Preoperative Risk Score for Predicting Incomplete Cytoreduction: A 12-Institution Study from the US HIPEC Collaborative.

BACKGROUND: For patients with peritoneal carcinomatosis undergoing cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC), incomplete cytoreduction (CCR2/3) confers morbidity without survival benefit. The aim of this study is to identify preoperative factors which predict CCR2/3. METHODS: All patients who underwent curative-intent CRS/HIPEC of low/high-grade appendiceal, colorectal, or peritoneal mesothelioma cancers in the 12-institution US HIPEC Collaborative from 2000 to 2017 were included (n = 2027). The primary aim is to create an incomplete-cytoreduction risk score (ICRS) to predict CCR2/3 CRS utilizing preoperative data. ICRS was created from a randomly selected cohort of 50% of patients (derivation cohort) and verified on the remaining patients (validation cohort). RESULTS: Within our derivation cohort (n = 998), histology was low-grade appendiceal neoplasms in 30%, high-grade appendiceal tumor in 41%, colorectal tumor in 22%, and peritoneal mesothelioma in 8%. CCR0/1 was achieved in 816 patients and CCR 2/3 in 116 patients. On multivariable analysis, preoperative factors associated with incomplete cytoreduction were male gender [odds ratio (OR) 3.4, p = 0.007], presence of ascites (OR 2.8, p = 0.028), cancer antigen (CA)-125 ≥ 40 U/mL (OR 3.4, p = 0.012), and carcinoembryonic antigen (CEA) ≥ 4.2 ng/mL (OR 3.2, p = 0.029). Each preoperative factor was assigned a score of 0 or 1 to form an ICRS from 0 to 4. Scores were grouped as zero (0), low (1-2), or high (3-4). Incidence of CCR2/3 progressively increased by risk group from 1.6% in zero to 13% in low and 39% in high. When ICRS was applied to the validation cohort (n = 1029), this relationship was maintained. CONCLUSION: The incomplete cytoreduction risk score incorporates preoperative factors to accurately stratify the risk of CCR2/3 resection in CRS/HIPEC. This score should not be used in isolation, however, to exclude patients from surgery.

Do differences in medical comorbidities and treatment impact racial disparities in epithelial ovarian cancer?

BACKGROUND: Population-based studies of women with epithelial ovarian cancer suggest that black women have worse survival compared to white women. The primary objective of this study was to determine if, at a National Cancer Institute (NCI)-Designated Comprehensive Cancer Center (CCC) serving a diverse racial and socioeconomic population, race is independently associated with differences in survival. METHODS: A retrospective review of women with EOC diagnosed between 2004-2009 undergoing treatment with follow-up at our institution was performed. Records were reviewed for demographics, comorbidities (as defined by the Charlson Comorbidity Index (CCI)), tumor characteristics, treatment, progression-free (PFS), and overall survival (OS). Survival was calculated using the Kaplan-Meier method and compared with the log-rank test. Multivariate survival analysis was performed with Cox (proportional hazards) model. RESULTS: 367 patients met inclusion criteria. 54 (15%) were black and 308 (84%) were white. Compared to white women, black women had higher BMI, lower rates of optimal surgical cytoreduction, lower rates of intraperitoneal chemotherapy, and higher CCI scores. The median PFS for black and white women were 9.7 and 14.6months, respectively (p=0.033). The median overall survival was 21.7months for black women and 42.6months for white women (p<0.001). On multivariate analysis, black race independently correlated with a worse overall survival (HR 1.61, 95% CI 1.06-2.43). CONCLUSION: In this cohort, racial disparities may be due to higher medical comorbidities and lower rates of optimal surgical cytoreduction. After accounting for these differences, race remained an independent predictor of worse overall survival.

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer.

