Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 7-Day Trial for You or Your Team.

Learn More →

Combination chemotherapy with or without s.c. IL-2 and IFN-α: results of a prospectively randomized trial of the Cooperative Advanced Malignant Melanoma Chemoimmunotherapy Group (ACIMM)

Combination chemotherapy with or without s.c. IL-2 and IFN-α: results of a prospectively... British Journal of Cancer (2002) 86, 179 – 184 ã 2002 The Cancer Research Campaign All rights reserved 0007 – 0920/02 $25.00 www.bjcancer.com Combination chemotherapy with or without s.c. IL-2 and IFN-a: results of a prospectively randomized trial of the Cooperative Advanced Malignant Melanoma Chemoimmunotherapy Group (ACIMM) ,1,2,4 3 4 4 5 6 7 8 J Atzpodien* , K Neuber , D Kamanabrou , M Fluck , EB Bro ¨ cker , C Neumann ,TM Ru ¨ nger , G Schuler , 8 9 9 1 1 P von den Driesch ,IMu ¨ ller , E Paul , T Patzelt and M Reitz 1 2 European Institute for Tumor Immunology and Prevention (EUTIP), Gotenstr. 152, 53175 Bonn, Germany; Medizinische Hochschule Hannover, Germany; 3 4 5 Universita ¨tshautklinik Hamburg, Germany; Fachklinik Hornheide an der Universita ¨t Mu ¨nster, Germany; Universita ¨tshautklinik Wu ¨rzburg, Germany; 6 7 8 9 Universita ¨tshautklinik Go ¨ttingen, Germany; Boston University School of Medicine, USA; Universita ¨tshautklinik Erlangen, Germany; Klinikum Nu ¨rnberg- Nord, Germany The purpose of this randomized trial was to evaluate the efficacy of combination chemoimmunotherapy compared with chemotherapy alone. A total of 124 patients were randomized to receive intravenous cisplatin (35 mg m , days 1 – 3), 72 72 72 carmustine (150 mg m , day 1, cycles 1 and 3 only), dacarbacine (220 mg m , days 1 – 3) and oral tamoxifen (20 mg m , daily) in combination with (n=64) or without (n=60) sequential subcutaneous IL-2 and IFN-a. In those patients who received 6 72 sequential immunotherapy, each cycle of chemotherapy was followed by outpatient s.c. IL-2 (10610 IU m , days 3 – 5, 6 72 6 72 week 4; 5610 IU m , days 1, 3, 5, week 5) and s.c. IFN-a (5610 IU m , day 1, week 4; days 1, 3, 5, week 5). The overall response rate of patients treated with the combination of chemotherapy and IL-2/IFN-a was 34.3% with seven complete responses (10.9%) and 15 partial responses (23.4%). In patients treated with chemotherapy, only, the overall response rate was 29.9% with eight complete responses (13.3%) and 10 partial responses (16.6%). There was no significant difference in median progression free survival (0 months vs 4 months) and in median overall survival (12 months vs 13 months) for combined chemoimmunotherapy and for chemotherapy, respectively. British Journal of Cancer (2002) 86, 179 – 184. DOI: 10.1038/sj/bjc/6600043 www.bjcancer.com ã 2002 The Cancer Research Campaign Keywords: melanoma; interleukin-2; interferon alpha; chemotherapy Metastatic melanoma responds poorly to the currently available patients has responded, response rates with immunochemothera- chemotherapeutic agents and, until today, no standard treatment pies have been lower than with the best chemotherapy regimens, has been established. Most single agent chemotherapeutics provide however, sustained responses have been consistently observed only low response rates. Dacarbazine (DTIC), the most active following IL-2 based chemoimmunotherapy. single agent in the treatment of melanoma, can be expected to yield Recently, several trials have investigated the combination of a response rate of about 20% (McClay and McClay, 1996). Even various cytotoxic agents with IL-2 and IFN-a. While primarily in though most trials of combination chemotherapy for the treatment phase II studies several authors claimed a clear advantage of this of metastatic melanoma clearly have not been superior to DTIC chemoimmunotherapy over chemotherapy alone (Legha et al, alone, the combination of carmustine (BCNU), DTIC, cisplatin, 1996; Richards et al, 1992), more recently randomized trials raised and tamoxifen has produced significant antitumour responses in doubts about the effectiveness and benefit of this combination (Johnston et al, 1998; Rosenberg et al, 1999). up to 50% of patients (McClay and McClay, 1994; Middleton et al, 2000; Richards et al, 1992). A further increase in the rate of We have performed a prospective randomized trial in patients objective responses may be achieved by introducing cytokines into with metastatic melanoma treated either with a chemotherapy regi- the therapeutic regimens, with interleukin-2 (IL-2) and interferon men of cisplatin, carmustine, dacarbazine, and tamoxifen, or with alpha (IFN-a) being the most widely acclaimed. Monotherapy with the identical chemotherapy followed by outpatient s.c. IL-2 and IL-2 results in up to 29% objective responses (Rosenberg et al, s.c. IFN-a. 1994). Different types of interferons have also been intensively explored (Creagan et al, 1990). While a defined subgroup of PATIENTS AND METHODS Patients *Correspondence: Professor Dr J Atzpodien; E-mail: [email protected] Between May 1995 and May 1999, 124 patients were randomized Received 7 February 2001; revised 22 October 2001; accepted 31 Octo- and considered evaluable for response (Table 1). Forty-one females ber 2001 and 83 males were treated either with combined chemoimmuno- Clinical Clinical Chemoimmunotherapy in advanced melanoma J Atzpodien et al Table 1 Patients’ characteristics complete response – disappearance of all signs of disease for a minimum of 8 weeks; partial response – 50% or more reduction Therapy in the sum of products of the greatest perpendicular diameters of measurable lesions, no increase in lesion size and no new lesions; Characteristics Arm A Arm B All stable disease – less than a partial response with no disease Entered 64 60 124 progression for at least 8 weeks; progressive disease – 25% or Sex more increase in sum of products in the longest perpendicular Men 46 37 83 diameters of measurable lesions or the development of new lesions. Women 18 23 41 Duration of response was measured from the initial date of Age response. Two patients were randomized, but did not receive ther- Median 57 57 57 apy and were evaluated as progressive disease patients. Treatment Range 28 – 72 29 – 77 28 – 77 efficacy was assessed on intent-to-treat basis. Histology Cutaneous Statistical analysis Nodular 13 18 31 Amelanotic 1 0 1 Survival was measured from start of therapy to date of death or to Superficial spreading 18 14 32 the last known date to be alive. The statistical end points in our Acral lentiginous 3 2 5 analysis were (1) objective response and (2) overall and progression Uveal 6 5 11 free survival of patients. The progression free survival after 1 year Unknown 14 13 27 was assumed to be 40% (chemoimmunotherapy) and 20% Pretreatment (chemotherapy), respectively. The intention was to find a Surgery 53 54 107 chemoimmunotherapy induced progression free survival benefit Local radiation 6 10 16 Chemotherapy 4 3 7 over chemotherapy alone at 20% with a probability of 95% Immunotherapy; 5 6 11 (a=0.05) and a sample power of 1-ß=0.80. Based on this assump- Chemo/immunotherapy 2 2 4 tion an intended patient accrual of 64 patients per therapy arm was Others 1 4 5 required in case of a statistically