A randomized phase II evaluation of weekly gemcitabine plus pazopanib versus weekly gemcitabine alone in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma.

OBJECTIVE: Angiogenesis inhibition is a valuable strategy for ovarian cancer (EOC). Pazopanib (paz) is a potent small molecular inhibitor of VEGF-1, -2, -3, PDGFR, c-kit, and has activity as a single agent in ovarian cancer. We designed a trial to assess the benefit of adding paz to gemcitabine (gem) in patients with recurrent EOC. METHODS: An open-label, randomized, multi-site, phase 2 trial was conducted (NCT01610206) including patients with platinum resistant or sensitive disease, ≤ 3 prior lines of chemotherapy, and measurable/evaluable disease. Patients were randomly assigned to weekly gem 1000 mg/m2 on days 1 and 8 of a 21 day cycle, with or without paz 800 mg QD, stratified by platinum sensitivity and number of prior lines (1 vs 2 or 3). The primary endpoint was PFS. RESULTS: 148 patients were enrolled 2012-2017. Median age was 63 years (30-82); 60% were platinum resistant; median surveillance was 13 months (0.4-54 months). Median PFS was 5.3 (95% CI, 4.2-5.8) vs 2.9 months (95% CI, 2.1-4.1) in the gem arm. The PFS effect was most pronounced in the platinum resistant group (5.32 vs 2.33 months Tarone-Ware p < 0.001). There was no difference in OS. Overall RR (PR 20% vs 11%, Chi-squre p = 0.02) and DCR (80% vs 60%, Chi-square p < 0.001) were higher in the combination. High grade AEs in the combination arm included ≥ Grade 3: hypertension (15%), neutropenia (35%), and thrombocytopenia (12%). CONCLUSIONS: The addition of paz to gem enhanced anti-tumor activity; those with platinum-resistant disease derived the most benefit from combination therapy, even in the setting of receiving prior bevacizumab.

Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response.

The antitumor antibiotic, adriamycin, induces severe cardiac toxicity associated with peroxidation of cardiac lipids in mice. Both this lipid peroxidation and cardiac toxicity of adriamycin are reduced by prior treatment of the animals with the free radical scavenger tocopherol. Such treatment with tocopherol does not, however, alter the magnitude or duration of the adriamycin-induced suppression of DNA synthesis in P388 ascites tumor, nor does it diminish the antitumor responsiveness of P388 ascites tumor. These results suggest that adriamycin has at least two mechanisms of tissue damage: one, which involves lipid peroxidation, is blocked by tocopherol and results in cardiac toxicity; the other, which involves binding to DNA, is not antagonized by tocopherol and is responsible for tumor response.

Clinical and pharmacologic reappraisal of dichloromethotrexate.

Dichloromethotrexate (DCMTX) has been the subject of sporadic clinical development for the last 30 years. Although DCMTX was developed in hopes of discovering a more potent antifolate, the potential pharmacologic and toxicologic advantages of the analog have become of greater interest. This phase I and pharmacokinetic trial of DCMTX given on days 1, 8, and 15 every 28 days was undertaken to test these potential advantages. The maximally tolerated dose on this schedule was 980 mg/m2. Hepatic toxicity was dose limiting. Malaise, myelosuppression, and mucositis were also major toxic effects. The recommended dose for subsequent phase II studies of DCMTX administered on this schedule is 785 mg/m2 with a reduction to 625 mg/m2 for patients with a poor performance status or extensive prior therapy. Plasma disappearance curves for most patients were biphasic or triphasic, although several demonstrated more complex kinetic patterns that suggested significant enterohepatic circulation. The magnitude of the area under the plasma disappearance curve was related to the severity of DCMTX-induced hepatotoxicity. The elimination kinetics were linear, with a mean plasma clearance of 294 mL/min (range, 128-715). The pharmacokinetic behavior of DCMTX does not support its use over methotrexate in regional perfusion. DCMTX's primarily nonrenal elimination suggests that it may have an advantage over methotrexate when combined with nephrotoxic drugs such as cisplatin. However, there is little reason to commit major resources to further evaluation of DCMTX unless significant advantages in antineoplastic activity are identified.

