Predictive factors of toxicity of TPF induction chemotherapy for locally advanced head and neck cancers.

BACKGROUND: The rate of toxic deaths related to induction chemotherapy in the treatment of locally advanced head and neck cancers is unacceptable and calls into question this therapeutic strategy, which is however highly effective in terms of rate and speed of response. The purpose of the study was to investigate predictive factors of toxicity of induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) in locally advanced head and neck cancers (LAHNC). METHODS: Between June 2009 and December 2017, 113 patients treated consecutively with TPF were included retrospectively. Patients were receiving induction chemotherapy for either an inoperable cancer or laryngeal preservation. For inoperable cancer, induction chemotherapy was proposed to patients presenting either a large tumor with strong symptoms (dyspnea, dysphagia, pain) or a tumor with rapid progression. Risk factors were chosen among the initial patient and tumour characteristics and chemotherapy modalities. RESULTS: Eighty-nine patients (79%) were male; the median age was 58 years [32-71]. Sixty-nine (61%) patients were treated for inoperable cancer and 44 (39%) for laryngeal preservation. 45% had stage IVa cancer, 28% stage III and 25% stage IVb. Sixty percent of patients had a partial response after TPF, 22% had a complete response, 12% were stable, 5% were progressing, and 1% had a discordant response. Thirty-four patients (30%) received enteral feeding during induction chemotherapy with TPF. The possibility of oral feeding without a tube was predictive of a better response (p = 0.003). Seven (6%) patients died during TPF. There was an increased risk of death with preexisting liver dysfunction (liver dysmorphia on imaging or decrease prothrombin rate) (p = 0.032). There was an increased risk of grade ≥ 3 infection if an enteral feeding occurred during the period of induction chemotherapy (p = 0.03). CONCLUSIONS: TPF induction chemotherapy had an 82% objective response rate with 6% toxic deaths. Nutritional status and the presence of hepatic dysfunction are significant risk factors to be taken into account in therapeutic decisions.

A multicenter prospective phase II study of postoperative hypofractionated stereotactic body radiotherapy (SBRT) in the treatment of early-stage oropharyngeal and oral cavity cancers with high risk margins: the STEREO POSTOP GORTEC 2017-03 trial.

BACKGROUND: Primary surgery is usually the mainstay treatment in early-stage oropharyngeal and oral cavity cancer. Typically, neck surgery is performed. Negative tumor margins are recommended (> 5 mm). If feasible, re-resection of any positive margin is preferred. Otherwise, postoperative radiotherapy is required. Adjuvant postoperative radiotherapy can be limited to the primary site for patients with pT1-T2 tumors and negative neck exploration. Currently, both fractionated external beam radiotherapy and brachytherapy can have a role in the postoperative management of early-stage oropharyngeal and oral cavity cancer with high risk margins. Another possible alternative could be postoperative stereotactic body radiotherapy (SBRT). The aim of this study is to evaluate postoperative SBRT in the treatment of early-stage oropharyngeal and oral cavity cancer with high risk margins. METHODS: The STEREO POSTOP study is a national, open-label, non-randomized phase II trial within the GORTEC network. Patients with early-stage oropharyngeal and oral cavity cancers with high risk margins indicating the need for postoperative radiation are eligible for enrollment. SBRT consists of a total dose of 36 Gy in 6 fractions over 2 weeks. The primary endpoint is severe late toxicity defined as 2-year toxicity of grade ≥ 3 according to CTCAE V4.03 classification. The secondary endpoints include acute toxicity (≤ 3 months), local and locoregional control, disease-free and overall survival, quality of life of patients, nutritional impact and predictive factors of toxicity. The experimental design chosen is a one-step Fleming plan design without interim analysis as the primary endpoint will be evaluated at a 2-year follow-up. Ninety patients will be recruited. The study was started in January 2018 with a 4-year enrollment period and an estimated completion in January 2024. DISCUSSION: This study is the first prospective trial to evaluate head and neck cancer postoperative SBRT in the setting of early-stage oropharyngeal and oral cavity cancers with high risk margins. SBRT is an attractive option because it delivers a highly conformal dose of radiation in a limited number of fractions (like brachytherapy but with less contraindication), with steep dose gradients resulting in reduced normal tissue irradiation and with a short overall treatment time. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03401840 , registered on 17-1-2018. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°ID - RCB 2017-A02058-45, registered on July 2017. Protocol version: Version 3 dated from 25th November 2019.

After 4 years of survival, patients treated for an oral or oropharyngeal cancer have more neurosensorial disorders than chronic pain and a better quality of life.

