HIPEC in recurrent ovarian cancer patients: morbidity-related treatment and long-term analysis of clinical outcome

Objective

To evaluate morbidity and mortality rates associated with the use of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) after optimal cytoreduction (CRS) in a large single-institutional series of platinum-sensitive recurrent ovarian cancer patients. Moreover, disease free (DFS) and overall survival (OS) of previously studied patients have been assessed after a longer follow-up period.

Method

From May 2005 to October 2010, recurrent ovarian cancer patients with a platinum-free interval of at least 6 months have been prospectively enrolled in a protocol of CRS plus HIPEC with oxaplatinum (460 mg/m²) heated to 41.5 °C for 30 min, followed by 6 cycles of systemic chemotherapy with taxotere 75 mg/m² and oxaliplatin 100 mg/m².

Results

Forty-one patients experienced 43 procedures (CRS + HIPEC). An optimal cytoreduction was achieved in all cases (CC-0 95.3%; CC-1 4.7%). A complication rate of 34.8% was registered, with no case of intraoperative death or within 30 days after surgery. Survival curves have been calculated in a group of 25 patients with a minimum follow-up of 18 months, obtaining a median DFS and OS of 24 (range 6-60) and 38 months (range 18-60), respectively.

Conclusion

In recurrent platinum-sensitive ovarian cancer patients, the use of CRS plus HIPEC represents a safe treatment, able to significantly influence the survival rates compared to chemotherapy alone or surgery plus standard chemotherapy.     

Minimally invasive secondary cytoreduction plus HIPEC for recurrent ovarian cancer: A case series

Objective

To analyze the feasibility of laparoscopic/robotic secondary cytoreductive surgery and hyperthermic intraperitoneal intra-operative chemotherapy (SCS + HIPEC) in a retrospective series of isolated platinum sensitive recurrent ovarian cancer.

Methods

We retrospectively evaluated a consecutive series of ovarian cancer patients with isolated platinum sensitive relapse. Isolated relapse was defined as the presence of a single nodule, in a single anatomic site. In all cases the presence of isolated relapse was assessed at pre-operative FDG-PET/CT scan, and confirmed with staging laparoscopy performed immediately before SCS + HIPEC.

Results

84 women with platinum sensitive relapse received SCS + HIPEC during a 4-year period. Among them, 10 cases (11.9%) showed isolated relapse and were treated with laparoscopic/robotic SCS + HIPEC. In all cases complete debulking was achieved. In HIPEC treatment, 9 women received cisplatin at 75 mg/m², and the remaining patient oxaliplatin 460 mg/m². In 7 patients SCS was performed through the laparoscopic route, and in 3 cases with a robotic approach. The median operative time from skin incision to the end of cytoreductive surgery was 122 min (95–140), estimated blood loss was 50 cm³ (50–100), and the median length of hospital stay was 4 days (3–7). The interval from surgery to adjuvant chemotherapy was 21 days (19–32). No grade 3/4 surgical, metabolic, or hematologic complications occurred. In all cases post-operative FDG-PET/CT scan was negative, and after a median time of 10 months (6–37) from SCS + HIPEC no secondary recurrence was observed.

Conclusions

Minimally invasive SCS + HIPEC can be safely performed in selected ovarian cancer patients with platinum sensitive isolated relapse.     

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.     

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as upfront therapy for advanced epithelial ovarian cancer: multi-institutional phase-II trial

Objective.

The primary end-point of this multi-institutional phase-II trial was to assess results in terms of overall survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in treatment-naive epithelial ovarian cancer (EOC) with advanced peritoneal involvement. Secondary end-points were treatment morbi-mortality and outcome effects of time to subsequent adjuvant systemic chemotherapy (TTC).

Methods.

Twenty-six women with stage III-IV EOC were prospectively enrolled in 4 Italian centers to undergo CRS and closed-abdomen HIPEC with cisplatin and doxorubicin. Then they received systemic chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m²) for 6 cycles.

Results.

