Follow-up of Memorial Sloan-Kettering Cancer Center patients treated on National Cancer Institute Treatment Referral Center protocol 9103: paclitaxel in refractory ovarian cancer.

PURPOSE: To examine the short-term and long-term results of paclitaxel therapy in patients with advanced heavily pretreated, cisplatin-refractory ovarian cancer. PATIENTS AND METHODS: The results of treatment for patients entered onto National Cancer Institute (NCI) Treatment Referral Center protocol 9103 at the Memorial Sloan-Kettering Cancer Center (MSKCC) were reviewed to evaluate toxicity, efficacy, and survival. RESULTS: Of 46 individuals with measurable disease treated on the protocol at MSKCC, the objective response rate was only 4%. However, the 2- and 3-year survival rates for all 103 patients (including both measurable and nonmeasurable populations) entered onto this study at MSKCC were 18% and 11%, respectively. Twenty-one percent of patients received > or = six courses of paclitaxel, which suggests treatment-related stabilization of disease may have had a greater impact on the natural history of the malignancy than indicated by the objective response rate. CONCLUSION: This experience supports the hypothesis that a more prolonged delivery of paclitaxel (ie, > six courses), a cell-cycle-specific cytotoxic agent with limited or no cumulative toxicity, may result in an improved therapeutic outcome in ovarian cancer. This concept will need to be tested in a randomized phase 3 clinical trial.

Phase II and pharmacologic study of docetaxel as initial chemotherapy for metastatic breast cancer.

PURPOSE: Because docetaxel (Taxotere, RP 56976; Rhone-Poulenc Rorer, Antony, France) appeared to be active against breast cancer in phase I trials, we performed this phase II study. PATIENTS AND METHODS: Thirty-seven patients with measurable disease were enrolled. Only prior hormone therapy was allowed, as was adjuvant chemotherapy completed > or = 12 months earlier. Docetaxel 100 mg/m2 was administered over 1 hour every 21 days. Diphenhydramine hydrochloride and/or corticosteroid premedication was added after hypersensitivity-like reactions (HSRs) were seen in two of the first six patients. Pharmacokinetic studies were performed during cycle 1 for correlation with toxicity. RESULTS: Thirty-seven patients were assessable. Nineteen (51%) required dose reductions, usually for neutropenic fever. The median nadir WBC count was 1.4 x 10(3)/microL. HSRs were noted in 20 patients (54%). At a median cumulative dose of 297 mg/m2 (range, 99.6 to 424.5 mg/m2), 30 patients (81%) developed fluid retention, for which 11 (30%) subsequently stopped treatment. The first-cycle plasma area under the concentration-time curve (AUC) did not correlate with toxicity, although an ineligible patient with hepatic metastases (pretreatment bilirubin level 1.8 mg/dL) had an elevated AUC and died of toxicity. Responses were seen at all sites. On an intent-to-treat basis, there were two (5%) complete responses (CRs) and 18 (49%) partial responses (PRs). The overall response proportion (CRs plus PRs) was 54% (95% confidence interval, 37% to 71%). The median time to response was 12 weeks (range, 3 to 15) and the median duration was 26 weeks (range, 10 to 58+). CONCLUSION: Docetaxel is active for metastatic breast cancer. Neutropenia and fluid retention are dose-limiting. The AUC did not predict toxicity, but caution is warranted when treating patients with liver dysfunction. An understanding of the pathophysiology of the fluid retention may facilitate prevention. Frequent HSR may warrant prophylactic premedication.

Phase I feasibility and pharmacologic study of weekly intraperitoneal paclitaxel: a Gynecologic Oncology Group pilot Study.

