The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
To evaluate the contribution of hexamethylmelamine (HMM) to the treatment of advanced ovarian cancer with combination chemotherapy, we compared the results of treatment with HMM, cyclophosphamide, doxorubicin, and cisplatin (H-CAP regimen) to treatment results using cyclophosphamide, doxorubicin, and cisplatin (CAP regimen). The treatment regimens were identical in dosage and schedule with the exception of the addition of HMM to one regimen. Fifty-five patients treated with H-CAP at Vanderbilt University Hospital between August 1977 and March 1980 were compared with a subsequent group of 22 patients who received CAP between October 1984 and October 1987. Following six months of therapy, patients were restaged either with second-look laparotomy or with clinical restaging. Fifty-three of 55 patients (96%) had objective responses to H-CAP compared with 14 of 21 patients (67%) treated with CAP (p = 0.001). The pathologic complete response rate was also higher in the patients who received H-CAP (35% versus 19%). The median survival of patients receiving H-CAP is 47 months compared to 21 months for the CAP patients. When patients with limited residual disease (maximum tumor diameter less than or equal to 3 cm) were compared, the median survival also favored the H-CAP treatment (101 months versus 21 months, p = 0.002). The median time to progression was also greater in patients receiving H-CAP versus those receiving CAP (67 months versus 16 months, p = 0.045). Treatment-related toxicity did not differ substantially between the two regimens. Our findings suggest that the addition of HMM to CAP chemotherapy prolongs the median survival in patients with ovarian cancer and limited residual disease following cytoreductive surgery.
The efficacy of the addition of prednisolone to tamoxifen as adjuvants to mastectomy in patients with primary breast cancer who were at a high risk of recurrence was investigated in a randomized trial. Primary carcinomas were collected from a series of 169 patients with loco-regional disease, undergoing mastectomy. The activities of alpha-glycerolphosphate dehydrogenase and 6-phosphogluconate dehydrogenase in the carcinomas were estimated biochemically and the ratio of the two enzymes was used to as the parameter to determine the risk of recurrence. 116 patients with a high risk of recurrence within five years of mastectomy were then randomized to either tamoxifen (2x20 mg/day) or tamoxifen+prednisolone (3x2.5 mg/per day) until recurrence. The patients are currently followed quarterly. The data were analysed at a median follow-up of 26 months (range 7-62 months). The probabilities of both disease-free and overall survival were not significantly different in either arm of the trial, indicating that there is no advantage in combining prednisolone with the antioestrogen. Recently, similar findings in terms of response have been reported for patients with metastatic disease treated with the same combination, raising doubts over the role of prednisolone in the management of patients with endocrine treatments.
Between 1979 and 1988, 26 patients with pulmonary metastases from adult soft-tissue sarcomas were treated with Adriamycin (doxorubicin hydrochloride), Cytoxan (cyclophosphamide), and DTIC before metastasectomy. Thirty-eight thoracotomies were performed with postoperative complications in 5 patients (5/38, 13.2%) and one postoperative death (1/38, 2.6%). Two patients had benign lesions at thoracotomy and were excluded from further survival analysis. The median survival of the remaining 24 patients after thoracotomy was 18.5 +/- 5.9 months, and the actuarial 5-year survival was 22%. Five patients (5/24, 21%) achieved a clinically complete response with preoperative chemotherapy, but all had recurrence in the lung and underwent resection of pulmonary metastases. Seven patients (7/24, 29%) achieved a partial response and had residual disease resected at thoracotomy. Twelve patients (12/24, 50%) showed either no change or disease progression while receiving chemotherapy and were referred for resection. Postthoracotomy disease-free survival and postthoracotomy overall survival did not differ significantly between the three groups. One patient in the group showing no change or progression of disease while receiving chemotherapy is alive without recurrence 57 months after initial pulmonary metastasectomy. Chemotherapy can be used for the initial treatment of pulmonary metastases from adult soft-tissue sarcomas. However, survival after resection of pulmonary metastases cannot be accurately predicted based on the clinical response to preoperative chemotherapy.