significant survival benefit after a combined chemoimmunotherapy. The probability of overall survi- Arm A (i.v. DTIC, i.v. cisplatin, i.v. BCNU, p.o. tamoxifen, s.c. IL-2, s.c. IFN-a); Arm B val was plotted over time according to the method of Kaplan and (i.v. DTIC, i.v. cisplatin, i.v. BCNU, p.o. tamoxifen). Meier. Statistical significance was assessed using the Log Rank, Tarone Ware and the Breslow test; SPSS software was employed. or chemotherapy alone. Median follow-up of these patients was 12 months (range 0 – 62 months). Ninety-seven patients had not been RESULTS treated with systemic therapy before, 27 patients had received previous systemic immuno- or chemotherapy treatment. A total of 124 patients were enrolled in this clinical trial and Criteria for entry into the study were: histologically confirmed randomized to receive combined chemoimmunotherapy (n=64) metastatic melanoma; Karnofsky performance status 480%; white or chemotherapy alone (n=60) (Table 1). Patient evaluation was 71 71 blood cell count 43500 ml ; platelet count 4100 000 ml ; performed according to the guidelines described above. haematocrit 430%; serum creatinin and bilirubin 51.5 of the Response to therapy was evaluated according to World Health upper normal limit; age between 18 and 75 years and a life expec- Organization (WHO) criteria with regular reevaluation intervals tancy of 43 months. every 8 weeks. This study was approved by the institutional review board of the Medizinische Hochschule Hannover and by participating centres; Treatment response written informed consent was obtained from all patients prior to entry into the study. Seven patients (10.9%) treated with chemoimmunotherapy achieved a complete response and 15 patients (23.4%) had a partial remission (Table 2). The overall objective response rate of Study design combined chemoimmunotherapy was 34.3% (median survival 29 All patients received a chemotherapy regimen comprising cisplatin 72 72 (35 mg m , i.v., days 1 – 3), carmustine (150 mg m , i.v., day 1, cycles 1 and 3 only), dacarbacine (220 mg m , i.v., days 1 – 3) Table 2 Sites of disease and response of patients receiving DTIC, cispla- and oral tamoxifen (20 mg m , daily) in combination with tin, BCNU and tamoxifen followed by immunotherapy with IL-2 and IFN-a (n=64) or without (n=60) subcutaneous IL-2 and IFN-a. In those patients, who were randomized to receive chemoimmunotherapy, Response each cycle of chemotherapy was followed by outpatient immu- 6 72 Tumour site CR PR SD PD Total notherapy with combined IL-2 (10610 IU m , days 3 – 5, week 6 72 4; 5610 IU m , days 1, 3, 5, week 5) and IFN-a Lymph nodes 5 7 5 21 38 6 72 (5610 IU m , day 1, week 4; days 1, 3, 5, week 5); randomiza- Liver 1 9 4 22 36 tion was performed centrally. Five week treatment cycles were Lung 1 8 3 15 27 repeated unless progression of disease occurred. Re-evaluation of Local relapse 0 1 1 4 6 the patients’ tumour status was performed between treatment cycles. Skin/subcutaneous 3 1 0 6 10 Brain 0 0 0 1 1 Patients received an average of 2.7 (Arm A, median 2.0; range 1 – 5) Bone 0 1 0 3 4 and 1.9 (Arm B, median 2.0; range 0 – 4) treatment cycles. Adrenal 0 2 1 2 5 Spleen 0 2 0 4 6 Assessment of response Other 0 0 1 6 7 Total 7 15 9 33 64 Response to therapy was evaluated according to World Health Organization (WHO) criteria with regular re-evaluation intervals Abbreviations: CR, complete remission; PR, partial remission; SD, stable disease; PD, progressive disease. Patients may have had more than one site. every 8 weeks; all repeated scans were reported to the data center: British Journal of Cancer (2002) 86(2), 179 – 184 ã 2002 The Cancer Research Campaign Chemoimmunotherapy in advanced melanoma J Atzpodien et al months; 95% CI, 9, 49) with a median duration of response of 9 months (chemoimmunotherapy) and 8 months (chemotherapy) as months (range 5 – 62 months). While in complete responders, the opposed to patients without liver metastases with a median survival median response duration was 25 months (range 5 – 62 months), of 20 months (chemoimmunotherapy) and 17 months (chemother- the median duration of partial responses was 7 months (range apy), respectively (Figure 3). 5 – 19 months). Objective tumour regressions were seen in lymph nodes (12), liver (10), lung (9), skin (4), bone (1), adrenal (2) Progression free survival and spleen (2). Nine patients (14.1%) showed disease stabilization and 33 patients (51.6%) exhibited continuous disease progression The progression free survival ranged from 0 to 62 (median 4 despite therapy. months) for all patients entered into the study. There was no In the chemotherapy group the overall objective response rate was significant difference in median progression free survival between 29.9% (median survival 24 months; 95% CI, 16, 32) with eight patients treated with chemoimmunotherapy (0 months, range 0 – patients (13.3%) achieving a complete response and 10 patients 62 months) or with chemotherapy (4 months, range 0 – 47 months) (16.6%) a partial remission (Table 3). The median duration of (Figure 4). response ranged from 5 to 47 months (CR, PR, median 15 months). The median progression free survival for patients with liver While in complete responders, the median duration of response metastases was 0 months independent of the treatment regimen ranged from 5 to 47 months (median 28 months), the median dura- as compared to a median progression free survival of 7 months tion of response in partial responders ranged from 5 to 34 months (range 0 – 62 months, chemoimmunotherapy) and 5 months (range (median 7 months), respectively. Objective tumour regressions were 0 – 47 months, chemotherapy) in patients without liver metastases seen in lymph nodes (14), liver (3), lung (9), skin (4) and adrenal (1). (data not shown). Fourteen patients (23.3%) showed disease stabilization. In 28 patients (46.7%) progression of disease occurred. Treatment toxicity Chemotherapy led to significant haematotoxicity with WHO grade Overall survival IV thrombocytopenia in 25% and leukopenia in approximately Overall median survival of all patients entered into the study was 26% of treatment cycles, respectively. Immunotherapy related side 13 months (95% CI 10; 16). There was no significant difference effects included WHO grade III and IV malaise in 21%, anorexia in in median overall survival for combined chemoimmunotherapy 21%, chills in 8%, diarrhoea in 5% and fevers in less than 25% of (12 months) and for chemotherapy (13 months), respectively treatment cycles, respectively (data not shown). (Figure 1). Patients’ sex had also no influence on median survival Overall, no life threatening toxicities were observed, and no (data not shown). Twenty-five patients are alive at a median toxic deaths occurred. Generally, immunotherapy could be admi- follow-up of 24 months (range 2 – 62 months). Two patients nistered in the outpatient setting. Chemotherapy required continue to be alive after more than 5 years from chemoimmu- inpatient stays of 4 days per cycle. notherapy. A 3-year survival of 12.96% and 11.42% was achieved with combined chemoimmunotherapy and with chemotherapy DISCUSSION alone, respectively. For complete responders, median survival has not been reached