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Japanese Journal of Clinical Oncology Pages 497-501

Efficacy of Dose-intensified MEC (Methotrexate, Epirubicin and Cisplatin) Chemotherapy for Advanced Urothelial Carcinoma: a Prospective Randomized Trial Comparing MEC and M-VAC (Methotrexate, Vinblastine, Doxorubicin and Cisplatin)
Introduction
Patients and Methods
Results
Discussion
Acknowledgments
Appendix
   The Japanese Urothelial Cancer Research Group
References
Efficacy of Dose-intensified MEC (Methotrexate, Epirubicin and Cisplatin) Chemotherapy for Advanced Urothelial Carcinoma: a Prospective Randomized Trial Comparing MEC and M-VAC (Methotrexate, Vinblastine, Doxorubicin and Cisplatin)

Efficacy of Dose-intensified MEC (Methotrexate, Epirubicin and Cisplatin) Chemotherapy for Advanced Urothelial Carcinoma: a Prospective Randomized Trial Comparing MEC and M-VAC (Methotrexate, Vinblastine, Doxorubicin and Cisplatin)

Masao Kuroda1, Toshihiko Kotake1, Hideyuki Akaza2, Shiro Hinotsu3, Tadao Kakizoe4 and the Japanese Urothelial Cancer Research Group

1Department of Urology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 2Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, 3Department of Epidemiology and Biostatistics, School of Health Sciences and Nursing, Faculty of Medicine, University of Tokyo, Tokyo and 4National Cancer Center Hospital, Tokyo, Japan

Background: To evaluate the antitumor activity in patients with T3b, T4 or metastatic urothelial carcinoma treated with MEC or M-VAC chemotherapy, by performing a multi-center randomized prospective study.
Methods: From 1991 to 1995, 89 patients with T3b, T4 or metastatic urothelial carcinoma were randomly allocated to a methotrexate, epirubicin and cisplatin chemotherapy group (arm 1: S-MEC therapy; n = 29), a dose-intensified MEC therapy combined with G-CSF group (arm 2: I-MEC therapy; n = 30) or a methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy (arm 3: M-VAC therapy; n = 30). At the registration center, the patients were stratified into previously untreated patients and patients with recurrence after radical operation and then randomly allocated to the treatment groups. In each arm, two or more courses of chemotherapy (4-week cycles) were performed.
Results: Of the 88 eligible patients, four treated with S-MEC therapy and two treated with I-MEC therapy showed CR. The response rates (CR + PR) were 52% (15/29) with S-MEC therapy, 76% (22/29) with I-MEC therapy and 47% (14/30) with M-VAC therapy. The response rate with I-MEC therapy was significantly higher than that with M-VAC therapy (P = 0.02). Although the incidence of leukopenia was low with I-MEC therapy, the incidence of thrombocytopenia was high with this therapy.
Conclusion: MEC therapy used in this study is promising in terms of the antitumor effects.

Key words: advanced urothelial carcinoma - chemotherapy

INTRODUCTION

The prognosis of patients with urothelial carcinoma showing T3b, T4 or metastatic disease is very poor. Even after radical operation, the 5-year survival rate is <30%. Most patients who cannot be surgically treated die within 1 year. To improve the poor prognosis of advanced urothelial carcinoma, systemic chemotherapy is the only method available at present. However, there is no established chemotherapeutic regimen. Nevertheless, M-VAC therapy (methotrexate, vinblastine, doxorubicin, cisplatin), proposed by the Memorial Sloan Kettering Cancer Center in 1985, has been widely accepted as a standard regimen of chemotherapy (1). M-VAC therapy is not a completely satisfactory chemotherapeutic method owing to its adverse drug reactions and problems in the administration schedule. A safer and more effective regimen with less adverse drug reactions needs to be urgently developed.

The major questions surrounding chemotherapy for advanced urothelial carcinoma are as follows: to what degree can the administered dose be increased?; does an increase in the administered dose lead to an increase in the antitumor effects?; in advanced urothelial carcinoma as in advanced systemic diseases, is induction therapy by chemotherapy possible?; and does chemotherapy performed prior to operation allow radical operation and complete cure of distant metastases?

