Economic analysis of a phase III clinical trial evaluating the addition of total androgen suppression to radiation versus radiation alone for locally advanced prostate cancer (Radiation Therapy Oncology Group protocol 86-10)

PURPOSE: To evaluate the cost-effectiveness of adding hormone therapy to radiation for patients with locally advanced prostate cancer, using a Monte Carlo simulation of a Markov Model. METHODS AND MATERIALS: Radiation Therapy Oncology Group (RTOG) protocol 86-10 randomized patients to receive radiation therapy (RT) alone or RT plus total androgen suppression (RTHormones) 2 months before and during RT for the treatment of locally advanced prostate cancer. A Markov model was designed with Data Pro (TreeAge Software, Williamstown, MA). The analysis took a payer's perspective. Transition probabilities from one state of health (i.e., with no disease progression or with hormone-responsive metastatic disease) to another were calculated from published rates pertaining to RTOG 86-10. Patients remained in one state of health for 1 year. Utility values for each health state and treatment were obtained from the literature. Distributions were sampled at random from the treatment utilities according to a second-order Monte Carlo simulation technique. RESULTS: The mean expected cost for the RT-only treatments was 29,240 dollars (range, 29,138-29,403 dollars). The mean effectiveness for the RT-only treatment was 5.48 quality-adjusted life years (QALYs) (range, 5.47-5.50). The mean expected cost for RTHormones was 31,286 dollars (range, 31,058-31,555 dollars). The mean effectiveness was 6.43 QALYs (range, 6.42-6.44). Incremental cost-effectiveness analysis showed RTHormones to be within the range of cost-effectiveness at 2,153 dollars/QALY. Cost-effectiveness acceptability curve analysis resulted in a >80% probability that RTHormones is cost-effective. CONCLUSIONS: Our analysis shows that adding hormonal treatment to RT improves health outcomes at a cost that is within the acceptable cost-effectiveness range.     

Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study.

PURPOSE: To compare survival and toxicity in adult patients treated with low-dose (50.4 Gy/28 fractions) versus high-dose (64.8 Gy/36 fractions) localized radiation therapy (RT) for supratentorial low-grade astrocytoma, oligodendroglioma, and mixed oligoastrocytoma. PATIENTS AND METHODS: From 1986 to 1994, 203 eligible/analyzable patients were randomized: 101 to low-dose RT, 102 to high-dose RT. Almost half were younger than 40 years, and 95% had grade 2 tumors. Histologic subtype was astrocytoma (or mixed oligo-astrocytoma with astrocytoma dominant) in 32% of patients and oligodendroglioma (or oligoastrocytoma with oligodendroglioma dominant) in 68%. Tumor diameter was less than 5 cm in 35% of patients, and 41% of tumors showed some degree of contrast enhancement. Extent of resection was gross total in 14% of patients, subtotal in 35%, and biopsy only in 51%. RESULTS: At the time of the present analysis, 83 patients (41%) are dead, and median follow-up is 6.43 years in the 120 who are still alive. Survival at 2 and 5 years is nonsignificantly better with low-dose RT; survival at 2 and 5 years was 94% and 72%, respectively, with low-dose RT and 85% and 64%, respectively, with high-dose RT (log rank P =.48). Multivariate analysis identified histologic subtype, tumor size, and age as the most significant prognostic factors. Survival is significantly better in patients who are younger than 40 years and in patients who have oligodendroglioma or oligo-dominant histology. Grade 3 to 5 radiation neurotoxicity (necrosis) was observed in seven patients, with one fatality in each treatment arm. The 2-year actuarial incidence of grade 3 to 5 radiation necrosis was 2.5% with low-dose RT and 5% with high-dose RT. CONCLUSION: This phase III prospective randomized trial of low- versus high-dose radiation therapy for adults with supratentorial low-grade astrocytoma, oligodendroglioma, and oligoastrocytoma found somewhat lower survival and slightly higher incidence of radiation necrosis in the high-dose RT arm. The most important prognostic factors for survival are histologic subtype, tumor size, and age. The study design of the ongoing intergroup trial in this population will be discussed.     

Surgical complications of intraoperative radiation therapy: the Radiation Therapy Oncology Group experience.

