Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial.

BACKGROUND: The standard of care for the treatment of locally advanced rectal cancer results in an excellent local disease control but the metastasis rates remain high. PRODIGE 23 demonstrated improved disease-free and metastatic-free survival with total neoadjuvant therapy versus standard of care in this population. Long-term analysis of overall survival is reported here. PATIENTS AND METHODS: The study design, participants, and primary endpoint disease-free survival (DFS) have been reported for this multicenter, randomized, open-label, phase 3 trial investigating the neoadjuvant chemotherapy with mFOLFIRINOX (6 cycles) followed by chemoradiotherapy, surgery, and adjuvant chemotherapy (6 cycles), versus chemoradiotherapy, surgery, and adjuvant chemotherapy (12 cycles) in patients with locally advanced rectal adenocarcinoma under peritoneal reflection on MRI, and staged cT3/T4. Key secondary endpoints included overall survival (OS), metastasis-free survival (MFS), and local and metastatic recurrence rate. RESULTS: With a median follow-up of 82.2 months, the 7-year DFS were 67.6% (95% CI 60.7%-73.9%) and 62.5% (95% CI 55.6%-68.6%) (RMST difference 5.73 months; 95% CI 0.05-11.41; p=0.048) in the neoadjuvant chemotherapy and the standard of care groups, respectively. The 7-year MFS was 79.2% (95% CI 73.0%-84.4%) in the neoadjuvant chemotherapy group and 72.3% (95% CI 65.8%-77.8%) in the standard of care group (RMST difference 6.1 months; 95% CI 0.93-11.37; p=0.021). The 7-year OS was 81.9% (95% CI 75.8%-86.6%) in the neoadjuvant chemotherapy group and 76.1% (95% CI 69.7-81.2) in the standard of care group (RMST difference 4.37 months; 95% CI 0.35-8.38; p=0.033). The safety profile remained unchanged since the previous analysis. CONCLUSION(S): Neoadjuvant chemotherapy with mFOLFIRINOX followed by chemoradiotherapy improved OS, confirmed long-term DFS and MFS benefits in locally advanced rectal cancer patients and should be considered as a one of the best options of care for these patients.

Quercetin improves and protects Calu-3 airway epithelial barrier function.

Introduction: In light of the impact of airway barrier leaks in COVID-19 and the significance of vitamin D in COVID-19 outcomes, including airway barrier protection, we investigated whether the very common dietary flavonoid quercetin could also be efficacious in supporting airway barrier function. Methods: To address this question, we utilized the widely used airway epithelial cell culture model, Calu-3. Results: We observed that treating Calu-3 cell layers with quercetin increased transepithelial electrical resistance while simultaneously reducing transepithelial leaks of 14C-D-mannitol (Jm) and 14C-inulin. The effects of quercetin were concentration-dependent and exhibited a biphasic time course. These effects of quercetin occurred with changes in tight junctional protein composition as well as a partial inhibition of cell replication that resulted in decreased linear junctional density. Both of these effects potentially contribute to improved barrier function. Quercetin was equally effective in reducing the barrier compromise caused by the pro-inflammatory cytokine TNF-α, an action that seemed to derive, in part, from reducing the elevation of ERK 1/2 caused by TNF-α. Discussion: Quercetin improved Calu-3 barrier function and reduced TNF-α-induced barrier compromise, mediated in part by changes in the tight junctional complex.

[Clinical research in radiation oncology: how to move from the laboratory to the patient?] / Recherche clinique en oncologie radiothérapie : comment passer du laboratoire au patient ?

Translational research in radiation oncology is undergoing intense development. An increasingly rapid transfer is taking place from the laboratory to the patients, both in the selection of patients who can benefit from radiotherapy and in the development of innovative irradiation strategies or the development of combinations with drugs. Accelerating the passage of discoveries from the laboratory to the clinic represents the ideal of any translational research program but requires taking into account the multiple obstacles that can slow this progress. The ambition of the RadioTransNet network, a project to structure preclinical research in radiation oncology in France, is precisely to promote scientific and clinical interactions at the interface of radiotherapy and radiobiology, in its preclinical positioning, in order to identify priorities for strategic research dedicated to innovation in radiotherapy. The multidisciplinary radiotherapy teams with experts in biology, medicine, medical physics, mathematics and engineering sciences are able to meet these new challenges which will allow these advances to be made available to patients as quickly as possible.