In an attempt to answer these questions, we carried out a multi-center randomized prospective study that compared multiple drug combination chemotherapies consisting of methotrexate, epirubicin and cisplatin (standard MEC therapy; S-MEC therapy), a dose-intensified MEC therapy (I-MEC therapy) combined with G-CSF and M-VAC therapy in patients with urothelial carcinoma showing T3b, T4 or metastatic disease. Granulocyte colony stimulating factor may provide the possibility of treating patients with high doses of chemotherapy, for longer periods, with less morbidity and improved results.

In single-agent trials for advanced urothelial carcinoma in patients specifically selected for bidimensionally measurable indicator lesions, cisplatin, methotrexate and doxorubicin produced complete remission (CR) and partial remission (PR) in 37, 36 and 18% of cases, respectively (2). The efficacy of epirubicin is the same as that of doxorubicin with lower cardiotoxicity. We combined methotrexate, epirubicin and cisplatin in the hope of increasing the response rate and decreasing the toxicity.

PATIENTS AND METHODS

A multi-center randomized prospective study was carried out at 13 institutions (see Appendix) with support from a grant from the Ministry of Health and Welfare of Japan. The subjects were patients with urothelial carcinoma of the renal pelvis, ureter or bladder classified as T3b or T4 or those showing regional lymph node metastases or distant metastases. Staging was based on the system of TNM classification, while the extent of disease was determined by a combination of the CT, chest X-ray film, excretory urography, ultrasonography and bone scan findings. Other inclusion criteria were an age of [le]75 years and a performance status of 0-2 according to the WHO system (3). All patients had an evaluable primary lesion or an evaluable recurrent lesion after radical operation. Patients who had previously undergone radiotherapy or systemic chemotherapy were excluded. Patients who had received intravesical instillation therapy or non-specific immunotherapy were included, but those with active double cancers were excluded. Full informed consent was obtained from all patients and this study was approved by the Institutional Review Board (IRB) of each institution.

All patients were prospectively randomized to a treatment arm in the registration office of the Department of Epidemiology and Biostatistics, School of Health Sciences and Nursing, Faculty of Medicine, University of Tokyo. The registered patients were stratified at the registration office into previously untreated patients and patients with recurrence after radical operation. They were then randomly allocated to the following three chemotherapeutic regimens (Fig. 1): arm 1, MEC therapy consisting of methotrexate, epirubicin and cisplatin (S-MEC therapy); arm 2, intensified MEC therapy at increased doses combined with G-CSF (I-MEC therapy); and arm 3, M-VAC therapy. In each arm, two or more courses of chemotherapy (4-week cycles) were performed. The administered dose was not reduced in each course. However, when necessary, initiation of the next course was delayed until after recovery of the leukocyte count to at least 3000/mm3 and the platelet count to at least 100 000/mm3. G-CSF was administered when necessary to increase the leukocyte count. Antiemetics, including 5-HT3 receptor antagonists and steroids, were used when deemed necessary by the investigator.


Figure 1. Protocol of the comparative randomized study. Cisplatin was permitted to be administered in two divided doses on days 2 and 3. Human recombinant G-CSF (Leugrastim) was obtained from Chugai Pharmacy. When the peripheral leukocyte count decreased after S-MEC or M-VAC therapy to <1500/mm3, subcutaneous administration of G-CSF (2 µg/kg/day) was initiated. In I-MEC therapy, when cisplatin was administered in two divided doses, G-CSF administration was initiated on day 4.

Complete response (CR) denoted disappearance of any previously present palpable lesions and all radiographic and/or endoscopic evidence of disease. Partial response (PR) indicated a >50% reduction in bidimensional or a greater than 30% reduction in unidimensional viable disease by physical examination, imaging and endoscopy.

The clinical antitumor effect was evaluated at 4-8 weeks after initiation of the second course of chemotherapy. When three courses or more were administered, the best result in all courses was employed as the best response. In each evaluation, the time of the appearance of the antitumor effect and the duration of that effect were also observed. The histopathological effect was evaluated only when resection of the tumor was possible after chemotherapy.