PURPOSE: This study was designed to define the maximum-tolerated dose (MTD) and pharmacology of paclitaxel administered by the intraperitoneal (IP) route on a weekly schedule. PATIENTS AND METHODS: Thirty-three patients with residual ovarian cancer following standard chemotherapy were entered onto this phase I trial. Patients were treated weekly with IP paclitaxel administered in 2 L of normal saline following premedication. Patients with nonassessable disease received 16 weekly courses. The initial dose level was 20 mg/m2/wk. There was no intrapatient dose escalation. RESULTS: Multiple grade 2 toxicities were observed at the 75-mg/m2/wk dose level. These toxicities included abdominal pain, nausea, vomiting, leukopenia, and fatigue. One episode of grade 4 vomiting thought to be secondary to a transient partial small-bowel obstruction occurred at this dose level. At dose levels > or = 60 to 65 mg/m2, pharmacology studies documented the persistence of significant IP paclitaxel levels 1 week after drug administration, suggesting very slow peritoneal clearance and continuous exposure of the peritoneal cavity to active concentrations of paclitaxel. Low plasma paclitaxel concentrations were detected in the majority of patients treated at dose levels > or = 55 mg/m2. CONCLUSION: Paclitaxel can be delivered by the IP route on a weekly schedule with both an acceptable toxicity profile and a major pharmacokinetic advantage for cavity exposure. The recommended dose and schedule for phase II study of IP paclitaxel is 60 to 65 mg/m2 weekly.

Quality of life of women with ovarian cancer.

The primary objectives of this study were to determine the nature and extent of physical problems and psychological distress experienced by women with ovarian cancer and to identify medical and sociodemographic factors that were predictive of distress. Quality of life was assessed at 3-month intervals, for a maximum of 12 months in 151 ovarian cancer patients, most with advanced-stage disease (86%). Patients' pain, other physical symptoms, level of physical functioning, psychological state, and social functioning were evaluated using the following measures: a detailed pain questionnaire, Memorial Pain Assessment Card, Memorial Symptom Assessment Scale, Mental Health Inventory (MHI), Functional Living Index--Cancer (FLIC), and the Karnofsky Performance Status. Upon entry, 33% of patients reported significant psychological distress, as indicated by MHI Psychological Distress scores (MHI-PD) equal or greater to 1.5 standard deviations above the mean of a nationwide community sample. Impaired physical functioning (FLIC subscale) was the most important predictor of heightened psychological distress (MHI-PD) at baseline (1.5 SD or greater above the norm) (P = 0.0004) in a stepwise logistic regression involving medical/physical and sociodemographic variables as predictors. Further, significant differences were found in all quality of life scales between patients with Karnofsky Performance Status scores of < or = 80, and those with ratings of 90 or greater (P = 0.036 to P < 0.0001). These data suggest the need for an improved and more frequent assessment of ovarian cancer patients' psychological status, particularly as physical functioning declines, to improve early detection and referral to treatment of those suffering from psychiatric sequelae of cancer.

Paclitaxel as second and subsequent therapy for metastatic breast cancer: activity independent of prior anthracycline response.

PURPOSE: Two phase II clinical trials were performed to determine efficacy and tolerability of paclitaxel (Taxol; Bristol-Myers Squibb Co, Wallingford, CT) and granulocyte colony-stimulating factor ([G-CSF] Neupogen; Amgen, Inc, Thousand Oaks, CA) as second or subsequent therapy for metastatic breast cancer. PATIENTS AND METHODS: Paclitaxel plus G-CSF was administered as a second stage IV regimen to 25 patients with metastatic breast cancer at a dose of 250 mg/m2 intravenously over 24 hours. Fifty-two patients received paclitoxel plus G-CSF at 200 mg/m2 as a third or subsequent regimen (no restriction on number of prior regimens or on prior high-dose chemotherapy). All patients had received prior anthracycline treatment, and ultimately had progressive bidimensionally measurable disease. RESULTS: Twenty-five of 76 patients (32.8%) had a major objective response (95% confidence interval [CI], 14% to 37%). The median duration of response was 7 months (range, 1 to 20+). Responses were as likely in patients with disease demonstrated to be unresponsive to anthracycline, ie, de novo resistance (11 of 37, or 30%) as in those with disease that once exhibited anthracycline sensitivity, ie, acquired resistance, (10 of 31, or 32%). G-CSF administration was associated with febrile neutropenic episodes in 36 of 402 cycles (9%) in 16 of 76 patients (21%). CONCLUSION: Paclitaxel's clinically significant activity against metastatic breast cancer extends to patients with many prior chemotherapy regimens. The lack of impact of prior doxorubicin therapy on the likelihood of subsequent response to paclitaxel suggests an important role for this agent in the treatment of refractory metastatic breast cancer.

