Contact X-ray brachytherapy for rectal cancer: Past, present, and future.

The Papillon experience and the Lyon R96-02 trial have shown that contact X-ray brachytherapy of 50kV is efficient and safe to achieve long term local control and organ preservation for cT1 and early cT2-3 rectal cancers. The OPERA trial, using the Papillon 50™ machine, brings further support to this preservation strategy for selected T2T3ab lesions. Future trials using a contact X-ray boost will try to consolidate and enlarge its place in organ preservation for rectal cancers.

Stereotactic Pelvic Reirradiation for Locoregional Cancer Relapse.

AIMS: Up to 40% of patients who have received radiation for a pelvic malignancy will develop locoregional recurrence in the previously irradiated volume. Stereotactic body radiotherapy (SBRT) has been used in the oligometastatic setting, and provides an ablative approach ideal for reirradiation. The purpose of this study was to evaluate the outcomes after SBRT reirradiation of extraosseous recurrences in the pelvis. MATERIALS AND METHODS: This single institution retrospective study evaluated patients treated with SBRT reirradiation in the pelvis from January 2011 to February 2018. Patients with more than five oligometastatic lesions, >7 cm in size, and recurrence within the prostate were excluded. RESULTS: In total, 30 patients were treated with SBRT with a median follow-up of 29.4 months. The primary tumour sites were most commonly rectum (30.8%) and prostate (30.8%). The median time interval between irradiation for the primary and SBRT reirradiation was 48 months (3-245). The typical reirradiation treatment was 35 Gy in five fractions, the median gross tumour volume size was 10.2 (0.3-110.5) ml and the most common target was the iliac nodes (40%). There were three (10%) acute grade 3 toxicities and no late grade 3 or more toxicities. At 12/24 months, local relapse-free survival, metastasis-free survival, progression-free survival and overall survival were 67.7%/50.7%, 67%/41.7%, 34.8%/14.9% and 83.2%/62.5%, respectively. On univariate analysis, improved local control was associated with low gross tumour volume (<10 ml) (P = 0.003) and prostate primary (P = 0.02), but was no longer significant on multivariate analysis. The proximity of organ at risk to the target did not significantly correlate with worse toxicity (P = 0.14) or tumour coverage (gross tumour volume: P = 0.8, planning target volume: P = 0.4). CONCLUSION: SBRT pelvic reirradiation in oligometastatic patients is a safe and effective treatment modality. Careful consideration should be taken with larger tumour size, as it may be associated with worse oncological and toxicity outcome.

A brief history of contact X-ray brachytherapy 50 kVp.

Contact X ray brachytherapy 50 kVp was initiated in the 1930s with the Siemens unit and popularized with the Philips unit in the 1950s. A renaissance was seen in the early 2000s with the Intrabeam™ unit for breast IORT. Presently the Papillon™ systems thanks to its high dose rate (>10Gy/mn) can be used to treat breast (IORT), skin, eyelid and rectal cancers. Future developments are expected to consolidate the place of contact radiotherapy as a safe and efficient treatment for accessible early tumors.

[Proton therapy for head and neck squamous cell carcinomas: From physics to clinic]. / Protonthérapie des carcinomes épidermoïdes des voies aérodigestives supérieures : de la physique à la clinique.

Intensity-modulated radiation therapy (IMRT) is presently the recommended technique for the treatment of locally advanced head and neck carcinomas. Proton therapy would allow to reduce the volume of irradiated normal tissue and, thus, to decrease the risk of late dysphagia, xerostomia, dysgeusia and hypothyroidism. An exhaustive research was performed with the search engine PubMed by focusing on the papers about the physical difficulties that slow down use of proton therapy for head and neck carcinomas. Range uncertainties in proton therapy (±3 %) paradoxically limit the use of the steep dose gradient in distality. Calibration uncertainties can be important in the treatment of head and neck cancer in the presence of materials of uncertain stoichiometric composition (such as with metal implants, dental filling, etc.) and complex heterogeneities. Dental management for example may be different with IMRT or proton therapy. Some uncertainties can be somewhat minimized at the time of optimization. Inter- and intrafractional variations and uncertainties in Hounsfield units/stopping power can be integrated in a robust optimization process. Additional changes in patient's anatomy (tumour shrinkage, changes in skin folds in the beam patch, large weight loss or gain) require rescanning. Dosimetric and small clinical studies comparing photon and proton therapy have well shown the interest of proton therapy for head and neck cancers. Intensity-modulated proton therapy is a promising treatment as it can reduce the substantial toxicity burden of patients with head and neck squamous cell carcinoma compared to IMRT. Robust optimization will allow to perform an optimal treatment and to use proton therapy in current clinical practice.