Phase I trial of trimetrexate glucuronate on a five-day bolus schedule: clinical pharmacology and pharmacodynamics.

Trimetrexate glucuronate (TMTX), a nonclassical folate antagonist, has been evaluated clinically on several schedules. We have studied TMTX administered as an iv bolus for 5 consecutive days every 3 weeks in 35 patients with advanced solid tumors. Drug was given at doses ranging from 7.6 to 18.8 mg/m2. The maximal tolerated dose was 13.1 mg/m2 per day x 5 for patients without prior myelotoxic treatment and 7.6 mg/m2 per day x 5 for previously treated patients. Because of wide individual differences in drug tolerance, dose escalation in 25% increments is recommended for patients not experiencing toxic effects. The dose-limiting toxicity was neutropenia. Rash and mucositis were also significant. TMTX concentrations were measured 1 and 24 hours after each dose, and the data were fit by use of a one-compartment pharmacokinetic model. With this simplified sampling and modeling scheme, the mean total body clearance (+/- SD) of trimetrexate was 31 +/- 20 mL/min per m2 and the volume of distribution was 13 +/- 7 L/m2. Mean plasma concentrations 1 hour after a dose were 1.12, 2.43, 3.33, and 3.25 mumol/L at 7.6, 9.1, 10.9, and 13.1 mg/m2, respectively. The mean TMTX concentration (+/- SD) 24 hours after a dose was 114 +/- 87 nmol/L. The mean area under the concentration-versus-time curve at 13.1 mg/m2 was 2,266 mumol.min/L. The drug concentration 1 hour after the first dose and the area under the concentration-versus-time curve were highly correlated with leukopenia and thrombocytopenia (r = .6 and .65 and P = .0007 and .0001, respectively). The maximal tolerated dose on the daily x 5 schedule was 30% of the dose tolerated on an iv bolus schedule. The choice of drug schedule for clinical trials when murine and human pharmacokinetics differ is discussed. Phase II trials are under way with both the iv bolus and the daily x 5 schedules.

Phase I study and pharmacodynamics of piroxantrone (NSC 349174), a new anthrapyrazole.

Piroxantrone (PRX, NSC 349174) is one of the first of a new class of intercalating agents, the anthrapyrazoles, to undergo clinical evaluation. Additionally, it is the first drug trial to prospectively test a new pharmacology-based dose escalation schema proposed for Phase I trials of anticancer compounds. In this Phase I trial, PRX was administered as a 1-h infusion every 3 weeks to patients with advanced cancer. Forty-four evaluable patients received 116 courses at doses ranging from 7.5 to 190 mg/m2. The dose-limiting toxicity was myelosuppression with leukopenia predominating. Nonhematological toxicities were minimal and consisted of nausea and vomiting, alopecia, mucositis, and phlebitis. Based on this trial, the maximum tolerated and recommended Phase II doses for PRX administered on this schedule are 190 and 150 mg/m2, respectively. PRX plasma elimination was rapid and best fit by a two-compartment model for 17 of 24 patients receiving greater than or equal to 90 mg/m2. The plasma clearance rate was 1290 +/- 484 ml/min (720 +/- 210 ml/min/m2) and did not vary with dose. The t1/2 alpha was 2.9 +/- 5.3 (SD) min and the t1/2 beta was 18.7 +/- 36.5 min. Area under the concentration versus time curve (AUC) at the maximal tolerated dose (MTD) was 435 mumol.min/liter, 40% higher than the predicted AUC from preclinical testing. The percentage decrease in WBC and neutrophil count was correlated with the AUC. The potential advantage of pharmacology-based dose escalation was limited in this study by assay insensitivity, extremely rapid plasma elimination, and the proximity of the starting dose to the dose where the target AUC was achieved and standard dose escalations were to begin. Consequently, there was no reduction in the number of dose escalations required to define the maximum tolerated dose. However, the practical aspects of this approach have been established and its use is recommended for further trials where detailed preclinical pharmacological studies are available.

