Improving olaparib exposure to optimize adverse effects management.

Background: Olaparib is an inhibitor of the human poly-(ADP-ribose)-polymerase enzymes (PARP1/2) needed to repair single-strand DNA breaks. It is used in breast, ovarian, prostate and pancreatic cancer. Objectives: This work aimed to describe the pharmacokinetics/pharmacodynamics (PK/PD) relationship between olaparib plasma concentrations and common adverse effects (i.e. anaemia and hypercreatininaemia), in a real-life setting, to propose a target concentration for therapeutic drug monitoring. Methods: Two PK/PD models describing the evolution of haemoglobinaemia and creatininaemia as a function of time were developed, based on data from, respectively, 38 and 37 patients receiving olaparib. The final model estimates were used to calculate the incidence of anaemia and creatinine increase according to plasma trough concentrations for 1000 virtual subjects to define target exposure. Results: The final models correctly described the temporal evolution of haemoglobinaemia and creatininaemia for all patients. The haemoglobinaemia PK/PD model is inspired by Friberg's model, and the creatininaemia PK/PD model is an indirect response model. Model parameters were in agreement with physiological values and close to literature values for similar models. The mean (population) plasma haemoglobin concentration at treatment initiation, as estimated by the model, was 11.62 g/dL, while creatinine concentration was 71.91 µmol/L. Using simulations, we have identified a target trough concentration of 3500-4000 ng/mL, above which more than 20% of patients would report grade ≥3 anaemia. Conclusion: Based on real-world data, we were able to properly describe the time course of haemoglobinaemia and plasma creatininaemia during olaparib treatment.

Effect of Adapted Physical Activity in Patients With Advanced Pancreatic Cancer: The APACaP GERCOR Randomized Trial.

BACKGROUND: The impact of adapted physical activity (APA) on health-related quality of life (HRQoL) in patients with advanced pancreatic ductal adenocarcinoma (aPDAC) is unknown. This study evaluated whether APA in addition to standard care improved HRQoL in patients who have aPDAC who are receiving first-line chemotherapy. PATIENTS AND METHODS: Patients with locally advanced/metastatic PDAC and an ECOG performance status of 0 to 2 were randomized (1:1) to receive standard care (standard arm) or standard care plus a home-based 16-week APA program (APA arm). The primary objective was the effect of the APA program on 3 dimensions of the EORTC QLQ-C30: global health status, physical function, and fatigue at week 16 (W16), with a one-sided type I error of 0.017 for each dimension. The primary HRQoL analysis was performed in patients with available baseline and W16 scores for the dimensions (ie, the modified intention-to-treat population 1 [mITT1]), and secondary longitudinal HRQoL analyses using the mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD) methods were performed in the mITT1 population and in patients with baseline and at least one follow-up questionnaire (mITT2 population). A difference of ≥5 points was considered to be clinically relevant. RESULTS: Of 326 included patients, 313 were randomized to the standard (n=157) or APA (n=156) arms. In the mITT1 population (n=172), the mean differences in global health status, physical function, and fatigue at W16 adjusted from baseline were -0.98 (SD, 23.9; P=.39), -2.08 (SD, 21.3; P=.26), and 4.16 (SD, 29.2; P=.17), respectively, showing a non-statistically significant benefit with APA. In the mITT2 population (n=259), APA was associated with statistically significant and clinically relevant improvement in 5 and 8 dimensions of the HRQoL in the longitudinal MMRM and TUDD analyses, respectively. CONCLUSIONS: APA improved several dimensions of HRQoL in patients with aPDAC receiving first-line chemotherapy and standard care.

Hepatic arterial oxaliplatin plus intravenous 5-fluorouracil and cetuximab for first-line treatment of colorectal liver metastases: A multicenter phase II trial.

