Intraperitoneal Carboplatin with or without Interferon-α in Advanced Ovarian Cancer Patients with Minimal Residual Disease at Second Look: A Prospective Randomized Trial of 111 Patients

From June 1990 to October 1994, 111 advanced ovarian cancer patients with minimal (less than 2 cm) residual disease after platinum-based front-line chemotherapy and second-look laparotomy entered a cooperative randomized study aimed at evaluating the effectiveness and the toxicity of the addition of interferon-α2 to carboplatin, both intraperitoneally (ip) administered. Patients were randomized to receive either 3 courses of ip Carboplatin 400 mg/m²Day 1 q 28 days (54 pts) (CBDCA) or ip interferon-α 25 × 10⁶U Day 1 + ip carboplatin 400 mg/m²Day 2 q 28 days (57 pts) (CBDCA + IFN). Patients treated with interferon experienced more severe (WHO grade 3–4) leukopenia (28% vs 17.1%) and anemia (14% vs 4.2%). Fever (P= 0.000) and flu-like syndrome (P= 0.02) were significantly more frequent in the combination arm. No difference in gastroenteric, neurologic, or renal toxicity was observed. At a median follow-up time of 13 months (range 1–72) 71 patients showed a disease progression (31 CBDCA, 40 CBDCA + IFN) and 44 patients died (21 CBDCA, 23 CBDCA + IFN). Median progression-free survival was 11 months in the CBDCA group and 10 months in the CBDCA + IFN arm. Median survival was 22 and 29 months in CBDCA and CBDCA + IFN arm, respectively. In conclusion, intraperitoneal interferon-α does not seem to improve the results achievable with intraperitoneal carboplatin in this subset of patients, while the toxicity and the costs of the combination are consistently higher than with chemotherapy alone.     

Intraperitoneal cisplatin-based chemotherapy vs. intravenous cisplatin-based chemotherapy for stage III optimally cytoreduced epithelial ovarian cancer.

OBJECTIVE: To compare the survival between intraperitoneal cisplatin-based chemotherapy (IPCT) and intravenous cisplatin-based chemotherapy (IVCT) in stage III epithelial ovarian cancer with minimal residual disease (<1 cm) after primary debulking surgery. METHOD: One hundred and thirty-two patients with stage III epithelial ovarian cancer after optimal primary debulking surgery with minimal residual disease between April 1990 and March 1995 were entered into a randomized clinical trial in which IPCT or IVCT was administered at 3-week intervals. Patients in the IPCT arm received cisplatin-based (100 mg/m(2)) intraperitoneal chemotherapy. Patients in the IVCT arm received cisplatin-based (50 mg/m(2)) intravenous chemotherapy. The tumor response was assessed every 3 months. The hematological toxicity using the South West Oncology Group (SWOG) toxicity criteria was assessed. Catheter complications associated with intraperitoneal chemotherapy were also analyzed. RESULT: The estimated median survival in the IPCT group was 43 months (95% confidence interval, 34-54) and IVCT group was 48 months (95% confidence interval, 37-59). The hazard ratio of death was not statistically significant between IPCT and IVCT (hazard ratio, 1.13; 95% CI, 0.69-1.86; P=0.317). The frequencies of hematological toxic effects were significantly lower in the IPCT group than in the IVCT group. CONCLUSION: Intravenous and intraperitoneal chemotherapy are associated with equivalent survival in patients with minimal residual stage III epithelial ovarian cancer after optimal cytoreductive surgery.     

腹腔灌注与静脉化疗治疗晚期卵巢癌的疗效对比研究

目的：比较单纯静脉给药化疗与腹腔灌注化疗2种给药途径治疗晚期上皮性卵巢癌的临床疗效。方法：选取天津市第五中心医院62例晚期上皮性卵巢癌患者,将患者随机分为静脉滴注组和腹腔灌注组。静脉滴注组方案：紫杉醇135 mg/m2静脉滴注,24 h 后顺铂75 mg/m2静脉滴注;腹腔灌注组方案：紫杉醇135 mg/m2静脉滴注,24 h 后顺铂100 mg/m2腹腔灌注,第8天给予紫杉醇60 mg/m2腹腔灌注。所有患者进行随访,分别对2组患者的近期疗效、远期疗效和不良反应等进行比较。结果：腹腔灌注组肿瘤缓解率较静脉滴注组有增高趋势,但差异无统计学意义（P＞0.05）;腹腔灌注组的疾病无进展生存期（progression-free survival,PFS）和2年生存率均显著高于静脉滴注组,差异有统计学意义（P＜0.01）。腹腔灌注组的不良反应发生率高于静脉滴注组,2组贫血、肝功能损害及神经毒性发生率差异有统计学意义（P＜0.05）。结论：腹腔灌注化疗可有效提高晚期上皮性卵巢癌患者的PFS和2年生存率,改善患者预后。     

