Advanced prescription of injectable anticancer drugs: Safety assessment in a European Comprehensive Cancer Centre using the risk matrix approach.

AIMS: The purpose of this work was to assess failures in the advanced prescription of parenteral anticancer agents in an adult day oncology care unit with more than 100 patients per day. METHODS: An a priori descriptive analysis was carried out by using the risk matrix approach. After defining the scope in a multidisciplinary meeting, we determined at each step the failure modes (FMs), their effects (E) and their associated causes (C). A severity score (S) was assigned to all effects and a probability of occurrence (O) to all causes. These S and O indicators, were used to obtain a criticality index (CI) matrix. We assessed the risk control (RC) of each failure in order to define a residual criticality index (rCI) matrix. RESULTS: During risk analysis, 14 FMs were detected, and 61 scenarios were identified considering all possible effects and causes. Nine situations (15%) were highlighted with the maximum CI, 18 (30%) with a medium CI, and 34 (55%) with a negligible CI. Nevertheless, among all these critical situations, only three (5%) had an rCI to process (i.e., missed dose adjustment, multiple prescriptions and abnormal biology data); the others required monitoring only. Clinicians' and pharmacists' knowledge of these critical situations enables them to manage the associated risks. CONCLUSIONS: Advanced prescription of injectable anticancer drugs appears to be a safe practice for patients when combined with risk management. The major risks identified concerned missed dose adjustment, prescription duplication and lack of consideration for abnormal biology data.

FOLFIRI plus BEvacizumab or aFLIbercept after FOLFOX-bevacizumab failure for COlorectal cancer (BEFLICO): An AGEO multicenter study.

After failure of first line FOLFOX-bevacizumab for metastatic colorectal cancer (mCRC), adding either bevacizumab or aflibercept to second-line FOLFIRI increases survival compared to FOLFIRI alone. In this French retrospective multicentre cohort, we included patients with a mCRC treated with either FOLFIRI-aflibercept or FOLFIRI-bevacizumab. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS), disease control rate (DCR: CR + PR + SD) and safety. We included 681 patients from 36 centers, 326 and 355 in the aflibercept and bevacizumab groups, respectively. Median age was 64.2 years and 45.2% of patients were men. Most patients had RAS-mutated tumors (80.8%) and synchronous metastases (85.7%). After a median follow up of 31.2 months, median OS was 13.0 months (95% CI: 11.3-14.7) and 10.4 months (95% CI: 8.8-11.4) in the bevacizumab and aflibercept groups, respectively (P < .0001). Median PFS was 6.0 months (95% CI: 5.4-6.5) and 5.1 months (95% CI: 4.3-5.6) (P < .0001). After adjustment on age, PS, PFS of first line, primary tumor resection, metastasis location and RAS/BRAF status, bevacizumab was still associated with better OS (HR: 0.71, 95% CI: 0.59-0.86, P = .0003). FOLFIRI-bevacizumab combination was associated with longer OS and PFS, and a better tolerability, as compared to FOLFIRI-aflibercept after progression on FOLFOX-bevacizumab.

Prospective Evaluation of Ultrafast Breast MRI for Predicting Pathologic Response after Neoadjuvant Therapies.

Background Ultrafast dynamic contrast-enhanced (DCE) MRI parameters are associated with breast cancer aggressiveness. However, the role of these parameters as predictive biomarkers for pathologic response after neoadjuvant chemotherapy (NAC) has been poorly investigated. Purpose To assess whether semiquantitative perfusion parameters calculated at initial ultrafast DCE MRI are associated with early prediction for pathologic response after NAC in participants with breast cancer. Materials and Methods This prospective single-center study included consecutive women with nonmetastatic invasive breast cancer treated with NAC followed by surgery who underwent initial ultrafast DCE MRI between December 2020 and August 2021. Six semiquantitative ultrafast DCE MRI parameters were calculated for each participant from the fitted time-signal intensity curve. Multivariable logistic regression was used to identify independent predictors of pathologic complete response (pCR) and residual cancer burden (RCB). Results Fifty women (mean age, 49 years ± 12 [SD]) were included in the study; 20 achieved pCR and 25 achieved low RCB (RCB-0 and I). A wash-in slope (WIS) cutoff value of 1.6% per second had a sensitivity of 94% (17 of 18 participants) and a specificity of 59% (19 of 32 participants) for pCR. A WIS of more than 1.6% per second (odds ratio [OR], 8.4 [95% CI: 1.5, 48.2]; P = .02), human epidermal growth factor receptor 2 (HER2) positivity (OR, 6.3 [95% CI: 1.5, 27.4]; P = .01), and tumor-infiltrating lymphocytes of more than 10% (OR, 6.9 [95% CI: 1.3, 37.7]; P = .03) were independent predictive factors of pCR. The area under the receiver operating characteristic curve of the three-component model, which included WIS, tumor-infiltrating lymphocytes, and HER2 positivity, was 0.92 (95% CI: 0.84, 0.99). A WIS of more than 1.6% per second was associated with higher pCR rates in the HER2-positive (OR, 21.7 [95% CI: 1.8, 260.6]; P = .02) breast cancer subgroup. For luminal HER2-negative and triple-negative breast cancers, a WIS of more than 1.6% per second was associated with low RCB (OR, 11.0 [95% CI: 1.1, 106.4]; P = .04). Conclusion The wash-in slope (WIS) assessment at initial ultrafast dynamic contrast-enhanced MRI may be used to predict pathologic complete response (pCR) in participants with breast cancer. The WIS value was used to identify two subsets of human epidermal growth factor receptor 2-positive cancers with distinct pCR rates. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Lee and Moy in this issue.

