Clinical impact of CA-125 ELIMination rate constant K (KELIM) on surgical strategy in advanced serous ovarian cancer patients.

OBJECTIVES: The modeled CA-125 elimination constant K (KELIM) is a pragmatic early marker of tumor chemosensitivity in ovarian cancer patients treated with neoadjuvant chemotherapy before interval surgery. The primary objective of this study was to assess the prognostic value of KELIM regarding the feasibility of complete surgery, and secondary objectives were to assess the prognostic value of KELIM for the risk of a platinum resistant relapse, progression free survival, and overall survival. METHODS: The study was based on a retrospective cohort of 284 patients treated for an advanced serous high grade ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) stages III-IV, with neoadjuvant chemotherapy, followed by interval surgery, in a comprehensive cancer center. CA-125 concentrations at baseline and during neoadjuvant chemotherapy were collected. The KELIM predictive value regarding the tumor radiological response rate, likelihood of complete surgery, risk of subsequent platinum resistant relapse, progression free survival, and overall survival were assessed with univariate and multivariate tests. RESULTS: In 232 patients, KELIM was an independent and major predictor of the probability of complete surgery and survival. The final logistic regression model, including KELIM (odds ratio (OR) 0.36, 95% confidence interval (CI)0.16 to 0.73, p=0.006) and complete surgery (no vs yes, OR 0.29, 95% CI 0.15 to 0.53, p<0.001), highlighted the complementary impact of chemosensitivity and surgical outcome relative to the complete surgery. In the multivariate analysis, KELIM and complete surgery were significantly associated with a lower risk of early relapse. In the case of an unfavorable KELIM, when surgical efforts allowed complete cytoreduction, median overall survival was similar to that reported in the case of a favorable KELIM (46.3 months (range 34.6-60.3) vs 46.5 months (range 40.6-68.7), respectively). CONCLUSION: Primary tumor chemosensitivity, assessed by the modeled CA-125 KELIM, calculated during neoadjuvant chemotherapy, is a major parameter to consider for decision making regarding interval surgery. Complementary to the RECIST score and laparoscopy, this non-invasive tool, available online, helps tailor the interval surgery strategy according to patient tumor chemosensitivity.

Role of Hyperthermic Intraperitoneal Chemotherapy Combined with Cytoreductive Surgery as Consolidation Therapy for Advanced Epithelial Ovarian Cancer.

BACKGROUND: Patients with advanced epithelial ovarian cancer who undergo incomplete surgery followed by six cycles of chemotherapy could benefit from second-look or consolidation cytoreductive surgery (CCRS). The primary goal of this study was to evaluate the overall survival (OS) in patients undergoing complete CCRS and the factors affecting survival. The secondary goal was to study the benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients. METHODS: This was a retrospective analysis of 173 patients with CCRS with (n = 118) or without (n = 55) HIPEC treated at 12 French centers. Only patients having a completeness of cytoreduction (CC) 0/1 resection and a minimum of 5 years of follow-up were included. HIPEC was performed systematically for all patients except those treated at the four centers that did not perform HIPEC. RESULTS: The median Peritoneal Cancer Index was 6 (range 0-33). Closed HIPEC was performed in 59 (34.1%) patients and open HIPEC was performed in 56 (32.3%) patients. Grade 3-4 complications occurred in 64 (36.9%) patients. The median OS was 35.67 months (95% confidence interval [CI] 29.8-46.1) and was significantly longer for CCRS + HIPEC (31.4 months without HIPEC and 42.5 months with HIPEC; p = 0.022). On multivariate analysis, closed HIPEC (hazard ratio [HR] 0.46, 95% CI 0.29-0.73; p < 0.001) resulted in a longer OS, and age > 65 years (HR 2.17, 95% CI 1.14-4.11; p = 0.018) and bowel resection (HR 1.98, 95% CI 1.27-3.08; p = 0.020) led to a shorter OS. On multivariate logistic regression analysis, closed HIPEC (odds ratio 0.18; p = 0.001) was associated with a lower risk of dying at 5 years. CONCLUSIONS: CCRS was performed with an acceptable morbidity and resulted in good overall survival. The role of HIPEC in addition to CCRS should be evaluated in prospective, randomized studies and the closed technique prospectively compared with the open technique.