PURPOSE: During follow-up, patients in remission after oral or oropharyngeal cancer are few to express pain, depression or anxiety, their chief complain are dry mouth and difficulties to chewing. The aim of the study is to estimate prevalence of pain, quality of life and their evolution over four years. METHODS: This prospective observational study included 21 patients between June and September 2017. Clinical examination, neurosensory examination and questionnaires (using visual analogic scale DN4, PCS-CF, HADS EORTC QLQ30 and H&N 35) were performed and a second time 4 years later. RESULTS: After 4 years, 17 patients could be reviewed. In 2017 as in 2021, two patients (11.8 %) experience neuropathic pain. In 2017, 14 (82.3 %) reported paresthesia or dysesthesia or hypo/anesthesia, none of them have provoked pain to a mechanical or thermal stimulus. In 2021, only 9 (53 %) still report those symptoms. Global analysis of the questionnaire QLQC30 reveals a significant increase quality of life of all 17 patients (p = 0.0003). For the two questionnaires QLQC30 and QLQ-H&N 35, dry mouth, sticky saliva, difficulties for eating and relation with food, are strong grievances which an absence of amelioration or a degradation. CONCLUSIONS: Neurosensory disturbance is a frequent symptom but pain concerns only 11.8 % of patients. Quality of life increase globally, yet difficulties concerning oral cavity functions endure. IMPLICATIONS FOR CANCER SURVIVORS: For remission patients, pain is an unfrequent situation unlike neurosensory disturbance. Support care improve life quality. In case of onset of pain, recurrence and osteoradionecrosis should be mentioned immediately.

[French national standard for the treatment of squamous cell carcinoma of upper aero-digestive tract - General principles of treatment]. / Référentiel national de traitement des carcinomes épidermoïdes des voies aérodigestives supérieures ­ Principes généraux de traitement.

OBJECTIVES: The management of upper aerodigestive tract cancers is a complex specialty. It is essential to provide an update to establish optimal care. At the initiative of the INCa and under the auspices of the SFORL, the scientific committee, led by Professor Béatrix Barry, Dr. Gilles Dolivet, and Dr. Dominique De Raucourt, decided to develop a reference framework aimed at defining, in a scientific and consensus-based manner, the general principles of treatment for upper aerodigestive tract cancers applicable to all sub-locations. METHODOLOGY: To develop this framework, a multidisciplinary team of practitioners was formed. A systematic analysis of the literature was conducted to produce recommendations classified by grades, in accordance with the standards of the French National Authority for Health (HAS). RESULTS: The grading of recommendations according to HAS standards has allowed the establishment of a reference for patient care based on several criteria. In this framework, patients benefit from differentiated care based on prognostic factors they present (age, comorbidities, TNM status, HPV status, etc.), conditions of implementation, and quality criteria for indicated surgery (operability, resectability, margin quality, mutilation, salvage surgery), as well as quality criteria for radiotherapy (target volume, implementation time, etc.). The role of medical and postoperative treatments was also evaluated based on specific criteria. Finally, supportive care must be organized from the beginning and throughout the patients' care journey. CONCLUSION: All collected data have led to the development of a comprehensive framework aimed at harmonizing practices nationally, facilitating decision-making in multidisciplinary consultation meetings, promoting equality in practices, and providing a state-of-the-art and reference practices for assessing the quality of care. This new framework is intended to be updated every 5 years to best reflect the latest advances in the field.

Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial.