BACKGROUND: Treatment of newly diagnosed advanced-stage ovarian cancer typically involves cytoreductive surgery and systemic chemotherapy. We conducted a trial to investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer. METHODS: In a multicenter, open-label, phase 3 trial, we randomly assigned 245 patients who had at least stable disease after three cycles of carboplatin (area under the curve of 5 to 6 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area) to undergo interval cytoreductive surgery either with or without administration of HIPEC with cisplatin (100 mg per square meter). Randomization was performed at the time of surgery in cases in which surgery that would result in no visible disease (complete cytoreduction) or surgery after which one or more residual tumors measuring 10 mm or less in diameter remain (optimal cytoreduction) was deemed to be feasible. Three additional cycles of carboplatin and paclitaxel were administered postoperatively. The primary end point was recurrence-free survival. Overall survival and the side-effect profile were key secondary end points. RESULTS: In the intention-to-treat analysis, events of disease recurrence or death occurred in 110 of the 123 patients (89%) who underwent cytoreductive surgery without HIPEC (surgery group) and in 99 of the 122 patients (81%) who underwent cytoreductive surgery with HIPEC (surgery-plus-HIPEC group) (hazard ratio for disease recurrence or death, 0.66; 95% confidence interval [CI], 0.50 to 0.87; P=0.003). The median recurrence-free survival was 10.7 months in the surgery group and 14.2 months in the surgery-plus-HIPEC group. At a median follow-up of 4.7 years, 76 patients (62%) in the surgery group and 61 patients (50%) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% CI, 0.48 to 0.94; P=0.02). The median overall survival was 33.9 months in the surgery group and 45.7 months in the surgery-plus-HIPEC group. The percentage of patients who had adverse events of grade 3 or 4 was similar in the two groups (25% in the surgery group and 27% in the surgery-plus-HIPEC group, P=0.76). CONCLUSIONS: Among patients with stage III epithelial ovarian cancer, the addition of HIPEC to interval cytoreductive surgery resulted in longer recurrence-free survival and overall survival than surgery alone and did not result in higher rates of side effects. (Funded by the Dutch Cancer Society; ClinicalTrials.gov number, NCT00426257 ; EudraCT number, 2006-003466-34 .).

Statin treatment is associated with survival in a nationally representative population of elderly women with epithelial ovarian cancer.

OBJECTIVE: Observational studies suggest that statin therapy for cardio-protection is associated with improved survival in cancer patients. We sought to evaluate the impact of statin treatment on ovarian cancer survival in a nationally representative elderly population. METHODS: The linked Surveillance, Epidemiology, and End Results (SEER) registries and Medicare claims data on patients diagnosed with epithelial ovarian cancer in 2007-2009 were used to extract data on statin prescription fills, population characteristics, primary treatment, comorbidity and survival. Cox regression models were used to examine the association between statin treatment and overall survival. RESULTS: Among the 1431 ovarian cancer patients who underwent surgical resection, 609 (42.6%) filled prescriptions for statin. The majority of statin-users (89%) were prescribed a lipophilic formulation. Mean overall survival among statin-users was 32.3months compared to 28.8months for non-users (p<0.0001). A 34% reduction in death was associated with statin therapy, independent of age, race, neighborhood median household income, stage, platinum therapy and comorbid conditions (HR=0.66, 95% CI 0.55-0.81). Improved overall survival with statin use was observed for both serous (HR=0.69, 95% CI 0.54-0.87) and non-serous (HR=0.63, 95% CI 0.44-0.90) histologies. When statin treatment was categorized by lipophilicity and intensity, a significant survival benefit was limited to lipophilic statin users and those who took statins of moderate intensity. CONCLUSIONS: This SEER-Medicare analysis demonstrates improvement in overall survival with lipophilic statin use after surgery in elderly patients with epithelial ovarian cancer. A clinical trial to evaluate the impact of statin treatment in ovarian cancer survival is warranted.

Evaluation of the efficacy and toxicity profile associated with intraperitoneal chemotherapy use in older women.

OBJECTIVE: Intraperitoneal (IP) chemotherapy (CT) for treatment of epithelial ovarian cancer (EOC) has been shown to provide a substantial OS advantage. This study aims to compare the toxicity and benefits of IP CT in patients ≥70 with those <70. METHODS: We performed a single institution retrospective review of patients diagnosed with Stage IIA-IIIC EOC from 2000 to 2013 who received IP CT. Clinicopathologic characteristics were extracted, and survival was calculated. RESULTS: 133 patients were included with 100 pts. <70years old and 33 pts. ≥70years old. Clinical trial enrollment was similar despite age. In trial enrolled patients, older patients received statistically fewer cycles of therapy (6.4 vs 5.8, p=0.002) but had similar dose delays (0.9 vs 0.7, p=0.72), and modifications (0.9 vs 0.36, p=0.11). Median PFS (27 vs 31months) and OS (71 and 62months) were not statistically different. Grade 3/4 neutropenia was significantly worse in the older patients (82% vs 100%, p=0.04). Neuropathy grade ≥2 and other non-hematologic toxicities were not different between age groups. CONCLUSIONS: Despite completing fewer cycles of IP CT, older EOC patients had comparable survival to younger patients. The population of older patients receiving IP CT in this study were on clinical trial and likely to be heartier than the general older population. IP CT appears well tolerated and effective among select older patients and is likely under-utilized outside of clinical trials.