BACKGROUND: The efficacy and tolerability of hepatic arterial infusion (HAI) oxaliplatin plus systemic 5-fluorouracil and cetuximab as frontline treatment in patients with colorectal liver metastases (CRLM) are unknown. METHODS: In this multicenter, single-arm phase II study, patients with CRLM not amenable to curative-intent resection or requiring complex/major liver resection, and no prior chemotherapy for metastatic disease, received HAI oxaliplatin and intravenous 5-fluorouracil, leucovorin and cetuximab, every two weeks until disease progression, limiting toxicity or at least 3 months after complete response or curative-intent resection/ablation. The primary endpoint was overall response rate (ORR). RESULTS: 35 patients, mostly with bilateral (89%), multiple CRLM (>4, 86%; >10, 46%) were enrolled in eight centers. The ORR was 88% (95% CI, 71%-96%) among evaluable patients (n = 32), and 95% (95% CI 70-100%) among the 22 wild-type RAS/BRAF evaluable patients. After a median follow-up of 8.8 years (95% CI, 8.7-not reached), median progression-free survival was 17.9 months (95% CI, 15-23) and median overall survival (OS) was 46.3 months (95% CI, 40.0-not reached). 23 of the 35 patients (66%), including 22 (79%) of the 25 patients with wild-type RAS tumor, underwent curative-intent surgical resection and/or ablation of CRLM. HAI catheter remained patent in 86% of patients, allowing for a median of eight oxaliplatin infusions (range, 1-19). Treatment toxicity was manageable, without toxic death. CONCLUSION: HAI oxaliplatin plus systemic 5-fluorouracil and cetuximab appears highly effective in the frontline treatment of patients with unresectable CRLM and should be investigated further.

Ovarian cancer in the older patient: where are we now? What to do next?

In recent years, major advances have been made toward the individualization of epithelial ovarian cancer care, leading to an overall improvement of patient outcomes. However, real-life data indicate that the oldest populations do not benefit from this, due to aspects related to cancer (more aggressive histopathological features), treatment (i.e. frequently suboptimal), and the host (increased toxicities in patients with lower physiological reserve). A specific risk-benefit perspective should therefore be taken when considering surgery, chemotherapy, and maintenance treatments: the decision for cytoreductive surgery should include geriatric vulnerability and surgical complexity, neo-adjuvant chemotherapy being an option when primary surgery appears at high risk; carboplatin paclitaxel association remains the standard even in vulnerable older patients; and bevacizumab and poly(ADP-ribose) polymerase inhibitors maintenance are interesting options provided they are prescribed according to their indications with a close monitoring of their toxicities. Future studies should aim to individualize care without limiting access of older patients to innovation. A specific focus is needed on age-specific translational analyses (focusing on tumor mutational burden and impaired biological pathways), a better patient stratification according to geriatric parameters, an adaptation of both oncological treatment and geriatric interventions, and treatment adaptations not a priori but according to formal pharmacokinetic data.

Associated Factors to Efficacy and Tolerance of Immunotherapy in Older Patients with Cancer Aged 70 Years and Over: Impact of Coprescriptions.

BACKGROUND: Immunotherapy with immune checkpoint blockers (ICB) significantly improves the prognosis for an increasing number of cancers. However, data on geriatric populations taking ICB are rare. OBJECTIVE: This study aimed to identify factors associated with the efficacy and tolerance of ICB in an older population. PATIENTS AND METHODS: This retrospective monocentric study included consecutive patients aged ≥ 70 years with solid cancer who received ICB between January 2018 and December 2019. Efficacy was assessed by progression-free survival (PFS) and tolerance was defined as cessation of immunotherapy due to the occurrence of any adverse event. RESULTS: One hundred and five patients (65.7% men) were included, mainly at the metastatic stage (95.2%); 50.5% had lung cancer. Most (80%) patients were treated with anti-PD1 (nivolumab, pembrolizumab), 19.1% with anti-PD-L1 (atezolizumab, durvalumab, and avelumab) and 0.9% with anti-CTLA4 ICB (ipilimumab). Median PFS was 3.7 months [95% confidence interval (CI) (2.75-5.70)]. PFS was shorter in univariate analysis when ICB was taken concomitantly with an antiplatelet agent (AP) [hazard ratio (HR) = 1.93; 95% CI (1.22-3.04); p = 0.005]. Tolerance was lower in univariate analysis for lung cancer [odds ratio (OR) = 3.03; 95% CI (1.07-8.56), p < 0.05] and in patients taking proton pump inhibitors (PPI) [OR = 5.50; 95% CI (1.96-15.42), p < 0.001]. There was a trend toward poorer tolerance among patients living alone [OR = 2.26; 95% CI (0.76-6.72); p = 0.14]. CONCLUSIONS: In older patients taking ICB for solid cancers, concomitant AP may influence efficacy and concomitant PPI may influence tolerance. Further studies are needed to confirm these results.

Impact of therapeutic strategy on disease-free and overall survival of early-stage cervical cancer: Surgery alone versus preoperative radiation.

