UHPLC-MS/MS method for the quantification of ultra-traces of irinotecan and its metabolites in red blood cells and plasma to detect caregivers' contamination.

The occupational exposure of caregivers to antineoplastic agents has been demonstrated since 1979. Since the early 1990s, numerous studies from several countries have demonstrated the contamination of care facilities by antineoplastic drugs. As it is easier to sample, most contamination measurements in workers are carried out in urine sample. The distribution and elimination half-lives of irinotecan suggest that blood can be considered as better than urine for the biomonitoring of a potential contamination of healthcare workers. We describe here the development and the validation of a UHPLC-MS/MS method to simultaneously quantify irinotecan, and two of its main metabolites, APC and SN-38, at ultra-trace levels in plasma and red blood cells (RBC). This method has been applied to blood samples collected from several healthcare services in a French comprehensive cancer center. The results demonstrate that the method is sensitive enough to identify a contamination of healthcare workers by irinotecan and SN-38 at very low concentrations. Moreover, the results show that analysis of RBC is of great interest and complementary to that of serum.

Perioperative treatment in resectable gastric cancer with spartalizumab in combination with fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT): a phase II study (GASPAR).

BACKGROUND: Perioperative chemotherapy and surgery are a standard of care for patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma. However, the prognosis remains poor for this population. The FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) regimen is considered as the new standard chemotherapy regimen for perioperative strategy, despite associated with a 5-year overall survival rate (OS) amounting 45% following radical surgery. Immunotherapy with antibodies that inhibit PD-1/ PD-L1 interaction has recently emerged as a new treatment option with promising and encouraging early trial results for patients with advanced or metastatic gastric or GEJ adenocarcinoma. Currently, no trials have investigated the impact of perioperative immunotherapy in combination with chemotherapy for resectable gastric or GEJ adenocarcinoma. METHODS: GASPAR trial is a multicenter open-label, nonrandomized, phase II trial to evaluate the efficacy and safety of Spartalizumab in combination with the FLOT regimen as perioperative treatment for resectable gastric or GEJ adenocarcinoma. The main endpoint is the proportion of patients with pathological complete regression (pCR) in the primary tumour after preoperative treatment. Systemic treatment will include a pre-operative neoadjuvant and a post-operative adjuvant treatment, during which FLOT regimen will be administered every two weeks for 4 cycles and Spartalizumab every four weeks for 2 cycles. For patients with confirmed tumor resectability on imaging assessment, surgery will be realized within 4-6 weeks after the last dose of preoperative chemotherapy. Post-operative systemic treatment will then be initiated within 4-10 weeks after surgery. Using a Simon's two-stage design, up to 67 patients will be enrolled, including 23 in the first stage. DISCUSSION: Currently, no trials have investigated the impact of immunotherapy in combination with FLOT chemotherapy as perioperative treatment for resectable gastric or GEJ adenocarcinoma. Some studies have suggested a change in the tumor immune micro-environment following neoadjuvant chemotherapy in this setting, reinforcing the relevance to propose a phase II trial evaluating efficacy and safety of Spartalizumab in combination with perioperative chemotherapy, with the aim of improving treatment efficacy and survival outcomes. TRIAL REGISTRATION: NCT04736485, registered February, 3, 2021.

Is the blood of a surgeon performing HIPEC contaminated by irinotecan, its major metabolites and platinum compounds?

OBJECTIVES: Hyperthermic intraperitoneal chemotherapy (HIPEC) is a beneficial surgical technique for patients, but the surgeons are being exposed to cytotoxic drugs. Few biomonitoring studies were led on blood samples in the context of HIPEC. This study aimed to evaluate the surgeon's plasmatic and red blood cell (RBC) contamination by irinotecan, two of its major metabolites and platinum compounds. METHODS: HIPEC procedures performed using the coliseum techniques were observed between September 2015 and April 2018 in a French comprehensive cancer center. Irinotecan and its metabolites SN-38 and APC were dosed by UHPLC with a limit of quantification determined at 50 pg/mL. Platinum compounds were dosed by inductively coupled plasma mass spectrometry with a limit of quantification determined at 16 pg/mL. RESULTS: Despite collective and personal protective equipment, 80% of plasma samples were contaminated by irinotecan and 33% by platinum compounds out of 21. The results showed that the surgeon was contaminated after HIPEC and even after a period of HIPEC inactivity. Nineteen percent of plasmatic samples and 45% of RBC samples were contaminated by SN-38, the active metabolite of irinotecan. APC was only found in some RBC samples (33%). CONCLUSIONS: Even if this study shows blood contamination by irinotecan, two of its major metabolites (including active SN-38) and platinum compounds both in the plasma and RBC of a surgeon performing the HIPEC procedures, further studies should be performed to confirm these results. Additional studies should be carried out to further investigate the contamination in the context of HIPEC and more broadly in the hospital.

Second-look surgery plus hyperthermic intraperitoneal chemotherapy versus surveillance in patients at high risk of developing colorectal peritoneal metastases (PROPHYLOCHIP-PRODIGE 15): a randomised, phase 3 study.

