Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240).

BACKGROUND: On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0·75 mg/m2 on days 1-3) plus paclitaxel (175 mg/m2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062. FINDINGS: Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death. INTERPRETATION: The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer. FUNDING: National Cancer Institute.

A phase I study of tasisulam sodium (LY573636 sodium), a novel anticancer compound, administered as a 24-h continuous infusion in patients with advanced solid tumors.

PURPOSE: To determine the recommended/maximum tolerated dose (MTD), pharmacokinetics (PK), and safety profile of tasisulam sodium (hereafter tasisulam), a novel anticancer agent. METHODS: In this phase I study, tasisulam was administered as a 24-h continuous intravenous infusion on day 1, every 28 days, to patients with advanced solid tumors. A flat-dosing schema was planned for four cohorts of 3-6 patients: 600, 1,200, 2,000, and 2,500 mg. RESULTS: Twenty-six patients were enrolled. No dose-limiting toxicities (DLTs) were observed until cohort 3 (grade 3 hyperbilirubinemia). Interim PK analyses of this and another ongoing phase I study suggested that a lower dose after cycle 1 was necessary for doses ≥2,500 mg because of the long half-life of tasisulam (~14 days). Therefore, a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg was implemented for cohort 4; one patient developed DLT (grade 4 neutropenia), and another developed grade 3 thrombocytopenia in cycles 2 and 3. These findings, together with PK data, which indicated a disproportionate increase in free drug relative to total tasisulam concentrations at doses >2,500 mg, led to the determination of the 2,500-/1,750-mg regimen as the MTD. Eight patients had stable disease, and two patients unconfirmed partial responses. CONCLUSIONS: When administered as a flat-dose, 24-h infusion, the MTD of tasisulam was a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg, every 28 days. Consistent with the profile of the 2-h infusion in clinical development, bone marrow suppression was the major DLT.

A phase II trial of pemetrexed in combination with carboplatin in patients with recurrent ovarian or primary peritoneal cancer.

OBJECTIVE: Carboplatin-based combinations are commonly used in platinum-sensitive ovarian cancer (PSOC). Pemetrexed in combination with carboplatin has been shown to be feasible in a phase I study in PSOC. The primary objective of this subsequent phase II study was to determine the overall response rate (ORR; defined by Response Evaluation Criteria in Solid Tumors) of this combination in patients with recurrent PSOC. Secondary objectives included progression-free survival (PFS), overall survival (OS), and toxicity. METHODS: Patients with PSOC (defined by recurrence ≥ 6 months after completion of up to two lines of prior platinum-based therapy), measurable disease, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function were eligible. Pemetrexed 500 mg/m(2) was administered as a 10-minute infusion followed by carboplatin AUC 6 as a 30-minute infusion on day 1 of a 21-day cycle. RESULTS: Sixty-six patients were treated. Of the 61 patients evaluable for response, there were 20 responders (one complete response and 19 partial responses), for an ORR of 32.8% (95% CI: 21.3%, 46.0%). For the intent-to-treat population (all 66 patients), the median PFS was 9.4 months (95% CI: 8.3, 11.1), with 22.7% censoring. Median OS was not reached due to the high censoring rate. There was one drug-related death (multi-organ failure). The most common drug-related grade 3/4 toxicities were neutropenia (39.4%), thrombocytopenia (24.2%), carboplatin hypersensitivity (9.1%), nausea (6.1%), and vomiting (6.1%). CONCLUSIONS: Carboplatin AUC 6 and pemetrexed 500 mg/m(2) has a low incidence of serious toxicities. Defining the platinum-based combination with the best therapeutic index would require a prospective phase III study.

Intraperitoneal radioactive phosphorus (32P) and vaginal brachytherapy as adjuvant treatment for uterine papillary serous carcinoma and clear cell carcinoma: the Indiana University experience.

