[Oligometastatic breast cancer : therapeutic implications of a new paradigm]. / Cancer du sein oligométastatique : implications thérapeutiques d'un nouveau paradigme.

INTRODUCTION: Oligometastatic breast cancer incidence is recently increasing thanks to screening and imaging improvements. Unlike patients with metastatic disease, a small number of oligometastatic patients may expect a definitive remission, in case of aggressive management performed with intent to cure. We report the atypical evolution of an oligometastatic breast cancer patient, who lately relapsed with a different Her2 status. RESULTS: A 46 year old women was treated for an infiltrating duct breast carcinoma, initially diagnosed with oligometastases and an Her2- negative status. Treatments were performed in intent to cure but the patient relapsed 5 years later with a solitary Her2-positive liver metastasis. The aggressive local and systemic (using an anti- Her2 targeted therapy) management induced a still complete remission at last follow-up. CONCLUSION: Prognosis of breast oligometastatic cancer is unpredictable, but an aggressive with intent-to-cure management may bring benefits to patients. However very rare, the switch of Her2 status between initial diagnosis and relapse highlights tumor heterogeneity, and the fact that a cell population featuring targetable characteristics may appear due to anticancer drug induced-cell selection.

INTRODUCTION: L'incidence des cancers du sein oligométastatiques est en augmentation, grâce aux progrès du dépistage et de l'imagerie. Au contraire de la maladie métastatique, un faible pourcentage de ces patientes peut espérer une guérison définitive en cas de prise en charge menée en intention curative sur toutes les cibles. Nous rapportons le cas de l'évolution atypique d'une patiente oligométastatique, avec une récidive tardive d'un cancer du sein, aux caractéristiques génétiques transformées. Résultats : Une patiente de 46 ans a été prise en charge initialement pour un adénocarcinome mammaire d'emblée oligo-métastatique ne surexprimant pas Her2. Après un traitement à visée curative, la patiente a rechuté 5 ans plus tard avec une métastase hépatique unique, surexprimant Her2. La prise en charge locale curative et systémique avec une thérapie ciblant Her2 a permis la rémission complète persistante après 3 ans de suivi. CONCLUSION: Le pronostic de la maladie oligométastatique du sein doit être abordé avec prudence, mais un traitement réalisé en intention curative peut apporter un bénéfice aux patientes. Le changement de statut Her2 entre le diagnostic primitif et la récidive -fait très rare- souligne l'hétérogénéité de la population tumorale, dont une fraction présentant des caractéristiques génétiques particulières peut émerger, sous la pression de sélection des drogues anticancéreuses.

Navigating the highlights of phase III trials: a watchful eye on evidence-based radiotherapy.

BACKGROUND: Phase III randomized controlled trials (RCTs) are the cornerstone of evidence-based oncology. However, there is no exhaustive review describing the radiotherapy RTCs characteristics. The objective of the present study was to describe features of all phase III RCTs including at least a radiation therapy. METHODS AND MATERIALS: Requests were performed in the Medline database (via PubMed). The latest update was performed in April 2016, using the following MESH terms: 'clinical trials: phase III as topic', 'radiotherapy', 'brachytherapy', as keywords. RESULTS: A total of 454 phase III RCTs were identified. Studies were mainly based on open (92.1%) multicenter (77.5%) designs, analyzed in intend to treat (67.6%), aiming at proving superiority (91.6%) through overall survival assessment (46.5%). Most frequently studied malignancies were head and neck (21.8%), lung (14.3%) and prostate cancers (9.9%). Patients were mainly recruited with a locally advanced disease (73.7%). Median age was 59 years old. Out of 977 treatment arms, 889 arms experienced radiotherapy, mainly using 3D-conformal radiotherapy (288 arms, 32.4%). Intensity-modulated techniques were tested in 12 arms (1.3%). The intervention was a non-cytotoxic agent addition in 89 studies (19.6%), a radiation dose/fractionation modification in 74 studies (16.3%), a modification of chemotherapy regimen in 63 studies (13.9%), a chemotherapy addition in 63 studies (13.9%) and a radiotherapy addition in 53 trials (11.7%). With a median follow-up of 50 months, acute all-grade and grade 3-5 toxicities were reported in 49.6% and 69.4% of studies, respectively. Radiotherapy technique, follow-up and late toxicities were reported in 60.1%, 74%, and 31.1% of studies, respectively. CONCLUSION: Phase III randomized controlled trials featured severe limitations, since a third did not report radiotherapy technique, follow-up or late toxicities. The fast-paced technological evolution creates a discrepancy between literature and radiotherapy techniques performed in daily-routine, suggesting that phase III methodology needs to be reinvented.

