Low-dose abdominal radiation as a docetaxel chemosensitizer for recurrent epithelial ovarian cancer: a phase I study of the Gynecologic Oncology Group

Objectives

The aim of this study was to determine the maximum tolerated dose and dose-limiting toxicity (DLT) of whole abdomen radiation as a chemosensitizer of weekly docetaxel for women with recurrent epithelial ovarian fallopian tube, or peritoneal cancers.

Patients and methods

Women were enrolled on one of three dose levels of docetaxel (20, 25, or 30 mg/m²) administered weekly with concurrent low-dose whole abdominal radiation given as 60 cGy bid 2 days weekly for a total of 6 weeks.

Results

Thirteen women were enrolled and received 70 weekly treatments of docetaxel in combination with radiation therapy. At the first dose level, docetaxel 25 mg/m², grade 3 fatigue and thrombocytopenia were observed. At the next dose level, docetaxel 30 mg/m², grade 3 febrile neutropenia, grade 4 thrombocytopenia with epistaxis, and grade 3 diarrhea were observed. Given these dose-limiting toxicities, a lower dose of docetaxel 20 mg/m² was administered and found to be tolerable. No objective responses were observed among the 10 patients with measurable disease; however, the median progression-free survival (PFS) in all patients was 3.3 months, and 3 of the patients with measurable disease were free of tumor progression after 6 months (30%; 90% confidence interval 8.7-61%).

Conclusions

Twice weekly low-dose whole abdomen radiation during weekly docetaxel 20 mg/m² was well-tolerated. Given the PFS demonstrated in these women with resistant ovarian cancer, further study of whole abdominal radiation and concurrent chemotherapy may be warranted.     

A phase II trial of radiation therapy and weekly cisplatin chemotherapy for the treatment of locally-advanced squamous cell carcinoma of the vulva: a gynecologic oncology group study

Objectives

To determine the efficacy and toxicity of radiation therapy and concurrent weekly cisplatin chemotherapy in achieving a complete clinical and pathologic response when used for the primary treatment of locally-advanced vulvar carcinoma.

Methods

Patients with locally-advanced (T3 or T4 tumors not amenable to surgical resection via radical vulvectomy), previously untreated squamous cell carcinoma of the vulva were treated with radiation (1.8 Gy daily × 32 fractions = 57.6 Gy) plus weekly cisplatin (40 mg/m²) followed by surgical resection of residual tumor (or biopsy to confirm complete clinical response). Management of the groin lymph nodes was standardized and was not a statistical endpoint. Primary endpoints were complete clinical and pathologic response rates of the primary vulvar tumor.

Results

A planned interim analysis indicated sufficient activity to reopen the study to a second stage of accrual. Among 58 evaluable patients, there were 40 (69%) who completed study treatment. Reasons for prematurely discontinuing treatment included: patient refusal (N = 4), toxicity (N = 9), death (N = 2), other (N = 3). There were 37 patients with a complete clinical response (37/58; 64%). Among these women there were 34 who underwent surgical biopsy and 29 (78%) who also had a complete pathological response. Common adverse effects included leukopenia, pain, radiation dermatitis, pain, or metabolic changes.

Conclusions

This combination of radiation therapy plus weekly cisplatin successfully yielded high complete clinical and pathologic response rates with acceptable toxicity.     

A phase II study of two topotecan regimens evaluated in recurrent platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer: a Gynecologic Oncology Group Study (GOG 146Q)

Objective.

To evaluate the efficacy and safety of topotecan in patients with recurrent ovarian, primary peritoneal, and fallopian tube carcinomas.

Methods.

A randomized phase II analysis of platinum-sensitive patients with measurable disease was performed independently assessing intravenous topotecan 1.25 mg/m² daily × 5 every 21 days (regimen I) and topotecan 4.0 mg/m²/day on days 1, 8, and 15 of a 28-day cycle (regimen II). All patients were treated until disease progression, unmanageable toxicity, or patient refusal. Insufficient accrual related to regimen I resulted in a redesign of the study as a single arm phase II trial assessing only regimen II. More complete efficacy data is presented for regimen II as enrollment on regimen I was insufficient for some analyses.

Results.