PURPOSE: To evaluate the outcomes of surgically staged patients with Stage I-IIIA uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CCC) of the uterus treated at Indiana University with intraperitoneal (32)P and vaginal brachytherapy. METHODS: Between 1997 and 2004, a total of 28 patients with Stage I-IIIA UPSC and CCC were treated with a standardized adjuvant therapy. All patients underwent comprehensive surgical staging with negative pelvic and para-aortic lymph nodes and no gross residual disease. After a Technetium-99m distribution study, (32)P was administered intraperitoneally. Subsequently, high dose rate (HDR) vaginal cuff brachytherapy was delivered to a total dose of 2100 cGy in three fractions prescribed to 0.5 cm depth. The records of these 28 patients were reviewed, including 18 patients who were treated on Hoosier Oncology Group 97-01 (Phase II trial), and whose followup was updated. RESULTS: Intraperitoneal (32)P was administered at a median of 4 weeks from surgery, followed by vaginal brachytherapy. One patient had no available followup information and is not included in the analysis. The median followup for the 27 evaluable patients was 40.9 months. No patients had Grade 2, 3, or 4 complications related to their adjuvant treatment. There were 4 patients with recurrent disease: 2 initially relapsed intraperitoneally, 1 in the distal vagina, and 1 had a scar recurrence. Three patients have died of the disease. For all 27 patients, the 3-year overall survival, cause-specific survival, and disease-free survival were 84.2%, 90.7%, and 74.4%, respectively. CONCLUSIONS: Adjuvant therapy for UPSC and CCC with intraperitoneal (32)P and vaginal brachytherapy after adequate surgical staging and maximal cytoreduction is well tolerated and appears to be effective. Further study is warranted.

Randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial ovarian carcinoma: a Gynecologic Oncology Group study.

OBJECTIVE: Compared to 3 cycles, to determine if 6 cycles of adjuvant carboplatin (C) and paclitaxel (P) significantly lower the rate of recurrence in surgically staged patients with stage IA grade 3, IB grade 3, clear cell, IC, and completely resected stage II epithelial ovarian cancer (EOC); and to compare toxicities. METHODS: Postoperatively, randomization was to either 3 or 6 cycles of chemotherapy consisting of P (175 mg/m2 over 3 h) and C (7.5 AUC over 30 min) every 21 days. Recurrence was any clinical or radiological evidence of new tumor. RESULTS: Of 457 patients, 427 (93%) were histologically and medically eligible. While thorough surgical staging was required, it was incomplete or inadequately documented in 29% of otherwise eligible patients. Median age was 55.5 years; 69% of patients had stage I disease. Median follow-up is 6.8 years for 344 women alive at last contact. Grade 3 or 4 neurotoxicity occurred in 4/211 (2%) and 24/212 (11%) treated patients on the 3- and 6-cycle regimens, respectively (p<0.01); 6 cycles also caused significantly more severe anemia and granulocytopenia. The recurrence rate for 6 cycles was 24% lower (hazard ratio [HR]: 0.761; 95% confidence interval [CI]: 0.51-1.13, p=0.18), and the estimated probability of recurrence within 5 years was 20.1% (6 cycles) versus 25.4% (3 cycles). The overall death rate was similar for these regimens (HR: 1.02; 95% CI: 0.662-1.57). CONCLUSIONS: Compared to 3 cycles, 6 cycles of C and P do not significantly alter the recurrence rate in high risk early stage EOC but are associated with more toxicity.

Carcinoma of the vulva.

The objective of this review is to summarize the published data about squamous carcinoma of the vulva and to identify promising areas for future investigation. Rather than the routine use of complete radical vulvectomy, a radical wide excision of the vulvar lesion to achieve at least a 1-cm gross margin appears sufficient to treat the primary lesion. A surgical assessment of the groin is required for all patients who have invasion greater than 1 mm. Ipsilateral groin node dissection can be performed through a separate incision. All the nodal tissue medial to the vessels and above the fascia should be removed. Sentinel node evaluation may be a significant step forward, but the false-negative rate is not well enough defined to consider this a standard. Patients with positive inguinal nodes at groin dissection should receive radiation therapy to the ipsilateral groin and hemipelvis. For those patients who have unresectable primary disease or if nodes are palpably suspicious, fixed, and/or ulcerated preoperatively, chemoradiation is the preferred option. Exenterative procedures may rarely be required. Chemotherapy for recurrent or metastatic disease has not been proven to be of value. Although survival rates are high for those with negative nodes, the morbidity associated with standard radical techniques has prompted innovation. Adequately powered trials aimed at further reducing morbidity without compromising survival are underway.