Real-World Data on Newly Diagnosed BRCA-Mutated High-Grade Epithelial Ovarian Cancers: The French National Multicenter ESME Database.

BACKGROUND: In spite of the frequency and clinical impact of BRCA1/2 alterations in high-grade epithelial ovarian cancer (HGEOC), real-world information based on robust data warehouse has been scarce to date. METHODS: Consecutive patients with BRCA-mutated HGEOC treated between 2011 and 2016 within French comprehensive cancer centers from the Unicancer network were extracted from the ESME database. The main objective of the study was the assessment of clinicopathological and treatments parameters. RESULTS: Out of the 8021 patients included in the ESME database, 266 patients matching the selection criteria were included. BRCA1 mutation was found in 191 (71.8%) patients, while 75 (28.2%) had a BRCA2 mutation only; 95.5% of patients received a cytoreductive surgery. All patients received a taxane/platinum-based chemotherapy (median = six cycles). Complete and partial response were obtained in 53.3% and 20.4% of the cases, respectively. Maintenance therapy was administered in 55.3% of the cases, bevacizumab being the most common agent. After a median follow up of 51.7 months, a median progression-free survival of 28.6 months (95% confidence interval (CI) [26.5; 32.7]) and an estimated 5-year median overall survival of 69.2% (95% CI [61.6; 70.3]) were reported. Notably, BRCA1- and BRCA2-mutated cases exhibited a trend towards different median progression-free survivals, with 28.0 (95% CI [24.4; 32.3]) and 33.3 months (95% CI [26.7; 46.1]), respectively (p-value = 0.053). Furthermore, five-year OS for BRCA1-mutated patients was 64.5% (95% CI [59.7; 69.2]), while it was 82.5% (95% CI [76.6; 88.5]) for BRCA2-mutated ones (p-value = 0.029). CONCLUSIONS: This study reports the largest French multicenter cohort of BRCA-mutated HGEOCs based on robust data from the ESME, exhibiting relevant real-world data regarding this specific population.

ACOSOG Z-0011 criteria impact on axillary surgery for early breast cancer in clinical practice: Evaluation in a retrospective cohort of 1900 patients.

BACKGROUND: There is a trend towards de-escalation in early breast cancer axillary surgery. In the American College of Surgeons Oncology Group (ACOSOG) Z-0011 trial, observation was shown to be non-inferior in terms of overall survival to complementary axillary lymph node dissection (cALND) in patients with up to two sentinel lymph node (SLN) metastases. The study included patients with T1-T2 invasive breast cancer, clinically node negative, undergoing breast-conserving surgery with SLN biopsy, followed by systemic therapy and radiotherapy. The aim of our study was to evaluate the impact of applying these ACOSOG Z-0011 inclusion criteria in routine practice. PATIENTS AND METHODS: This retrospective observational study was conducted in a French comprehensive cancer center where patients treated for breast cancer with primary surgery were prospectively included between 2010 and 2016. Patients meeting ACOSOG Z-0011 inclusion criteria were analyzed. RESULTS: Among the 1900 included patients, 1497 (79 %) met the ACOSOG Z-0011 criteria before surgery. Of these, 390 (20 %) had one or two metastatic SLN and could have avoided cALND. Out of these patients, 319 (81 %) presented cT1 tumors. During the study period, cALND was performed in 320 (82 %) patients and was free of metastases in 80 % of cases, having an impact on eligibility for adjuvant chemotherapy in only 3 (0.8 %) patients. CONCLUSIONS: In situations of primary breast cancer surgery, use of ACOSOG Z-0011 criteria could reduce the rate of cALND by 20 %. Further studies are needed to help select patients for whom abstention from any axillary surgery would be reasonable.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for First Relapse of Ovarian Cancer.

