Limitations of the paclitaxel-doxorubicin-cisplatin (TAP) regimen in the treatment of endometrial cancer include tolerability and cumbersome scheduling. The Gynecologic Oncology Group studied ...carboplatin plus paclitaxel (TC) as a noninferior alternative to TAP.
GOG0209 was a phase III, randomized, noninferiority, open-label trial. Inclusion criteria were stage III, stage IV, and recurrent endometrial cancers; performance status 0-2; and adequate renal, hepatic, and marrow function. Prior radiotherapy and/or hormonal therapy were permitted, but chemotherapy, including radiosensitization, was not. Patients were treated with doxorubicin 45 mg/m
and cisplatin 50 mg/m
(day 1), followed by paclitaxel 160 mg/m
(day 2) with granulocyte colony-stimulating factor or paclitaxel 175 mg/m
and carboplatin area under the curve 6 (day 1) every 21 days for seven cycles. The primary endpoint was overall survival (OS; modified intention to treat). Progression-free survival (PFS), health-related quality of life (HRQoL), and toxicity were secondary endpoints.
From 2003 to 2009, 1,381 women were enrolled. Noninferiority of TC to TAP was concluded for OS (median, 37
41 months, respectively; hazard ratio HR, 1.002; 90% CI, 0.9 to 1.12), and PFS (median, 13
14 months; HR, 1.032; 90% CI, 0.93 to 1.15). Neutropenic fever was reported in 7% of patients receiving TAP and 6% of those receiving TC. Grade > 2 sensory neuropathy was recorded in 26% of patients receiving TAP and 20% receiving TC (
= .40). More grade ≥ 3 thrombocytopenia (23%
12%), vomiting (7%
4%), diarrhea (6%
2%), and metabolic (14%
8%) toxicities were reported with TAP. Neutropenia (52%
80%) was more common with TC. Small HRQoL differences favored TC.
With demonstrated noninferiority to TAP, TC is the global first-line standard for advanced endometrial cancer.
This phase III randomized trial (NCT00954174) tested the null hypothesis that paclitaxel and carboplatin (PC) is inferior to paclitaxel and ifosfamide (PI) for treating uterine carcinosarcoma (UCS).
...Adults with chemotherapy-naïve UCS or ovarian carcinosarcoma (OCS) were randomly assigned to PC or PI with 3-week cycles for 6-10 cycles. With 264 events in patients with UCS, the power for an overall survival (OS) hybrid noninferiority design was 80% for a null hazard ratio (HR) of 1.2 against a 13% greater death rate on PI with a type I error of 5% for a one-tailed test.
The study enrolled 536 patients with UCS and 101 patients with OCS, with 449 and 90 eligible, respectively. Primary analysis was on patients with UCS, distributed as follows: 40% stage I, 6% stage II, 31% stage III, 15% stage IV, and 8% recurrent. Among eligible patients with UCS, PC was assigned to 228 and PI to 221. PC was not inferior to PI. The median OS was 37 versus 29 months (HR = 0.87; 90% CI, 0.70 to 1.075;
< .01 for noninferiority,
> .1 for superiority). The median progression-free survival was 16 versus 12 months (HR = 0.73;
= < 0.01 for noninferiority,
< .01 for superiority). Toxicities were similar, except that more patients in the PC arm had hematologic toxicity and more patients in the PI arm had confusion and genitourinary hemorrhage. Among 90 eligible patients with OCS, those in the PC arm had longer OS (30
25 months) and progression-free survival (15
10 months) than those in the PI arm, but with limited precision, these differences were not statistically significant.
PC was not inferior to the active regimen PI and should be standard treatment for UCS.