Phase II trial of intraperitoneal cisplatin with intravenous doxorubicin and cyclophosphamide in previously untreated patients with advanced ovarian cancer-long-term follow-up

Forty-three patients with ovarian cancer were entered on this trial and treated with intravenous (iv) cyclophosphamide (C) and doxorubicin (A), and intraperitoneal (ip) cisplatin (DDP), every 21 days for eight cycles. Following iv hydration, the cisplatin was administered through an intraperitoneal catheter in 2 L of 0.9% normal saline with a 4-h dwell. All patients are evaluable for overall and progression-free survival with a median follow-up of 70 months (range: 3-162 months); 39 patients are evaluable for response. All complete responses were surgically confirmed. The median age was 59 (range 28-82 years); 3 patients were stage IC, 5 were IIC, 14 patients were stage III (optimally debulked), 14 patients were stage III (suboptimally debulked), and 7 patients were stage IV. Two patients had received prior alkylator therapy. Six of 8 patients with Stage IC or II remain without evidence of disease at a mean of 12 years following chemotherapy. Of 14 optimally debulked stage III patients, there were 7 complete responses, 3 partial responses, 1 patient with stable disease, and 3 inevaluable patients. Of 14 suboptimally debulked stage III patients there were 4 complete responses, 4 partial responses, 3 with stable disease, 2 progressions on treatment, and 1 inevaluable patient. Five-year progression-free and overall survivals for stage III optimally debulked patients are 21 and 64%, respectively. At 10 years, progression-free and overall survivals for this group are 21 and 29%, respectively. Toxicity included neutropenia (complicated by sepsis in 2 patients), infrequent thrombocytopenia, and mild anemia. Three patients developed transient serum creatinine elevations >2.0 mg/dl; however, decreased creatinine clearance was noted in 93/258 (36%) of evaluable courses which required a cisplatin dose reduction per protocol. Controllable hypomagnesemia, nausea, and emesis were also observed. We conclude that the combination of iv CA and ip DDP is an effective regimen with long-term progression-free and overall survivals that compare favorably with those of other published studies of intravenous or intraperitoneal chemotherapy. This report is unusual in terms of the prolonged follow-up for all patients enrolled. These long-term results lend further support to recently published trials documenting the efficacy of intraperitoneal chemotherapy for patients with this disease.     

Chemotherapy in Advanced Ovarian Carcinoma: Current Standards of Care Based on Randomized Trials

The mainstay of the treatment of advanced (stage III or IV) ovarian carcinoma is systemic therapy. The following review bases conclusions regarding standards of care on large, randomized trials of chemotherapy in advanced ovarian carcinoma. As of 1976, "standard" chemotherapy was single alkylating agent usually with melphalan. Studies of combination chemotherapy failed to show superiority over single alkylating agent until the introduction of cisplatin. The Gynecologic Oncology Group conducted a series of two trials in patients with large-volume disease, the first randomizing patients to either single-agent melphalan or a combination of doxorubicin and cyclophosphamide and the second to doxorubicin plus cyclophosphamide with or without cisplatin. These studies demonstrated superiority for the cisplatin-based combination in terms of overall response rate, clinical complete response rate, progression-free survival, and overall survival. Subsequent randomized trials demonstrated several important facts. First, platinum-based combinations yielded results superior to single-agent cisplatin. Second, a two-drug combination of cisplatin plus cyclophosphamide provides benefit equivalent to the three-drug combination of the same two drugs plus doxorubicin. Third, substitution of carboplatin for cisplatin yields similar results. Finally, dose escalation of chemotherapy by a factor of 2 does not offer a therapeutic advantage. The next major advance after the introduction of the platinum compounds was the demonstration of the activity of taxol, a new agent with a unique mechanism of action and apparent clinical non-cross-resistance with the platinum compounds. A recently completed GOG trial of cisplatin plus cyclophosphamide versus cisplatin plus taxol in patients with large-volume disease shows that the taxol-based combination has a superior overall response rate, clinical complete response rate, rate of achieving a state of no gross residual disease at second-look laparotomy, and progression-free survival. Survival analysis awaits maturation of the data, but the control arm has already been shown to have a median survival of 23.2 months with the median not yet reached for the taxol-based arm. These data suggest that a combination of taxol plus cisplatin should be considered the standard of care for patients with advanced ovarian carcinoma. Ongoing trials seek to define further the role of taxol in frontline chemotherapy for ovarian carcinoma. In conclusion, the standard chemotherapy for advanced ovarian carcinoma should be considered a combination of taxol plus a platinum compound.     