Adverse drug reactions were evaluated according to the WHO criteria (3). The total number of patients with each adverse drug reaction was determined for each course.

The primary endpoint of this study was a comparison of antitumor effect of MEC versus M-VAC therapy and efficacy of dose-intensified MEC therapy. The secondary endpoint included survival of patients receiving chemotherapy.

To assess homogeneity of the treatment groups with respect to certain baseline characteristics, the chi-squared test was used. The tumor response rate for three groups of patients was analyzed for statistical significance using Fischer's exact test.

Table 1. Patients' characteristics
  S-MEC I-MEC M-VAC
Age (yr)
   30-39 0 0 1
   40-49 1 3 1
   50-59 9 5 5
   60-69 12 13 16
   70-79 5 9 6
   80-89 2 0 1
   Median 62 64 65
Gender
   Male 22 25 24
   Female 7 5 6
PS
   0 20 19 22
   1 8 10 6
   2 1 1 2
PS: performance status.

Table 2. Histological grade and clinical stage of previously untreated patients and foci of carcinoma in recurrent patients
Patients S-MEC I-MEC M-VAC
Previously untreated patients G2 6 2 3
G3 17 20 20
GX 1 3 1
T2 5 2 0
T3 7 9 12
T3b 0 2 0
T4 12 12 12
N0 12 15 17
N1 4 2 1
N2 4 5 3
N3 4 3 2
NX 0 0 1
M0 16 18 18
M1 8 7 6
Total 24 25 24
Recurrent patients Local recurrence
   Yes 2 1 2
   No 3 4 4
Distant metastasis
   Yes 4 5 5
   No 1 0 1
Total 5 5 6

RESULTS

Eighty-nine patients were enrolled: 29 were treated with S-MEC therapy, 30 with I-MEC therapy and the remaining 30 with M-VAC therapy. Their background factors (age, gender, performance status, clinical stage of previously untreated patients and site of recurrence in patients with recurrence) are shown in Tables 1 and 2. No significant differences were observed for any of the factors among the three treatment groups.

Of the 89 patients, one was ineligible because of the absence of evaluable lesions and two were excluded from evaluation of the antitumor effect because of violation of the administration schedule and rejection of the second course by the patient. Evaluation was impossible in six patients, of whom two treated with S-MEC therapy and one treated with I-MEC therapy (total: three patients) died as a result of the toxicity of the chemotherapy. In the other three patients, the chemotherapy was discontinued after the first course because of the development of adverse drug reactions (two patients) or aggravation of the general condition due to progression of the cancer (one patient).

Of the 88 eligible patients, four treated with S-MEC therapy and two treated with I-MEC therapy achieved CR. The response rates (CR + PR) were 52% (15/29) with S-MEC therapy, 76% (22/29) with I-MEC therapy and 47% (14/30) with M-VAC therapy. The response rate with I-MEC therapy was significantly higher than that with M-VAC therapy (P = 0.02, Table 3).

The antitumor effect was evaluated in the previously untreated patients and the patients with recurrence. In both, the response rate with I-MEC therapy was high. In the patients with recurrence, the response rate with S-MEC therapy was slightly lower (40%).

Of 51 patients without distant metastasis, 14 treated with S-MEC, 17 treated with I-MEC and 15 treated with M-VAC underwent radical surgery after the chemotherapy.

Table 3. Antitumor effect
  CR PR NC PD NE CR + PR Total
All patients
   S-MEC 4 11 9 3 2 15 (52%) 29
   I-MEC 2 20 2 1 4 22 (76%) 29
   M-VAC   14 9 5 2 14 (47%) 30
Previously untreated patients
   S-MEC 3 10 7 2 2 13 (54%) 24
   I-MEC 2 16 2 1 3 18 (75%) 24
   M-VAC   10 8 4 2 10 (42%) 24
Recurrent patients
   S-MEC 1 1 2 1   2 (40%) 5
   I-MEC   4     1 4 (80%) 5
   M-VAC   4 1 1   4 (67%) 6
NE: not evaluable.