Genomic alterations and radioresistance in breast cancer: an analysis of the ProfiLER protocol.

BACKGROUND: Breast cancer (BC) patients with comparable prognostic features have heterogeneous outcomes, party related to a possible radiotherapy resistance leading to local-regional recurrences (LRR). The objective of the present study was to identify predictive molecular biomarkers of LRR of BC. PATIENTS AND METHODS: Genetic profile of 146 BC patients' tumours included in the ProfiLER clinical trial (NC01774409) between 2013 and 2016 were analysed using next-generation-sequencing and comparative-genomic-hybridization tests. Patients and tumour characteristics were retrospectively collected and analysed for association with genomic rearrangements (mutations, amplification, deletions). Only gene alterations observed in >3% of the tumours were selected. RESULTS: A total of 193 genomic rearrangements were identified, and 16 were observed in >3% of tumours. One was statistically correlated to the risk of local relapse. A median loco-regional progression-free survival (LRPFS) of 23.6 years was reported for PIK3CA mutation carriers (n = 31, 21.2%) versus 9.9 years for PIK3CA wild-type patients (HR 0.27, 95% CI 0.12-0.65, P = 0.002 in univariate analysis). PIK3CA mutation was identified as an independent protective factor on LRR using multivariate analysis (HR 0.29, 95% CI 0.09-0.99, P = 0.047). All other mutations, amplifications or deletions were not found associated with LRPFS. CONCLUSION: PIK3CA mutation was associated with a lower risk of local relapse in this population of BCs. This is consistent with recent studies suggesting PIK3CA to be part of biological pathways impacting the radiosensitivity.

Prospective evaluation of systematic use of peripherally inserted central catheters (PICC lines) for the home care after allogeneic hematopoietic stem cells transplantation.

PURPOSE: Long-term catheters are often necessary for outpatient care after an allogeneic hematopoietic stem cell transplantation (HSCT), However, there is paucity of data on the use of peripherally inserted central catheter (PICC) in post-HSCT setting. METHODS: We prospectively evaluated the systematic use of PICC in 37 consecutive patients returning home after HSCT. RESULTS: In 6 out of 37 patients, the PICC was exclusively used for weekly blood controls. In 31 patients, the PICC line was used at home for hydration (18), antibiotics (3), intravenous human Ig (7), transfusions (10), extracorporeal photopheresis (3), chemotherapy (2), artificial nutrition (1), and/or palliative care (1). PICC complications were reported in ten patients (27%), causing eight PICC removals. At the end of the study, 35 patients had their PICC removed. PICCs were used with a median duration of 67 days. Reasons for removal were that PICC was not considered to be useful any longer (16), suspicion of infection (inflammation without documentation) (5) or infection (2), patient's wish (4), death (4), accidental withdrawal (2), puncture site bleeding (1), and catheter change due to extracorporeal photopheresis (1). Three venous thromboses were reported (8%), requesting one PICC removal because of associated infection. In other cases, an antithrombotic treatment was initiated. CONCLUSIONS: Although the number of patients included in the study was small, our results suggest that PICC is a safe long-term venous access for home care after HSCT.

[Atypical presentation of a breast cancer pituitary metastasis]. / Découverte fortuite d'une métastase hypophysaire d'un cancer du sein : cas clinique.

