Evidence for a schedule-dependent deleterious interaction between paclitaxel, vinblastine and cisplatin (PVC) in the treatment of advanced transitional cell carcinoma

Abstract

A phase II study to evaluate the efficacy and toxicity of the combination of vinblastine, paclitaxel and cisplatin (PVC) in previously untreated patients with advanced transitional cell carcinoma. Chemotherapy naive patients with locally advanced or metastatic transitional cell carcinoma received the intravenous combination of paclitaxel 175 mg/m 2 over three hours followed by cisplatin 70 mg/m 2 over 3 hours on day 1 and vinblastine 3 mg/m 2 as a bolus on days 1 and 8 on a 21-day cycle, to a maximum of 6 cycles. The day 8 vinblastine was omitted if the total neutrophil count was <1.0. 15 patients (13 M, 2 F) of median age 66 (54–75) received a median of 5 cycles of treatment. There were two complete responses (13%; 95% CI 2–40%) and five partial responses (33%; 95% CI 12–62%), for an overall response rate of 46% (95% CI 21–73%). Responses occurred only in those with locally recurrent tumours and/or lymph nodes involved. Neutropenia at Grade 3–4 occurred in 14 of 67 cycles (21%) resulting in 7 episodes of neutropenic sepsis. Grade 3–4 thrombocytopenia was not observed. Other Grade 3 toxicity included alopecia (10 pts), diarrhoea (2 pts), constipation resulting in bowel obstruction (2 pts), nephrotoxicity (1 pt), myalgic pain (1 pt) and peripheral neuropathy (1 pt). Six patients developed Grade 2 paraesthesia. The median time to progression was 6 months and the median survival was 11 months. The regimen PVC was both less effective against transitional cell carcinoma and less toxic than expected. This may reflect an inhibitory interaction between vinblastine and paclitaxel and this schedule cannot be recommended for further investigation. © 2000 Cancer Research Campaign http://www.bjcancer.com

Changes in Lognormal Shape Parameter Guide Design of Patient-Specific Radiochemotherapy Cocktails

“…However, observed inconsistencies in treatment outcomes may be due to the widely varying chemotherapeutic drug concentrations and radiation-absorbed doses used (7)(8)(9)(10). In addition, there is evidence that optimization of radiation dose and drug concentration, and the time sequence for administering drugs and radiation, play important roles in treatment responses both in vitro and in vivo (4,(11)(12)(13). Also, regardless of the quality of radiation used, the wide variability in drug toxicity in normal cells of different histologies has to be considered, with favor given to the most sensitive tissue in chemoradiotherapy (14).…”

Induction of CYP3A4 by Vinblastine: Role of the Nuclear Receptor NR1I2

“…Indeed, CYP3A4 induction by vinblastine may provide a plausible explanation for the outcomes of 2 earlier clinical studies involving this drug. 33,34 For example, it was reported that treatment of patients with testicular cancer using a combination regimen of cisplatin, vinblastine, and bleomycin resulted in a 30% increase in the clearance of antipyrine, which lasted for 6 weeks. 34 Although antipyrine is metabolized by several CYP isoenzymes, CYP3A4 is responsible for the formation of a major metabolite, 4-hydroxyantipyrine.…”

“…35 Additionally, the combination of paclitaxel, vinblastine, and cisplatin was found to be less effective and less toxic than expected in the treatment of advanced transitional cell carcinoma of the urothelium. 33 In this combination, vinblastine was administered as a bolus prior to paclitaxel, which is very extensively metabolized by CYP2C8 and CYP3A4. 36,37 Thus, induction of the CYP3A4-mediated metabolism of paclitaxel by vinblastine could contribute to the low response rate and the low incidence of peripheral neuropathy reported.…”

Phase II multicentre study of docetaxel plus cisplatin in patients with advanced urothelial cancer

“…The last study was comprised of patients with normal and poor renal function (Hussain et al, 2001). The association of paclitaxel, vinblastine and cisplatin, however, resulted in a poor efficacy (Mulatero et al, 2000). Another new approach studied, with preliminary encouraging results, consisted of a sequential schedule with doxorubicin and gemcitabine followed by ifosfamide, paclitaxel and cisplatin (Dodd et al, 2000).…”