Clinical factors associated with prolonged response and survival under olaparib as maintenance therapy in BRCA mutated ovarian cancers.

OBJECTIVE: To investigate clinical factors associated with prolonged progression-free survival (PFS) and overall survival (OS) in relapsing epithelial ovarian cancer (EOC) patients with BRCA mutations and receiving olaparib as maintenance therapy in daily practice. METHODS: Multicenter (8 hospitals) European retrospective study of relapsing EOC patients having germline or somatic mutations of BRCA1/BRCA2 genes and treated with olaparib as maintenance therapy after platinum-based chemotherapy. RESULTS: One hundred and fifteen patients were included. Median age was 54 years. There were 90 BRCA1 carriers, 24 BRCA2 carriers and one patient had germline mutation of BRCA1 and BRCA2. Six patients had somatic mutations (all BRCA1) and 109 had germline mutations. Ninety percent had serous carcinomas and were platinum-sensitive. Following ultimate platinum-based chemotherapy, 69% of the patients had normalization of CA-125 levels and 87% had RECIST objective responses, either partial (53%) or complete (34%). After a median follow-up of 21 months, median PFS was 12.7 months and median OS was 35.4 months. In multivariate analysis, factors associated with prolonged PFS under olaparib were: platinum-free interval (PFI) ≥ 12 months, RECIST complete response (CR) or partial response (PR) and normalization of CA-125 upon ultimate platinum-based chemotherapy. Factors associated with prolonged OS were PFI ≥ 12 months, CR and normalization of CA-125. CONCLUSIONS: Platinum-free interval ≥ 12 months, complete response and normalized CA-125 levels after ultimate platinum-based chemotherapy are associated with prolonged PFS and OS in relapsing BRCA1/BRCA2 mutated ovarian cancer patients who received olaparib as maintenance therapy.

Sacituzumab govitecan in metastatic triple-negative breast cancer patients treated at Institut Curie Hospitals: efficacy, safety, and impact of brain metastases.

BACKGROUND: Sacituzumab govitecan (SG) has been approved by FDA in April 2021 for pre-treated metastatic triple-negative breast cancer (mTNBC), following the ASCENT trial results. METHODS: We set up an ambispective bicentric cohort study to assess the real-world effectiveness and safety of SG in patients with mTNBC treated at Institut Curie Hospitals, with a focus on patients with brain metastases. RESULTS: This study included 99 patients treated through the French Early Access Program to SG from May 2021 to January 2023. Median age was 55 years [26-89], N = 8 patients (8%) had BRCA1/2 mutation, N = 12 (12%) de novo stage IV disease and N = 31 (31%) brain metastases. Patients had previously received a median of two [1-10] lines of treatment in advanced setting. After a median follow-up of 9.7 months, the median progression-free survival (PFS) and overall survival (OS) were 3.9 months (95%CI[3.4-5.0]) and 8.6 months (95%CI[7.1-11.9]), respectively, while objective response rate was 29% (95%CI[21-39]). Among patients with brain metastases, median PFS and OS were 3.7 months (95%CI[2.6-6.2]) and 6.7 months (95%CI[6.3-NR]), respectively, with intracranial tumor responses. Dose reductions were required in N = 17 patients (17%) within a median of three [2-11] cycles, due to gastrointestinal toxicity (N = 6; 6%), hematological toxicity (N = 9; 9%) including febrile neutropenia (N = 2; 2%), liver enzyme elevation (N = 1; 1%), and physical deterioration (N = 1; 1%). There was no related death to SG. CONCLUSIONS: The observed response rate and safety of SG are consistent with the results of the ASCENT trial, with efficacy observed in patients with brain metastases, but observed PFS and OS are numerically shorter.