Pituitary metastasis occur in 1-5 % of patients with cancer. We report the discovery of a unique pituitary metastasis of breast cancer. A 67 years old woman was treated in 2003 for local adenocarcinoma. After bone metastatic relapse in 2008, the patient developed diplopia and diabetes insipidus. An MRI revealed a histologically proven metastatic pituitary nodule. Further explorations revealed failure of multiple endocrine axes. Pituitary metastases are relatively rare, but are probably under-diagnosed in the presence of advanced cancers with impaired general condition. This diagnosis should be considered in the context of cancer patients, with a recent history of diabetes insipidus, especially if the latter is associated with other neurological signs (ophthalmoplegia, cephallagia).

Les métastases hypophysaires surviennent chez 1 à 5 % des patients atteints de cancers. Nous rapportons ici la découverte fortuite d'une métastase hypophysaire d'un cancer du sein. Une patiente de 67 ans est prise en charge en 2003 pour un adénocarcinome mammaire localisé. Après une récidive métastatique osseuse en 2008, elle présente une diplopie et un diabète insipide. L'IRM cérébrale décèle une lésion hypophysaire dont l'origine métastatique est confirmée en anatomopathologie; une extension du bilan permet de diagnostiquer une insuffisance des multiples axes endocriniens. Les métastases hypophysaires sont des lésions relativement rares, mais qui restent probablement sous-diagnostiquées dans le contexte du cancer avancé avec altération majeure de l'état général. Ce diagnostic doit être évoqué en cas de découverte récente d'un diabète insipide, en particulier s'il est associé à des signes neurologiques (ophtalmoplégie ou céphalées).

[Prostate cancer of elderly patients: Place and role of geriatric assessment]. / Cancer de prostate des sujets âgés : place et rôle de l'évaluation gériatrique.

INTRODUCTION: The aim of this study was to appreciate the place and role of geriatric assessment in elderly patients with prostate cancer. MATERIALS AND METHODS: We performed a retrospective analysis of prostate cancer patients who underwent geriatric assessment during the therapeutic management from 2008 to 2014. Patient, tumor, treatment characteristics and their associated toxicity as well as the parameters of geriatric assessment were studied. The occurrence of geriatric assessment within the 3 months preceding a therapeutic decision was reviewed. RESULTS: Data of seventy-four patients were analyzed with a median follow-up of 15.6 years. The average age at diagnosis was 74.3 and 80.6 at the geriatric assessment. At the time of the geriatric assessment 64 patients had metastatic disease, 39 were in poor condition more than 50% of patients had walking ability disorders. Thirteen patients underwent radical surgery, 28 received radiotherapy, 30 patients had chemotherapy and hormonotherapy was prescribed for 72 patients. The geriatric assessment, requested on average 15 years after diagnosis, was not carried out within the 3 months preceding treatment decision for 55 patients. CONCLUSION: The recourse to geriatric assessment is predominantly used to endorse a decision of supportive care for elderly patients with prostate cancer. An early intervention by a geriatrician consultant for the initial management and then at each therapeutic event is a sine qua non condition for efficient personalized therapeutic management suitable to every patient according to physiological age. LEVEL OF EVIDENCE: 4.

Five-fraction HDR brachytherapy in locally advanced cervical cancer: A monocentric experience.

