Clinical Papers © 1991 S. Karger AG, Basel 0302-2838/91/0202-0089S2.75/0
EurUrol 1991;20:89-92
Methotrexate, Vinblastine, Adriamycin and Cisplatin versus Methotrexate and Cisplatin in Advanced Urothelial Cancer A Randomized Study1 Giorgio Pizzocaro, Angelo Milani, Luigi Pirn, Marco Faustini, Erica Spino Division of Urologie Oncology, Department of Surgery, Istituto Nazionale Tumori, Milano, Italy
1606011
Key Words. Metastatic urothelial cancer • Chemotherapy • Toxicity • Response Abstract. From September 1984 to December 1988, 28 consecutive patients with metastatic urothelial cancer entered a randomized study to compare 4 courses of modified methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) to 4 courses of methotrexate followed by folinic acid rescue and cisplatin (MP). Non-responders or relapsing patients were to be crossed to the other therapy. Hematological toxicity was more frequent (85%), but less severe, in patients treated with M-VAC than in patients treated with MP (21 %, with 1 septic death). Complete plus partial remissions were achieved in 10 (71.4 %) of 14 patients treated with M-VAC and in 6 (50 %) of the 12 evaluable patients treated with MP. The 20% difference lay only on complete remissions, which were 8.3% in the MP versus 28.5% in the M-VAC group. At cross-over, however, only 1 of 5 patients resistant to MP responded to M-VAC, while 3 of 5 patients resistant to M-VAC responded to MP. It seems that M-VAC should be considered as the first-line thrapy of choice in metastatic urothelial cancer, while MP, or high-dose methotrexate, could be considered for salvage.
In November 1983, Carmichael et al. [1] reported 2 complete and 6 partial remissions (72% CR plus PR) of 11 patients treated with medium-dose methotrexate, fol lowed by folinic acid rescue and cisplatin 100 mg/m2 (MP) without significant hematological toxicity. Six months later, Sternberg et al. [2] presented 13 (72%) CR + PR of 18 patients treated with methotrexate, vin blastine, adryamicin and cisplatin (M-VAC) with signif icant hematological toxicity in 83% of cases. It seemed logical to compare these two regimens which gave the same promising preliminary results with so different toxicities.
l Presented before the ECCO 5, London, 1989. Supported in part by grant No. 88.00819.44, Finalized Project ‘Oncology’, Italian Na tional Research Council (C.N.R.), Rome, Italy.
Material and Methods We designed a randomized study to compare the hematological toxicity of 4 courses of MP to 4 courses of M-VAC in patients with metastatic or unresectable urothelial cancer of the urinary tract. Nonresponders to the first 2 courses of therapy and patients with persistent disease at the end of the 4 courses were to be crossed to the other regimen. Only one block of 7 plus 7 patients was necessary to verify the hypothesis of no hematological toxicity in the MP group and of toxicity in 70 % of cases in the M-VAC group. A second block of 7 plus 7 patients was to be added to the series if at least 1 patient treated with MP had had hematological toxicity. We decided to modify the M-VAC regimen by omitting the administration of vinblastine and methotrexate on day 22 in order to make sure to recycle the therapy every 4 weeks. We were not able to know exactly the Carmichael et al. [1] schedule at the time we designed the study. So far, we decided to use the same MP regimen which was in use at the Department of Pediatric Oncology in our Institute for osteosarcoma at that time. Only patients with histologically documented metastatic transi tional cell carcinoma of the urinary tract were admitted into the study. Patients over the age of 70, with an ECOG performance sta-
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Introduction
Pizzocaro/Milani/Piva/Faustini/Spino
90
groups Involved sites
Bladder Pelvic relapse Lymph nodes Lung Liver Soft tissues Bones
Total number of sites
n
13 8 12 8 3 3 2a
6 5 6 5 2 2 2a
M-VAC
MP %
46.2 62.5 50.0 62.5 66.7 66.7 100.0
n 7 3 6 3 1
1
53.8 37.5 50.0 37.5 33.3 33.3
Another patient actually did not have bone métastasés.