at 62 months (range 20 – 62 months). In contrast, In the present prospective randomized trial we reported the partial responders and patients with disease stabilization had both a results of 124 patients with progressive metastatic melanoma median survival of 16 months (range 5 – 40 months and 2 – 38 who received a combined chemoimmunotherapy (IFN-, IL-2 months) as opposed to a median survival of 8 months (range combined with DTIC, cisplatin, BCNU, and tamoxifen) or a 0 – 40 months) in progressive disease patients (Figure 2). chemotherapy (DTIC, cisplatin, BCNU, and tamoxifen) alone. In the chemoimmunotherapy group, median overall survival of We observed an overall objective response in 34.3% of patients objective responses was 29 months (range 5 – 62 months, 95% CI treated with the combined chemoimmunotherapy which is 9, 49), while in the chemotherapy group a median survival of 24 comparable with earlier trials achieving response rates between months (range 8 – 47 months, 95% CI 16, 32) was achieved (data 23% to 64% (Atkins et al, 1994; Atzpodien et al, 1995; Feun not shown). et al, 1995; Hoffmann et al, 1998; Johnston et al, 1998; Legha, There was a significant (P50.0001) difference in overall survival 1998; Middleton et al, 2000; Pyrhonen et al, 1992; Rosenberg for all patients with liver metastases with a median survival of 9 et al, 1999; Thompson et al, 1997). Whereas in previous clinical trials, introducing cytokines in chemotherapeutic regimens yielded an enhanced efficacy (Atkins et al, 1994; Legha et al, 1996), our results raise doubts concerning the potential benefits Table 3 Sites of disease and response of patients receiving DTIC, cispla- of the presently used dosages of IL-2 and INF-a for therapy of tin, BCNU and tamoxifen metastatic melanoma since objective response rates of patients treated with chemotherapy alone were similar (29.9%) to sequen- Response tial chemoimmunotherapy (34.3%). Tumour site CR PR SD PD Total In addition, in our trials no significant difference in survival time was observed for patients treated with chemoimmunother- Lymph nodes 5 9 8 17 39 apy (median 12 months) and chemotherapy (median 13 Liver 1 2 4 19 26 months), respectively, which is also supported by recent results Lung 4 5 8 17 34 Local relapse 1 2 2 2 7 of other cytokine based therapy regimens (Johnston et al, 1998; Skin/subcutaneous 1 3 4 4 12 Rosenberg et al, 1999). Although overall survival of objective Brain 0 0 1 2 3 responses was slightly increased in the chemoimmunotherapy Bone 0 0 3 3 6 group (median 29 months, 95% CI 9, 49) than in the Adrenal 1 0 0 4 5 chemotherapy group (median 24 months, 95% CI 16, 32), the Spleen 0 0 1 4 5 response duration of patients was shorter after chemoimmu- Other 0 2 2 2 6 notherapy (median 9 months) when compared to Total 8 10 14 28 60 chemotherapy (15 months). In contrast, Legha et al (1997) Abbreviations: CR, complete remission; PR, partial remission; SD, stable disease; PD, reported a significantly increased proportion (10%) of long-term progressive disease. Patients may have had more than one site. responders after chemoimmunotherapy. ã 2002 The Cancer Research Campaign British Journal of Cancer (2002) 86(2), 179 – 184 Clinical Clinical Chemoimmunotherapy in advanced melanoma J Atzpodien et al 1.0 Arm A vs Arm B Log Rank P = 0.7904 Breslow P = 0.9313 Tarone P = 0.9697 0.8 0.6 Arm A 0.4 DTIC, Cisplatin, BCNU Tamoxifen, IL-2, IFN-a Arm B n = 64 patients DTIC, Cisplatin Median = 12 months BCNU, Tamoxifen 0.2 3-year survival = 12.96% n = 60 patients Median = 13 months 3-year survival = 11.42% 0.0 0 12 2436 48 6072 Months No. of patients at risk Arm A 64 32 17 8 4 2 Arm B 60 31 15 5 – – Figure 1 Overall survival (Kaplan-Meier estimates) of 124 patients treated with chemoimmunotherapy (i.v. DTIC, i.v. cisplatin, i.v. BCNU, p.o. tamoxifen, s.c. interleukin-2 and s.c. interferon-a) or chemotherapy (i.v. DTIC, i.v. cisplatin, i.v. BCNU and p.o. tamoxifen) alone. Survival was measured from start of therapy. CR 1.0 n = 15 patients Median not reached 3-year survival = 60.67% CR vs PR 0.8 Log Rank P = 0.0002 PR Breslow P = 0.0002 n = 25 patients Tarone P = 0.0002 Median = 16 months CR 0.6 3-year survival = 20.27% PR vs SD SD Log Rank P = 0.5499 n = 23 patients Breslow P = 0.5617 0.4 Median = 16 months Tarone P = 0.5679 3-year survival = 8.85% SD vs PD 0.2 Log Rank P = 0.0059 PD Breslow P = 0.0028 n = 61 patients SD Tarone P = 0.0030 Median = 8 months PR PD 3-year survival = 1.96% 0.0 012 24 36 48 60 72 Months No. of patients at risk CR 15 15 13 8 4 2 PR 15 18 8 3 0 0 SD 23 11 6 2 – – PD 61 20 6 2 – – Figure 2 Overall survival (Kaplan-Meier estimates) of 124 patients classified by treatment response. CR=complete remission, PR=partial remission, SD=stable disease, PD=progressive disease. Survival was measured from start of therapy. British Journal of Cancer (2002) 86(2), 179 – 184 ã 2002 The Cancer Research Campaign P Chemoimmunotherapy in advanced melanoma J Atzpodien et al 1 = Arm A, without liver metastases, 1.0 DTIC, Cisplatin, BCNU Tamoxifen, IL-2, IFN-a n = 28 patients 0.8 Median = 20 months 3-year survival = 29.61% 0.6 2 = Arm B, without liver metastases, DTIC, Cisplatin BCNU, Tamoxifen 0.4 n = 36 patients Median = 17 months 3-year survival = 15.08% 0.2 3 = Arm A, with liver metastases, 4 3 DTIC, Cisplatin, BCNU, 0.0 Tamoxifen, IL-2, IFN-a 012 24 36 48 60 72 n = 36 patients Median = 9 months Months 3-year survival = 7.9% No. of patients at risk 4 = Arm B, with liver metastases, 1 = 28 19 12 6 4 2 DTIC, Cisplatin BCNU, Tamoxifen 2 = 35 22 12 4 – – n = 26 patients Median = 8 months 3 = 36 13 6 3 0 0 3-year survival = 4.8% 4 = 25 10 3 2 – – Figure 3 Overall survival (Kaplan-Meier estimates) of 124 patients classified by risk (liver metastases). Survival was measured from start of therapy. Arm A vs Arm B 1.0 Log Rank P = 0.8245 Breslow P = 0.8123 Tarone P = 0.8447 0.8 0.6 0.4 Arm B Arm A DTIC, Cisplatin DTIC, Cisplatin, BCNU BCNU, Tamoxifen Tamoxifen, IL-2, IFN-a n = 60 patients n = 64 patients Median = 4 months 0.2 Median = 0 months 3-year survival = 10.91% 3-year survival = 8.13% 0.0 0 12 2436 48 6072 Months No. of patients at risk Arm A 64 11 6 4 3 2 Arm B 60 12 6 5 – – Figure 4 Progression free survival for all 124 patients treated with chemoimmunotherapy (i.v. DTIC, i.v. cisplatin, i.v. BCNU, p.o. tamoxifen, s.c. interleukin- 2 and s.c. interferon-a) or chemotherapy (i.v. DTIC, i.v. cisplatin, i.v. BCNU and i.v. tamoxifen) alone. Plots were generated by the Kaplan-Meier method and progression free survival was measured from start of therapy. ã 2002 The Cancer Research Campaign British Journal of Cancer (2002) 86(2), 179 – 184 Clinical Clinical Chemoimmunotherapy in advanced melanoma J Atzpodien et al The discrepancy in the effect of cytokines in metastatic melanoma While median duration of objective responses appeared to be therapies might be best explained by the following uncontrolled vari- prolonged in patients receiving chemotherapy only, overall survival ables: (A) patient selection and clinical/biological risk; (B) variations analysis yielded few (n=2) long term (448 months) surviving in the rIL-2 based regimen (e.g., reconstitution of drug, route and patients in the chemoimmunotherapy