BACKGROUND AND OBJECTIVES: There is no international consensus for management of early-stage cervical cancer (ESCC). This study aimed to retrospectively investigate disease-free survival (DFS) and overall survival (OS) in patients with ESCC according to the therapeutic strategy used, surgery alone versus preoperative radiation following by surgery. METHODS: Data were retrospectively collected from 1998 to 2015 using the Gynecological Cancer Registry of the Côte d'Or. The inclusion criteria were FIGO 2018 ≤ IB2; squamous cell carcinoma, adenocarcinoma or adenosquamous type. Survival curves were compared using the log-rank test. RESULTS: One hundred twenty-six patients were included. Median survival was 90 months. There was no significant difference in DFS (HR = 0.91, 95%CI [0.32-2.53], p = 0.858) or in OS between surgery alone versus preoperative radiation following by surgery (HR = 0.97, 95%CI [0.31-2.99], p = 0.961). In the subgroup of patients with stage ≥IB1, there was no significant difference in DFS (HR = 3.26, p = 0.2) or in OS (HR = 3.87, p = 0.2). CONCLUSION: Our study did not identify any difference in survival according to the treatment strategy. Preoperative radiation following by surgery can be an alternative to surgery alone for ESCC.

Impact of complete surgical staging on survival of patients with early-stage (FIGO I or II) ovarian cancer: Data from the Cote d'Or Registry of Gynecological Cancers from 1998 to 2015.

INTRODUCTION: Early-stage ovarian cancer represents 20 to 33% of all ovarian cancers and is thus quite rare in France, with around 1200 new cases per year. No study to date has convincingly demonstrated the utility of lymphadenectomy in early-stage ovarian cancer. We sought to evaluate the impact on overall survival of complete surgical staging in patients management for FIGO stage I and II ovarian cancer. METHODS: We performed a retrospective observational study using data from the Cote d'Or Registry of Gynecological Cancers. We included patients with invasive early stage epithelial ovarian cancer (FIGO stages I and II), diagnosed between 1 January 1998 and 31 December 2015. RESULTS: A total of 179 patients were included in the study. Patients who had lymphadenectomy were younger on average (P<0.001) and had fewer comorbidities (P=0.03). Lymphadenectomy was performed during the first surgery in 59.2% of cases (58 patients) and during a second, re-staging surgery in 40.8% (n=40). When complete surgical staging was performed, the rate of up-staging (to at least FIGO stage III) was 11.2% (11/98). The median follow-up was 8.4 years. At the study, 31.6% patients with complete surgical staging had died and 48.4% patients also died in the group without lymphadenectomy, HR 0.59 CI [0.36-0.97] P<0.04. CONCLUSION: In patients with early-stage ovarian cancer, complete surgical staging appears to yield a benefit in terms of overall survival. In 10 to 15% of cases, it leads to upstaging, with the resultant indication for maintenance therapy, which has also shown a survival benefit.

Quality of life and perceived burden of the primary caregiver of patients aged 70 and over with cancer 5 years after initial treatment.

PURPOSE: Long-term effects of being the primary caregiver of an older patient with cancer are not known. This study aimed to assess health-related quality of life (HRQoL) in primary caregivers of patients aged 70 and older with cancer, 5 years after initial treatment. Secondly, to compare the HRQoL between former primary caregivers whose caregiving relationship had ceased (primary caregiver no longer directly assisting the patient because of patient death or removal to another city or admission to an institution) and current caregivers, and to determine the perceived burden of the primary caregivers. METHODS: Prospective observational study including primary caregivers of patients aged 70 and older with cancer. HRQoL and perceived burden were assessed using the SF-12 and Zarit Burden Interview (ZBI) at baseline and 5 years after initial treatment. RESULTS: Ninety-six caregivers were initially included; at 5 years, 46 caregivers completed the SF-12 and ZBI between June 15 and October 26, 2020. Primary caregiver's HRQoL scores had significantly decreased over time for physical functioning (mean difference = -10, p=0.04), vitality (MD= -10.5, p=0.02), and role emotional (MD= -8.1, p=0.01) dimensions. The comparison at 5 years according to caregiving status showed no difference for all HRQoL dimensions. There was no decrease in perceived burden at 5 years. CONCLUSION: Some dimensions of HRQoL decreased at 5 years with a stable low perceived burden. TRIAL REGISTRATION: NCT04478903.

Adherence to oral anti-cancer therapies in older patients is similar to that of younger patients.