Intraoperative radiotherapy (IORT) is being used with increasing frequency in many institutions in the United States but little is known about the surgical complication rates. The Radiation Therapy Oncology Group initiated three prospective studies in IORT in 1986 and we report here the experience in advanced malignancies of the stomach, pancreas, and rectum. The incidence and nature of major surgical complications were reviewed and presented with their implications in regard to future IORT trials. Two hundred twenty-seven patients were entered on three studies by 20 participating institutions between 1985 and 1989. One hundred twenty-nine patients received IORT while 98 patients were found to have too advanced disease to be benefited by IORT and underwent palliative surgical procedures only. IORT doses ranged from 12-22 Gy and bowel anastomoses were not irradiated. Wound infection in the IORT group was 6% vs. 2% in the non-IORT patients but this was not significant at the P = 0.05 level. Other complications included anastomotic leak (n = 5), operative bleeding (n = 10), pancreatitis (n = 2), and were not statistically different in the IORT and non-IORT groups. The mortality rate for the IORT and non-IORT groups combined was 1.8%. This large multi-institutional experience in patients with advanced malignancy demonstrates that patients receiving IORT do not have a higher surgical complication rate than those not receiving IORT. Long-term survival data await the implementation of Phase III trials in advanced intra-abdominal malignancy.     

Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413.

PURPOSE: This trial tested the hypothesis that combined androgen suppression (CAS) and whole-pelvic (WP) radiotherapy (RT) followed by a boost to the prostate improves progression-free survival (PFS) by 10% compared with CAS and prostate-only (PO) RT. This trial also tested the hypothesis that neoadjuvant and concurrent hormonal therapy (NCHT) improves PFS compared with adjuvant hormonal therapy (AHT) by 10%. MATERIALS AND METHODS: Eligibility included localized prostate cancer with an elevated prostate-specific antigen (PSA) < or = 100 ng/mL and an estimated risk of lymph node (LN) involvement of 15%. Between April 1, 1995, and June 1, 1999, 1,323 patients were accrued. Patients were randomly assigned to WP + NCHT, PO + NCHT, WP + AHT, or PO + AHT. Failure for PFS was defined as the first occurrence of local, regional, or distant disease; PSA failure; or death for any cause. RESULTS: With a median follow-up of 59.5 months, WP RT was associated with a 4-year PFS of 54% compared with 47% in patients treated with PO RT (P =.022). Patients treated with NCHT experienced a 4-year PFS of 52% versus 49% for AHT (P =.56). When comparing all four arms, there was a progression-free difference among WP RT + NCHT, PO RT + NCHT, WP RT + AHT, and PO RT + AHT (60% v 44% v 49% v 50%, respectively; P =.008). No survival advantage has yet been seen. CONCLUSION: WP RT + NCHT improves PFS compared with PO RT and NCHT or PO RT and AHT, and compared with WP RT + AHT in patients with a risk of LN involvement of 15%.     

Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate

PURPOSE: To determine the potential advantage of androgen ablation following standard external-beam radiation therapy in patients with locally advanced (clinical or pathologic T3; clinical or pathologic node positive) carcinoma of the prostate. METHODS AND MATERIALS: In 1987 the RTOG initiated a Phase III trial of long-term adjuvant goserelin in definitively irradiated patients with carcinoma of the prostate. A total of 977 patients were accrued to the study of which 945 remain analyzable: 477 on the adjuvant hormone arm (Arm I); and 468 on the radiation only arm (Arm II) with hormones initiated at relapse. The initial results were reported in the Journal of Clinical Oncology in 1997. RESULTS: With a median follow up of 5.6 years for all patients and 6.0 years for living patients local failure at 8 years was 23% for Arm I and 37% for Arm II (p < 0.0001). Distant metastasis was likewise favorably impacted with the immediate use of hormonal manipulation with a distant metastasis rate in Arm I of 27% and 37% in Arm II (p < 0.0001). Disease-free survival (NED survival) and NED survival with PSA of 1.5 ng/mL (bNED) or less were both statistically significant in favor of the immediate hormone arm (both p < 0.0001). Cause-specific failure was not statistically different with a cause-specific failure of 16% for Arm I and 21% in Arm II (p = 0.23). Overall survival was likewise not statistically different between two arms, with a 49% overall survival at 8 years in Arm I and 47% in Arm II (p = 0.36). Subset analysis of centrally reviewed Gleason 8-10 patients who did not undergo prostatectomy showed that for patients receiving radiation therapy plus adjuvant hormones there was a statistically significant improvement in both absolute (p = 0.036) and cause-specific survival (p = 0.019). CONCLUSIONS: Use of long-term adjuvant androgen deprivation in addition to definitive radiation therapy results in a highly significant improvement in regards to local control, freedom from distant metastasis, and biochemical free survival in unfavorable prognosis patients with carcinoma of the prostate.     