Macroscopically complete cytoreduction was achieved in 15 patients; only minimal residual disease (≤ 2.5 mm) remained in 11. Major complications occurred in four patients and postoperative death in one. After a median follow-up of 25 months, 5-year overall survival was 60.7% and 5-year progression-free survival 15.2% (median 30 months). Excluding operative death, all the patients underwent systemic chemotherapy at a median of 46 days from combined treatment (range: 29-75). The median number of cycles per patient was 6 (range: 1-8). The time to chemotherapy did not affect the OS or PFS.

Conclusions.

In selected patients with advanced stage EOC, upfront CRS and HIPEC provided promising results in terms of outcome. Morbidity was comparable to aggressive cytoreduction without HIPEC. Postoperative recovery delayed the initiation of adjuvant systemic chemotherapy but not sufficiently to impact negatively on survival. These data warrant further evaluation in a randomized clinical trial.     

A phase II trial of oxaliplatin,docetaxel, and bevacizumab as first-line therapy of advanced cancer of the ovary,peritoneum, and fallopian tube

Objective

To determine the safety and efficacy of the novel combination of docetaxel, oxaliplatin, and bevacizumab as first-line treatment of advanced cancer of the ovary, peritoneum or fallopian tube after initial debulking surgery.

Methods

Eligible patients (stage IB-IV) were treated with 6 cycles of oxaliplatin (85 mg/m²), docetaxel (75 mg/m²), and bevacizumab (15 mg/kg) every 3 weeks, followed by single-agent bevacizumab 15 mg/kg every 3 weeks to complete one year of therapy. The primary endpoint was 12-month progression-free survival (PFS).

Results

A total of 132 patients (80 with measurable disease at baseline; 52 with non-measurable, evaluable disease at baseline) enrolled and received study treatment. At diagnosis, 76.5% of patients had stage III disease and 20% had stage IV. 62.9% were optimally cytoreduced. The most common grade 3/4 adverse events were neutropenia (42.4%), leukopenia (13.6%), hypertension (8.3%), fatigue (6.1%), and nausea (6.1%). One patient (0.8%) had a fatal gastrointestinal perforation. The best overall confirmed response rate (complete response + partial response [measurable disease subgroup]) was 58.6% (95% CI 49%, 67%). CA-125 response rates for the measurable and non-measurable disease subgroups were 83.0% and 81.5%, respectively. The 12-month PFS rate for the measurable disease subgroup was 65.7% (95% CI 53.4%, 76.7%); median PFS was 16.3 (95% CI 12.6, 19.6) months. Median overall survival was 47.3 (95% CI 34.1, upper limit not applicable) months.

Conclusions

This novel treatment regimen may provide a promising therapeutic approach for women with ovarian, primary peritoneal, or fallopian tube carcinoma. No unanticipated safety concerns were identified.     

Impact of obesity on the results of fertility-sparing management for atypical hyperplasia and grade 1 endometrial cancer

Objectives

The aim of the present study was to evaluate the impact of obesity on reproductive and oncologic outcomes on the success of fertility-sparing management.

Methods

This retrospective multicenter cohort study included women treated conservatively for atypical hyperplasia (AH) and endometrial cancer (EC) to preserve fertility. Five inclusion criteria were defined: (i) the presence of AH or grade 1 EC confirmed by two pathologists; (ii) adequate radiological examination before conservative management; (iii) available body mass index (BMI) at the beginning of treatment; and (iv) a minimum follow-up time of six months.

Results

Forty patients fulfilled the inclusion criteria (17 had EC, and 23 had AH), mean age and BMI were 33 years and 29 kg/m² respectively. Among the 15 obese patients, after medical treatment, 10 patients responded (67%) and three relapsed, whereas in the 25 non-obese patients, 19 responded (76%) and three relapsed (p = 0.72). The overall pregnancy rate and follow-up time were 35% and 35 months respectively. Among the 15 obese patients, after medical treatment, two patients became pregnant, whereas in the 25 non-obese patients, 12 became pregnant (p = 0.04).