A total of 81 patients were enrolled. One patient was ineligible. Fifteen patients received regimen I, while 65 patients were treated with regimen II. The response rate on regimen I (daily × 5) was 27% (90% CI: 10-51%) and 12% (90% CI: 6-21%) on regimen II (weekly). The median PFS and OS were 4.8 and 27.8 months, respectively, for regimen II. Grade 3/4 neutropenia rate was 93% with daily × 5 dosing and 28% for weekly treatment. Febrile neutropenia was very low in both groups.

Conclusion.

The weekly regimen of topotecan appeared less active but resulted in less toxicity than the daily regimen in platinum-sensitive recurrent ovarian cancer patients.     

A phase I study with an expanded cohort to assess the feasibility of intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with untreated ovarian, fallopian tube or primary peritoneal carcinoma: a Gynecologic Oncology Group study

Objective

To define the maximum tolerated dose (MTD) and assess the feasibility of intravenous (IV) paclitaxel, intraperitoneal (IP) carboplatin, and IP paclitaxel in women with newly diagnosed Stages II-IV ovarian, fallopian tube, or primary peritoneal carcinoma.

Methods

Patients received escalating doses of paclitaxel IV and carboplatin IP on day 1 and paclitaxel IP 60 mg/m² on day 8. A standard 3 + 3 design was used in the escalation phase. A two-stage group sequential design with 20 patients at the MTD was used in the feasibility phase. Patient-reported neurotoxicity was assessed pre and post treatment.

Results

Patients were treated with paclitaxel 175 mg/m² IV and carboplatin IP from AUC 5-7 on day 1 and paclitaxel 60 mg/m² IP on day 8. The MTD was estimated at carboplatin AUC 6 IP and 25 patients enrolled at this dose level. Within the first 4 cycles, seven (35%) of twenty evaluable patients had dose-limiting toxicities (DLTs) including grade 4 thrombocytopenia (1), grade 3 neutropenic fever (3), > 2 week delay due to ANC recovery (1), grade 3 LFT (1), and grade 3 infection (1). De-escalation to paclitaxel 135 mg/m² IV was given to improve the safety. After six evaluable patients completed 4 cycles without a DLT, bevacizumab was added and six evaluable patients completed 4 cycles with one DLT (grade 3 hyponatremia).

Conclusions

Paclitaxel at 175 mg/m² IV, carboplatin AUC 6 IP day 1 and paclitaxel 60 mg/m² IP day 8 yield 18-56% patients with DLTs. The tolerability of the regimen in combination with bevacizumab was indicated in a small cohort.     

A Phase I Study using low-dose fractionated whole abdominal radiotherapy as a chemopotentiator to full-dose cisplatin for optimally debulked stage III/IV carcinoma of the endometrium

Objective

To evaluate the feasibility of combining low-dose fractionated whole abdominal radiation (LDF-WAR) with weekly full-dose cisplatin (FD-CDDP) for patients with stage III/IV endometrial carcinoma.

Methods

Patients with optimally debulked stage III/IV carcinoma of the endometrium (without extra-abdominal disease) were eligible for the study. Postoperatively, patients received the institutional standard systemic chemotherapy and vaginal brachytherapy. Patients then underwent experimental six weekly cycles of FD-CDDP (40 mg/m², maximum 70 mg IV) followed by LDF-WAR 6-8 hours after initiation of chemotherapy. In a conservative design, 6 patients were accrued to two sequential cohorts of LDF-WAR, at 0.5 Gy/fraction [Fx] (total 3 Gy) and 0.75 Gy/Fx (total 4.5 Gy). Toxicities and laboratory studies were evaluated at each visit.

Results

Twelve patients were enrolled from January 2005 to June 2009 with median follow-up of 13.5 months (range: 5-27 months). Seventy-five percent of enrolled patients had uterine papillary serous histology. Eleven patients at least partially completed therapy (range: 2-6 cycles of FD-CDDP/LDF-WAR) with one additional patient opting out at the higher dose level. Combination therapy overall was well tolerated. Three patients in each cohort experienced grade 3 acute hematologic events with one recorded grade 4 toxicity in the second cohort. Of patients receiving any of the experimental treatment, five have experienced recurrences. Three of these patients were in cohort one and received 0.5 Gy/Fx LDF-WAR.

Conclusion

Combination therapy with LDF-WAR as a novel chemopotentiator to FD-CDDP is a feasible adjuvant regimen in optimally debulked patients with stage III/IV endometrial carcinoma. Further investigation is warranted to determine treatment efficacy.     