Prolonged infusion of hexamethylene bisacetamide: a phase I and pharmacological study.

Hexamethylene bisacetamide (HMBA, NSC 95580), a potent polar-planar differentiating agent in vitro, was studied in a phase I trial as a 10-day continuous infusion administered every 4 weeks. Since preclinical evidence had demonstrated that the duration of HMBA exposure was an important variable in the induction of differentiation, and HMBA steady-state concentrations (Css) achieved during 5-day infusions were minimally effective at inducing in vitro differentiation, this study was conducted to evaluate the feasibility of maintaining HMBA Css for 10 days similar to levels achieved and maintained for 5 days. Twelve patients received 17 evaluable courses at three dose levels, 12, 15.8, and 20 g/m2/day. Platelet toxicity limited further dose escalation. Mean nadir and percentage of decrement in platelet counts were 175,000/microliter and 66%, and 43,500/microliter and 83%, at 15.8 and 20 g/m2/day, respectively. In this 10-day study, the percentage of decrement of platelet counts was linearly related to mean HMBA Css and to the area under the plasma concentration versus time curve (AUC). However, when combined platelet and pharmacological data from both 5- and 10-day studies were analyzed, it was apparent that the duration of HMBA exposure was an additional significant variable in predicting the magnitude of thrombocytopenia. Renal and metabolic toxicities that precluded dose escalation in previous 5-day trials of HMBA were mild and insignificant in this study. Mean HMBA Css were 0.65 +/- 0.09 mmol/liter at 15.8 g/m2/day, and 0.99 +/- 0.22 mmol/liter at 20 g/m2/day. Depletion of intracellular polyamines in peripheral blood mononuclear leukocytes was noted during several courses that were associated with profound myelosuppression, but no clear relationships were apparent between the magnitude of polyamine changes and toxicity or between fluctuations in polyamines and the magnitude of mean HMBA Css values. Based on this study, the maximum tolerated and recommended phase II doses for HMBA administered on this schedule were 20 and 15.8 g/m2/d, respectively. The administration of HMBA by a ten-day infusion at the maximum tolerated dose resulted in the delivery of lower daily doses and lower HMBA Css than on the 5-day schedule. The major toxicities differed on these schedules with thrombocytopenia being most prominent on the 10-day schedule and metabolic and CNS toxicities on the 5-day schedule.(ABSTRACT TRUNCATED AT 400 WORDS)

Phase I and pharmacokinetic study of hepsulfam (NSC 329680).

Hepsulfam (NSC 329680), a bifunctional alkylating agent structurally related to busulfan, has entered clinical trial based on its broader preclinical antitumor activity compared with that of busulfan and its i.v. formulation which may circumvent the many problems arising from the p.o. administration of busulfan, such as significant individual differences in bioavailability. In this Phase I study, 53 patients received 95 courses of hepsulfam at doses ranging from 30 to 480 mg/m2 administered i.v. over 30 min every 28 days. Hematological toxicity was dose limiting. Leukopenia and thrombocytopenia were dose related, delayed in onset, and sustained for long durations. Toxicity was cumulative in most patients receiving more than one course. This pattern of myelosuppression suggests that hepsulfam is cytotoxic to hematopoietic stem cells. Although hematological toxicity was not particularly severe during most courses, its lengthly duration precluded the prompt administration of subsequent courses. Minimal nonhematological effects were observed. Pharmacokinetic studies revealed that the clearance rate of hepsulfam is linear over the dose range studied and that its plasma disposition is biphasic with mean alpha and beta half-lives of 19 +/- 18 (SE) min and 337 +/- 248 (SE) min, respectively. The area under the plasma clearance curve correlated with the percentage of change in WBC using a sigmoidal Emax model and with the duration of thrombocytopenia in patients with hematological toxicity. Based on the protracted duration of the toxicity of multiple doses that were greater than 210 mg/m2, the recommended starting dose for Phase II trials is 210 mg/m2. However, these trials should be pursued with caution because of the protracted nature of hepsulfam's myelosuppression. Because hepsulfam produced minimal nonhematological toxicity, substantial dose escalation above 480 mg/m2 may be possible with hematopoietic stem cell support.

