Long-term follow-up in patients treated with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) for transitional cell carcinoma of urinary bladder: Cause for concern

Connor, John P.; Olsson, Carl A.; Benson, Mitchell C.; Sawczuk, Ihor S.; Rapoport, Frederick

doi:10.1016/0090-4295(89)90440-8

Cited by 45 publications

(24 citation statements)

References 12 publications

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“…Another study reported the use of MVAC in 21 patients with high-stage TCC. This study, with long-term followup, suggested that the durability of response was disappointing (Connor et al, 1989). Long-term follow-up evaluation of the intergroup trial confirmed that MVAC was superior to single-agent cisplatin in patients with advanced urothelial carcinoma.…”

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confidence: 81%

“…Indeed, a significant proportion of otherwise fit patients (around 50% in our institution) have a calculated glomerular filtration rate o60 mls min À1 , the usual cutoff for combination studies with cisplatin. Treatment with MVAC can result in clinically significant myelosuppression (up to 25% incidence of neutropenic fever and a 3% drug-related mortality) and significant mucositis (up to 50% incidence of grade 2 -3 mucositis) (Sternberg et al, 1985(Sternberg et al, , 1989Connor et al, 1989;Tannock et al, 1989;Igawa et al, 1990;Logothetis et al, 1990;Boutan-Laroze et al, 1991;Loehrer et al, 1992). Recent efforts to improve the outcome for patients with metastatic transitional cell carcinoma have focused on the identification of new drugs with single-agent activity and on their incorporation into platinum-based combination regimens.…”

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confidence: 99%

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A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer

et al. 2004

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A randomised phase III trial of MVAC (methotrexate, vincristine, doxorubicin, cisplatin) vs gemcitabine and cisplatin (GC) (G 1000 mg m À2 days 1, 8, and 15 plus C 70 mg m À2 day 2, q 4 wks) indicated GC had similar efficacy and lower toxicity (JCO 2000). Significant haematologic toxicities in the GC arm occurred on day 15, necessitating dose adjustments in 37% of cycles. We conducted a phase I/II dose escalation trial using GC on a 21-day cycle, with G and C split between days 1 and 8. The objective of the study to define maximum-tolerated dose and dose-limiting toxicity (DLT), objective response rate, and overall survival. In all, 32 patients with locally advanced, relapsed, or metastatic disease received: dose level 1, G/C 1000/35; level 2, 1100/35; level 3, 1200/35; level 4, 1200/ 45 mg m À2 (G and C given on days 1 and 8 every 3 wks). A total of 19 patients had glomerular filtration rate o60 ml min À1 and 19 patients had metastatic disease. Dose-limiting toxicity was haematologic (grade 4 thrombocytopenia) at dose level 2. Of 151 cycles, at day 15, platelets were o100 in 61 cycles; neutrophils o0.5, platelets o50 in 26 cycles. Only seven cycles were deferred due to haematological toxicity; four for renal toxicity (chemotherapy instituted posthydration). Overall response rate was 65.5% on an intention-to-treat analysis (75% [21/28] for assessable patients), with four complete responses (12.5%) and 17 partial responses (53%). After the median follow-up of 17.2 months (range 13.1 -32.4 months), 12 patients remain alive. The overall median survival was 16 months (range 10.1 -26.6 months). G plus C every 3 weeks is active and well tolerated in an outpatient setting, even in patients receiving prior platinum-based regimens and with poor renal reserve.

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confidence: 81%

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confidence: 99%

A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer

et al. 2004

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“…On the other hand, systemic chemotherapy using methotrexate, vinblastine, adriamycin and cisplatinum (M-VAC) has become widespread as a promising regimen for invasive bladder tumours because of its improved effectiveness over previous chemotherapeutic regimens (Sternberg et al, 1985;Geller et al, 1991). Nevertheless, the prognosis is still poorer than might be expected (Conner et al, 1990). Therefore, elucidation of the underlying molecular mechanisms for recurrence and progression from superficial to invasive disease may offer new treatment strategies.…”

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confidence: 99%

Decreasing of p27Kip1and cyclin E protein levels is associated with progression from superficial into invasive bladder cancer

et al. 2001

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Summary The p27Kip1 (p27) protein is a cyclin-dependent kinase inhibitor of the transition from G1 to S phase. It has been reported that decreased p27 protein level is a negative prognostic indicator in human tumours including bladder cancer. We studied the relationship between protein levels of p27, cyclin E and Ki-67 and clinicopathological features of 145 consecutive Japanese patients with transitional cell carcinoma of the bladder using immunohistochemical staining. Low protein levels of p27 were associated with low staining of cyclin E (P = 0.0302), high Ki-67 index (P = 0.0306), poorly differentiated grade (P = 0.0006), muscle invasion (P = 0.0019) and lymph node metastsis (P = 0.0002). Low staining of cyclin E and high Ki-67 index correlated with poorly differentiated grade, muscle invasion and lymph node metastsis. Cyclin E protein levels was inversely related with Ki-67 index (P = 0.0002). Kaplan-Meier plots of survival rate in patients with low versus high p27 staining showed that low protein levels of p27 were associated with a shortened disease-free and overall survival (P < 0.0001 and P < 0.0001, respectively). Similarly, low staining of cyclin E and high Ki-67 index correlated with a shortened disease-free and overall survival. On multivariate analysis using Cox proportional hazards model, low protein levels of p27 and high Ki-67 index were independent predictors of shortened disease-free (P < 0.0001, P = 0.0031, respectively), and low protein levels of p27, low staining of cyclin E and high Ki-67 index of overall survival (P = 0.0017, P = 0.0009, P = 0.0003, respectively). In superficial bladder tumours (Ta, T1; 86 patients), significant correlations were observed between low p27 staining and high Ki-67 index and early recurrence (P = 0.0048, P = 0.0178, respectively). Among the recurrenced superficial tumours (35 patients), the tumours which remained at a low stage showed high protein levels of p27 and cyclin E, and the tumours which progressed to invasive disease showed a gradual decrease in p27 and cyclin E protein levels over time. Our findings suggest that decreased protein levels of p27 and cyclin E play a role in the progression of bladder cancer and to evaluate these protein levels may be useful in management of the diseases.

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“…Regrettably, the separate reporting of survival for responding and non-responding patients (Sternberg et al, 1988) initially created the illusion that the problem of metastatic bladder cancer may have been solved (Olsson, 1987). However, with increased experience (Tannock et al, 1989;Connor et al, 1989;Sternberg et al, 1989) it has become clear that a substantial proportion of tumours that respond to these regimens are ultimately destined to relapse, and that the percentage of patients who are potentially cured (20-30 per cent) would be lower than anticipated.…”

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confidence: 99%

“…There has thus been a risk that these regimens would be abandoned and the search for a new panacea resumed (Connor et al, 1989). However, a recently completed randomised trial, carried out by investigators in North America and Australia has set the situation into a more realistic perspective (Loehrer et al, 1990).…”

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confidence: 99%

Chemotherapy for advanced bladder cancer: 'Midsummer Night's Dream' or 'Much Ado About Nothing'?

Raghavan

1990

Br J Cancer

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Long-term follow-up in patients treated with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) for transitional cell carcinoma of urinary bladder: Cause for concern

Cited by 45 publications

References 12 publications

A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer

A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer

Decreasing of p27Kip1and cyclin E protein levels is associated with progression from superficial into invasive bladder cancer

Chemotherapy for advanced bladder cancer: 'Midsummer Night's Dream' or 'Much Ado About Nothing'?

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