Phase II study of cisplatin plus cetuximab in advanced, recurrent, and previously treated cancers of the cervix and evaluation of epidermal growth factor receptor immunohistochemical expression: a Gynecologic Oncology Group study

Background

The purpose of this study was to evaluate the safety and efficacy of cetuximab (C225), an antibody that inhibits epidermal growth factor receptor (EGFR) activity, with cisplatin and to explore associations between EGFR protein expression with patient demographics or clinical outcome.

Methods

Women with advanced, persistent, or recurrent carcinoma of the cervix were eligible. The women received cisplatin at 30 mg/m² on days 1 and 8 with a loading dose of cetuximab at 400 mg/m² followed by 250 mg/m² on days 1, 8, and 15 in a 21 day cycle. Adverse events were assessed with CTCAE v 3.0. Primary measure of efficacy was tumor response by RECIST. The study was stratified by prior chemotherapy (CT). EGFR protein expression in pre-treatment tumor was analyzed by immunohistochemistry.

Results

Between September 2004 and March 2008, 76 patients were enrolled. Of these, 69 were eligible and evaluable; 44 (64%) received prior chemotherapy. There were 4 responses in each group, prior chemotherapy and no chemotherapy, 9% and 16%, respectively. Grade 4 toxicities included anemia (1), allergy (1), metabolic (1), and vascular (1). The most common grade 3 toxicities were metabolic (15), dermatologic (8), fatigue (6), and gastrointestinal (6). EGFR protein was expressed in 47/48 (98%) of tumors analyzed with a median cellular expression of 81%. Exploratory analyses revealed a trend between the percentage of cells expressing EGFR protein and PFS (hazard ratio = 1.76, 95% confidence interval = 0.96-3.21).

Conclusions

The combination of cetuximab with cisplatin was adequately tolerated but did not indicate additional benefit beyond cisplatin therapy.     

Chemoradiation and adjuvant chemotherapy in advanced cervical adenocarcinoma

Purpose

The optimal treatment of women with advanced adenocarcinoma of uterine cervix is still undefined. We compared concurrent chemoradiation (CCRT) and adjuvant cisplatin-based chemotherapy with CCRT alone for advanced cervical adenocarcinoma in a randomized trial at the Hunan Provincial Tumor Hospital in China.

Methods

From 1998 to 2007, 880 patients with clinical FIGO stages IIB-IVA cervical adenocarcinoma were randomized to receive either CCRT or chemoradiation with one cycle of neo-adjuvant chemotherapy with Paclitaxel (135 mg/m²) + Cisplatin (75 mg/m²) before receiving radiation and two cycles of consolidation chemotherapy with the same drugs after radiotherapy in 3-week intervals. The disease control and survival rates were calculated using the Kaplan-Meier method.

Results

All patients completed the treatment plan. 340 patients have relapsed, with a median follow-up duration of 60 months. Patients who received chemoradiation with adjuvant chemotherapy showed a significantly longer disease-free (P < .05), cumulative survival (P < .05) and long-term local tumor control (P < .05). Patients who received CCRT alone had significantly more distant metastasis and pelvic failure than those who received chemoradiation with adjuvant chemotherapy (P < .05).

Conclusion

Incorporating neo-adjuvant and consolidation chemotherapy with Paclitaxel and Cisplatin into concomitant chemoradiation is highly effective, safe and may be a very promising treatment protocol for advanced cervical adenocarcinoma.     

A prospective phase II study of topotecan (Hycamtin®) and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer

Objectives

To evaluate the feasibility, toxicity and activity of neoadjuvant chemotherapy (NACT) using cisplatin and topotecan in patients affected by locally advanced cervical cancer (IB2-IIIB).

Methods

Patients with histologically confirmed FIGO stage IB2-IIIB uterine cervical cancer were treated with topotecan 0.75 mg/m²/day (days 1-3) followed by cisplatin 75 mg/m² (day 1), every 21 days for three consecutive cycles. After the last cycle of chemotherapy, within 3 or 4 weeks, patients underwent radical surgery with lymph node dissection.