Obstetrics-Gynecology resident satisfaction.

OBJECTIVE: The objective of the study was to identify factors associated with satisfaction in the Indiana University School of Medicine Obstetrics-Gynecology residency program and the residents' and faculty's perception of whether these factors were extant in our program. STUDY DESIGN: Residents and faculty at the Indiana University School of Medicine Obstetrics-Gynecology program were surveyed using an instrument based on prior primary care specialty investigations. Multivariate regression evaluated the impact of various factors on resident satisfaction. RESULTS: Seventy-seven percent (44 of 57) and 100% (35 of 35) of faculty and residents, respectively, completed the survey. Relevant training, collegiality, adequate resources, workload, care continuity, supportive coworkers, learning environment, autonomy, role ambiguity, and supportive faculty were significantly associated with resident satisfaction. Care continuity, role ambiguity, and learning environment were the areas of largest faculty/resident disagreement. CONCLUSION: Relevant training and collegiality were most strongly linked to resident satisfaction. Three areas of dissatisfaction were identified, and we will seek to remedy these areas.

Factors detracting students from applying for an obstetrics and gynecology residency.

OBJECTIVE: This study compares perception about the characteristics of obstetrics-gynecology (OG) of medical students who choose to pursue a residency in OG and those students who choose to enter another specialty. STUDY DESIGN: Fourth-year medical students were asked to complete a survey addressing their perceptions about OG. Responses were compared of (1) those entering OG to those entering other specialties, (2) those entering OG to those who seriously considered entering OG but chose another discipline, and (3) males to females. Chi-square tests were used for the comparisons. RESULTS: Of the 267 eligible students, 137 (51.1%) completed the survey. Clerkship satisfaction was rated as high by 88.9% of students choosing OG vs 10.2% (P<.0005) of those who chose another discipline. The emerging predominance of female providers detracted 38.5% of males vs 10.2% of females (P<.0005). CONCLUSION: Student perception of an OG clerkship may detract them from pursuing OG as a career.

Phase II trial of liposomal doxorubicin at 40 mg/m(2) every 4 weeks in endometrial carcinoma: a Gynecologic Oncology Group Study.

OBJECTIVE: In patients with disseminated endometrial carcinoma, liposomal doxorubicin has possible advantages over doxorubicin which has proven single agent activity but well known cardiac toxicity. Before replacing doxorubicin in clinical trials, the Gynecologic Oncology Group (GOG) decided to conduct a phase II clinical trial of liposomal doxorubicin (Ortho Biotech Products L. P., Raritan, NJ) in first-line therapy of patients with disseminated endometrial carcinoma. METHODS: Patients with initial histologic confirmation of endometrial carcinoma presenting with disseminated or recurrent cancer who had not previously received cytotoxic drugs were considered for participation in this clinical trial. Eligible patients had measurable disease, GOG performance status 0-2, and adequate bone marrow, renal, and hepatic function according to standard criteria. Liposomal doxorubicin 40 mg/m(2) was given by intravenous injection on an every 4-week cycle until toxicity or progression. Patients who remained free from tumor progression or intolerable toxicity received at least one to a maximum of 20 cycles of liposomal doxorubicin. RESULTS: Fifty-six patients were registered, of whom three were determined ineligible (prior malignancy = 2, inadequate pathology material = 1). One patient never received therapy, leaving 52 evaluable patients. Two patients (3.8%) achieved a complete response, four (7.7%) exhibited a partial response, and 31 (59.7%) had stable disease. The most common adverse events were constitutional (32/52), anemia (28/52), pain (27/52), dermatologic (25/52), and cardiovascular (12/52). CONCLUSIONS: In this trial, liposomal doxorubicin had a response rate of 11.5% in first-line treatment of disseminated endometrial carcinoma when given at 40 mg/m(2) every 4 weeks. In view of the associated skin toxicity at this dose, liposomal doxorubicin does not appear to be a suitable replacement for the more active doxorubicin for therapy of endometrial carcinoma.