[Re-irradiation of head and neck cancers: Target volumes, technical evolutions and prospects]. / Réirradiation des tumeurs de la tête et du cou : volumes cibles, évolutions techniques et perspectives.

Malignant tumors of the head and neck have a predominantly regional recurrence pattern, with most deaths resulting from this progression. Optimization of re-radiation in recurrence setting is a major objective for these patients. Extensive research has been carried out with the PubMed search engine to find publications dealing with this topic. The first attempts to reirradiate the ORL sphere date back to the 1980s and the first to be performed by intensity modulation conformational radiotherapy (IMRT) date back to the late 1990s. Compared to 3 dimensional conformal radiotherapy, IMRT improves clinical outcomes and reduces toxicity. In IMRT series, associated or not with concomitant chemotherapy, the locoregional control obtained at 2 years was of the order of 45 to 65% and the overall survival of 15 to 60%, depending on predictive factors. Grade 3 acute toxicity occurred on the order of 10 to 30% and late-grade 3 toxicity on the order of 15 to 50%. In a selected population with low volumes tumors, stereotactic re-irradiation at a minimum dose of 35Gy obtained outcome comparable to IMRT. Re-irradiation of head and neck tumors by proton therapy is rare. The toxicity rate appears to be lower than that usually seen after photon therapy. However, we do not have a long follow-up. This technique therefore remains reserved for search protocols and represents a future perspective in these situations.

[Reirradiation of head and neck cancers]. / Réirradiation des cancers des voies aérodigestives supérieures.

Locoregional relapse in previously irradiated region for head and neck tumours is associated with a bad locoregional and distant prognosis. Reirradiation might be exclusive, or feasible in addition with surgery and/or chemotherapy, according to histopronostic factors. Data show that reirradiation is feasible with some severe toxicity due to the bad prognosis of this situation. Hyperfractionnated regimen with split course or normofractionnated regimen without split course are possible with similar efficacy. If tumour size is small, stereotactic ablative radiotherapy may be considered, and if the treatment centre has proton therapy, it could be proposed because of better organs at risk sparing. There is no standard regarding reirradiation schedules and several trials have to be done in order to determine the best technique. Nevertheless, it is agreed that a total dose of 60Gy (2Gy per fraction) is needed. Other trials testing the association with new systemic agents have to be performed, among them agents targeting the PD1/PD-L1 axis.

Candidate apoptotic and DNA repair gene approach confirms involvement of ERCC1, ERCC5, TP53 and MDM2 in radiation-induced toxicity in head and neck cancer.

INTRODUCTION: Single nucleotide polymorphisms (SNPs) of DNA repair and apoptosis genes have been associated with outcome in head and neck squamous cell carcinoma (HNSCC) patients receiving radiotherapy (RT). Our goal was to conduct a candidate gene study in HNSCC patients receiving RT or chemoRT. METHODS: 122 non-resectable HNSCC patients undergoing RT (N=38) or chemoRT (N=84) between 1992 and 2006 were retrospectively analyzed. ERCC1 Lys259Thr (rs735482), ERCC2 Lys751Gln (rs13181), ERCC5 His46His C>T (rs1047768), XRCC1 Arg399Gln (rs25487), TP53 Arg72Pro (rs1042522) and MDM2 309T>G (rs2279744) were analyzed on tumor DNA. SNP profile was considered to assess RT-related toxicity. RESULTS: All 120 evaluable patients experienced RT-related toxicity at any time. Among them, 83% had G3-4 acute side-effects during RT, mainly dysphagia, mucositis, epithelitis and/or xerostomia (DMEX). 28/105 patients (27%) had early G3-4 toxicity up to 3months after the end of RT. 29/96 patients (30%) had G3-4 late toxicity thereafter. The presence of G allele of MDM2 or Thr allele of ERCC1 was associated with a significantly higher risk of acute and/or early DMEX toxicity. The MDM2 309GG genotype was linked to a higher risk of acute G3-4 dermatitis. The ERCC5 TT genotype was associated with more frequent G3-4 late cervical skin fibrosis or xerostomia. Pro allele of TP53 72 was associated with a higher risk of G3-4 osteoradionecrosis. CONCLUSION: Relevant SNPs in DNA repair (ERCC1 and ERCC5) and apoptosis (MDM2 and TP53) genes might influence the severity of radiation-related side-effects in HNSCC patients. Prospective clinical SNP-based validation studies are needed on these bases.