Radiation therapy of cutaneous cancers.

We present the update of the recommendations of the French society of oncological radiotherapy on radiotherapy of cutaneous cancers. The indications of radiotherapy for skin cancers are not clearly defined because of the lack of randomized trials or prospective studies. For basal cell carcinomas, radiotherapy frequently offers a good local control, but a randomized trial showed that surgery is more efficient and less toxic. Indications of radiotherapy are contra-indications of surgery for patients older than 60, non-sclerodermiform histology and located in non-sensitive areas. Adjuvant radiotherapy could be proposed to squamous cell carcinomas, in case of poor prognostic factors. Dose of 60 to 70Gy are usually required, and must be modulated to the size of the lesions. Adjuvant radiotherapy seems beneficial for desmoplastic melanomas but not for the other histological types. Prophylactic nodal irradiation (45 to 50Gy), for locally advanced tumors (massive nodal involvement), decreases the locoregional failure rate but do not increase survival. Adjuvant radio- therapy (50 to 56Gy) for Merkel cell carcinomas increases also the local control rate, as demonstrated by meta-analysis and a large epidemiological study. Nodal areas must be included, if there is no surgical exploration (sentinel lymph node dissection). Kaposi sarcomas are radiosensitive and could be treated with relatively low doses (24 to 30Gy). Also, cutaneous lymphomas are good indications for radiotherapy: B lymphomas are electively treated with limited fields. The role of total skin electron therapy for T-lymphomas is still discussed; but palliative radiotherapy is very efficient in case of cutaneous nodules.

Hepatic tumours and radiotherapy.

We present the update of the recommendations of the French society of oncological radiotherapy on hepatic tumours. Recent technological progress led to develop the concept of focused liver radiation therapy. We must distinguish primary and secondary tumours, as the indications are restricted and must be discussed as an alternative to surgical or medical treatments. The tumour volume, its liver location close to the organs at risk determine the irradiation technique (repositioning method, total dose delivered, dose fractionation regimens). Tumour (and liver) breathing related motions should be taken into account. Strict dosimetric criteria must be observed with particular attention to the dose-volume histograms of non-tumoral liver as well as of the hollow organs, particularly in case of hypofractionated high dose radiotherapy "under stereotaxic conditions". Stereotactic body radiotherapy is being evaluated and is often preferred to radiofrequency for primary or secondary tumours (usually less than 5cm). An adaptation can be proposed, with a conformal fractionated irradiation protocol with or without intensity modulation, for hepatocellular carcinomas larger than 5cm.

ROV assessment of mesophotic fish and associated habitats across the continental shelf of the Amathole region.

Understanding how fish associate with habitats across marine landscapes is crucial to developing effective marine spatial planning (MSP) in an expanding and diversifying ocean economy. Globally, anthropogenic pressures impact the barely understood temperate mesophotic ecosystems and South Africa's remote Amathole shelf is no exception. The Kei and East London region encompass three coastal marine protected areas (MPAs), two of which were recently extended to the shelf-edge. The strong Agulhas current (exceeding 3 m/s), which runs along the narrow shelf exacerbates sampling challenges. For the first time, a remotely operated vehicle (ROV) surveyed fish and their associated habitats across the shelf. Results indicated fish assemblages differed between the two principle sampling areas, and across the shelf. The number of distinct fish assemblages was higher inshore and on the shelf-edge, relative to the mid-shelf. However, the mid-shelf had the highest species richness. Unique visuals of rare Rhinobatos ocellatus (Speckled guitarfish) and shoaling Polyprion americanus (wreckfish) were collected. Visual evidence of rhodolith beds, deep-water lace corals and critically endangered endemic seabreams were ecologically important observations. The ROV enabled in situ sampling without damaging sensitive habitats or extracting fish. This study provided information that supported the Amathole MPA expansions, which extended protection from the coast to beyond the shelf-edge and will guide their management. The data gathered provides baseline information for future benthopelagic fish and habitat monitoring in these new MPAs.