Intraperitoneal radioactive phosphorus (32P) and vaginal brachytherapy as adjuvant treatment for uterine papillary serous carcinoma and clear cell carcinoma: a phase II Hoosier Oncology Group (HOG 97-01) study.

OBJECTIVE: A phase II study was conducted to evaluate the role of adjuvant intraperitoneal radioactive phosphorus (32P) and vaginal brachytherapy in patients with uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CCC), after complete surgical staging. METHODS: Patients were required to have undergone complete surgical staging including maximal surgical resection. Residual < or =3 mm intraperitoneal disease, and pelvic and para-aortic lymph node dissection with negative nodes, were required. A dose of 15 mCi of intraperitoneal 32P was administered within 8 weeks of surgery. Vaginal brachytherapy was delivered using either high dose rate, total dose of 2100 cGy in 3 fractions (700 cGy per fraction prescribed to 0.5 cm depth from the vaginal surface) or low dose rate to 6500 cGy (prescribed to the vaginal surface) in 1-2 fractions. RESULTS: For the 21 evaluable patients, distribution by FIGO stage was as follows: Stages I-IIB (17), Stages III-IV (4). The median follow-up was 39.6 months (range: 5-63 months). No patients experienced grade 2-4 complications from their adjuvant therapy. Five patients suffered a recurrence: intraperitoneal [n = 2], distal vaginal [n = 2], and one at the surgical scar. Following the 2 distal vagina recurrences early in the trial, the entire length of the vagina was treated with intracavitary brachytherapy. No additional vaginal recurrences were observed. The two-year overall survival, cause-specific survival, and disease-free survival for the entire series were 89.2%, 89.2%, and 79.7%, respectively. CONCLUSIONS: Adjuvant therapy for UPSC and CCC with intraperitoneal 32P and vaginal brachytherapy after comprehensive surgical staging is feasible, well tolerated, and warrants further study on a larger scale.

Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study.

PURPOSE: To determine whether the addition of paclitaxel to doxorubicin plus cisplatin improves overall survival (OS) in women with advanced or recurrent endometrial carcinoma. Secondary comparisons included progression-free survival (PFS), response rate (RR), and toxicities. PATIENTS AND METHODS: Eligible, consenting patients received doxorubicin 60 mg/m(2) and cisplatin 50 mg/m(2) (AP), or doxorubicin 45 mg/m(2) and cisplatin 50 mg/m(2) (day 1), followed by paclitaxel 160 mg/m(2) (day 2) with filgrastim support (TAP). The initial doxorubicin dose in the AP arm was reduced to 45 mg/m(2) in patients with prior pelvic radiotherapy and those older than 65 years. Both regimens were repeated every 3 weeks to a maximum of seven cycles. Patients completed a neurotoxicity questionnaire before each cycle. RESULTS: Two hundred seventy-three women (10 ineligible) were registered. Objective response (57% v 34%; P <.01), PFS (median, 8.3 v 5.3 months; P <.01), and OS (median, 15.3 v 12.3 months; P =.037) were improved with TAP. Treatment was hematologically well tolerated, with only 2% of patients receiving AP, and 3% of patients receiving TAP experiencing neutropenic fever. Neurologic toxicity was worse for those receiving TAP, with 12% grade 3, and 27% grade 2 peripheral neuropathy, compared with 1% and 4%, respectively, in those receiving AP. Patient-reported neurotoxicity was significantly higher in the TAP arm following two cycles of therapy. CONCLUSION: TAP significantly improves RR, PFS, and OS compared with AP. Evaluation of this regimen in the high-risk adjuvant setting is warranted, but close attention should be paid to the increased risk of peripheral neuropathy.

Phase II study of ifosfamide plus daily oral etoposide in previously treated ovarian cancer: a Hoosier Oncology Group (HOG) study.