Etoposide is a schedule-dependent drug with excellent activity against small cell lung cancer (SCLC). Single-agent etoposide achieves overall response rates ranging from 15% to 84%, depending on the schedule of drug administration and the characteristics of the treated population. The route of etoposide administration (intravenous versus oral) has little impact on response rate, provided appropriate dose adjustments are made for oral therapy. In combination with other active agents, etoposide has proven particularly effective in the management of SCLC. Etoposide can be substituted for doxorubicin or vincristine in the cyclophosphamide, doxorubicin, and vincristine (CAV) regimen without loss of efficacy. The etoposide and cisplatin (EP) combination is thought to be synergistic and has proven to be an effective salvage regimen for CAV failures. A regimen that alternates CAV and EP has been found by some investigators to be modestly more effective against SCLC than CAV alone; however, EP alone may be as useful as an alternating regimen. Most studies to date have demonstrated that EP induction is at least as effective as any other standard induction regimen. However, EP has the potential advantage of being more easily integrated with thoracic radiation therapy (RT). This is particularly important in limited-disease patients: two recent pilot studies employing EP induction with hyperfractionated thoracic RT yielded 2-year survival rates of greater than 50%. These promising results are being evaluated further in an ongoing Phase III trial in the United States. The available data indicate that etoposide is one of the most active agents against SCLC and therefore should be included as a component of induction therapy in all patients. New schedules of etoposide administration warrant further study.
Twenty-eight patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) received neoadjuvant chemotherapy with cisplatin (120 mg/m2 on days 1 and 29) and vinblastine (4 mg/m2 weekly for 6 weeks). At the completion of induction chemotherapy, all patients were assessed for resectability. Those patients judged to be resectable underwent thoracotomy. All remaining patients received thoracic radiation therapy (5500 cGy) followed by additional chemotherapy in those patients responding to neoadjuvant treatment. There were 15 partial responses to neoadjuvant chemotherapy for an overall response rate of 54% (95% confidence interval, 36% to 71%). Only five partially responding patients (18%) were thought to have had sufficient tumor regression to allow for a potentially curative resection. However, a complete resection was done in only two patients. Overall median survival was 12 months (range, 4 to 72 months) with 1-year, 2-year, and 3-year survival rates of 54%, 39%, and 11%, respectively. The primary toxicity associated with neoadjuvant chemotherapy was moderate to severe (Eastern Cooperative Oncology Group Grade 3 or 4) nausea and emesis in 25% of patients. Hematologic toxicity was relatively modest; only one patient had Grade 4 leukopenia (less than 1000/microliter). Fever and neutropenia were uncommon, and there were no documented septic episodes or treatment-related deaths. Compared with historic controls treated with radiation therapy alone, cisplatin-based neoadjuvant chemotherapy appeared to improve the median and long-term survival of Stage III NSCLC patients modestly.
From April 1989 to August 1990, 17 patients with Stage 3 or 4 epithelial ovarian cancer (EOC) were treated with intravenous carboplatin (160-400 mg/m2) for refractory or recurrent disease after first-line treatment with cisplatin-based combination chemotherapy. Of fifteen patients evaluable for activity, two complete responses and two partial responses were seen, for a response rate of 27%. The duration of response was 4.5, 5, 8, and 9.2 months, respectively, and responders survived longer than nonresponders. Of the nine evaluable patients receiving carboplatin as the first salvage treatment, four responses were seen. Dose selection for the first cycle of carboplatin was based on previous treatment, and adjustments were made on the basis of myelosuppression. In general, treatment was well tolerated--severe myelosuppression occurred after 6 of 73 cycles. This review confirms previous reports of anti-tumor activity of carboplatin in patients with refractory or recurrent advanced EOC who respond to first-line treatment with cisplatin. Further evaluation may help define the toxicity and efficacy of salvage treatment with carboplatin compared to cisplatin in patients who recur after a prolonged disease-free interval after first-line cisplatin-based therapy.
Chronic administration of etoposide over multiple days has proved to be an effective schedule against a variety of neoplasms. The usual duration of etoposide administration is 3 to 5 days. However, recent studies have demonstrated this agent can be administered for up to 21 consecutive days with acceptable toxicity. Studies are currently under way to determine whether more protracted etoposide administration will prove to be more efficacious in the management of selected malignancies. Previous work at our institution has confirmed the activity of protracted administration of single-agent etoposide against small cell lung cancer and non-small cell lung cancer. More recently, we have combined either cisplatin or carboplatin with etoposide given orally for 21 consecutive days in phase II trials in patients with small cell lung cancer and non-small cell lung cancer. The results of these trials are reviewed.