[Combination radiotherapy-immunotherapy in genitourinary cancer]. / Combinaison radiothérapie-immunothérapie en cancérologie génito-urinaire.

Immunotherapy occupies a growing place in urologic oncology, mainly for kidney and bladder cancers. On the basis of encouraging preclinical work, the combination of immunotherapy with radiotherapy aims to increase the tumor response, including in metastatic tumors, which raises many hopes, which this article reviews.

Perineal recurrence of prostate cancer along a brachytherapy needle track: A case report.

Metastatic recurrence in an atypical site, such as the perineum, can occur after prostatectomy, cryotherapy, or brachytherapy, but is uncommon. To our knowledge, this is only the third case of perineal recurrence of prostatic cancer along a low dose rate brachytherapy needle track. A 64-year-old man was referred to an urologist with an increased PSA of 6.9ng/mL in December 2008. There were no urinary symptoms. Prostatic biopsies revealed a Gleason 6 adenocarcinoma (3+3), and he was treated with low dose rate brachytherapy in May 2009. Sixty-seven seeds of iodine 125 were loaded under ultrasound control, and the PSA subsequently fell to a nadir of 1.19ng/mL in November 2015. Eight years (May 2017) after the initial treatment, the PSA rose to 5.2ng/mL. Pelvic MRI and choline PET revealed a nodule in the region of the left internal obturator muscle. Nodule biopsies confirmed prostatic origin. This perineal recurrence is thus most likely related to seeding of tumour cells along the track of a brachytherapy needle. To our knowledge, this is only the fourth case of perineal recurrence of prostatic cancer along a low-dose rate brachytherapy needle track. Perineal recurrence of prostatic cancer along a LDR brachytherapy needle track can occur. Improved imaging techniques may help to identify this type of recurrence earlier and optimise treatment.

Prognostic factors for parotid metastasis of cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) develops on the head in 80% of cases. Parotid metastasis (PM) is rare, but treatment, which associates surgery and radiation therapy, is heavy and prognosis poor. MATERIAL AND METHODS: All cases of parotidectomy for PM of CSCC of the head and neck between 2005 and 2015 were studied retrospectively. Epidemiologic, oncologic and therapeutic data were analyzed. Overall and specific survival were calculated following Kaplan-Meier. Log-rank and Cox models were used to identify prognostic factors for PM. OBJECTIVES: The principal study objective was to identify factors for survival in PM from CSCC of the head and neck. RESULTS: Thirty-five patients were included. Mean time to onset of PM was 13months. Overall 1-, 2- and 5-year survival was respectively 70, 66 and 59%. Independent prognostic factors comprised immunodepression, age at treatment, positive CSCC margins, macroscopic facial nerve involvement, and metastatic cervical adenopathies. CONCLUSION: The study confirmed an association of several independent prognostic factors at the stage of parotid lymph-node metastasis, related to patient, primary CSCC and PM. Complete primary resection is essential to reduce the risk of PM. Intensified radiologic and clinical surveillance should enable early diagnosis.

[Stereotactic body radiation therapy for hepatic malignancies: Organs at risk, uncertainties margins, doses]. / Radiothérapie stéréotaxique hépatique : organes à risque, marges d'incertitudes, doses.

Stereotactic body radiation therapy for primary and metastatic hepatic malignancies can be performed in association and/or as an alternative to surgery and radiofrequency. The consequences of the great number of techniques available are heterogeneity in contouring, dose prescription and in determination of dose constraints for organs at risk. The objective of this paper is to improve the quality and safety and to help the diffusion of this technique for a majority of patients. In 2016, the French Society of Radiation Oncology (SFRO) published guidelines for external radiotherapy and brachytherapy ("Recorad"). This paper is an update of these recommendations considering recent publications.

