Results of modified M-VAC chemotherapy for advanced urothelial carcinoma

PURPOSE: We retrospectively evaluated the efficacy and toxicity of modified M-VAC therapy for locally advanced or metastatic urothelial carcinoma. PATIENTS AND METHOD: From 1993 October to 2005 February, 28 patients were treated with modified M-VAC therapy and 25 of 28 patients had lesions suitable for the evaluation. The modified regimen was the combination of methotrexate at a dose of 30 mg/m2 on day 1, vinblastine at a dose of 3 mg/m2 on day 2, doxorubicin at a dose of 30 mg/m2 on day 2, and cisplatin at a dose of 70 mg/m2 on day 2 with courses repeated every three weeks. RESULTS: The median number of cycle was 3 (1 to approximately 7 cycles). Six of 25 patients achieved complete response (CR) and six partial response (PR), resulting in a 48% response rate. With a median followup time of 65.6 months, the median survival was 9.3 months and the 1-year and 2-year survival rates were 33.5% and 9.6%, respectively. The median progression-free survival was 6.0 months. Grade 3 and 4 toxicities included neutropenia (84.4%), thrombocytopenia (40%), anemia (56%), febrile neutropenia (20%), nausea, vomiting (8%). CONCLUSION: Although response rate of modified M-VAC therapy was similar to classic M-VAC therapy, but modified M-VAC therapy had shorter response duration and more frequent toxicities. We were not able to find the benefits of modified M-VAC therapy.     

Outcome of treatment with surgical resection of the remaining tumor after modified M-VAC treatment for advanced urothelial carcinoma

We retrospectively evaluated the effect of the surgical resection of the remaining tumor after modified M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) (m-M-VAC) treatment for locally advanced or metastatic urothelial carcinoma. In m-M-VAC therapy, methotrexate and vinblastine on 15 and 22 days were omitted from the classical M-VAC to avoid the discontinuation and the dose reduction, and duration of 1 course was shortened to 21 days from 28 days of the classical M-VAC. Seven patients with locally invasive or metastatic carcinoma of the renal pelvis, ureter, and bladder, 6 males and 1 female, with a median age 64.1 years, ranging from 49 to 77 years received m-M-VAC chemotherapy without severe side effects. In all patients, the residual viable carcinoma was completely resected and they achieved complete remission. The median survival time was 20 months (range, 7 to 61). Five of these 7 patients were still alive. Two patients had no recurrence and achieved long-term survival (survival duration; 61 and 39 months). Although further studies and long-term follow up are required, these results suggest that patients who present with locally advanced or metastatic urothelial carcinoma may benefit from surgical resection after m-M-VAC.     

Clinical study of modified M-VAC therapy with one 21-day cycle for advanced urothelial cancer

Although M-VAC therapy is a standard chemotherapy for advanced transitional cell carcinoma, the treatment schedule has to be delayed or cancelled in many patients because of the toxicity. To reduce the toxicity we modified the treatment schedule of M-VAC treatment. The dosages of this simplified M-VAC therapy were 30 mg/m2 methotrexate (on day 1), 3 mg/m2 vinblastine (on day 2), 30 mg/m2 doxorubicin (on day 2) and 70 mg/m2 cisplatin (on day 2), with courses repeated every 21 days for four cycles as a principle. Seventeen patients with histologically proven advanced transitional cell carcinoma were treated with this simplified M-VAC therapy without dose modification or delay. The median number of cycles was 4. Neutropenia, anemia and thrombopenia (grade 4) was observed in 2, 1 and 2 patients respectively, but no drug-related deaths were observed. Complete response and partial response were achieved in 2 (12%) and 10 (59%) patients respectively. Of 2 complete responders one patient was alive without evidence of disease at 12 months and another patient died of the disease at 42 months. Of 10 partial responders 6 patients underwent the additional surgical resection of residual tumors. Of these 6 patients 3 patients are alive without evidence of disease at 6, 30 and 31 months. The remaining 3 developed recurrence and 2 died of the disease at 13 and 29 months. Five non-responders died of the disease at 5 months after the start of the therapy. Response rate of simplified M-VAC therapy was excellent and treatment duration was short. However, relapses were commonly observed as well as the original M-VAC treatment.     