combination, only. Similar dose of administration); and (C) different standards of patient care results were reported when comparing dacarbazine/INF- with or (e.g., supportive care upon IL-2 therapy). In fact, previous reports without IL-2. Since cytokines in chemotherapies also alter the toxi- have repeatedly shown that overall survival is higly risk-dependent city profile (Falkson et al, 1998; Johnston et al, 1998; Stark et al, (Hoffmann et al, 1998; Rusthoven et al, 1996). This is confirmed 1998), future clinical trials might focus on new combinations, by our study since we reported that patients with liver metastases different dosages and dose distribution regimens of IL-2 and had a significantly shorter survival and shorter progression free survi- INF- to increase both efficacy and tolerability for patients with val compared to patients without liver metastases. Notably, the metastatic melanoma. proportion of patients with hepatic metastases varied between 56% (chemoimmunotherapy) and 43% (chemotherapy alone). In summary, this prospectively randomized clinical trial showed ACKNOWLEDGEMENTS no statistically significant benefit of IL-2, INF- based combined chemoimmunotherapy in patients with metastatic melanoma The authors would like to thank Dr Susanne Scha ¨d and Dr compared to chemotherapy alone. So far, also no standard was estab- Eckhardt Ka ¨mpgen for support. J Atzpodien is supported by grants lished confirming a significant survival benefit of polychemotherapy of the Deutsche Krebshilfe, Wilhelm Sander-Stiftung, and when compared to DTIC, alone (Chiarion Sileni et al, 2001). Gesellschaft zur Fo ¨ rderung immunologischer Krebstherapien e.V. REFERENCES Atkins MB, O’Boyle KR, Sosman JA, Weiß GR, Margolin KA, Ernest ML, Legha SS, Ring S, Eton O, Bedikian A, Plager C, Papadopoulos N (1997) Kappler K, Mier JW, Sparano JA, Fischer RI (1994) Multiinstitutional Development and results of biochemotherapy in metastatic melanoma: phase II trial of intensive combination chemoimmunotherapy for meta- the University of Texas M.D. Anderson Cancer Center experience. Cancer static melanoma. J Clin Oncol 12: 1553 – 1560 J Sci Am 3(1 Suppl): 9 – 15 ¨ ¨ Atzpodien J, Lopez Hanninen E, Kirchner H, Franzke A, Korfer A, Volke- McClay EF, McClay ME (1994) Tamoxifen: is useful in the treatment of nandt M, Duensing S, Schomburg A, Chaitchik S, Poliwoda H (1995) patients with metastatic melanoma?. J Clin Oncol 12: 617 – 626 Chemoimmunotherapy of advanced malignant melanoma: sequential McClay EF, McClay ME (1996) Systemic chemotherapy for the treatment of administration of subcutaneous interleukin-2 and interferon-a after intra- metastatic malignant melanoma. Semin Oncol 23: 744 – 753 venous dacarbazine, cisplatin, carmustine and tamoxifen. Eur J Cancer 31: Middleton MR, Lorigan P, Owen J, Asshcroft L, Lee SM, Harper P, Thatcher 876 – 881 N (2000) A randomized phase III study comparing dacarbazine, BCNU, Chiarion Sileni V, Nortilli R, Aversa SM, Paccagnella A, Medici M, Corti I, cisplatin and tamoxifen with dacarbazine and interferon in advanced mela- Favaretto AG, Cetto GL, Monfardini S (2001) Phase II randomized study noma. Br J Cancer 82: 1158 – 1162 of dacarbazine, carmustine, cisplatin and tamoxifen versus dacarbazine Pyrhonen S, Hahka-Kemppinen M, Muhonen T (1992) A promising interfer- alone in advanced melanoma patients. Melanoma Res 11: 189 – 196 on plus four-drug chemotherapy regimen for metastatic melanoma. J Clin Creagan ET, Schaid DJ, Ahmann DL, Fryak S (1990) Disseminated malignant Oncol 10: 1919 – 1926 melanoma and recombinant interferon: analysis of seven consecutive phase Richards JM, Mehta N, Ramming K, Skosey P (1992) Sequential chemoim- II investigations. J Invest Dermatol 95(6 Suppl): 188 – 192 munotherapy in the treatment of metastatic melanoma. J Clin Oncol 10: Falkson CI, Ibrahim J, Kirkwood JM (1998) Phase III of dacarbazine versus 1338 – 1343 dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen Rosenberg JM, Yang JC, Topalian SL, Schwarzentruber DJ, Web JS, Parkinson versus dacarbazine with interferon alpha-2b and tamoxifen in patients with DR, Seipp CA, Einhorn JH, White DE (1994) Treatment of 283 consecu- metastatic melanoma: an Eastern Cooperative Oncology Group study. J tive patients with metastatic melanoma or renal cell cancer using high-dose Clin Oncol 16: 1743 – 1751 bolus interleukin-2. JAMA 271: 907 – 913 Feun LG, Savaraj N, Moffat F, Robinson D, Liebmann A, Hurley J, Raub Jr Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topa- WA, Richman SP (1995) Phase II trial of recombinant interferon-alpha lian SL, Seipp CA, Einhorn JH, White DE, Steinberg SM (1999) with BCNU, cisplatin, DTIC and tamoxifen in advanced malignant mela- Prospective randomized trial of the treatment of patients with metastatic noma. Melanoma Res 5: 273 – 276 melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen Hoffmann R, Mu ¨ ller I, Neuber K, Laßmann S, Buer J, Probst M, Oevermann alone or in combination with interleukin-2 and interferon alfa-2b. J Clin K, Franzke A, Kirchner H, Ganser A, Atzpodien J (1998) Risk and outcome Oncol 17: 968 – 975 in metastatic malignant melanoma patients receiving DTIC, cisplatin, Rusthoven JJ, Quirt IC, Iscoe NA, McCulloch PB, James KW, Lohmann RC, BCNU and tamoxifen followed by immunotherapy with interleukin 2 Jensen J, Burdette-Radoux S, Bodurtha AJ, Silver HK, Verma S, Armitage and interferon alpha2a. Br J Cancer 78: 1076 – 1080 GR, Zee B, Bennett K (1996) Randomized, double-blind, placebo- Johnston SR, Constenla DO, Moore J, Atkinson H, A’Hern RP, Dadian G, controlled trial comparing the response rates of carmustine, dacarbazine, Riches PG, Gore ME (1998) Randomized phase II trial of BCDT [carmus- and cisplatin with and without tamoxifen in patients with metastatic mela- tine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen] with or noma. National Cancer Institute of Canada Clinical Trials Group. J Clin without interferon alpha (IFN-alpha) and interleukin (IL-2) in patients Oncol 14: 2083 – 2090 with metastatic melanoma. Br J Cancer 77: 1280 – 1286 Stark JJ, Dillman RO, Schulof R, Wiemann MC, Barth NM, Honeycutt PJ, Legha SS (1998) Development of a biochemotherapy regimen with concur- Soori G (1998) Interferon alpha and chemohormonal therapy for patients rent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, with advanced melanoma: final results of a phase I-II study for the Cancer and interleukin-2 for patients with metastatic melanoma. J Clin Oncol Biotherapy Research Group and the Mid-Atlantic Oncology Program. 16: 1752 – 1759 Cancer 82: 1677 – 1681 Legha SS, Ring S, Bedikan A, Plager C, Eton O, Buzaid AC, Papadopoulos Thompson JA, Gold PJ, Markowitz DR, Byrd DR, Lindgren CG, Fefer A N (1996) Treatment of metastatic melanoma with combined chemother- (1997) Updated analysis of an outpatient chemoimmunotherapy regimen apy containing cisplatin, vinblastine and dacarbazine (CVD) and for treating metastatic melanoma. Cancer J Sci Am 3(1 Suppl): 29 – 34 biotherapy using interleukin-2 and interferon-alpha. Ann Oncol 7: 827 – 835 British Journal of Cancer (2002) 86(2), 179 – 184 ã 2002 The Cancer Research Campaign http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Pubmed Central