[Indications and results for protontherapy in cancer treatments]. / Indications et résultats de la protonthérapie dans le traitement des cancers.

Purpose was to summarize results for proton therapy in cancer treatment. A systematic review has been done by selecting studies on the website www.pubmed.com (Medline) and using the following keywords: proton therapy, radiation therapy, cancer, chordoma, chondrosarcoma, uveal melanoma, retinoblastoma, meningioma, glioma, neurinoma, pituitary adenoma, medulloblastoma, ependymoma, craniopharyngioma and nasal cavity. There are several retrospective studies reporting results for proton therapy in cancer treatments in the following indications: ocular tumors, nasal tumors, skull-based tumors, pediatric tumors. There is no prospective study except one phase II trial in medulloblastoma. The use of proton therapy for these indications is due to dosimetric advantages offering better tumor coverage and organ at risk sparing in comparison with photon therapy. Clinical results are historically at least as efficient as photon therapy with a better toxicity profile in pediatric tumors (cognitive and endocrine functions, radiation-induced cancer) and a better tumoral control in tumors of the nasal cavity. Clinical advantages of proton therapy counterbalance its cost especially in pediatric tumors. Proton therapy could be used in other types of cancer. Proton therapy showed good outcome in ocular, nasal tumors, pediatric, skull-based and paraspinal tumors. Because of some dosimetric advantages, proton therapy could be proposed for other indications in cancer treatments.

A Nomogram to predict parotid gland overdose in head and neck IMRT.

PURPOSES: To generate a nomogram to predict parotid gland (PG) overdose and to quantify the dosimetric benefit of weekly replanning based on its findings, in the context of intensity-modulated radiotherapy (IMRT) for locally-advanced head and neck carcinoma (LAHNC). MATERIAL AND METHODS: Twenty LAHNC patients treated with radical IMRT underwent weekly computed tomography (CT) scans during IMRT. The cumulated PG dose was estimated by elastic registration. Early predictors of PG overdose (cumulated minus planned doses) were identified, enabling a nomogram to be generated from a linear regression model. Its performance was evaluated using a leave-one-out method. The benefit of weekly replanning was then estimated for the nomogram-identified PG overdose patients. RESULTS: Clinical target volume 70 (CTV70) and the mean PG dose calculated from the planning and first weekly CTs were early predictors of PG overdose, enabling a nomogram to be generated. A mean PG overdose of 2.5Gy was calculated for 16 patients, 14 identified by the nomogram. All patients with PG overdoses >1.5Gy were identified. Compared to the cumulated delivered dose, weekly replanning of these 14 targeted patients enabled a 3.3Gy decrease in the mean PG dose. CONCLUSION: Based on the planning and first week CTs, our nomogram allowed the identification of all patients with PG overdoses >2.5Gy to be identified, who then benefitted from a final 4Gy decrease in mean PG overdose by means of weekly replanning.

[Current situation and perspectives of proton therapy]. / État des lieux et perspectives de la protonthérapie.

Proton beam therapy is indicated as a treatment for some rare tumours and paediatric tumours because the technique allows a good local control with minimal toxicity; the growing number of centres that use proton beam therapy is associated with an increase of dosimetric and clinical data for other malignant tumours as well. This paper reviews potential indications of proton beam therapy. A systematic review on Medline was performed with the following keywords proton beam therapy, cancer, heavy particle, charged particle. No phase III trial has been published using proton beam therapy in comparison with the best photon therapy, but numerous retrospective and dosimetric studies have revealed an advantage of proton beam therapy compared to photons, above all in tumours next to parallel organs at risk (thoracic and abdominal tumours). This could be accompanied with a better safety profile and/or a better tumoural control; numerous phase 0, I, II, III and IV studies are ongoing to examine these hypotheses in more common cancers. Use of proton beam therapy is growing for common cancers within clinical trials but some indications could be applied sooner since in silico analysis showed major advantages with this technique.