[Radiotherapy of oligometastatic pelvic node relapses in patients with prostate cancer]. / Rechutes oligométastatiques ganglionnaires pelviennes au cours des cancers de la prostate : rôle de la prise en charge par radiothérapie.

The Oligopelvis 2 studies is based on the assumption that salvage pelvic radiotherapy may prolong the interval between the first and the second intermittent hormone therapy sequence in pelvic lymph node oligometastatic prostate cancer. This phase 3 study will compare intermittent hormone therapy (standard arm) alone or combined with salvage pelvic radiotherapy (experimental arm).

[Clinical to target volume margins determination in radiotherapy for anal cancers]. / Détermination des marges du volume cible anatomoclinique au volume cible prévisionnel pour la radiothérapie des cancers du canal anal.

There are very few data on the expansion from the clinical target volume (CTV) to the planning target volume (PTV) in the anal cancer treatment. This article aims to collect the different elements needed for the construction of a PTV from scientific data based on a literature analysis. We reviewed the articles published in the medical literature from the last 20years. They concerned setup errors and internal organ mobility of the different volumes of patients treated by conformational radiotherapy and intensity-modulated radiotherapy (anal canal, meso-rectum, common, intern and extern, inguinal and pre-sacral lymph nodes). CTV to PTV margins admitted in the guidelines and atlas of consensus groups (SFRO, RTOG, AGITG) are from 0.7 to 1cm in all directions, based on expert's opinions but not on scientific data. There are no specific studies on the canal anal mobility. Most of the data are from other pelvis cancers (gynecologic, rectum and prostate). Setup errors can be reduced by daily imaging. Patient repositioning and immobilization modalities are mostly local habits rather than scientific consensus. A three-dimensional 1cm margin is generally admitted. Margins reduction must be careful and has to be assessed.

[Radiotherapy of skin cancers]. / Radiothérapie des cancers cutanés.

The indications of radiotherapy for skin cancers are not clearly defined because of the lack of randomised trials or prospective studies. For basal cell carcinomas, radiotherapy frequently offers a good local control, but a randomized trial showed that surgery is more efficient and less toxic. Indications of radiotherapy are contra-indications of surgery for patients older than 60, non-sclerodermiform histology and occurring in non-sensitive areas. Adjuvant radiotherapy could be proposed to squamous cell carcinomas, in case of poor prognostic factors. Dose of 60 to 70Gy are usually required, and must be modulated to the size of the lesions. Adjuvant radiotherapy seems beneficial for desmoplastic melanomas but not for the other histological types. Prophylactic nodal irradiation (45 to 50Gy), for locally advanced tumours (massive nodal involvement), decreases the locoregional failure rate but do not increase survival. Adjuvant radiotherapy (50 to 56Gy) for Merckel cell carcinomas increases also the local control rate, as demonstrated by meta-analysis and a large epidemiological study. Nodal areas must be included, if there is no surgical exploration (sentinel lymph node dissection). Kaposi sarcomas are radiosensitive and could be treated with relatively low doses (24 to 30Gy). Also, cutaneous lymphomas are good indications for radiotherapy: B lymphomas are electively treated with limited fields. The role of total skin electron therapy for T-lymphomas is still discussed; but palliative radiotherapy is very efficient in case of cutaneous nodules.

[Role of radiotherapy in the management of node-positive prostate cancer]. / Place de la radiothérapie dans la prise en charge des cancers de prostate avec atteinte ganglionnaire pelvienne initiale sans métastase à distance.

Node-positive prostate cancer patients represent a small proportion of all prostate cancers for whom limited prospective information is available. Most retrospective or cohort data strongly suggest however that radiotherapy combined with androgen-depriving therapies is the preferable treatment in this setting. Only randomized clinical trials would be able to better define both radiotherapy (dose? volume? fractionation?) and androgen-depriving therapies (duration? role of novel androgen-depriving therapy?) modalities.

[Hepatic tumors and radiotherapy]. / Radiothérapie des tumeurs hépatiques.