Conclusion

Despite similar response and recurrence rates, our results suggest that fertility-sparing management for AH and EC is associated with a lower probability of pregnancy in obese patients.     

Oxaliplatin salvage for recurrent ovarian cancer: A single institution's experience in patient populations with platinum resistant disease or a history of platinum hypersensitivity

Objective

Hypersensitivity reactions can preclude platinum re-challenge for patients receiving second-line and higher carboplatin/cisplatin salvage therapy. The objective is to report our patient experience with oxaliplatin in recurrent or progressive epithelial ovarian (EOC), primary peritoneal (PPC) or fallopian tube cancer (FTC), including those with prior hypersensitivity reaction.

Methods

A single institution, retrospective review from 1995 to 2012 of patients receiving oxaliplatin for treatment of recurrent or progressive EOC, PPC, or FTC was performed. Data collected included patient demographics, diagnosis date, prior chemotherapy regimens, platinum-free interval(s), prior hypersensitivity reactions, oxaliplatin toxicity, length of therapy, disease response, and last follow-up. Those who received ≥ 1 cycles were included. A response to therapy was determined after ≥ 2 cycles.

Results

Forty-four patients were identified. All had prior carboplatin and 38.6% had prior cisplatin therapy. Twenty-three had a prior platinum hypersensitivity reaction. Patients received a median of 2 prior platinum containing regimens and 5 chemotherapy lines prior to oxaliplatin exposure. One patient experienced grade 3 pain. No grade 4 toxicities occurred. No treatment delays for pancytopenia noted. Nausea and dysesthesias were controlled medically and weren't dose-limiting. No nephropathy or neuropathy progressed on oxaliplatin or were dose-limiting. Disease response was observed in 43.2%. Of the responders, 36.8% had a prior platinum hypersensitivity reaction. Median number of 5 cycles of an oxaliplatin containing regimen was given. Median follow-up was 15.5 months.

Conclusions

In our experience, oxaliplatin is well tolerated and should be considered for platinum challenge after hypersensitivity even in patients with platinum resistant disease with a reasonable chance of response.     

Activity of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with cisplatin and doxorubicin in women with recurrent,platinum-resistant ovarian cancer: Preliminary clinical experience

Objective

To assess the activity of laparoscopic Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in women with recurrent, platinum-resistant ovarian cancer.

Methods

Prospective case series using repeated courses q 28–42 days of PIPAC containing cisplatin 7.5 mg/m² and doxorubicin 1.5 mg/m² at 12 mm Hg and 37 °C for 30 min. Objective tumor response was defined as tumor regression on histology and peritoneal carcinomatosis index (PCI) improvement on repeated video-laparoscopy.

Results

34 PIPAC procedures were performed in 18 women, in 8 instances combined with cytoreductive surgery (CRS). Eight women had repeated PIPAC and objective tumor response was observed in 6 (complete remission: 1; partial remission: 2; stable disease: 3). Five adverse events WHO grade ≥ 2 were noted, 3 of them after combined CRS. No perioperative mortality occurred. Median follow-up was 192 days (min. 13–max. 639). Cumulative survival after 400 days was 62% and mean actuarial survival time was 442 days. In a multivariable regression analysis with objective tumor response (yes vs. no) as the dependent variable and PIPAC (1 vs. > 1), patient age (< 75 vs. ≥ 75 years), serum CA-125 (< 1000 vs. > 1000 U/mL), and the presence of ascites (yes vs. no) as independent variables, PIPAC independently predicted objective tumor response.

Conclusion

PIPAC has activity in women with recurrent, platinum-resistant ovarian cancer and should be investigated in prospective clinical trials.     