Complications relating to intraperitoneal administration of cisplatin or carboplatin for ovarian carcinoma

BACKGROUND: Complications associated with intraperitoneal (ip) chemotherapy is one of the factors that should be taken into consideration upon performing long-term intraperitoneal administration of chemotherapeutic agents for ovarian carcinoma. METHODS: From 1987 to 1996, 78 patients with primary ovarian carcinoma were treated with a total of 365 courses of ip administration of cisplatin (CDDP) or carboplatin (CBDCA) as a part of an initial chemotherapy regimen in combination with surgery including systematic retroperitoneal lymph node dissection using an implantable peritoneal cavity access catheter system. The complications that occurred in association with ip chemotherapy were analyzed. RESULTS: Complications associated with ip chemotherapy were seen in 27 of 78 (34.6%) patients, which included extensive intestinal adhesion, abdominal pain, local infection, ileus, bleeding at the site of implanted port, obstruction of the catheter, vaginal vault perforation, and bowel perforation. Major complications that required surgical treatment occurred in 3 patients, which included ileus, vaginal perforation, and an intestinal perforation. The perforations occurred after 18 and 36 months after the implantation of the catheter, respectively. CONCLUSIONS: It has been suggested that primary CDDP/CBDCA ip chemotherapy using an implantable catheter system can be carried out safely with rare major complications if employment of this method is restricted in 12 months after the installation of catheter.     

Randomized trial of adjuvant intraperitoneal alpha-interferon in stage III ovarian cancer patients who have no evidence of disease after primary surgery and chemotherapy: An intergroup study

OBJECTIVE: Despite the improvement in progression-free and overall survival in patients with advanced ovarian cancer associated with platinum-taxane chemotherapy, strategies are needed to prevent the greater than 70% recurrence rate. METHOD: The Southwest Oncology Group (SWOG) initiated a phase III intergroup trial of alpha-interferon (IFNalpha-26, Schering-Plough, Kenilworth, NJ) in weekly doses of 50 x 10(6) IU (for 6 doses) versus observation only in patients with no pathological evidence of residual disease at second-look surgery in 1988. RESULTS: Patient accrual was extremely slow and the trial was permanently closed in 1999 by the SWOG Data and Safety Monitoring Committee with 74 registered patients. Of these patients, 70 were evaluable for progression-free and overall survival. There was no significant difference between the two study arms in relation to median progression-free survival (P = 0.56). The median survival duration associated with intraperitoneal alpha-interferon had not been reached versus 87 months on the observation arm. In general, intraperitoneal alpha-interferon was well tolerated. There were no treatment-related deaths or grade 4 adverse events. Although no efficacy conclusions can be drawn from this prematurely closed trial, it should be noted that 57% of the patients on the observation arm recurred and all died, whereas 63% recurred and only 43% died on the intraperitoneal alpha-interferon arm. CONCLUSION: Although this was a negative study, there should continue to be interest in the use of biological therapy to improve survival of patients in complete remission following primary chemotherapy.     