INTRODUCTION: The use of oral anti-cancer therapies is becoming increasingly common in the management of cancers, raising the question of adherence. The objective of this study was to assess adherence to oral anti-cancer therapies, as well as the impact of various factors that may influence it. METHODS: Patients starting oral chemotherapy (tyrosine kinase inhibitor or cytotoxic) were followed up for 3 months using a medication diary, which was given to the patient by the pharmacist during a multidisciplinary consultation. Adherence was assessed using the diary, as well as by counting the tablets they brought back. RESULTS: One hundred and fifty patients were included in the study. The main oral chemotherapy agents prescribed were palbociclib (23.3%), everolimus (18.7%), and capecitabine (13.3%). The adherence at the end of the 3 months, by means of dose intensity (i.e. percent of the dose prescribed that has been taken), was 95.5%. No significant difference in adherence was found based on age, sex, family circumstances, health status, co-medication, type of oral therapy, tumor location, number of previous treatment lines, or presence of toxicity. The main reasons for non-adherence were forgetting (50%) and toxicity (21%). Fifty-seven patients prematurely discontinued the study: 40.3% for toxicity and 36.8% for disease progression. CONCLUSION: Adherence in this study is high in comparison to literature, which can be explained by close multidisciplinary follow-up. Moreover, no significant difference was observed between younger and older patients.

Paclitaxel with or without pazopanib for ovarian cancer relapsing during bevacizumab maintenance therapy: The GINECO randomized phase II TAPAZ study.

BACKGROUND: Anti-angiogenic rechallenge with bevacizumab plus chemotherapy is effective in recurrent ovarian cancer (rOC); however, data are limited on tyrosine kinase inhibitors after progression on maintenance bevacizumab. METHODS: In the randomized phase II TAPAZ trial, patients with rOC during the first year of bevacizumab maintenance therapy were assigned 2:1 to either weekly paclitaxel 65 mg/m2 plus pazopanib 600-800 mg daily or standard weekly paclitaxel 80 mg/m2. The primary endpoint was 4-month progression-free survival (PFS) rate. RESULTS: Overall, 116 patients were randomized and treated: 79 with combination therapy and 37 with single-agent paclitaxel. Median follow-up was 13.1 months. There was no difference between treatment arms in 4-month PFS rate (61% [95% CI, 51-73%] with the combination versus 68% [95% CI, 54-85%] with paclitaxel alone), median PFS (4.9 [95% CI, 4.1-6.1] versus 5.8 [95% CI, 4.8-7.4] months, respectively) or median overall survival (13.6 versus 12.9 months, respectively). The combination was associated with more grade 3/4 toxicities (87% versus 70%, respectively) and toxicity-related paclitaxel discontinuations (22% versus 11%). Pazopanib was discontinued for toxicity in 44% of patients, most commonly for gastrointestinal and vascular events. There were two treatment-related deaths, both in the combination arm (pulmonary embolism and gastrointestinal perforation). At month 4, patient-reported outcomes deteriorated from baseline in the combination arm, particularly for abdominal/gastrointestinal symptoms, which showed a clinically important difference versus paclitaxel alone. CONCLUSIONS: In rOC progressing during maintenance bevacizumab, adding pazopanib to paclitaxel did not improve efficacy, increased toxicity, and compromised chemotherapy delivery. CLINICALTRIALS: govregistration:NCT02383251.

Management and Outcomes of Pancreatic Cancer in French Real-World Clinical Practice.

Background: Our objective was to describe real-world patterns of care and outcomes in pancreatic cancer. Methods: 912 patients diagnosed with pancreatic cancer from 2014 to 2017 were registered by the population-based cancer registry of Burgundy (France). Progression-free and net survival were estimated. Results: at diagnosis, 52% of tumors were associated with metastases. Among the 20% of patients fulfilling resectability criteria, half of those aged 75−84 years and none of those ≥85 years actually underwent resection. Age was not associated with 3-year observed survival in patients who underwent resection. Overall, 77% of patients aged <75 years, 55% of those aged 75−84 years and 8% of those ≥85 years received chemotherapy. Among patients who were offered chemotherapy, 73% of those aged ≥85 years refused. Chemotherapy toxicity was higher with Gemcitabine_Oxaliplatin/Gemcitabine_Abraxane and FOLFIRINOX than with Gemcitabine alone. Patients resected after induction FOLFIRINOX and those treated with adjuvant Gemcitabine presented the lowest risk of progression. Three-year net survival was 35% in patients with non-metastatic resectable tumors and under 10% for other patients. Conclusions: Only half of patients aged 75−84 years with a resectable tumor actually underwent resection. Two thirds of patients aged ≥85 years refused chemotherapy, thus underlining the need to expand geriatric assessments.

Cervical cancer in older women: Does age matter?