A Phase II evaluation of ixabepilone (IND #59699, NSC #710428) in the treatment of recurrent or persistent leiomyosarcoma of the uterus: An NRG Oncology/Gynecologic Oncology Group Study

Objective

The combination of gemcitabine and docetaxel is the standard first-line therapy for recurrent or metastatic uterine leiomyosarcoma. There is no standard second-line therapy. Ixabepilone is a semi-synthetic analog of epothilone B that binds to the same site on beta tubulin as paclitaxel and may be a more potent polymerizer of tubulin. We sought to determine the activity of ixabepilone as a single agent as second-line treatment for patients with metastatic uterine leiomyosarcoma who had received taxane based therapy.

Methods

Eligible women with unresectable uterine leiomyosarcoma progressing after prior cytotoxic therapy containing a taxane were treated with ixabepilone 40 mg/m² on day one of a 21 day cycle. Patients with prior pelvic radiation were treated without dose reduction. Response Evaluation Criteria in Solid Tumors (RECIST) response was assessed by computed tomography (CT).

Results

Twenty-three of 26 women were evaluable (two wrong histology, one never treated) with two of 23 receiving 1 cycle of therapy. There were no complete or partial responses. Stable disease (SD) was seen in four patients (17.4%, median 3.4 months). Seventeen patients (73.9%) had increasing disease (PD) and two patients were inevaluable per RECIST. One patient had SD over 6 cycles of treatment. Median PFS for all 23 patients was 1.4 months and overall survival was 7.0 months. The predominant grade 3 or 4 toxicity was uncomplicated myelosuppression: neutropenia grade 3 (13%), grade 4 (17%), and anemia grade 3 (22%).

Conclusion

Ixabepilone as a single agent is not an active second-line therapy for uterine leiomyosarcoma previously treated with a taxane.     

A phase II trial of a surgical protocol to decrease the incidence of wound complications in obese gynecologic oncology patients

Objectives

Obese women have a high incidence of wound separation after gynecologic surgery. We explored the effect of a prospective care pathway on the incidence of wound complications.

Methods

Women with a body mass index (BMI) ≥ 30 kg/m² undergoing a gynecologic procedure by a gynecologic oncologist via a vertical abdominal incision were eligible. The surgical protocol required: skin and subcutaneous tissues to be incised using a scalpel or cutting electrocautery, fascial closure using #1 polydioxanone suture, placement of a 7 mm Jackson-Pratt drain below Camper's fascia, closure of Camper's fascia with 3-0 plain catgut suture and skin closure with staples.Wound complication was defined as the presence of either a wound infection or any separation. Demographic and perioperative data were analyzed using contingency tables. Univariable and multivariable regression models were used to identify predictors of wound complications. Patients were compared using a multivariable model to a historical group of obese patients to assess the efficacy of the care pathway.

Results

105 women were enrolled with a median BMI of 38.1. Overall, 39 (37%) had a wound complication. Women with a BMI of 30–39.9 kg/m² had a significantly lower risk of wound complication as compared to those with a BMI > 40 kg/m² (23% vs 59%, p < 0.001). After controlling for factors associated with wound complications the prospective care pathway was associated with a significantly decreased wound complication rate in women with BMI < 40 kg/m² (OR 0.40, 95% C.I.: 0.18–0.89).

Conclusion

This surgical protocol leads to a decreased rate of wound complications among women with a BMI of 30–39.9 kg/m².     

Perceptions of obesity and cancer risk in female bariatric surgery candidates: Highlighting the need for physician action for unsuspectingly obese and high risk patients

Objectives

To determine: 1) whether obese women perceive themselves to be obese or at risk for malignancy, 2) perceived impact of obesity on cancer risks, 3) compliance with cancer screening, and 4) rates of menstrual dysfunction.

Methods

Surveys were administered to female patients presenting for bariatric weight loss surgery. Demographics, gynecologic history, perception of cancer risk, and screening history were collected/analyzed. Women were categorized as obese (BMI: 30–39 kg/m²), morbidly obese (40–49 kg/m²), super obese (≥ 50 kg/m²) and compared.

