Delayed care for patients with newly diagnosed cancer due to COVID-19 and estimated impact on cancer mortality in France.

BACKGROUND: The impact of the first coronavirus disease 2019 (COVID-19) wave on cancer patient management was measured within the nationwide network of the Unicancer comprehensive cancer centers in France. PATIENTS AND METHODS: The number of patients diagnosed and treated within 17 of the 18 Unicancer centers was collected in 2020 and compared with that during the same periods between 2016 and 2019. Unicancer centers treat close to 20% of cancer patients in France yearly. The reduction in the number of patients attending the Unicancer centers was analyzed per regions and cancer types. The impact of delayed care on cancer-related deaths was calculated based on different hypotheses. RESULTS: A 6.8% decrease in patients managed within Unicancer in the first 7 months of 2020 versus 2019 was observed. This reduction reached 21% during April and May, and was not compensated in June and July, nor later until November 2020. This reduction was observed only for newly diagnosed patients, while the clinical activity for previously diagnosed patients increased by 4% similar to previous years. The reduction was more pronounced in women, in breast and prostate cancers, and for patients without metastasis. Using an estimated hazard ratio of 1.06 per month of delay in diagnosis and treatment of new patients, we calculated that the delays observed in the 5-month period from March to July 2020 may result in an excess mortality due to cancer of 1000-6000 patients in coming years. CONCLUSIONS: In this study, the delays in cancer patient management were observed only for newly diagnosed patients, more frequently in women, for breast cancer, prostate cancer, and nonmetastatic cancers. These delays may result is an excess risk of cancer-related deaths in the coming years.

Identification of CD245 as myosin 18A, a receptor for surfactant A: A novel pathway for activating human NK lymphocytes.

CD245 is a human surface antigen expressed on peripheral blood lymphocytes, initially delineated by two monoclonal antibodies DY12 and DY35. Until now, CD245 molecular and functional characteristics remained largely unknown. We combined immunological and proteomic approaches and identified CD245 as the unconventional myosin 18A, a highly conserved motor enzyme reported as a receptor for the surfactant protein A (SP-A), that plays a critical role in cytoskeleton organization and Golgi budding. We report that the recruitment of CD245 strongly enhanced NK cell cytotoxicity. Further, we show that the enhancement of the NK lymphocytes killing ability toward CD137-ligand expressing target cells could result from the induction of CD137 expression following CD245 engagement. The SP-A receptor could therefore represent a novel and promising target in cancer immunotherapy.

Is oral chemotherapy prescription safe for patients? A cross-sectional survey.

BACKGROUND: Oral chemotherapies are increasingly prescribed. Yet wide variations in prescription practices and in monitoring of toxicity have been underlined despite existing guidelines. There is little recent information available as regard to these practices. We aimed to obtain exhaustive information on oral chemotherapy prescription practices and safety monitoring in French hospitals. METHODS: A cross-sectional multicentre survey was carried out to collect information on drug prescription, administration and surveillance: prescribing practices, coordination and monitoring of adherence, safety monitoring and side-effects occurrence prevention. Participants were a large sample of the French oncologists prescribing oral chemotherapy (20%). RESULTS: One hundred and fifty-seven oncologists from 112 hospitals (public, comprehensive cancer centres and private) replied (23.7% of cancer hospitals). The majority (56.1%) of the prescriptions were hand-written on a blank sheet. Eighty-four physicians (53.5%) included dose information and 36 (23%) declared having no monitoring procedures for adherence. Only 84 responders (54%) provided education material at first prescription of oral chemotherapy in way to limit avoidable side-effects. Sixty-one (39%) responders stated that they recalled at least one serious adverse event in the previous year declared in their centre. CONCLUSIONS: In this 2012 study, the majority of prescribers followed no standards in prescription writing, safety monitoring and toxicity prevention. The implementation of the international recommendations for oral chemotherapy administration should be considered as a top priority-for both prescribers and health authorities-as regards to the dynamic of development of these molecules and their potential side-effects.

Phase II study assessing lapatinib added to letrozole in patients with progressive disease under aromatase inhibitor in metastatic breast cancer-Study BES 06.

