| Japanese Journal of Clinical Oncology | Pages |
Long-term Follow-up Results of a Pilot Phase II Study of Multidrug Chemotherapy (MVP-CAB) in Patients with Advanced Urothelial Cancer
Introduction
Patients and Methods
Patients' Characteristics
Chemotherapeutic Regimen
Disease Evaluation and Patient Monitoring
End-point and Statistical Analysis
Results
Response Rates
Survival
Toxicity
Discussion
References
Long-term Follow-up Results of a Pilot Phase II Study of Multidrug Chemotherapy (MVP-CAB) in Patients with Advanced Urothelial Cancer
Methods: Forty patients with metastatic urothelial cancer were treated with a new combination chemotherapy, MVP-CAB (methotrexate, doxorubicin, vincristine, cyclophosphamide, bleomycin and cisplatin every 28 days). Of the 40 patients, 26 had not undergone prior chemotherapy or radiotherapy; the remaining 14 patients had undergone prior cisplatin-based chemotherapy.
Results: The clinical response rate to MVP-CAB therapy for all 40 patients was 63% [complete response (CR), six patients; partial response (PR), 19 patients]. The median duration of the effects was 22 and 13 months in the patients with CR and PR, respectively. The clinical response rate for the 26 patients without prior chemotherapy was 77% (CR, four patients; PR, 16 patients). The rate for the 14 patients with prior chemotherapy was 36% (CR, two patients; PR, three patients). The response rate according to metastatic site was highest for the liver (80%), followed by the lymph nodes (74%) and lungs (67%). The effect on bone metastasis was poor (22%). There was good compliance with the MVP-CAB chemotherapy regimen and toxicity was tolerable. The 1-, 3- and 5-year overall survival rates were 42.5, 10 and 5%, respectively.
Conclusions: MVP-CAB combination chemotherapy was found to be effective for the treatment of advanced urothelial cancer, especially for liver metastasis.
INTRODUCTION
Metastatic urothelial cancer is a chemosensitive disease and cisplatin-based chemotherapy is generally used in such cases (1). M-VAC chemotherapy, consisting of a combination of methotrexate (MTX), vinblastine (VBL), doxorubicin (ADM) and cisplatin (CDDP), is the most commonly administered chemotherapy regimen for this cancer around worldwide (1-4). Initially, this regimen showed a higher complete response (CR) rate, superior to any single agent and to combination therapy with CDDP, cyclophosphamide (CPM) and ADM (CISCA) in randomized studies (1-3).
However, the effectiveness of M-VAC therapy has been called into question (5,6). The CR rate for therapy for metastatic bladder cancer patients was 31% and the duration of the effect was 8-21 months (6). Long-term follow-up evaluation of patients treated by M-VAC therapy showed that only 3.2% of the patients survived longer than 5 years after the initial application of chemotherapy (7). In addition, the toxicity of M-VAC therapy including bone marrow suppression and gastrointestinal complications is comparatively severe (1-4). Severe nausea/vomiting occurs in 12% of M-VAC-treated patients; grade 3 or greater neutropoenia occurs in 24-58%, grade 3 or greater mucositis in 13-17% and significant renal insufficiency in 7% (1,2). These side effects are occasionally very severe in Japanese patients with a concomitant long-term hospital stay with disturbance of the patient's quality of life. The development of such side effects indicates that the M-VAC regimen should be discontinued. Another chemotherapeutic regimen which has equivalent or greater effectiveness and mild toxicity compared with those of M-VAC therapy is thus required for the treatment of metastatic urothelial cancer. We investigated the clinical effects, long-term survival and toxicity of combination chemotherapy based on CDDP (MVP-CAB) for patients with advanced urothelial cancer. The period of this phase II study was 12 years. However, the number of patients with unresectable or metastatic urothelial cancer was smaller than in similar studies in the USA. To consider further chemotherapeuitic regimens, we analyzed the clinical results of all patients treated with MVP-CAB chemotherapy for the period.
PATIENTS AND METHODS
Patients' Characteristics
The patients' characteristics are shown in Table 1. Between May 1985 and August 1997, 40 patients with unresectable and metastatic urothelial cancer (bladder and upper urinary tract) were treated with the new combination chemotherapy at Hyogo Medical Center for Adults. The patients' median age was 65 years (range: 40-87 years). The median Karnofsky performance status was 70% (range: 40-90%). Histologically, pure transitional cell carcinoma was observed in 37 patients and the mixed type with transitional cell carcinoma and squamous cell carcinoma or adenocarcinoma which consisted predominantly of transitional cell carcinoma was detected in the remaining three. The most common metastatic site was the lung.
