Clinical and pathological evaluations of methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) chemotherapy for advanced urothelial cancers

Fifteen patients with advanced transitional cell carcinoma of the urothelial tract were treated with methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) chemotherapy. Eleven patients were treated to metastatic lesions after surgical resection of primary cancers. One out of 15 patients died of chemotherapy. Of the remaining 14 patients, CR was achieved in one and PR was achieved in seven, clinically. The response rate was 57.1% and the median response duration was 12.6 months. In the patients who had been resected their primary lesions, the response rate was 70% and the duration was 14.1 months. Six patients, including five PRs and one NC, underwent surgical resection and re-staging of the residual tumors after chemotherapy. Clinical response coincided with pathological one in all 6 cases. Three patients were observed the decrease of the lung metastasis, which rate was more than 90%. Two out of 3 who did not show any invasion into the lymph channels in the resected residual tumors, have been free of a recurrence through-out the course of at 47 or at 42 months. However, another patient with lymph channel invasion died of metastasis of the mediastinal and paraaortic lymph nodes. Regarding the frequency of side effects, it seemed to be no significant difference between full and 80% doses administration. In the effectual cases, the residual tumors should be resected surgically and re-staged pathologically.     

Factors affecting the outcome of patients with advanced urothelial cancer following chemotherapy with methotrexate, vinblastine, Adriamycin, and cisplatin

Attempts were made to identify factors related to the response of patients treated with intravenous methotrexate, vinblastine, Adriamycin, and cisplatin (M-VAC). The subjects consisted of 54 patients with advanced urothelial cancer whose histological type was transitional-cell carcinoma. The effects of various factors on the response were studied using univariate analysis and a multiple logistic regression model. The following factors were included in the anlayses: (1) age, (2) sex, (3) performance status (PS), (4) primary site, (5) histological grade, (6) T category, (7) N category, (8) M category, (9) tumor status, and (10) dose of drugs. In all, 9 patients achieved a complete response and 23 showed a partial response, for an overall response rate of 59% (95% confidence limits, 46%–72%). Univariate analysis revealed that the PS, M category, and dose of drugs were related to the response, and there was a significant correlation among these three factors. In the multiple logistic regression model, the absolute value oft was high for the M category. The presence of distant metastases is an important factor in predicting poor efficacy for the present regimen. The management of metastatic disease will be the subject of further study in the treatment of advanced urothelial cancer.Presented at the 4th International Conference on Treatment of Urinary Tract Tumors with Adriamycin/Farmorubicin, 16–17 November 1990, Osaka, Japan     

Evaluation of systemic chemotherapy with methotrexate, vinblastine, Adriamycin, and cisplatin for advanced bladder cancer

In a cooperative study of the Japanese Urological Cancer Research Group for Adriamycin, the usefulness of chemotherapy with methotrexate, vinblastine, Adriamycin, and cisplatin (M-VAC therapy) in treating advanced or recurrent bladder cancer was examined. Evaluation of the clinical responses obtained in 86 evaluable patients revealed 13 complete responses, 29 partial responses, 4 minor responses, 19 cases of no change, and 21 cases of progressive disease. The overall response rate was 48.8% (42/86). The rate of response to M-VAC therapy at each disease site was as low as 21.4% (3/14) in bone lesions but exceeded 40% in the primary lesion, the lymph nodes, the lung, the liver, and other lesions. The clinical response to M-VAC therapy was not significantly influenced by the performance status of the patients, the dose intensity, or previous therapy. The median duration of response for the 42 responders was 22.7 weeks (range, 8.1–134.1 weeks), and the median duration of survival for the 86 evaluable patients was 9.8 months. Side effects were frequently encountered; the patients experienced anorexia, nausea, vomiting, malaise, alopecia, and leukopenia, but all of these symptoms were tolerable.Presented at the 4th International Conference on Treatment of Urinary Tract Tumors with Adriamycin/Farmorubicin, 16–17 November 1990, Osaka, Japan     

Prognostic factors for survival of patients with advanced urothelial tumors treated with methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy

Between February 1983 and February 1986, 132 patients with advanced urothelial tract tumors were treated with methotrexate, vinblastine, Adriamycin (doxorubicin), and cisplatin (M-VAC) chemotherapy. Analysis of prognostic factors for survival of the first 92 patients was undertaken using the Cox proportional hazards model. Normal alkaline phosphatase and high Karnofsky performance status (KPS) were predominant for long survival. Patients 60 years or older at initiation of therapy were likely to survive longer than younger patients, perhaps indicating physician selectivity of older patients for this therapy, and those with initial hemoglobin in the normal range were also likely to survive longer. The additional 40 patients' data were used to validate the model. Clinical implications of the prognostic factors are discussed.     