Kinetic modeling and efficacy of intraperitoneal paclitaxel combined with intravenous cyclophosphamide and carboplatin as first-line treatment in ovarian cancer

OBJECTIVE: The purpose of this study was to determine the efficacy, tolerability, and pharmacokinetics of intraperitoneal (ip) paclitaxel combined with intravenous (iv) carboplatin and cyclophosphamide. PATIENTS AND METHODS: Twenty-five newly diagnosed patients with Stage IC-IV epithelial ovarian cancer received ip paclitaxel with iv carboplatin and cyclophosphamide as a first-line treatment. Paclitaxel pharmacokinetics was determined during the first cycle on day 1 or 8. RESULTS: This regimen was well tolerated, as abdominal pain and hematological toxicities were minor, while neurotoxicity grade I/II was reported in only 20% and myalgia in 24% of patients and were fully reversible. After treatment 13 of 18 (72%) of the patients had no evidence of disease. At a median follow-up of 30 months patients with residual disease after surgery (n = 10) had a median progression-free survival (PSF) of 13 months; for the optimally debulked group (n = 15) the actuarial PFS was 60% at 48 months. The elimination of paclitaxel from the peritoneal cavity and plasma followed first-order kinetics and was not influenced by adding carboplatin with cyclophosphamide. CONCLUSION: This regimen was well tolerated, with minimal hematologic or neurotoxicity, and allowed the application of a triple-drug schedule without compromising dose intensity. To judge its efficacy, comparison with a standard iv paclitaxel-based schedule should be performed in a formal phase III study.     

The antiemetic efficacy of oral ondansetron plus intravenous dexamethasone in patients with gynecologic malignancies receiving carboplatin-based chemotherapy

PURPOSE: The purpose of this study was to develop a cost-effective prophylactic antiemetic regimen for the prevention of carboplatin-induced emesis. METHODS: Patients being treated in the Gynecologic Cancer Program of the Cleveland Clinic Taussig Cancer Center with a carboplatin-based chemotherapy regimen received a prophylactic antiemetic program consisting of a single dose of oral ondansetron (16 mg) plus intravenous dexamethasone (20 mg) approximately 30 min prior to chemotherapy. Evaluation of the effectiveness of this antiemetic regimen was performed during a single treatment course. RESULTS: A total of 27 patients (median age, 62; range, 41-83) participated in this phase 2 trial. Three patients received single-agent carboplatin, and 24 were treated with either a carboplatin/paclitaxel or carboplatin/docetaxel regimen. The carboplatin AUC dosing level was 4, 5, or 6 in 6, 5, and 16 individuals, respectively. No patient developed vomiting; 2 (7%) individuals experienced nausea during the 24-h period following chemotherapy administration. CONCLUSION: The combination of a single dose of oral ondansetron (16 mg) plus intravenous dexamethasone (20 mg) is an effective prophylactic antiemetic regimen for patients receiving carboplatin-based chemotherapy.     

Intraperitoneal hyperthermic chemotherapy in ovarian cancer

We investigated the effect of intraperitoneal hyperthermic perfusion chemotherapy as consolidation therapy in stage IIIB-IIIC ovarian cancer, following cytoreductive surgery and systemic chemotherapy (cisplatin-cyclophosphamide--six cycles). Disease-free survival, overall survival, and side effects were compared with a control group of patients who refused a second-look surgery and intraperitoneal chemotherapy. In a multicenter prospective trial, 29 patients with complete or optimal cytoreductive surgery and systemic treatment were included in the consolidation group and received intraperitoneal hyperthermic perfusion chemotherapy. Patients were recruited between January 1991 and December 1997. The intraperitoneal hyperthermic perfusion was performed with open-abdomen technique, using physiologic solution containing cisplatin 100 mg/m2, for 60 min in hyperthermic phase (41-43 degrees C). Intraperitoneal hyperthermic perfusion chemotherapy was locally and systemically well tolerated. The consolidation therapy group showed a better 5-year survival rate and lower recurrent disease rate, but differences were not statistically significant. Our results suggest that intraperitoneal hyperthermic perfusion chemotherapy is a feasible, well-tolerated, and promising alternative as consolidation therapy in ovarian cancer.     