Combination chemotherapy with or without s.c. IL-2 and IFN-α: results of a prospectively randomized trial of the Cooperative Advanced Malignant Melanoma Chemoimmunotherapy Group (ACIMM)

Download PDF
6 pages

Loading next page...
 
/lp/pubmed-central/combination-chemotherapy-with-or-without-s-c-il-2-and-ifn-results-of-a-hlGwuVKBqg

References (43)

Publisher
Pubmed Central
Copyright
Copyright © 2002 The Cancer Research Campaign
ISSN
0007-0920
eISSN
1532-1827
DOI
10.1038/sj.bjc.6600043
Publisher site
See Article on Publisher Site

Abstract

British Journal of Cancer (2002) 86, 179 – 184 ã 2002 The Cancer Research Campaign All rights reserved 0007 – 0920/02 $25.00 www.bjcancer.com Combination chemotherapy with or without s.c. IL-2 and IFN-a: results of a prospectively randomized trial of the Cooperative Advanced Malignant Melanoma Chemoimmunotherapy Group (ACIMM) ,1,2,4 3 4 4 5 6 7 8 J Atzpodien* , K Neuber , D Kamanabrou , M Fluck , EB Bro ¨ cker , C Neumann ,TM Ru ¨ nger , G Schuler , 8 9 9 1 1 P von den Driesch ,IMu ¨ ller , E Paul , T Patzelt and M Reitz 1 2 European Institute for Tumor Immunology and Prevention (EUTIP), Gotenstr. 152, 53175 Bonn, Germany; Medizinische Hochschule Hannover, Germany; 3 4 5 Universita ¨tshautklinik Hamburg, Germany; Fachklinik Hornheide an der Universita ¨t Mu ¨nster, Germany; Universita ¨tshautklinik Wu ¨rzburg, Germany; 6 7 8 9 Universita ¨tshautklinik Go ¨ttingen, Germany; Boston University School of Medicine, USA; Universita ¨tshautklinik Erlangen, Germany; Klinikum Nu ¨rnberg- Nord, Germany The purpose of this randomized trial was to evaluate the efficacy of combination chemoimmunotherapy compared with chemotherapy alone. A total of 124 patients were randomized to receive intravenous cisplatin (35 mg m , days 1 – 3), 72 72 72 carmustine (150 mg m , day 1, cycles 1 and 3 only), dacarbacine (220 mg m , days 1 – 3) and oral tamoxifen (20 mg m , daily) in combination with (n=64) or without (n=60) sequential subcutaneous IL-2 and IFN-a. In those patients who received 6 72 sequential immunotherapy, each cycle of chemotherapy was followed by outpatient s.c. IL-2 (10610 IU m , days 3 – 5, 6 72 6 72 week 4; 5610 IU m , days 1, 3, 5, week 5) and s.c. IFN-a (5610 IU m , day 1, week 4; days 1, 3, 5, week 5). The overall response rate of patients treated with the combination of chemotherapy and IL-2/IFN-a was 34.3% with seven complete responses (10.9%) and 15 partial responses (23.4%). In patients treated with chemotherapy, only, the overall response rate was 29.9% with eight complete responses (13.3%) and 10 partial responses (16.6%). There was no significant difference in median progression free survival (0 months vs 4 months) and in median overall survival (12 months vs 13 months) for combined chemoimmunotherapy and for chemotherapy, respectively. British Journal of Cancer (2002) 86, 179 – 184. DOI: 10.1038/sj/bjc/6600043 www.bjcancer.com ã 2002 The Cancer Research Campaign Keywords: melanoma; interleukin-2; interferon alpha; chemotherapy Metastatic melanoma responds poorly to the currently available patients has responded, response rates with immunochemothera- chemotherapeutic agents and, until today, no standard treatment pies have been lower than with the best chemotherapy regimens, has been established. Most single agent chemotherapeutics provide however, sustained responses have been consistently observed only low response rates. Dacarbazine (DTIC), the most active following IL-2 based chemoimmunotherapy. single agent in the treatment of melanoma, can be expected to yield Recently, several trials have investigated the combination of a response rate of about 20% (McClay and McClay, 1996). Even various cytotoxic agents with IL-2 and IFN-a. While primarily in though most trials of combination chemotherapy for the treatment phase II studies several authors claimed a clear advantage of this of metastatic melanoma clearly have not been superior to DTIC chemoimmunotherapy over chemotherapy alone (Legha et al, alone, the combination of carmustine (BCNU), DTIC, cisplatin, 1996; Richards et al, 1992), more recently randomized trials raised and tamoxifen has produced significant antitumour responses in doubts about the effectiveness and benefit of this combination (Johnston et al, 1998; Rosenberg et al, 1999). up to 50% of patients (McClay and McClay, 1994; Middleton et al, 2000; Richards et al, 1992). A further increase in the rate of We have performed a prospective randomized trial in patients objective responses may be achieved by introducing cytokines into with metastatic melanoma treated either with a chemotherapy regi- the therapeutic regimens, with interleukin-2 (IL-2) and interferon men of cisplatin, carmustine, dacarbazine, and tamoxifen, or with alpha (IFN-a) being the most widely acclaimed. Monotherapy with the identical chemotherapy followed by outpatient s.c. IL-2 and IL-2 results in up to 29% objective responses (Rosenberg et al, s.c. IFN-a. 1994). Different types of interferons have also been intensively explored (Creagan et al, 1990). While a defined subgroup of PATIENTS AND METHODS Patients *Correspondence: Professor Dr J Atzpodien; E-mail: [email protected] Between May 1995 and May 1999, 124 patients were randomized Received 7 February 2001; revised 22 October 2001; accepted 31 Octo- and considered evaluable for response (Table 1). Forty-one females ber 2001 and 83 males were treated either with combined chemoimmuno- Clinical Clinical Chemoimmunotherapy in advanced melanoma J Atzpodien et al Table 1 Patients’ characteristics complete response – disappearance of all signs of disease for a minimum of 8 weeks; partial response – 50% or more reduction Therapy in the sum of products of the greatest perpendicular diameters of measurable lesions, no increase in lesion size and no new lesions; Characteristics Arm A Arm B All stable disease – less than a partial response with no disease Entered 64 60 124 progression for at least 8 weeks; progressive disease – 25% or Sex more increase in sum of products in the longest perpendicular Men 46 37 83 diameters of measurable lesions or the development of new lesions. Women 18 23 41 Duration of response was measured from the initial date of Age response. Two patients were randomized, but did not receive ther- Median 57 57 57 apy and were evaluated as progressive disease patients. Treatment Range 28 – 72 29 – 77 28 – 77 efficacy was assessed on intent-to-treat basis. Histology Cutaneous Statistical analysis Nodular 13 18 31 Amelanotic 1 0 1 Survival was measured from start of therapy to date of death or to Superficial spreading 18 14 32 the last known date to be alive. The statistical end points in our Acral lentiginous 3 2 5 analysis were (1) objective response and (2) overall and progression Uveal 6 5 11 free survival of patients. The progression free survival after 1 year Unknown 14 13 27 was assumed to be 40% (chemoimmunotherapy) and 20% Pretreatment (chemotherapy), respectively. The intention was to find a Surgery 53 54 107 chemoimmunotherapy induced progression free survival benefit Local radiation 6 10 16 Chemotherapy 4 3 7 over chemotherapy alone at 20% with a probability of 95% Immunotherapy; 5 6 11 (a=0.05) and a sample power of 1-ß=0.80. Based on this assump- Chemo/immunotherapy 2 2 4 tion an