Results

Ninety-three women (mean age: 44.9 years, mean BMI: 48.7 kg/m²) participated and 45.7% felt they were in ‘good’, ‘very good’, or ‘excellent’ health despite frequent medical comorbidities. As BMI increased, women were more likely to correctly identify themselves as obese (23% of obese vs. 77% of morbidly obese vs. 85% of super obese; p < 0.001) but there were no significant differences in comorbidities. Two-thirds of women correctly identified obesity as a risk factor for uterine cancer, yet 48% of those retaining a uterus perceived that it was “not likely/not possible” to develop uterine cancer. Menstrual irregularities were common as was evaluation and interventions for the same; 32% had prior hysterectomy. Participation in cancer screening was robust.

Conclusions

Women presenting for bariatric surgery have high rates of menstrual dysfunction. While they perceive that obesity increases uterine cancer risk, they often do not perceive themselves to be at risk. This disconnect may stem from the fact that many failed to identify themselves as obese perhaps because overweight/obesity has become the norm in U.S. society.     

Impact of obesity on surgical and oncologic outcomes in ovarian cancer

Objectives

The aim of this study is to determine the impact of obesity on surgical and oncologic outcomes after primary debulking surgery (PDS) in advanced epithelial ovarian cancer (EOC).

Methods

Women with stage IIIC/IV EOC who underwent PDS with curative intent between 1/2/2003 and 12/30/2011 were included. Patient characteristics, intraoperative and postoperative outcomes, recurrence and status were abstracted. Complications were graded according to the 4-point Accordion classification. For analyses, patients were divided into three groups according to body mass index (BMI): group 1—BMI < 25.0 kg/m²; group 2—BMI 25.0–39.9 kg/m²; and group 3—BMI ≥ 40.0 kg/m².

Results

Of the 620 patients included in the study, 36.6%, 56.9%, and 6.5% were in weight groups 1, 2, and 3, respectively.Weight group 3 was an independent predictor of severe complications after adjusting for confounders (adjusted odds ratio (95% CI): 2.93 (1.38, 6.20) for group 3 vs. group 2). Weight group was not associated with differences in residual disease (p = 0.80). The 90-day mortality rates were 11.9%, 6.7%, and 15.7%, respectively, in weight group 1, 2, and 3 (p = 0.049 unadjusted, p = 0.01 adjusted). There was no difference in OS (p = 0.52) or PFS (p = 0.23) between weight groups.

Conclusions

BMI ≥ 40.0 kg/m² is an independent predictor of severe 30-day postoperative morbidity and 90-day mortality after PDS for EOC—information useful in preoperative counseling. BMI does not appear to impact long-term oncologic outcomes including residual disease at PDS, although we had limited power at the extremes of BMI. BMI may be an important factor to consider in risk-adjustment models and reimbursement strategies.     

Quality of life in patients with endometrial cancer treated with or without systematic lymphadenectomy

Objective

To compare the quality of life (QoL) of women affected by endometrial cancer treated with surgery with or without systematic lymphadenectomy.

Study design

Consecutive patients affected by stages I and II endometrial cancer and treated with surgery between 2008 and 2011 were selected. Eligible subjects were divided into two groups: Group A consisted of 36 patients who had hysterectomy plus bilateral salpingo-oophorectomy without lymphadenectomy; Group B consisted of 40 patients who had hysterectomy plus salpingo-oophorectomy plus pelvic and aortic lymphadenectomy. The EORTC Quality of Life Questionnaire-Cancer Module (QLQ-C30) and Quality of Life Questionnaire-Endometrial Cancer Module (QLQ-EN24) were administered to selected patients. All data were recorded and then analyzed using the scoring manual of the EORTC Quality of Life Group.

Results

Among symptom scales, only lymphedema gave a statistically significant difference among two groups, with a score of 10.64 ± 17.43 in Group A and 21.66 ± 24.51 in Group B (p = 0.0285). The p value obtained comparing the “Global Health Status” (items 29 and 30) in Group A and in Group B was not statistically significant.