Advanced epithelial ovarian carcinoma is a chemosensitive tumor to platinum plus paclitaxel combination chemotherapy. However, most patients develop recurrences following their initial platinum-based regimen and are candidates for subsequent chemotherapy. Several chemotherapeutic drugs have been tested as single therapeutic agents or in combination for relapsed epithelial ovarian carcinoma. The response rate has been modest with no obvious advantage to combination chemotherapy versus single agents. Both oral etoposide and ifosfamide have shown activity as single agents in pretreated patients. We completed a phase II study at the Hoosier Oncology Group utilizing oral etoposide plus ifosfamide in patients with relapsed ovarian epithelial carcinoma. Fourteen patients entered the study. Ifosfamide was given intravenously (IV) at a dose of 1.2 g/m2/d on days 1 to 4 with mesna 300 mg/m2 IV 15 minutes prior to and 4 and 8 hours after ifosfamide infusion. Etoposide was administered as 37.5 mg/m2/d orally on days 1 to 14. This regimen was repeated every 28 days until disease progression or for a maximum of 6 cycles. Grade III to IV granulocytopenia occurred in 9 patients (64%), with 2 neutropenic infections, but with no therapy-related deaths. Grade III to IV thrombocytopenia occurred in 3 patients (21%), and grade III to IV nausea and vomiting in 1 patient. No renal, pulmonary, hepatic, cardiac, or serious neurotoxicity was observed. Two patients (14%) achieved partial response, and additional 5 (35%) patients had stable disease. The 1-year survival probability using Kaplan-Meier analysis was 0.8. In this small sample-size trial, we did not demonstrate an advantage to this combination regimen compared to these or other single agents.

Cisplatin as initial chemotherapy in ovarian carcinosarcomas: a Gynecologic Oncology Group study.

OBJECTIVES: Carcinosarcomas of the ovary are rare; hence, although most patients recur after surgical resection or have metastatic disease at the time of diagnosis, only anecdotal information is available concerning the activity of cytotoxic drugs against these lesions. The Gynecologic Oncology Group (GOG) initiated a concerted effort to study cytotoxic therapy for these cancers in 1976. This report presents data on cisplatin, the first of the agents to be studied in this disease. METHODS: One hundred thirty-six eligible patients with ovarian carcinosarcoma received cisplatin (50 mg/m(2)) every 3 weeks until disease progression or unacceptable toxicity. RESULTS: Among 44 patients evaluable for response, one complete (2%) and eight partial (18%) responses resulted. An additional 10 (23%) patients exhibited stable disease, while 25 (57%) had increasing disease. Median progression-free survival in 130 patients evaluable for this endpoint was 5.2 months. Median survival in the same 130 patients was 11.7 months. Adverse effects >/=grade 2 among the 132 patients evaluable for toxicity included leukopenia (14%), neutropenia (17%), thrombocytopenia (2%), anemia (10%), nausea and vomiting (40%), azotemia (3%), neurotoxicity (4%), fever (2%), and tinnitus (1%). CONCLUSIONS: These data provide the first objective evidence that cisplatin is active as an initial therapy for patients who have carcinosarcoma of the ovary. The overall response rate (20%) is similar to that seen in carcinosarcomas of the uterus.

Phase II trial of gemcitabine as second-line chemotherapy of uterine leiomyosarcoma: a Gynecologic Oncology Group (GOG) Study.