Table 2. Toxic signs of first-line MP and M-VAC Toxic signs
Nausea and vomit Leukopenia: grade 2 grade 3 grade 4 Trombocytopenia (2-3) Anemia (Hb loss > 3 g) Mucositis Creatinine (>1.8 mg/100 ml) Pulmonary edema Myocardial infarction
MP (n = 14) n
%
8 2
57.1 14.3
la
7.1 7.1 7.1 7.1 14.3 7.1 7.1
la 1
la
2
1 1
M-VAC (n- 14) n 9 10
1 1 2 1
1
1
%
64.2 71.4 7.1 7.1 14.3 7.1 7.1 7.1
This patient died of sepsis.
tus greater than 2, pretreated with radiotherapy or systemic chemo therapy were excluded. Every patient had a full clinical examina tion, blood chemistry profile, chest x-ray, computed tomography (CT) or magnetic resonance imaging (RMI) of the abdomen and pelvis, liver echography and bone scan. Cystoscopy with cold cup biopsy and bimanual palpation was performed under general anes thesia in every patient who had the primary tumor still present. We recruited 28 patients, because in the first block of 7 plus 7 cases 1 patient in the MP group showed evidence of hematological toxicity. Recruitment lasted from September 1984 to December 1988: 21 patients were men and 7 were women; their age ranged between 43 and 68 years (median age: 58). All patients had histologically docu mented transitional cell carcinoma: the tumor had originated from the bladder in 25 patients and from the renal pelvis in the remaining 3. The distribution of involved sites is shown in table 1. Toxicity was evaluated by repeating the whole blood chemistry profile at the start of every course of therapy and by checking white
blood cells and platelet counts twice a week, between cycles. Stan dard WHO response criteria were used to permit the definition of clinical response, hematological and other toxicities. The duration of responses was evaluated by December 31, 1990. Chemotherapeutic Regimens The M-VAC regimen required hospitalization for 2-3 days every 4 weeks. Methotrexate 30 mg/m2 i.v. was administrated on day 1. It was followed by 0.5 liter normal saline and 0.5 liter 5% dextrose plus 10 mEq NaHCC>3. On day 2, 3 mg/m2 vinblastine sulfate and 30 mg/m2 i.v. adriamycin were given, followed by 0.5 liter normal saline and 1 liter 5 % dextrose plus 20 mEq KC1 and 10 mEq MgSÛ4. Then, cisplatin 70 mg/m2 was administered in 250 cm3 3 % saline over a 30- to 60-min intravenous infusion. Hydration was continued with 1 liter 5% dextrose and 0.5 liter normal saline. Antiemetic medication consisted of metilprednisolone 100 mg/m2 in 100 ml 5 % dextrose plus metochlopramide 2 mg/kg. Methotrexate and vinblas tine were repeated on day 15 as described above. The MP regimen required a longer hospitalization (4-5 days) every 3 weeks. On day 1, methotrexate was administered at the dos age of 300 mg/m2 diluted in 250 ml normal saline in a 2-hour intra venous infusion, followed by 1 liter 5 % dextrose and 1 liter normal saline plus 30 mEq NaHCÛ3 and 20 mEq KC1. The hydration con tinued on days 2 and 3, on which days folinic acid rescue was insti tuted at the dosage of 9 mg/m2 i.m. every 6 h. On day 4, 100 mg/m2 cisplatin was administered in a 24-hour continuous intravenous infusion with 4 liters half-normal saline in 2.5% dextrose plus 40 mEq KC1 and 40 mEq MgS04.