Results

In the years 2007-2010, 46 women were enrolled into the study. Hematologic toxicity was the most relevant side effect. Thirty-eight patients (82.6%) underwent radical surgery after neoadjuvant chemotherapy (NACT) and were assessable for pathologic responses; surgery was not performed in 8 (17.4%) non-responder patients or with progression disease. Objective pathological response was recorded in 34 patients (89.5%); 6 patients (15.8%) achieved a complete response (CR), 28 (73.7%) patients achieved a partial response (PR); stable disease (SD) occurred in 2 patients (5.3%) with IIA initial disease and progression disease (PD) was registered in 2 patients (5.3%) with IIIB initial disease. The cumulative 2-year progression free survival (PFS) and overall survival (OS) of the 46 enrolled patients in the study were 70% and 81%, respectively; the 2-year PFS and OS of the 38 operated patients were respectively 79% and 95%.

Conclusions

The cisplatin-topotecan combination seems to be feasible and with an acceptable toxicity profile and a promising response rate for the treatment of locally advanced cervical cancer (LACC). Phase II and III studies are needed to compare this combination with other platinum-based chemotherapeutic associations.     

A phase 1b study of trebananib in combination with pegylated liposomal doxorubicin or topotecan in women with recurrent platinum-resistant or partially platinum-sensitive ovarian cancer

Objective

To examine the tolerability and antitumor activity of trebananib plus pegylated liposomal doxorubicin (PLD) or topotecan in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer.

Methods

In this open-label phase 1b study, patients received trebananib 10 mg/kg or 15 mg/kg IV QW plus PLD 50 mg/m² (cohorts A1 and A3, respectively) or topotecan 4 mg/m² (cohorts B1 and B3, respectively). Endpoints were dose-limiting toxicity (DLT; primary); treatment-emergent adverse events (AEs), overall response rate, anti-trebananib antibodies, and pharmacokinetics (secondary).

Results

103 patients were enrolled. One patient in A1 and B1 had DLTs. Across all cohorts, the most common AEs were nausea, fatigue, and peripheral edema. Across both trebananib plus PLD cohorts (A1/A3), grade 4 AEs were pulmonary embolism, disease progression, and anemia. Two patients had grade 5 intestinal perforation (n = 1) and sudden death (n = 1). Across both trebananib plus topotecan cohorts (B1/B3), grade 4 AEs were neutropenia, hypokalemia, decreased granulocyte count, chest pain, dyspnea, decreased neutrophil count, and pulmonary embolism. Two patients had grade 5 disease progression. One patient had grade 5 pleural effusion associated with progressive disease. Confirmed objective response rates were 36.0% (A1), 34.8% (A3), 16.7% (B1), and 0.0% (B3). Median progression-free survival duration (months) was 7.4 (A1), 7.1 (A3), 3.5 (B1), and 3.1 (B3), respectively. No drug–drug interactions were apparent.

Conclusions

Trebananib 10 mg/kg and 15 mg/kg IV QW plus PLD or topotecan appear to have acceptable toxicity profiles in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Antitumor activity was evident across all cohorts.     

Progression-free and overall survival of a modified outpatient regimen of primary intravenous/intraperitoneal paclitaxel and intraperitoneal cisplatin in ovarian, fallopian tube, and primary peritoneal cancer

Objective

GOG study 172 demonstrated improved progression-free (PFS) and overall (OS) survival for patients with stage III optimally debulked ovarian and peritoneal carcinoma treated with IV/IP paclitaxel and IP cisplatin compared to standard IV therapy. The inpatient administration, toxicity profile, and limited completion rate have been blamed for the lack of acceptance and widespread use of this regimen. We sought to evaluate the PFS, OS, toxicity, and completion rate of a modified outpatient IP regimen.

Methods

Using a prospectively maintained database, we evaluated the outcomes of patients who underwent primary optimal cytoreduction for stage III ovarian, tubal, or peritoneal carcinoma followed by IV/IP chemotherapy from 1/05-3/09. Our modified regimen was as follows: IV paclitaxel (135 mg/m²) over 3 h on day 1, IP cisplatin (75 mg/m²) on day 2, and IP paclitaxel (60 mg/m²) on day 8, given every 21 days for 6 cycles.