OBJECTIVES: Cervical cancer is frequently diagnosed in older women, but few studies have focused on cervical cancer in this specific population. The objectives of this study were to provide an overview of the demographic profile and therapeutic care of women with cervical cancer, and to identify whether age is a prognostic factor. STUDY DESIGN: Retrospective population-based study from a gynecological cancer registry in a French Regional University Hospital and Comprehensive Cancer Center. 292 women diagnosed with cervical cancer between January 1, 2005, and December 31, 2015, were included. They were classified into younger women (YW), that is, under 70 years of age (N = 228), and older women (OW), that is, aged 70 years or more (N = 64). MAIN OUTCOME MEASURES: The primary outcome was overall survival (OS). Cox proportional hazards models were developed to assess the impact of age on OS. RESULTS: Compared with YW, larger proportions of OW had comorbidities (14% vs 7% with a score ≥ 2 on the Charlson Comorbidity Index, P <0.001) and more advanced tumors (37.3% vs 19.7% with FIGO IV, P <0.001); the OW group had a lower treatment rate (81.3% vs 95.6%, P <0.001), and a smaller proportion had undergone surgery (37.5% vs 81.7%, P<.001) but a larger proportion had radiotherapy (67.2% vs 49.6%, P = .01). One-year, 5-year and 10-year OS rates were: 91.6%, 74.1% and 63.9% for YW, and 69.9%, 36.4% and 12.3% for OW, respectively (P <0.001). The hazard ratio for death was twice as high in OW compared with YW with cervical cancer (HR = 2.19 [1.41 - 3.40], P <0.001), independently of FIGO stage, histology, and comorbidities. CONCLUSIONS: The prognosis for cervical cancer depends on age. Screening with the G8 tool followed by a comprehensive geriatric assessment could lead to more suitable treatment being offered to older patients.

Parallel evolution and differences in seroprevalence of SARS-CoV-2 antibody between patients with cancer and health care workers in a tertiary cancer centre during the first and second wave of COVID-19 pandemic: canSEROcov-II cross-sectional study.

BACKGROUND: Patients with cancer are a population at high risk of severe infection from SARS-CoV-2. Patients with cancer regularly attend specialised healthcare centres for management and treatment, where they are in contact with healthcare workers (HCWs). Numerous recommendations target both patients with cancer and HCWs to minimise the spread of SARS-CoV-2 during these interactions. OBJECTIVE: To investigate the parallel evolution of the COVID-19 epidemic in these 2 populations over time, we studied the seroprevalence of anti-SARS-CoV-2 antibodies after both the first and second waves of the pandemic, and in both cancer patients and HCWs from a single specialised anti-cancer centre. Factors associated with seropositivity were identified in both populations. METHODS: We conducted a cross-sectional study after the second wave of the COVID pandemic in France. All participants were invited to undergo serological testing for SARS-CoV-2 and complete a questionnaire collecting data about their working conditions (for HCWs) or medical management (for patients) during this period. Results after the second wave were compared to those of a previous study among 1011 patients with cancer and 663 HCWs performed in the same centre after the first wave, using the same evaluations. FINDINGS: We included 502 HCWs and 507 patients with cancer. Seroprevalence of anti-SARS-CoV-2 antibodies was higher after the second wave than after the first wave in both HCWs (15.1% versus 1.8%; p < 0.001), and patients (4.1% versus 1.7%; p = 0.038). By multivariate analysis, the factors found to be associated with seropositivity after the second wave for HCWs were: working in direct patient care (p = 0.050); having worked in a dedicated COVID-19 unit (p = 0.0036); contact with a person with COVID-19-positive in the workplace (p = 0.0118) or outside of the workplace (p = 0.0297). Among patients with cancer, only a contact with someone who tested positive for COVID-19 was found to be significantly associated with positive serology. The proportion of reported contacts with individuals with COVID-19-positive was significantly lower among patients with cancer than among HCWs (7.6% versus 40.7%, respectively; p < 0.0001) INTERPRETATION: Between the first and second waves of the epidemic in France, the seroprevalence of anti-SARS-CoV-2 antibodies increased to a lesser extent among patients with cancer than among their HCWs, possibly due to better self-protection, notably social distancing. The risk factors for infection identified among HCWs plead in favour of numerous intra-hospital contaminations, especially for HCWs in contact with high-risk patients. This underlines the compelling need to pursue efforts to implement strict hygiene and personal protection measures (including vaccination) to protect HCWs and patients with cancer.

Surgical treatment of digestive cancer in a well-defined elderly population.