Prognostic Significance of Preoperative Prognostic Nutritional Index in Epithelial Ovarian Cancer Patients Treated with Platinum-Based Chemotherapy.

BACKGROUND: The aim of present study was to investigate the role of the prognostic nutritional index (PNI) used as a prognostic marker for predicting response and survival outcomes in patients with epithelial ovarian cancer (EOC) who are receiving platinum-based chemotherapy. PATIENTS AND METHODS: Patients with a new diagnosis of EOC receiving postoperative platinum-based chemotherapy were identified. The PNI was calculated as 10 × serum albumin value (g/dl) + 0.005 × peripheral lymphocyte count (per mm3). Patients were divided into a platinum-resistant (P-R) group and a platinum-sensitive (P-S) group according to the chemotherapeutic response. A receiver operating characteristic (ROC) curve was used to calculate the optimal cut-off value for PNI to predict chemotherapeutic response and prognosis. RESULTS: A total of 344 patients were enrolled. Area under the curve, sensitivity, and specificity of PIN < 45 to predict platinum resistance were: 0.688, 62.50%, and 83.47%, respectively. Patients with a lower PNI (< 45) had shorter progression-free survival (PFS) and overall survival (OS). PNI showed a significant association with PFS (hazard ratio (HR) 1.890, 95% confidence interval (CI) 1.396-2.560; p < 0.001) and OS (HR 1.747, 95% CI 1.293-2.360; p < 0.001). CONCLUSION: Our results suggest that PNI assessment could assist the identification of patients with a poor prognosis and has potential clinical value in predicting platinum resistance in patients with EOC.

The American Society of Peritoneal Surface Malignancies Multi-Institution evaluation of 1,051 advanced ovarian cancer patients undergoing cytoreductive surgery and HIPEC: An introduction of the peritoneal surface disease severity score.

BACKGROUND: Standard treatment for ovarian epithelial cancer (OEC) consists of cytoreductive surgery (CRS) and a platinum-taxane chemotherapy combination. There is increasing interest in evaluating hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with stage IIIC/IV disease. The peritoneal surface disease severity score (PSDSS) was introduced as a basis to improve patient selection for this therapy in OEC. METHODS: The charts of 1,051 patients with advanced OEC who underwent CRS/HIPEC were retrospectively evaluated using the following preoperatively obtained criteria: symptoms, peritoneal dissemination, and tumor histology. Overall survival was analyzed according to PSDSS as well as the timings and agents used during CRS/HIPEC. RESULTS: Median survival for all 1,051 patients was 73.4 months. PSDSS information was available for 553 patients. Survival correlated negatively with PSDSS (P < 0.001). Furthermore, combining PSDSS scores into I/II and III/IV described two distinct patient populations with vastly different outcomes, 100 versus 55 months, respectively (P < 0.001). Multivariate analysis failed to describe any differences between timings of HIPEC or chemotherapy agents used. CONCLUSION: PSDSS was capable of identifying a better surviving patient population in advanced-stage OEC. While randomized trials to evaluate the benefit of HIPEC are needed, the PSDSS may be a useful tool for selecting and stratifying OEC patients in clinical trials. J. Surg. Oncol. 2016;114:779-784. © 2016 2016 Wiley Periodicals, Inc.

Paclitaxel is necessary for improved survival in epithelial ovarian cancers with homologous recombination gene mutations.

PURPOSE: To investigate the impact of somatic mutations in homologous recombination (HR) genes on the chemotherapeutic response and survival of patients with epithelial ovarian cancer (EOC). EXPERIMENTAL DESIGN: We performed targeted massively parallel sequencing of tumor DNA from 158 patients with EOC. We associated adjuvant chemotherapy and clinical outcome with mutations in selected genes, focusing on those encoding HR proteins. RESULTS: HR mutations were found in 47 (30%) tumors. We did not detect an overall survival (OS) difference in advanced stage patients whose tumors had HR mutations compared to those without (median OS of 49.6 months (95% CI 29.9-57.7) vs. 43.3 months (95% CI 31.9-75.47), p = 0.87). However, when stratified by chemotherapy regimen, patients whose tumors had TP53 and HR mutations demonstrated a marked survival advantage when treated with platinum and paclitaxel vs. platinum +/- cyclophosphamide (median OS of 90 months (95% CI 50-NA) vs. 29.5 months (95% CI 17.7-50.5), p = 0.0005). CONCLUSIONS: Previous studies demonstrating a survival advantage for EOC patients with somatic HR mutations have been conducted with almost universal use of both platinum and paclitaxel. Our study is the first to our knowledge to compare cohorts with somatic HR gene mutations treated with and without paclitaxel containing platinum regimens. The survival benefit attributed to the platinum sensitivity of HR deficient ovarian cancers may depend upon the combined use of paclitaxel.