Errors in prescribing injectable anticancer drugs: benefits of a pharmaceutical long-term monitoring to improve patient safety in a European comprehensive cancer centre.

OBJECTIVES: We aimed to assess the impact of pharmacist interventions on injectable chemotherapy prescription and the safety of early prescription practice in an adult daily care unit. METHODS: Prescription errors were recorded before and after implementing corrective measures. Errors identified from the pre-intervention period (i) were analysed to identify areas for improvement. During the post-intervention period (ii) we compared the errors in anticipated prescription (AP) with those in real-time prescriptions (RTP). We performed Chi-square statistical tests (α=0.05). RESULTS: Before implementing corrective measures (i), 377 errors were recorded (ie, 3.02% of prescriptions). After the implementation of corrective measures (ii), there was a significant decrease in errors, with 94 errors recorded (ie, 1.20% of prescriptions). The error rate in AP and RTP groups was 1.34% and 1.02%, respectively, without a significant difference between the two groups. CONCLUSIONS: This study highlights the importance of prescription review, as well as collaboration between pharmacists and physicians, in reducing prescription errors, whether these prescriptions were anticipated or not.

DCF versus doublet chemotherapy as first-line treatment of advanced squamous anal cell carcinoma: a multicenter propensity score-matching study.

Triplet DCF (docetaxel, cisplatin and 5-flurouracil) and doublet CP/CF (carboplatin and paclitaxel/cisplatin and 5-fluorouracil) regimens were prospectively evaluated in advanced squamous anal cell carcinoma (SCCA), and validated as standard treatments. Even though the high efficacy and good tolerance of DCF regimen were confirmed in 3 independent prospective trials, doublet CP regimen is still recommended in several guidelines based in its better safety profile with similar efficacy compared to CF regimen. We performed a propensity score-adjusted method with inverse probability of treatment weighted (IPTW) and matched case control (MCC) comparison among patients with metastatic or non-resectable locally advanced recurrent SCCA, treated with chemotherapy as first line regimen. The primary endpoint was the overall survival (OS), and the secondary endpoint was the progression-free survival (PFS). 247 patients were included for analysis. 154 patients received DCF and 93 patients received a doublet regimen. The median OS was 32.3 months with DCF and 18.3 months with doublet regimens (HR 0.53, 95%CI 0.38-0.74; p = 0.0001), and the median PFS was 11.2 months with DCF versus 7.6 months with doublet regimens (HR 0.53, 95%CI 0.39-0.73; p < 0.0001). The hazard ratios by IPTW and MCC analyses were 0.411 (95% CI, 0.324-0.521; p < 0.0001) and 0.406 (95% CI, 0.261-0.632; p < 0.0001) for OS, and 0.466 (95% CI, 0.376-0.576; p < 0.0001) and 0.438 (95% CI, 0.298-0.644; P < 0.0001) for PFS. The triplet DCF regimen provides a high and significant benefit in OS and PFS over doublet regimens, and should be considered as upfront treatment for eligible patients with advanced SCCA.

Atezolizumab and paclitaxel as first line therapy in advanced triple-negative breast cancer patients included in the French early access program.

Following the results of the IMpassion130 trial, an early access program (EAP) was opened in France, allowing patients with PD-L1-positive advanced triple negative breast cancer (aTNBC) to receive a combination of paclitaxel and atezolizumab as first line therapy. This EAP was later discontinued when the IMpassion131 trial read out with negative results. We performed a retrospective multicentric analysis in patients who were prospectively enrolled in the French EAP. Efficacy and toxicity data were obtained on 64 patients treated from August 2019 to August 2020 in 10 French cancer centers. Median progression-free survival (PFS) and overall survival (OS) were 4.1 months (95% CI [3.0-5.8]) and 17.9 months (95% CI [12.4-NR]), respectively. The 6-months PFS rate was 28% (95% CI [16-40%]) (N = 18/64), while N = 33/64 patients (52%, 95% CI [38-63%]) experienced a tumor response. Exploratory subgroup analyses retrieved that corticosteroid use at inclusion in the EAP, before treatment initiation, was the only independent unfavorable prognostic factor for PFS (HR 2.7, 95% CI [1.3-5.6]). No new safety signal was observed. This real-life study, unique by its setting (EAP granted by anticipation and later withdrawn), suggests atezolizumab and paclitaxel has a limited efficacy in PD-L1-positive aTNBC, especially in patients receiving corticosteroids as comedication before treatment start.

