foshag LJ, Hoon DSB, et al: Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine. Ann Surg 216: 463-482, 1992[Medline] 19. Chan AD, Morton DL: Active immunotherapy with allogeneic tumor cell vaccines: Present status. Semin Oncol 25: 611-622, 1998[Medline] 20. Hsueh EC, Nathanson L, Foshag LJ, et al: Active specific immunotherapy with polyvalent melanoma cell vaccine in patients with in-transit melanoma metastases. Cancer 85: 2160-2169, 1999[CrossRef][Medline] 21. Legha SS, Ring S, Eton O, et al: Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol 16: 1752-1759, 1998[Abstract]
22. O’Day SJ, Gammon G, Boasberg PD, et al: Advantages of concurrent biochemotherapy modified by decrescendo interleukin-2, granulocyte colony-stimulating factor, and tamoxifen for patients with metastatic melanoma. J Clin Oncol 17: 2752-2761, 1999
23. Lewis MG, Ikonopisov RL, Nairn RC, et al: Tumour-specific antibodies in human malignant melanoma and their relationship to the extent of the disease. BMJ 3: 547-552, 1969
24. Bodurtha AJ, Chee DO, Laucius JF, et al: Clinical and immunological significance of human melanoma cytotoxic antibody. Cancer Res 35: 189-193, 1975 25. Canevari S, Fossati G, Della Porta G, et al: Humoral cytotoxicity in melanoma patients and its correlation with the extent and course of the disease. Int J Cancer 16: 722-729, 1975[Medline] 26. Hellstrom I, Hellstrom KE, Sjogren HO, et al: Demonstration of cell-mediated immunity to human neoplasms of various histological types. Int J Cancer 7: 1-16, 1971[Medline] 27. Hsueh EC, Essner R, Foshag LJ, et al: Active immunotherapy by reinduction with a polyvalent allogeneic cell vaccine correlates with improved survival in recurrent metastatic melanoma. Ann Surg Oncol 9: 486-492, 2002[CrossRef][Medline] 28. Morton DL, Hsueh EC, Essner R, et al: Prolonged survival of patients receiving active immunotherapy with Canvaxin therapeutic polyvalent vaccine after complete resection of melanoma metastatic to regional lymph nodes. Ann Surg 236: 438-449, 2002[CrossRef][Medline] Submitted January 31, 2002; accepted August 2, 2002.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