Secondary cytoreductive surgery, hyperthermic intraperitoneal intraoperative chemotherapy, and chemotherapy alone: a retrospective comparison of alternative approaches in relapsed platinum sensitive ovarian cancer.

INTRODUCTION: The best treatment for relapsed platinum sensitive epithelial ovarian cancer (EOC) is controversial. The aim of the study was to compare progression-free survival (PFS) and overall survival (OS) in platinum-sensitive EOC patients treated with chemotherapy alone (CTA), secondary cytoreductive surgery (SCR) or SCR plus hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC). MATERIALS AND METHODS: Retrospective analysis of the clinical outcome of 46 EOC patients with at least 30 months of follow-up. RESULTS: Median follow-up time was 32 months for the CTA group, 30 months for the SCR group, and 45 months for the SCR + HIPEC group. Fifteen recurrences were observed in the CTA group, seven in the SCR group, and 16 in the SCR + HIPEC group. The median time elapsed between first and second recurrence (PFI-2) was significantly higher among patients treated with SCR + HIPEC, in comparison with patients treated with CTA (p = 0.012 andp = 0.017, respectively). On the contrary, PFI-2 did not significantly differ between the SCR and SCR + HIPEC groups (p = 0.877). A statistically significant difference in OS favouring SCR + HIPEC in comparison with CTA (p = 0.04) was observed. CONCLUSIONS: SCR HIPEC compared with CTA improves PFI-2 in patients with platinum-sensitive EOC recurrence. SCR + HIPEC might also improve OS in comparison with CTA. No improvement in favor of SCR + HIPEC vs SCR was observed,. These results further support the need of a randomized trial comparing chemotherapy with SCR ± HIPEC in this setting.

Impact of National Cancer Institute Comprehensive Cancer Centers on ovarian cancer treatment and survival.

BACKGROUND: The regional impact of care at a National Cancer Institute Comprehensive Cancer Center (NCI-CCC) on adherence to National Comprehensive Cancer Network (NCCN) ovarian cancer treatment guidelines and survival is unclear. STUDY DESIGN: We performed a retrospective population-based study of consecutive patients diagnosed with epithelial ovarian cancer between January 1, 1996 and December 31, 2006 in southern California. Patients were stratified according to care at an NCI-CCC (n = 5), non-NCI high-volume hospital (≥ 10 cases/year, HVH, n = 29), or low-volume hospital (<10 cases/year, LVH, n = 158). Multivariable logistic regression and Cox-proportional hazards models were used to examine the effect of NCI-CCC status on treatment guideline adherence and ovarian cancer-specific survival. RESULTS: A total of 9,933 patients were identified (stage I, 22.8%; stage II, 7.9%; stage III, 45.1%; stage IV, 24.2%), and 8.1% of patients were treated at NCI-CCCs. Overall, 35.7% of patients received NCCN guideline adherent care, and NCI-CCC status (odds ratio [OR] 1.00) was an independent predictor of adherence to treatment guidelines compared with HVHs (OR 0.83, 95% CI 0.70 to 0.99) and LVHs (OR 0.56, 95% CI 0.47 to 0.67). The median ovarian cancer-specific survivals according to hospital type were: NCI-CCC 77.9 (95% CI 61.4 to 92.9) months, HVH 51.9 (95% CI 49.2 to 55.7) months, and LVH 43.4 (95% CI 39.9 to 47.2) months (p < 0.0001). National Cancer Institute Comprehensive Cancer Center status (hazard ratio [HR] 1.00) was a statistically significant and independent predictor of improved survival compared with HVH (HR 1.18, 95% CI 1.04 to 1.33) and LVH (HR 1.30, 95% CI 1.15 to 1.47). CONCLUSIONS: National Cancer Institute Comprehensive Cancer Center status is an independent predictor of adherence to ovarian cancer treatment guidelines and improved ovarian cancer-specific survival. These data validate NCI-CCC status as a structural health care characteristic correlated with superior ovarian cancer quality measure performance. Increased access to NCI-CCCs through regional concentration of care may be a mechanism to improve clinical outcomes.