Recent technological developments led to develop the concept of focused liver radiation therapy. We must distinguish primary and secondary tumors as the indications are restricted and must be discussed as an alternative to surgical or medical treatments. For hepatocellular carcinoma 5 to 10cm (or more), a conformational radiation with or without intensity modulation is performed. Stereotactic body radiotherapy (SBRT) is being evaluated and is increasingly proposed as an alternative to radiofrequency ablative treatment for primary or secondary tumors (typically less than 5cm). Tumor (and liver) movements induced by respiratory motions must be taken into account. Strict dosimetric criteria must be met with particular attention to the dose-volume histograms to liver and the hollow organs, including cases of SBRT.

[Prognostic value of the metabolically active tumour volume]. / Valeur pronostique du volume tumoral métabolique sur la TEP au ((18)F)-fluorodésoxyglucose préthérapeutique pour le cancer de l'œsophage localisé.

PURPOSE: The purpose of this study was to assess the prognostic value of different parameters on pretreatment fluorodeoxyglucose [((18)F)-FDG] positron emission tomography-computed tomography (PET-CT) in patients with localized oesophageal cancer. PATIENTS AND METHOD: We retrospectively reviewed 83 cases of localised oesophageal cancer treated in our institution. Patients were treated with curative intent and have received chemoradiotherapy alone or followed by surgery. Different prognostic parameters were correlated to survival: cancer-related factors, patient-related factors and parameters derived from PET-CT (maximum standardized uptake value [SUV max], metabolically active tumor volume either measured with an automatic segmentation software ["fuzzy locally adaptive bayesian": MATVFLAB] or with an adaptive threshold method [MATVseuil] and total lesion glycolysis [TLGFLAB and TLGseuil]). RESULTS: The median follow-up was 21.8 months (range: 0.16-104). The median overall survival was 22 months (95% confidence interval [95%CI]: 15.2-28.9). There were 67 deaths: 49 associated with cancer and 18 from intercurrent causes. None of the tested factors was significant on overall survival. In univariate analysis, the following three factors affected the specific survival: MATVFLAB (P=0.025), TLGFLAB (P=0.04) and TLGseuil (P=0.04). In multivariate analysis, only MATVFLAB had a significant impact on specific survival (P=0.049): MATVFLAB<18 cm(3): 31.2 months (95%CI: 21.7-not reached) and MATVFLAB>18 cm(3): 20 months (95%CI: 11.1-228.9). CONCLUSION: The metabolically active tumour volume measured with the automatic segmentation software FLAB on baseline PET-CT was a significant prognostic factor, which should be tested on a larger cohort.

French multicentre clinical evaluation of helical TomoTherapy for anal cancer in a cohort of 64 consecutive patients.

PURPOSE/OBJECTIVES: To assess feasibility and toxicity of Helical TomoTherapy for treating anal cancer patients. METHODS: From 2007 to 2011, 64 patients were consecutively treated with TomoTherapy in three centres for locally advanced squamous-cell anal carcinoma (T2 > 4 cm or N positive). Prescribed doses were 45 Gy to the pelvis including inguinal nodes and 59.4 Gy to the primary site and involved nodes with fractions of 1.8 Gy, five days a week. A positional Megavoltage Computed Tomography was performed before each treatment session. All acute and late toxicities were graded according to Common Terminology Criteria for Adverse Events version 3.0. Survival analysis was performed using the Kaplan-Meier method. RESULTS: Median follow-up was 22.9 months. Fifty-four women and 10 men were treated (median age: 62 years). Nineteen patients (29.7%) had T2, 16 patients (25.0%) T3, and 27 patients (42.2%) T4 tumours. Thirty-nine patients (60.9%) had nodal involvement. Median tumour size was 45 mm (range, 10-110 mm). Seven patients had a colostomy before treatment initiation. Fifty-seven patients received concomitant chemotherapy (5-FU/cisplatin or 5-FU/mitomycin-based therapy). Forty-seven patients (73.4 %) experienced a complete response, 13 a partial response or local recurrence, and 11 had salvage surgery; among these, six became complete responders, three experienced metastatic failure, and two local failure. At least four patients experienced metastatic recurrence (concomitant to a local failure for one patient). The two-year overall survival was 85.6% (95 %CI [71.1%-93.0%]), and the one-year disease-free survival, and colostomy-free survival were 68.7% (95 %CI [54.4%-79.4]), and 75.5% (95 %CI [60.7%-85.3%]) respectively. Overall survival, disease-free survival and colostomy free-survival were significantly better for women than men (p = 0.002, p = 0.004, and p = 0.002 respectively). Acute grade ≥3 toxicity included dermatologic (46.9% of patients), gastrointestinal (20.3%), and hematologic (17.2%) toxicity. Acute grade 4 hematologic toxicity occurred in one patient. No grade 5 event was observed. CONCLUSIONS: TomoTherapy for locally advanced anal cancer is feasible. In our three centres of expertise, this technique appeared to produce few acute gastrointestinal toxicities. However, high rates of dermatologic toxicity were observed. The therapeutic efficacy was within the range of expectations and similar to previous studies in accordance with the high rates of locally advanced tumours and nodal involvement.