Abstract Background Metastatic and recurrent, platinum resistant cervix cancer has an extremely poor prognosis. The Gynecologic Oncology Group has studied > 20 cytotoxic drugs or drug combinations in ...the second-line, phase II setting of advanced, drug resistant cervix cancer. Methods Nanoparticle, albumin-bound paclitaxel (nab-paclitaxel) was administered at 125 mg/m2 IV over 30 minutes on days 1, 8 and 15 of each 28 day cycle to 37 women with metastatic or recurrent cervix cancer that had progressed or relapsed following first-line cytotoxic drug treatment. A flexible, 2-stage accrual design that allowed stopping early for lack of treatment activity was utilized. Because of slow patient accrual, the second stage was not completed. Results Of 37 patients enrolled, 2 were ineligible due to no prior cytotoxic chemotherapy, which left 35 eligible patients evaluable for response and tolerability. All of the eligible patients had 1 prior chemotherapy regimen and 27 of them had prior radiation therapy with concomitant cisplatin. The median number of nab-paclitaxel cycles were 4 (range 1–15). Ten (28.6%; CI 14.6%–46.3%) of the 35 patients had a partial response and another 15 patients (42.9%) had stable disease. The median progression-free and overall survival were 5.0 and 9.4 months, respectively. The only NCI CTCAE grade 4 event was neutropenia in 2 patients (5.7%) which resolved following dose reduction. Grade 3 neurotoxicity was reported in 1 (2.9%) patient and resolved to grade 2 following dose discontinuation. Conclusions Nab-paclitaxel has considerable activity and moderate toxicity in the treatment of drug resistant, metastatic and recurrent cervix cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Purpose GOG 152 was a randomized trial of secondary cytoreductive surgery (SCS) in patients with suboptimal residual disease (residual tumor nodule > 1 cm in greatest diameter) following ...primary cytoreductive surgery for advanced stage ovarian cancer. The current analysis was undertaken to evaluate the impact of disease findings at SCS on progression-free survival (PFS) and overall survival (OS). Methods Among the 550 patients enrolled on GOG-152, two-hundred-sixteen patients were randomly assigned following 3 cycles of cisplatin and paclitaxel to receive SCS. In 15 patients (7%) surgery was declined or contraindicated. In the remaining 201 patients the operative and pathology reports were utilized to classify their disease status at the beginning of SCS as; no gross disease/microscopically negative N = 40 (19.9%), no gross disease/microscopically positive N = 8 (4.0%), and gross disease N = 153 (76.1%). Results The median PFS for patients with no gross disease/microscopically negative was 16.1 months, no gross disease/microscopically positive was 13.5 months and for gross disease was 11.7 months, P = 0.002. The median OS for patients with no gross disease/microscopically negative was 51.5 months, no gross disease/microscopically positive was 42.6 months and for gross disease was 34.9 months, P = 0.018. Conclusion Although as previously reported SCS did not change PFS or OS, for those who underwent the procedure, their operative and pathologic findings were predictive of PFS and OS. Surgical/pathological residual disease is a biomarker of response to chemotherapy and predictive of PFS and OS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Background The objective of this study was to estimate antitumor activity and toxicity of weekly docetaxel and gemcitabine as second-line chemotherapy for patients with recurrent uterine ...carcinosarcoma. Methods Patients with recurrent carcinosarcoma of the uterus who had failed one regimen of chemotherapy, had a Gynecologic Oncology Group (GOG) performance status of 0–2 and had measurable disease were included. Treatment consisted of gemcitabine 600 mg/m2 and docetaxel 35 mg/m2 intravenously on days 1, 8 and 15 of a 28-day cycle until disease progression or intolerable adverse effects. This study employed an optimal but flexible two-stage design with an early stopping rule. If more than 3 out of 22–24 or more than 4 out of 25–29 patients responded, accrual to the second stage was to be initiated. Results Twenty-eight patients were enlisted. Three patients were not eligible after pathology review. One patient was never treated. Twenty-four patients were evaluable. Nine patients had previous radiation therapy. There were no complete responses. Partial responses were seen in two patients (8.3%), stable disease in eight (33.3%) and progressive disease in 12 patients (50%). Two patients were not evaluable (8.3%). The median progression-free survival was 1.8 months. The median survival was 4.9 months. The treatment caused myelosuppression, mainly neutropenia, but also thrombocytopenia and anemia. Dose modifications became necessary in the majority of patients. In five patients, treatment was discontinued due to toxicity. Conclusions This regimen of docetaxel and gemcitabine is not active in patients with recurrent carcinosarcoma of the uterus as second-line chemotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A quality improvement initiative (QII) was conducted with five community-based health systems' oncology care centers (sites A–E). The QII aimed to increase referrals, genetic counseling (GC), and ...germline genetic testing (GT) for patients with ovarian cancer (OC) and triple-negative breast cancer (TNBC).