Results A total of 48 cycles of M-VAC and 39 cycles of MP were administered. In the M-VAC group, there was no reduction of therapy on days 1 and 2. The therapy was not administered on day 15 in 35% of cases during the first cycle, 7% in cycle 2, 30% in cycle 3. No patient had omission of therapy on day 15 during the 4th cycle. In 40% of cases in whom the therapy was omitted on day 15, it was not for toxic signs but for poor cooperation by the family doctor, especially in cycle 1. In the MP group, only 1 patient did not receive cisplatin on cycle 2 be cause the intravenous infusion had to be suspended for pulmonary edema. All drugs were given at full dosage during the remaining 38 courses of therapy. All patients were evaluable for toxicity (table 2). He matological toxicity was very frequent in the M-VAC group (85%), but, due to omission of therapy on day 22, only 2 patients had grade 3 or 4 leukopenia. On the other hand, 1 patient in the MP group had a grade 4 hemato logical toxicity on the first cycle and died of sepsis. The median peak serum creatinine for 48 cycles of M-VAC was 1.5 mg/100 ml and 1.3 mg/100 ml for 39 cycles of MP. Only 3 patients (2 MP and 1 M-VAC) had a slight
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Table 1. Distribution of metastatic sites in the two treatment
M-VAC versus MP in Advanced Urothelial Cancer
Discussion The main goal of our study was to compare the hema tological toxicity of the two regimens, because the pre liminary results reported hematological toxicity in 83% of cases treated with M-VAC versus none for MP [1, 2], The frequent hematological toxicity of M-VAC is con firmed in our study (85%), but the majority of patients (71 %) had only grade 1-2 leukopenia. Sternberg et al. [3, 4] reported more severe toxicity. The difference can be
Table 3. Responses to first-line MP and M-VAC MP (n = 12)
Responses1
%
n
8.3
M-VAC (n= 14) n
%
3
Clinical CR Pathological CR Surgically, NED Unresectable PR
2 3
16.7 25.0
2 4
21.4 7.1 14.3 28.6
Total
6
50.0
10
71.4
1
1
a Duration, months: CR: MP = 13+; M-VAC = 15, 21+, 24+, 29; NED: MP = 9,72+; M-VAC = 11,15; PR: MP = 5,5,9; M-VAC = 4,4,5,10.
Table 4. Responses to first-line chemotherapy according to met astatic sites Involved sites
Bladder Pelvic relapse Lymph nodes Lung Liver Soft tissues Bones
MP
M-VAC
n
CR + % NED
n
CR + % NED
6 5 5 5 2 2 2
1
17
4
57
3
60
7 3 6 3
5
83 33
1 1
50
1
1
Table 5. Responses to second-line MP and M-VAC Responses1
MP (5 cases)
M-VAC (5 cases)
n
%
n
%
Surgically, NED Unresectable PR
2
40.0 20.0
1
20.0
1
Total responses
3
60.0
1
20.0
a Duration, months: surgically, NED: MP = 6,16; M-VAC = 10; unresectable PR: MP = 4.
ascribed to the omission of the administration of metho trexate and vinblastine on day 22 which we did routinely in order to recycle the therapy every 4 weeks. Actually, in the original M-VAC schedule [3, 4] the average duration of each cycle is 5 weeks. Furthermore, at least 1 admin-
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increase of serum creatinine above normal values, which returned to normal after a few days of intravenous hydration. Other toxic signs included: mucositis, which was very serious in the patient of the MP group who died of sepsis; nausea and vomiting which occurred in 8 and in 9 patients in the two groups, respectively. It was grade 3 in 1 patient (12.5%) of the MP group and in 5 (62.5%) of the M-VAC group. All 14 patients treated with M-VAC and 12 of 14 treated with MP are evaluable for response: we excluded the patient who died of sepsis following the first course of therapy, and another patient who was treated for bone métastasés which had not been confirmed at réévalua tion. Therapy was discontinued immediately in this pa tient, and he has been alive and free of disease for 4 years. The overall response rate (CR + PR) was 50% in the MP group and 71.4% in the M-VAC group. The differ ence was not statistically significant (table 3). However, the 20% difference lay on the CR rate only (8.3% in the MP and 28.5% in the M-VAC group). Other 4 patients (2 MP and 2 M-VAC) were rendered free of disease with surgery (NED). The CR + NED status was achieved in the bladder, node, lung and soft tissues only (table 4). Partial remission held from 5 to 10 months (median 5) in both groups. NED status held from 9 to 15 months with the exception of 1 patient in the MP group who was alive and free of disease 6 years after resection of a solitary soft tissue metastasis. Two of 5 complete responders relapsed after 15 and 29 months, respectively. The other 3 have been alive and free of disease for 13 to 24 months after starting therapy (table 3). Only 5 patients in each group were crossed to the other therapy (table 5). It is interesting to note that 3 of 5 patients treated with second-line MP responded and 2 of them could be rendered disease-free with surgery. How ever, the disease-free status lasted only 6 and 16 months, respectively.