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). Japanese Urothelial Cancer Research Group

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.      

Adriamycin,vinblastine and mitomycin C as second-line chemotherapy in advanced breast cancer

Summary Thirty-six evaluable patients with metastatic measurable breast carcinoma previously treated with CMF or CMFVP were given second-line chemotherapy with Adriamycin, vinblastine, and mitomycin C (AVM), as follows: Adriamycin 20 mg/m² and vinblastine 6 mg/m² by i. v. push on days 1, 8, and 15, and mitomycin C 10 mg/m² i. v. on day 1, every 6 weeks. Ten patients (28%) achieved partial remission (PR) lasting a median of 10 months, and eight patients (22%) experienced improvement of a lesser level than PR. An additional nine patients (25%) had disease stabilization; in the remaining nine patients (25%), persistent disease progression was observed. The median survival from the onset of AVM was 7 months for all patients; patients with PR survived a median of 13 months.Myelotoxicity was substantial and frequently interfered with the optimal administration of AVM, especially in patients with skeletal metastases; four patients were hospitalized with leukopenia and fever; all recovered promptly; one death was probably related to thrombocytopenia and CNS bleeding.Our results with AVM are similar to the average response rate published in the literature with the use of Adriamycin as a single agent in previously treated patients with advanced breast cancer.     

Evaluation of drug delivery and survival impact of dose-intense relative to conventional-dose methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy in urothelial cancer

The efficacy of dose-intense methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy relative to conventional-dose M-VAC in patients with advanced transitional cell carcinoma is unknown. The outcomes of 33 patients on two successive protocols using dose-intense M-VAC with granulocyte colony-stimulating factor (G-CSF) support were compared with those of 129 patients treated with conventional-dose M-VAC to assess for an impact of dose-intense therapy on long-term survival. The mean relative dose intensity of chemotherapy delivered to the dose-intense cohort was 55% higher than that delivered to the conventional-dose cohort (p = 0.0001). However, no significant differences were observed with regard to response proportion (72% vs. 76%), median survival (13.3 vs. 16.7 months, p =0.31), or 5-year survival (16% vs. 15%). Growth factor support enabled a statistically significant increase in the delivered close intensity of M-VAC chemotherapy, but no survival advantage relative to conventional-dose M-VAC was observed.     

Combination chemotherapy with vinblastine, BCNU and cisplatin in advanced malignant melanoma

A combination chemotherapy including vinblastine (6 mg/m2 i.v. days 1-2), BCNU (100 mg/m2 i.v. day 3), and cisplatin (50 mg/m2 i.v. day 5) was given as salvage treatment in 46 consecutive, previously treated patients affected by metastatic malignant melanoma. Courses were planned every 4 weeks provided that a complete bone marrow recovery occurred, otherwise they were delayed for 1-2 additional weeks. Objective responses (3 CRs and 10 PRs) were observed in 13/46 (28%) patients; 12 cases had stable disease and 21 patients progressive disease during treatment. Median duration of response was 13 months (range, 5-18), and median survival was 11 months (range, 3-20) for all patients. Nausea and vomiting were the most distressing side effects, whereas a grade I leukopenia caused a delayed treatment in 90% of patients. In conclusion, the combination chemotherapy was moderately toxic and did not seem to give substantially better results than obtained with other reported regimens.     

Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis

BACKGROUND: This Phase II study was undertaken to assess the activity of methotrexate plus vinblastine in the treatment of patients with inoperable aggressive fibromatosis (AF) and to observe the evolution of the disease after such low-dose chemotherapy. METHODS: Thirty patients with a median age of 27 years who were affected by primary (20%) or recurrent (80%), advanced, inoperable AF were treated with weekly methotrexate at a dose of 30 mg/m(2) plus vinblastine at a dose of 6 mg/m(2) for a median interval of 1 year. Patients with recurrent disease had received surgery, radiotherapy, tamoxifen, and antracycline-based chemotherapy. Tumor response was assessed in all patients as well as time to disease progression. RESULTS: Eighteen patients (60%) showed stable disease or minor tumor shrinkage along with symptom relief. A partial response was detected in 12 patients (40%). No complete responses were observed, and no patients had tumor progression during treatment. Four patients received fewer than 15 cycles of chemotherapy, mainly because of severe myelotoxicity. One of these patients died of local disease progression 33 months later, and the other three patients were stable. After a median follow-up of 75 months, the 10-year actuarial progression free interval is 67%. CONCLUSIONS: Methotrexate plus vinblastine given every 7-10 days for several months is associated with prolonged stable disease in a substantial subset of patients with advanced (inoperable) aggressive fibromatosis.     

Neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin for locally advanced transitional cell carcinoma of the bladder

Nine patients with locally advanced transitional cell carcinoma (TCC) of the bladder were treated with neoadjuvant methotrexate, vinblastine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (M-VAC) followed by radical cystoprostatectomy and modified pelvic lymphadenectomy. Five patients, including three with pelvic sidewall fixation, had clinical stage T4N0M0 tumors whereas the remaining patients had T3N0M0 tumors. All patients were pathologically restaged by a referee pathologist after surgery. The complete response rate was 22% and an additional 44% experienced a partial response. Neutropenia preventing a second cycle of M-VAC occurred in one patient. Downstaging of locally advanced TCC of the bladder was achieved in the majority of patients treated with neoadjuvant M-VAC.     

Combination chemotherapy of cyclophosphamide, adriamycin and cisplatin in advanced urothelial cancer

Sixteen patients with advanced evaluable urothelial cancer were treated with a chemotherapy regimen of cyclophosphamide, adriamycin and cisplatin (CAP). Cisplatin 50 mg/m2 and adriamycin 30 mg/m2 were given on the first day and cyclophosphamide 200 mg/m2 was given from the second to the fifth day. This course was repeated every 3 weeks. The objective response rate was 25% (4 of 16 patients), with 1 patient achieving complete remission. The survival time of responders was longer than that of nonresponders, although the difference was not significant (generalized Wilcoxon method). As side effects, nausea with vomiting (43.8%), renal dysfunction (6.3%), anemia (12.5%), leucopenia (12.5%), thrombocytopenia (25.0%), alopecia (68.8%), heart failure (6.3%) and peripheral neuropathy (6.3%) were noticed. One patient died of sepsis due to agranulocytosis and another died suddenly of heart failure.     

Adjuvant chemotherapy with vinblastine,Adriamycin, and UFT for renal-cell carcinoma

Summary VAU therapy (vinblastine, Adriamycin, and UFT) was given postoperatively to 31 patients with stage I, II, or III renal-cell carcinoma, and the incidence of relapse as well as the survival of patients were studied. Administration was started at 7–14 days post-surgery; 5 mg/m² vinblastine and 30 mg/m² Adriamycin were given i.v. once every 4 weeks for a total of five courses, and three capsules of UFT (containing 300 mg tegafur) were given p.o. every day for 2–3 years. The postoperative observation period ranged from 2 years and 6 months to 7 years and 1 month (mean, 4 years and 2 months). The 1-year survival of patients was 100%, and the 3- and 5-year survival values were 96%. These results were significantly better (P<0.01) than the respective values (81%, 72%, and 60%) obtained for the historical controls, i.e., the 60 patients with stage I, II, or III renal-cell carcinoma who received no chemotherapy. Side effects such as alopecia, gastrointestinal symptoms, and myelosuppression were encountered, but all symptoms were so mild and transient that discontinuation of the treatment was not necessary. As VAU therapy might be useful as adjuvant chemotherapy for renal-cell carcinoma, it seems to merit further study.     