QII activities occurred at sites over several years, all concluding by December 2020. Medical records of patients with OC and TNBC were reviewed, and rates of referral, GC, and GT of patients diagnosed during the 2 years before the QII were compared to those diagnosed during the QII. Outcomes were analyzed using descriptive statistics, two-sample t-test, chi-squared/Fisher's exact test, and logistic regression.
For patients with OC, improvement was observed in the rate of referral (from 70% to 79%), GC (from 44% to 61%), GT (from 54% to 62%) and decreased time from diagnosis to GC and GT. For patients with TNBC, increased rates of referral (from 90% to 92%), GC (from 68% to 72%) and GT (81% to 86%) were observed. Effective interventions streamlined GC scheduling and standardized referral processes.
A multi-year QII increased patient referral and uptake of recommended genetics services across five unique community-based oncology care settings.
•A coordinated quality improvement initiative was completed in five community-based health system oncology care centers.•Referral, genetic counseling, and genetic testing improved for patients with ovarian and triple-negative breast cancer.•Average time to completion of genetic testing for patients with ovarian cancer significantly decreased at almost all sites.•The most effective quality improvement interventions standardized genetic counseling referral and delivery processes.
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Abstract Purpose Dose-dense regimens have been shown to improve outcome when given as adjuvant therapy to patients with breast cancer compared with their three weekly counterparts. We investigated ...the feasibility of a dose-dense regimen with carboplatin/paclitaxel followed by pegfilgrastim in patients with advanced ovarian cancer. We also investigated the toxicities including the percentage of patients with grade 2 or greater peripheral neurotoxicity and the clinical response of this regimen. Patients and methods Women with untreated Stage III or IV epithelial ovarian, (fallopian) tubal, or primary peritoneal cancer were treated with carboplatin area under the curve (AUC) 5 and paclitaxel 175 mg/m2 day one, and pegfilgrastim 6 mg day two every 2 weeks for six cycles. Results Between 9/06 and 9/08, 43 patients enrolled. Thirty-one patients completed six or more cycles of therapy. The dose limiting toxicities resulting in treatment discontinuation included: grade 3 and 4 neuropathy, grade 4 thrombocytopenia, grade 4 thrombocytopenia/grade 3 febrile neutropenia, and grade 4 supraventricular tachycardia. Twelve patients (30%) had ≥ grade 2 neuropathy from this regimen. The overall response rate in patients with measurable disease was 58% (11 out of 19). Conclusion Dose-dense carboplatin/paclitaxel appears to be effective. However, based on dose limiting toxicities occurring when administering 6 cycles of treatment, it is not feasible. Given the neuropathy and thrombocytopenia, we do not recommend 6 cycles of this regimen without modification.
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This multicenter phase 2 trial was conducted by the Gynecologic Oncology Group to evaluate the activity and the safety of irofulven in patients with recurrent epithelial ovarian cancer. Eligible ...patients had documented recurrent ovarian cancer 6 to 12 months after receiving a front-line platinum-based regimen and no other chemotherapy. Patients were required to have measurable disease, performance status of 0 to 2, and adequate bone marrow, hepatic, and renal functions before study entry. The dose of irofulven was 0.45 mg/kg intravenously on days 1 and 8 every 21 days. Responses were defined by Response Evaluation Criteria in Solid Tumors. Fifty-five of 61 enrolled patients were evaluable for response and toxicity. There were 7 partial responses (12.7%), and 30 patients (54.6%) had stable disease. Median progression-free and overall survival were 6.4 months (1.3-37.5 months) and 22.1 months or more (2.8-57.8+ months), respectively. Patients received a median of 3 cycles (range, 1-21) of protocol therapy. Grade 4 hematologic toxicity was limited to reversible neutropenia and thrombocytopenia. Grade 4 nonhematologic toxicity was limited to one patient with anorexia and another with hypomagnesemia. Irofulven administered at this dose and schedule was well tolerated but had modest activity as a single agent.