This trial evaluated the effect of adding lapatinib to letrozole after clinical resistance to aromatase inhibitor (IA) treatment in hormone receptor-positive metastatic breast cancer. Postmenopausal women received daily letrozole plus lapatinib (1,500 mg). The primary end point was objective rate response (ORR) at week 12. Secondary objectives included time to response, duration of response, clinical benefit (CB), progression-free survival (PFS), overall survival, and safety. Twenty-four human epidermal growth factor receptor 2 (HER2)-negative patients were included with secondary resistance to IA. ORR at 12 weeks was 4 % (95 % confidence interval (CI), 0.7-20). Stable and progression diseases were reported in 25 % (95 % CI, 12-45) and 71 % (95 % CI, 51-85) of cases, respectively. At 24 weeks, the ORR increased to 8 %. CB was 21 % (95 % CI, 9-40). At a median follow-up of 27 months, median PFS was 3.4 months (95 % CI, 2.8-5.4). Grade 3 or 4 adverse events were rarely reported. No clinical cardiac toxicity was observed. Lapatinib was discontinued in two patients due to severe diarrhea. This trial was prematurely closed due to low recruitment. These preliminary results suggest that the addition of lapatinib to letrozole has a favorable safety profile and could overcome tumoral resistance to letrozole among HER2-negative tumors.

[Use of anti-EGFR antibodies (cetuximab and panitumumab) in the treatment of metastatic colorectal cancer in KRAS wild type patients]. / La place des anticorps anti-EGFR (cetuximab et panitumumab) dans le traitement des patients atteints de cancer colorectal métastatique non mutés pour le gène KRAS.

Cetuximab and panitumumab are anti-EGF receptor antibodies, used in the treatment of colorectal cancer. Phase I and II studies have shown an interest in these molecules, after failure of chemotherapy combining 5-fluorouracil, folinic acid and oxaliplatin (Folfox) or irinotécan (IFL and Folfiri). Cetuximab with irinotécan has been approved by regulatory authorities following the results of a randomized phase II study where the combination arm (cetuximab-irinotécan) was superior to cetuximab alone. Retrospective studies have highlighted the impact of KRAS mutational status in the efficacy of EGFR antibodies. KRAS mutation is associated with a lack of response. Subgroup analysis of prospective studies have confirmed these hypothesis in first and second line metastatic treatment in combination with chemotherapy and in third line in monotherapy. At present cetuximab is approved in combination with chemotherapy in patients with non mutated KRAS metastatic colorectal cancer while panitumumab is only approved in monotherapy after failure of conventional chemotherapy.

Relationship between nutritional status and quality of life in patients with cancer.

Patients with cancer frequently suffer a deteriorated quality of life and this is an important factor in the therapeutic decision. The correlation between quality of life and malnutrition seems obvious and bidirectional. The aim of our study was to describe the global quality of life and its various dimensions in patients with cancer, as a function of the nutritional status. A transversal observational study was performed in wards in hospitals in Clermont-Ferrand and Saint Etienne on 907 patients. The EORTC questionnaire, QLQ-C30, was used to assess the quality of life. The mean global quality of life score was 48.8 for patients who had a weight loss of more than 10% since the beginning of their illness, compared with 62.8 for the other patients (p<0.001). A significant association with weight was observed for the main dimensions of the quality of life: physical, functional, cognitive, social, fatigue, nausea, pain, loss of appetite, constipation and diarrhoea. This strong relation between quality of life and weight loss shows the importance of dietary management in patients with cancer.

Carcinoma of an unknown primary: are EGF receptor, Her-2/neu, and c-Kit tyrosine kinases potential targets for therapy?