Intravenous chemotherapy, early debulking surgery, and consolidation intraperitoneal chemotherapy in advanced ovarian carcinoma

OBJECTIVE: The efficacy of a cisplatin-anthracycline combination, early debulking surgery, and intraperitoneal chemotherapy has been demonstrated through separate studies. We evaluated a multimodal treatment strategy integrating these therapeutic options. METHODS: Women with stage III or IV ovarian carcinoma received six cycles of cisplatin/epirubicin alternating with leucovorin and 5-fluorouracil. Patients with a residual disease (RD) measuring more than 2 cm after the initial laparotomy underwent an early debulking surgery after the first three cycles of chemotherapy. A second-look laparotomy (SLL) was performed after six cycles of intravenous chemotherapy. Intraperitoneal chemotherapy with cisplatin, VP16, and mitoxantrone was then administered in patients with no or RD < 2 cm after SLL. RESULTS: A total of 87 patients were included. After initial laparotomy, 11 patients (12%) had no macroscopic residual disease, 38 (44%) had a RD < or =2 cm, and 38 (44%) had a RD > 2 cm. After early debulking surgery, an additional 18 patients (21%) had a RD < 2 cm. Seventy-five patients were evaluable for response to intravenous chemotherapy: the overall response rate was 80%, and 30 patients achieved a pathological complete response (40%). Eight percent of the patients had stable disease and 12% had a progression. Sixty-eight patients received intraperitoneal chemotherapy after second-look laparotomy. With a 72-month median follow-up, median overall survival and progression-free survival were, respectively, 37 and 19 months. Five-year survival was 41%. CONCLUSION: The prognosis of patients with advanced ovarian carcinoma may be improved by a sequential treatment strategy including intravenous chemotherapy, early debulking surgery, and intraperitoneal chemotherapy.     

Phase II trial of combination intraperitoneal cisplatin and 5-fluorouracil in previously treated patients with advanced ovarian cancer: long-term follow-up

OBJECTIVES: This trial was performed to determine the response rate and progression-free and overall survivals of patients with advanced recurrent ovarian cancer who were treated with intraperitoneal cisplatin and 5-fluorouracil. METHODS: Twenty-four patients with ovarian cancer were entered on this trial and treated with intraperitoneal (ip) cisplatin (DDP) and ip 5-fluorouracil, every 3 weeks for eight cycles. Following iv hydration, the cisplatin and 5-fluorouracil were administered through an ip catheter in 2 liters of 0.9% normal saline with a 4-h dwell. RESULTS: All patients were evaluable for progression-free and overall survival and toxicity analysis, and 22 patients for response. The median age was 59 (range, 35-71); initial disease status included 9 patients with residual disease following chemotherapy prior to entry on this study; 5 patients had progressed, and 10 patients had recurrent disease more than 6 months following initial chemotherapy. Of the 9 patients with residual disease, 1 complete response and 3 partial responses were observed; of 10 patients with recurrent disease, 1 complete and 1 partial response were observed for an overall response rate of 27%. No objective responses were seen in the 7 patients who were platinum-refractory on protocol entry. The median progression-free and overall survivals are 7.0 (range, 0.5-137) and 15.5 (range, 3-147) months, respectively. Toxicity included hypomagnesemia, vomiting, abdominal pain, and mild anemia. Only one patient required a dosage adjustment of cisplatin for a serum creatinine elevation >2.0 mg/dl. CONCLUSIONS: We conclude that the combination of ip cisplatin and 5-FU is an effective regimen for patients with residual or relapsed epithelial ovarian cancer with survival durations, response rates, and toxicity profiles that compare favorably with those of other second-line ovarian cancer regimens. Patients who are primarily platinum-refractory are unlikely to benefit from these agents administered into the peritoneal cavity.     

Intraperitoneal hyperthermic chemotherapy using carboplatin: a phase I analysis in ovarian carcinoma