Dose escalation of paclitaxel with high-dose cyclophosphamide, with analysis of progenitor-cell mobilization and hematologic support of advanced ovarian cancer patients receiving rapidly sequenced high-dose carboplatin/cyclophosphamide courses.

PURPOSE: We commenced a phase I study of escalating dose Taxol (paclitaxel; Bristol-Myers Squibb Co, Wallingford, CT) in addition to cyclophosphamide, to assess its impact on both antitumor efficacy and mobilization of peripheral-blood progenitor cells (PBP). PATIENTS AND METHODS: Induction therapy consisted of two cycles of cyclophosphamide 3.0 g/m2 plus escalating-dose Taxol (dose levels I to IV, 150, 200, 250, and 300 mg/m2, respectively) in cohorts of three, plus filgrastim granulocyte colony-stimulating factor [G-CSF]) and leukaphereses to harvest PBP, followed by four courses of rapidly cycled carboplatin and cyclophosphamide (1,000 and 1,500 mg/m2 per course, respectively), for which hematopoietic rescue was achieved with PBP. RESULTS: Sixteen patients completed all planned cycles of Taxol/cyclophosphamide. Fifty-four cycles of carboplatin/cyclophosphamide were given and rescued with PBP. The median interval between treatments for Taxol/cyclophosphamide courses was 14 days (range, 13 to 21). Twelve patients completed all planned cycles of carboplatin/cyclophosphamide. The median inter-treatment interval for carboplatin/cyclophosphamide courses when rescue was achieved with Taxol/cyclophosphamide-primed PBP was 17 days (range, 14 to 25). The median number of days to recovery of an absolute neutrophil count (ANC) greater than 0.5 was 8 (range, 5 to 12), and of self-sustaining platelet count greater than 20 x 10(9)/L, 11 (range, 8 to 15). There was one episode of fatal sepsis. Of 13 patients assessable for response, there were five patients with pathologic complete responses (38.5%), six patients with microscopic residual disease (46%), and two patients with pathologic partial responses, for an overall response rate of 100%. CONCLUSION: The addition of escalating-dose Taxol to high-dose cyclophosphamide does not compromise PBP mobilization. The use of PBP mobilized in this fashion provides reliable engraftment after sequential administration of high-dose carboplatin/cyclophosphamide. Toxicities produced with this approach are manageable. The response rates demonstrated are promising and warrant further evaluation.

A phase II trial of extracorporeal plasma immunoadsorption of patient plasma with PROSORBA columns for treating metastatic breast cancer.