OBJECTIVE: To determine the antitumor activity and toxicity profile of gemcitabine as second-line chemotherapy in patients with recurrent or persistent uterine leiomyosarcoma (LMS). METHODS: Intravenous gemcitabine was administered over 30 min at a dose of 1000 mg/m(2) on days 1, 8, 15, with cycles repeated every 28 days. Eligibility criteria included measurable disease, performance status 0-2, adequate bone marrow function, creatinine <1.5 mg%, bilirubin <1.5x institutional normal, SGOT/alkaline phosphatase <3x institutional normal, and signed informed consent. Standard Gynecologic Oncology Group (GOG) toxicity and response criteria were utilized. RESULTS: Forty-eight patients were enrolled on the study. Three were deemed ineligible upon central pathology review, another received an inadequate course of protocol treatment, and two others were not reassessed for response; thus 44 patients were evaluable for toxicity and 42 for toxicity and response. The median age was 52.5 (range: 31-82) years. Thirty-five patients had received prior chemotherapy and 11 had undergone prior radiotherapy. Sites of measurable disease were pelvic (n = 9) and extrapelvic (n = 35). A median of two (range: 1-13) cycles was received. The schedule was well tolerated; there were no treatment-related deaths. The only grade 4 toxicities included neutropenia (n = 7), nausea and vomiting (n = 2), and dermatologic (n = 1). One (2.3%) patient achieved a complete response and eight (18.2%) experienced a partial response, for an overall response rate of 20.5%. CONCLUSION: Gemcitabine demonstrates activity in patients with persistent or recurrent uterine LMS and should be considered in multiagent regimens treating this patient population.

Phase I feasibility trial of carboplatin, paclitaxel, and gemcitabine in patients with previously untreated epithelial ovarian or primary peritoneal cancer: a Gynecologic Oncology Group study.

PURPOSE: To determine the feasibility of administering a minimum of four cycles of carboplatin, paclitaxel, and gemcitabine (CPG) every 21 days without excessive dose modification or cycle delay in patients with previously untreated epithelial ovarian cancer or primary peritoneal cancer. METHODS: Paclitaxel 175 mg/m(2) was given over 3 h followed by carboplatin concentration time curve (AUC) 5 (day 1) and gemcitabine 1 g/m(2) (days 1 and 8) in the first cohort. A second cohort received paclitaxel 135 mg/m(2) over 3 h followed by carboplatin AUC 5 (day 1) and gemcitabine 800 mg/m(2) (days 1 and 8). A maximum of eight cycles was administered. RESULTS: Fourteen patients received 89 cycles during the first cohort. Seven patients experienced 19 hematologic dose-limiting events (DLEs) within the first four cycles, including grade 4 thrombocytopenia (n = 9), febrile neutropenia (n = 3), and omission of gemcitabine on day 8 (n = 7). This exceeded the threshold for nonfeasibility. In the second, less intense regimen, 36 patients were entered. Thirty-one evaluable patients received a total of 200 and median of 6 (range: 2-8) cycles. Thirteen of the thirty-one had 27 DLEs within the first four cycles including grade 4 thrombocytopenia (n = 5), prolonged grade 4 neutropenia (n = 2), febrile neutropenia (n = 2), and omission of day 8 gemcitabine (n = 18). There was one patient death secondary to a wound abscess and febrile neutropenia. Myelosuppression as expected was the dose-limiting toxicity. CONCLUSION: The schedule of paclitaxel 135 mg/m(2) (day 1, 3 h), carboplatin AUC 5 (day 1), and gemcitabine 800 mg/m(2) (days 1 and 8) is feasible, with an acceptable toxicity profile.

A randomized phase II evaluation of bryostatin-1 (NSC #339555) in recurrent or persistent platinum-sensitive ovarian cancer: a Gynecologic Oncology Group Study.

OBJECTIVES: The Gynecologic Oncology Group (GOG) performed a randomized phase II study to determine the antitumor activity and toxicity of two different schedules of bryostatin-1 administration in patients with recurrent or persistent platinum-sensitive epithelial ovarian cancer or primary peritoneal carcinoma. METHODS: Eligible patients were randomized to receive either bryostatin-1 25 microg/m2 as a 1h infusion weekly for 3 weeks followed by a 1-week rest (Regimen I) or bryostatin-1 120 microg/m2 as a 72 h continuous infusion every 2 weeks (Regimen II). RESULTS: Fifty-five patients were enrolled on this study. There was one durable response among 27 eligible patients (response rate=3.7%) on Regimen II and no responses in the 27 eligible patients on Regimen I. Nineteen patients (eleven on Regimen I and eight on Regimen II) had stable disease. The most common adverse event was myalgia, with 12 of 27 patients (44%) on each regimen experiencing some degree of myalgia. There were no other significant toxicities on either treatment arm. CONCLUSIONS: Both of these schedules and doses of bryostatin-1 are inactive as single agents in previously treated epithelial ovarian cancer.