High- versus standard-dose megestrol acetate in women with advanced breast cancer: a phase III trial of the Piedmont Oncology Association

One hundred seventy-two patients with advanced breast cancer were randomized to receive oral standard-dose megestrol acetate (MA), 160 mg/d or high-dose MA, 800 mg/d. All but two patients had one prior trial of tamoxifen therapy for either metastatic disease (74%) or as adjuvant treatment (26%). Pretreatment characteristics were similar for both arms. High-dose MA resulted in a superior complete plus partial response rate (27% v 10%, P = .005), time to treatment failure (median, 8.0 v 3.2 months, P = .019), and survival (median, 22.4 v 16.5 months, P = .04) when compared with standard-dose therapy. These differences remained significant after adjustment for other covariates. Thirty-four patients were given high-dose MA after failure of standard-dose MA treatment, and none responded. Weight gain was the most distressing side effect, with 13% of standard-dose and 43% of high-dose patients gaining more than 20 lbs. Four major cardiovascular events occurred in patients receiving high-dose treatment and one in patients given standard doses. Other toxicity was modest. High-dose MA may represent a significant improvement in secondary endocrine therapy for advanced breast cancer patients refractory to initial endocrine treatment, but its use on a regular basis should be reserved until these results are confirmed by other clinical trials.     

Radiation Therapy Oncology Group (RTOG) trials for head and neck cancer

Clinical investigations for cancer of the head and neck, primarily tumors of the upper respiratory and digestive tracts, have been one of the most important components of the Radiation Therapy Oncology Group (RTOG) since its inception 30 years ago. Emphasis from the very beginning to the present time has been on altered fractionation. Studies of hypoxic cell sensitizers were also explored for many years. More recently, combinations of radiation therapy with cytotoxic chemotherapeutic agents, either sequentially or concurrently, have been a major focus. Although the majority of the trials have been for unresectable tumors, surgical adjuvant radiation therapy alone or combined with chemotherapy has also been an important activity. Combined modality trials emphasizing organ conservation have been carried out within the last decade. The RTOG represents a national and international resource for studies of cancer of the head and neck. Its results influence the care of patients and the clinical research environment.     

Survival advantage from higher-dose radiation therapy for clinically localized prostate cancer treated on the Radiation Therapy Oncology Group trials.

PURPOSE: We evaluated the effect of external-beam radiation therapy on disease-specific survival (death from causes related to prostate cancer) and overall survival in men with clinically localized prostate cancer. METHODS: From 1975 to 1992, 1,465 men with clinically localized prostate cancer received radiation therapy on four Radiation Therapy Oncology Group phase III randomized trials and were pooled for this analysis. No one received androgen-deprivation therapy with his initial treatment. All original histology had central pathologic review for grading using the Gleason classification system. Total delivered radiation dose ranged from 60 to 78 Gy (median, 68.4 Gy). The median follow-up time was 8 years. RESULTS: A Cox regression model revealed that Gleason score was an independent predictor of disease-specific survival and overall survival. The 10-year disease-specific survival rates by Gleason score were as follows: score of 2 through 5, 85%; score of 6, 79%; score of 7, 62%; and score of 8 through 10, 43%. Stratifying outcome by this important prognostic factor revealed that higher radiation dose was a significant predictor for improved disease-specific survival and overall survival only for those patients whose cancers had Gleason scores of 8 through 10 (P <.05). After adjusting for clinical T stage, nodal status, and age, treating with a higher radiation dose was associated with a 29% lower relative risk of death from prostate cancer and 27% reduced mortality rate (P <.05). CONCLUSION: These data demonstrate that higher-dose radiation therapy can significantly reduce the risk of dying from prostate cancer in men with clinically localized disease. This survival benefit is restricted to men with poorly differentiated cancers.     