BACKGROUND: Concomitant chemoradiotherapy and accelerated radiotherapy independently improve outcomes for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC). We aimed to assess the efficacy and safety of a combination of these approaches. METHODS: In our open-label phase 3 randomised trial, we enrolled patients with locally advanced, stage III and IV (non-metastatic) HNSCC and an Eastern Cooperative Oncology Group performance status of 0-2. We randomly allocated patients centrally with a computer program (with centre, T stage, N stage, and localisation as minimisation factors) in a 1:1:1 ratio to receive conventional chemoradiotherapy (70 Gy in 7 weeks plus three cycles of 4 days' concomitant carboplatin-fluorouracil), accelerated radiotherapy-chemotherapy (70 Gy in 6 weeks plus two cycles of 5 days' concomitant carboplatin-fluorouracil), or very accelerated radiotherapy alone (64·8 Gy [1·8 Gy twice daily] in 3·5 weeks). The primary endpoint, progression-free survival (PFS), was assessed in all enrolled patients. This trial is completed. The trial is registered with ClinicalTrials.gov, number NCT00828386. FINDINGS: Between Feb 29, 2000, and May 9, 2007, we randomly allocated 279 patients to receive conventional chemoradiotherapy, 280 to accelerated radiotherapy-chemotherapy, and 281 to very accelerated radiotherapy. Median follow-up was 5·2 years (IQR 4·9-6·2); rates of chemotherapy and radiotherapy compliance were good in all groups. Accelerated radiotherapy-chemotherapy offered no PFS benefit compared with conventional chemoradiotherapy (HR 1·02, 95% CI 0·84-1·23; p=0·88) or very accelerated radiotherapy (0·83, 0·69-1·01; p=0·060); conventional chemoradiotherapy improved PFS compared with very accelerated radiotherapy (0·82, 0·67-0·99; p=0·041). 3-year PFS was 37·6% (95% CI 32·1-43·4) after conventional chemoradiotherapy, 34·1% (28·7-39·8) after accelerated radiotherapy-chemotherapy, and 32·2% (27·0-37·9) after very accelerated radiotherapy. More patients in the very accelerated radiotherapy group had RTOG grade 3-4 acute mucosal toxicity (226 [84%] of 268 patients) compared with accelerated radiotherapy-chemotherapy (205 [76%] of 271 patients) or conventional chemoradiotherapy (180 [69%] of 262; p=0·0001). 158 (60%) of 265 patients in the conventional chemoradiotherapy group, 176 (64%) of 276 patients in the accelerated radiotherapy-chemotherapy group, and 190 (70%) of 272 patients in the very accelerated radiotherapy group were intubated with feeding tubes during treatment (p=0·045). INTERPRETATION: Chemotherapy has a substantial treatment effect given concomitantly with radiotherapy and acceleration of radiotherapy cannot compensate for the absence of chemotherapy. We noted the most favourable outcomes for conventional chemoradiotherapy, suggesting that acceleration of radiotherapy is probably not beneficial in concomitant chemoradiotherapy schedules. FUNDING: French Ministry of Health.

Postoperative SBRT in the treatment of early-stage oropharyngeal and oral cavity cancers with high-risk margins: A dosimetric comparison of volumetric modulated arc therapy with or without non-coplanar arcs and acute toxicity outcomes from the STEREOPOSTOP GORTEC 2017-03 phase 2 trial.

Background and purpose: The STEREO POSTOP GORTEC 2017-03 phase 2 trial (NCT03401840) evaluates postoperative stereotactic body radiotherapy (SBRT) in case of high-risk margins for pT1-T2/N0 oropharyngeal and oral cavity tumors. The present ancillary study aimed to compare the dosimetric impact of adding non-coplanar arcs to the volumetric modulated arc therapy (VMAT) technique and to evaluate acute toxicities on the first patients included in this trial. Materials and methods: Ten patients were included. Patients were treated with Novalis TX®. The total dose was 36 Gy (100 % isodose line) in 6 fractions, treated every other day. Two treatment plans were created for each patient: one plan using 2 coplanar arcs only (VMATc) and one plan using coplanar and 3 non-coplanar arcs (VMATc + nc). Acute toxicity was evaluated according to NCI CTCAE criteria V4.03. Results: Median age was 62 years. Localization of tumor was the mobile tongue for 6 patients, floor of mouth for 2, cheek for 1, and gingiva for 1. Six patients had pT2N0 tumors (AJCC 7th edition) and 4 had pT1N0. Mean CTV and PTV volumes were 36.4 and 56.1 cc respectively. Mean PTV coverage by the 36 Gy isodose was 98.2 % for both techniques (p = ns), with comparable conformity indexes (1.1 for VMATc vs 1.07 for VMATc + nc; p = 0.23). VMATc + nc had a significantly better gradient index (3.45 vs 2.97; p = 0.01), resulting in a significantly better sparing of most organs at risk. For example, mean Dmean to the oral cavity, lips, and homolateral parotid were respectively of 16.8 Gy, 11.1 Gy, and 10.4 Gy for VMATc vs 14.8 Gy (p = 0.005), 8.1 Gy (p = 0.001), 6.5 Gy (p = 0.04) for VMATc + nc. No grade ≥ 4 or higher acute toxicity was reported. The most common acute toxicity was grade ≥ 2 mucositis. Conclusion: VMATc + nc had better dosimetric outcomes than VMATc and has become the standard technique for patients treated in the STEREO POSTOP GORTEC 2017-03 trial (NCT03401840) in our institution. Acute toxicity appears acceptable.