Cardiac disturbances during the administration of taxol.

The clinical development of taxol, a new antimicrotubule agent with a unique mechanism of cytotoxic action, has proceeded slowly due to serious hypersensitivity reactions (HSRs) and shortages in its supply. Nevertheless, large-scale phase II trials have been initiated as taxol has recently demonstrated impressive activity in advanced and cisplatin-refractory ovarian carcinoma. Furthermore, the incidence of HSRs has been reduced substantially with premedications and modifications in the administration schedule. However, various manifestations of potential cardiotoxicity have been observed in several patients who participated in four phase I and II studies of taxol. Asymptomatic bradycardia has occurred in a high proportion of patients, including 29% of ovarian cancer patients who were treated with maximally tolerated doses of taxol in a phase II study. More profound cardiac disturbances, including a range of atrioventricular conduction blocks, left bundle branch block, ventricular tachycardia (VT), and manifestations of cardiac ischemia, have been observed in seven of 140 patients (5%) who received taxol. Descriptions of these events are presented in this report to alert investigators to the potential for these adverse effects. Although these disturbances did not result in serious sequelae in most patients, investigators should continue to maintain a high degree of caution until precise risk factors, frequency, and clinical significance of these adverse cardiac effects are determined.

Topotecan has substantial antitumor activity as first-line salvage therapy in platinum-sensitive epithelial ovarian carcinoma: A Gynecologic Oncology Group Study.

PURPOSE: Topotecan is known to be active in recurrent ovarian cancer, but most prior studies have focused on platinum-resistant or refractory populations. This study was undertaken to define the response rate and progression-free interval in platinum-sensitive patients. PATIENTS AND METHODS: Patients with recurrent ovarian cancer after one or two prior chemotherapy regimens and in whom the interval between prior platinum therapy and the initiation of protocol therapy was greater than 6 months were treated with topotecan 1.5 mg/m(2) intravenously over 30 minutes daily for 5 days, with this cycle repeated every 21 days. RESULTS: Forty-eight patients were entered onto the study; 47 were assessable for toxicity and 46 for response. The response rate was 33% (two complete responses and 13 partial responses), with a median response duration of 11.2 months. Hematologic toxicity predominated but was manageable in most patients with frequent incorporation of cytokines and RBC and platelet transfusions. Fatigue was reported in 15 patients and resulted in the discontinuation of therapy in five responding patients. CONCLUSION: Topotecan is an active drug in platinum-sensitive ovarian cancer, with significant but manageable hematologic toxicity. Fatigue is also a common problem that may be dose-limiting in some patients.

Paclitaxel has moderate activity in squamous cervix cancer. A Gynecologic Oncology Group study.

PURPOSE: Taxol (paclitaxel; Bristol-Myers Squibb, Princeton, NJ) is a new antineoplastic drug with broad-spectrum activity in solid tumors, including epithelial ovarian cancer, head and neck cancer, esophageal cancer, breast cancer, bladder cancer, and lung cancer. Its unique mechanism of action, polymerization of tubulin monomers, has stimulated both clinical and preclinical research on this agent. As limited drug supplies became more plentiful, a phase II trial of Taxol was initiated in patients with advanced squamous cervix cancer who had received no prior chemotherapy. PATIENTS AND METHODS: In this trial, 30 assessable patients were initially entered onto the study and four partial responses were seen. Further accrual of 22 assessable patients was then accomplished to define better the response rate with smaller confidence intervals. The starting dose of Taxol was 170 mg/m2 (135 mg/m2 for patients with prior pelvic radiation) given as a 24-hour continuous intravenous infusion with courses repeated every 3 weeks. Dose escalations to 200 mg/m2 and deescalations to 110 mg/m2 were allowed based on adverse effects. RESULTS: The final response rate was 17% (two complete responses and seven partial responses). The primary and dose-limiting toxicity was neutropenia. CONCLUSION: The response rate makes Taxol a drug with sufficient activity to explore it in combination with other agents with similar activity.