[COVID-19 and patients with cancer: Experiment of a French comprehensive cancer center]. / Première vague COVID-19 : expérience d'un centre de lutte contre le cancer.

The emergence of the Coronavirus Disease 2019 (COVID-19) has caused profound upset in health systems around the world. As cancer patients seem to be at greater risk, the organization of oncological care had to be adapted. We first report the progress of the "first wave" of COVID-19 at the Institut Curie, a French comprehensive cancer center, by describing the measures implemented to limit the risk of transmission of COVID-19 while ensuring as much as possible the continuation of anticancer treatments. Then, we present the results of a prospective institutional database in which the characteristics and outcome of our patients with cancer and suffering from COVID-19 were collected. From March 13 to April 25, 2020, 141 patients followed at Institut Curie for cancer developed COVID-19, of which 26 (18%) died from it. The minimum incidence of COVID-19 in Institut Curie is estimated at 1.4% over this period. No risk factors for developing a severe form of COVID-19 related to cancer have been identified. Cancer patients do not appear to be at greater risk of developing COVID-19, nor of having a more severe form than the general population. With the current increase of COVID-19 cases, it seems essential to share the experience already acquired to minimize the impact of this crisis on the long-term outcome of patients followed for cancer.

Dissociated Responses in Patients with Metastatic Solid Tumors Treated with Immunotherapy.

BACKGROUND: Immune checkpoint inhibitors have been demonstrated to improve overall survival. Atypical patterns of response have been reported, including dissociated response (DR). We evaluated the prevalence of DR. PATIENTS AND METHODS: Patients had to have a baseline computed tomography (CT) scan and at least one follow-up CT scan and two target lesions (TLs). Three types of DR were evaluated using RECIST1.1: DR1, defined as at least one progressive and one responding TL; DR2, defined as at least one progressive and one stable TL; and DR3, defined as at least one stable and one responding TL. RESULTS: A total of 1244 measurements of 272 TLs were performed in 100 patients. Forty-nine out of the 272 TLs (18%) had received old or recent radiotherapy, and 42 (15%) had been biopsied. An objective response was observed in 22 patients (22%) and on 52 TLs (19%). DR1 were observed in 8% of patients. At the tumor measurement level, the response rate was lower in the case of prior radiotherapy (29% vs 34%, p = 0.01) and higher in the case of prior biopsy (40% vs 32%, p = 0.02). CONCLUSIONS: A DR was observed in 8% of patients. Response rate was lower in the case of prior radiotherapy and higher in the case of prior biopsy.

Advanced cancer and COVID-19 comorbidity: medical oncology-palliative medicine ethics meetings in a comprehensive cancer centre.

OBJECTIVES: In managing patients with cancer in the COVID-19 era, clinical oncologists and palliative care practitioners had to face new, disrupting and complex medical situations, challenging the quality of the shared decision-making process. During the first lockdown in France, we developed an onco-palliative ethics meeting to enhance the quality of the decision-making process for patients with advanced cancer treated for COVID-19. METHODS: A least one of the institutional ethics committee members was present along with oncologists, palliative care teams, psycho-oncologists, radiologists and intensive care specialists. Specific medical parameters were systematically collected to form a standardised framework for the discussions. RESULTS: The main raised issues were the definition of new criteria for the implementation of invasive resuscitation techniques, optimal ways to adapt or delay anticancer treatment and best procedures to address terminal respiratory failure and end-of-life care. The main clinical and ethical guidelines that emerged during these debates are presented. The palliative care team played a major role in assessing and reporting patients' awareness of cancer-related prognosis and their wishes concerning invasive therapies or transfer to intensive care units, enabling an individualised benefit-risk balance assessment. The ethics committee members ensured continuous monitoring during the discussions. Their function was to recall the main ethical principles including dignity, which is conferred on people when there are treated as having equal status. CONCLUSIONS: The onco-palliative ethics meeting provided a powerful avenue for improvement of collegiality and reinforcement of teamwork, which could be a major protection against burnout for healthcare professionals facing an epidemic onslaught.

Comparative Analysis of Durable Responses on Immune Checkpoint Inhibitors Versus Other Systemic Therapies: A Pooled Analysis of Phase III Trials.