BACKGROUND: Circulating immune complexes (CIC) have been implicated as a cause of malignancy-associated immunosuppression and disease progression. Previous attempts to remove CIC by pheresis or immunoadsorption over a Staphylococcus aureus protein A column have resulted in a few clinical responses, however the relationship between removal of CIC and tumor response in these trials is not clear. Based on these data, a Phase II trial of immunoadsorption over a Staphylococcus aureus protein A column was initiated for patients with metastatic breast cancer. The authors sought to correlate clinical response with amount of CIC eluted from the columns after immunoadsorption. METHODS: The potential role of extracorporeal immunoadsorption was determined using protein A columns in treating patients with advanced breast cancer. An immunoadsorbent column composed of protein A was bound covalently to an inert silica matrix (PROSORBA [IMRE Corporation, Seattle, WA] column). Patients underwent a 3-hour on-line procedure phlebotomizing 2000 ml of whole blood. Patient plasma was passed over PROSORBA columns to remove immunoglobulin G (IgG) and IgG-related CIC. The treated plasma then was reunited with formed elements and reinfused into the patient. Patients were treated three times per week for a total of 4 weeks. Analyses of tumor-associated Le(x)-containing CIC adsorbed on PROSORBA columns were performed using an enzyme-linked immunosorbent assay technique with a monoclonal antibody specific for the Le(x) moiety. RESULTS: Sixteen patients were entered in this Phase II study, with a mean age of 57 years (range, 40-69 years). All patients received prior treatment for Stage IV breast cancer. The median number of PROSORBA treatments was 12 (range, 1-15 treatments). No toxicities or major objective responses were seen noted the 16 patients. One patient with severe chest wall pain had a symptomatic response. The remaining patients all had disease progression. Analyses of column eluates from 11 patients in this study revealed no detectable Le(x)-containing immune complexes when compared with control subjects. CONCLUSIONS: Immunoadsorption over a Staphylococcus aureus Protein A column had no meaningful antitumor activity in patients with advanced breast cancer. In this cohort of patients, an elevated level of Le(x) CIC was not confirmed in the eluates of the column compared with a control group of patients without cancer.

Simultaneous dose escalation and schedule intensification of carboplatin-based chemotherapy using peripheral blood progenitor cells and filgrastim: a phase I trial.

Our purpose was to determine the maximum tolerated dose of, and the minimum interval between treatments with, multiple cycles of carboplatin (CBDCA) rescued with peripheral blood progenitors and filgrastim. Eligible patients had advanced cancers without prior chemotherapy or radiotherapy. The study design involved a sequential cross-over in which patients initially received two or three courses of cyclophosphamide (CPA) at a dose of 3.0 g/m2, supported by filgrastim. Multiple leukaphereses were then performed during the rebound phase of hematological recovery following each CPA-induced nadir to harvest peripheral blood progenitors, which were then reinfused as rescue following each of four courses of CBDCA. We attempted to administer the CBDCA at 14-day intervals. The CBDCA dose (mg/m2/course) was escalated as follows in successive cohorts of patients: Level I, 500; Level II, 800; Level III, 1200; Level IIIa, 1000. Following determination of the maximum tolerated dose of CBDCA administered in this fashion, a subsequent cohort of patients (Level IV) were treated with two courses of high-dose CPA and four courses of the combination of CBDCA (1000 mg/m2) plus CPA (1500 mg/m2). Thirty-one patients were enrolled in the trial. Five patients were removed from study prior to completion of protocol therapy, three due to toxicity and two who developed progressive cancer while on study. The maximum tolerated dose of CBDCA was 1000 mg/m2, with dose-limiting ototoxicity occurring at 1200 mg/m2. The median inter-treatment interval for all cycles was 15 days (range, 12-30). The median intervals between CBDCA courses for each dose level were: Level I, 17 days; Level II, 17 days; Level III, 14 days; Level IIIa, 15 days; Level IV, 16 days. The median dose intensity of the CPA phase was 1493 mg/m2/week. The median (and range) CBDCA dose intensities (measured from the start of CBDCA) for each dose level were: I, 185 (151-222); II, 328 (305-380); III, 567 (512-646); IIIa, 465 (363-481); Level IV, 468 (333-500). Neutropenic fever complicated 35 of 113 CBDCA or CBDCA/CPA courses. Platelet transfusion was required in 51 of 113 courses. One patient had severe epistaxis. There were no treatment-related deaths. Among 27 patients with ovarian cancer who were evaluable for response, there were 5 pathologically documented complete (including 3 of 10 at Level IV) and 16 partial responses. We concluded that peripheral blood progenitors facilitate the simultaneous dose escalation and schedule intensification of carboplatin chemotherapy. The effect is sustained over four courses of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Phase II trial of docetaxel in patients with platinum-refractory advanced ovarian cancer.