INTRODUCTION: Digestive cancer is of concern because of its frequency and severity with an increasing older median age of onset. The purpose of this study was to describe in a well-defined population presenting with non-metastatic digestive cancer the frequency of surgical resection and outcomes according to age. PATIENTS AND METHODS: We analyzed 7760 patients with a non-metastatic digestive cancer, recorded in the Burgundy population-based digestive cancer registry between 2009 and 2017. There were 3506 non-colorectal cancers and 4254 colorectal cancers with 3292 colon and 962 rectal cancers. The frequency of surgical resection was analyzed according to age (classified into four categories <70, [70-80[, [80-85[, and ≥85), sex, comorbidities and obesity. Postoperative mortality at 30 and 90 days was determined according to age, sex, comorbidity, obesity, location, surgery R0 or not. The 5-year survival study included 2952 patients with colorectal cancer, non-metastatic and who benefited from an R0 resection. RESULTS: Overall, 64% of the patients with M0 digestive cancer underwent a surgical resection, varying from 31% for Non colorectal Digestive cancers to 94% for colon site. The percentage of patients operated on for a resectable disease decreases from 71% before age 70 to 43% from age 85. Age and comorbidities were the main criteria influencing the probability of resection. At 30 days, postoperative mortality was 3%, all localizations and ages combined. At 90 days, this rate was 5%. In patients over 85 years old it gradually increases from 7% at 30 days and to 10% at 90 days. A man under 70 years of age has a net survival of 0.88 at 5 years, and 0.91 for a woman. For a man between 70 and 80 years old, it decreases to 0.81 and to 0.66 from 80 years old. In women, net survival is 0.87 between 70 and 80 years of age at 5 years, then drops to 0.75 from age 80. CONCLUSION: Our study shows a drop in access to surgery at different pivotal ages depending on the tumor location. This sudden drop in the resection rate is not justified by the increase in mortality with age, which is linear. In addition, the expected benefits of surgery are significant, with a net survival, mainly after the 1st year, of the same order as for younger patients. Age by itself should not be the only criterion in the medical decision. The challenge is to detect and treat the comorbidities that worsen the operative risk and the prognosis. There are few data on the management of digestive cancers specifically in the elderly. Our study shows that access to surgery is strongly linked to age and this in a non-linear way, whereas the expected benefits of surgery are significant, of the same order as for younger patients. Age itself should not be the only criterion in the medical decision.

Phase I Dose-Escalation Trial of an Innovative Chemotherapy Regimen Combining a Fractionated Dose of Irinotecan Plus Bevacizumab, Oxaliplatin, 5-Fluorouracil, and Folinic Acid (bFOLFIRINOX-3) in Chemorefractory Metastatic Colorectal Cancer.

The care of metastatic colorectal cancers is based on combination chemotherapies including 5-fluorouracil, oxaliplatin, irinotecan, and monoclonal antibodies targeting the epidermal growth factor receptor or vascular endothelial growth factor. The regimen is determined based on the patient's molecular biology and general condition. Irinotecan bifractionation showed efficacy in chemorefractory patients in a previous study, FOLFIRI-3, but a desynchronized triplet has never been tested. The aim of bFOLFIRINOX-3 is to determine the safety, tolerance, and efficacy of a new regimen (FOLFIRINOX-3 bevacizumab) in chemorefractory patients. The aim of this study was to evaluate the safety and efficacy of FOLFIRINOX-3 bevacizumab in chemorefractory metastatic colorectal cancer (mCRC). A standard phase I, "3 + 3" design study was performed. The standard protocol comprised simplified FOLFOX 4 (folinic acid 400 mg/m2), 5-fluorouracil (a 400 mg/m2 bolus followed by 2400 mg/m2 for 46 h), oxaliplatin (85 mg/m2) and irinotecan (administered before and after 5-fluorouracil infusion), plus bevacizumab (5 mg/kg). In a "3 + 3" design, three different doses of irinotecan were tested: 60, 70 and 90 mg/m2. The primary endpoint was the maximum tolerable dose (MTD) of irinotecan. The secondary endpoints included the objective response (at 8 and 16 weeks) according to the RECIST 1.1 criteria and progression free survival. Thirteen patients were enrolled, and twelve patients were finally evaluated for dose-limiting toxicity (DLT). The dose level defined was 70 mg/m2 irinotecan. A total of three DLTs were observed (grade 3 diarrhea): two DLTs at the 90 mg/m2 dose level and one at the 70 mg/m2 dose level. The most frequently described adverse events were asthenia (93%), diarrhea (77%), nausea (62%) and peripheral sensory neuropathy (46%). The most frequent biological event was thrombopenia (54%). Regarding efficacy, among the 11 evaluable patients, no progression was observed at 8 weeks, and the partial response rate was 18.2%. At 16 weeks, a partial response rate of 27.3% was observed, and five patients had a stable disease. The new regimen of bFOLFIRINOX-3 with irinotecan at 70 mg/m2 was well tolerated. In chemorefractory patients, this protocol shows a high response rate.