91
Pizzocaro/Milani/Piva/Faustini/Spino
92
References 1 Carmichael J, Combleet MA, Laurie S, Duncan W, Wolf R, Smyth J: Clinical and laboratory evaluation of methotrexate and cisplatinum for the treatment of advanced bladder cancer (ab stract). Proc ECCO 1983;2:150. 2 Sternberg CN, Yagoda A, Scher HI, Hollander P, Watson RC, Ahmed T: Methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) for transitional cell carcinoma of the urothelium (ab stract). Proc Am Soc Clin Oncol 1984;3:156. 3 Sternberg CN, Yagoda A, Scher HI, Watson RC, Ahmed T, Wei selberg LR, Geller N, Hollander PS, Herr HW, Sogani PC, Morse MJ, Whitmore WF: Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transi tional cell carcinoma of the urothelium. J Urol 1985; 133:403407. 4 Sternberg CN, Yagoda A, Scher HI, Watson RC, Herr HW, Morse MJ, Sogani PC, Vaughan ED, Bander N, Weiselberg LR, Geller N, Hollander PS, Lipperman R, Fair WR, Whitmore WF: M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol 1988;139:461-469. 5 Carmichael J, Combleet MA, MacDougall RH, Allan SG, Duncann W, Chisholm GD, Smyth JF: Cisplatin and methotrexate in the treatment of transitional cell carcinoma of the urinary tract. Br J Urol 1985;57:299-302. 6 Stoter G, Splinter TAW, Child JA, Fossa SD, Denis L, Van Oosteron AT, De Paw M, Silvester R, EORTC GU group: Combina tion chemotherapy with cisplatin and methotrexate in advanced transitional cell cancer of the bladder. J Urol 1987; 137:662— 667. 7 Sternberg CN, Yagoda A, Scher HI, Watson RC, Geller N, Herr UW, Morse MJ, Sogani PC, Vaughan ED, Bander N, Weiselberg L, Rosado K, Smart T, Yun Lin S, Penemberg D, Fair WR, Whitmore WF: Methotrexate, vinblastine, doxorubicin and cis platin for advanced transitional cell carcinoma of the urothe lium. Cancer 1989;64:2448-2458. 8 Longothetis C, Dexeus F, Sella A, Amato R, Finn L: A prospec tive randomized trial of CISCA versus M-VAC chemotherapy in advanced metastatic urothelial tumors (abstract). J Urol 1989; 14LA216.
Dr. Giorgio Pizzocaro Istituto Nazionale Tumori Via G. Venezian 1 1-20133 Milano (Italy)
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istration of methotrexate and vinblastine has to be omit ted for myelotoxicity on day 15 or 22 [3, 4], So far, the weekly dose of both cisplatin and adriamycin was higher in our schedule than in the original one (17.5 mg/m2 vs. 14 mg/m2 for cisplatin, and 7.6 mg/m2 vs. 6 mg/m2 for adriamycin). The dose intensity of vinblastine and meth otrexate was only a little less in our schedule (1.5 mg/m2 vs. 1.7 mg/m2 and 15 mg/m2 vs. 17 mg/m2, respectively). The MP regimen, as modified by us, showed hemato logical toxicity in 3 cases (21 %) versus no toxicity in the Carmichael report [5]: leukopenia was of grade 2 in 2 cases and of grade 4, followed by septic death, in 1. We were not able to find an explanation for this event. Fur thermore, another 2 patients of the MP group developed severe cardiac complications (table 2), probably related to the very high volume of intravenous infusion. In another experience, a different combination of cisplatin and methotrexate [6] had such a severe hematological toxicity that only 17% of the patients could stay on schedule. As far as the therapeutic results of the different MP combinations are concerned, only Carmichael et al. [5] reported 68% objective responses (CR + PR) of 19 cases. The objective response rate was only 50% (6 of 12 patients) in our series and 46% in the EORTC series (20 of 43 evaluable cases) [6]. However, in all 3 series the complete remission rate ranged between 21 and 25%, which is less than the 36% CR rate reported by Sternberg et al. [7] in the last paper concerning 133 patients treated with M-VAC. It seems that the difference in the objec tive response rate between M-VAC and MP regimens lies principally in the complete remission rate. A random ized study comparing M-VAC to CISCA [8] confirmed the superiority of the M-VAC regimen as far as the CR rate is concerned. Last but not least, we observed in our series objective remissions in 3 of 5 patients treated with second-line MP for M-VAC failure, versus only 1 objective response of 5 patients treated with second-line M-VAC for MP failure. If such results could be confirmed in a larger series, it would be worthwhile to try high-dose methotrexate as second-line therapy, while the M-VAC regimen seems to be the best available first-line therapy for advanced tran sitional cell cancer of the urinary tract.