Table 1.
| Number of patients | 40 |
| Males/females | 31/9 |
| Age: median (range) (years) | 65 (40-87) |
| KPS (%) | |
| [ge]80 | 12 |
| <80 | 28 |
| Site of primary disease | |
| Bladder | 26 |
| Upper tract | 14 |
| Histology | |
| Transitional cell | 37 |
| Other | 3 |
| Site of disease | |
| Unresectable primary (with/without other sites) | 18 |
| Lymph node only | 4 |
| Lung (with/without other sites) | 14 |
| Liver (with/without other sites) | 5 |
| Bone (with/without other sites) | 9 |
| Prior treatment | |
| Chemotherapy | 14 |
| Neoadjuvant | |
| CDDP alone | 2 |
| M-VAC | 1 |
| Adjuvant | |
| CDDP alone | 2 |
| M-VAC | 2 |
| Initial therapy for metastatic foci | |
| CDDP alone | 3 |
| M-VAC | 4 |
Twenty-six of the patients had undergone no prior chemotherapy, whereas the other 14 had undergone prior CDDP-based chemotherapy; seven patients underwent initial chemotherapy for metastatic foci and neoadjuvant and adjuvant therapy was performed in three and four patients, respectively. Patients with adequate bone marrow reserves of WBC count [ge]3000/µl, platelet count [ge]100 000/µl and hemoglobin level [ge]10 g/dl were included in the study. Patients with inadequate liver function as shown by bilirubin level >1.5 mg/dl or transaminases levels of more than threefold the normal range, inadequate renal function with serum creatinine concentration >2.0 mg/dl or severe heart or respiratory disease were excluded from the study. Informed consent to participate in the study was obtained orally or in written form from all patients.
Chemotherapeutic Regimen
The MVP-CAB regimen was described previously (8,9). Briefly, the regimen consisted of 20 mg/m2 methotrexate (MTX), 20 mg/m2 doxorubicin (ADM), 0.6 mg/m2 vincristine (VCR), 500 mg/m2 cyclophosphamide (CPM) and 30 mg bleomycin (BLM) on day 1 and 60 mg/m2 cisplatin (CDDP) on day 2 in 28-day cycles. The rationale of MVP-CAB therapy is as follows. BLM is effective against urothelial cancer with histological squamous cell carcinoma (10). Although the response rates to BLM and VCR in urothelial cancer in general were shown to be poor [approximately 15% (11) and 8% (12), respectively], these drugs are most effective in combination with other anti-neoplastic drugs (13) and the extent of bone marrow suppression is low (14). The other four drugs consistuting the MVP-CAB therapy are effective against urothelial cancer (15). We therefore used these six drugs for treating advanced urothelial cancer. BLM was administered in three courses of therapy, but omitted from the fourth course onward because of possible toxicity of pulmonary fibrosis. After November 1990, we administered granulocyte colony-stimulating factor for leukocytopenia (<2000). After January 1991, a new antiemetic drug (granisetron) was used to control severe vomiting.
Disease Evaluation and Patient Monitoring
Disease evaluation in all patients included a chest X-ray and computed tomography (CT) or magnetic resonance imaging (MRI) before and after every two courses of chemotherapy. Bone scans were performed for patients with bone metastasis. Cystoscopic evaluation of patients with intact bladders was not routinely performed. Therapy was discontinued in patients with CR, progressive disease (PD) or with severe side effects. Partially responding patients received the therapy until the disease became progressive with respect to the tumor size before MVP-CAB therapy. Physical examination, routine serum chemistry, complete blood count and urinalysis were repeated after each cycle to monitor safety and toxic effects. The response to the chemotherapy was evaluated with standard accepted response criteria (16). Briefly, CR was defined as the complete disappearance of all of the disease foci and no new lesions for at least 4 weeks. Partial response (PR) was defined as the development of no new lesions and a 50% reduction in the sum of the perpendicular diameters of all measured lesions maintained for at least 4 weeks. Progressive disease (PD) was defined as the development of new metastatic lesions or an increase of more than 25% in the sum of the perpendicular diameters of all measured lesions. The responses were confirmed by review of relevant radiographs by all investigators along with an independent radiologist not affiliated with the study.