PURPOSE: The 5-fraction scheme (5×5-5.5Gy) is a common High-Dose Rate (HDR) intracavitary brachytherapy regimen for locally advanced cervical cancer (LACC). Yet, its equivalence with Pulse-Dose rate (PDR) schemes remains unproved. The present study aimed at reporting on the outcome of LACC patients treated with 5-fraction HDR brachytherapy. MATERIALS AND METHODS: The medical records of all consecutive patients treated with curative-intent HDR brachytherapy for a LACC in a French Cancer Center were retrospectively reviewed. RESULTS: Thirty-eight LACC patients underwent a 5-fraction intracavitary HDR brachytherapy between 2015 and 2019 (median dose=25Gy/5 fractions, following external-beam radiotherapy). Median age at diagnosis was 60 (range: 29-87). Thirty-one patients (81.5%) underwent concurrent chemotherapy. Tumor stages ranged from 3 IB2 (7.8%), 4 IB3 (10.5%), 4 IIA2 (10.5%), 12 IIB (31.7%), 1 IIIA (2.6%), 2 IIIB (5.3%), 7 IIIC1 (18.5%), 4 IIIC2 (10.5%), 1 IVA (2.6%) (2018 FIGO). Median D90% to CTVHR reached 79.5Gy (EQD2). Median D90% to CTVIR reached 59.5Gy (EQD2). Median Bladder D2cc was 69.8Gy (EQD2). Median Rectum D2cc was 58.3Gy (EQD2). Acute/late grade 3 toxicity was reported in one patient (2.6%). No grade 4-5 toxicity occurred. At a median 38 months follow-up, 10 patients (26.3%) had local (n=7, 18.4%), nodal (n=6, 15.7%) and/or distant (n=7, 18.4%) relapse. Three-year overall survival rate was of 81.6%. CONCLUSION: The 5-fraction HDR scheme was well tolerated even in frail patients. Three-year local control was lower than expected. Treatment (absence of parametrial interstitial implants and use of cervical EBRT boost) and patients' characteristics (age, comorbidities) may explain such results.

[Predictors of asthenia in breast and prostate cancer patients undergoing curative radiotherapy]. / Facteurs de risque d'asthénie en cours de la radiothérapie des cancers du sein et de la prostate.

PURPOSE: Patients frequently report asthenia during radiation. The present study aimed at identifying the correlation between numerous clinical and tumoral factors and asthenia in breast and prostate cancer patients treated by curative radiotherapy. MATERIALS AND METHODS: A retrospective study was conducted at the Lucien Neuwirth Cancer Institute (France). All breast and prostate cancer patients undergoing curative radiotherapy during 2015 were screened (n=806). Patient's self-evaluation of asthenia and radiotherapy tolerance was assessed through verbal analogic scale (0/10 to 10/10). Data about toxicities, travel distance and travel time, tumor's characteristics, radiotherapy treatment planning, previous cancer therapies, were collected from medical records. RESULTS: 500 patients were included (350 in the breast cancer group and 150 in the prostate cancer group). In all, 86% of patients in the breast cancer group reported asthenia, with a 5/10 median score. In all, 54% of patients in the prostate cancer group reported asthenia, with a 2/10 median score. Univariate analysis showed correlation between asthenia and radiotherapy tolerance as well as tumor staging, in the prostate cancer group. No other correlation was evidenced. CONCLUSION: Radiotherapy-related fatigue is a common side effect. This study showed that most of the factors related to patients or disease that are commonly used to explain fatigue during curative treatments, seem finally to be not correlated with asthenia.

[Treatment de-intensification strategies for HPV-driven oropharyngeal cancer: A short review]. / Désescalade thérapeutique dans les cancers de l'oropharynx induit par les HPV : mise au point.

The incidence of oropharyngeal cancer induced by human papillomavirus (HPV) infection is steadily increasing in developed countries. These tumors are more chemoradiosensitive and have a better prognosis than HPV-negative one. In addition, they occur in younger and better-off patients with longer life expectancy. Current radiotherapy and chemotherapy protocols are currently being questioned as they may expose HPV-positive patients to excessive treatment and unnecessary toxic effects. Less intensive treatment regimens could possibly achieve similar efficacy with lower toxicity and improved quality of life. The aim of this work was to summarize the knowledge on these tumors and their implications for radiation oncologists. In this update, we will discuss ongoing de-escalation trials and highlight the issues raised by these studies. We will also comment on the results of recently published de-intensification studies. Three main strategies are analyzed in the present article: the de-escalation of the drug associated with radiotherapy, the de-escalation of the radiotherapy dose (in concomitant chemoradiotherapy, after induction chemotherapy, in a postoperative setting) and de-escalation of radiation target volumes. Our findings ultimately indicate that clinicians should not change the management of oropharyngeal cancer patients outside of clinical trials.