EurUrol 1991;20:89-92
Methotrexate, Vinblastine, Adriamycin and Cisplatin versus Methotrexate and Cisplatin in Advanced Urothelial Cancer A Randomized Study1 Giorgio Pizzocaro, Angelo Milani, Luigi Pirn, Marco Faustini, Erica Spino Division of Urologie Oncology, Department of Surgery, Istituto Nazionale Tumori, Milano, Italy
1606011
Key Words. Metastatic urothelial cancer • Chemotherapy • Toxicity • Response Abstract. From September 1984 to December 1988, 28 consecutive patients with metastatic urothelial cancer entered a randomized study to compare 4 courses of modified methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) to 4 courses of methotrexate followed by folinic acid rescue and cisplatin (MP). Non-responders or relapsing patients were to be crossed to the other therapy. Hematological toxicity was more frequent (85%), but less severe, in patients treated with M-VAC than in patients treated with MP (21 %, with 1 septic death). Complete plus partial remissions were achieved in 10 (71.4 %) of 14 patients treated with M-VAC and in 6 (50 %) of the 12 evaluable patients treated with MP. The 20% difference lay only on complete remissions, which were 8.3% in the MP versus 28.5% in the M-VAC group. At cross-over, however, only 1 of 5 patients resistant to MP responded to M-VAC, while 3 of 5 patients resistant to M-VAC responded to MP. It seems that M-VAC should be considered as the first-line thrapy of choice in metastatic urothelial cancer, while MP, or high-dose methotrexate, could be considered for salvage.
In November 1983, Carmichael et al. [1] reported 2 complete and 6 partial remissions (72% CR plus PR) of 11 patients treated with medium-dose methotrexate, fol lowed by folinic acid rescue and cisplatin 100 mg/m2 (MP) without significant hematological toxicity. Six months later, Sternberg et al. [2] presented 13 (72%) CR + PR of 18 patients treated with methotrexate, vin blastine, adryamicin and cisplatin (M-VAC) with signif icant hematological toxicity in 83% of cases. It seemed logical to compare these two regimens which gave the same promising preliminary results with so different toxicities.
l Presented before the ECCO 5, London, 1989. Supported in part by grant No. 88.00819.44, Finalized Project ‘Oncology’, Italian Na tional Research Council (C.N.R.), Rome, Italy.
Material and Methods We designed a randomized study to compare the hematological toxicity of 4 courses of MP to 4 courses of M-VAC in patients with metastatic or unresectable urothelial cancer of the urinary tract. Nonresponders to the first 2 courses of therapy and patients with persistent disease at the end of the 4 courses were to be crossed to the other regimen. Only one block of 7 plus 7 patients was necessary to verify the hypothesis of no hematological toxicity in the MP group and of toxicity in 70 % of cases in the M-VAC group. A second block of 7 plus 7 patients was to be added to the series if at least 1 patient treated with MP had had hematological toxicity. We decided to modify the M-VAC regimen by omitting the administration of vinblastine and methotrexate on day 22 in order to make sure to recycle the therapy every 4 weeks. We were not able to know exactly the Carmichael et al. [1] schedule at the time we designed the study. So far, we decided to use the same MP regimen which was in use at the Department of Pediatric Oncology in our Institute for osteosarcoma at that time. Only patients with histologically documented metastatic transi tional cell carcinoma of the urinary tract were admitted into the study. Patients over the age of 70, with an ECOG performance sta-
Downloaded by: University of Exeter 144.173.6.94 - 6/6/2020 11:06:53 PM
Introduction
Pizzocaro/Milani/Piva/Faustini/Spino
90
groups Involved sites
Bladder Pelvic relapse Lymph nodes Lung Liver Soft tissues Bones
Total number of sites
n
13 8 12 8 3 3 2a
6 5 6 5 2 2 2a
M-VAC
MP %
46.2 62.5 50.0 62.5 66.7 66.7 100.0
n 7 3 6 3 1
1
53.8 37.5 50.0 37.5 33.3 33.3
Another patient actually did not have bone métastasés.