A randomized comparison of high-dose infusion methotrexate versus standard-dose weekly therapy in head and neck squamous cancer.

Forty-seven patients with recurrent or metastatic head and neck squamous cancer were entered into a prospectively controlled study comparing high-dose infusion methotrexate with leucovorin against standard-dose methotrexate without leucovorin. Patients were stratified for prior treatment and hematogenous metastases prior to randomization. Patients received either methotrexate (1,500 mg/m2) infused over 24 hours with leucovorin or 40 mg/m2 intramuscularly. Each treatment was given weekly for the first six weeks and followed a dose escalation schedule to toxicity. After six weeks patients received the high-dose regimen every two weeks and the low-dose schedule continued weekly. One patient was ineligible and four had inadequate follow-up to assess response (less than two weeks). Forty-two patients were evaluable for survival and 37 for response. Six of 19 patients (32%) treated with high-dose infusion responded (one complete response) and four of 18 patients (22%) receiving standard dosage responded (P = .52). Treatment with high-dose methotrexate resulted in an improved duration of disease control over standard dosage with the respective median times to progression of 11 weeks and five weeks (P = .04). These differences were most marked in good performance status patients (P = .007) and those without hematogenous dissemination (P = .02). Toxicity, however, was also significantly worse in the high-dose treatment group (P = .01) and survival was identical between treatments (4.2 months). The authors conclude that any treatment advantage to high-dose methotrexate may be attributable to its greater toxicity rather than to a selective therapeutic effect and this regimen does not result in improved patient survival. Good performance status patients may benefit from more aggressive therapy.

Successful re-treatment with taxol after major hypersensitivity reactions.

PURPOSE: To describe the successful re-treatment of eight patients who had major hypersensitivity reactions (HSRs) to taxol and to suggest a regimen for re-treating patients who develop major HSRs. PATIENTS AND METHODS: The treatment courses of eight patients who developed major HSRs and were rechallenged with taxol were reviewed. Patients in this report represent all patients who are known to have been rechallenged with taxol after major HSRs. RESULTS: The most common approach used to rechallenge patients consisted of premedication with multiple high doses of corticosteroids and H1- and H2-histamine antagonists followed by the initiation of the taxol infusion at a reduced rate. All patients who experienced major HSRs were rechallenged successfully. After the rechallenge, these patients received 32 additional courses of taxol without HSRs. CONCLUSION: Re-treatment with taxol after major HSRs is feasible using multiple high doses of corticosteroids and antihistamine premedications and a reduced taxol infusion rate under close supervision. This approach may represent a valid alternative to the termination of taxol; however, a prospective evaluation is required to determine the true efficacy of this approach.

A randomized comparative trial of carboplatin and iproplatin in advanced squamous carcinoma of the uterine cervix: a Gynecologic Oncology Group study.

A total of 394 patients with advanced, measurable squamous carcinoma of the uterine cervix and no prior chemotherapy were randomized to therapy with either carboplatin or iproplatin. There were 23 patients ineligible for the study and 10 patients who were not evaluable; the remaining 361 patients were evaluable for response and adverse effects. Randomization was well balanced for age, performance status, and prior therapy. Both platinum analogs were given every 28 days with starting doses of 400 mg/m2 for carboplatin (340 mg/m2 if the patient underwent prior radiation) and 270 mg/m2 for iproplatin (230 mg/m2 if the patient underwent prior radiation). These doses are equivalent to cisplatin doses of 75 to 100 mg/m2. Hematologic toxicity was dose-limiting, among which thrombocytopenia was slightly more common than leukopenia. Gastrointestinal toxicity was also prominent with both agents; however, iproplatin was significantly more toxic than carboplatin (P less than .001). Renal, otic, and peripheral nervous system toxicities were absent or infrequent with both analogs. No electrolyte abnormalities were observed. The percentage of planned dosages that were actually administered was 100% of carboplatin doses and 85% of iproplatin doses (P less than .0001). The reduction in iproplatin dose was apparently due to gastrointestinal toxicity. Response rates were similar for both agents (15% for carboplatin, 11% for iproplatin) and appear to be inferior to those noted with the parent compound, cisplatin.