M-VAC versus CisCA--chemotherapy in the treatment of advanced bladder cancer.

The results of this study do not demonstrate a superiority of M-VAC chemotherapy over a modified CisCA regimen chemotherapy. M-VAC, however, proved less toxic than CisCA in terms of side effects. Neither CisCA nor M-VAC was effective as a curative treatment for patients with distant metastases. A durable complete remission of 22.5 months was seen in only 2 of the 12 patients with locally advanced tumors without distant metastases treated with M-VAC, and one of 35 months was observed in only 1 of the 6 cases with locally advanced tumors treated with CisCA chemotherapy.     

Clinical evaluation of M-VAC chemotherapy (methotrexate, vinblastine, adriamycin and cisplatin) for advanced urothelial cancer

Combination chemotherapy with methotrexate, vinblastine, adriamycin and cisplatin (M-VAC regimen) was administered to 12 patients with advanced epithelial cancer of the urinary tract in a clinical trial undertaken to assess clinical efficacy of this multiagent therapy. This series comprised 11 males and 1 female ranging in age from 46 to 76 years (mean age: 63), with performance status (PS) being rated 0 in 2, 1 in 5, 2 in 2, 3 in 2 and 4 in 1 of these 12 patients. The site of primary lesion was bladder in 8, renal pelvis in 3 and ureter in 1. Histologically, these tumors were all identified as transitional cell carcinoma (grade 3) with the exception of 1 mixed type (transitional cell carcinoma plus squamous carcinoma). Nine of the patients had already their primary tumor resected surgically while the remaining 3 had undergone only biopsy. The site of metastasis was lung in 7, bone in 4 and lymph nodes in 3. In consideration of the patients' general condition, the dosages of the chemotherapeutic agents were set at 80% of those recommended by Sternberg. Of the 9 patients with primary tumor resected, 1 died of chemotherapy; of the remaining 9 patients, the M-VAC regimen brought about CR in 1 and PR in 4, hence with a response rate of 62.5%. The 4 patients showing PR underwent surgical resection of residual tumor and 2 of them achieved CR and have been free of a recurrence during a 33- or 29-month period of the chemotherapeutic regimen.(ABSTRACT TRUNCATED AT 250 WORDS)     

Experience with combination chemotherapy consisting of methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) in advanced urothelial cancer

The M-VAC (methotrexate, vinblastine, adriamycin and cisplatin) regimen was used to treat 6 patients with metastatic transitional cell carcinoma of the urothelial tract. Three patients showed a partial response, all of them were made surgically disease free. Two of them are still alive 1 year and for 6 months after surgery with no evidence of disease and one other died of disease 11 months after surgery. The response in one case was no change and that in two others was a progressive disease. From our experience, we suggest that treatment with M-VAC is effective but that surgery after M-VAC appears essential for the successful management of the patients with metastatic transitional cell carcinoma of the urothelial tract.     

Novel agents for muscle-invasive and advanced urothelial cancer

Conventional front-line platinum-based combination chemotherapy yields high response rates but suboptimal long-term outcomes for advanced urothelial cancer. Salvage therapy is an unmet need, with disappointing outcomes. The profusion of novel biological agents offers the promise of improved outcomes. Neoadjuvant therapy before cystectomy for muscle-invasive bladder cancer provides an important paradigm and an interesting approach in developing novel agents. Patients who are not candidates for cisplatin require special attention. A multidisciplinary approach and collaboration among laboratory scientists, oncologists, urologists and radiation oncologists is necessary to make therapeutic advances. Recent and ongoing trials of novel chemotherapeutic and biologic agents are reviewed.     