Carcinomas of an unknown primary site (CUP) are heterogeneous tumours with a median survival of only 8 months. Tyrosine kinase inhibitors are promising new drugs. The aim of this study was to determine the expression of EGF-receptor, Her-2/neu, and c-Kit tyrosine kinases in CUP. Paraffin-embedded specimens were obtained from 54 patients with a CUP who were included in the GEFCAPI 01 randomised phase II trial. Immunohistochemistry was performed using the Dako autostainer with antibodies directed against HER-2/neu protein, EGFR protein, and c-Kit protein (CD117). EGFR expression was found in 36 out of 54 samples (66%). In contrast, Her-2/neu overexpression and c-Kit positivity were only detected in 4 and 10% of patients, respectively. No significant association was found between the expression of the tyrosine kinase receptors and prognosis. EGFR expression was significantly associated with response to cisplatin-based chemotherapy: the response rates were 50 and 22% in patients with EGFR-positive tumours and EGFR-negative tumours, respectively (P<0.05). This study shows that EGFR is frequently expressed in CUP. This finding may prompt clinical trials investigating EGFR inhibitors in this setting. In contrast, c-Kit expression and Her-2/neu overexpression occur infrequently in CUP. EGFR expression was correlated to tumour chemosensitivity.

Estimation of the risk for nutritional state degradation in patients with cancer: development of a screening tool based on results from a cross-sectional survey.

BACKGROUND: In routine practice, the evaluation of the nutritional status of patients with cancer is not always performed although there is frequent modification as disease progresses. The validated screening and evaluation tools currently available are time-consuming and costly. In this study we analysed factors that could be used to identify patients likely to need nutritional surveillance or intervention. PATIENTS AND METHODS: A cross-sectional survey was carried out for 2 weeks in June 2006 on 477 patients with cancer. RESULTS: 30.2% of the patients had lost more than 10% of their body weight since the start of the illness. After adjustment, the factors significantly associated with weight loss were: depressive state (OR = 3.49; P = 0.002), digestive or ENT tumours (OR = 3.20; P = <0.001), chemotherapy (OR = 2.66; P = 0.011), male gender (OR = 2.30; P = 0.001) and professional status (OR = 2.08; P = 0.02). Using a logistic model, we calculated the risk of weight loss as a function of the presence of the identified predictive factors. CONCLUSION: We report a simple screening tool, which will not replace the available evaluation methods but will enable targeting of the patients most likely, after a specific evaluation, to benefit from nutritional intervention. This remains to be validated in further prospective studies.

[Clinical practice guidelines: 2004 Standards, Options and Recommendations for the management of patient with adenocarcinoma of the stomach--radiotherapy]. / Recommandations pour la pratique clinique : standards, options et recommandations 2004 pour la prise en charge par radiothérapie des patients atteints d'adénocarcinomes de l'estomac (cancers du cardia, autres types histologiques exclus).

CONTEXT: "The Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French regional cancer centers, and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. OBJECTIVES: To elaborate clinical practice guidelines for patients with stomach adenocarcinoma. These recommendations cover the diagnosis, treatment and follow-up of these tumors. METHODS: The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. The Standards, Options and Recommendations are thus based on the best available evidence and expert agreement. RESULTS: Adjuvant radiation therapy alone is not a standard treatment for patients with stomach adenocarcinoma. Adjuvant concomitant chemoradiotherapy is not a standard treatment for patients with stage II or III stomach adenocarcinoma R0, with Dl or D2 lymphadenectomy who have undergone surgery. Following surgical resection, adjuvant concomitant chemoradiotherapy should be proposed to patients without denutrition with a lymphadenectomy < Dl (fewer than 15 lymph nodes examined) and those with T3 and/or N+ tumours following the protocol used in the MacDonald trials (SWOG-9008) (Level of evidence B1). Adjuvant concomitant chemoradiotherapy can be administered to patients without denutrition with DI or D2 lymphadenectomy and with involvement of regional lymph nodes (N2 or N3).

High-dose, single-agent irinotecan as first-line therapy in the treatment of metastatic colorectal cancer.