[Physiopathology and pharmacological perspectives in the treatment of radiation enteritis]. / Physiopathologie et modulation pharmacologique de l'entérite radique.

The small intestine is an organ frequently exposed in abdominal and pelvic irradiations. Acute and late toxicity can sometimes be difficult to manage and can significantly affect the quality of life of patients. Currently there is no guideline on the management of acute and late side effects induced by therapeutic irradiation. The aim of this review is to summarize available data on the pathophysiology of radiation enteritis, and to highlight potential preventive strategies and principles of treatment of radiation enteritis.

Use of 4D-CT for radiotherapy planning and reality in France: Data from a national survey.

PURPOSE: Lung and some digestive tumours move during a respiratory cycle. Four-dimensional scanography (4D-CT) is commonly used in treatment planning to account for respiratory motion. Although many French radiotherapy centres are now equipped, there are no guidelines on this subject to date. We wanted to draw up a description of the use of the 4D-CT for the treatment planning in France. METHODS AND MATERIAL: We conducted a survey in all French radiotherapy centres between March and April 2017. RESULTS: One hundred and seventy-two were contacted. The participation rate was 88.37%. The use of the 4D-CT seems to be common and concerned planning for 15.28% of kidney and adrenal cancers, 19.72% of pancreatic cancers, 27.78% of oesophageal cancers and 73.24% of lung cancers in case of normofractionated treatments. The use of the 4D-CT was also widespread in the case of stereotactic body radiation therapy: with 61.11% in the case of pulmonary irradiation and 34.72% in the case of hepatic irradiation. Many centres declared they carried out several 4D-CT for treatment planning (29, 55% in case of stereotactic body radiation therapy for lung tumours and 20% for liver tumours). Private centres tend to repeat 4D-CT more. CONCLUSION: Although the use of the 4D-CT appears to be developing, it remains very heterogeneous. To date, the repetition of the 4D-CT has been very poorly studied and could be the subject of clinical studies, allowing to define in which indications and for which populations there is a real benefit.

Rare histologic types of rectal cancer: A monocentric cases series report.

PURPOSE: There is paucity of data on rectal cancer with uncommon histologic types. The objective was to describe managements of care and outcomes in patients with rectal cancer of histologic types other than adenocarcinoma. MATERIAL AND METHODS: This monoinstitutional retrospective study included all patients with rectal cancer undergoing rectal radiotherapy. RESULTS: From 2004 to 2015, 744 patients were treated for rectal cancer, and ten had a histologic type other than adenocarcinoma. The median age was 60.7 years (range: 34.6-80.4 years). Histologic types were neuroendocrine (four), adenosquamous (one), undifferentiated with large cell (one), clear cell (one), anaplastic with small cell (one), signet ring cell (one) and adenocarcinoma with choriocarcinomatous differentiation (one). Four patients were initially diagnosed with a stage IV rectal cancer, and two ultimately became metastatic. Six patients underwent surgery, with four neoadjuvant chemoradiotherapies. None experienced complete response and two had incomplete resections. First-line and concomitant chemotherapies were adapted to histology results, mainly with etoposide and platinum salts for neuroendocrine and small cells tumours. Four patients experienced progression before first line treatments were achieved. Median progression free survival and overall survival were 3.8 and 10.1 months respectively. Two patients were long survivors (22 and 54.7 months, both still alive). All other died of rectal cancer. CONCLUSION: The present study highlights the rarity and the specificities of uncommon histologic types of rectal cancer. We report the real-life management and outcome of rare histologic types of rectal cancers, with dismal prognosis of stage IV tumours. We also report that treatments were adapted to histology.

Pharmacological modulation of radiation-induced oral mucosal complications.