Phase II study of paclitaxel and valspodar (PSC 833) in refractory ovarian carcinoma: a gynecologic oncology group study.

PURPOSE: A phase II study was conducted to determine the efficacy of paclitaxel and valspodar (PSC 833) in patients with advanced epithelial ovarian cancer. Valspodar, a nonimmunosuppressive cyclosporine D analogue that reverses P-glycoprotein-mediated multidrug resistance, in combination with paclitaxel might be active in paclitaxel-resistant and refractory ovarian cancer. PATIENTS AND METHODS: Patients received valspodar 5 mg/kg orally qid x 12 doses. Paclitaxel (70 mg/m(2) intravenously for 3 hours) was administered on day 2, 2 hours after the fifth or sixth dose of valspodar. This treatment was repeated every 21 days. One blood sample was collected before the sixth dose of valspodar for the first three cycles to evaluate valspodar trough concentration. Tumor tissue was obtained from patients for immunohistochemical staining of P-glycoprotein. RESULTS: Of 60 patients entered, 58 were assessable for response. There were five partial responses (8.6%; 90% confidence interval [CI], 3.8 to 20.0; median duration of response, 5.0 months [range, 1.9 to 10.5 months]). Median progression-free survival was 1.5 months (90% CI, 1.4 to 2.4). Grade 3 or 4 toxicities observed were neutropenia, anemia, nausea and vomiting, peripheral neuropathy, and cerebellar ataxia. The trough concentrations of valspodar were > or = 1,000 ng/mL in all but two of 40 patients in the first cycle. Immunohistochemical staining for P-glycoprotein was positive for one of two responding patients. CONCLUSION: Valspodar in combination with paclitaxel has limited activity in patients with paclitaxel-resistant ovarian carcinoma. An international randomized clinical trial of paclitaxel and carboplatin with or without valspodar as first-line therapy in advanced ovarian cancer is underway.

Phase I study of paclitaxel, carboplatin, and increasing days of prolonged oral etoposide in ovarian, peritoneal, and tubal carcinoma: a gynecologic oncology group study.

PURPOSE: Given the activity of prolonged oral etoposide in platinum and paclitaxel-resistant ovarian carcinoma, a phase I trial was conducted that combined increasing days of oral etoposide therapy with paclitaxel and carboplatin in chemotherapy-naive patients with ovarian peritoneal and tubal carcinoma to establish a maximum-tolerated dose (MTD) of this combination. PATIENTS AND METHODS: Paclitaxel at 175 mg/m(2) given over 3 hours and carboplatin at an area under the curve of 5 were administered on day 1 followed by oral etoposide 50 mg/m(2)/d beginning on day 2. The number of days of etoposide therapy was escalated on the basis of toxicity. Toxicity end points included neutropenic sepsis, grade 4 thrombocytopenia, or grade 3 neutropenia or thrombocytopenia during etoposide administration. Cycles were repeated every 21 days for a maximum of six courses. Due to hematologic toxicity, the duration of the paclitaxel infusion was decreased to 1 hour for a second stage of accrual. RESULTS: Of 52 patients studied, 29 were in the first stage of accrual. Dose-limiting toxicity occurred with 8 days of oral etoposide, making the MTD six days of therapy. Twenty-three patients were entered into the second stage of accrual. Dose-limiting toxicity occurred at 12 days of oral etoposide, making the MTD 10 days of therapy. Three patients developed acute myeloid leukemia 16, 27, and 35 months after receiving a cumulative dose of 200 mg/m(2), 1,200 mg/m(2), and 2,400 mg/m(2), respectively. CONCLUSION: One-hour paclitaxel, carboplatin, and oral etoposide at 50 mg/m(2)/d for 10 days is tolerable without supportive therapy. The leukemogenic potential is cause for concern and precludes its use in chemotherapy-naive ovarian carcinoma.