Table 4. Hematological toxicities
Grade 0 1 2 3 4 Total courses
Anemia (%)*
   S-MEC 12 (17) 25 (35) 18 (25) 17 (24) 0 72
   I-MEC 14 (22) 17 (27) 22 (34) 11 (17) 0 64
   M-VAC 9 (13) 18 (27) 29 (43) 9 (13) 2 (3) 67
Leukopenia (%)[dagger]
   S-MEC 7 (10) 16 (22) 21 (29) 21 (29) 7 (10) 72
   I-MEC 15 (23) 14 (22) 19 (30) 11 (17) 5 (8) 64
   M-VAC 9 (13) 10 (15) 18 (27) 23 (34) 7 (10) 67
Thrombocytopenia (%)[Dagger]
   S-MEC 41 (57) 12 (17) 10 (14) 2 (3) 7 (10) 72
   I-MEC 20 (31) 6 (9) 8 (13) 13 (20) 17 (27) 64
   M-VAC 44 (66) 10 (15) 4 (6) 1 (1) 8 (12) 67
*S-MEC vs I-MEC, NS; S-MEC vs M-VAC, NS; I-MEC vs M-VAC, NS. [dagger]S-MEC vs I-MEC, NS; S-MEC vs M-VAC, NS; I-MEC vs M-VAC, P = 0.02. [Dagger]S-MEC vs I-MEC, P < 0.001; S-MEC vs M-VAC, NS; I-MEC vs M-VAC, P < 0.001.

Table 5. Non-hematological toxicities ([ge]grade 3)
  S-MEC I-MEC M-VAC
Nausea, vomiting 25/72 (35%) 20/64 (31%) 19/64 (30%)
Alopecia 9/72 (13%) 12/64 (19%) 14/64 (22%)
Stomatitis 5/72 (6.9%) 4/64 (6.3%) 5/64 (7.8%)
Diarrhea 2/72 (2.8%) 0/64 0/64
Nephropathy 0/72 0/64 1/64 (1.6%)

The relative dose intensity (RDI), which was calculated according to the equation of Longo et al. (4) for each regimen, was 0.95 with S-MEC therapy, 0.90 with I-MEC therapy and 0.82 with M-VAC therapy. Drug administration tended to be easier in S-MEC and I-MEC therapy than in M-VAC therapy.

As adverse drug reactions, bone marrow suppression, vomiting and alopecia were frequently observed. Stomatitis was less frequently observed but became severe in some patients. Of the 89 patients, three died as a result of the adverse drug reactions of the chemotherapy (two treated with S-MEC therapy and one treated with I-MEC therapy). These three patients died from septicemia associated with leukopenia in the first or second cycle of the chemotherapy. Severe adverse drug reactions which interfered with continuation of the treatment were nephropathy (one patient) and bone marrow suppression. Adverse drug reactions occurring at different frequencies among the three regimens were leukopenia, thrombocytopenia and nephropathy. The incidence of grade 4 leukopenia was 8% with I-MEC therapy, 10% with S-MEC therapy and 10% with M-VAC therapy. The incidence of thrombocytopenia was significantly higher with I-MEC therapy than with S-MEC or M-VAC therapy (Table 4). Nephropathy was the most significant non-hematological adverse drug reaction. The incidence of nephropathy was slightly higher with I-MEC therapy, while severe nephropathy was observed in only one patient treated with M-VAC therapy (Table 5).

Since many patients were followed for a period of <2 years after the initiation of therapy, further follow-up is necessary to evaluate the cumulative survival rate.

DISCUSSION

The prognosis of bladder carcinoma accompanied by metastasis has been extremely poor. Survival for [ge]2 years is rare. Local therapy, such as operation and radiotherapy, has no radical effect and the only effective method is systemic chemotherapy. Until the development of cisplatin, chemotherapy was not useful for prolonging survival since it showed a response rate of less than 50%. Multiple drug combination chemotherapy including cisplatin has considerably improved the antitumor effect. In 1985, M-VAC therapy with four drugs was reported (1) and has now become established as a standard regimen for urothelial carcinoma. At present, M-VAC therapy is widely performed as standard chemotherapy for urothelial carcinoma and it is also used as neoadjuvant chemotherapy before radical operation (5-7) or as postoperative adjuvant chemotherapy (8).