End-point and Statistical Analysis
The primary study end-point was the response rate. Survival curves were generated by the Kaplan-Meier method. The significance was determined by a log rank test. A P value <0.05 was considered significant. The end of the follow-up study period for analysis was December 31, 1997.
RESULTS
Response Rates
The responses of the 40 patients to MVP-CAB chemotherapy are shown in Table 2; six cases showed CR and 19 PR. The overall response rate was 63% and the median durations of CR and PR were 22 and 13 months, respectively. All of the patients with PD died within 18 months after the initiation of chemotherapy. Among the 26 patients who were not previously treated with chemotherapy, there were four cases of CR and 16 of PR; the response rate was 77%. The median durations of CR and PR in this patient group were 26 and 12 months, respectively (Table 2). Among the 14 patients previous treated with chemotherapy, two cases showed CR and three PR (response rate 36%) and their median durations were 11 and 8 months, respectively. The response rates according to metastatic lesions are shown in Table 3. The response rate for liver metastasis was highest; four of five patients with liver metastasis responded (80%), followed by the lymph nodes and lung. The response rate of the patients with bone metastasis was poor (22%).
Survival
The median number of courses of MVP-CAB received was three (range: 1-20). Thirty-six patients died of urothelial cancer, one patient died of pulmonary fibrosis induced by the chemotherapy and one died of another disease (myocardial infarction). Two patients with CR are alive with no evidence of disease 41 months and 126 months after the commercement of MVP-CAB therapy; they were treated with four and seven courses of chemotherapy, respectively. The overall survival for all patients from the commercement of MVP-CAB therapy is shown in Fig. 1. The 1-, 3- and 5-year overall survival rates of the 40 patients were 42.5, 10 and 5%, respectively. The median survival period was 10 months. The 1-, 3- and 5-year survival rates of the 26 patients who had no previous chemotherapy were similar to those of the total 40 patient population (53.8, 15.4 and 7.7%, respectively) (data not shown). The progression-free survival rates for all patients are shown in Fig. 2. The 1-, 3- and 5-year progression-free survival rates were 26.0, 7.0 and 7.0%, respectively.
Toxicity
MVP-CAB therapy was in general well tolerated; World Health Organization (WHO) grade 4 toxicity was observed in 12 patients. Grade 4 leukocytopenia or thrombocytopenia was seen in 11 (28%) and six patients (15%), respectively (Table 4). Only two patients had grade 4 leukocytopenia after the introduction of granulocyte colony-stimulating factor. There were no patients with grade 3 nausea/vomiting after the introduction of granisetron. Grade 4 renal dysfunction was seen in one patient (2.5%) and pulmonary fibrosis was observed in one patient (2.5%) who died owing to this toxic complication. None of the patients died of sepsis induced by severe leukocytopenia caused by the chemotherapy. Moreover, grade 3 or 4 neutropenic fever and mucositis were not detected.
DISCUSSION
We observed a 63% positive response rate to MVP-CAB chemotherapy; for the patients without prior chemotherapy, the response rate was 77%, which was similar to that produced by M-VAC therapy in initial clinical trials (1-4). The positive response rate of patients who underwent prior CDDP-based chemotherapy including M-VAC therapy was 36% (5/14); CR and PR were obtained in two (14%) and three patients (21%), respectively. Hence the effects of the MVP-CAB regimen were not reduced in the patients with prior M-VAC chemotherapy and it was interesting that 36% of such patients showed a response. These results indicated that MVP-CAB therapy could be used for patients who have undergone prior CDDP-based chemotherapy.
Table 2.
| Response | No prior chemotherapy (n = 26) | Prior chemotherapy (n = 14) | Overall (n = 40) | |||
| No. of patients (%) | Duration (months): median (range) | No. of patients (%) | Duration (months): median (range) | No. of patients (%) | Duration (months): median (range) | |
| CR | 4 (15) | 26 (3-118) | 2(14) | 11(5-17) | 6(15) | 22(7-118) |
| PR | 16 (62) | 12 (3-59) | 3 (21) | 8 (3-12) | 19 (48) | 13 (3-37) |
| PD | 6 (23) | ND | 9 (64) | ND | 15 (38) | ND |
| Overall | ||||||
| (CR + PR) | 20 (77) | 12 (3-118) | 5 (36) | 8 (3-17) | 25 (63) | 12 (3-118) |
Table 3.