intended patient accrual of 64 patients per therapy arm was Others 1 4 5 required in case of a statistically significant survival benefit after a combined chemoimmunotherapy. The probability of overall survi- Arm A (i.v. DTIC, i.v. cisplatin, i.v. BCNU, p.o. tamoxifen, s.c. IL-2, s.c. IFN-a); Arm B val was plotted over time according to the method of Kaplan and (i.v. DTIC, i.v. cisplatin, i.v. BCNU, p.o. tamoxifen). Meier. Statistical significance was assessed using the Log Rank, Tarone Ware and the Breslow test; SPSS software was employed. or chemotherapy alone. Median follow-up of these patients was 12 months (range 0 – 62 months). Ninety-seven patients had not been RESULTS treated with systemic therapy before, 27 patients had received previous systemic immuno- or chemotherapy treatment. A total of 124 patients were enrolled in this clinical trial and Criteria for entry into the study were: histologically confirmed randomized to receive combined chemoimmunotherapy (n=64) metastatic melanoma; Karnofsky performance status 480%; white or chemotherapy alone (n=60) (Table 1). Patient evaluation was 71 71 blood cell count 43500 ml ; platelet count 4100 000 ml ; performed according to the guidelines described above. haematocrit 430%; serum creatinin and bilirubin 51.5 of the Response to therapy was evaluated according to World Health upper normal limit; age between 18 and 75 years and a life expec- Organization (WHO) criteria with regular reevaluation intervals tancy of 43 months. every 8 weeks. This study was approved by the institutional review board of the Medizinische Hochschule Hannover and by participating centres; Treatment response written informed consent was obtained from all patients prior to entry into the study. Seven patients (10.9%) treated with chemoimmunotherapy achieved a complete response and 15 patients (23.4%) had a partial remission (Table 2). The overall objective response rate of Study design combined chemoimmunotherapy was 34.3% (median survival 29 All patients received a chemotherapy regimen comprising cisplatin 72 72 (35 mg m , i.v., days 1 – 3), carmustine (150 mg m , i.v., day 1, cycles 1 and 3 only), dacarbacine (220 mg m , i.v., days 1 – 3) Table 2 Sites of disease and response of patients receiving DTIC, cispla- and oral tamoxifen (20 mg m , daily) in combination with tin, BCNU and tamoxifen followed by immunotherapy with IL-2 and IFN-a (n=64) or without (n=60) subcutaneous IL-2 and IFN-a. In those patients, who were randomized to receive chemoimmunotherapy, Response each cycle of chemotherapy was followed by outpatient immu- 6 72 Tumour site CR PR SD PD Total notherapy with combined IL-2 (10610 IU m , days 3 – 5, week 6 72 4; 5610 IU m , days 1, 3, 5, week 5) and IFN-a Lymph nodes 5 7 5 21 38 6 72 (5610 IU m , day 1, week 4; days 1, 3, 5, week 5); randomiza- Liver 1 9 4 22 36 tion was performed centrally. Five week treatment cycles were Lung 1 8 3 15 27 repeated unless progression of disease occurred. Re-evaluation of Local relapse 0 1 1 4 6 the patients’ tumour status was performed between treatment cycles. Skin/subcutaneous 3 1 0 6 10 Brain 0 0 0 1 1 Patients received an average of 2.7 (Arm A, median 2.0; range 1 – 5) Bone 0 1 0 3 4 and 1.9 (Arm B, median 2.0; range 0 – 4) treatment cycles. Adrenal 0 2 1 2 5 Spleen 0 2 0 4 6 Assessment of response Other 0 0 1 6 7 Total 7 15 9 33 64 Response to therapy was evaluated according to World Health Organization (WHO) criteria with regular re-evaluation intervals Abbreviations: CR, complete remission; PR, partial remission; SD, stable disease; PD, progressive disease. Patients may have had more than one site. every 8 weeks; all repeated scans were reported to the data center: British Journal of Cancer (2002) 86(2), 179 – 184 ã 2002 The Cancer Research Campaign Chemoimmunotherapy in advanced melanoma J Atzpodien et al months; 95% CI, 9, 49) with a median duration of response of 9 months (chemoimmunotherapy) and 8 months (chemotherapy) as months (range 5 – 62 months). While in complete responders, the opposed to patients without liver metastases with a median survival median response duration was 25 months (range 5 – 62 months), of 20 months (chemoimmunotherapy) and 17 months (chemother- the median duration of partial responses was 7 months (range apy), respectively (Figure 3). 5 – 19 months). Objective tumour regressions were seen in lymph nodes (12), liver (10), lung (9), skin (4), bone (1), adrenal (2) Progression free survival and spleen (2). Nine patients (14.1%) showed disease stabilization and 33 patients (51.6%) exhibited continuous disease progression The progression free survival ranged from 0 to 62 (median 4 despite therapy. months) for all patients entered into the study. There was no In the chemotherapy group the overall objective response rate was significant difference in median progression free survival between 29.9% (median survival 24 months; 95% CI, 16, 32) with eight patients treated with chemoimmunotherapy (0 months, range 0 – patients (13.3%) achieving a complete response and 10 patients 62 months) or with chemotherapy (4 months, range 0 – 47 months) (16.6%) a partial remission (Table 3). The median duration of (Figure 4). response ranged from 5 to 47 months (CR, PR, median 15 months). The median progression free survival for patients with liver While in complete responders, the median duration of response metastases was 0 months independent of the treatment regimen ranged from 5 to 47 months (median 28 months), the median dura- as compared to a median progression free survival of 7 months tion of response in partial responders ranged from 5 to 34 months (range 0 – 62 months, chemoimmunotherapy) and 5 months (range (median 7 months), respectively. Objective tumour regressions were 0 – 47 months, chemotherapy) in patients without liver metastases seen in lymph nodes (14), liver (3), lung (9), skin (4) and adrenal (1). (data not shown). Fourteen patients (23.3%) showed disease stabilization. In 28 patients (46.7%) progression of disease occurred. Treatment toxicity Chemotherapy led to significant haematotoxicity with WHO grade Overall survival IV thrombocytopenia in 25% and leukopenia in approximately Overall median survival of all patients entered into the study was 26% of treatment cycles, respectively. Immunotherapy related side 13 months (95% CI 10; 16). There was no significant difference effects included WHO grade III and IV malaise in 21%, anorexia in in median overall survival for combined chemoimmunotherapy 21%, chills in 8%, diarrhoea in 5% and fevers in less than 25% of (12 months) and for chemotherapy (13 months), respectively treatment cycles, respectively (data not shown). (Figure 1). Patients’ sex had also no influence on median survival Overall, no life threatening toxicities were observed, and no (data not shown). Twenty-five patients are alive at a median toxic deaths occurred. Generally, immunotherapy could be admi- follow-up of 24 months (range 2 – 62 months). Two patients nistered in the outpatient setting. Chemotherapy required continue to be alive after more than 5 years from chemoimmu- inpatient stays of 4 days per cycle. notherapy. A 3-year survival of 12.96% and 11.42% was achieved with combined chemoimmunotherapy and with chemotherapy DISCUSSION alone, respectively. For