Phase I trial of combined-modality therapy for localized esophageal cancer: escalating doses of continuous-infusion paclitaxel with cisplatin and concurrent radiation therapy.

PURPOSE: To define the maximum-tolerated dose (MTD) of paclitaxel when given as a weekly 96-hour infusion with cisplatin and radiotherapy for patients with esophageal cancer. PATIENTS AND METHODS: Thirty-four patients with locally advanced esophageal cancer and three patients with local recurrence or positive resection margins were treated. Weekly paclitaxel doses of 10, 20, 30, 40, 60, and 80 mg/m(2), given as a continuous 96-hour infusion, were administered with weekly cisplatin, 30 mg/m(2) on day 1, weeks 1 to 6, and concurrent radiation (50.4 Gy). Plasma paclitaxel steady-state levels were measured. RESULTS: Dose-limiting toxicity, defined as a treatment break longer than 2 weeks for toxicity, occurred in one patient in the 80-mg/m(2)/wk dose level. Major causes for any (including < or = 2 weeks) treatment breaks were mediport complications and neutropenic fever, which occurred mostly at that dose level. At a paclitaxel dose of 60 mg/m(2)/wk, myelosuppression, mostly neutropenia, was relatively mild and transient; stomatitis, esophagitis, diarrhea. and peripheral neuropathy were uncommon and usually of grade 2 or less. Therefore, the MTD was established at 60 mg/m(2)/wk. The mean steady-state concentration of paclitaxel at the MTD was 17.2 nmol/L. Complete (R0) resection was possible in 16 (73%) of 22 patients who underwent subsequent surgery, and the pathologic complete response rate was 24%. CONCLUSION: Weekly, 96-hour infusion of paclitaxel 60 mg/m(2)/wk, given with concurrent cisplatin and radiotherapy, is a safe and tolerable regimen for patients with localized esophageal cancer. Preliminary efficacy data are encouraging. This regimen is the basis of ongoing Radiation Therapy Oncology Group phase II randomized trials in esophageal and gastric cancers.     

Accelerated hyperfractionation for bronchogenic cancer: Radiation Therapy Oncology Group 9205

RTOG 92-05 was a phase II trial developed to evaluate the feasibility, toxicity, and acceptance of a three times daily accelerated hyperfractionation radiation therapy schedule delivering 110 cGy, three times daily, to 79.2 Gy uncorrected tumor dose in 72 fractions, in 24 treatment days, in patients with bronchogenic cancer. The radiographically visible tumor received accelerated hyperfractionation and the other radiation volume received standard hyperfractionation. Three times a day, a dose of 110 cGy was delivered, with an interfractional interval of 4 hours; the middle fraction was a gross tumor boost. This schedule allowed treatment to be completed in approximately 4 1/2 weeks in an effort to minimize repopulation, to have a better biologically modeled therapeutic ratio than other schedules that have been completed in cooperative groups, and to use doses within cooperative group experience. In 33 months 35 patients were entered into the study; 15 of the patients had squamous cell carcinomas, 10 had adenocarcinomas, 8 had large-cell undifferentiated carcinomas, and 2 had unspecified non-small-cell cancers. Nineteen patients had AJCC stage IIIB; 13, IIIA; 14, T4; 10, T3; 13, N2; and 7, N3. Twenty-one patients (60%) had greater than 5% weight loss. The Karnofsky performance status was 90 to 100 in 12 patients and 70 to 80 in 23 patients. Treatment was completed in 91% of patients. Acute toxicity >RTOG grade II occurred in three patients: one skin, one lung, and two esophagus (one each III and IV, the only grade IV in the study). Overall late toxicity > or = grade III occurred in six patients: three lung, one thyroid, one esophagus, and one subcutaneous tissue (all grade III). The median survival was 10.5 months, 1-year survival was 42%, and 3-year survival was 18%. The outcome in this group of patients with many adverse prognostic variables compared favorably to prior RTOG radiation-alone studies.     

Intraoperative radiation therapy of pancreatic carcinoma: a report of RTOG-8505. Radiation Therapy Oncology Group.