Results

We identified 102 patients who initiated the modified IV/IP regimen and completed chemotherapy. The median follow-up was 43 months. The median age at diagnosis was 57 years (range, 23-76). Primary disease site was: ovary, 77 (75%); fallopian tube, 13 (13%); peritoneum, 12 (12%). FIGO stage was: IIIA, 8 (8%); IIIB, 4 (4%); IIIC, 90 (88%). Residual disease after cytoreduction was: none, 58 (57%); ≤ 1 cm, 44 (43%). The most frequent grade 3/4 toxicities were: neutropenia, 12 (12%); gastrointestinal, 8 (8%); neurologic, 6 (6%). Eighty-two (80%) of 102 patients completed 4 or more cycles of IV/IP therapy; 56 (55%) completed all 6 cycles. The median PFS and OS were 29 and 67 months, respectively.

Conclusions

By modifying the GOG 172 treatment regimen, convenience, toxicity, and tolerability appear improved, with survival outcomes similar to those of GOG 172. This modified IV/IP regimen warrants further study.     

Phase II trial of adjuvant pelvic radiation "sandwiched" between ifosfamide or ifosfamide plus cisplatin in women with uterine carcinosarcoma

Objective

Uterine carcinosarcoma (CS) is a rare uterine tumor with an extremely poor prognosis. In the adjuvant setting, efficacy has been shown with radiotherapy (RT), systemic chemotherapy, or both. This is the first report describing the efficacy and toxicity of adjuvant ifosfamide or ifosfamide plus cisplatin “sandwiched” with RT in patients with surgically staged and completely resected uterine carcinosarcoma.

Methods

Women with surgically staged CS with no gross residual disease were initially administered ifosfamide (1.2 g/m²/day × 5 days) with cisplatin (20 mg/m²/day × 5 days) every 3 weeks for 3 cycles followed by pelvic external beam RT and brachytherapy followed by 3 additional cycles of ifosfamide (1.0 g/m2/day) with cisplatin (20 mg/m²/day × 5 days) every 3 weeks. Similar to the GOG trial in recurrent CS (Sutton et al., 2000), the addition of cisplatin added toxicity without additional efficacy, so mid-study, the cisplatin was eliminated from the regimen. Toxicities were recorded and disease-free survival (DFS) was calculated with Kaplan-Meier statistical methods.

Results

In total, 12 patients received ifosfamide and cisplatin and 15 patients received ifosfamide alone, both ‘sandwiched’ with RT. The median follow up was 35.9 months (range 6-88). The 2 year DFS was similar in both the ifosfamide/cisplatin and ifosfamide groups (log-rank p = 0.16), so they were combined for analysis. 19 patients (70%) completed the protocol. As expected, stage 1 patients had a better 2-year DFS (18.75 ± 1.12 months; log-rank p = 0.008 when compared to stages 2, 3, 4). Also, in stages 2, 3 and 4 patients, the DFS was 15.81 ± 1.73 months. Grade 3/4 neutropenia, anemia and thrombocytopenia occurred in 18%, 4% and 4% of cycles, respectively.

Conclusions

Ifosfamide “sandwiched” with RT appears to be an efficacious regimen for surgically staged CS patients with no residual disease, even in patients with advanced stage. The addition of cisplatin to the regimen added toxicity without improving efficacy. Even with ifosfamide alone, the efficacy of this ‘sandwich’ regimen comes with a moderate but tolerable toxicity profile.     

An open-label, single-arm Phase II study of intravenous weekly (Days 1 and 8) topotecan in combination with carboplatin (Day 1) every 21 days as second-line therapy in patients with platinum-sensitive relapsed ovarian cancer

Objective

To evaluate clinical activity of weekly topotecan plus carboplatin in patients with platinum-sensitive recurrent ovarian, fallopian tube, or peritoneal carcinoma.

Methods

An open-label, single-arm, multicenter Phase I/II study. Phase II was the activity assessment phase, with overall response rate (ORR) as the primary endpoint. Eligible patients (females aged ≥ 18 years) received study treatment at the maximum-tolerated dose (MTD) identified in Phase I: intravenous topotecan 2.5 mg/m² (Days 1 and 8), followed by carboplatin AUC 5 (Day 1), every 21 days. A two-stage Green-Dahlberg design was used to assess efficacy of treatment. An ORR of ≤ 30% was required to conclude that treatment was ineffective.