complete responders, median survival has not been reached at 62 months (range 20 – 62 months). In contrast, In the present prospective randomized trial we reported the partial responders and patients with disease stabilization had both a results of 124 patients with progressive metastatic melanoma median survival of 16 months (range 5 – 40 months and 2 – 38 who received a combined chemoimmunotherapy (IFN-, IL-2 months) as opposed to a median survival of 8 months (range combined with DTIC, cisplatin, BCNU, and tamoxifen) or a 0 – 40 months) in progressive disease patients (Figure 2). chemotherapy (DTIC, cisplatin, BCNU, and tamoxifen) alone. In the chemoimmunotherapy group, median overall survival of We observed an overall objective response in 34.3% of patients objective responses was 29 months (range 5 – 62 months, 95% CI treated with the combined chemoimmunotherapy which is 9, 49), while in the chemotherapy group a median survival of 24 comparable with earlier trials achieving response rates between months (range 8 – 47 months, 95% CI 16, 32) was achieved (data 23% to 64% (Atkins et al, 1994; Atzpodien et al, 1995; Feun not shown). et al, 1995; Hoffmann et al, 1998; Johnston et al, 1998; Legha, There was a significant (P50.0001) difference in overall survival 1998; Middleton et al, 2000; Pyrhonen et al, 1992; Rosenberg for all patients with liver metastases with a median survival of 9 et al, 1999; Thompson et al, 1997). Whereas in previous clinical trials, introducing cytokines in chemotherapeutic regimens yielded an enhanced efficacy (Atkins et al, 1994; Legha et al, 1996), our results raise doubts concerning the potential benefits Table 3 Sites of disease and response of patients receiving DTIC, cispla- of the presently used dosages of IL-2 and INF-a for therapy of tin, BCNU and tamoxifen metastatic melanoma since objective response rates of patients treated with chemotherapy alone were similar (29.9%) to sequen- Response tial chemoimmunotherapy (34.3%). Tumour site CR PR SD PD Total In addition, in our trials no significant difference in survival time was observed for patients treated with chemoimmunother- Lymph nodes 5 9 8 17 39 apy (median 12 months) and chemotherapy (median 13 Liver 1 2 4 19 26 months), respectively, which is also supported by recent results Lung 4 5 8 17 34 Local relapse 1 2 2 2 7 of other cytokine based therapy regimens (Johnston et al, 1998; Skin/subcutaneous 1 3 4 4 12 Rosenberg et al, 1999). Although overall survival of objective Brain 0 0 1 2 3 responses was slightly increased in the chemoimmunotherapy Bone 0 0 3 3 6 group (median 29 months, 95% CI 9, 49) than in the Adrenal 1 0 0 4 5 chemotherapy group (median 24 months, 95% CI 16, 32), the Spleen 0 0 1 4 5 response duration of patients was shorter after chemoimmu- Other 0 2 2 2 6 notherapy (median 9 months) when compared to Total 8 10 14 28 60 chemotherapy (15 months). In contrast, Legha et al (1997) Abbreviations: CR, complete remission; PR, partial remission; SD, stable disease; PD, reported a significantly increased proportion (10%) of long-term progressive disease. Patients may have had more than one site. responders after chemoimmunotherapy. ã 2002 The Cancer Research Campaign British Journal of Cancer (2002) 86(2), 179 – 184 Clinical Clinical Chemoimmunotherapy in advanced melanoma J Atzpodien et al 1.0 Arm A vs Arm B Log Rank P = 0.7904 Breslow P = 0.9313 Tarone P = 0.9697 0.8 0.6 Arm A 0.4 DTIC, Cisplatin, BCNU Tamoxifen, IL-2, IFN-a Arm B n = 64 patients DTIC, Cisplatin Median = 12 months BCNU, Tamoxifen 0.2 3-year survival = 12.96% n = 60 patients Median = 13 months 3-year survival = 11.42% 0.0 0 12 2436 48 6072 Months No. of patients at risk Arm A 64 32 17 8 4 2 Arm B 60 31 15 5 – – Figure 1 Overall survival (Kaplan-Meier estimates) of 124 patients treated with chemoimmunotherapy (i.v. DTIC, i.v. cisplatin, i.v. BCNU, p.o. tamoxifen, s.c. interleukin-2 and s.c. interferon-a) or chemotherapy (i.v. DTIC, i.v. cisplatin, i.v. BCNU and p.o. tamoxifen) alone. Survival was measured from start of therapy. CR 1.0 n = 15 patients Median not reached 3-year survival = 60.67% CR vs PR 0.8 Log Rank P = 0.0002 PR Breslow P = 0.0002 n = 25 patients Tarone P = 0.0002 Median = 16 months CR 0.6 3-year survival = 20.27% PR vs SD SD Log Rank P = 0.5499 n = 23 patients Breslow P = 0.5617 0.4 Median = 16 months Tarone P = 0.5679 3-year survival = 8.85% SD vs PD 0.2 Log Rank P = 0.0059 PD Breslow P = 0.0028 n = 61 patients SD Tarone P = 0.0030 Median = 8 months PR PD 3-year survival = 1.96% 0.0 012 24 36 48 60 72 Months No. of patients at risk CR 15 15 13 8 4 2 PR 15 18 8 3 0 0 SD 23 11 6 2 – – PD 61 20 6 2 – – Figure 2 Overall survival (Kaplan-Meier estimates) of 124 patients classified by treatment response. CR=complete remission, PR=partial remission, SD=stable disease, PD=progressive disease. Survival was measured from start of therapy. British Journal of Cancer (2002) 86(2), 179 – 184 ã 2002 The Cancer Research Campaign P Chemoimmunotherapy in advanced melanoma J Atzpodien et al 1 = Arm A, without liver metastases, 1.0 DTIC, Cisplatin, BCNU Tamoxifen, IL-2, IFN-a n = 28 patients 0.8 Median = 20 months 3-year survival = 29.61% 0.6 2 = Arm B, without liver metastases, DTIC, Cisplatin BCNU, Tamoxifen 0.4 n = 36 patients Median = 17 months 3-year survival = 15.08% 0.2 3 = Arm A, with liver metastases, 4 3 DTIC, Cisplatin, BCNU, 0.0 Tamoxifen, IL-2, IFN-a 012 24 36 48 60 72 n = 36 patients Median = 9 months Months 3-year survival = 7.9% No. of patients at risk 4 = Arm B, with liver metastases, 1 = 28 19 12 6 4 2 DTIC, Cisplatin BCNU, Tamoxifen 2 = 35 22 12 4 – – n = 26 patients Median = 8 months 3 = 36 13 6 3 0 0 3-year survival = 4.8% 4 = 25 10 3 2 – – Figure 3 Overall survival (Kaplan-Meier estimates) of 124 patients classified by risk (liver metastases). Survival was measured from start of therapy. Arm A vs Arm B 1.0 Log Rank P = 0.8245 Breslow P = 0.8123 Tarone P = 0.8447 0.8 0.6 0.4 Arm B Arm A DTIC, Cisplatin DTIC, Cisplatin, BCNU BCNU, Tamoxifen Tamoxifen, IL-2, IFN-a n = 60 patients n = 64 patients Median = 4 months 0.2 Median = 0 months 3-year survival = 10.91% 3-year survival = 8.13% 0.0 0 12 2436 48 6072 Months No. of patients at risk Arm A 64 11 6 4 3 2 Arm B 60 12 6 5 – – Figure 4 Progression free survival for all 124 patients treated with chemoimmunotherapy (i.v. DTIC, i.v. cisplatin, i.v. BCNU, p.o. tamoxifen, s.c. interleukin- 2 and s.c. interferon-a) or chemotherapy (i.v. DTIC, i.v. cisplatin, i.v. BCNU and i.v. tamoxifen) alone. Plots were generated by the Kaplan-Meier method and progression free survival was measured from start of therapy. ã 2002 The Cancer Research Campaign British Journal of Cancer (2002) 86(2), 179 – 184 Clinical Clinical Chemoimmunotherapy in advanced melanoma J Atzpodien et al The discrepancy in the effect of cytokines in metastatic melanoma While median duration of objective responses appeared to be therapies might be best explained by the following uncontrolled vari- prolonged in patients receiving chemotherapy only, overall survival ables: (A) patient selection and clinical/biological risk; (B) variations analysis yielded few (n=2) long term (448 months) surviving in the rIL-2 based regimen (e.g., reconstitution of drug, route and patients in the chemoimmunotherapy