Radiation-induced mucositis is a common toxicity, especially in patients with head and neck cancers. Despite recent technological advances in radiation therapy, such as intensity-modulated radiotherapy, radiation-induced mucositis is still causing treatment disruptions, negatively affecting patients' long and short term quality of life, and impacting medical resources use with economic consequences. The objective of this article was to review the latest updates in the management of radiation-induced mucositis, with a focus on pharmaceutical strategies for the prevention or treatment of mucositis. Although numerous studies analysing the prevention and management of oral radiation-induced mucositis have been conducted, there are still few reliable data to guide daily clinical practice. Furthermore, most of the tested drugs have shown no (anti-inflammatory cytokine, growth factors) or limited (palifermin) effect. Therapies for acute oral mucositis are predominantly focused on improving oral hygiene and providing symptoms control. Although low-level laser therapy proved efficient in preventing radiation-induced oral mucositis in patients with head and neck cancer, this intervention requires equipment and trained medical staff, and is therefore insufficiently developed in clinical routine. New effective pharmacological agents able to prevent or reverse radio-induced mucositis are required.

Outcomes and treatments of IB1 cervical cancers with high recurrence risk: A 13 years' experience.

PURPOSE: The aim of the present study was to identify management strategies and outcomes of patients with stage IB1 cervical cancer with high recurrence risk. MATERIALS AND METHODS: Medical files of all consecutive patients treated between 2004 and 2017 with external beam radiotherapy and/or brachytherapy for IB1 cervical cancer, whatever the lymph node status, were retrospectively reviewed. RESULTS: Forty-two patients were included, with a median age of 49.8 years old. Median tumour size, estimated with the initial pelvic magnetic resonance imaging, was 26mm (interquartile range [IQR]=19.5-35). Histological types were mainly squamous cell carcinoma (59.5%) and adenocarcinoma (33.3%). Lymphovascular invasion was reported for 38.1% of patients. Pelvic lymph nodes were involved for eight patients (19.0%). Surgery was performed for 39 patients (92.9%). A neoadjuvant treatment was delivered for 20 patients (47.6%), an adjuvant treatment for 19 patients (45.2%) and an exclusive radiotherapy (with or without chemotherapy) followed by brachytherapy for three patients (7.1%). Pathologic complete response was achieved in 61.5% of patients. With a median follow-up of 5.8 years (IQR=2.6-9.4), five patients (11.9%) experienced a tumour relapse. The five-year disease-free survival was 79.5% (95% confident interval [CI]=66.9-94.4), the five-year overall survival was 87.8% (95% CI=77.2-99.8), and the five-year disease-specific survival was 94.2% (95% CI=86.7-100). CONCLUSION: In current clinical practice, tailored treatments are delivered, and seems to give correct therapeutic index. However, clinical trials are needed to standardise treatment according to patient characteristics and recurrence risk factors.

Harnessing drug/radiation interaction through daily routine practice: Leverage medical and methodological point of view (MORSE 02-17 study).

BACKGROUND: Safety profile of the interaction between anticancer drugs and radiation is a recurrent question. However, there are little data regarding the non-anticancer treatment (NACT)/radiation combinations. The aim of the present study was to investigate concomitant NACTs in patients undergoing radiotherapy in a French comprehensive cancer center. METHODS: A prospective cross-sectional study was conducted. All cancer patients undergoing a palliative or curative radiotherapy were consecutively screened for six weeks in 2016. Data on NACTs were collected. RESULTS: Out of 214 included patients, a NACT was concomitantly prescribed to 155 patients (72%), with a median number of 5 NACTs per patient (range: 1-12). The most prescribed drugs were anti-hypertensive drugs (101 patients, 47.2%), psychotropic drugs (n = 74, 34.6%), analgesics (n = 78, 36.4%), hypolipidemic drugs (n = 57, 26.6%), proton pump inhibitors (n = 46, 21.5%) and antiplatelet drugs (n = 38, 17.8%). Although 833 different molecules were reported, only 20 possible modifiers of cancer biological pathways (prescribed to 74 patients (34.5%)) were identified. Eight out of the 833 molecules (0.9%), belonging to six drug families, have been investigated in 28 ongoing or published clinical trials in combo with radiotherapy. They were prescribed to 63 patients (29.4%). CONCLUSION: Drug-radiation interaction remains a subject of major interest, not only for conventional anticancer drugs, but also for NACTs. New trial designs are thus required.