[Are extensive fields useful for radiotherapy of esophageal cancer?]. / Des marges extensives sont-elles nécessaires pour la radiothérapie du cancer de l'œsophage ?

PURPOSE: Study of the pattern of relapse for locally advanced oesophageal cancer and analysis of the local recurrences according to irradiated volume. PATIENTS AND METHODS: We performed a monocentric retrospective study of patients treated in the integrated centre of oncology (Angers, France). Two treatment strategies were used: concurrent chemoradiation alone or followed by surgery. Recurrences were classified as: locoregional, either isolated or associated with distant metastasis, and metastatic only. Locoregional relapses were subclassified as in-field, out-field, or mixed. RESULTS: Between March 2004 and October 2011, 168 patients were treated: 130 by chemoradiation, and 38 by chemoradiation followed by surgery. The median supero-inferior margins added to the gross tumour volume in order to create the planning tumour volume was 5cm (range: 0.5-21). Sixty-two percent of patients (n=104) relapsed: 82 locoregional relapses (49%), including 45 isolated relapses (27%) and 37 associated with distant metastasis relapses (22%), and 22 metastatic relapses (13%). From the 82 locoregional relapses, only four isolated relapses were exclusively out-field. CONCLUSION: With 5cm supero-inferior margins added to gross tumour volume, less than 3% of patients had an isolated out-field recurrence. However, half of the patients suffered in-field local recurrence and one third had metastases. These findings advocate for a limited prophylactic nodal irradiation. Trials are ongoing to assess dose escalation or surgery in order to increase local control.

Genetic variations in the VEGF pathway as prognostic factors in metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy.

Angiogenesis is a significant biological mechanism in the progression and metastasis of solid tumors. Vascular endothelial growth factor (VEGF), its receptors and signaling effectors have a central role in tumor-induced angiogenesis. Genetic variation in the VEGF pathway may impact on tumor angiogenesis and, hence, on clinical cancer outcomes. This study evaluates the influence of common genetic variations within the VEGF pathway in the clinical outcomes of 172 metastatic colorectal cancer (mCRC) patients treated with first-line oxaliplatin/5-fluorouracil chemotherapy. A total of 27 single-nucleotide polymorphisms (SNPs) in 16 genes in the VEGF-dependent angionenesis process were genotyped using a dynamic array on the BioMark™ system. After assessing the KRAS mutational status, we found that four SNPs located in three genes (KISS1, KRAS and VEGFR2) were associated with progression-free survival. Five SNPs in three genes (ITGAV, KRAS and VEGFR2) correlated with overall survival. The gene-gene interactions identified in the survival tree analysis support the importance of VEGFR2 rs2071559 and KISS1 rs71745629 in modulating these outcomes. This study provides evidence that functional germline polymorphisms in the VEGF pathway may help to predict outcome in mCRC patients who undergo oxaliplatin/5-fluorouracil chemotherapy.