PURPOSE: Immune checkpoint inhibitors (ICIs) have been demonstrated to improve overall survival (OS) in several tumor types. Durable responses have been reported with these agents in patients with melanoma and lung cancer. We aimed to quantify the proportion of patients who experience durable responses on ICIs and to compare it with other drug classes. PATIENTS AND METHODS: We retrieved published phase III randomized trials that included at least one ICI arm in the recurrent and/or metastatic setting. A durable response to treatment was defined as a progression-free survival that exceeded three times the median progression-free survival of the whole population. The proportion of patients who experienced an OS that exceeded two times the median OS of the whole patient population also was estimated. RESULTS: Nineteen studies involving 11,640 patients treated in 42 treatment arms (26 ICI and 16 non-ICI arms) were included. The mean proportion of patients who experienced a durable response was 2.3 times higher in those treated with an ICI compared with those treated in the control arms (25% v 11%). Durable responses were more frequent in patients treated with anti-PD-1/PD-L1 agents than in patients treated with anti-CTLA-4 agents (28% v 18%). The mean proportion of patients who had an OS that exceeded two times the median OS was also higher in those treated with ICIs than in those treated in the control arms (30% v 23%). In multivariable analysis, the effects of treatment with anti-PD-1/PD-L1 agents and of first-line treatment were statistically associated with a higher mean proportion of durable responses. CONCLUSION: Durable responses were more frequent in patients treated with ICIs, although they also occurred in patients treated with other drug classes.

[Fluoropyrimidines cardiac toxicity: 5-fluorouracil, capecitabine, compound S-1 and trifluridine/tipiracil]. / La toxicité cardiaque des fluoropyrimidines : 5-fluorouracile, capécitabine, le composé S-1 et le trifluridine/tipiracil.

The incidence of cardiac toxicity of 5-flurorouracil (5-FU) IV and capecitabine varies from 1.2 to 18%. The physiopathology of this toxicity is still under study, various hypotheses are mentioned. In the absence of identified prophylactic treatment, reintroduction of this cytotoxic is at risk. A discussion between oncologists and cardiologists is essential to estimate the balance between benefit and risk and the careful reintroduction of treatment. An alternative compound might be raltitrexed which is currently the treatment recommended in case of intolerance to fluoropyrimidines. The compound S-1 does not have any cardiac toxicity. Of a total of 2910 patients in phase II or III studies, no grade III or IV cardiovascular events were reported. However, the treatment is not reimbursed in France and therefore not available. The trifluridine/tipiracil, for which approval from French authorities was obtained in November 2016 for patients with metastatic colorectal cancer in progress despite standard treatment lines, does not appear to have cardiac toxicity according to studies published to date. The pivotal phase III study (RECOURSE), that led to this marketing authorization, was performed in 800 patients with metastatic colorectal cancer refractory and only one patient (less than 1% of patients) treated with trifluridine/tipiracil presented an episode of cardiac ischemia. Thus, trifluridine/tipiracil, which is well tolerated, could be an alternative to raltitrexed for patients with cardiovascular history contraindicating or discouraging the use of fluoropyrimidines.

Relevance of a molecular tumour board (MTB) for patients' enrolment in clinical trials: experience of the Institut Curie.

BACKGROUND: High throughput molecular screening techniques allow the identification of multiple molecular alterations, some of which are actionable and can be targeted by molecularly targeted agents (MTA). We aimed at evaluating the relevance of using this approach in the frame of Institut Curie Molecular Tumor Board (MTB) to guide patients with cancer to clinical trials with MTAs. PATIENTS AND METHODS: We included all patients presented at Institut Curie MTB from 4 October 2014 to 31 October 2017. The following information was extracted from the chart: decision to perform tumour profiling, types of molecular analyses, samples used, molecular alterations identified and those which are actionable, and inclusion in a clinical trial with matched MTA. RESULTS: 736 patients were presented at the MTB. Molecular analyses were performed in 442 patients (60%). Techniques used included next-generation sequencing, comparative genomic hybridisation array and/or other techniques including immunohistochemistry in 78%, 51% and 58% of patients, respectively. Analyses were performed on a fresh frozen biopsy in 91 patients (21%), on archival tissue (fixed or frozen) in 326 patients (74%) and on both archival and fresh frozen biopsy in 25 patients (6%). At least one molecular alteration was identified in 280 analysed patients (63%). An actionable molecular alteration was identified in 207 analysed patients (47%). Forty-five analysed patients (10%) were enrolled in a clinical trial with matched MTA and 29 additional patients were oriented and included in a clinical trial based on a molecular alteration identified prior to the MTB analysis. Median time between date of specimen reception and molecular results was 28 days (range: 5-168). CONCLUSIONS: The implementation of an MTB at Institut Curie enabled the inclusion of 10% of patients into a clinical trial with matched therapy.