PURPOSE: This phase II study was conducted to evaluate the efficacy and toxicity of docetaxel in the treatment of patients with platinum-refractory ovarian cancer. PATIENTS AND METHODS: Twenty-five patients with platinum-refractory advanced ovarian cancer were treated. Twenty of the patients had failed to respond to platinum-based front-line chemotherapy and five had failed to respond to platinum-based therapy repeated at relapse. One patient had received prior pelvic radiation therapy. Patients were required to have bidimensionally measurable disease. Docetaxel was administered at a dose of 100 mg/m2 intravenously (i.v.) over 1 hour every 21 days. Twenty patients received no corticosteroid premedication and five received premedication with corticosteroids and antihistamines. RESULTS: Eight of 23 assessable patients (35%) had a partial response (PR; 95% confidence interval, 16% to 57%). The median response duration was 5 months. Hospitalization for toxicity, predominantly neutropenic fever, occurred in 12 patients (48%) and 16% of courses. Anemia was common in the study population. Nonhematologic toxicities included alopecia, rash, fluid retention, diarrhea, peripheral neuropathy, and hypersensitivity reactions. CONCLUSION: Docetaxel demonstrates significant activity in patients with platinum-refractory advanced ovarian cancer. Routine premedication is recommended. Further investigations of this agent in ovarian cancer, including combinations with other active agents, appear indicated.

Taxol (paclitaxel) plus recombinant human granulocyte colony-stimulating factor in the treatment of metastatic breast cancer.

We treated 28 patients who had no prior chemotherapy for stage IV breast cancer and 51 patients with extensive prior exposure to other chemotherapeutic agents with a 24-hour infusion of Taxol (paclitaxel) as a single agent. Prophylactic recombinant human granulocyte colony-stimulating factor was administered routinely to ameliorate the anticipated dose-limiting toxicity of neutropenia. Nonhematologic toxicity was mild to moderate in most cases. Taxol was more active in patients with chemotherapy-naive stage IV disease, but activity was also observed in extensively treated patients as well. There is a strong clinical suggestion of at least partial noncross-resistance with doxorubicin. Taxol is a very promising agent for the treatment of metastatic breast cancer; its optimal application in this disease will be the subject of future trials.

Pain in ovarian cancer patients. Prevalence, characteristics, and associated symptoms.

BACKGROUND: The prevalence, characteristics, and impact of pain and other symptoms have not been studied systematically in women with ovarian cancer. Anecdotally, pain has been associated with the onset of the disease and is a common problem among those with advanced cancer; symptoms other than pain appear to be highly prevalent. Given the profound influence of pain and other symptoms on quality of life, the evaluation of these phenomena could provide data relevant to the clinical management of these patients and advance quality of life research in the area of symptom assessment. METHODS: Questionnaires were completed by 111 inpatients and 40 outpatients with ovarian cancer who were undergoing treatment at a cancer center. Measures included a comprehensive pain questionnaire; the Rand Mental Health Inventory, Functional Living Index--Cancer; and the Memorial Symptom Assessment Scale. RESULTS: The sample (N = 151) represented 74% of the eligible patients. The median age was 55 years (range, 23-86), 82% had Stage III or IV disease at presentation, and 69% had active disease at the time of the survey. Pain, fatigue, and psychologic distress were the most prevalent symptoms. Sixty-two percent (N = 94) described a pain syndrome that preceded the onset or recurrence of the disease, and 42% (N = 63) reported "persistent or frequent pain" during the preceding 2 weeks. The latter pain had a median duration of 2 weeks (range, less than 1 to 756 weeks) and usually was in the abdominopelvic region (80%), frequent or almost constant (66%), and moderate to severe. Most patients reported moderate or greater pain-related interference with various aspects of function, particularly activity (68%), mood (62%), work (62%), and overall enjoyment of life (61%). Performance status, inpatient status, and unmarried status were significant predictors of pain presence or intensity, and both performance status and extent of tumor were significant predictors of pain interference with function. CONCLUSIONS: Among those with ovarian cancer, greater than 40% experienced pain that substantially undetermined function in one half to two thirds of these patients. Impaired performance status is associated most strongly with pain. The onset or recurrence of disease often is heralded by a stereotypic pain syndrome.