The Radiation Therapy Oncology Group in 1985 began a study of IORT plus external beam radiation therapy for patients with locally unresected, non-metastatic pancreatic cancer. Patients were treated with a combination of 2000 cGy of IORT and postoperative external beam radiation therapy to 5040 cGy in combination with IV 5-FU (500 mg/m2/day on the first 3 days of the external beam treatment). As patients were registered on study prior to exploration, it was expected that a number of patients would be excluded from further analysis at the time of surgery. Eighty-six patients were entered on study through 6/1/88 and analyzed through 4/90. Fifty-one patients were fully analyzable. Median survival time of the 51 patients was 9 months with an 18-month actuarial survival rate of 9%. Local control could not be adequately evaluated in this multi-institutional study. Major postoperative complications were not excessive and occurred in 12% of patients. Two patients had major late morbidity leading to death, one from duodenal bleeding and the second from biliary obstruction. Although this study does demonstrate the feasibility of IORT in a multi-institutional setting, it does not demonstrate any advantage of IORT over conventional therapy for this disease.     

A randomized trial of accelerated hyperfractionated radiation therapy and bis-chloroethyl nitrosourea for malignant glioma. A preliminary report of Radiation Therapy Oncology Group 83-02.

BACKGROUND. The third and final randomization of Radiation Therapy Oncology Group (RTOG) 83-02 was performed to identify the maximal tolerated dose and potential efficacy of accelerated hyperfractionated radiation therapy (AHRT) in 1.6 Gy twice-daily fractions for adult malignant glioma. METHODS. From December 1987 to July 1989, 304 patients with malignant glioma were stratified by age, performance status, and histologic findings and randomized to receive total AHRT doses of 48.0 or 54.4 Gy, with 80 mg/m2 of bis-chloroethyl nitrosourea (BCNU) for 3 days every 8 weeks. Distribution of other prognostic factors, including neurologic function, extent of surgery, tumor size, and sex, was comparable in each treatment arm. RESULTS. One Grade 5 radiation therapy (RT)-related toxic effect was reported (in the 54.4-Gy treatment arm), and the incidence of late Grade 3-5 RT-related toxic effects at 18 months was 1% at 48.0 Gy and 4% at 54.4 Gy. The median survival times (MST) for the 48.0 Gy and 54.4 Gy treatment arms were 11.7 and 10.8 months, respectively, comparable to the MST in prior RTOG trials with a similar proportion of patients with glioblastoma multiforme (79%). For the 123 patients who were 60 years of age or older, the MST for the 48.0 Gy and 54.4 Gy treatment arms were 8.9 and 10.4 months, respectively, and compare favorably with the MST of 6.0 months reported with standard RT and BCNU treatment used for 101 patients who were 60 years of age or older in two prior RTOG malignant glioma trials (74-01 and 79-18). Although these results differ significantly (P = 0.0015), this contrast is not significant when adjusted by performance status. CONCLUSIONS. The maximum tolerated dose of AHRT has yet to be identified, and pursuit of this information may most benefit patients with malignant glioma who are 60 years of age or older.     

Final report of the phase I trial of continuous infusion etanidazole (SR 2508): a Radiation Therapy Oncology Group study.

Seventy-eight patients have been treated on a Phase I trial using continuous infusion etanidazole while undergoing brachytherapy for locally advanced tumors. There were two sequential schemata, the first treated 63 patients with doses ranging from 8-23 g/m2 over 48 hr and the second treated 15 patients with doses ranging from 20-23 g/m2 over 96 hr. The tumor sites were: brain (n = 42), cervix (n = 22), and breast (n = 14). Patients received a loading dose of etanidazole of 2 g/m2 followed by a continuous infusion for a total of 48 or 96 hr while radioactive implants were in place. Of the 63 patients in the 48-hr study, 52 were entered at doses of less than or equal to 21 g/m2 and there were no definite neuropathies but two patients with the cramping/arthralgia syndrome. Of the 11 patients entered at 22-23 g/m2, 1 patient had symptoms of peripheral neuropathy (Grade II) and 6 had the cramping/arthralgia syndrome. This is a new syndrome, distinct from the peripheral neuropathy, characterized by transient alterations in sensations consisting of cramping, arthralgias, or tingling that resolved completely at intervals varying from a few hours to about 1 week post-treatment. The cramping/arthralgia syndrome limited dose escalation; therefore, the maximum tolerated dose over 48 hr was determined to be 20-21 g/m2. The 96-hr infusion was limited to patients with recurrent gliomas undergoing stereotactic implantation. To date, 15 patients have been treated with doses of 20-23 g/m2. No toxicity was encountered at doses less than or equal to 22 g/m2. At 23 g/m2, one patient developed Grade III neuropathy and three patients had mild cramping/arthralgia syndrome, for whom the drug was discontinued. Therefore, it appears the maximum tolerated dose at 96 hr will be approximately 23 g/m2, which is 10-15% higher than for the 48-hr infusion.     