Table 2. Toxic signs of first-line MP and M-VAC Toxic signs
Nausea and vomit Leukopenia: grade 2 grade 3 grade 4 Trombocytopenia (2-3) Anemia (Hb loss > 3 g) Mucositis Creatinine (>1.8 mg/100 ml) Pulmonary edema Myocardial infarction
MP (n = 14) n
%
8 2
57.1 14.3
la
7.1 7.1 7.1 7.1 14.3 7.1 7.1
la 1
la
2
1 1
M-VAC (n- 14) n 9 10
1 1 2 1
1
1
%
64.2 71.4 7.1 7.1 14.3 7.1 7.1 7.1
This patient died of sepsis.
tus greater than 2, pretreated with radiotherapy or systemic chemo therapy were excluded. Every patient had a full clinical examina tion, blood chemistry profile, chest x-ray, computed tomography (CT) or magnetic resonance imaging (RMI) of the abdomen and pelvis, liver echography and bone scan. Cystoscopy with cold cup biopsy and bimanual palpation was performed under general anes thesia in every patient who had the primary tumor still present. We recruited 28 patients, because in the first block of 7 plus 7 cases 1 patient in the MP group showed evidence of hematological toxicity. Recruitment lasted from September 1984 to December 1988: 21 patients were men and 7 were women; their age ranged between 43 and 68 years (median age: 58). All patients had histologically docu mented transitional cell carcinoma: the tumor had originated from the bladder in 25 patients and from the renal pelvis in the remaining 3. The distribution of involved sites is shown in table 1. Toxicity was evaluated by repeating the whole blood chemistry profile at the start of every course of therapy and by checking white
blood cells and platelet counts twice a week, between cycles. Stan dard WHO response criteria were used to permit the definition of clinical response, hematological and other toxicities. The duration of responses was evaluated by December 31, 1990. Chemotherapeutic Regimens The M-VAC regimen required hospitalization for 2-3 days every 4 weeks. Methotrexate 30 mg/m2 i.v. was administrated on day 1. It was followed by 0.5 liter normal saline and 0.5 liter 5% dextrose plus 10 mEq NaHCC>3. On day 2, 3 mg/m2 vinblastine sulfate and 30 mg/m2 i.v. adriamycin were given, followed by 0.5 liter normal saline and 1 liter 5 % dextrose plus 20 mEq KC1 and 10 mEq MgSÛ4. Then, cisplatin 70 mg/m2 was administered in 250 cm3 3 % saline over a 30- to 60-min intravenous infusion. Hydration was continued with 1 liter 5% dextrose and 0.5 liter normal saline. Antiemetic medication consisted of metilprednisolone 100 mg/m2 in 100 ml 5 % dextrose plus metochlopramide 2 mg/kg. Methotrexate and vinblas tine were repeated on day 15 as described above. The MP regimen required a longer hospitalization (4-5 days) every 3 weeks. On day 1, methotrexate was administered at the dos age of 300 mg/m2 diluted in 250 ml normal saline in a 2-hour intra venous infusion, followed by 1 liter 5 % dextrose and 1 liter normal saline plus 30 mEq NaHCÛ3 and 20 mEq KC1. The hydration con tinued on days 2 and 3, on which days folinic acid rescue was insti tuted at the dosage of 9 mg/m2 i.m. every 6 h. On day 4, 100 mg/m2 cisplatin was administered in a 24-hour continuous intravenous infusion with 4 liters half-normal saline in 2.5% dextrose plus 40 mEq KC1 and 40 mEq MgS04.