| Site | No. of patients | No. of patients (%) | ||
| CR | PR | Overall | ||
| Primary | 18 | 5 (28) | 7 (39) | 12 (67) |
| Lymph node | 23 | 4 (17) | 13 (57) | 17 (74) |
| Lung | 14 | 2 (14) | 6 (43) | 8 (57) |
| Liver | 5 | 1 (20) | 3 (60) | 4 (80) |
| Bone | 9 | 0 (0) | 2 (22) | 2 (22) |
Table 4.
| Toxicity | No. of patients (%) | ||
| Grade 3 | Grade 4 | Grade 3 + 4 | |
| Neutropenia | 16 (40) | 11 (28)* | 7 (68) |
| Neutropenic fever | 0 (0) | 0 (0) | 0 (0) |
| Anemia | 2 (5) | 1 (2.5) | 3 (7.5) |
| Thrombocytopenia | 1 (2.5) | 6 (15) | 7 (17.5) |
| Mucositis | 0 (0) | 0 (0) | 0 (0) |
| Nausea/vomiting | 2 (5)[dagger] | 0 (0) | 2 (5) |
| Renal dysfunction | 0 (0) | 1 (2.5) | 1 (2.5) |
| Pulmonary fibrosis | 0 (0) | 1 (2.5) | 1 (2.5) |
Pulmonary metastasis shows positive responses to M-VAC therapy (1-4), whereas liver and bone metastases did not respond (1-3).
The most effective metastatic site was the liver and bone metastasis showed a low response rate, as it did to M-VAC. The present results indicated that MVP-CAB therapy could be effective for the treatment of liver metastasis.
The major drawback of M-VAC therapy was its comparatively severe toxicity, preventing its repeated application. A new chemotherapeutic regimen with milder toxicity and a high response rate is thus required. The chemotherapeutic regimen examined in the present study was well tolerated and had good compliance; the median number of cycles was three and the maximuml number was 20 even before introduction of granulocyte colony-stimulating factor and granisetron. The reasons for good compliance were unclear; however, a reduced dosage of CDDP, ADM and MTX was used compared with those in M-VAC chemotherapy and instead of VBL in M-VAC therapy, VCR, BLM and CPM were used. However, pulmonary fibrosis was observed in one patient. This toxicity was detected at an early period of the MVP-CAB therapy and the patient demonstrated respiratory dysfunction before treatment. Bleomycin (BLM) presents the risk of the toxicity of pulmonary fibrosis. Therefore, after July 1988, BLM was not initially administered to eight patients with respiratory dysfunction. After that time, pulmonary fibrosis was not detected. Although the drug administration was performed under hospitalization, the number of hospital days was small (median 5 days; range 3-21 days). After discharge, the majority of the patients were cared for at out-patient clinics. Therefore, we were able to continue the MVP-CAB therapy until the disease progressed without disturbance of the patients' quality of life.
Figure 1. Overall survival of 40 metastatic urothelial cancer patients treated with MVP-CAB chemotherapy. Figure 2. Progression-free survival of the 40 metastatic urothelial cancer patients treated with MVP-CAB chemotherapy. The 5-year overall survival rate of the patients treated with MVP-CAB was 5%. This result indicated that MVP-CAB did not have a significant impact on the long-term outcome in patients with metastatic urothelial cancer, similarly to M-VAC therapy. Although a randomized study with M-VAC and MVP-CAB therapy would be necessary to test the present findings further, MVP-CAB therapy showed relatively mild toxicity and a high response rate, especially for liver metastasis. The effects of new anticancer agents such as gallium nitrate and paclitaxel for metastatic urothelial cancer have been described (17-20). These new drugs show relatively mild toxicity. We therefore believe that a more effective and less toxic regimen than MVP-CAB can be developed for patients with metastatic urothelial carcinoma. Our results indicated that the combined MVP-CAB therapy was effective against metastatic urothelial cancer and useful for patients who had undergone previous CDDP-based chemotherapy and for patients with liver metastasis. The long-term survival was, however, still comparatively low. To improve patient survival, the MVP-CAB regimen together with new chemotherapeutic drugs with mild toxicity may be effective.
References
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Last modification: 13 Apr 1999
Copyright© 1999 Foundation for Promotion of Cancer Research.
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