combination, only. Similar dose of administration); and (C) different standards of patient care results were reported when comparing dacarbazine/INF- with or (e.g., supportive care upon IL-2 therapy). In fact, previous reports without IL-2. Since cytokines in chemotherapies also alter the toxi- have repeatedly shown that overall survival is higly risk-dependent city profile (Falkson et al, 1998; Johnston et al, 1998; Stark et al, (Hoffmann et al, 1998; Rusthoven et al, 1996). This is confirmed 1998), future clinical trials might focus on new combinations, by our study since we reported that patients with liver metastases different dosages and dose distribution regimens of IL-2 and had a significantly shorter survival and shorter progression free survi- INF- to increase both efficacy and tolerability for patients with val compared to patients without liver metastases. Notably, the metastatic melanoma. proportion of patients with hepatic metastases varied between 56% (chemoimmunotherapy) and 43% (chemotherapy alone). In summary, this prospectively randomized clinical trial showed ACKNOWLEDGEMENTS no statistically significant benefit of IL-2, INF- based combined chemoimmunotherapy in patients with metastatic melanoma The authors would like to thank Dr Susanne Scha ¨d and Dr compared to chemotherapy alone. So far, also no standard was estab- Eckhardt Ka ¨mpgen for support. J Atzpodien is supported by grants lished confirming a significant survival benefit of polychemotherapy of the Deutsche Krebshilfe, Wilhelm Sander-Stiftung, and when compared to DTIC, alone (Chiarion Sileni et al, 2001). Gesellschaft zur Fo ¨ rderung immunologischer Krebstherapien e.V. REFERENCES Atkins MB, O’Boyle KR, Sosman JA, Weiß GR, Margolin KA, Ernest ML, Legha SS, Ring S, Eton O, Bedikian A, Plager C, Papadopoulos N (1997) Kappler K, Mier JW, Sparano JA, Fischer RI (1994) Multiinstitutional Development and results of biochemotherapy in metastatic melanoma: phase II trial of intensive combination chemoimmunotherapy for meta- the University of Texas M.D. Anderson Cancer Center experience. Cancer static melanoma. J Clin Oncol 12: 1553 – 1560 J Sci Am 3(1 Suppl): 9 – 15 ¨ ¨ Atzpodien J, Lopez Hanninen E, Kirchner H, Franzke A, Korfer A, Volke- McClay EF, McClay ME (1994) Tamoxifen: is useful in the treatment of nandt M, Duensing S, Schomburg A, Chaitchik S, Poliwoda H (1995) patients with metastatic melanoma?. J Clin Oncol 12: 617 – 626 Chemoimmunotherapy of advanced malignant melanoma: sequential McClay EF, McClay ME (1996) Systemic chemotherapy for the treatment of administration of subcutaneous interleukin-2 and interferon-a after intra- metastatic malignant melanoma. Semin Oncol 23: 744 – 753 venous dacarbazine, cisplatin, carmustine and tamoxifen. Eur J Cancer 31: Middleton MR, Lorigan P, Owen J, Asshcroft L, Lee SM, Harper P, Thatcher 876 – 881 N (2000) A randomized phase III study comparing dacarbazine, BCNU, Chiarion Sileni V, Nortilli R, Aversa SM, Paccagnella A, Medici M, Corti I, cisplatin and tamoxifen with dacarbazine and interferon in advanced mela- Favaretto AG, Cetto GL, Monfardini S (2001) Phase II randomized study noma. Br J Cancer 82: 1158 – 1162 of dacarbazine, carmustine, cisplatin and tamoxifen versus dacarbazine Pyrhonen S, Hahka-Kemppinen M, Muhonen T (1992) A promising interfer- alone in advanced melanoma patients. Melanoma Res 11: 189 – 196 on plus four-drug chemotherapy regimen for metastatic melanoma. J Clin Creagan ET, Schaid DJ, Ahmann DL, Fryak S (1990) Disseminated malignant Oncol 10: 1919 – 1926 melanoma and recombinant interferon: analysis of seven consecutive phase Richards JM, Mehta N, Ramming K, Skosey P (1992) Sequential chemoim- II investigations. J Invest Dermatol 95(6 Suppl): 188 – 192 munotherapy in the treatment of metastatic melanoma. J Clin Oncol 10: Falkson CI, Ibrahim J, Kirkwood JM (1998) Phase III of dacarbazine versus 1338 – 1343 dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen Rosenberg JM, Yang JC, Topalian SL, Schwarzentruber DJ, Web JS, Parkinson versus dacarbazine with interferon alpha-2b and tamoxifen in patients with DR, Seipp CA, Einhorn JH, White DE (1994) Treatment of 283 consecu- metastatic melanoma: an Eastern Cooperative Oncology Group study. J tive patients with metastatic melanoma or renal cell cancer using high-dose Clin Oncol 16: 1743 – 1751 bolus interleukin-2. JAMA 271: 907 – 913 Feun LG, Savaraj N, Moffat F, Robinson D, Liebmann A, Hurley J, Raub Jr Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topa- WA, Richman SP (1995) Phase II trial of recombinant interferon-alpha lian SL, Seipp CA, Einhorn JH, White DE, Steinberg SM (1999) with BCNU, cisplatin, DTIC and tamoxifen in advanced malignant mela- Prospective randomized trial of the treatment of patients with metastatic noma. Melanoma Res 5: 273 – 276 melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen Hoffmann R, Mu ¨ ller I, Neuber K, Laßmann S, Buer J, Probst M, Oevermann alone or in combination with interleukin-2 and interferon alfa-2b. J Clin K, Franzke A, Kirchner H, Ganser A, Atzpodien J (1998) Risk and outcome Oncol 17: 968 – 975 in metastatic malignant melanoma patients receiving DTIC, cisplatin, Rusthoven JJ, Quirt IC, Iscoe NA, McCulloch PB, James KW, Lohmann RC, BCNU and tamoxifen followed by immunotherapy with interleukin 2 Jensen J, Burdette-Radoux S, Bodurtha AJ, Silver HK, Verma S, Armitage and interferon alpha2a. Br J Cancer 78: 1076 – 1080 GR, Zee B, Bennett K (1996) Randomized, double-blind, placebo- Johnston SR, Constenla DO, Moore J, Atkinson H, A’Hern RP, Dadian G, controlled trial comparing the response rates of carmustine, dacarbazine, Riches PG, Gore ME (1998) Randomized phase II trial of BCDT [carmus- and cisplatin with and without tamoxifen in patients with metastatic mela- tine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen] with or noma. National Cancer Institute of Canada Clinical Trials Group. J Clin without interferon alpha (IFN-alpha) and interleukin (IL-2) in patients Oncol 14: 2083 – 2090 with metastatic melanoma. Br J Cancer 77: 1280 – 1286 Stark JJ, Dillman RO, Schulof R, Wiemann MC, Barth NM, Honeycutt PJ, Legha SS (1998) Development of a biochemotherapy regimen with concur- Soori G (1998) Interferon alpha and chemohormonal therapy for patients rent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, with advanced melanoma: final results of a phase I-II study for the Cancer and interleukin-2 for patients with metastatic melanoma. J Clin Oncol Biotherapy Research Group and the Mid-Atlantic Oncology Program. 16: 1752 – 1759 Cancer 82: 1677 – 1681 Legha SS, Ring S, Bedikan A, Plager C, Eton O, Buzaid AC, Papadopoulos Thompson JA, Gold PJ, Markowitz DR, Byrd DR, Lindgren CG, Fefer A N (1996) Treatment of metastatic melanoma with combined chemother- (1997) Updated analysis of an outpatient chemoimmunotherapy regimen apy containing cisplatin, vinblastine and dacarbazine (CVD) and for treating metastatic melanoma. Cancer J Sci Am 3(1 Suppl): 29 – 34 biotherapy using interleukin-2 and interferon-alpha. Ann Oncol 7: 827 – 835 British Journal of Cancer (2002) 86(2), 179 – 184 ã 2002 The Cancer Research Campaign

Journal

British Journal of Cancer – Pubmed Central

Published: Jan 21, 2002

There are no references for this article.