Assessment of dose-intensive therapy in suboptimally debulked ovarian cancer: a Gynecologic Oncology Group study.

PURPOSE: We report a prospective randomized trial in women with advanced ovarian cancer to evaluate the importance of chemotherapy dose-intensity on survival, progression-free survival (PFS), and response. PATIENTS AND METHODS: A total of 485 patients with epithelial ovarian cancer and residual masses more than 1 cm following surgery (stage III presentation) or any stage IV presentation were randomly assigned to receive either standard therapy (cyclophosphamide 500 mg/m2 and cisplatin 50 mg/m2 intravenously every 3 weeks for eight courses) or intense therapy (cyclophosphamide 1,000 mg/m2 and cisplatin 100 mg/m2 intravenously every 3 weeks for four courses). Dose modification was rigidly controlled to maintain intensity. Clinical and pathologic responses were assessed, when appropriate, as well as PFS interval and survival. RESULTS: A total of 458 patients met all eligibility criteria and were assessed for survival and PFS. The dose-intensive group received the same total dose of cyclophosphamide and cisplatin, but 1.97 times greater dose-intensity than the standard group. Clinical and pathologic response rates; response duration, and survival were similar in both groups of patients. Hematologic, gastrointestinal, febrile episodes, septic events, and renal toxicities were significantly more common and severe in the dose-intensive group. CONCLUSION: A doubling of the dose-intensity in the treatment of bulky ovarian epithelial cancers led to no discernible improvement in patient outcome and was associated with more severe toxicity. This study provides no evidence to support the hypothesis that modest increases in dose-intensity without increasing total dose are associated with significant improvement in overall survival or PFS.

Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125.

PURPOSE: To produce definitions based on serial CA 125 levels to measure response of ovarian carcinoma in patients receiving first-line chemotherapy. PATIENTS AND METHODS: Definitions were derived from analysis of 277 patients in North Thames Ovary Trial 3. Patient data were then incorporated into a computer program and tested against 254 patients in North Thames Ovary Trial 4 and 458 patients in Gynecologic Oncology Group (GOG) protocol 97. For optimum detection of response, three response definitions have been combined into a computer program. The precise definitions use mathematic logic and take account of factors such as intervening samples. Response to a specific treatment has occurred if after two samples there has been a 50% decrease, confirmed by a fourth sample (50% response), or a serial decrease over three samples of greater than 75% (75% response). The final sample has to be at least 28 days after the previous sample. RESULTS: Six hundred twenty of 989 patients were considered assessable for response according to CA 125 level. Only two patients (0.3%) had a CA 125 response at the time of clinical progression. The CA 125 response rate was 62% and 54% in the North Thames trials. In the GOG trial, it was 66% in all 317 patients assessable for CA 125 and 67% in 221 patients whose CA 125 level was not measurable according to GOG criteria, compared with a GOG-defined response rate of 62%. The sensitivity for detecting GOG-defined response was at least 68%. CONCLUSION: Definitions based on a 50% or 75% decrease of CA 125 levels have been shown reliably to define partial response of ovarian cancer in patients receiving first-line chemotherapy. These definitions should be used in addition to or instead of standard response criteria.

Carboplatin and paclitaxel in ovarian carcinoma: a phase I study of the Gynecologic Oncology Group.