BACKGROUND: To assess impact of surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients treated for a first relapse of ovarian cancer (FROC). PATIENTS AND METHODS: Patients with a FROC treated with second-line chemotherapy, surgery and HIPEC were retrospectively included from 13 Institutions. Studied parameters were interval free between the end of initial treatment and the first relapse, second-line chemotherapy, peritoneal cancer index and completeness of surgery, HIPEC, mortality and morbidity, pathological results and survival. RESULTS: From 2001 to 2010, 314 patients were included. The main strategy was secondary chemotherapy followed by surgery and HIPEC (269/314-85.6%). Mortality and morbidity rates were respectively 1% and 30.9%. Median follow-up was 50 months, 5-year overall survival was 38.0%, with no difference between platinum-sensitive or -resistant patients and 5-year disease-free survival was 14%. CONCLUSION: HIPEC allows encouraging survival in the treatment of FROC, better in case of complete surgery, with acceptable mortality and morbidity rates.

Survival benefit of hyperthermic intraperitoneal chemotherapy for recurrent ovarian cancer: a multi-institutional case control study.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) and complete surgical removal of the tumor, in relapsing patients may provide a clinical benefit. There is no consensus considering the place of HIPEC for patients who had first ovarian cancer relapse. To assess for possible efficacy of HIPEC on overall survival (OS) rates in this situation, we performed a multi-institutional study. METHODS: The current study was a retrospective case control multi-institutional study comparing a group of patients treated with HIPEC to a group of patients treated without HIPEC. Inclusion criteria were first relapse of a serous ovarian carcinoma and >6 months after the end of initial treatment. Exclusion criteria were another pathological subtype of ovarian cancer, a relapse at <6 months after initial treatment, and a second relapse or more. We aimed to assess OS, morbidity, and mortality rates and prognostic factors. RESULTS: From June 1997-July 2011, 42 patients were included, 23 in the HIPEC group and 19 in the control group. Each patient from the two groups had a complete secondary surgery at the time of the first relapse. At 4 years OS was 75.6 % in the HIPEC group and 19.4 % in the control group (p = 0.013). In a multivariate analysis, HIPEC and interval-free before the end of initial treatment were both independent prognostic factors. CONCLUSION: When compared to the control group, complete secondary surgery and HIPEC appear to afford a better OS rate than complete secondary surgery alone, in case of first ovarian cancer relapse. Further randomized trials are warranted to confirm these results.

Cytotoxic effect of hyperthermia and chemotherapy with platinum salt on ovarian cancer cells: results of an in vitro study.

PURPOSE: Hyperthermic intraperitoneal chemotherapy is continuously under evaluation in ovarian cancer. The purpose of the present study was to evaluate the effect of chemotherapy, drug concentration and temperature. MATERIALS AND METHODS: A human ovarian carcinoma cell line was used. The effect of hyperthermia combined with chemotherapy was analyzed. RESULTS: When hyperthermia was combined with chemotherapy, the 50% lethal dose (LD(50)) decreased with the duration of exposure. The effect of temperature was similar between 39 and 43 °C for a 30-min exposure. For a 60- to 90-min exposure, the LD(50) was equivalent between 38 and 43 °C. Beyond 40 °C, an increase in platinum salt concentration was necessary to obtain similar results according to the duration of exposure. CONCLUSIONS: The cytotoxic effect of the combination seemed to be potentiated and limited at 40 °C.

Oxaliplatin-based hyperthermic intraperitoneal chemotherapy in primary or recurrent epithelial ovarian cancer: A pilot study of 31 patients.

BACKGROUND: The feasibility and safety of oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) associated with cytoreductive surgery (CRS) was assessed in patients with peritoneal carcinomatosis resulting from primary advanced or relapsing epithelial ovarian cancer (EOC). METHODS: Thirty-one patients received neoadjuvant platin-based chemotherapy followed by oxaliplatin-based HIPEC associated with CRS as consolidation of primary therapy (n = 19) or for relapsing disease (n = 12). Grade 3/4 complications were recorded according to National Cancer Institute definitions. RESULTS: Median peritoneal carcinomatosis index (PCI) was 2.7 after neoadjuvant chemotherapy. Mean duration of surgery was 352 min (range 105-614) and median hospital stay was 11 days (range 6-87). Grade 3 toxicity was observed in nine patients: five required repeat surgery, two an invasive procedure, four rehospitalization, and three a return to the ICU. No grade 4 toxicity occurred, excepted one hypokalemia. Median progression-free survival (PFS) for primary advanced EOC was 13.2 months and 1-year PFS was 59.3%. Median PFS for relapsing patients was 14.3 months and 1-year PFS was 54.4%. CONCLUSION: CRS with oxaliplatin-based HIPEC is feasible and relatively safe in recurrent and primary EOC. HIPEC after neoadjuvant chemotherapy reduces the PCI and decreases the number of surgical procedures and morbidity. Further evaluations of this procedure are required to assess the survival benefits.

Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin.

PURPOSE: To compare the long-term survival of patients with isolated and resectable peritoneal carcinomatosis (PC) in comparable groups of patients treated with systemic chemotherapy containing oxaliplatin or irinotecan or by cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC). PATIENTS AND METHODS: All patients with gross PC from colorectal adenocarcinoma who had undergone cytoreductive surgery plus HIPEC from 1998 to 2003 were evaluated. The standard group was constituted by selecting patients with colorectal PC treated with palliative chemotherapy during the same period, but who had not benefited from HIPEC because the technique was unavailable in the center at that time. RESULTS: Forty-eight patients were retrospectively included in the standard group and were compared with 48 patients who had undergone HIPEC and were evaluated prospectively. All characteristics were comparable except age and tumor differentiation. There was no difference in systemic chemotherapy, with a mean of 2.3 lines per patient. Median follow-up was 95.7 months in the standard group versus 63 months in the HIPEC group. Two-year and 5-year overall survival rates were 81% and 51% for the HIPEC group, respectively, and 65% and 13% for the standard group, respectively. Median survival was 23.9 months in the standard group versus 62.7 months in the HIPEC group (P < .05, log-rank test). CONCLUSION: Patients with isolated, resectable PC achieve a median survival of 24 months with modern chemotherapies, but only surgical cytoreduction plus HIPEC is able to prolong median survival to roughly 63 months, with a 5-year survival rate of 51%.

Cost-effectiveness of intraperitoneal chemohyperthermia in the treatment of peritoneal carcinomatosis from colorectal cancer.

OBJECTIVES: Our purpose was to assess the cost-effectiveness of intraperitoneal chemohyperthermia (IPCH) compared to palliative chemotherapy (STANDARD) against peritoneal carcinomatosis arising from colorectal cancer. METHODS: We performed a retrospective study of 96 patients whose peritoneal carcinomatosis had been diagnosed between January 1998 and December 2003 and treated either with IPCH or with palliative chemotherapy in French comprehensive cancer centers. Patients were followed up over a 3-year period. Effectiveness was measured by restricted mean survival at 3 years. The Bang and Tsiatis method was used to handle cost-censored data. The confidence limits of the mean cost per patient in each group and the mean incremental cost per life-year saved were computed using 1000 bootstrapreplicates. We also computed an acceptability curve for the incremental cost-effectiveness ratio (ICER). RESULTS: We found that IPCH improved survival and was more costly than STANDARD treatment. Over a 3-year observation period, IPCH yielded an average survival gain of 8.3 months at the additional cost of euro58,086 (95% confidence interval 35,893-112,839) per life-year saved. CONCLUSION: The ICER of IPCH is acceptable given the severity and burden of peritoneal carcinomatosis for which there is no alternative curative treatment.

Feasibility of laparoscopic peritonectomy followed by intra-peritoneal chemohyperthermia: an experimental study.

OBJECTIVE: Hyperthermic intraperitoneal chemotherapy (HIPEC) is being evaluated for patients with minimal residual or no residual disease after primary surgery and chemotherapy for stage III ovarian carcinoma. The use of operative laparoscopy to perform peritonectomy and HIPEC is reported. METHODS: Five adult pigs were used. The placement of trocars in the four quadrants was planned in order to complete a total peritonectomy and then to place the HIPEC drains. The umbilical trocar was then replaced manually by the surgeon through a Lapdisc to manipulate the bowel loops. The abdominal cavity was filled with heated saline (43 degrees C), and the pumps were activated for 30 min. RESULTS: The procedure was successfully completed with an adequate intraabdominal temperature and distribution. CONCLUSION: These preliminary data suggest the technical feasibility of the laparoscopic approach for HIPEC, in an animal model without carcinomatosis. Our ongoing research is designed to gather pharmacokinetic data in an experimental controlled randomized fashion to compare a laparoscopic to a laparotomy approach on the same model.