Conclusion

Lymphadenectomy did not influence negatively global health status, but lymphadenectomy maintained its importance in determining a patient's prognosis and in tailoring adjuvant therapies. We therefore support its practice as part of the surgical procedure in patients affected by high risk endometrial cancer.     

A phase II trial of intraperitoneal EGEN-001, an IL-12 plasmid formulated with PEG–PEI–cholesterol lipopolymer in the treatment of persistent or recurrent epithelial ovarian,fallopian tube or primary peritoneal cancer: A Gynecologic Oncology Group study

Objective

The purpose of this phase II trial was to evaluate the toxicity and antitumor activity of EGEN-001 in platinum resistant recurrent ovarian cancer.

Methods

Eligible patients had weekly IP infusion of EGEN-001 at a dose of 24 mg/m². Toxicity and antitumor activity were evaluated using CTCAE and RESIST criteria, respectively. Co-primary endpoints were tumor response and survival without progression (PFS) for at least 6 months. Survival without progression before going onto a subsequent therapy (EFS) for at least six months was also considered.

Results

A total of 58 EGEN-001 cycles were administered to 20/22 enrolled patients (median 2 cycles, range 1–9). The most frequently associated adverse events related specifically to EGEN-001 treatment were grade 1/2 fatigue, fever, chills, abdominal pain, nausea, vomiting, anemia, thrombocytopenia, and leukopenia. Three of 20 EGEN-001 treated patients evaluable for toxicity elected to withdraw from the study motivated in part by grade 1 treatment related toxicities. There were no patients with partial or complete response (0%; 90% CI 0–10.9%). Seven (35%) of 16 patients evaluable for response had stable disease, and 9 (45%) had progressive disease. Six (30%) patients had a PFS of greater than six months, although three had gone off study and onto other therapies before six months. The estimated six-month EFS was 15%. The median PFS and OS were 2.89 and 9.17 months, respectively.

Conclusion

EGEN-001 at the dose and schedule evaluated was associated with some but limited activity and was seemingly less tolerated in platinum resistant recurrent ovarian cancer patients.     

Phase II trial of vaginal cuff brachytherapy followed by chemotherapy in early stage endometrial cancer patients with high-intermediate risk factors

Objective

To determine the progression free survival (PFS), toxicity, and patterns of failure for early stage, high-intermediate risk (H-IR) patients in a phase II trial with adjuvant vaginal cuff brachytherapy (VCB) and three cycles of carboplatin and paclitaxel.

Methods

Surgically staged patients with stage I-IIb endometrial cancer with H-IR factors were treated with VCB (2100 cGy) followed by three cycles of carboplatin (AUC 6) and paclitaxel (175 mg/m²). The primary endpoint was PFS at 2 years, with toxicity and sites of failure as secondary endpoints. Toxicity was assessed by patient report (CTCAE v. 3) as well as by delays or dose modifications in treatment.

Results

All patients completed VCB and 19/23 (83%) completed both VCB and 3 cycles of chemotherapy. Mean time to complete VCB was 14.5 days with minimal acute toxicity noted. At 6 months, all toxicity related to VCB had resolved. In total 60 cycles of chemotherapy were given, with one dose reduction (1.6%) for grade 2 neuropathy and seven delays (11.6%) in treatment due to hematologic toxicity. At a median follow-up of 44.5 months, 91% of patients remained progression free at 2 years. Four patients experienced a recurrence; they recurred both locally and distant.

Conclusions

Adjuvant therapy with VCB and chemotherapy is well tolerated in a population of patients with H-IR endometrial carcinoma and provides 2 year PFS of 91%. A randomized trial is currently underway to assess whether combined VCB and chemotherapy reduces the rate of recurrence compared to external beam radiation therapy (EBRT) in this patient population.     

Intraoperative hypothermia during primary surgical cytoreduction for advanced ovarian cancer: Risk factors and associations with postoperative morbidity

Objective

The objective of this study was to evaluate the risk factors and potential morbidity associated with intraoperative hypothermia (IH) during cytoreductive surgery (CRS) for advanced ovarian cancer.