Results A total of 48 cycles of M-VAC and 39 cycles of MP were administered. In the M-VAC group, there was no reduction of therapy on days 1 and 2. The therapy was not administered on day 15 in 35% of cases during the first cycle, 7% in cycle 2, 30% in cycle 3. No patient had omission of therapy on day 15 during the 4th cycle. In 40% of cases in whom the therapy was omitted on day 15, it was not for toxic signs but for poor cooperation by the family doctor, especially in cycle 1. In the MP group, only 1 patient did not receive cisplatin on cycle 2 be cause the intravenous infusion had to be suspended for pulmonary edema. All drugs were given at full dosage during the remaining 38 courses of therapy. All patients were evaluable for toxicity (table 2). He matological toxicity was very frequent in the M-VAC group (85%), but, due to omission of therapy on day 22, only 2 patients had grade 3 or 4 leukopenia. On the other hand, 1 patient in the MP group had a grade 4 hemato logical toxicity on the first cycle and died of sepsis. The median peak serum creatinine for 48 cycles of M-VAC was 1.5 mg/100 ml and 1.3 mg/100 ml for 39 cycles of MP. Only 3 patients (2 MP and 1 M-VAC) had a slight
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Table 1. Distribution of metastatic sites in the two treatment
M-VAC versus MP in Advanced Urothelial Cancer
Discussion The main goal of our study was to compare the hema tological toxicity of the two regimens, because the pre liminary results reported hematological toxicity in 83% of cases treated with M-VAC versus none for MP [1, 2], The frequent hematological toxicity of M-VAC is con firmed in our study (85%), but the majority of patients (71 %) had only grade 1-2 leukopenia. Sternberg et al. [3, 4] reported more severe toxicity. The difference can be
Table 3. Responses to first-line MP and M-VAC MP (n = 12)
Responses1
%
n
8.3
M-VAC (n= 14) n
%
3
Clinical CR Pathological CR Surgically, NED Unresectable PR
2 3
16.7 25.0
2 4
21.4 7.1 14.3 28.6
Total
6
50.0
10
71.4
1
1
a Duration, months: CR: MP = 13+; M-VAC = 15, 21+, 24+, 29; NED: MP = 9,72+; M-VAC = 11,15; PR: MP = 5,5,9; M-VAC = 4,4,5,10.
Table 4. Responses to first-line chemotherapy according to met astatic sites Involved sites
Bladder Pelvic relapse Lymph nodes Lung Liver Soft tissues Bones
MP
M-VAC
n
CR + % NED
n
CR + % NED
6 5 5 5 2 2 2
1
17
4
57
3
60
7 3 6 3
5
83 33
1 1
50
1
1
Table 5. Responses to second-line MP and M-VAC Responses1
MP (5 cases)
M-VAC (5 cases)
n
%
n
%
Surgically, NED Unresectable PR
2
40.0 20.0
1
20.0
1
Total responses
3
60.0
1
20.0
a Duration, months: surgically, NED: MP = 6,16; M-VAC = 10; unresectable PR: MP = 4.
ascribed to the omission of the administration of metho trexate and vinblastine on day 22 which we did routinely in order to recycle the therapy every 4 weeks. Actually, in the original M-VAC schedule [3, 4] the average duration of each cycle is 5 weeks. Furthermore, at least 1 admin-
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increase of serum creatinine above normal values, which returned to normal after a few days of intravenous hydration. Other toxic signs included: mucositis, which was very serious in the patient of the MP group who died of sepsis; nausea and vomiting which occurred in 8 and in 9 patients in the two groups, respectively. It was grade 3 in 1 patient (12.5%) of the MP group and in 5 (62.5%) of the M-VAC group. All 14 patients treated with M-VAC and 12 of 14 treated with MP are evaluable for response: we excluded the patient who died of sepsis following the first course of therapy, and another patient who was treated for bone métastasés which had not been confirmed at réévalua tion. Therapy was discontinued immediately in this pa tient, and he has been alive and free of disease for 4 years. The overall response rate (CR + PR) was 50% in the MP group and 71.4% in the M-VAC group. The differ ence was not statistically significant (table 3). However, the 20% difference lay on the CR rate only (8.3% in the MP and 28.5% in the M-VAC group). Other 4 patients (2 MP and 2 M-VAC) were rendered free of disease with surgery (NED). The CR + NED status was achieved in the bladder, node, lung and soft tissues only (table 4). Partial remission held from 5 to 10 months (median 5) in both groups. NED status held from 9 to 15 months with the exception of 1 patient in the MP group who was alive and free of disease 6 years after resection of a solitary soft tissue metastasis. Two of 5 complete responders relapsed after 15 and 29 months, respectively. The other 3 have been alive and free of disease for 13 to 24 months after starting therapy (table 3). Only 5 patients in each group were crossed to the other therapy (table 5). It is interesting to note that 3 of 5 patients treated with second-line MP responded and 2 of them could be rendered disease-free with surgery. How ever, the disease-free status lasted only 6 and 16 months, respectively.