Mutations of the human putative protein tyrosine phosphatase (PTEN/MMAC1) gene at chromosome 10q23 have been found frequently
in type I endometrial carcinomas. Endometrioid adenocarcinoma is the most ...frequent histology seen in patients with clinically
determined synchronous endometrial and ovarian carcinomas. We report a high incidence of PTEN/MMAC1 mutations and 10q23 loss
of heterozygosity (LOH) in patients with synchronous endometrial and ovarian carcinomas. Paraffin-embedded precision microdissected
tumors were analyzed for 10 matched synchronous endometrial and ovarian cancers and 11 matched control metastatic endometrial
cancers. Single-stranded conformation polymorphism analysis was used to screen for mutations in all tumors and corresponding
normal lymphocyte DNA. LOH was determined using a panel of four microsatellite markers within the PTEN/MMAC1 locus. PTEN/MMAC1
mutations were found in 43% (9 of 21) of the endometrial cancers studied, similarly represented in the clinically synchronous
group (5 of 10 or 50%) and the advanced metastatic group (4 of 11; 36%; P = 0.53). In two of the five cases of clinically
synchronous cancers, identical or progressive PTEN mutations were found in both the endometrial and ovarian cancers, suggesting
that the ovarian tumor is a metastasis from the endometrial primary. PTEN/MMAC1 mutations in the advanced endometrial cancers
were similar in the corresponding metastases. In one case, the mutation was seen in only one of two metastatic lymph nodes.
The LOH analysis demonstrated 55% LOH in at least one PTEN/MMAC1 marker. These findings suggest that the putative tumor suppressor
gene PTEN/MMAC1 may be a viable molecular marker to differentiate synchronous versus metastatic disease in a subset of clinically
synchronous endometrial and ovarian carcinomas.
Study Objectives. To evaluate the analgesic and hemodynamic effects of a single dose of intravenous morphine 7.5 mg in patients experiencing moderate‐to‐severe postoperative pain, and to determine ...any gender differences in analgesic response.
Design. Randomized, double‐blind, parallel‐group, multicenter study.
Setting. Postanesthesia care unit of a university teaching hospital.
Patients. Eighty‐eight patients who underwent total abdominal hysterectomy or prostatectomy.
Intervention. Thirty‐seven patients received a single dose of morphine sulfate 7.5 mg and 51 patients received placebo, both administered intravenously for 1 minute.
Measurements and Main Results. Overall, morphine had no significant effect on systolic or diastolic blood pressure, heart rate, oxygen saturation, or respiratory rate. Compared with baseline, morphine significantly reduced pain intensity at 2, 5, and 10 minutes after administration (p<0.05). The difference in pain intensity between patients who received morphine and those who received placebo, however, was significant only at the 5‐minute time point (p<0.02). Patients receiving morphine also reported mild pain relief at 2 and 5 minutes after its administration. Peak analgesic effect was reported 2 minutes after its administration in three quarters of the patients. Significant gender differences also were observed in response to analgesic effect. In women, no significant differences in pain intensity were seen at any time between the morphine and placebo groups, whereas in men receiving morphine, pain intensity was significantly less at 2, 5, and 10 minutes compared with baseline and that seen in the placebo group. Women were generally more satisfied with their pain treatment than were men.
Conclusion. A single 7.5‐mg intravenous bolus dose of morphine did not appear to provide adequate reduction in perceived pain intensity in patients with moderate‐to‐severe postoperative pain. In addition, in contrast to the findings of other experimental pain studies, our data suggest that women are more tolerant of postoperative pain than are men.
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