However, M-VAC therapy causes marked adverse drug reactions such as bone marrow suppression and stomatitis. Although the response rate is high, prolongation of survival is only infrequently observed (9). Randomized comparative trials of M-VAC therapy and other regimens in many patients have shown no regimen to be better than M-VAC therapy (10,11). CISCA (cisplatin, cyclophosphamide and doxorubicin) therapy was reported to be inferior to M-VAC therapy in terms of the survival rate (9). Studies on M-VAC therapy at increased doses (12-15) showed even more severe adverse drug reactions but no improvement in the survival rate. Regimens which are safer and more effective in terms of the survival rate than M-VAC therapy need to be urgently developed.

A study of the long-term results of chemotherapy suggested that PR is inadequate for prolonging survival, but CR is associated with prolongation of the survival period (9). The purpose of chemotherapy is achievement of CR. When CR is not achieved by chemotherapy alone, multidisciplinary treatment which combines operation and radiotherapy with chemotherapy is necessary.

In this randomized study, the response rates with I-MEC and S-MEC therapy were higher than that with M-VAC therapy. In addition, since CR was more frequently achieved by the former two regimens, prolongation of the survival period is expected. When analyzed as a function of the metastatic organ, the rates of responses of both primary and metastatic lesions to I-MEC therapy were high, suggesting that this therapy is a promising regimen which may be more effective than M-VAC therapy. However, this regimen had marked adverse drug reactions. In particular, the incidence of thrombocytopenia was high: grade 4 (<30 000) was observed in 27% of cases. Leukopenia could be reduced by G-CSF, but platelet transfusion is the only method available for treatment of thrombocytopenia. To perform I-MEC therapy more safely, development of thrombopoietin which increases platelets is awaited.

S-MEC therapy showed a slightly higher response rate than M-VAC therapy. The incidence of bone marrow suppression after S-MEC therapy was similar to that after M-VAC therapy, whereas the incidences of other adverse drug reactions were slightly lower than those after M-VAC therapy. In addition, the adverse drug reactions of S-MEC therapy improved relatively early and chemotherapy on a 3-week cycle was possible in a considerable number of patients. We are considering a change in the regimen to a 3-week cycle in the future.

MEC therapy in this study is promising in terms of its antitumor effects.

Acknowledgments

This work was supported by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare, Japan.

Appendix

The Japanese Urothelial Cancer Research Group

Hokkaido University Dr Nobuo Shinohara
Tohoku University Dr Senji Hoshi
University Of Tsukuba Dr Hideyuki Akaza
Keio University Dr Masaaki Tachibana
National Cancer Center Hospital Dr Kenichi Tobisu
Jikei University School Of Medicine Dr Yukihiko Oishi
Chiba University Dr Shigeo Isaka
Yokohama City University Dr Yoshinobu Kubota
Kyoto University Dr Toshiro Terachi
Osaka Medical Center For Cancer And Cardiovascular Diseases Dr Toshihiko Kotake
Nara Medical University Dr Seiichiro Ohzono
Kyushu University Dr Seiji Naito
Kagoshima University Dr Yoshitada Ohi

References

1. Sternberg CN, Yagoda A, Scher HI, Watson RC, Ahmed T, Weiselberg LR, et al. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol 1985;133:403-7. MEDLINE Abstract

2. Yagoda, A. Phase II trials of single agents and combination regimens in the treatment of urothelial tract tumours: Memorial Hospital experience. In: Oliver RTD, Hendry WF, Bloom HJG, editors. Bladder Cancer. London: Butterworth, 1981;193-206.