PURPOSE: The efficacy and safety of single-agent, high-dose irinotecan (CPT-11, Campto) 500 mg/m(2) every 3 weeks were investigated as first-line treatment for advanced colorectal cancer (CRC). PATIENTS AND METHODS: Patients were enrolled into the study to receive a first cycle of therapy with irinotecan at a dose of 350 mg/m(2) every 3 weeks, which could be escalated to 500 mg/m(2) for the second and subsequent cycles depending on toxicity. Efficacy, safety and pharmacokinetics were determined in the intent to treat (ITT) population and the high-dose population (i.e. patients who had received at least three cycles of irinotecan, the second and third at 500 mg/m(2)). RESULTS: Of 49 patients enrolled into the study (ITT population), 31 (63%) received at least three cycles of treatment with cycles 2 and 3 at an irinotecan dose of 500 mg/m(2) (the high-dose population). The response rates (RR) for the ITT and high-dose populations were 24.5% and 35.5%, respectively. The main grade 3/4 toxicities per cycle in the ITT and high-dose populations were neutropenia 22% and 17%, febrile neutropenia 5% and 3%, and diarrhoea 12% and 7%, respectively. The pharmacokinetics of irinotecan and its metabolite SN-38 were investigated in 31 patients in cycle 1 and 22 patients in cycle 2. Irinotecan clearance and SN-38 exposure were not sufficiently correlated with toxicity in cycle 1 to identify patients for dose increase in subsequent cycles. The exposure to irinotecan and SN-38 increased in proportion to dose from 350 to 500 mg/m(2). CONCLUSION: These results suggest that high-dose irinotecan can be safely administered as first-line monotherapy to approximately two-thirds of patients who present with advanced CRC following a selective first cycle.

Doxorubicin and ifosfamide in patients with metastatic sarcomatoid renal cell carcinoma: a phase II study of the Genitourinary Group of the French Federation of Cancer Centers.

PURPOSE: We assessed the efficacy and toxicity of a chemotherapy regimen combining doxorubicin and ifosfamide in patients with metastatic sarcomatoid renal cell carcinoma. MATERIALS AND METHODS: Of the 25 patients included in a prospective multicenter phase II trial 23 were evaluable for efficacy and toxicity studies after pathological review. RESULTS: A median of 3 cycles per patient (range 1 to 8) was administered. No objective response was observed. Median time to progression was 2.2 months and median overall survival was 3.9 months. A single patient died of toxicity. CONCLUSIONS: The results do not support the standard use of doxorubicin/ifosfamide chemotherapy in patients with metastatic sarcomatoid renal cell carcinoma.

Small-cell carcinoma of the esophagus: report of three cases and review of the literature with emphasis on therapy.

Primary small-cell carcinoma (SCC) of the esophagus is rare, with about 200 cases reported up till now in the literature. Like pulmonary SCC, it is an aggressive tumor associated with a poor prognosis. Between 1994 and 1997, three patients with SCC of the esophagus were treated at Besançon University Hospital and this represented 1.85% of all esophageal malignancies diagnosed during this period: one patient had a limited tumor and underwent initial surgical resection, then chemotherapy with cisplatine and etoposide, and radiotherapy for recurrences. The other patients had extensive disease at diagnosis and were treated by the same chemotherapy. This retrospective study reports our experience of patients with this particular tumor and outlines the management strategy based on the available literature.

[Standards, options and recommendations: practice guidelines for difficult diagnosis in surgical pathology or cytopathology in cancer patients]. / Standards, options et recommandations: conduite a tenir devant une lésion de diagnostic anatomo-cyto-pathologique difficile en cancérologie.

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993 is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for difficult diagnoses in surgical pathology or cytopathology in cancer patients. METHODS: Data were identified by searching Medline and using the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to 71 independent reviewers. RESULTS: The main recommendations to prevent and reduce the number of difficult diagnoses in surgical pathology or cytopathology are: 1) The development of quality insurance programs with use of written procedures in each pathology laboratory (standard). 2) The knowledge of clinical data in order to explain surgical pathology or cytopathology results (standard). 3) The availability of complementary patient informations (radiologic data . . .) can be useful to explain surgical pathology or cytopathology results (option). The main recommendations to detect lesions associated with difficult diagnosis in surgical pathology or cytopathology are: 1) Tumor types known as potential difficult diagnosis in surgical pathology or cytopathology should be reviewed by a second pathologist. 2) The systematic second reviewing for every case is expensive but has to be done when the difficulty is know (sarcoma, lymphoma . . .) by experienced pathologists. The main recommendations to solve difficult diagnosis in surgical pathology or cytopathology are: 1) Block recuts, use of special techniques (immunocytohistochemistry and molecular biology), additional data from clinicians, second opinion by a local pathologist, or new specimen can be required for establishing the diagnosis (options). 2) Outside second opinion by expert pathologist has to be considered once the other steps did not allow to establish surgical or cytopathology diagnosis (recommendations, expert agreement).