OBJECTIVE: Cyclic platinum-based intraperitoneal chemotherapy has proven to be effective after optimal surgical cytoreduction in ovarian carcinoma. Hyperthermia is directly cytotoxic and enhances chemotherapy tumoricidal effects. This study was designed to determine the maximum tolerated dose (MTD) of carboplatin used intraoperatively as intraperitoneal hyperthermic chemotherapy (IPHC), the effect on postoperative systemic chemotherapy administration, and the potential for repeat IPHC at second look surgery. METHODS: Using the ThermoChem HT System, escalating doses of carboplatin (400, 600, 800, 1000, and 1200 mg/m(2)) were administered intraoperatively as IPHC with a perfusion time of 90 min. A subgroup of eight patients that received initial IPHC and subsequent systemic chemotherapy underwent second look reassessment surgery with IPHC. RESULTS: The first 4 dose levels were well tolerated without dose-defining toxicity. The initial two patients treated at 1200 mg/m(2) developed grade 4 myelosuppression thus defining the MTD at 1000 mg/m(2). Newly diagnosed ovarian cancer patients receiving the initial IPHC at the MTD defined above completed standard systemic chemotherapy with six courses of systemic chemotherapy. Eight patients having initial IPHC and systemic chemotherapy subsequently had repeat IPHC performed at second look laparotomy without grade 3 or 4 toxicities. Four patients were found to have extensive adhesions at the time of second look reassessment surgery yet completed IPHC. CONCLUSIONS: The MTD for intraperitoneal carboplatin administered as IPHC was established at 1000 mg/m(2). IPHC at the initial cytoreductive procedure did not preclude subsequent systemic chemotherapy. In addition, repetitive IPHC was feasible at second look reassessment surgery.     

Phase I/II study of weekly paclitaxel plus carboplatin and gemcitabine as first-line treatment of advanced-stage ovarian cancer: pathologic complete response and longitudinal assessment of impact on cognitive functioning

BACKGROUND: To determine the pathologic complete response rate of advanced ovarian cancer to weekly paclitaxel plus gemcitabine and carboplatin with filgrastim, and assess the longitudinal impact of this regimen on quality-of-life and cognitive functioning. METHODS: Fourteen patients with advanced ovarian, peritoneal, or fallopian tube cancer were treated in the phase I portion of the study. Initial doses were paclitaxel: 60 mg/m(2) days 1, 8, and 15; gemcitabine: 800 mg/m(2) days 1 and 8; and carboplatin: area under the curve (AUC) 5 day 1, every 21 days for 6 cycles with filgrastim. Twenty-seven patients were treated at the phase II dose. Pathologic response was assessed by second-look laparoscopy in patients with complete response. Patients completed longitudinal assessments of quality-of-life and cognitive functioning. RESULTS: Maximally tolerated doses were paclitaxel: 80 mg/m(2) days 1 and 8; gemcitabine: 800 mg/m(2) days 1 and 8; and carboplatin: AUC 5 day 1, every 21 days. Forty-eight percent of patients (13/27) experienced at least 1 grade 3 nonhematologic toxicity. Fifty percent (95% confidence interval [CI], 31-69%) of assessable patients achieved pathologic complete response. Median progression-free survival was 27.3 months (95% CI, 17.7 months to not reached), and overall survival 43.6 months (95% CI, 42 months to not reached). Cognitive functioning did not decline during or after chemotherapy. More highly educated women reported a perceived decline in concentration and memory while on chemotherapy. Quality-of-life scores were maintained during therapy. CONCLUSIONS: Fifty percent of patients with advanced-stage ovarian cancer achieved pathologic complete response to weekly paclitaxel plus gemcitabine and carboplatin. Cognitive functioning did not decline by objective measures, although highly educated women reported subjective impairment.     

Intraperitoneal carboplatin in the treatment of minimal residual ovarian cancer

Thirty-one ovarian cancer patients with minimal residual disease after intravenous cisplatin combination chemotherapy were treated with intraperitoneal carboplatin (IP-Ca). The dose of IP-Ca was escalated from 150 to 350 mg/m2. Twenty-two patients received at least three courses of IP-Ca and were evaluable for efficacy. Third-look laparotomy was done in 10 patients. Two patients obtained a complete pathological response (CPR) lasting 33+ and 41+ months, respectively; 8 patients had minimal residual disease. Median survival for all patients was 14+ months. All patients were eligible for toxicity. Maximum tolerable dose in these heavily pretreated patients was 300 mg/m2 IP-Ca. The dose-limiting toxicity was thrombocytopenia; in 27% of the patients who received 350 mg/m2 IP-Ca, WHO grade 4 thrombocytopenia was seen. No patient had WHO grade 4 leukopenia. Subjective side effects consisted of mild nausea and vomiting (WHO). In conclusion, IP-Ca can produce CPR in heavily pretreated patients with only minor side effects.     