Results

Twenty-two patients in Phase I permitted identification of the MTD. In Phase II, 55 patients (median age 64.0 years) were enrolled and included in the intent-to-treat population. There were six complete responses (10.9%) and 11 partial responses (20.0%), giving an ORR of 30.9% (17 patients; 95% CI: 18.7%, 43.1%). Median time to response and progression-free survival were 6.57 weeks (95% CI: 5.86, 12.57) and 44.29 weeks (95% CI: 36.14, 52.14), respectively. Grade 3/4 hematological toxicity caused dose reductions, treatment delays and study discontinuation. Neutropenia (Grade 3: 29%; Grade 4: 11%) was the most common hematological adverse event (AE). Fatigue (71%) and nausea (71%) were the most common drug-related non-hematologic AEs.

Conclusions

This study showed an acceptable benefit-risk profile for topotecan plus carboplatin. Further studies using alternative dose levels could help define an optimal dosing schedule for this treatment combination in patients with platinum-sensitive recurrent disease.     

Metabolic and endocrine effects of metformin and metformin plus cyclic medroxyprogesterone acetate in women with polycystic ovary syndrome

Objective

To evaluate the metabolic and endocrine effects of treatment with cyclic medroxyprogesterone acetate (MPA) plus metformin compared with metformin alone in women with PCOS.

Methods

In this prospective randomized study of women with PCOS, 20 women received 850 mg of metformin twice a day, and 20 women received 850 mg of metformin plus 5 mg of MPA twice a day. Body mass index, hormonal and lipid blood profiles, homocysteine blood level, and insulin sensitivities assessed by homeostasis model assessment (HOMA) were recorded at baseline and at 3 months.

Results

Total cholesterol levels decreased in the metformin plus MPA group (P = 0.002) but did not change significantly in the metformin group (P = 0.159). While homocysteine levels remained unchanged in the metformin plus MPA group, they increased significantly in the metformin group (P = 0.002).

Conclusion

There were no adverse effects of short-term cyclic MPA plus metformin treatment on metabolic parameters or insulin resistance in patients with PCOS over a 3-month treatment period.     

Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study

Purpose

The Gynecologic Oncology Group (GOG) conducted a phase II trial to assess the efficacy and tolerability of the anti-EGFR antibody cetuximab, in persistent or recurrent carcinoma of the cervix.

Patients and methods

Eligible patients had cervical cancer, measurable disease, and GOG performance status ≤ 2. Treatment consisted of cetuximab 400 mg/m² initial dose followed by 250 mg/m² weekly until disease progression or prohibitive toxicity. The primary endpoints were progression-free survival (PFS) at 6 months and response. The study used a 2-stage group sequential design.

Results

Thirty-eight patients were entered with 3 exclusions, leaving 35 evaluable for analysis. Thirty-one patients (88.6%) received prior radiation as well as either 1 (n = 25, 71.4%) or 2 (n = 10) prior cytotoxic regimens. Twenty-four patients (68.6%) had a squamous cell carcinoma. Grade 3 adverse events possibly related to cetuximab included dermatologic (n = 5), GI (n = 4), anemia (n = 2), constitutional (n = 3), infection (n = 2), vascular (n = 2), pain (n = 2), and pulmonary, neurological, vomiting and metabolic (n = 1 each). No clinical responses were detected. Five patients (14.3%; two-sided 90% CI, 5.8% to 30%) survived without progression for at least 6 months. The median PFS and overall survival (OS) times were 1.97 and 6.7 months, respectively. In this study, all patients with PFS at 6 months harbored tumors with squamous cell histology.

Conclusion

Cetuximab is well tolerated but has limited activity in this population. Cetuximab activity may be limited to patients with squamous cell histology.     

Addition of bevacizumab to weekly paclitaxel significantly improves progression-free survival in heavily pretreated recurrent epithelial ovarian cancer

Objective

Weekly paclitaxel has been shown to be an effective cytotoxic regimen for recurrent epithelial ovarian cancer (EOC), and may act through inhibition of angiogenesis. Bevacizumab, a potent angiogenesis inhibitor, has also been shown to have activity in patients with EOC. Therefore, we sought to determine if the addition of bevacizumab to weekly paclitaxel led to an increased survival compared to weekly paclitaxel alone.

