[Evolution of cancer treatment modalities]. / Évolution des modalités de traitement des cancers.

EVOLUTION OF CANCER TREATMENT MODALITIES. Innovation in oncology faces many challenges: increasing costs for the communities, constant changes in practices and organizations, and a desire to benefit as many patients as possible while respecting safety and effectiveness rules. It is essential to encourage innovation and support its development in order to reduce the loss of opportunities. Innovation is not restricted to the development stages of a molecule, or to clinical trials, but also concerns the organization of care paths. Mechanisms are in place to enable innovations to be implemented quickly and safely in France, and some recent examples of treatments have profoundly changed practices.

ÉVOLUTION DES MODALITÉS DE TRAITEMENT DES CANCERS. L'innovation en cancérologie fait face à de nombreux défis : accroissement des coûts pour la collectivité, modification constante des pratiques et des organisations, et volonté de faire bénéficier au plus grand nombre de patients possible des traitements les plus novateurs tout en respectant les règles de sécurité et d'efficacité. Il est essentiel de faire émerger l'innovation et d'accompagner son développement afin de diminuer les pertes de chance. L'innovation n'est pas limitée aux étapes du développement d'une molécule ou aux essais cliniques mais elle concerne également l'organisation des parcours de soins. Des dispositifs permettent la mise en oeuvre accélérée et sécurisée des innovations en France, et certains exemples récents de traitements ont profondément modifié les pratiques.

[Covid-19 and cancers: how to do better in a crisis?] / Covid-19 et cancers : comment faire mieux en situation de crise ?

COVID-19 AND CANCERS: HOW TO DO BETTER IN A CRISIS? The occurrence of the Sars-CoV-2 pandemic has profoundly disorganized the care pathways. The situation of oncology quickly appeared as specific because of the high and frequent risk of loss of chance, limited by the he mobilization of screening and care actors, as well as the deployment of a dedicated crisis organization. However, the persistence of a decrease in the activity of surgical removal of esophageal and gastric cancers still raises questions and prompts to remain vigilant and active. The experience of the Covid-19 pandemic has allowed practices to evolve in the long term, for example the better consideration of the immunodepression of cancer patients. Crisis management has highlighted the need for management based on updated indicators and the need to improve information systems in this respect. These elements have been integrated into the ten-year cancer control strategy, which includes actions dedicated to crisis management.

COVID-19 ET CANCERS : COMMENT FAIRE MIEUX EN SITUATION DE CRISE ? La survenue de la pandémie de Sars-CoV-2 a désorganisé profondément les parcours de soins. La situation de la cancérologie est rapidement apparue comme spécifique en raison du risque élevé et fréquent de pertes de chance, limité par la mobilisation des acteurs du dépistage et du soin ainsi que le déploiement d'une organisation de crise dédiée. Pourtant, la persistance d'une diminution d'activité de chirurgie d'exérèse des cancers de l'oesophage et de l'estomac interroge encore et incite à rester vigilant et actif. L'expérience de la pandémie de Covid-19 a permis de faire évoluer durablement les pratiques, par exemple par la meilleure prise en compte de l'immunodépression des patients atteints de cancer. La gestion de crise a mis en évidence l'enjeu d'un pilotage sur indicateurs actualisés et la nécessité d'améliorer en ce sens les systèmes d'information. Ces éléments ont été intégrés à la stratégie décennale de lutte contre les cancers qui prévoit des actions dédiées à la gestion de crise.

Estimation of Oncologic Surgery Case Volume Before and After the COVID-19 Pandemic in France.