The effects of CO2 pneumoperitoneum on the survival of women with persistent metastatic ovarian cancer

OBJECTIVES: The effects of CO(2) pneumoperitoneum on the survival of women with metastatic ovarian cancer have not been documented. We sought to describe the survival of women with persistent stage III-IV ovarian cancer as documented by positive second-look laparoscopy or laparotomy and to see whether the laparoscopic approach with CO(2) pneumoperitoneum has a negative effect on overall survival. METHODS: We conducted a retrospective review of all patients with FIGO stage III-IV invasive epithelial ovarian cancer who were found to have persistent disease at second-look surgery. All patients underwent primary surgery followed by intravenous chemotherapy and were clinically without evidence of disease prior to second-look surgery. Second-look laparoscopy began to be utilized regularly in 1994. The selection of the second-look surgical approach depended on the surgeon's discretion. CO(2) pneumoperitoneum was utilized for all laparoscopic cases with the maximum intra-abdominal pressure maintained at 15 mm Hg. Patients received a variety of additional intravenous, intraperitoneal, or oral chemotherapy following positive second-look surgery. RESULTS: Between 6/1/91 and 6/30/02, 289 patients were found to have persistent ovarian/peritoneal cancer at second look. Second-look operations included 131 (45%) transperitoneal laparoscopies and 139 (48%) laparotomies. Nineteen (7%) patients underwent laparoscopy followed immediately by laparotomy. The mean age, stage distribution, histology, grade, and size of residual disease at second look did not differ between the two groups. The median overall survival for patients who underwent laparoscopy, 41.1 months (95% CI, 33.2-58.1), did not significantly differ from that of the laparotomy group, 38.8 months (95% CI, 31.9-44.2) (P = 0.742). CONCLUSIONS: Transperitoneal laparoscopy with CO(2) pneumoperitoneum does not appear to reduce the overall survival of women with persistent metastatic intra-abdominal carcinoma of ovarian/peritoneal origin. The overall survival appears to be independent of the second-look surgical approach.     

Phase II study of sequential doublets: topotecan and carboplatin, followed by paclitaxel and carboplatin, in patients with newly diagnosed advanced ovarian cancer

OBJECTIVE: Incorporating topotecan into standard platinum/taxane chemotherapy for advanced ovarian cancer has been complicated by myelosuppression. This study evaluated sequential doublets of topotecan and carboplatin, followed by paclitaxel and carboplatin, in newly diagnosed advanced ovarian cancer patients. METHODS: Forty-five patients (median age, 56 years; range, 38-77 years) with stage III/IV disease and GOG performance status <2 were enrolled and received four cycles of topotecan (1.0 mg/m(2)/day on days 1 to 3) and carboplatin (AUC 4 on day 1), followed by four cycles of paclitaxel (175 mg/m(2) via 3-h IV infusion on day 1) and carboplatin (AUC 5 on day 1). All cycles were 21 days. Antitumor response was assessed after four and eight cycles; patients with clinical complete response (CR) underwent second-look laparotomy for determination of pathologic CR (PCR). Dose reductions were instituted for grade 4 neutropenia and thrombocytopenia, and for grade 3/4 nonhematologic toxicity. RESULTS: Among 41 CA-125 evaluable patients, complete and partial responses were observed in 29 (70.7%) and 11 (26.8%) patients, respectively. Of the 12 clinical CRs (43%) in 28 evaluable patients, 10 patients underwent second-look laparotomy, with 3 PCRs (30%). Median time to progression was 14 months and actuarial survival was 23 months. Neutropenia was the primary toxicity and cause of dose adjustments and delays, including two deaths. CONCLUSION: The antitumor activity observed is comparable with other series, although neutropenic complications were increased. Progression-free and actuarial survivals were slightly inferior. A Phase III trial (GOG 182) of sequential doublets in the reverse sequence is ongoing.     

Chemotherapy by the intravenous and intraperitoneal routes combined in ovarian cancer

Intraperitoneal (ip) administration allows delivery of concentrations of cytotoxic drugs to the site of tumor development that could not be attained by the intravenous (iv) route. Rather than leaving ip delivery systems (Tenckhoff catheter, Port à Cath, etc.) in position for several months, with the attendant risk of complications, we prefer to use a simple needle for lumbar puncture and leave it in place between 1 and 2 hr at each infusion of chemotherapy. Results observed at second-look laparotomy in 31 patients with stage III (FIGO) common epithelial carcinoma, treated from January 1980 to December 1986, are reported after six to ten courses of ip and iv chemotherapy combined. In five patients in whom complete surgical excision had been possible, there was still complete remission (CR). In 26 patients in whom initial surgical excision had been incomplete, there was complete remission in 20 (76%). In the other 6 cases, there were small residual masses (incomplete remission), which could readily be excised by the surgeon. Following second-look laparotomy, these 6 patients received ip maintenance chemotherapy for a further 6 months. During follow-up periods of 22 to 105 months (average 45 months), 8 recurrences were observed (4 of them died); 23 of 31 patients are disease free. At 4 years, actuarial survival was 81.5% and actuarial disease-free survival was 66.2%.     