3. WHO Handbook for Reporting Results of Cancer Treatment. Geneva: World Health Organization, 1979.

4. Longo DL, Duffy PL, DeVita VT Jr, Wesley MN, Hubbard SM, Young RC. The calculation of actual or received dose intensity: a comparison of published methods. J Clin Oncol 1991;9:2042-51. MEDLINE Abstract

5. Scher HI, Yagoda A, Herr HW, Sternberg CN, Bosl G, Morse MJ, et al. Neoadjuvant M-VAC (methotrexate, vinblastine, adriamycin and cisplatin) effect on the primary bladder lesion. J Urol 1988;139:470-4. MEDLINE Abstract

6. Boutan-Laroze A, Mahjoubi M, Droz JP, Charrot P, Fargeot P, Kerbrat P, et al. M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced carcinoma of the bladder. The French Federation of Cancer Centers experience. Eur J Cancer 1991;27:1690-4. MEDLINE Abstract

7. Splinter TA, Scher HI, Denis L, Bukowski R, Simon S, Klimberg I, et al. The prognostic value of the pathological response to combination chemotherapy before cystectomy in patients with invasive bladder cancer. European Organization for Research on Treatment of Cancer-Genitourinary Group. J Urol 1992;147:606-8. MEDLINE Abstract

8. Stöckle M, Meyenburg W, Wellek S, Voges G, Gertenbach U, Thuroff JW, et al. Advanced bladder cancer (stages pT3b, pT4a, pN1 and pN2): improved survival after radical cystectomy and 3 adjuvant cycles of chemotherapy. Results of a controlled prospective study. J Urol 1992;148:302-6.

9. Sternberg CN, Yagoda A, Scher HI, Watson RC, Geller N, Herr HW, et al. M-VAC for advanced transitional cell carcinoma of the urothelium: efficacy and patterns of response. Cancer 1989;64:2448-58. MEDLINE Abstract

10. Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, et al. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol 1990;8:1050-5. MEDLINE Abstract

11. Heimbach D, Wirth M, Frohmuller H. M-VAC versus CisCA chemotherapy in the treatment of advanced bladder cancer. Urol Int 1992;48:157-61. MEDLINE Abstract

12. Logothetis CJ, Dexeus FH, Sella A, Amato RJ, Kilbourn RG, Finn L, et al. Escalated therapy for refractory urothelial tumors: methotrexate-vinblastine-doxorubicin-cisplatin plus unglycosylated recombinant human granulocyte-macrophage colony-stimulating factor. J Natl Cancer Inst 1990;82:667-72. MEDLINE Abstract

13. Seidman AD, Scher HI, Gabrilove JL, Bajorin DF, Motzer RJ, O'Dell M, et al. Dose-intensification of MVAC with recombinant granulocyte colony stimulating factor as initial therapy in advanced urothelial cancer. J Clin Oncol 1993;11:408-14. MEDLINE Abstract

14. Loehrer PJ Sr, Elson P, Dreicer R, Hahn R, Nichols CR, Williams R, et al. Escalated dosages of methotrexate, vinblastine, doxorubicin and cisplatin plus recombinant human granulocyte colony-stimulating factor in advanced urothelial carcinoma: an Eastern Cooperative Oncology Group trial. J Clin Oncol 1994;12:483-8. MEDLINE Abstract

15. Logothetis CJ, Finn LD, Smith T, Kilbourn RG, Ellerhorst JA, Zukiwski AA, et al. Escalated MVAC with or without recombinant human granulocyte-macrophage colony-stimulating factor for the initial treatment of advanced malignant urothelial tumors: Results of a randomized trial. J Clin Oncol 1995;13:2272-7. MEDLINE Abstract

Received March 12, 1998; accepted May 7, 1998
For reprints and all correspondence: Masao Kuroda, Department of Urology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3, Nakamichi, Higashinari-ku, Osaka, 537-8511, Japan
Abbreviations: TCC, transitional cell carcinoma; MTX, methotrexate; EpiADM, epirubicin; CDDP, cisplatin; G-CSF, granulocyte colony stimulating factor; VBL, vinblastine; ADM, doxorubicin; S-MEC, standard regimen of methotrexate, epirubicin and cisplatin chemotherapy; I-MEC, dose-intensified regimen of methotrexate, epirubicin and cisplatin chemotherapy; M-VAC, methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy

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