Outcomes among oropharyngeal and oral cavity cancer patients treated with postoperative volumetric modulated arctherapy.

Background: Presently, there are few published reports on postoperative radiation therapy for oropharyngeal and oral cavity cancers treated with IMRT/VMAT technique. This study aimed to assess the oncological outcomes of this population treated with postoperative VMAT in our institution, with a focus on loco-regional patterns of failure. Material and methods: Between 2011 and 2019, 167 patients were included (40% of oropharyngeal cancers, and 60% of oral cavity cancers). The median age was 60 years. There was 64.2% of stage IV cancers. All patients had both T and N surgery. 34% had a R1 margin, 42% had perineural invasion. 72% had a positive neck dissection and 42% extranodal extension (ENE). All patients were treated with VMAT with simultaneous integrated boost with three dose levels: 66Gy in case of R1 margin and/or ENE, 59.4-60Gy on the tumor bed, and 54Gy on the prophylactic areas. Concomittant cisplatin was administrated concomitantly when feasible in case of R1 and/or ENE. Results: The 1- and 2-year loco-regional control rates were 88.6% and 85.6% respectively. Higher tumor stage (T3/T4), the presence of PNI, and time from surgery >45 days were significant predictive factors of worse loco-regional control in multivariate analysis (p=0.02, p=0.04, and p=0.02). There were 17 local recurrences: 11 (64%) were considered as infield, 4 (24%) as marginal, and 2 (12%) as outfield. There were 9 regional recurrences only, 8 (89%) were considered as infield, and 1 (11%) as outfield. The 1- and 2-year disease-free survival (DFS) rates were 78.9% and 71.8% respectively. The 1- and 2-year overall survival (OS) rates were 88.6% and 80% respectively. Higher tumor stage (T3/T4) and the presence of ENE were the two prognostic factors significantly associated with worse DFS and OS in multivariate analysis. Conclusion: Our outcomes for postoperative VMAT for oral cavity and oropharyngeal cancers are encouraging, with high rates of loco-regional control. However, the management of ENE still seems challenging.

Prognosis in Head and Neck Cancer: Importance of Nutritional and Biological Inflammatory Status.

OBJECTIVES: To determine the importance of nutritional status, social status, and inflammatory status in the prognosis of head and neck cancer. STUDY DESIGN: Single-center retrospective study of prospectively collected data. SETTING: Tertiary referral center. METHODS: Ninety-two consecutive patients newly diagnosed for cancer of the upper aerodigestive tract without metastases were assessed at time of diagnosis for several prognostic factors. Nutritional status was assessed by the nutritional risk index, social status by the EPICES score, and inflammatory status by the systemic inflammatory response index. The primary endpoint was overall survival. RESULTS: In multivariable analysis, the main prognostic factors were the TNM classification (hazard ratio [HR] = 3.34, P = .002, for stage T3-4), malnutrition as assessed by the nutritional risk index (HR = 3.64, P = .008, for severe malnutrition), and a systemic inflammatory response index score ≥1.6 (HR = 3.32, P = .02). Social deprivation was not a prognostic factor. CONCLUSION: Prognosis in head and neck cancer is multifactorial; however, malnutrition and inflammation are important factors that are potentially reversible by early intervention.

Toxicity of induction chemotherapy in head and neck cancer: The central role of skeletal muscle mass.

BACKGROUND: To assess the impact of nutritional status on tolerance to induction chemotherapy by docetaxel, cisplatin and 5-fluorouracil (ICT) in head and neck cancer (HNC). METHODS: Ninety-two HNC patients were included. Toxicity was assessed according to common terminology criteria for adverse events. Nutritional status was assessed by body mass index (BMI), serum albumin, nutritional risk index (NRI), and CT scan (skeletal muscle mass index [SMI] at the first lumbar vertebral level). RESULTS: Before treatment, average BMI was 22.7 ± 4.6 kg/m2 , serum albumin 38.7 ± 5.8 g/L, NRI 97.6 ± 10.6, and SMI 36.4 ± 7.9 cm2 /m2 . After treatment, BMI was 23 ± 4.5, serum albumin 30.2 ± 7.1, and NRI 88.1 ± 9.2. During ICT, 52 (62%) patients developed at least one toxicity ≥ Grade 3. Pre-treatment SMI was the only predictive factor of toxicity irrespective of BMI (p = 0.04). CONCLUSION: Low skeletal muscle mass is a predictive factor of toxicity to ICT in HNC.