Methods

A single institutional review was conducted for patients with recurrent EOC treated with weekly paclitaxel (60-70 mg/m²) on days 1, 8, 15, and 22 of a 28 day cycle and those treated with weekly paclitaxel and bevacizumab (10-15 mg/kg on day 1 and 15). Response rates (RR) were calculated, and progression-free survival (PFS), and overall survival (OS) were compared using Kaplan-Meier survival analysis.

Results

Twenty-nine patients treated with weekly paclitaxel and 41 patients treated with paclitaxel/bevacizumab were identified. The groups were similar in demographics, initial optimal cytoreduction, stage, histology, grade, platinum sensitivity, and median number of previous regimens (4 vs. 4, p = 0.69).The overall response rate (ORR) was 63% (complete response (CR) 34% and partial response (PR) 29%) for paclitaxel/bevacizumab and 48% (CR 17% and PR 31%) for weekly paclitaxel (p = 0.23). Improvement in PFS was seen in those treated with paclitaxel/bevacizumab in comparison to weekly paclitaxel alone (median PFS 13.2 vs. 6.2 months, p < .01). There was a trend towards improved OS for paclitaxel/bevacizumab (median OS 20.6 vs. 9.1 months; p = 0.12). Toxicities were similar between the two regimens although more bowel perforations (2 vs. 0) were seen in the paclitaxel/bevacizumab group.

Conclusion

A significant increase in PFS with a trend towards improved OS was demonstrated in this heavily pretreated population treated with paclitaxel/bevacizumab as compared to weekly paclitaxel alone. This data should be helpful in guiding future trials to determine the optimal care for women with recurrent EOC.     

Beyond mere obesity: Effect of increasing obesity classifications on hysterectomy outcomes for uterine cancer/hyperplasia

Objective

To assess the impact of obesity severity on hysterectomy outcomes for uterine hyperplasia/cancer.

Methods

The data from women undergoing hysterectomies for endometrial hyperplasia/uterine cancer with a BMI ≥ 30 kg/m² were abstracted from records at the University of Virginia and Duke University following IRB approval. Univariate and multivariate statistical analyses were performed.

Results

Mean age of the 659 patients was 58.1 yrs; mean body mass index (BMI) was 43 kg/m². Women were grouped based on BMI: 39.6% (261) were obese (30-39 kg/m²), 41.7% (275) were morbidly obese (40-49 kg/m²) and 18.7% (123) were super obese (≥ 50 kg/m²). Minimally invasive surgical procedures (MIS) were attempted in 280 patients with a conversion rate of 16.1%; BMI was higher in the converted group (47.3 vs. 40.6 kg/m²; p < 0.001). As obesity group increased, there was a decreased frequency of lymphadenectomy (63.8% vs. 37.1% vs. 20.3%; p < 0.001), increased blood loss (242 vs. 281 vs. 378 mL; p < 0.001) and fewer nodes removed (p < 0.001). On multivariate analysis, type of surgery (open vs. MIS) and obesity classification were independently and significantly associated with wound complications (p < 0.001) and the presence of postoperative complications (p < 0.001, p = 0.003). Surgical staging with lymphadenectomy was significantly associated with obesity (p < 0.001) but not procedure type (p = 0.11). Blood transfusion (p < 0.001), hospital readmission (p = 0.025), and ileus (p < 0.001) were significantly associated with open procedures but not obesity. There were no significant differences in progression-free or disease-specific survival based on obesity group.

Conclusion

Women with BMI's exceeding 40 kg/m² have worse surgical outcomes than their less obese counterparts.     

Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers

Objectives

Currently, pegylated liposomal doxorubicin (PLD) is regarded as one of the standard treatment options in recurrent ovarian cancers (ROC). Bevacizumab has shown significant antitumor activity for ROC in single-agent or in combination with cytotoxic agents. We have conducted a preliminary study to investigate effects of combination of bevacizumab and PLD for heavily pretreated patients with ROC.

Methods

Thirty patients with ROC were treated with combination therapy with weekly bevacizumab and PLD, 2 mg/kg of continuous weekly bevacizumab and 10 mg/m² of PLD (3 weeks on, 1 week off). The treatment was continued until development of disease progression, or unmanageable adverse effects. Response evaluation was based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and Gynecologic Cancer Intergroup (GCIG) CA125 response criteria. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

Results

Overall response rate was 33%, and clinical benefit rate (CR + PD + SD) was 73%. Median progression-free survival was 6 months (range: 2-20 months), and a 6-months progression-free survival was 47%. Any hematological toxicities more than grade 3 were not observed. Two cases developed non-hematologic toxicities more than grade 2; a case with grade 3 hand-foot syndrome, another with grade 3 gastrointestinal perforation (GIP). The case with GIP was conservatively treated and recovered after 2 months, and there was no case with treatment-related death.