Preliminary results of concurrent methotrexate,cisplatin and radiation treatment for locally advanced urothelial cancers

Ten patients with invasive bladder cancer and one with locally advanced renal pelvic cancer were treated with concurrent methotrexate, cisplatin and radiotherapy. Methotrexate 30 mg/m² was administered intravenously on the day of the initiation of radiotherapy and cisplatin 70 mg/m² on the second day. The number of chemotherapy cycles delivered was 1 in 7 patients and 2 in 4. The median dose of radiation was 50 Gy. Of 11 patients, 7 (64%) achieved a partial response and 4 had no change in disease. The median duration of response was 16 months for patients with a partial response. Six patients with a partial response (55%) are alive for a median of 22.5 months and 2 of 4 with no change are alive for 4 and 15 months, respectively. Leukopenia less than 3000 cell/mm³ was observed in 4 (36%) and thrombocytopenia less than 100,000 cells/mm³ in 3 (27%). Local control could be achieved safely with concurrent methotrexate, cisplatin and radiation therapy in patients with locally advanced urothelial cancer who were unsuitable for surgery.     

Recent developments in advanced urothelial cancer

PURPOSE OF REVIEW: Metastatic or unresectable urothelial cancer of the urinary bladder has traditionally been treated with systemic chemotherapy, which is most often platinum-based. The long-term survival data and the associated toxicities from this form of therapy have spurred continuing interest in finding novel treatment options for this malignancy. RECENT FINDINGS: Recently, trials of new chemotherapy combinations, many incorporating platinum analogs or deleting platinum entirely, have been reported. None has yet been shown to be superior to cisplatin-based regimens. In addition, recent advances in imaging and laboratory technologies have provided new avenues to understand urothelial cancer behavior and prognosis. These advances provide optimism for improvements in the diagnosis, staging, and ultimately, selection of therapy for patients with urothelial cancer. SUMMARY: This review will summarize recent developments (circa 2004) in the diagnosis and management of advanced bladder cancer.     

Chemotherapy in the treatment of advanced urothelial tumors

Progress has been made in the management of patients with advanced metastatic and muscle-invasive urothelial tract tumors. Combination chemotherapy has proved effective, and, in those who attain complete remission it prolongs survival. Chemotherapy alone or combined with radiotherapy and TURB may now make less aggressive surgery and bladder conservation possible in selected patients. Improvements in perioperative care, coupled with surgical, radiotherapeutic and diagnostic achievements, have led to substantial progress. Recombinant DNA technology has led to the availability of sufficient quantities of hematopoietic factors, which are now available for clinical trials. Today, CSFs can complement therapy and ameliorate the myelosuppression and mucositis associated with chemotherapy, permitting safer administration of therapy and increased dose intensity of treatment programs. Investigations of the biology of bladder cancer aimed at defining the malignant and metastatic potential of an individual tumor are very promising. Immunohistochemistry of cell surface antigens, such as blood group antigens, monoclonal antibody technology, and assessment of the chromosomal complement or DNA content will have increasing importance for this aim in the future. Future trials will need to consider the biology of bladder cancer and more sophisticated prognostic variables than performance status. Mixed-histology tumors are probably less responsive. Why certain tumors metastasize and others remain restricted to the bladder or nodes is still a matter of conjecture. Hopefully, future studies will throw some light on these still-unexplained areas.     

Clinical efficacy of modified M-VAC chemotherapy for advanced urothelial carcinoma and influence of squamous cell carcinoma-associated antigen on efficacy of the chemotherapy

The efficacy of modified M-VAC chemotherapy was evaluated in twenty-two patients with advanced urothelial carcinoma (18 cases of transitional cell carcinoma, 3 of transitional cell associated with squamous cell carcinoma and 1 of squamous cell carcinoma). Among the 22 patients, 14 underwent two or more courses of modified M-VAC chemotherapy and had lesions suitable for the evaluation. Three of the 14 patients achieved complete response and 6 partial response, resulting in a 64.3% response rate. With regard to the direct effect according to the site of the lesion, the response rate was 75% for the urinary bladder, 100% for lung, 100% for subcutaneous tissues, and 75% for lymph nodes metastasis, whereas the chemotherapy was ineffective for metastasis in the bone and muscle. With this neoadjuvant chemotherapy the primary tumor of the urinary bladder was downstaged from T2 to T0 in one patient who showed complete response. In 4 of 5 patients achieving partial response, the primary tumors were downstaged from T2 to T1. Of 9 patients given this chemotherapy for metastatic lesions, 2 achieved complete response and are alive, whereas all 3 without response died of cancer within the 1 year following the chemotherapy. Since most of the cases associated with the squamous cells carcinoma component showed no response to the therapy, it seems that the level of serum squamous cell carcinoma-associated antigen may be helpful for predicting the efficacy of modified M-VAC chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Second-line chemotherapy with gemcitabine and cisplatin for urothelial cancer previously treated with or resistant to M-VAC therapy