Local control and radionecrosis of brain metastases from non-small-cell lung cancer treated by hypofractionated stereotactic radiotherapy: Evaluation of predictive factors.

Background: The objective of our study was to report predictive factors of local control (LC) and radionecrosis (RN) of brain metastases (BM) of non-small cell lung carcinoma (NSCLC) treated by multifractionated stereotactic radiotherapy (MF-SRT) according to French recommendations. Method: From 2012 to 2020, 87 patients with 101 BM were retrospectively included. The median age was 63 years (37-85). GTV was defined using contrast-enhanced T1w MRI and was isotropically extended by 2 mm to form PTV. Mean maximum BM diameter was 24.5 mm (10-46). Patients were treated with dynamic arctherapy from May 2012 to February 2016 and then with VMAT. The total prescribed dose was 23.1 Gy prescribed to the encompassing 70% isodose, in 3 fractions. Results: LC rates at 6 months, 1 year and 2 years was 95.7%, 90.7% and 87.9% respectively. In multivariate analysis, high GTV Dmin (HR = 0.822, p = 0.012) was in favor of better LC whereas a large maximum diameter was predictive of poor LC (HR = 1.124, p = 0.02). GTV Dmin of 27.4 Gy was identified as a discriminant threshold of LC. In case of GTV Dmin ≥ 27.4 Gy, LC at 1 year was 95.3% versus 75.1% with GTV Dmin < 27.4 Gy. Cumulative incidence of RN at 6 months, 1 year and 2 years was 6.3%, 15.4% and 18.1%, respectively. In multivariate analysis, only dyslipidemia was predictive of RN (HR = 2.69, p = 0.03). No dosimetric predictive factor of RN was found in our study. Conclusion: MF-SRT (3x7.7 Gy on 70% isodose line, with PTV = GTV + 2 mm; according to French recommendations) of BM from NSCLC gives high LC rates with acceptable RN rate. A GTV Dmin of at least 27.4 Gy could be proposed to optimize dosimetric objectives. No dosimetric predictive factors of RN were found in this study. However, dyslipidemia was identified as a potential predictive factor of RN.

Radiographic-anatomy, natural history and extension pathways of parotid and submandibular gland cancers.

Intensity-modulated radiotherapy has been widely used routinely in recent past years for post-operative radiotherapy of salivary gland cancers Because of the sharp dose fall off outside of target volumes with IMRT, each volume must be strictly and rigorously defined, as the areas not specifically included in the target volume will not be treated to a therapeutic dose. The selection and delineation of these volumes is complex and requires extensive knowledge of parotid and submandibular gland cancer radiographic-anatomy, natural history and extension pathways (including local tumor spread, PNI risks and regional spread), which are detailed in the present article.

Treatment related factors associated with the risk of breast radio-induced-sarcoma.

BACKGROUND AND PURPOSE: The Radiation Induced Sarcoma (RIS) is a rare but serious adverse event following radiotherapy (RT). Current RT techniques are more precise, but irradiate a larger volume at a low dose. This study aimed to describe radiation characteristics in a large series of patients suffering from RIS. MATERIALS AND METHODS: Patient-representative voxel-based anthropomorphic phantoms were used to reconstruct patient-specific RT fields for 125 patients diagnosed with RIS after primary breast cancer. For each patient, the location of the RIS onset site was determined and transferred onto the phantom as a contour. Using a treatment planning system (TPS), the dose distribution on the RIS in the phantom was calculated. RESULTS: The mean dose (Dmean) received in the area where RIS subsequently developed was 47.8 ± 11.6 Gy. The median dose in the zones where RIS later developed ranged from 11 Gy to 58.8 Gy. The median time from RT to RIS development was 8 years (range 2-32 years). Analysis for predictors of time to radiation-induced sarcoma development highlighted a significant impact of age of patient during the RT whereas in multivariable analysis chemotherapy and hormonotherapy for primary breast cancer were not associated with a significant difference in time to diagnosis of RIS. CONCLUSIONS: This study highlights that the dose received by the tissue in which the RIS developed was almost 47 Gy. These results are encouraging for the use of new RT techniques increasing volumes receiving low doses, without fear of an excess of RIS over the next 10 years.

AIRO GORTEC consensus on postoperative radiotherapy (PORT) in low-intermediate risk early stages oral squamous cell cancers (OSCC).