Conclusion

The present investigation suggested that combination therapy with bevacizumab and PLD was active and well tolerated for patients with ROC. We recommend the regimen be evaluated in further clinical studies.     

Five-year outcomes of adjuvant carboplatin/paclitaxel chemotherapy and intravaginal radiation for stage I-II papillary serous endometrial cancer

Objective

The purpose of this study is to report our single-institution experience with concurrent adjuvant intravaginal radiation (IVRT) and carboplatin/paclitaxel chemotherapy for early stage uterine papillary serous carcinoma (UPSC).

Methods

From 10/2000 to 12/2009, 41 women with stage I-II UPSC underwent surgery followed by IVRT (median dose of 21 Gy in 3 fractions) and concurrent carboplatin (AUC = 5-6) and paclitaxel (175 mg/m²) for six planned cycles. IVRT was administered on non-chemotherapy weeks. The Kaplan-Meier method was used to estimate survival, and the log-rank test was used for comparisons.

Results

Median patient age was 67 years (51-80 years). Surgery included hysterectomy, bilateral salpingo-oophorectomy, peritoneal washings, omental biopsy, and pelvic and paraaortic lymph node sampling. FIGO 2009 stage was IA in 73%, IB in 10%, and II in 17%. Histology was pure serous in 71% of cases. Thirty-five patients (85%) completed all planned treatment. With a median follow-up time of 58 months, the 5-year disease-free (DFS) and overall survival (OS) rates were 85% (95%CI, 73-96%) and 90% (95%CI, 80-100%). The 5-year pelvic, para-aortic, and distant recurrence rates were 9%, 5%, and 10%, respectively. There were no vaginal recurrences. Of the 4 pelvic recurrences, 2 were isolated and were successfully salvaged. Patients with stage II disease had lower DFS (71% vs. 88%; p = 0.017) and OS (71% vs. 93%; p = 0.001) than patients with stage I disease.

Conclusions

Concurrent adjuvant carboplatin/paclitaxel chemotherapy and IVRT provide excellent outcomes for early stage UPSC. Whether this regimen is superior to pelvic radiation will require confirmation from the ongoing randomized trial.     

Effectiveness of the association micronized N-Palmitoylethanolamine (PEA)-transpolydatin in the treatment of chronic pelvic pain related to endometriosis after laparoscopic assessment: a pilot study

Objective

Aim of our study was to evaluate the effectiveness of the association between N-Palmitoylethanolamine and transpolydatin in the management of chronic pelvic pain related to EMS.

Study design

This was a randomized, double-blind, parallel-group, placebo-controlled clinical trial involving 61 subjects, submitted to a first line laparoscopic conservative surgery, who were randomized into 3 groups receiving: group A (n = 21) the association N-Palmitoylethanolamine-transpolydatin 400 mg + 40 mg twice a day for 3 months; group B (n = 20) the placebo for 3 months; group C (n = 20) a single course of Celecoxib 200 mg twice a day for 7 consecutive days. Assessments of the severity of pelvic endometriosis (pelvic pain, dysmenorrhoea and dyspareunia) were recorded before and after treatment on a questionnaire and a 10-point VAS. Differences between groups were verified with Kruskal-Wallis ANOVA for non-parametric multiple comparisons.

Results

A marked decrease in dysmenorrhoea, dyspareunia and pelvic pain was observed in all groups, and the association between N-Palmitoylethanolamine and transpolydatin resulted to be more effective than placebo (P < .001). Additionally, the treatment with Celecoxib resulted in a decrease in pelvic pain more effective either than the association N-Palmitoylethanolamine and transpolydatin or placebo.

Conclusion

These preliminary results show that the association between micronized N-Palmitoylethanolamine and transpolydatin is effective in the management of pelvic pain related to endometriosis after laparoscopy. Additionally, this association seems to be safe, shows an optimal control of pain and can be used in patients who are unable to receive other therapies.