Importance: COVID-19 has had a major effect on health care activities, especially surgery. At first, comparisons were proposed using 2019 activities as the highest standard. However, while such an approach might have been suitable during the first months of the pandemic, this might no longer be the case for a longer period. Objective: To examine approaches that may better assess the use of cancer surgeries. Design, Setting, and Participants: In a cross-sectional design, the nationwide French hospital facility data (Medicalised Information System Program) were used to assess cancer surgery for 6 cancer site categories in adults from January 1, 2010, to December 31, 2021. Exposure: Estimated cancer surgery activity during the COVID-19 pandemic. Main Outcomes and Measures: Three models were proposed to assess the expected number of surgical procedures between 2020 and 2021 and make a comparison with those observed in earlier years. Results: In France, cancer removal surgeries account for approximately 7000 hospitalizations per year for liver cancer; 4000 for pancreatic cancer; 7700 for ovarian cancer; 1300 for esophagus cancer; 23 000 for ear, nose, and throat (ENT) cancer; 78 000 for breast cancer; and 16 600 for thoracic cancers. For most cancer sites, the number of surgical procedures increased from 2010 to 2019: liver, 14%; pancreas, 38%; ovary, 14%; esophagus, 18%; breast, 8%; and thoracic, 29%. Assuming stability, these values underestimate the gap in activity observed in 2020-2021. For other procedures, a decrease was observed: stomach, -10%, and ENT, -6%. Assuming stability, these values overestimate the gap in activity observed in 2020-2021. At the end of 2021, according to the model, the gap in activity observed in 2020-2021 was estimated at between -1.4% and 1.7% for breast, -6.6% and -7.3% for thoracic, -3.1% and -2.5% for ovarian, -4.2% and -1.7% for pancreas, -6.7% and 5.9% for stomach, and -13.0% and -13.9% for esophageal cancers. For ENT, liver, and urologic cancers, because the trend was different before and after 2015, it was necessary to opt for modeling using only the most recent period. The cumulative gap in activity observed in 2020-2021 was estimated at -1.0% for ENT cancers, -5.3% for liver cancers, and -2.9% for urologic cancers. Conclusions and Relevance: The findings of this study suggest that short- and medium-term trends must be considered to estimate COVID-19 cancer surgery activities. Breast cancer is the site for which the activity showed the smallest decrease during the pandemic, with almost full recovery in 2021.

Improve the management of cancer-related cognitive impairment in clinical settings: a European Delphi study.

PURPOSE: Cancer-related cognitive impairment (CRCI) is under-addressed by healthcare professionals owing to a lack of clinical management guidelines. This European Delphi study proposes recommendations to healthcare professionals for the management of CRCI in patients with non-central nervous system (non-CNS) cancers. METHODS: Twenty-two recommendations were developed based on a literature review and authors' clinical experience, split into three categories: screening, cognitive assessment, intervention. The survey included European professionals, experts in CRCI. The Delphi method was used: experts rated the clinical relevancy of recommendations on a 9-point Likert scale in three rounds. A recommendation was accepted if all votes were between 7 and 9. Recommendations not accepted in round 1 and round 2 were deleted, or modified and rated in round 3. RESULTS: Eighteen professionals (psychologists, physicians, researchers) voted and accepted 15 recommendations. Experts recommended the systematic screening of CRCI, followed by a short objective cognitive assessment, if complaints screened. A comprehensive evaluation is recommended if CRCI persists 6 months post-treatment. Cognitive rehabilitation, physical activity, meditative-movement therapy, and multimodal intervention should be offered. Recommendations about frequency and duration of interventions, the professional to administer cognitive rehabilitation and the use of meditation and cognitive training without psychoeducation were not accepted. CONCLUSIONS: This survey provides 15 recommendations to assist healthcare professionals in detecting, assessing and offering interventions for CRCI. IMPLICATIONS FOR CANCER SURVIVORS: These recommendations should be included in supportive care to help healthcare professionals to detect CRCI and propose the best available intervention for patients with cognitive complaints. Developing CRCI management in clinical settings would improve patients' quality of life.

Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder predisposing humans to cutaneous and uterine leiomyomas; in 20% of affected families, type 2 papillary renal cell cancers (PRCCII) also occur with aggressive course and poor prognosis. HLRCC results from heterozygous germline mutations in the tumour suppressor fumarate hydratase (FH) gene. METHODS: As part of the French National Cancer Institute (INCa) 'Inherited predispositions to kidney cancer' network, sequence analysis and a functional study of FH were preformed in 56 families with clinically proven or suspected HLRCC and in 23 patients with isolated PRCCII (5 familial and 18 sporadic). RESULTS: The study identified 32 different germline FH mutations (15 missense, 6 frameshifts, 4 nonsense, 1 deletion/insertion, 5 splice site, and 1 complete deletion) in 40/56 (71.4%) families with proven or suspected HLRCC and in 4/23 (17.4%) probands with PRCCII alone, including 2 sporadic cases. 21 of these were novel and all were demonstrated as deleterious by significant reduction of FH enzymatic activity. In addition, 5 asymptomatic parents in 3 families were confirmed as carrying disease-causing mutations. CONCLUSIONS: This study identified and characterised 21 novel FH mutations and demonstrated that PRCCII can be the only one manifestation of HLRCC. Due to the incomplete penetrance of HLRCC, the authors propose to extend the FH mutation analysis to every patient with PRCCII occurring before 40 years of age or when renal tumour harbours characteristic histologic features, in order to discover previously ignored HLRCC affected families.