High-intensity chemotherapy with peripheral blood progenitor cell support.

In a series of clinical studies at Memorial Sloan-Kettering Cancer Center, we have used hematopoietic growth factors and peripheral blood-derived hematopoietic progenitor cells to facilitate delivery of multiple courses of high-dose chemotherapy at abbreviated treatment intervals. In these studies, we have demonstrated the feasibility of cross-over regimens involving induction chemotherapy with high-dose cyclophosphamide, supported by granulocyte colony-stimulating factor and followed by multiple peripheral blood leukapheresis to harvest progenitor cells. These cells are then used as rescue for the consolidation component of treatment, which, in the earlier-generation studies, consisted of a single course of high-dose carboplatin/etoposide/cyclophosphamide chemotherapy. In subsequent studies, patients received either four courses of high-dose carboplatin or carboplatin/cyclophosphamide or tandem courses of thiotepa. In all cases, the planned interval between treatments was 14 days, and the achieved median was approximately 16 days. These studies show that the administration of high-intensity regimens that deliver multiple courses of very high-dose chemotherapy at relatively brief intervals is feasible. Our current research focuses on exploiting these findings to devise disease-specific regimens for breast and ovarian cancer.

Intraperitoneal Taxol (paclitaxel) in the management of ovarian cancer.

In an effort to examine the safety and pharmacology of the intraperitoneal (i.p.) delivery of paclitaxel, 25 patients (24 with ovarian cancer) were treated in a phase I dose escalation trial. The drug was administered in normal saline every 3 to 4 weeks, starting at a dose of 25 mg/m2. The dose-limiting toxicity at doses at or above 175 mg/m2 was abdominal pain. A 3-log pharmacokinetic advantage for peritoneal cavity exposure to paclitaxel, compared with the systemic compartment, was observed. High levels of drug persisted within the cavity for longer than 48 hours following a single treatment. In addition, significant paclitaxel concentrations were found in the systemic compartment after i.p. treatment, despite the pharmacokinetic advantage demonstrated for cavity exposure. Several patients exhibited clinical and laboratory evidence of an antitumor response. On the basis of these data, further exploration of a potential role for i.p. paclitaxel in the management of ovarian cancer appears justified.

Paclitaxel and recombinant human granulocyte colony-stimulating factor as initial chemotherapy for metastatic breast cancer.

PURPOSE: A phase II study of Taxol (paclitaxel; Bristol-Myers Squibb Co, Princeton, NJ) as initial chemotherapy for metastatic breast cancer was conducted. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was used to ameliorate myelosuppression, the anticipated dose-limiting toxicity. PATIENTS AND METHODS: Twenty-eight patients with bidimensionally measurable breast cancer who had not received prior chemotherapy for metastatic disease were treated. Taxol was administered at 250 mg/m2 as a continuous 24-hour intravenous (i.v.) infusion every 21 days. rhG-CSF was administered at 5 micrograms/kg/d subcutaneously on days 3 through 10. RESULTS: Objective responses were observed in 16 of 26 assessable patients (62%; 95% confidence interval, 41% to 80%). There were three (12%) complete responses (CRs) and 13 (50%) partial responses (PRs). Ten of 16 patients (63%) who had received prior adjuvant chemotherapy responded, which included one CR and four PRs among eight patients who had received prior doxorubicin-containing therapy. Responses were observed in all sites of metastatic disease. The median time to first objective response was 5 weeks (range, 1 to 14). Administration of rhG-CSF was associated with a short duration of neutropenia (median, 2 days with absolute neutrophil count < 500 cells/microL). Eight of 26 patients (31%) who received more than one course received subsequent therapy without dose reduction. One hundred seventy-eight cycles of treatment were administered, with a median of six cycles per patient (range, one to 19). Eight courses (4.5%) were associated with admissions for neutropenic fever. Twenty-two patients (79%) did not require admission for neutropenic fever. Treatment was well tolerated. Adverse effects included generalized alopecia in all patients. Myalgias, arthralgias, and peripheral neuropathy were mild. No hypersensitivity reactions and no cardiac toxicity were observed. CONCLUSION: Taxol is highly active as initial chemotherapy for metastatic breast cancer. Administration of rhG-CSF reduced the incidence, depth, and duration of neutropenia, compared with published prior experience. Further studies of Taxol in breast cancer, including combinations with other active agents, are clearly warranted.