Peritoneal metastases: challenges for the surgeon.

Peritoneal surface malignancies (PSM) include peritoneal metastases from gastrointestinal and gynecological tumor and rare primary peritoneal malignancies. PSM have been historically considered as end-stage metastatic conditions only amenable to palliative options. Only in recent years, better knowledge of their natural history and pattern of disease-progression has evolved into the concept that PSM represent a local-regional disease stage. A novel treatment approach aiming at definitive disease eradication combines aggressive cytoreductive surgery (CRS) and perioperative local-regional chemotherapy, either in the form of hyperthermic intraperitoneal chemotherapy (HIPEC), or normothermic early postoperative chemotherapy. Such a combined treatment approach has reportedly resulted in a survival improvement over historical controls, and it is gaining an increasing acceptance as standard of care for selected patients with PSM. This article reviews the most recent literature data on the surgical and comprehensive management of PSM. Epidemiology and natural history of the different disease entities are briefly discussed. Cytoreductive surgical procedures and intraperitoneal chemotherapy administration techniques are described, focusing on the technical variants adopted in our institution. Indications for combined treatment, and outcomes following CRS/HIPEC, are addressed, including peritoneal metastases from appendiceal tumors (pseudomyxoma peritonei), colorectal cancer, gastric cancer, epithelial ovarian cancer, and rare primary peritoneum based neoplasms, such as diffuse malignant peritoneal mesothelioma, and primary peritoneal (extra-ovarian) serous papillary carcinoma.

Sociodemographic disparities in advanced ovarian cancer survival and adherence to treatment guidelines.

OBJECTIVE: To estimate whether race or ethnic and socioeconomic strata are independently associated with advanced-stage ovarian cancer-specific survival after adjusting for adherence to National Comprehensive Cancer Network treatment guidelines. METHODS: The design was a retrospective population-based cohort study of patients with stage IIIC-IV epithelial ovarian cancer identified from the Surveillance, Epidemiology, and End Results-Medicare database (1992-2009). Quartile of census tract median household income was used as the measure of socioeconomic status (quartiles 1-4). A multivariable logistic regression model was used to identify characteristics predictive of adherence to National Comprehensive Cancer Network guidelines for surgery and chemotherapy. Cox proportional hazards models and propensity score matching were used for survival analyses. RESULTS: A total of 10,296 patients were identified, and 30.2% received National Comprehensive Cancer Network guideline-adherent care. Among demographic variables, black race (adjusted odds ratio [OR] 1.53, 95% confidence interval [CI] 1.22-1.92) and low socioeconomic status (quartile 1, adjusted OR 1.32, 95% CI 1.14-1.52) were independently associated with nonguideline care. Stratified multivariate survival analysis using the propensity score-matched sample (n=5,124) revealed that deviation from treatment guidelines was associated with a comparable risk of disease-related death across race-ethnicity: whites (adjusted hazard ratio [HR] 1.59, 95% CI 1.48-1.71), blacks (adjusted HR 1.66, 95% CI 1.19-2.30), Asian or Pacific Islanders (adjusted HR 1.52, 95% CI 0.99-1.92), and Hispanics (adjusted HR 1.91, 95% CI 0.98-3.72). Across socioeconomic status, deviation from treatment guidelines was also associated with a comparable risk of ovarian cancer mortality for quartile 1 (adjusted HR 1.69, 95% CI 1.47-1.95), quartile 2 (adjusted HR 1.63, 95% CI 1.42-1.87), quartile 3 (adjusted HR 1.51, 95% CI 1.32-1.73), and quartile 4 (adjusted HR 1.57, 95% CI 1.38-1.79). CONCLUSION: Adherence to treatment guidelines for advanced-stage ovarian cancer is associated with equivalent survival benefit across racial or ethnic and socioeconomic strata. Ensuring equal access to standard treatment is a viable strategic approach to reduce survival disparities.

Spatial analysis of advanced-stage ovarian cancer mortality in California.