Care pathway of women with interval breast cancer in 2016, based on medico-administrative data.

BACKGROUND: Since 2004, an organised screening programme (OS) for breast cancer has been in place for 50-74 years women who are not at an increased risk. Despite this, 17% of cancers diagnosed within 24 months following an OS mammogram are interval cancers (IC), diagnosed even though the OS had not reported cancer. After identifying IC from the French administrative healthcare database (SNDS), our objective was to describe the care pathways of women with IC in 2016. MATERIALS AND METHODS: The IC identification algorithm is based on breast imaging tests conducted in the 24 months prior to diagnosis and on the compatibility of their timeline with ACR3 lesion follow-up (BIRADS guidelines). The care pathways of 3 groups were compared: women with IC, diagnosed through the OS, and diagnosed outside the OS programme (personalised screening or based on clinical signs, PSCS group). RESULTS: Respectively, 12,965 (46%), 3433 (12%), and 11,761 women (42%) were classified in the OS, IC and PSCS groups, i.e. 20.9% IC cases among the women taking part in the OS programme. The women from the IC group presented with more forms with lymph node or metastatic involvement than those of the OS group. Their pathways were more complex than in the OS group: at an equivalent stage, more total mastectomies and more adjuvant or neoadjuvant chemotherapy regimens. CONCLUSION: The care pathways of women with IC are intermediate with respect to those of the OS or PSCS group.Cases of IC probably include several cancer prognosis profiles.

Monitoring the impact of COVID-19 in France on cancer care: a differentiated impact.

The COVID-19 pandemic has had a substantial and lasting impact on care provision, particularly in the field of cancer care. National steering has helped monitor the health situation and adapt the provision and organisation of care. Based on data from the French administrative healthcare database (SNDS) on the entire French population (67 million people), screening, diagnostic and therapeutic activity was monitored and compared 2019 on a monthly basis. A noteworthy decline in all activities (with the exception of chemotherapy) was observed during the first lockdown in France. Over the months that followed, this activity returned to normal but did not make up for the shortfall from the first lockdown. Finally, during the lockdown in late 2020, cancer care activity was conserved. In brief, in 2020, the number of mammograms decreased by 10% (- 492,500 procedures), digestive endoscopies by 19% (- 648,500), and cancer-related excision by 6% (- 23,000 surgical procedures). Hospital radiotherapy activity was down 3.8% (- 4400 patients) and that in private practice was down 1.4% (- 1600 patients). Chemotherapy activity increased by 2.2% (7200 patients), however. To summarize, COVID-19 had a very substantial impact during the first lockdown. Safeguarding cancer care activity helped limit this impact over the months that followed, but the situation remains uncertain. Further studies on the medium- and long-term impact on individuals (survival, recurrence, after-effects) will be conducted.

Cyclooxygenase-2 as a target for anticancer drug development.

The two isoforms cyclooxygenase-1 and -2 catalyze the initial step in the formation of prostaglandins in a variety of pathophysiological processes. More recently their role in carcinogenesis has become more evident. They seem to influence apoptosis, angiogenesis, and invasion, and play a role in the production of carcinogens. Usually, a high level of COX-2 expression is found in cancer cells. However, low COX-2 expression is observed in some cancers like prostate or breast cancer. This phenomenon is quite surprising and should influence on clinical trial designs. Large epidemiological trials studying users and non-users of aspirin have shown that cyclooxygenase (COX) inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) could be of benefit against the development and growth of malignancies. Moreover, clinical trials in patients with familial adenomatosis polyposis syndrome have shown too the efficacy of non-selective COX inhibitors and recently also of selective COX-2 inhibitors in the reduction of the number and the size of colorectal polyps. However, a primary chemopreventive effect has not been demonstrated yet. NSAIDs are also supposed to have a preventive and growth inhibitory effect in extra-colonic epithelial malignancies. Several preclinical studies show promising results with combination treatments of either chemotherapy or radiotherapy with COX inhibitors. Preclinical studies with the simultaneous use of inhibitors of the epidermal growth factor receptor and COX-2 inhibitors have shown also promising results. Encouraging results with the first clinical trials combining chemotherapy with COX-2 inhibitors in patients with cancer in the advanced and neoadjuvant setting have recently been reported. However, NSAIDs effects in cancer cells are mediated not only by COX enzymes but also by interactions with downstream effectors of COX-2. Hence, we can state that targeting the COX-2 pathway is a promising strategy in the prevention and treatment of solid tumors. Ongoing trials are expected to answer - at least partly - the remaining questions concerning COX-2 and cancer.