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92
References 1 Carmichael J, Combleet MA, Laurie S, Duncan W, Wolf R, Smyth J: Clinical and laboratory evaluation of methotrexate and cisplatinum for the treatment of advanced bladder cancer (ab stract). Proc ECCO 1983;2:150. 2 Sternberg CN, Yagoda A, Scher HI, Hollander P, Watson RC, Ahmed T: Methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) for transitional cell carcinoma of the urothelium (ab stract). Proc Am Soc Clin Oncol 1984;3:156. 3 Sternberg CN, Yagoda A, Scher HI, Watson RC, Ahmed T, Wei selberg LR, Geller N, Hollander PS, Herr HW, Sogani PC, Morse MJ, Whitmore WF: Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transi tional cell carcinoma of the urothelium. J Urol 1985; 133:403407. 4 Sternberg CN, Yagoda A, Scher HI, Watson RC, Herr HW, Morse MJ, Sogani PC, Vaughan ED, Bander N, Weiselberg LR, Geller N, Hollander PS, Lipperman R, Fair WR, Whitmore WF: M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol 1988;139:461-469. 5 Carmichael J, Combleet MA, MacDougall RH, Allan SG, Duncann W, Chisholm GD, Smyth JF: Cisplatin and methotrexate in the treatment of transitional cell carcinoma of the urinary tract. Br J Urol 1985;57:299-302. 6 Stoter G, Splinter TAW, Child JA, Fossa SD, Denis L, Van Oosteron AT, De Paw M, Silvester R, EORTC GU group: Combina tion chemotherapy with cisplatin and methotrexate in advanced transitional cell cancer of the bladder. J Urol 1987; 137:662— 667. 7 Sternberg CN, Yagoda A, Scher HI, Watson RC, Geller N, Herr UW, Morse MJ, Sogani PC, Vaughan ED, Bander N, Weiselberg L, Rosado K, Smart T, Yun Lin S, Penemberg D, Fair WR, Whitmore WF: Methotrexate, vinblastine, doxorubicin and cis platin for advanced transitional cell carcinoma of the urothe lium. Cancer 1989;64:2448-2458. 8 Longothetis C, Dexeus F, Sella A, Amato R, Finn L: A prospec tive randomized trial of CISCA versus M-VAC chemotherapy in advanced metastatic urothelial tumors (abstract). J Urol 1989; 14LA216.
Dr. Giorgio Pizzocaro Istituto Nazionale Tumori Via G. Venezian 1 1-20133 Milano (Italy)
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istration of methotrexate and vinblastine has to be omit ted for myelotoxicity on day 15 or 22 [3, 4], So far, the weekly dose of both cisplatin and adriamycin was higher in our schedule than in the original one (17.5 mg/m2 vs. 14 mg/m2 for cisplatin, and 7.6 mg/m2 vs. 6 mg/m2 for adriamycin). The dose intensity of vinblastine and meth otrexate was only a little less in our schedule (1.5 mg/m2 vs. 1.7 mg/m2 and 15 mg/m2 vs. 17 mg/m2, respectively). The MP regimen, as modified by us, showed hemato logical toxicity in 3 cases (21 %) versus no toxicity in the Carmichael report [5]: leukopenia was of grade 2 in 2 cases and of grade 4, followed by septic death, in 1. We were not able to find an explanation for this event. Fur thermore, another 2 patients of the MP group developed severe cardiac complications (table 2), probably related to the very high volume of intravenous infusion. In another experience, a different combination of cisplatin and methotrexate [6] had such a severe hematological toxicity that only 17% of the patients could stay on schedule. As far as the therapeutic results of the different MP combinations are concerned, only Carmichael et al. [5] reported 68% objective responses (CR + PR) of 19 cases. The objective response rate was only 50% (6 of 12 patients) in our series and 46% in the EORTC series (20 of 43 evaluable cases) [6]. However, in all 3 series the complete remission rate ranged between 21 and 25%, which is less than the 36% CR rate reported by Sternberg et al. [7] in the last paper concerning 133 patients treated with M-VAC. It seems that the difference in the objec tive response rate between M-VAC and MP regimens lies principally in the complete remission rate. A random ized study comparing M-VAC to CISCA [8] confirmed the superiority of the M-VAC regimen as far as the CR rate is concerned. Last but not least, we observed in our series objective remissions in 3 of 5 patients treated with second-line MP for M-VAC failure, versus only 1 objective response of 5 patients treated with second-line M-VAC for MP failure. If such results could be confirmed in a larger series, it would be worthwhile to try high-dose methotrexate as second-line therapy, while the M-VAC regimen seems to be the best available first-line therapy for advanced tran sitional cell cancer of the urinary tract.