We evaluated the efficacy of gemcitabine-cisplatin (GC) therapy as a second line chemotherapy for recurrent urothelial cancer previously treated with or resistant to methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) therapy. Four patients who had recurrent cancer after adjuvant M-VAC therapy and five patients with resistant lesions to M-VAC were treated by GC. Of the nine patients, three completely responded to GC and three obtained partial response. These complete responders were cancer-free for 34, 32 and 24 months. In one partial responder, the metastatic masses have been decreasing in size for 12 months after completion of GC therapy. Our findings suggested that GC would be useful as a second line chemotherapy for urothelial cancer previously treated with M-VAC.     

Methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) in advanced urothelial cancer--analysis of efficacy and toxicity]

Seventy-seven patients with advanced urothelial cancer were treated with methotrexate, vinblastine, adriamycin, and cisplatin (M-VAC). Of these 77 patients, 65 could be evaluated for response and 74 for toxicity. Response rates were 65% in the primary organs (62% in the renal pelvis and ureter, 67% in the bladder), 68% in the lymph nodes, 60% in the lung, 25% in the bone and 14% in the liver. Complete responses were noted in 11 patients (17%) and partial responses in 26 patients for an overall response rate of 57% (95% confidence limits 45 to 69%). The median durations of response were 11 months for complete response patients and 7 months for partial response patients. Of the 65 patients 20 (31%) are alive, and 1-, 2-, and 3-year survival rates were 65%, 37%, and 25%, respectively. While survival rates of responders were higher than those of nonresponders with a statistical significance until 15 months, no significant differences were observed in survival rates between these two groups in the subsequent period. The M-VAC regimen was used for 15 patients as a neoadjuvant chemotherapy. Of the 15 patients, 8 responded and primary organs were preserved in 6 of the 8 responders. Histological effects classified according to Oboshi-Shimosato's criteria were G.I in 9, G.IIA in 3, G.IIB in 1, and G.IVC in 2. There were no significant differences in survival rates according to responses and histological effects. Factors related to response were analyzed with a multiple logistic regression model on 54 patients treated with intravenous administration of drugs and whose histological type was transitional cell carcinoma. The analysis results indicate that the presence of distant metastases is an important factor in predicting poor efficacy. Sixteen of 74 patients (22%) had white blood cell count of less than 1,000 cells per mm3 in the first cycle, while the decrease of platelet count was mild in degree compared with that of the white blood cell count. Patients with elevations of serum creatinine, GOT, and GPT were low in frequency, and toxic symptoms were controllable. Factors significantly related to the occurrence of side effects were sex, performance status, prior radiotherapy, prior chemotherapy, and the method of drug administration. Among these factors, prior radiotherapy was related to severe decrease of white blood cell count. While an excellent overall response rate was provided with the M-VAC regimen, disadvantages of the present regimen were low effectiveness in the bone and liver, and short duration of response.(ABSTRACT TRUNCATED AT 400 WORDS)     

Ketoconazole therapy for advanced prostatic cancer: feasibility and treatment results

To investigate the feasibility and antitumoral effect of ketoconazole in the treatment of disseminated prostatic cancer, 22 patients with stage D2 disease were treated with 400 mg. ketoconazole orally every 8 hours. Of the 17 patients evaluable for antitumoral effect an initial tumor response of 88 per cent was observed (1 complete and 8 partial responses, and 6 with stable disease) with a mean duration of 15.8 months (range 5 to more than 30 months). Treatment-related side effects were encountered in 21 patients and consisted of asthenia, gastrointestinal complaints, skin reactions and cardiovascular complications. They were judged to be mild in 8 patients, moderate in 5 and severe in 8. Treatment had to be discontinued because of side effects in 7 patients (32 per cent). During treatment with ketoconazole serum testosterone levels decreased rapidly and attained nearly castrate levels at the end of week 3. However, after 1 month a steady increase was noted and the testosterone levels reached low normal ranges after 5 months. No hormonal or biochemical indications of adrenocortical insufficiency were noted. High dose ketoconazole is effective in the treatment of disseminated prostatic cancer. Its use is limited by the side effects and the inability to maintain castrate levels of testosterone.     