Real-life efficacy of volumetric modulated arc therapy in head and neck squamous cell carcinoma.

OBJECTIVES: There is paucity of data on the efficacy of volumetric modulated arc therapy (VMAT) in head and neck squamous cell carcinoma (HNSCC). The objective of the present study was to investigate outcomes and patterns of recurrence in locally advanced HNSCC treated by VMAT. METHODS: A retrospective study included all patients with stage III or IV HNSCC undergoing curative VMAT. RESULTS: From 2010 to 2013, 130 patients were treated for locally advanced oropharynx (n=55; 42%), hypopharynx (n=38; 29%), larynx (n=22; 17%) or oral cavity (n=15; 12%) SCC. Median age was 60 years (range, 39-85). Median follow-up was 18.1 months (range, 0-43.7). By end of follow-up, 60 patients (46%) had died. Two-year progression-free and overall survival were respectively 63.6% and 77.3% for laryngeal tumors, 60% and 60% for oral cavity tumors, 52.6% and 57.6% for oropharyngeal tumors, and 38.8% and 54.7% for hypopharyngeal tumors. Most recurrences were located within or marginal to radiation therapy fields. CONCLUSION: This retrospective analysis is, to our knowledge, the largest study of the efficacy of VMAT in HNSCC. Recurrence patterns and outcomes were consistent with those previously reported for intensity-modulated radiotherapy.

HPV-16 variants' impact on uterine cervical cancer response to radiotherapy: A descriptive pilot study.

PURPOSE: Although the large impact of Human papilloma virus (HPV) in cervical cancer is established, its place as a therapeutic target is new and according to the growing literature, could be promising. In the present study, radiosensitivity's difference based on HPV-16 variants is assessed. PATIENTS AND METHODS: Variants of Human papilloma virus were identified before the exclusive radiotherapy in patients with cervical cancer. Data were prospectively collected. Fifty-nine patients were screened. RESULTS: Among the 59 screened patients, 34 (57.6%) were identified to be HPV-16 (+), with 13 European and two non-European variants. Of the 34 patients, 15 experienced exclusive radiotherapy. Among them, eight had complete response (seven with European and one with non-European variants), four with European variant had partial response, three with European variant had tumour persistence and one with non-European variant progressed at 3 months. CONCLUSION: No radiosensitivity difference was established, probably because of the limited population. Non-European variant aggressiveness might be suggested in accordance with the literature, as it was associated with the only tumour progression. Exclusive radiotherapy provides a unique and "pure" model of radioresistance in cervical cancer and could be the missing link between in vitro studies and state of the art chemoradiotherapy studies that probably feature too many parameters to identify radioresistance causes. The present study was a first step, with the future prospects of building a larger cohort study in order to better understand HPV-induced radioresistance and then to be able to propose new made-to-measure treatments.

Biomarkers of resistance to radiation therapy: a prospective study in cervical carcinoma.