OBJECTIVE: We sought to determine the impact of geographic location on advanced-stage ovarian cancer mortality in relation to adherence to National Comprehensive Cancer Network (NCCN) treatment guidelines and hospital case volume. STUDY DESIGN: This was a retrospective observational cohort study of patients diagnosed with stage IIIC/IV epithelial ovarian cancer (Jan. 1, 1996, through Dec. 31, 2006) identified from the California Cancer Registry. Generalized additive models were created to assess the effect of spatial distributions of geographic location, demographic characteristics, disease-related variables, adherence to NCCN guidelines, and hospital case volume, with simultaneous smoothing of geographic location and adjustment for confounding variables. RESULTS: A total of 11,765 patients were identified. Twelve of the 378 hospitals (3.2%) were high-volume hospitals (HVH) (≥20 cases/y) and cared for 2112 patients (17.9%). For all patients, the median distance to an HVH was 22.7 km/14.1 miles and 80% were located within 79.6 km/49.5 miles of an HVH. Overall, 45.4% of patients were treated according to NCCN guidelines. The global test for location revealed that geographic position within the state was significantly correlated with ovarian cancer mortality after adjusting for other variables (P < .001). Distance to receive care ≥32 km/20 miles was protective against mortality (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.79-0.93), while distance from an HVH ≥80 km/50 miles was associated with an increased risk of death (HR, 1.13; 95% CI, 1.03-1.23). The effects of geographic predictors were attenuated when nonadherence to NCCN guidelines (HR, 1.25; 95% CI, 1.18-1.32) and care at an HVH (HR, 0.87; 95% CI, 0.81-0.93) were introduced into the model. CONCLUSION: Geographic location is a significant predictor of advanced-stage ovarian cancer mortality and the effect is primarily related to the likelihood of receiving NCCN guideline adherent care and treatment at an HVH.

Paclitaxel/carboplatin with or without sorafenib in the first-line treatment of patients with stage III/IV epithelial ovarian cancer: a randomized phase II study of the Sarah Cannon Research Institute.

This trial compared the efficacy and toxicity of standard first-line treatment with paclitaxel/carboplatin versus paclitaxel/carboplatin plus sorafenib in patients with advanced ovarian carcinoma. Patients with stage 3 or 4 epithelial ovarian cancer with residual measurable disease or elevated CA-125 levels after maximal surgical cytoreduction were randomized (1:1) to receive treatment with paclitaxel (175 mg/m(2) , 3 h infusion, day 1) and carboplatin (AUC 6.0, IV, day 1) with or without sorafenib 400 mg orally twice daily (PO BID). Patients were reevaluated for response after completing 6 weeks of treatment (two cycles); responding or stable patients received six cycles of paclitaxel/carboplatin. Patients receiving the sorafenib-containing regimen continued sorafenib (400 PO BID) for a total of 52 weeks. Eighty-five patients were randomized and received treatment.Efficacy was similar for patients receiving paclitaxel/carboplatin/sorafenib versus paclitaxel/carboplatin: overall response rates 69% versus 74%; median progression-free survival 15.4 versus 16.3 months; 2 year survival 76% versus 81%. The addition of sorafenib added substantially to the toxicity of the regimen; rash, hand-foot syndrome, mucositis, and hypertension were significantly more common in patients treated with sorafenib. The addition of sorafenib to standard paclitaxel/carboplatin did not improve efficacy and substantially increased toxicity in the first-line treatment of advanced epithelial ovarian cancer. Based on evidence from this study and other completed trials, sorafenib is unlikely to have a role in the treatment of ovarian cancer.

The role of hyperthermic intraperitoneal chemotherapy using paclitaxel in platinum-sensitive recurrent epithelial ovarian cancer patients with microscopic residual disease after cytoreduction.

BACKGROUND: We analyzed the role of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) on the microscopic component of the disease in patients with a first recurrence of platinum-sensitive ovarian cancer after complete cytoreduction (CCR). PATIENTS AND METHODS: We analyzed the data of 54 patients who were operated on between January 2001 and July 2012 with the diagnosis of platinum-sensitive recurrent ovarian cancer. In all patients, it was possible to achieve a CCR. Patients were divided into two groups: group I (cytoreduction alone) consisted of 22 surgical patients and group II (cytoreduction and HIPEC) consisted of 32 patients. RESULTS: There were no significant differences in any of the preoperative variables studied. After a multivariate analysis of factors identified in the univariate analysis, only the presence of tumors with undifferentiated histology (hazard ratio 2.57; 95% CI 1.21-5.46; p < 0.05) was an independent factor associated with a reduced disease-free survival. The 1- and 3-year disease-free survival was 77 and 23% in patients from group I and 77 and 45% in patients from group II, respectively, with a tendency, but no significant differences (p = 0.078). There was no significant difference in postoperative morbidity between the two groups. CONCLUSIONS: The administration of HIPEC in patients in whom it is possible to achieve a CCR of the disease has not increased postoperative morbidity and mortality rates in our center. HIPEC with paclitaxel is effective in the treatment of microscopic disease in platinum-sensitive recurrent epithelial ovarian cancer patients with microscopic residual disease after cytoreduction, although with no statistically significant difference.