Methods

Demographic and perioperative data were collected for all patients with stage IIIC–IV ovarian, fallopian tube, and primary peritoneal carcinoma who underwent primary CRS at our institution from 2001 to 2010. Only patients with carcinomatosis and/or bulky upper abdominal disease and residual disease of < 1 cm were included. Intraoperative hypothermia was defined as temperature of < 36.0 degrees Celsius (°C). Associations with 21 perioperative factors, 12 systems-based complications, and specific complications including but not limited to venous thromboembolism and surgical site infection were evaluated.

Results

Two hundred ninety-seven patients met the inclusion criteria. An intraoperative temperature < 36 °C was noted in 72.1% of patients, and a temperature < 36 °C at the time of abdominal closure was noted in 45.5%. Intraoperative vasopressors (P = 0.02), epidural anesthesia (P = 0.01), transfusion of fresh frozen plasma (P < 0.05), and blood loss (P = 0.01) were associated with IH. There was no association between IH and postoperative complications in general (P = 0.48) or specifically grade 3–5 complications (P = 0.34). Univariate analysis did show an association between hematologic complications and IH; however, this did not persist on multivariate analysis (P = 0.14).

Conclusions

In patients who underwent optimal primary CRS for advanced ovarian cancer, IH alone was not associated with the development of postoperative complications. Postoperative morbidity in these patients is multifactorial and further investigation into modifiable risk factors is warranted.     

Diabetes mellitus and ovarian cancer: More complex than just increasing risk

Objective

Diabetes mellitus (DM) is a risk factor for endometrial cancer and is associated with poorer outcomes in breast and colon cancers. This association is less clear in epithelial ovarian cancer (EOC). We sought to examine the effect of DM on progression-free (PFS) and overall survival (OS) in women with EOC.

Methods

A retrospective cohort study of EOC patients diagnosed between 2004 and 2009 at a single institution was performed. Demographic, pathologic and DM diagnosis data were abstracted. Pearson chi-square test and t test were used to compare variables. The Kaplan–Meier method and the log rank test were used to compare PFS and OS between non-diabetic (ND) and DM patients.

Results

62 (17%) of 367 patients had a diagnosis of DM. No differences in age, histology, debulking status, or administration of intraperitoneal chemotherapy between ND and DM patients were present, although there were more stage I and IV patients in the ND group (p = 0.04). BMI was significantly different between the two groups (ND vs. DM, 27.5 vs. 30.7 kg/m², p < 0.001). While there were no differences in survival based on BMI, diabetic patients had a poorer PFS (10.3 vs. 16.3 months, p = 0.024) and OS (26.1 vs. 42.2 months, p = 0.005) compared to ND patients. Metformin use among diabetic patients did not appear to affect PFS or OS.

Conclusions

EOC patients with DM have poorer survival than patients without diabetes; this association is independent of obesity. Metformin use did not affect outcomes. The pathophysiology of this observation requires more inquiry.     

Efficacy and safety of AEZS-108 (INN: Zoptarelin Doxorubicin Acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors: A multicenter Phase II trial of the ago-study group (AGO GYN 5)

Objectives

To evaluate the activity and toxicity of AEZS-108 (Zoptarelin Doxorubicin Acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors.

Methods

Women with epithelial ovarian, fallopian tube or primary peritoneal cancer, expressing LHRH receptors were eligible for this trial, when they had progression during treatment with a platinum based regimen or within 6 months after receiving a platinum based regimen and a previous taxane treatment. At least one measurable target lesion (RECIST) or CA-125 levels higher than twice the upper limit of normal range (GCIG-criteria) were required. Patients received AEZS-108 (267 mg/m² equimolar to 76.8 mg/m² of free doxorubicin) every 3 weeks as a two hour i.v. infusion.