Oral vinorelbine pharmacokinetics and absolute bioavailability study in patients with solid tumors.

BACKGROUND: Vinorelbine is a vinca alkaloid obtained by hemisynthesis, which makes the molecule more lipophilic than the other vincas. An injectable formulation is already marketed for the treatment of non small cell lung cancer (NSCLC) and advanced breast cancer (ABC). A new oral form has been developed and its file registration is being submitted. As part of its development, a clinical study was conducted to determine the absolute bioavailability and pharmacokinetics of oral vinorelbine administered as softgel capsules, and to evaluate its safety profile compared with intravenous administration. PATIENTS AND METHODS: Thirty-two patients with solid tumours were included in the study. Patients fasted and were randomised to receive vinorelbine on day 1, either as a 20 minute intravenous (i.v.) infusion of 25 mg/m2 or as softgel capsules at a dose of 80 mg/m2. Patients were treated with the alternate route after a one week wash-out period. Blood and urine samples for pharmacokinetic analysis were collected during each vinorelbine administration. Safety was assessed after each administration using the CALGB/expanded CTC classification. RESULTS: Twenty-four patients were eligible for pharmacokinetic evaluation. Oral vinorelbine was rapidly absorbed at 80 mg/m2 (Tmax 1.4 +/- 0.7 h) and showed a bioavailability of 43 +/- 14, and close to 40% based on AUC(last) and AUC(inf), respectively. A bioequivalence analysis was conducted on dosage-normalised blood exposures. Equivalence was demonstrated between 80 mg/m2 oral and 30 mg/m2 i.v., and between 60 mg/m2 oral and 25 mg/m2 i.v. The inter-individual variability was equivalent for both routes (CV: 38% and 39% for oral and i.v., respectively). A correlation was found in both methods between AUClast and % nadir variation in white blood cells (WBC) and polymorphonuclears (PMN). More cases of neutropenia (all grades pooled), leucopenia (grades 3-4 only) and nausea (grades 2-3) were induced by 80 mg/m2 oral vinorelbine than by 25 mg/m2 i.v. The greatest intensity of these effects, following oral administration, probably reflects the higher, observed drug exposure. CONCLUSION: At therapeutic dosage levels, pharmacokinetic behaviour and safety profiles were similar for both routes. The absolute bioavailability of the oral vinorelbine (new, soft gelatine capsule) was close to 40%. Inter-individual variability in drug exposure was equivalent in both routes. The pharmacokinetic/pharmacodynamic (PK/PD) relationship in haematological toxicity was independent of the routes of administration. Reliable, corresponding doses between oral and i.v. vinorelbine were established, which will result in bioequivalent AUC.

Multicentric phase II study of cisplatin and etoposide in patients with metastatic carcinoma of unknown primary.

The aim of this study was to determine the efficacy and toxicity of combination cisplatin and etoposide chemotherapy in patients with metastatic carcinoma of unknown primary. Patients were treated with cisplatin (100 mg/m2 iv day 1) followed by etoposide (100 mg/m2 iv days 1-3) every 3 weeks for a maximum of 6 cycles. Patients with progressive disease after two or four courses could receive FAC (fluorouracil, doxorubicin, and cyclophosphamide) until progression. Twenty-five patients were entered and were assessable for response and toxicity. Fifteen (60%) patients had adenocarcinomas. Patients received a median of four courses. Toxicity was mainly hematologic including grade III/IV neutropenia. The overall response rate was 32%. There was no complete response, 32% partial responses, 32% stable disease, and 36% disease progression. Median response duration was 4 months (range: 2-5 months). The median overall survival of the 25 patients was 8 months. No objective response could be obtained with FAC, but 33% of patients achieved stabilization of the disease for at least 3 months. This cisplatin-etoposide combination demonstrated some activity against an usually resistant disease.