Cytoreductive surgery and HIPEC in recurrent epithelial ovarian cancer: a prospective randomized phase III study.

BACKGROUND: The current treatment of ovarian cancer consists of cytoreductive surgery (CRS) and systemic chemotherapy. The aim of this study was to examine if hyperthermic intraperitoneal chemotherapy (HIPEC) is an alternative modality to treat this category of patients along with a second attempt of surgical resection and second- or third-line systemic chemotherapy afterward. METHODS: In an 8-year period (2006-2013), 120 women with advanced ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] IIIc and IV) who experienced disease recurrence after initial treatment with conservative or debulking surgery and systemic chemotherapy were randomized into two groups. Group A comprised 60 patients treated with CRS followed by HIPEC and then systemic chemotherapy. Group B comprised 60 patients treated with CRS only and systemic chemotherapy. RESULTS: The mean survival for group A was 26.7 versus 13.4 months in group B (p < 0.006). Three-year survival was 75 % for group A versus 18 % for group B (p < 0.01). In the HIPEC group, the mean survival was not different between patients with platinum-resistant disease versus platinum-sensitive disease (26.6 vs. 26.8 months). On the other hand, in the non-HIPEC group, there was a statistically significant difference between platinum-sensitive versus platinum-resistant disease (15.2 vs. 10.2 months, p < 0.002). Complete cytoreduction was associated with longer survival. Patients with a peritoneal cancer index score of <15 appeared also to have longer survival. CONCLUSIONS: The use of HIPEC along with the extent of the disease and the extent of cytoreduction play an important role in the survival of patients with recurrence in an initially advanced ovarian cancer.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in recurrent epithelial ovarian cancer with peritoneal metastases: a single centre experience.

BACKGROUND: This investigation aims to assess morbidity, mortality and postoperative outcomes of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in recurrent epithelial ovarian cancer (REOC) with peritoneal metastases (PM). METHODS: Consecutive patients with radiographic evidence of REOC with PM were scheduled for CRS and HIPEC at the Comprehensive Cancer Center, University Hospital Tübingen, Germany. Clinical data were retrospectively analyzed. RESULTS: In total, 90 patients were analyzed. Complete cytoreduction and HIPEC could be performed in 69 % of patients. When categorizing patients with respect to the completeness of cytoreduction (CC-0/1 vs CC-2/3), there was no difference considering baseline demographic characteristics. Cumulative morbidity was 42 %. Morbidity rates did not statistically differ between CC-0/1 patients with HIPEC and CC-2/3 patients without HIPEC. No surgery-related and 90-day postoperative mortality was observed. In CC-0/1 patients, median overall survival was 35 months as opposed to 14 months in CC-2/3 patients. There was no difference in survival with respect to the peritoneal carcinomatosis index (PCI) as long as complete cytoreduction could be achieved. CONCLUSIONS: CRS and HIPEC can be performed with acceptable morbidity and low mortality in specialized centres. Our data do not suggest that HIPEC necessarily increases the risk of postoperative adverse events.

Recurrence season impacts the survival of epithelial ovarian cancer patients.

BACKGROUND: Several studies indicated that the diagnosis season affects the prognosis of some cancers, such as examples in the prostate, colon and breast This retrospective study aimed to investigate whether the diagnosis and recurrent season impacts the prognosis of epithelial ovarian cancer patients. METHODS: From January 2005 to August 2010, 161 epithelial ovarian cancer patients were analyzed and followed up until August 2013. Kaplan- Meier survival curves and the log-rank test were used to make the survival analysis. Multivariate analysis was conducted to identify independent prognostic factors. RESULTS: The prognostic factors of overall survival in epithelial ovarian cancer patients included age, clinical stage, pathological type, histological grade, residual disease after primary surgery, recurrent season and adjuvant chemotherapy cycles. Moreover, clinical stage, histological grade, residual disease after primary surgery, recurrent season and adjuvant chemotherapy cycles also impacted the progression-free survival of epithelial ovarian cancer patients. The diagnosis season did not have a significantly relationship with the survival of operable epithelial ovarian cancer patients. Median overall survival of patients with recurrent month from April to November was 47 months, which was longer (P < 0.001) than that of patients with recurrence month from December to March (19 months). Median progression-free survival of patients with recurrence month from April to November and December to March was 20 and 8 months, respectively (P < 0.001). CONCLUSION: The recurrence season impacts the survival of epithelial ovarian cancer patients. However, the diagnosed season does not appear to exert a significant influence.