Results

Fifty-five of 59 (93%) of ovarian cancer samples screened expressed LHRH receptors. 42 patients were enrolled in this study and received at least 1 infusion of AEZS-108 (ITT population). Of these 42 patients 6 (14.3%) had a partial response, 16 (38%) stable disease, 16 (38%) progressive disease and 4 patients were not evaluable. Median time to progression was 12 weeks (95% CI: 8–20 weeks), and median overall survival was 53 weeks (95% CI: 39–73 weeks). Toxicity profile was favorable.

Conclusion

AEZS-108 has a clinical activity in platinum refractory/resistant ovarian cancer which seems to be comparable to that of pegylated liposomal doxorubicin or to topotecan. Toxicity was comparably low. These data support the concept of a targeted chemotherapy for tumors expressing LHRH receptors.     

Adjuvant treatment and analysis of failures in patients with high-risk FIGO Stage Ib–II endometrial cancer: An Italian multicenter retrospective study (CTF study)

Objectives

The purpose of this retrospective study was to assess the clinical outcome of patients with high-risk, early-stage endometrioid endometrial cancer (stage Ib or II with myometrial invasion > 50%, grade 2–3).

Methods

We assessed 192 patients who underwent hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy, had histologically negative pelvic nodes, and had negative CT findings for aortic node involvement.

Results

Tumor relapsed in 36 patients after a median time of 21.2 months. The recurrence was vaginal in 7 (19.4%), distant in 16 (44.4%), aortic in 8 (22.2%), and involved multiple sites in 5 (13.9%). There was a trend to a lower vaginal recurrence rate in the 143 patients who received adjuvant radiotherapy (+ chemotherapy) compared with the 46 who did not (2.1% versus 8.7%). Distant or aortic recurrences were lower in the 37 patients who received adjuvant chemotherapy (+ radiotherapy) than in the 152 who did not (2.7% versus 18.4%, p = 0.02). Of the 29 patients who received sequential adjuvant chemotherapy and radiotherapy, none developed local recurrence and only one had distant recurrence. There was a trend for a better 5-year progression-free survival and overall survival for the patients who received chemotherapy (+ radiotherapy) compared with those who did not (86.0% versus 71.3%, and 92.3% versus 75.6%, respectively).

Conclusions

Our data appear to suggest that adjuvant chemotherapy reduces the risk of distant or aortic recurrences and that sequential adjuvant chemotherapy and radiotherapy achieve an excellent local and distant control of disease in these clinical settings.     

A phase II trial of sunitinib in women with metastatic or recurrent endometrial carcinoma: A study of the Princess Margaret,Chicago and California Consortia

Objective

Treatment options remain limited for women with relapsed/metastatic endometrial cancer (EC). Angiogenesis is one of the major components of tumor progression and thus an attractive target. The aim of this phase II trial was to assess the efficacy and tolerability of sunitinib, an oral multitargeted receptor tyrosine-kinase inhibitor with antiangiogenic and antitumor activity in the treatment of recurrent EC.

Methods

We performed a multicenter, single arm, two-stage phase II study of sunitinib, 50 mg daily administered on a 4 weeks on–2 weeks off schedule. Eligibility criteria included recurrent/metastatic EC or carcinosarcoma with no more than one prior line of chemotherapy. The primary endpoint was objective response rate.

Results

34 women were enrolled; 33 received at least one dose of sunitinib and were included in the analyses. Six women (18.1%) had a partial response and six additional women (18.1%) stable disease. In total, ten patients (30.3%) had disease control for at least 6 months and of these, seven were controlled for more than one year. Median progression free and overall survival times were 3 months and 19.4 months, respectively. Adverse events related to treatment were frequent. At least one grade 3 toxicity occurred in 30 patients and dose reductions were required in 17 patients (52%). The most common grade 3 toxicities were fatigue, hypertension, palmar–plantar erythrodysesthesia, diarrhea and hematologic.

Conclusion

Sunitinib therapy showed promising activity in women with recurrent EC. Toxicity was seen frequently but was manageable. Anti-angiogenic agents warrant further investigation in EC to define which patients will derive the greatest benefit.