Seroprevalence of SARS-CoV-2 among the staff and patients of a French cancer centre after first lockdown: The canSEROcov study.

BACKGROUND: In view of the potential gravity of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection for patients with cancer, epidemiological data are vital to assess virus circulation among patients and staff of cancer centres. We performed a prospective study to investigate seroprevalence of SARS-CoV-2 antibodies among staff and patients with cancer at a large cancer centre, at the end of the period of first national lockdown in France and to determine factors associated with the risk of SARS-CoV-2 infection. METHODS: After the first lockdown, all medical and non-medical staff, as well as all patients attending the medical oncology department were invited to undergo serological testing for SARS-CoV-2 between 11 May and 30 June 2020. All participants were also invited to complete a questionnaire collecting data about their living and working conditions, and for patients, medical management during lockdown. FINDINGS: A total of 1,674 subjects (663 staff members, 1011 patients) were included. Seroprevalence was low in both staff (1.8%) and patients (1.7%), despite more features of high risk for severe forms among patients. None of the risk factors tested in our analysis (working or living conditions, comorbidities, management characteristics during lockdown) was found to be statistically associated with seroprevalence in either staff or patients. There was no significant difference in the proportion of symptomatic and asymptomatic subjects between staff and patients. Only fever, loss of smell, and loss of taste were significantly more frequent among seropositive patients, in both staff and patients. INTERPRETATION: We report very low seroprevalence of antibodies against SARS-CoV-2 in the staff (caregiving and non-caregiving) and patients of a large cancer care centre in which strict hygiene, personal protection, and social distancing measures were implemented.

Long-term quality of life and sexual function of elderly people with endometrial or ovarian cancer.

BACKGROUND: With the growing number of older endometrial cancer (EC) and ovarian cancer (OC) survivors, data on long-term health-related quality of life (HRQoL) became an important issue in the management of older patients. So, the aim of this study was to describe and compare according to age long-term HRQoL, sexual function, and social deprivation of adults with either EC or OC. METHODS: A cross-sectional study was set up using data from the Côte d'Or gynecological cancer registry. A series of questionnaires assessing HRQoL (SF-12), sexual function (FSFI), anxiety/depression (HADS), social support (SSQ6) and deprivation (EPICES) were offered to women with EC or OC diagnosed between 2006 and 2013. HRQoL, sexual function, anxiety/depression, social support and deprivation scores were generated and compared according to age (< 70 years and ≥ 70 years). RESULTS: A total of 145 women with EC (N = 103) and OC (N = 42) participated in this study. Fifty-six percent and 38% of EC and OC survivors respectively were aged 70 and over. Treatment did not differ according to age either in OC or EC. The deprivation level did not differ between older and younger survivors with OC while older survivors with EC were more precarious. The physical HRQoL was more altered in older EC survivors. This deterioration concerned only physical functioning (MD = 24, p = 0.012) for OC survivors while it concerned physical functioning (MD = 30, p < 0.0001), role physical (MD = 22, p = 0.001) and bodily pain (MD = 21, p = 0.001) for EC survivors. Global health (MD = 11, p = 0.011) and role emotional (MD = 12, p = 0.018) were also deteriorated in elderly EC survivors. Sexual function was deteriorated regardless of age and cancer location with a more pronounced deterioration in elderly EC survivors for desire (p = 0.005), arousal (p = 0.015) and orgasm (p = 0.007). Social support, anxiety and depression were not affected by age regardless of location. CONCLUSION: An average 6 years after diagnosis, the impact of cancer on HRQoL is greatest in elderly survivors with either EC or OC.

PARP inhibitor resistance and TP53 mutations in patients treated with olaparib for BRCA-mutated cancer: Four case reports.