Twenty-eight patients with unresectable, metastatic non-small cell lung cancer (NSCLC) were treated with carboplatin/oral etoposide. Carboplatin was administered intravenously on day 1 at a dose of 300 mg/m2 (12 patients) or 350 mg/m2 (16 patients); oral etoposide was administered at a dose of 50 mg/m2/d for 21 consecutive days. Treatment was repeated every 28 days. Patient characteristics included male:female ratio of 23:5, median age of 60 years, median Eastern Cooperative Oncology Group performance status of 1, weight loss of 5% or more in seven patients; stage IIIB disease in two patients and stage IV in 26. Twenty-five patients were evaluable for response and seven (28%) achieved a partial response (95% confidence interval, 14% to 48%). Median duration of response was 3+ months (range, 2+ to 6+) and median survival was 4+ months (range, 1+ to 10+). Myelosuppression was the predominate toxicity; leukocyte and platelet nadirs occurred between days 22 and 29, with median counts of 2,900/microL and 172,000/microL, respectively. The median interval between the start of cycle 1 and the start of cycle 2 was 33 days (range, 26 to 42). Carboplatin/oral etoposide is a moderately active regimen against advanced NSCLC that can be administered in an outpatient setting with manageable toxicity. Its impact on survival remains to be determined.
Forty-two patients with unresectable non-small cell lung cancer (NSCLC) were treated with carboplatin (300, 350 or 400 mg/m2) and 21 days of oral etoposide (50 mg/m2/day). Thirty-three patients were evaluable for response (too early to assess the remaining patients) and 9 patients (27%) achieved a partial remission. Median survival was 29 weeks (range, 4+ to 71+ weeks). The primary toxicity was myelosuppression. Leukocyte and platelet count nadirs occurred between days 22 and 29. In cycle 1, median leukocyte nadir was 2.8 x 10(9)/l and the platelet nadir was 142 x 10(9)/l. Nonhematologic toxicities were modest and included alopecia in all patients, mild nausea, mild to moderate diarrhea, and an occasional increase in serum creatinine. Carboplatin plus oral etoposide is a tolerable outpatient regimen with modest activity against unresectable NSCLC.
Etoposide is a highly schedule-dependent agent. We previously reported that a 21-day schedule of oral etoposide had good activity in small cell lung cancer (SCLC). The current phase II study was designed to test the combination of 21-day oral etoposide with cisplatin in hopes of capitalizing on etoposide's schedule dependency. Sixteen extensive stage SCLC patients were treated with cisplatin 100 mg/m2 day 1 plus 21 days of low-dose oral etoposide 50 mg/m2/day. Chemotherapy was repeated every 28 days for 4 cycles. Blood counts were monitored weekly, and etoposide was discontinued if the leukocyte or platelet count dropped below 2.0 x 10(9)/l or 75 x 10(9)/l, respectively. Fifteen of 16 patients were evaluable for response; 13 achieved either a complete (13%) or partial response (73%), for an overall response rate of 86% (95% confidence interval, 62-93%). Median response duration was approximately 7 months; median survival was not reached. Thirteen patients (81%) received all the planned cycles of chemotherapy. In cycle 1 of chemotherapy, the median leukocyte nadir was 2.8 x 10(9)/l (range, 0.1-6.3 x 10(9)/l; median platelet nadir was 180 x 10(9)/l (range, 51-397 x 10(9)/l). Life-threatening leukopenia (less than 1.0 x 10(9)/l) was unusual (2 of 58 cycles). There was 1 treatment-related death. One patient developed mild renal insufficiency that resolved after therapy. Nonhematologic toxicities were uncommon, but alopecia occurred in all patients. These data do not suggest that a major survival benefit will be derived for patients with extensive stage SCLC by increasing the duration of etoposide administration when used in combination with cisplatin. A randomized study is needed to determine if this long-term schedule of etoposide plus cisplatin is superior to the standard schedule of etoposide plus cisplatin.