Evidence on the efficacy of postoperative radiotherapy (PORT) in low-intermediate risk squamous cell carcinoma of the oral cavity (OSCC) remains inconclusive. Members of a task force from two national radio-oncology Associations (AIRO and GORTEC) defined 14 clinically relevant questions to identify "gray areas" pertinent to the indication for PORT in this clinical setting. Consequently, a literature review was performed on the topic. The resulting statements were then rated by an Expert Panel (EP) using a modified Delphi method. Only radiation oncologists were part of the discussion and voting on the scenarios. There was agreement on the 14 statements at the first round of voting. The task force then decided to propose clinical cases for the two more controversial statements that had received a lower agreement to better capture the Experts' attitudes. The clinical cases highlighted a more significant decisional heterogeneity. However, the good level of consensus reached among the two Associations gives relevant support in informing clinical choices while acknowledging general indications cannot fit all clinical situations and do not replace multidisciplinary discussion.

Significant correlation between gross tumor volume (GTV) D98% and local control in multifraction stereotactic radiotherapy (MF-SRT) for unresected brain metastases.

BACKGROUND: Stereotactic radiotherapy (SRT) should be applied with a biologically effective dose with an α/ß of 12 (BED12) ≥ 40 Gy to reach a 1-year local control (LC) ≥ 70%. The aims of this retrospective study were to report a series of 81 unresected large brain metastases treated with Linac-based multifraction SRT according to the ICRU 91 and to identify predictive factors associated with LC. METHODS: Included in this study were the first 81 brain metastases (BM) consecutively treated with Linac-based volumetric modulated arc therapy (VMAT) multifraction SRT from 2017 to 2019. The prescribed dose was 33 Gy for the GTV and 23.1 Gy (70% isodose line) for the PTV in 3 fractions (3f). Mean BM largest diameter and GTV were 25.1 mm and 7.2 cc respectively. Mean follow-up was 10.2 months. RESULTS: LC was 79.7% and 69.7% at 1 and 2 years respectively. Significant predictive factors of LC were GTV D98% (HR = 0.84, CI 95% = 0.75-0.95, p = 0.004) and adenocarcinoma as the histological type (HR = 0.29, CI 95% = 0.09-0.96, p = 0.042) in univariate and multivariate analysis. A threshold of 29 Gy for GTV D98% was significantly correlated to LC (1-year LC = 91.9% for GTV D98% ≥ 29 Gy vs 69.6% for GTV D98% < 29 Gy (p = 0.030)), corresponding to a BED12 = 52.4 Gy. No tumor progression was observed for a BED12 ≥ 53.4 Gy, corresponding to a GTV D98% ≥ 20 Gy /1f and GTV D98% ≥ 29.4 Gy 3f. Median OS was 15 months. Symptomatic radionecrosis occurred in 4.9% of cases. CONCLUSION: The GTV D98% is a strong reproducible significant predictive factor of LC for brain SRT. Dose prescription should lead to a GTV BED12 98% ≥ 52.4-53.4 Gy to significantly improve LC, corresponding to respectively a GTV D98% ≥ 19.7-20 Gy/1f and 29-29.4 Gy/3f.

Recommendations for postoperative radiotherapy in head & neck squamous cell carcinoma in the presence of flaps: A GORTEC internationally-reviewed HNCIG-endorsed consensus.

INTRODUCTION: Head and neck reconstructive surgery using a flap is increasingly common. Best practices and outcomes for postoperative radiotherapy (poRT) with flaps have not been specified. We aimed to provide consensus recommendations to assist clinical decision-making highlighting areas of uncertainty in the presence of flaps. MATERIAL AND METHODS: Radiation, medical, and surgical oncologists were assembled from GORTEC and internationally with the Head and Neck Cancer International Group (HNCIG). The consensus-building approach covered 59 topics across four domains: (1) identification of postoperative tissue changes on imaging for flap delineation, (2) understanding of tumor relapse risks and target volume definitions, (3) functional radiation-induced deterioration, (4) feasibility of flap avoidance. RESULTS: Across the 4 domains, international consensus (median score ≥ 7/9) was achieved only for functional deterioration (73.3%); other consensus rates were 55.6% for poRT avoidance of flap structures, 41.2% for flap definition and 11.1% for tumor spread patterns. Radiation-induced flap fibrosis or atrophy and their functional impact was well recognized while flap necrosis was not, suggesting dose-volume adaptation for the former. Flap avoidance was recommended to minimize bone flap osteoradionecrosis but not soft-tissue toxicity. The need for identification (CT planning, fiducials, accurate operative report) and targeting of the junction area at risk between native tissues and flap was well recognized. Experts variably considered flaps as prone to tumor dissemination or not. Discrepancies in rating of 11 items among international reviewing participants are shown. CONCLUSION: International GORTEC and HNCIG-endorsed recommendations were generated for the management of flaps in head and neck radiotherapy. Considerable knowledge gaps hinder further consensus, in particular with respect to tumor spread patterns.