BACKGROUND: Clinical parameters and proteins have recently been suggested as possible causes of radiotherapy (RT) resistance in cervical carcinoma (CC). The objective of the present study was to validate prognostic biomarkers of radiation resistance. METHODS: The present prospective study included patients undergoing RT with curative intent for histologically proven locally advanced squamous cell CC. Tissues and blood samples were systematically collected before RT initiation. Immuno-histochemistry was performed (IGF-IR α and ß, GAPDH, HIF-1 alpha, Survivin, GLUT1, CAIX, hTERT and HKII). Response to radiation was assessed through tumour response 3 months after RT completion, through overall survival (OS) and through progression-free survival (PFS). RESULTS: One hundred forty nine patients with a mean age of 46 years were included, with FIGO IIB (n = 53) and FIGO IIIB (n = 96) CCs. 61 patients were treated with exclusive RT + brachytherapy and 88 underwent chemo-radiotherapy + brachytherapy. Our findings suggest an association between hemoglobin level (Hb) (>11 g/dL) and 3 months complete response (p = 0.02). Hb level < 11 g/dL was associated with decreased PFS (p = 0.05) and OS (p = 0.08). Overexpression of IGF-1R ß was correlated with a decreased OS (p = 0.007). Overexpression of GLUT1 was marginally correlated with reduced OS (p = 0.05). PFS and OS were significantly improved in patients undergoing chemoradiation versus exclusive radiotherapy (PFS: p = 0.04; OS: p = 0.01). CONCLUSIONS: IGF-1R ß overexpression and Hb level (≤11 g/dl) were associated with poor prognosis, and thus appear to be possible interesting biomarkers of radiation resistance. Our results corroborate previous pre-clinical studies suggesting IGF-1R and hypoxia to be part of the biological pathways leading to radio-resistance.

[Medical prevention and treatment of radiation-induced pulmonary complications]. / Prévention médicale et traitement des complications pulmonaires secondaires à la radiothérapie.

Radiation-induced lung injuries mainly include the (acute or sub-acute) radiation pneumonitis, the lung fibrosis and the bronchiolitis obliterans organizing pneumonia (BOOP). The present review aims at describing the diagnostic process, the current physiopathological knowledge, and the available (non dosimetric) preventive and curative treatments. Radiation-induced lung injury is a diagnosis of exclusion, since clinical, radiological, or biological pathognomonic evidences do not exist. Investigations should necessarily include a thoracic high resolution CT-scan and lung function tests with a diffusing capacity of the lung for carbon monoxide. No treatment ever really showed efficacy to prevent acute radiation-induced lung injury, or to treat radiation-induced lung fibrosis. The most promising drugs in order to prevent radiation-induced lung injury are amifostine, angiotensin-converting-enzyme inhibitors and pentoxifylline. Inhibitors of collagen synthesis are currently tested at a pre-clinical stage to limit the radiation-induced lung fibrosis. Regarding available treatments of radiation-induced pneumonitis, corticoids can be considered the cornerstone. However, no standardized program or guidelines concerning the initial dose and the gradual tapering have been scientifically established. Alternative treatments can be prescribed, based on clinical cases reporting on the efficacy of immunosuppressive drugs. Such data highlight the major role of the lung dosimetric protection in order to efficiently prevent radiation-induced lung injury.

[Ototoxicity in head and neck cancers after radiotherapy and chemoradiotherapy: From primary prevention to tertiary prevention]. / Ototoxicité radio-induite et chimio-induite dans les cancers ORL : de la prévention primaire à la prévention tertiaire.

Each year, 15,000 head and neck cancer are treated in France. Prognosis is steadily improving. Consequently, limitation of late toxicities becomes essential. Ototoxicity is common, disabling and undervalued. We aimed to inventory primary, secondary and tertiary prevention measures to reduce ototoxicity induced by radiotherapy and chemotherapy, as well as its impact on quality of life of patients treated for head and neck cancer. External radiation therapy induced 30 to 40% of ototoxicity, including irreversible sensorineural hearing loss. Primary prevention of this risk is based on limiting the dose to the cochlea: 40Gy in case of radiotherapy alone, 10Gy during concomitant chemoradiotherapy with cisplatin. Dose gradients allowed by intensity-modulated radiotherapy help respecting these limits. Concurrent chemotherapy with high dose cisplatin (100mg/m2) also causes hearing loss by cochlear damages. Prescription of carboplatin-5-fluorouracil combination or cetuximab should be preferred in case of high risk of ototoxicity. This risk must be precisely evaluated before treatment. Ototoxicity monitoring during treatment allows early management, and lower long-term impact. Radiosensitivity predictive tests and research of genetic factors predisposing to chemo-induced ototoxicity should enable optimization of therapeutic choices and monitoring.