Phase III trial of paclitaxel at two dose levels, the higher dose accompanied by filgrastim at two dose levels in platinum-pretreated epithelial ovarian cancer: an intergroup study.

PURPOSE: To determine if increasing the dose of paclitaxel increases the probability of clinical response, progression-free survival, or overall survival in women who have persistent or recurrent ovarian cancer, and whether doubling the dose of prophylactic filgrastim accompanying the higher paclitaxel dose decreases the frequency of neutropenic fever. PATIENTS AND METHODS: Consenting patients with persistent, recurrent, or progressing ovarian cancer, despite first-line platinum therapy (but no prior taxane), were randomly assigned to paclitaxel 135 mg/m2, 175 mg/m2, or 250 mg/m2 over 24 hours every 3 weeks. Patients receiving paclitaxel 250 mg/m2 were also randomly assigned to 5 or 10 microg/kg of filgrastim per day subcutaneously. RESULTS: Accession to the paclitaxel 135-mg/m2 arm was closed early. Among the 271 patients on the other regimens with measurable disease, partial and complete response on paclitaxel 250 mg/m2 (36%) was significantly higher than on 175 mg/m2 (27%, P =.027). This difference was more evident among patients who never responded to prior platinum. However, progression-free and overall survival results were similar. The median durations of overall survival were 13.1 and 12.3 months for paclitaxel 175 mg/m2 and 250 mg/m2, respectively. Thrombocytopenia, neuropathy, and myalgia were greater with paclitaxel 250 mg/m2 (P <.05). The incidence of neutropenic fever after the first cycle of paclitaxel 250 mg/m2 was 19% and 18% on the 5-microg/kg and 10-microg/kg filgrastim dose, respectively (22% for paclitaxel 175 mg/m2 without filgrastim). CONCLUSION: Paclitaxel exhibits a dose effect with regard to response rate, but there is more toxicity and no survival benefit to justify paclitaxel 250 mg/m2 plus filgrastim. Doubling the filgrastim dose from 5 to 10 microg/kg did not reduce the probability of neutropenic fever after high-dose paclitaxel.

Phase I escalation of gemcitabine combined with protracted oral etoposide in gynecologic malignancies: A Gynecologic Oncology Group study.

OBJECTIVE: Although improvements have been made in the management of patients with advanced ovarian cancer, long-term survivors are still uncommon. Gemcitabine and prolonged oral etoposide have shown reproducible single-agent activity in patients with platinum/paclitaxel-resistant ovarian cancer. This, combined with preclinical synergism, prompted the Gynecologic Oncology Group to determine the maximum tolerated dose (MTD) of this combination. METHODS: Eligible patients had recurrent epithelial ovarian cancer, primary papillary peritoneal, or fallopian tube carcinoma. All had received prior platinum/paclitaxel-based chemotherapy and had adequate hepatic, renal and bone marrow function. Oral etoposide was administered at 50 mg/m2 for ten days, with three proposed dose levels for gemcitabine on days 1 and 8: 400, 550 and 700 mg/m2. Cycles were to be repeated every 28 days. Three patients were to enter at each dose level. RESULTS: Patients were enrolled only to dose level 1 as this dose exceeded MTD. Of six patients initially enrolled, one was removed after three days with fever, ascites and decreased albumin believed not to be treatment related. Five patients were evaluable for toxicity and response. One of the first three patients developed dose limiting toxicity (DLT) manifested as grade 4 neutropenia. A second DLT (neutropenic fever and thrombocytopenia associated with bleeding) occurred among the next three patients: therefore, MTD was reached at dose level 1. Grade 4 toxicities included episodes of neutropenia (4) and thrombocytopenia (3). No objective response was observed. CONCLUSIONS: Oral etoposide and gemcitabine at this dose and schedule was associated with substantial toxicity in this population. Patients who are previously treated with platinum/paclitaxel-based chemotherapy may be at particular risk for toxicity.