Does regional lymph node irradiation improve the outcome of N0 and pN0 breast cancer?

This study compares the outcome of 76 patients with N0 breast carcinoma, node-negative at axillary lymph node dissection (pN0) after neoadjuvant chemotherapy (NeoCT), treated with (RLNI+, 39 patients) or without (RLNI-, 37 patients) elective regional lymph node areas irradiation. For RLNI- and RLNI+ groups respectively at 10 years, survival without local-regional recurrence was 95% and 91% (p = .59), survival without distant metastasis was 97% and 78% (p = .018) and overall survival was 96% and 75% (p = .013). Clinical size < 4 cm was a strong pronostic factor.

Significant Correlation Between Overall Survival and Mean Lung Dose in Lung Stereotactic Body Radiation Therapy (SBRT).

BACKGROUND: After stereotactic body radiation therapy (SBRT) for medically inoperable stage I non-small-cell lung cancer (NSCLC), more patients die of comorbidities, particularly severe pulmonary insufficiency, than of tumor progression. The aim of this study was to evaluate correlation between lung biologically effective dose (BED) with an α/ß ratio of 3 Gy (BED3) and overall survival (OS) for these patients. METHODS: From 2012 to 2017, we have developed a prospectively updated institutional database for all first 100 consecutively treated patients with inoperable Stage 1 (T1T2N0M0) NSCLC. All SBRT were conducted on a Novalis Tx® LINAC with two coplanar dynamic conformal arcs (84%) or with coplanar volumetric modulated arc therapy (VMAT) (16%). Mean GTV and PTV were 8.6 cc and 50.8 cc, respectively. The marginal dose prescribed to the PTV was the 80% isodose line (IDL), i.e., 54 Gy in 3 fractions for 76 patients (BED10 = 126 Gy) and 50 Gy in 5 fractions for 24 patients (BED10 = 83.3 Gy). Pulmonary heterogeneity has been taken into account by using Monte Carlo or AAA algorithms. Median follow-up was 25 months. RESULTS: At 1, 2, 3 and 5 years, local control (LC) was respectively 100, 98.2, 98.2, and 77.7%, and OS was respectively 83, 71.2, 58.1, and 33.2% (median OS was 49 months). Significant OS prognostic factors in univariate and multivariate analysis were mean lung BED3 (HR = 1.14, p = 0.01) and PTV volume (HR = 1.01, p = 0.004). A mean lung BED3 ≤ 5 Gy was significantly associated with a doubling of median OS from 29 months to more than 60 months (not achieved, p = 0.0068). For patients with a forced expiratory volume in 1 second (FEV1) ≤ 40%, a mean lung BED3 ≤ 4 Gy was significantly associated with a doubling of median OS from 23 to 46 months (p = 0.019). CONCLUSION: Mean lung BED3 is strongly and significantly associated with OS in SBRT for inoperable Stage I NSCLC. For all treated patients, a mean lung BED3 ≤ 5 Gy lead to a doubling of median OS. This threshold value should be reduced to 4 Gy for patients with FEV1 ≤ 40%.

Stereotactic Radiosurgery for Vestibular Schwannomas: Reducing Toxicity With 11 Gy as the Marginal Prescribed Dose.

BACKGROUND: Stereotactic radiosurgery (SRS) is a common treatment option for vestibular schwannomas. Historically, a dose de-escalation of the marginal prescribed dose from 16 Gy to 12-13 Gy has been done to limit toxicity without reducing local control (LC). We aimed to retrospectively report outcomes of Linac-based SRS for vestibular schwannomas treated with different doses. METHODS: Included in the study were 97 stage 1 (1%), 2 (56%), 3 (21.5%), and 4 (21.5%) vestibular schwannomas treated with Linac-based (Novalis®) SRS from 1995 to 2019. No margin was added to the GTV to create the PTV. The median marginal prescribed dose was 14 Gy (range: 12-16 Gy) before 2006 and then 11 Gy for all patients (61 pts). Mean tumor volume was 1.96 cm3, i.e., about 1.6 cm in diameter. Mean follow-up was 8.2 years. RESULTS: Following SRS, LC at 3, 5, and 10 years was 100%, 98.4%, and 95.6%, respectively [100% for those with ≤ 13 Gy as the marginal prescribed dose (NS)]. Toxicity to the trigeminal nerve was reported in 7.2% of cases (3.3% and 0% for transient and permanent toxicity for 11 Gy). The marginal prescribed dose was the only significant predictive factor in univariate and multivariate analysis (HR = 1.77, 95% CI = 1.07-3.10, p = 0.028). Toxicity to the facial nerve was reported in 6.2% of cases. The marginal prescribed dose was again the only significant predictive factor in univariate and multivariate analysis (HR = 1.31, 95% CI = 0.77-2.23, p = 0.049). CONCLUSION: Linac-based SRS for stages 1-3 vestibular schwannomas provides excellent outcomes: a 10-year LC rate of over 95%, with a permanent facial or trigeminal toxicity rate of under 5%. A marginal prescribed dose of 11 Gy seems to decrease nerve toxicity and facial toxicity in particular, without reducing LC. Prospective studies with longer follow-up are needed.