Neoadjuvant gemcitabine and cisplatin chemotherapy for locally advanced urothelial cancer of the bladder

BACKGROUND:

The purpose of this study was to investigate the effect of neoadjuvant chemotherapy with gemcitabine and cisplatin (GC) on pathologic down‐staging of patients with locally advanced urothelial cancer (UC) of the bladder.

METHODS:

This was a retrospective cohort study of patients treated with radical cystectomy (RC) for clinical stage cT2‐T4, N any, M0 bladder UC at Strong Memorial Hospital from 1999 to 2009. The primary exposure variable was use of neoadjuvant chemotherapy (GC vs none). The primary outcome was stage pT0 at RC. Secondary outcomes included other down‐staging end points in the bladder ( RESULTS: A total of 160 eligible patients were identified, of whom 25 were treated with neoadjuvant GC before RC (GC + RC) and 135 without neoadjuvant chemotherapy (RC only). Stage pT0 at cystectomy was found in 20% of patients in the GC + RC group and in 5% of patients in the RC group (adjusted risk difference [aRD] = 16%, P = .03). For other down‐staging end points, the estimated treatment effect was as follows (all point estimates favoring chemotherapy): P = .005); P = .004); P = .008); margins aRD = 8% (P = .41); nodes aRD = 4% (P = .74).

CONCLUSIONS:

Neoadjuvant GC was found to be capable of down‐staging UC in the bladder; however, no effect on disease in nodes was seen in this study. Cancer 2012;. © 2011 American Cancer Society.     

Ifosfamide,cisplatin, vinblastine combination chemotherapy in the treatment of advanced non-small-cell lung cancer

Summary A total of 42 evaluable patients with previously untreated advanced non-small-cell lung cancer were treated with a combination of cisplatin (80 mg/m², day 1), vinblastine (5 mg/m², days 1 and 15), and ifosfamide (1.2 g/m², days 1–3). In all, 1 complete response and 15 partial responses were obtained, for an overall response rate of 38% (95% confidence limits, 23.6%–54.4%). The median duration of response was 15 weeks, and the median overall survival was 56 weeks. Toxicity mainly consisted of moderate to severe alopecia in 28 patients (67%), moderate to severe nausea and vomiting in 27 subjects (64%), and leukopenia comprising <1,000 leukocytes/mm³ in 6 cases (14%). In all, 16 patients (38%) had microscopic hematuria (WHO grade 1), but no hemorrhagic cystitis was documented. Although this three-drug combination appears to have moderate antitumor activity against nonsmall-cell lung cancer, the addition of ifosfamide to the combination of cisplatin and vinblastine did not seem to improve the response rate.     

Effective chemotherapy for advanced carcinoma of the cervix with bleomycin, cisplatin, vincristine, and methotrexate

This study was designed as a Phase II clinical trial in advanced recurrent or metastatic squamous cell carcinoma of the cervix with a combination of bleomycin (B: 10 u/m2/d) and cisplatin (P: 20 mg/m2/d) administered for five consecutive days in intravenous infusion for 7 hours and vincristine (V: 1 mg/m2) and methotrexate (M: 40 mg/m2) administered only on day one of each cycle which was repeated every 28 days up to a maximum of 6 times. Over a period of 2 years, 15 evaluable patients with measurable disease received at least 3 courses of therapy. Six had recurrent disease and nine had distant metastases. All had previous radiation therapy. There were two dropouts after the first course due to nausea and vomiting which was practically universal. Other side effects included: mild paresthesias of the extremities (89%), stomatitis (41%), diarrhea (17%), moderate pancytopenia and hypomagnesemia which was reduced from 65% to 17% when magnesium sulfate 10% was administered with cisplatin. Sixty-six percent of the evaluable patients achieved remission (7 partial and 3 complete) usually before the fourth course of therapy. The disease-free interval was of 29.7 +/- 15 weeks in all responders (40.6 +/- 15.5 weeks in complete responders). The mean survival from the start of BPVM therapy was of 55.8 +/- 33.3 weeks in responders and of only 14 +/- 2.9 weeks in nonresponders (P less than 0.01). It is concluded that BPVM is an effective combination chemotherapy in advanced squamous cell carcinoma of the cervix. These results should be confirmed in a Phase III trial.     