Results of combination chemotherapy in advanced urothelial cancer

Between April 1982 and March 1988, 28 patients with advanced urothelial cancer were treated with combination chemotherapy incorporating cisplatin at our hospital and the response was evaluated. Fourteen of them were managed by the CAP chemotherapy (cyclophosphamide 300-500 mg/m2 day 1, doxorubicin 30-50 mg/m2 day 1, cisplatin 40-90 mg/m2 day 2), 7 by the FAP chemotherapy (fluorouracil 300 mg/m2 day 1-5, doxorubicin 30 mg/m2 day 1, cisplatin 15 mg/m2 day 1-5) and 7 by the MEP chemotherapy (etoposide 100 mg/m2 day 1-3, cisplatin 20 mg/m2 day 1-5, methotrexate 300 mg/body day 6). Four patients (28.6%) responded to the CAP regimen; a complete response was gained in one patient who had pulmonary metastasis of excised ureteral cancer and a partial response in 3 patients with intravesical and nodal (N3, N4) cancer. A partial response was noted in 3 patients (42.9%) in the FAP group. They had intravesical lesions and two of them had regional node metastasis (N3). A higher response rate (85.7%) was obtained by the MEP regimen; a complete response in 2, who had intravesical and nodal (N2, N4) cancer, and a partial response in 4 patients, 1 had intravesical cancer, 1 had nodal (N2) and intravesical cancer and 2 had nodal or lung metastasis of excised renal pelvic cancer. Toxicity included mild to severe vomiting, alopecia, myelosuppression and mild renal or liver dysfunction. High dose metoclopramide provided a high degree of protection against cisplatin induced emesis. The results with the MEP regimen are promising for the advanced, metastatic urothelial cancer.     

Two cases of urothelial cancer responsive to high-dose-intensity methotrexate vinblastine doxorubicin and cisplatin (M-VAC) therapy

We report two cases of metastatic urothelial cancer treated with high-dose-intensity (HD) methotrexate vinblastine, doxorubicin and cisplatin (MVAC). After HD-MVAC, the size of primary and lymph node tumors decreased by 57-67% as compared with the standard M-VAC therapy. By shortening the dose interval, HD-MVAC may increase the anti-tumor effect without increasing side effects.     

Usefulness and limitations of methotrexate, vinblastine, doxorubicin and cisplatin for the treatment of advanced urothelial cancer

Methotrexate, vinblastine, doxorubicin and cisplatin were used to treat 66 patients with advanced urothelial cancer. Of these 66 patients 58 could be evaluated for response. A total of 84 sites was evaluated in these patients. Response rates were 73% in the bladder, 67% in the renal pelvis, 50% in the ureter, 60% in the lung, 68% in the lymph nodes, 14% in the liver and 25% in the bone. Ten patients (17%) had a complete response and 23 (40%) had a partial response, with an over-all response rate of 57% (the 95% confidence limits are 44 to 69%). The mean durations of response were 10.1 months for complete response patients and 6.2 months for partial response patients. The most prominent toxicity was severe myelosuppression that resulted in 2 septic deaths. While this chemotherapy regimen provided an excellent over-all response rate, the matters of concern were the short duration of response and low effectiveness in the liver and bone.     

An effective case of M-VAC therapy of advanced bladder cancer with extramammary Paget's disease

A 66-year-old man complained of gross hematuria, lower abdominal mass and perineal skin erosion. Intravenous pyelography showed a filling defect in the right bladder wall. CT scan demonstrated multiple liver metastasis and lower abdominal mass. Skin biopsy of perineal lesion revealed extramammary Paget's disease. The histopathological study of bladder tumor and lower abdominal mass revealed both to be transitional cell carcinoma grade 3. After four courses of M-VAC therapy described by Sternberg in 1985, bladder tumor and metastatic lower abdominal mass disappeared with CT scan and this effect continued over 6 months. Skin biopsy after chemotherapy revealed a marked reduction in Paget's cell number.