PURPOSE: To develop a tolerable, dose-intense regimen of carboplatin and paclitaxel for the treatment of primary epithelial ovarian carcinoma. PATIENTS AND METHODS: Patients underwent initial surgical assessment and tumor debulking. Patients with stage III/IV disease received six cycles of chemotherapy on a planned 21-day cycle. Carboplatin dose was calculated based on projected area under the curve (AUC) for concentration over time (mg. mL-1.min) and escalated to determine the maximum-tolerated dose (MTD). Paclitaxel dose was also escalated as a 3-, 24-, or 96-hour infusion. Granulocyte colony-stimulating factors (G-CSFs) were required at selected dose levels or could be added based on hematologic toxicity. RESULTS: Thirty-nine patients were enrolled and assessable for toxicity and response. Dose-limiting toxicity (DLT) was hematologic, primarily neutropenia. Less than 2% of all cycles with paclitaxel as a 3- or 24-hour infusion were associated with either grade 4 thrombocytopenia or febrile neutropenia. The carboplatin MTD was AUC 7.5 (equivalent to a median dose of 471 mg/m2). The MTD for paclitaxel was 135 mg/m2 over 24 hours and 175 mg/m2 over 3 hours without initial G-CSF. A 96-hour infusion of paclitaxel at a dose of 120 mg/m2 was associated with excessive single-cycle and cumulative myelosuppression, and was not further evaluated. Measured carboplatin AUC agreed well with the calculated AUC. The overall complete (n = 16) and partial (n = 2) response rate among 24 patients with measurable disease was 75%, with a median progression-free survival time of 15 months. CONCLUSION: Carboplatin could be safely combined with paclitaxel using a dose formula based on projected renal clearance. The recommended outpatient regimen is carboplatin AUC 7.5 and paclitaxel 175 mg/m2 over 3 hours without initial G-CSF. This treatment safely achieved a greater dose-intensity of carboplatin than would have been achieved with conventional dosing based on body-surface area.

Comparison of standard and CA-125 response criteria in patients with epithelial ovarian cancer treated with platinum or paclitaxel.

PURPOSE: To assess CA-125 as a measure of response in patients treated with paclitaxel. PATIENTS AND METHODS: One hundred forty-four patients treated with paclitaxel derived from four different trials and 625 patients treated with platinum from two trials were analyzed using precisely defined 50% and 75% reductions in CA-125. The standard and CA-125 response rates to paclitaxel and platinum were compared. In addition, we analyzed individual patient groups in which there was a difference in response according to the two response criteria. RESULTS: Patients with stable disease as determined by standard criteria who were treated with platinum and responded according to CA-125 criteria have an improved median progression-free survival compared with patients with stable disease who did not respond according to CA-125 criteria (10.6 v 4.8 months; P<.001). Standard and CA-125 response rates for patients treated with platinum (58.93% v 61.31%, respectively) and paclitaxel (30.65% v 31.67%, respectively) were very similar, as were rates of false-positive prediction of response by CA-125 (platinum 2.2% and paclitaxel 2.9%). Responders to paclitaxel had a significantly improved progression-free survival compared with non-responders by both standard criteria (median progression-free survival, 6.8 v 2.5 months; P<.001) and CA-125 criteria (median progression-free survival, 6.8 v 3.4 months; P<.001). CONCLUSION: Forassessing activity of therapy for ovarian cancer, these data show that precise 50% or 75% CA-125 response criteria are as sensitive as standard response criteria. We propose that they may be used as a measure of response in lieu of or in addition to standard response criteria in clinical trials involving epithelial ovarian cancer. Sensitivity is maintained whether patients are treated with platinum or paclitaxel.

Ninety-six-hour infusional paclitaxel as salvage therapy of ovarian cancer patients previously failing treatment with 3-hour or 24-hour paclitaxel infusion regimens.

PURPOSE: To test the hypothesis that prolonged infusion of paclitaxel (96 hours) might overcome resistance to shorter infusion schedules (3 or 24 hours) in ovarian cancer. PATIENTS AND METHODS: A total of 30 patients with advanced ovarian cancer (24 patients), primary carcinoma of the peritoneum (four patients), or fallopian tube cancer (two patients) who previously had received paclitaxel administered on either a 3-hour or 24-hour schedule were treated with the agent delivered as a 96-hour infusion (30 to 35 mg/m2/d x 4 days) on an every 3-week program. RESULTS: Although the regimen generally was well tolerated, no objective responses were observed. CONCLUSION: In patients with ovarian cancer who have shown resistance to shorter paclitaxel infusion schedules, ninety-six hour infusional paclitaxel is an inactive treatment strategy. This makes it less likely that protracted infusion of paclitaxel will improve outcome when used as part of primary therapy of ovarian cancer. An ongoing randomized study will answer that question.