Use of a murine model for comparison of intravenous and intraperitoneal cisplatin in the treatment of microscopic ovarian cancer

The most effective method for the delivery of cisplatin chemotherapy in the treatment of epithelial ovarian cancer limited to the presence of microscopic intraperitoneal disease is a controversial issue. The use of intravenous (iv) versus intraperitoneal (ip) cisplatin was evaluated in a murine tumor model of human epithelial ovarian cancer. Using single dose cisplatin therapy for microscopic disease limited to positive cytology of abdominal disease and microscopic peritoneal involvement, ip therapy had significantly greater (P less than 0.001) survival time than iv therapy (28 +/- 1.6 days vs. 23 +/- 1.6 days, respectively). Once ascites and macroscopically evident intraperitoneal tumor became apparent, no difference could be found in survival time based on iv versus ip therapy (16 +/- 3 days for both groups); though both forms of therapy significantly (P less than 0.05) prolonged survival in mice with macroscopic disease when compared to control animals (13 +/- 1.2 days). The evidence presented implies that ip cisplatin therapy is significantly more effective than iv therapy when dealing with microscopic intraperitoneal disease.     

First-line intraperitoneal carboplatin-based chemotherapy for 165 patients with epithelial ovarian carcinoma: results of long-term follow-up

OBJECTIVE: Currently, no long-term follow-up data are available on intraperitoneal (IP) carboplatin-based chemotherapy for ovarian carcinoma. In this study we evaluated retrospectively the survival and recurrence of a retrospective cohort of patients with epithelial ovarian cancer treated with first-line IP carboplatin-based therapy. METHODS: Records were reviewed of 174 patients with epithelial ovarian cancer who received IP carboplatin-based therapy between 1990 and 2000. All patients underwent surgical staging, and implantable port systems were placed regardless of residual tumor size. The pathological slides were submitted and reviewed, and then nine patients were excluded because of borderline malignancies (n = 8), and wrong histology (n = 1). Therefore, the records of 165 patients were analyzed for survival. Tumor grade was determined by the Universal grading system. Statistical analysis included tests for association between potential prognostic factors, and between prognostic factors and survival. Survival probabilities were estimated by Kaplan-Meier methods, and prognostic factors for survival were evaluated by a Cox regression model. RESULTS: The mean age of the patients was 53.7 years (range 21-83). The median follow-up was 41 months. The distribution by stage and histology was as follows: high risk (grade 2/3, clear cell, capsule rupture) stage I, 54; II, 21; III, 72; IV, 18; and serous, 75; clear cell, 30; mucinous, 27; endometrioid, 20; others, 13. The chemotherapy regimen was either carboplatin alone (n = 22) or in combination with cyclophosphamide (n = 116) or paclitaxel (n = 27). Catheter-related complications occurred in 16 (9.7%) cases. The chemotherapeutic response in 54 patients with measurable disease was 66.4%. The 5-year survival was 94.4% for stage I, and 87.9% for stage II. The median survival for optimal and suboptimal stage III/IV patients was 51 months and 34 months, respectively. The median survival of patients with stage III/IV disease was 51 months with carboplatin doses of 400 mg/m(2) or more, but it was only 25 months with carboplatin doses smaller than 400 mg/m(2). Poor prognostic factors, determined by Cox regression multivariate analysis, were clear cell histology (P < 0.001) and a carboplatin dose smaller than 400 mg/m(2) (P = 0.002). CONCLUSIONS: Survival of patients who underwent carboplatin-based IP chemotherapy was excellent when the dose of carboplatin was higher than 400 mg/m(2). A prospective evaluation of IP carboplatin therapy with modern combination is warranted.