A randomized trial of cisplatin versus cisplatin plus methotrexate in advanced cancer of the urothelial tract

One hundred eight patients with recurrent or metastatic transitional cell carcinoma of the urothelial tract were randomized to receive cisplatin (C) 80 mg/m2 on day 1 every 4 weeks, or methotrexate (M) 50 mg/m2 on days 1 and 15 plus C 80 mg/m2 on day 2 every 4 weeks (C + M). Fifty-three eligible patients were randomized to C + M and 55 to C. In the C + M arm, 45% of patients responded (complete response [CR], 9%) and 31% (CR, 9%) in the C arm (P = .18). In the C arm, 20 patients failing or relapsing after C received M. Two patients responded, and four with progressive disease (PD) and one with a previous partial response (PR) showed no change. The median survival was 8.7 months (C + M arm) and 7.2 months (C arm), P = .7. Relapse-free survival was not significantly different, but C + M was associated with a significantly increased time to disease progression (median, 5.0 months, v 2.8 months for C arm). The response of untreated patients (37%) was not different from those with prior treatment (39%). On the C + M arm, 92% of patients and 96% of patients on the C arm received 85% or more of the scheduled C dose. Significantly more grade 3 or 4 hematological toxicity (27% v 2%; P = .01) and mucositis (20% v 0%; P = .0005) occurred in patients on the C + M arm. Although the initial response rates seen on the combination arm look superior, and the time to disease progression is increased, these effects have not translated into a clinically important increase in the duration of survival and were associated with increased toxicity.     

Docetaxel and cisplatin as primary chemotherapy for treatment of locally advanced breast cancers

A phase II trial was designed to evaluate the effectiveness of docetaxel/cisplatin as primary or neoadjuvant chemotherapy of locally advanced breast carcinoma (LABC). Patients with newly diagnosed breast cancers > or = 5 cm in size by palpation were treated with docetaxel/cisplatin, both at 70 mg/m2 intravenously every 21 days for 4 courses. Upon completion of chemotherapy, all patients underwent modified radical mastectomy with axillary nodal dissection. Pathologic complete response (pCR) was defined as absence of any invasive carcinoma in the breast. Standard AC (doxorubicin/cyclophosphamide) at 60 mg/m2 and 600 mg/m2, respectively, for 4 cycles was given as adjuvant therapy to maximally eradicate occult distant disease. Between March 1998 and October 2001, 57 women were entered onto this trial, 28 (49%) with inoperable T4 and inflammatory cancers. Pretreatment median tumor size was 9 cm. Thirty-six patients (63%) had estrogen receptor-positive tumors and 10 patients (18%) had tumors with HER2 overexpression. All tumors became operable after neoadjuvant chemotherapy. Pathologic complete response in the breast was achieved in 15 patients (26%) and pCR in the breast and the axilla was achieved in 11 patients (20%). All neoadjuvant chemotherapy courses were administered at full doses without treatment delays caused by toxicity. The most common side effects were hyperglycemia, anemia, and mild neuropathy. The results of this study suggest that the docetaxel/cisplatin combination can be an effective and well-tolerated induction treatment of LABC, even in very large mostly HER2-nonoverexpressing tumors.     

Combination chemotherapy with mitomycin C, methotrexate, cisplatin, and vinblastine in the treatment of non-small cell lung cancer

The combination of mitomycin C, methotrexate, cisplatin, and vinblastine was administered to 45 patients with unresectable non-small cell lung cancer. Thirty-nine patients satisfied criteria for assessment of response to chemotherapy. All patients had a performance status of greater than 50%, had evaluable disease, and had not received previous chemotherapy. The overall response rate was 54% with responses seen in 12 of 19 squamous cell, 8 of 16 adenocarcinoma, and 1 of 4 undifferentiated large cell lung cancer patients. Median survival was increased by 3 months in those patients with an objective response to chemotherapy. Drug-associated toxicity was rare, but apparent mitomycin C-related pulmonary fibrosis was observed in two patients. This four-drug combination was shown to be an active regimen in the treatment of non-small cell bronchogenic carcinoma.