Preliminary experience with paclitaxel (Taxol) plus recombinant human granulocyte colony-stimulating factor in the treatment of breast cancer.

Single-agent paclitaxel (TAXOL) was administered to 79 patients with stage IV breast cancer. Twenty-eight patients had no prior chemotherapy (for metastatic disease), and 51 patients had extensive exposure to other chemotherapeutic agents before beginning the 24-hour paclitaxel infusion. Routine use of recombinant human granulocyte colony-stimulating factor helped to ameliorate neutropenia, the dose-limiting toxicity, in some cases. Other toxicity was generally mild to moderate. Paclitaxel was more active in patients whose stage IV disease had not yet been exposed to chemotherapy, but activity was seen in the patients previously treated extensively as well. There is a strong clinical suggestion of non-cross-resistance with doxorubicin. In one case, an excellent response in previously irradiated skin was seen. Paclitaxel is a very promising agent for the treatment of metastatic breast cancer.

Second-look laparotomy in stage I ovarian cancer following comprehensive surgical staging.

OBJECTIVE: To evaluate the role of second-look laparotomy in patients with comprehensively staged stage I epithelial ovarian cancer. METHODS: We reviewed the medical records and obtained long-term follow-up on 54 stage I patients who had second-look laparotomies following complete surgical staging and chemotherapy. RESULTS: The distribution by stage was as follows: stage IA 18 (33%), stage IB two (4%), and stage IC 34 (63%). Eighteen patients (33%) had endometrioid tumors, 12 (22%) clear cell, 13 (24%) mucinous, eight (15%) serous, and three (6%) undifferentiated. Forty-four patients (82%) had grade 2 or 3 tumors. Thirty-eight (70%) were treated with platinum-based regimens and 16 (30%) received non-platinum regimens. At second-look laparotomy, tumor was identified in three women (5.5%). Stage, cell type, and grade did not predict the second-look laparotomy result, although no patient with a grade 1 tumor had a positive second-look laparotomy. With a mean follow-up of 48 months from second-look laparotomy, 11 women (22%) have had recurrences following negative second looks. Tumor grade was a strong predictor of recurrence following negative second-look laparotomy (P < .0001), with the risk of recurrence being 0% for grades 1 and 2 and 52% for grade 3. Substage, cell type, and chemotherapy type and duration did not predict recurrence. CONCLUSIONS: The likelihood of a positive second-look laparotomy is about 5% in well-staged stage I ovarian cancer. Patients with stage I, grade 3 tumors have a risk of recurrence of approximately 50% following negative second-look laparotomy.

Platinum-based chemotherapy of high-risk stage I epithelial ovarian cancer following comprehensive surgical staging.