Optimal treatment of early-stage ovarian cancer.

BACKGROUND: There is no clear consensus regarding systemic treatment of early-stage ovarian cancer (OC). Clinical trials are challenging because of the relatively low incidence and good prognosis. Initial results of the International Collaborative Ovarian Neoplasm (ICON)1 trial demonstrated benefit in both overall survival (OS) and recurrence-free survival (RFS) with adjuvant chemotherapy. We report results of 10-year follow-up to establish whether benefits are maintained longer term and discuss how this and other available evidence from randomised trials can be used to guide treatment options regarding the need for, and choice of, adjuvant chemotherapy regimen. PATIENTS AND METHODS: ICON1 recruited women with OC following primary surgery in whom there was uncertainty as to whether adjuvant chemotherapy was indicated. Patients were randomly assigned to adjuvant or no adjuvant chemotherapy. Platinum-based chemotherapy was recommended and 87% received single-agent carboplatin. Analyses of long-term treatment benefits and interaction with risk groups were carried out. A high-risk group of women was defined with stage 1B/1C grade 2/3, any stage 1 grade 3 or clear-cell histology. RESULTS: With a median follow-up of 10 years, the estimated hazard ratio (HR) for RFS was 0.69 [95% confidence interval (CI) 0.51-0.94, P = 0.02] and OS 0.71 (95% CI 0.52-0.98, P = 0.04) in favour of chemotherapy. In absolute terms, there was a 10% (60%-70%) improvement in RFS and a 9% (64%-73%) improvement in OS; the benefit of chemotherapy might be greater in high-risk disease (18% improvement in OS). Uncertainty remains about the optimal chemotherapy regimen. The only randomised trial data available are from a subset of 120 stage 1 patients in ICON3 where the treatment difference, comparing carboplatin with carboplatin/paclitaxel was estimated with relatively wide CIs [progression-free survival HR = 0.71 (95% CI 0.39-1.32) and OS HR = 0.98 (95% CI 0.49-1.93)]. CONCLUSIONS: Extended follow-up from ICON1 confirms that adjuvant chemotherapy should be offered to women with early-stage OC, particularly those with high-risk disease. CLINICAL TRIAL NUMBERS: ISRCTN11916376 for ICON1 and ISRCTN57157825 for ICON3.

Reasons for failure to deliver National Comprehensive Cancer Network (NCCN)-adherent care in the treatment of epithelial ovarian cancer at an NCCN cancer center.

OBJECTIVE: The National Comprehensive Cancer Network (NCCN) has established guidelines for treating epithelial ovarian cancer (EOC) which includes cytoreductive surgery and platinum and taxane-based chemotherapy (CT). The objective of this study was to determine the reasons for failure to deliver NCCN-adherent care at an NCCN cancer center serving a diverse racial and socioeconomic population. METHODS: Medical records of women with EOC diagnosed between 2004 and 2009 were reviewed for demographic, clinical, tumor, treatment, and survival data. Independent reviewers determined if their treatment met criteria for being NCCN-adherent. Progression-free survival (PFS) and overall survival (OS) were calculated with Kaplan-Meier estimates and compared with the log-rank test. RESULTS: 367 patients were identified. 79 (21.5%) did not receive NCCN-adherent care. Non-adherent CT in 75 patients was the most common reason for failure to receive NCCN-adherent care. 39 patients did not complete CT due to treatment toxicities or disease progression. 12 patients received single agent CT only and 4 received no CT due to comorbidities. 2 patients declined CT. 18 patients died in the postoperative period without receiving CT. 8 patients did not undergo cytoreduction due to disease progression or comorbidities. PFS and OS were improved in the NCCN-adherent cohort (PFS: 5.7 vs. 18.3 months, p<.005) (OS: 11.4 vs. 49.5 months, p<.005). CONCLUSIONS: The vast majority of patients at an NCCN cancer center received NCCN-adherent treatment. Reasons for failure to receive NCCN-adherent care were variable, but most did not receive chemotherapy in accordance with guidelines due to comorbidities or disease progression.