G. Deppe

Concurrent Cisplatin-Based Radiotherapy and Chemotherapy for Locally Advanced Cervical Cancer

BACKGROUND AND METHODS On behalf of the Gynecologic Oncology Group, we performed a randomized trial of radiotherapy in combination with three concurrent chemotherapy regimens -- cisplatin alone; cisplatin, fluorouracil, and hydroxyurea; and hydroxyurea alone -- in patients with locally advanced cervical cancer. Women with primary untreated invasive squamous-cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix of stage IIB, III, or IVA, without involvement of the para-aortic lymph nodes, were enrolled. The patients had to have a leukocyte count of at least 3000 per cubic millimeter, a platelet count of at least 100,000 per cubic millimeter, a serum creatinine level no higher than 2 mg per deciliter (177 micromol per liter), and adequate hepatic function. All patients received external-beam radiotherapy according to a strict protocol. Patients were randomly assigned to receive one of three chemotherapy regimens: 40 mg of cisplatin per square meter of body-surface area per week for six weeks (group 1); 50 mg of cisplatin per square meter on days 1 and 29, followed by 4 g of fluorouracil per square meter given as a 96-hour infusion on days 1 and 29, and 2 g of oral hydroxyurea per square meter twice weekly for six weeks (group 2); or 3 g of oral hydroxyurea per square meter twice weekly for six weeks (group 3). RESULTS The analysis included 526 women. The median duration of follow-up was 35 months. Both groups that received cisplatin had a higher rate of progression-free survival than the group that received hydroxyurea alone (P<0.001 for both comparisons). The relative risks of progression of disease or death were 0.57 (95 percent confidence interval, 0.42 to 0.78) in group 1 and 0.55 (95 percent confidence interval, 0.40 to 0.75) in group 2, as compared with group 3. The overall survival rate was significantly higher in groups 1 and 2 than in group 3, with relative risks of death of 0.61 (95 percent confidence interval, 0.44 to 0.85) and 0.58 (95 percent confidence interval, 0.41 to 0.81), respectively. CONCLUSIONS Regimens of radiotherapy and chemotherapy that contain cisplatin improve the rates of survival and progression-free survival among women with locally advanced cervical cancer.

Inhibition of paclitaxel-induced apoptosis by the specific COX-2 inhibitor, NS398, in epithelial ovarian cancer cells

OBJECTIVE In vitro studies have revealed that treatment of various human cancer cell lines with specific cyclo-oxygenase 2 (COX-2) inhibitors induces apoptotic cell death. It is currently proposed that the combination of COX-2 inhibitors with chemotherapeutic agents improves the efficacy of cancer treatment. MATERIALS AND METHODS In this study we sought to determine the effects of combining paclitaxel and the COX-2 inhibitor NS398 on apoptosis of epithelial ovarian cancer (EOC) cells. Two EOC cell lines, SKOV3 and MDAH2774, were exposed to increasing concentrations of paclitaxel (0.1, 10, and 100 microM) and NS398 (10, 100 microM) as well as a combination of both drugs. Apoptosis was evaluated by the Tunel assay. The fluorescein-labeled DNA was visualized directly by fluorescence microscopy and quantitated by flow cytometry. RESULTS While NS398 did not significantly alter apoptosis of either EOC cell lines after 24 h of continuous exposure, treatment of both cell lines with paclitaxel resulted in a significant increase in the rate of apoptosis (60-70%). Concomitant treatment of both SKOV3 and MDAH2774 cells with paclitaxel and NS398 resulted in marked impairment of paclitaxel-induced apoptosis. Similarly, sequential treatment during which both cell lines were treated with NS398 for 4 h, triple-washed, and then exposed to paclitaxel for 24 h resulted in a significant inhibition of paclitaxel-induced apoptosis. Similar inhibition was seen when NS398 was replaced by aspirin. CONCLUSIONS Combining COX-2 inhibitors and paclitaxel does not have an additive or synergistic tumoricidal effect. On the contrary, NS398 treatment markedly inhibited the apoptotic effects of paclitaxel in each of these two EOC cell lines.

A preliminary report of combination chemotherapy with cisplatin and mitomycin-C followed by radical hysterectomy or radiation therapy in patients with locally advanced cervical cancer

Neoadjuvant chemotherapy with cisplatin and mitomycin-C was used in the primary treatment of 17 patients with locally advanced cervical cancer (stages Ib-IIIb; tumor diameter greater than 5 cm) prior to definitive local treatment with radical hysterectomy or radiotherapy. Thirteen of the seventeen patients (76.5%) responded to initial chemotherapy, permitting a radical hysterectomy in ten patients. At histologic examination of the surgically resected primary tumor and lymph nodes, complete pathologic responses were found in 2 patients and partial pathologic responses in 8 patients. The median follow-up time is 14.5 months with a median survival for all patients of 52 weeks. All responders are alive. No therapy-related deaths, major complications, or delay in treatment occurred. Neoadjuvant chemotherapy with mitomycin-C and cisplatin is feasible and may be of benefit for patients with locally advanced cervical cancer.

Phase I trial of carboplatin-cyclophosphamide and iproplatin-cyclophosphamide in advanced ovarian cancer: a Southwest Oncology Group study☆

The Southwest Oncology Group has carried out a phase I clinical trial of carboplatin plus cyclophosphamide and iproplatin plus cyclophosphamide in 20 patients with stages III and IV ovarian cancer prior to initiating a phase III trial to compare these platinum analog-cyclophosphamide combinations with standard cisplatin-cyclophosphamide therapy. Myelosuppression proved the dose-limiting toxicity of both the carboplatin (300 mg/m2) plus cyclophosphamide (600 mg/m2) and iproplatin (180 mg/m2) plus cyclophosphamide (600 mg/m2) regimens. Evaluating up to six courses of therapy (repeated at 4-week intervals), the median nadir WBC and platelet counts associated with carboplatin-cyclophosphamide therapy were 1800 (range, 900-4000) and 69 000 per microliter, respectively, and those associated with iproplatin-cyclophosphamide therapy were 1400 (1100-1600) and 140 000 per microliter, respectively. Although the starting doses of carboplatin and iproplatin required a median decrease of 25%, the median doses of each administered through six courses of therapy were 300 and 180 mg/m2, respectively. Neither nephrotoxicity nor neuropathy were experienced by the patients, but mild to moderate nausea and vomiting occurred in more than 75% of those treated with either drug combination. Alopecia of mild to severe degree was observed in 40% of patients. Although the results of this phase I trial are still preliminary, we can recommend for future phase III trials 300 mg/m2 carboplatin and 180 mg/m2 iproplatin when combined with 600 mg/m2 cyclophosphamide repeated a 4-week intervals for six treatment courses.