OBJECTIVE: To determine the long-term outcome in patients with high-risk stage I epithelial ovarian cancer treated with adjuvant platinum-based chemotherapy following comprehensive surgical staging. METHODS: We conducted a retrospective review of 62 patients with stage IA and IB (grades 2 or 3) and stage IC (all grades) epithelial ovarian cancer treated with platinum-based chemotherapy following comprehensive surgical staging. Clinicopathologic correlations were performed using disease-free survival as the end point. RESULTS: The mean patient age was 47 years. The distribution by stage was IA in 19 (31%), IB in four (6%), and IC in 39 (63%). Eighty percent of the patients had grade 2 or 3 tumors. The distribution by cell type was as follows: clear-cell 22 (35%), endometrioid 15 (24%), mucinous 11 (18%), serous eight (13%), and undifferentiated six (10%). The patients underwent an average of six cycles of platinum-based therapy. With a median follow-up of 40 months among survivors, 15 patients (24%) have relapsed, at a median interval of 22 months from diagnosis. Relapses occurred primarily in the peritoneal cavity and retroperitoneal lymph nodes. No patient has been rendered free of disease after relapse. Patients with grade 3 tumors had an increased risk of relapse as compared to those with grade 1 or 2 tumors (46 versus 8%; P = .002). Patients with clear-cell tumors had a higher risk of relapse than those with other cell types (41 versus 15%; P = .05). There was no statistically significant relationship between risk of recurrence and substage. None of 11 patients with stage IA, grade 2 disease had recurrence. Actuarial 5-year disease-free survival for the entire group of 62 patients was 73%. CONCLUSION: Platinum-based chemotherapy for high-risk stage I ovarian cancer does not appear to improve survival over that previously reported with non-platinum regimens.

Evidence supporting the superiority of intraperitoneal cisplatin compared to intraperitoneal carboplatin for salvage therapy of small-volume residual ovarian cancer.

PURPOSE: To examine the relative efficacy of cisplatin-based intraperitoneal (IP) therapy versus carboplatin-based IP therapy as salvage treatment of small-volume residual ovarian cancer. PATIENTS AND METHODS: We retrospectively examined the surgically defined response rates of patients with ovarian cancer treated at the Memorial Sloan-Kettering Cancer Center on four organoplatinum-based salvage IP trials (cisplatin/etoposide, cisplatin/cytarabine, carboplatin/etoposide, carboplatin/etoposide + recombinant human erythropoietin). Additional criteria for inclusion in this analysis were: (a) small-volume residual disease (microscopic disease only or largest residual tumor mass < or = 0.5 cm) when IP therapy was initiated; (b) prior response to organoplatinum-based systemic therapy; (c) laparotomy evaluation for response to the IP salvage program. RESULTS: The surgically documented complete response rate for patients with microscopic disease treated with cisplatin-based or carboplatin-based therapy was 46% (6/13) versus 38% (6/16), respectively (P > 0.25). In contrast, the surgically documented overall and complete response rates for patients with small-volume macroscopic disease treated with cisplatin or carboplatin were 71% (12/17) versus 32% (6/19) (P < 0.05, chi 2 test with Yates' correction), and 41% (6/17) versus 11% (2/19) (p < 0.1), respectively. CONCLUSION: In agreement with experimental data demonstrating that the concentration of platinum within tumor is higher following equimolar doses of cisplatin, compared to carboplatin, we have observed, in this retrospective analysis, a higher surgically documented response rate for patients with small-volume residual macroscopic ovarian cancer receiving salvage cisplatin-based IP therapy. While a randomized trial will be required to definitively address the question of the relative effectiveness of the two commercially available organoplatinum agents for IP treatment of ovarian cancer, our data suggest that cisplatin is the superior agent for regional therapy in this disease.

Mitomycin-C plus a 3-day continuous intravenous infusion of 5-fluorouracil: an inactive salvage regimen for platinum-resistant ovarian carcinoma.

In a Phase II trial, patients with refractory ovarian cancer were given 10 mg/m2 mitomycin-C i.v. every 8 weeks and 1000 mg/m2/day 5-fluorouracil for 3 consecutive days by continuous intravenous infusion repeated every 4 weeks. Sixteen heavily pretreated patients with platinum-resistant disease were treated and no major responses were observed. Only 2 patients required subsequent dose reduction for myelotoxicity. No sign of gastrointestinal toxicity was seen. This regimen is inactive as salvage treatment for refractory ovarian cancer.