Concurrent cisplatin and dose escalation with intensity-modulated radiotherapy (IMRT) versus conventional radiotherapy for locally advanced head and neck squamous cell carcinomas (HNSCC): GORTEC 2004-01 randomized phase III trial.

BACKGROUND: Concurrent chemoradiotherapy (CRT) is the standard of care (SoC) in locally advanced (LA) head and neck squamous cell carcinomas (HNSCC). This trial was designed to test whether dose-escalated IMRT and cisplatin could improve locoregional control without increasing complications over 3D-radiotherapy. METHODS: Patients were randomized between 70 Gy/35F in 7 weeks with 3D-RT (Arm A) versus 75 Gy/35F with IMRT (Arm B). Both arms received 50 Gy in 25 fractions followed by a sequential boost of 20 Gy/10F in Arm A and 25 Gy/10F to gross tumor volume in Arm B, as well as 3 cycles of cisplatin at 100 mg/m2 during RT. The primary endpoint was locoregional progression (LRP). RESULTS: 188 patients were randomized: 85% oropharynx and 73% stage IVa. P16 status was documented for 137 oropharyngeal tumors with P16+ in 53 (39%) patients; and 90% were smokers. Median follow-up was 60.5 months. Xerostomia was markedly decreased in arm B (p < 0.0001). The 1-year grade ≥2 xerostomia (RTOG criteria) was 63% vs 23% and 3-year 45% vs 11% in arms A and B, respectively. Xerostomia LENT-SOMA scale was also reduced in arm B. Dose-escalated IMRT did not reduce LRP with an adjusted HR of 1.13 [95%CI = 0.64-1.98] (p = 0.68). Survival was not different (adjusted HR: 1.19 [95%CI = 0.78-1.81], p = 0.42). No interaction between p16 and treatment effect was found. CONCLUSION: Dose-escalated IMRT did not improve LRC in LA-HNSCC patients treated with concomitant CRT over standard 3D-RT. This trial reinforces the evidence showing IMRT reduces xerostomia in LA-HNSCC treated with radiotherapy. Clinicaltrial.gov: NCT00158678.

Practical clinical guidelines for contouring the trigeminal nerve (V) and its branches in head and neck cancers.

PURPOSE: The trigeminal nerve (V) is a major route of tumor spread in several head and neck cancers. However, only limited data are currently available for its precise contouring, although this is absolutely necessary in the era of intensity-modulated radiation therapy (IMRT). The purpose of this article is to present practical clinical guidelines for contouring the trigeminal nerve (V) in head and neck cancers at risk of spread along this nerve. METHOD: The main types of head and neck cancers associated with risks of spread along the trigeminal nerve (V) and its branches were comprehensively reviewed based on clinical experience, literature-based patterns of failure, anatomy and radio-anatomy. A consensus for contouring was proposed based on a multidisciplinary approach among head and neck oncology experts including radiation oncologists (JBi, ML, MO, VG and JB), a radiologist (VD) and a surgeon (CS). These practical clinical guidelines have been endorsed by the GORTEC (Head and Neck Radiation Oncology Group). RESULTS: We provided contouring and treatment guidelines, supported by detailed figures and tables to help, for the trigeminal nerve and its branches: the ophthalmic nerve (V1), the maxillary nerve (V2) and the manidibular nerve (V3). A CT- and MRI-based atlas was proposed to illustrate the whole trigeminal nerve pathway with its main branches. CONCLUSION: Trigeminal nerve (V) invasion is an important component of the natural history of various head and neck cancers. Recognizing the radio-anatomy and potential routes of invasion is essential for optimal contouring, as presented in these guidelines.