Radiation Therapy Oncology Group (RTOG) studies in head and neck cancer

Since its foundation in 1971, the RTOG has conducted a successful clinical research program in head and neck mucosal squamous cell carcinoma with 22 treatment protocols and one registry study which combined have accumulated data on over 5,500 patients. The RTOG was the first multicenter group to evaluate neoadjuvant chemotherapy before definitive radiation with its methotrexate study. Although the study was negative, RTOG has since conducted five pilot or phase II studies of neoinduction or concurrent chemotherapy with radiation therapy in patients with inoperable tumors. The last study showed that radiation concurrent with cisplatinum was tolerable with a suggestion of increased antitumor effect. In patients with potentially resectable tumors, RTOG has completed a pilot study of combination chemotherapy administered either before or after the surgery with radiotherapy. Based upon its findings, the treatment sequence, surgery-chemotherapy-radiotherapy, was chosen as the experimental arm for a new phase III study. This study was subsequently adopted by the head and neck intergroup mechanism as its study (INT 0034/RTOG 8503). RTOG has investigated the optimal timing of radiotherapy with surgery. The 7303 study established that postoperative radiotherapy achieved significantly better locoregional control but not improved absolute survival. Approximately 30% of the patients on each arm failed to complete both modalities. Even when comparison is restricted to patients who completed both modalities, postoperative radiotherapy still produced the better locoregional control. Efforts to overcome the limitations imposed by tumor hypoxia through use of carbogen (95% O2 and 5% CO2) breathing or the radiosensitizer misonidazole during radiotherapy have been unsuccessful. In a phase I study, RTOG showed that 15 to 18 sessions of sensitized radiation can be safely delivered with the new radiosensitizer SR 2508 in contrast to only six such sessions with misonidazole. This promising radiosensitizer is now being tested in a phase III trial. RTOG has also investigated variations in fraction size, fraction number, and total radiation dose. In the 7102 study, split-course irradiation achieved equivalent antitumor results as compared to continuous daily irradiation but with less social alteration and cost to the patient. In the hyperfraction pilot study 7703, twice a day irradiation with 120 cGys up to 6,000 cGys proved to be tolerable.(ABSTRACT TRUNCATED AT 400 WORDS)     

Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group.

PURPOSE: To compare the progression-free and overall survival in small-volume residual ovarian cancer after treatment with intravenous (IV) cisplatin and paclitaxel or an experimental regimen of IV carboplatin followed by IV paclitaxel and intraperitoneal cisplatin. PATIENTS AND METHODS: Patients were randomized to receive either IV paclitaxel 135 mg/m(2) over 24 hours followed by IV cisplatin 75 mg/m(2) every 3 weeks for six courses or IV carboplatin (area under curve 9) every 28 days for two courses, then IV paclitaxel 135 mg/m(2) over 24 hours followed by intraperitoneal (IP) cisplatin 100 mg/m(2) every 3 weeks for six courses. RESULTS: Of the 523 patients who entered this trial, 462 were determined to be assessable, with prognostic factors well balanced between the treatments. Neutropenia, thrombocytopenia, and gastrointestinal and metabolic toxicities were greater in the experimental arm. As a result, 18% of the patients received < or = two courses of IP therapy. Progression-free survival was superior for patients randomized to the experimental treatment arm (median, 28 v 22 months; relative risk, 0.78; log-rank P =.01, one-tail). There was a borderline improvement in overall survival associated with this regimen (median, 63 v 52 months; relative risk, 0.81; P =.05, one-tail). CONCLUSION: An experimental regimen including moderately high-dose IV carboplatin followed by IP paclitaxel and IV cisplatin yielded a significant improvement in progression-free survival when compared with a standard regimen of IV cisplatin and paclitaxel. Because the improvement in overall survival was of borderline statistical significance and toxicity was greater, the experimental arm is not recommended for routine use. However, the results provide direction for further clinical investigation in small-volume ovarian cancer.