Pretreatment serum interleukin-6 concentration as a prognostic factor of overall survival in metastatic malignant melanoma patients treated with biochemotherapy: a retrospective study.

Biological response parameters during biochemotherapy, including chemotherapy with immune modulating agents, have been studied extensively. Of these parameters, interleukin-6 (IL-6) has been implicated in advanced stage disease and tumour recurrence. However, there is limited information available about the significance of IL-6 in metastatic malignant melanoma (MMM). In this study, we evaluated the possible relationship between serum IL-6 level and overall survival. This retrospective study included 125 patients with MMM. Pretreatment serum IL-6 levels were determined using a highly sensitive enzyme-linked immunosorbent assay (ELISA) test. Kaplan-Meier survival curves were constructed and compared using the log-rank test. Cox proportional analysis was performed to assess the predictors of overall survival, which was calculated from the beginning of biochemotherapy until death. In order to establish the possible relationship between IL-6 level and overall survival, patients were divided into two groups according to a cut-off of 5 pg/ml, corresponding to the first quartile obtained by descriptive statistics of the pretreatment IL-6 level in all patients. Thirty-five patients were in the low IL-6 group and 76 patients were in the high IL-6 group. Based on this stratification, overall survival was shown to be affected by IL-6 serum level: it was higher (24.6 months) in the low IL-6 group when compared with the high IL-6 group (9.7 months) (P=0.0006). Furthermore, Cox multivariate analysis including standard melanoma prognostic factors showed that IL-6, as a variable, lactate dehydrogenase (LDH) and tumour burden were significant prognostic factors for overall survival. On the basis of this evidence, the pretreatment serum IL-6 level is a predictive factor of overall survival in MMM.

Management of primary anal canal adenocarcinoma: a large retrospective study from the Rare Cancer Network.

PURPOSE: Primary adenocarcinoma of the anus is a rare tumor. The current standard treatment consists of abdominoperineal resection (APR). The aim of this Rare Cancer Network study was to evaluate the prognostic factors and outcome after the three most commonly used treatment approaches. METHODS AND MATERIALS: This multicenter study collected data from 82 patients: 15 with T1 (18%), 34 with T2 (42%), 22 with T3 (27%), and 11 with T4 (13%) tumors according to the TNM classification (International Union Against Cancer, 1997). Patients were separated into, and analyzed according to, three treatment categories: radiotherapy/surgery (RT/S group, n = 45), combined radiochemotherapy (RT/CHT group, n = 31), and APR alone (APR group, n = 6). The main patient characteristics were evenly distributed among the three groups. RESULTS: The actuarial locoregional relapse rate at 5 years was 37%, 36%, and 20%, respectively, in the RT/S, RT/CHT, and APR groups (RT/S vs. RT/CHT, p = 0.93; RT/CH vs. APR, p = 0.78). The 3-, 5-, and 10-year overall survival rate was 47%, 29%, and 23% in the RT/S group, 75%, 58%, and 39% in the RT/CHT group, and 42%, 21%, and 21% in the APR group (RT/CHT vs. RT/S, p = 0.027), respectively. The 5- and 10-year disease-free survival rate was 25% and 18% in the RT/S group, 54% and 20% in the RT/CHT group, and 22% and 22% in the APR group (RT/CHT vs. RT/S, p = 0.038), respectively. Multivariate analysis revealed four independent prognostic factors for survival: T stage, N stage, histologic grade, and treatment modality. CONCLUSION: Primary adenocarcinoma of the anal canal requires rigorous management. Multivariate analysis showed that T and N stage, histologic grade, and treatment modality are independent prognostic factors for survival. We observed better survival rates after combined RT/CHT. We also recommend using APR only for salvage treatment.

[Anemia in cancer patients before treatment]. / Les anémies des cancéreux avant traitement.

Thirty per cent of cancer patients suffer from anemia before any treatment. This anemia is caused by haematopoiesis troubles related to cytokines production and by endogenous erythropoietin deficiency. Clinically, its symptoms, including fatigue, spoils patients'quality of life. Known as a prognostic factor for several cancers, anemia also lowers radiotherapy or chemotherapy efficiency by tumor hypoxia. Recombinant EPO restores normal haemoglobin level, quality of life and treatment efficiency.

Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours.

BACKGROUND: To determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2). PATIENTS AND METHODS: In this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6 mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2 weeks. RESULTS: Two grade 3/4 aflibercept-associated DLTs occurred with 4 mg/kg: proteinuria lasting >2 weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6 mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4 mg/kg. Twenty-two patients had stable disease (five with 4 mg/kg), lasting >3 months in 17 patients. No anti-aflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4 mg/kg. CONCLUSION: Based on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4 mg/kg was selected as the RPTD with irinotecan and LV5FU2 every 2 weeks.

Multicenter, phase II study of axitinib, a selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, in patients with metastatic melanoma.

PURPOSE: This multicenter, open-label, phase II study evaluated the safety and clinical activity of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, 2, and 3, in patients with metastatic melanoma. EXPERIMENTAL DESIGN: Thirty-two patients with a maximum of one prior systemic therapy received axitinib at a starting dose of 5 mg twice daily. The primary endpoint was objective response rate. RESULTS: Objective response rate was 18.8% [95% confidence interval (CI), 7.2-36.4], comprising one complete and five partial responses with a median response duration of 5.9 months (95% CI, 5.0-17.0). Stable disease at 16 weeks was noted in six patients (18.8%), with an overall clinical benefit rate of 37.5%. Six-month progression-free survival rate was 33.9%, 1-year overall survival rate was 28.1%, and median overall survival was 6.6 months (95% CI, 5.2-9.0). The most frequently (>15%) reported nonhematologic, treatment-related adverse events were fatigue, hypertension, hoarseness, and diarrhea. Treatment-related fatal bowel perforation, a known class effect, occurred in one patient. Axitinib selectively decreased plasma concentrations of soluble VEGFR (sVEGFR)-2 and sVEGFR-3 compared with soluble stem cell factor receptor (sKIT). No significant association was noted between plasma levels of axitinib and response. However, post hoc analyses indicated potential relationships between efficacy endpoints and diastolic blood pressure of 90 mm Hg or higher as well as baseline serum lactate dehydrogenase levels. CONCLUSIONS: Axitinib was well tolerated, showed a selective VEGFR-inhibitory profile, and showed single-agent activity in metastatic melanoma. Further evaluations of axitinib, alone and combined with chemotherapy, are ongoing.

[Angiogenesis targeting in gastro-intestinal cancers]. / Le ciblage de l'angiogenèse dans les cancers digestifs.

Colorectal cancers have been the first cancers to benefit from an efficient anti-angiogenic treatment, represented by bevacizumab, which has been approved for first-line metastatic treatment in combination with reference chemotherapies and which is under study in the adjuvant setting. Other gastro-intestinal malignancies appear less responsive to anti-angiogenic therapy, but inhibitors of the VEGF receptors (sorafenib, sunitinib, axitinib) are in development with encouraging results. The safety profile of anti-angiogenic agents is quite different from that of classical chemotherapy and may require a modification of treatment strategies.

[Angiogenesis and renal cell carcinoma]. / Angiogenèse et cancer du rein.

Developments in the knowledge of molecular biology of renal cell carcinoma (RCC) over the past 20 years have been identified. Angiogenesis is playing a key role in the physiopathology of RCC. Von Hippel-Lindau (VHL) alterations, HIFalpha accumulation and vascular endothelial growth factor (VEGF) overexpression are important mediators of this process. Several stategies have been developped to target angiogenesis for the treatment of metastatic RCC. These include inhibition of VEGF receptors (inhibition of the tyrosine kinase activity) or binding to the VEGF protein. Several additional kinases inhibitions including PDGF receptors are also targeted. Sunitinib (SU11248) is an orally biovailable small molecule that has demonstrated superiority over interferon-alpha for the treatment of metastatic RCC. In a recent randomized phase III study conducted in 750 patients, the response rate to sunitinib was 31% and to interferon 6%. The median of progression free survival (PFS) was 11 months for sunitinib and 5 months for interferon (p < 0.001). Sorafenib (BAY43-9006) was found to inhibit Raf1, but also VEGFR2 and 3, Flt3, PDGFR-a and b and c-kit, has been tested in a phase III study against placebo after one prior systemic therapy. The median of the time to progression (TTP) for sorafenib was 24 weeks versus 12 weeks for patients in the placebo arm (p = 0,01). Other molecules tested in metastatic RCC will be presented including axitinib, pazopanib and bevacizumab.