BACKGROUND: Diagnosis and treatment of colorectal peritoneal metastases at an early stage, before the onset of signs, could improve patient survival. We aimed to compare the survival benefit of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC), with surveillance, in patients at high risk of developing colorectal peritoneal metastases. METHODS: We did an open-label, randomised, phase 3 study in 23 hospitals in France. Eligible patients were aged 18-70 years and had a primary colorectal cancer with synchronous and localised colorectal peritoneal metastases removed during tumour resection, resected ovarian metastases, or a perforated tumour. Patients were randomly assigned (1:1) to surveillance or second-look surgery plus oxaliplatin-HIPEC (oxaliplatin 460 mg/m2, or oxaliplatin 300 mg/m2 plus irinotecan 200 mg/m2, plus intravenous fluorouracil 400 mg/m2), or mitomycin-HIPEC (mitomycin 35 mg/m2) alone in case of neuropathy, after 6 months of adjuvant systemic chemotherapy with no signs of disease recurrence. Randomisation was done via a web-based system, with stratification by treatment centre, nodal status, and risk factors for colorectal peritoneal metastases. Second-look surgery consisted of a complete exploration of the abdominal cavity via xyphopubic incision, and resection of all peritoneal implants if resectable. Surveillance after resection of colorectal cancer was done according to the French Guidelines. The primary outcome was 3-year disease-free survival, defined as the time from randomisation to peritoneal or distant disease recurrence, or death from any cause, whichever occurred first, analysed by intention to treat. Surgical complications were assessed in the second-look surgery group only. This study was registered at ClinicalTrials.gov, NCT01226394. FINDINGS: Between June 11, 2010, and March 31, 2015, 150 patients were recruited and randomly assigned to a treatment group (75 per group). After a median follow-up of 50·8 months (IQR 47·0-54·8), 3-year disease-free survival was 53% (95% CI 41-64) in the surveillance group versus 44% (33-56) in the second-look surgery group (hazard ratio 0·97, 95% CI 0·61-1·56). No treatment-related deaths were reported. 29 (41%) of 71 patients in the second-look surgery group had grade 3-4 complications. The most common grade 3-4 complications were intra-abdominal adverse events (haemorrhage, digestive leakage) in 12 (23%) of 71 patients and haematological adverse events in 13 (18%) of 71 patients. INTERPRETATION: Systematic second-look surgery plus oxaliplatin-HIPEC did not improve disease-free survival compared with standard surveillance. Currently, essential surveillance of patients at high risk of developing colorectal peritoneal metastases appears to be adequate and effective in terms of survival outcomes. FUNDING: French National Cancer Institute.

Is hyperthermic intraperitoneal chemotherapy (HIPEC) safe for healthcare workers?

BACKGROUND: During hyperthermic intraperitoneal chemotherapy (HIPEC), caregivers are exposed by different routes to cytotoxic drugs. This review proposes an overview of the safety of HIPEC by assessing existing data on protection procedures, biological and non-biological samples. Based on these data, relevant good practices, eventual irrelevant overprotection procedures and missing data to implement adapted protections are highlighted. MATERIALS AND METHODS: Data were extracted from a systematic review of literature from 1980 till 2016: number and type of surgical procedure, healthcare professionals present, protective equipment, samples, pre-analytical method and analytical method. RESULTS AND DISCUSSION: Only 55 HIPEC procedures have been evaluated. The majority of antineoplastic drugs used have all required characteristics to penetrate the organism and are recognized as very dangerous. Moreover, a great heterogeneity in protective equipment used, either individual or collective is observed. Environmental contamination occurs during HIPEC, especially for all surfaces in the operating room. Compounds penetration into caregivers lungs cannot be excluded. Priority remains to prove professionals contamination by focusing on biological samples. Biological material is rarely sampled or samples are not necessarily adapted. CONCLUSION: Repeated blood tests should be preferred using appropriate sampling schedules and validated sensitive analytical methods. Furthermore, there is a great need of new biological indicators to monitor caregivers exposure. During hyperthermic intraperitoneal chemotherapy (HIPEC), healthcare workers are exposed by different routes to cytotoxic drugs. There are currently few available occupational exposure data and environmental monitoring and biomonitoring must be improved in order to ensure optimal protection against antineoplastic drugs.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis in the Elderly: A Case-Controlled, Multicenter Study.

OBJECTIVE: This study was designed to identify factors associated with morbidity and mortality in patients older than 70 years who underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis (PC). BACKGROUND: Major surgery is associated with higher morbidity and mortality in elderly patients. For PC, CRS and HIPEC is the only current potential curative therapy, but the risks inherent to this patient population have called its benefits into question. METHODS: We retrospectively analyzed a multi-center database from 1989 to 2015. All patients who underwent CRS and HIPEC for PC were selected and patients older than 70 years were matched 1:4 with a younger cohort according to cancer origin, peritoneal cancer index (PCI), and completeness of cytoreduction. Major morbidity and mortality were analyzed. RESULTS: Of 2328 patients, 188 patients older than aged 70 years were matched with 704 younger patients. Patients older than aged 70 years demonstrated a higher American Society of Anesthesiologist score (≥ASA III 10.8 vs. 6.6 %, p = 0.008). There was no difference in overall 90-day morbidity (≥70: 45.7 % vs. <70: 44.5 %; p = 0.171); however, patients older than 70 years had significantly more cardiovascular complications (13.8 vs. 9.2 %, p = 0.044). Differences between the older and younger cohorts failed to reach significance for 90-day mortality (5.4 and 2.7 %, respectively; p = 0.052), and failure-to-rescue (11.6 and 6.1 %, respectively; p = 0.078). In multivariate analysis, PCI > 7 (95 % CI 1.051-5.798, p = 0.038) and HIPEC duration (95 % CI 1.106-6.235, p = 0.028) were independent factors associated with morbidity in elderly patients. CONCLUSIONS: CRS and HIPEC appear feasible for selected patients older than aged 70 years, albeit with a higher risk of medical complications associated with increased mortality.

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.