Loss­of­function BRCA mutations are frequent in high­grade serous ovarian carcinoma. BRCA1 and ­2 mutations lead to homologous recombination (HR) deficiency. Poly(ADP­ribose) polymerases (PARP) are enzymes involved in DNA repair. PARP inhibitors (PARPi) lead to DNA damage accumulation in cells deficient in HR. Olaparib (a PARPi) is currently used for the treatment of high­grade serous ovarian carcinoma with germline or somatic BRCA mutations; however, numerous patients do not respond or eventually develop resistance to these agents. The TP53 gene encodes the p53 protein, which is often referred to as the 'guardian of the genome'. TP53 mutations at diagnosis are known to promote resistance to chemotherapy. In the present study, four cases of patients with BRCA­mutated cancer treated with olaparib, who progressed following the PARPi treatment, are reported. Exome analyses were performed on a primary tumor biopsy at diagnosis, then on a progressing metastasis following olaparib treatment. Exome analyses following olaparib treatment identified de novo TP53 mutations, as well as increased frequencies of pre­existing TP53 mutations compared with the primary tumor. In HCT116 TP53­/­ cells carrying BRCA2 pathogenic mutations, TP53 inactivating mutations were associated with lower sensitivity to olaparib in vitro. Thus, inactivating TP53 mutations may be associated to olaparib resistance in the presence of BRCA mutations. In conclusion, the present findings demonstrated resistance to PARPi with de novo TP53 mutations that may be clinically relevant. As TP53 mutations are easily detectable with targeted next­generation sequencing panels, these may serve as surrogate markers for the onset of PARPi resistance in the context of routine patient management strategies.

Association of 5-FU Therapeutic Drug Monitoring to DPD Phenotype Assessment May Reduce 5-FU Under-Exposure.

In order to limit 5-fluorouracil (5-FU) toxicity, some health agencies recommend evaluating dihydropyrimidine dehydrogenase (DPD) deficiency before any 5-FU treatment introduction. In our study, we investigated relationships between 5-FU clearance and markers of DPD activity such as uracilemia (U), dihydrouracilemia (UH2)/U ratio, or genotype of the gene encoding DPD (DPYD). All patients with gastrointestinal cancers who received 5-FU-based regimens form March 2018 to June 2020 were included in our study. They routinely benefited of a pre-therapeutic DPYD genotyping and phenotyping. During 5-FU infusion, blood samples were collected to measure 5-FU steady-state concentration in order to adapt 5-FU doses at the following cycles. A total of 169 patients were included. Median age was 68 (40-88) years and main primary tumor sites were colorectal (40.8%) and pancreas (31.4%), metastatic in 76.3%. 5-FU was given as part of FOLFIRINOX (44.4%), simplified FOLFOX-6 (26.6%), or docetaxel/FOLFOX-4 (10.6%). Regarding DPD activity, median U and UH2/U were, respectively, 10.8 ng/mL and 10.1, and almost 15% harbored a heterozygous mutation. On the range of measured U and UH2/U, no correlation was observed with 5-FU clearance. Moreover, in patients with U < 16 ng/mL, 5-FU exposure was higher than in other patients, and most of them benefited of dose increase following 5-FU therapeutic drug monitoring (TDM). If recent guidelines recommend decreasing 5-FU dose in patients harboring U ≥ 16 ng/mL, our study highlights that those patients are at risk of under-exposure and that 5-FU TDM should be conducted in order to avoid loss of efficacy.

Impact of granulocyte colony-stimulating factor on FOLFIRINOX-induced neutropenia prevention: A population pharmacokinetic/pharmacodynamic approach.

AIMS: Granulocyte colony-stimulating factor (G-CSF) is frequently prescribed to prevent chemotherapy-induced neutropenia, but the administration schedule remains empirical in case of bimonthly chemotherapy such as FOLFIRINOX regimen. This pharmacokinetic/pharmacodynamic (PK/PD) study was performed to determine the effect of different G-CSF regimens on the incidence and duration of neutropenia following FOLFIRINOX administration in order to propose an optimal G-CSF dosing schedule. METHODS: A population PK/PD model was developed to describe individual neutrophil time course from absolute neutrophil counts (ANC) obtained in 40 advanced cancer patients receiving FOLFIRINOX regimen. The structural model considered ANC dynamics, neutropenic effect of cytotoxics and the stimulating effect of G-CSF on neutrophils. Final model estimates were used to simulate different G-CSF dosing schedules for 1000 virtual subjects. The incidence and duration of neutropenia were then calculated for different G-CSF dosing schedules. RESULTS: The final model successfully described the myelosuppressive effect induced by the 3 cytotoxics for all patients. Simulations showed that pegfilgrastim administration reduced the risk of severe neutropenia by 22.9% for subjects with low ANC at the start of chemotherapy. Median duration in this group was also shortened by 3.1 days when compared to absence of G-CSF. Delayed G-CSF administration was responsible for higher incidence and longer duration of neutropenia compared to absence of administration. CONCLUSION: The PK/PD model well described our population's ANC data. Simulations showed that pegylated-G-CSF administration 24 hours after the end of chemotherapy seems to be the optimal schedule to reduce FOLFIRINOX-induced neutropenia. We also underline the potential negative effect of G-CSF maladministration.