Aims of combined modality therapy in rectal cancer (M0).

UNLABELLED: OPTIMIZING THE COST/BENEFIT RATIO OF TREATMENT: Evidence Based The aim of a cancer treatment is always to achieve the maximum of cure rate with a minimum of toxicity and best quality of life at an acceptable cost for the society. It is always a multifactorial challenge depending on the patient, the tumor, the doctor, and the society cultural and financial backgrounds. The goal is to find the best cost/benefit ratio between all possible strategies in agreement with a well-informed patient. In rectal cancer (M0) surgery is the cornerstone of treatment. Combined modality therapies aim at optimizing the cost/benefit ratio of possible strategies and only randomized trials can bring strong evidence regarding their results and recommendations. LESSONS FROM RANDOMIZED TRIALS: quite modest During the past decades many phase III trials have shown that: (1) neoadjuvant treatment even with "TME" surgery was better than adjuvant, (2) chemoradiotherapy (CRT) was better than RT alone, (3) long course CRT was probably more efficient (in terms of ypCR) than short course (25/5), and (4) capecitabine was as efficient as 5 FU but oxaliplatin was not adding benefit. Overall, the gains of nCRT remain modest and it is mainly a reduction in local relapse not exceeding 5 %, but no benefit in survival and neither in sphincter saving surgery has been proven. The way forwards organ preservation in case of CCR. Local control: can probably be improved for T4 tumors by RT dose escalation. Survival: can be increased by innovative medical treatment either before or after surgery. TOXICITY: may be reduced by a less aggressive treatment in elderly. Conservative treatment: A new field of clinical research is to achieve "organ preservation" (and not only sphincter saving). To modify the surgical approach and preserve the whole rectum, neoadjuvant treatment must achieve safely a clinical complete response. As rectal adenocarcinoma is a relatively radioresistant tumor endocavitary irradiation (contact X-Ray) is a promising safe approach and this hypothesis will be addressed by the OPERA randomized trial.

Impact of preoperative radiotherapy on head and neck free flap reconstruction: a report on 429 cases.

BACKGROUND: The primary objective of this study was to evaluate the impact of preoperative radiotherapy on the outcomes of head and neck microvascular reconstruction. The secondary objective was to assess the specific effects of irradiation doses (IDs) ≥60 Gy on the outcomes of head and neck microvascular reconstruction. METHODS: All patients who underwent head and neck free-flap reconstruction in our institution between 2000 and 2010 were included in this retrospective study. A total of 429 patients were enrolled including 136 patients previously irradiated on the head and neck. The impact of preoperative radiotherapy on free-flap success, local and general complications, postoperative mortality, time of decannulation, duration of enteral nutrition and length of stay was assessed in univariate and multivariate analyses. RESULTS: In multivariate analysis, preoperative radiotherapy (irrespective of ID) was a significant risk factor for fistula formation (p = 0.003) and wound infection (p = 0.005). Previous neck irradiation at doses ≥60 Gy was associated with an increased risk of free-flap failure (p = 0.04), overall local complications (p = 0.05), haematoma (p = 0.04) and longer duration of enteral nutrition (p = 0.006) and hospital stay (p = 0.004). CONCLUSIONS: Preoperative radiotherapy, particularly for ID ≥ 60 Gy, is one of the main determinants of the outcomes of head and neck microvascular reconstruction.

Clinical and histological prognostic factors in locally advanced oral cavity cancers treated with primary surgery.

OBJECTIVE: The primary objective of this study was to determine the clinical and pathological prognostic factors in locally advanced oral cavity cancers treated by primary surgery. METHODS: All patients treated by primary surgery with free-flap reconstruction for locally advanced oral cavity squamous cell carcinoma in our institution between 2000 and 2010 were included in this retrospective study. Overall, cause-specific and locoregional disease-free survivals were determined by Kaplan-Meier analyses. Clinical and histological prognostic factors were assessed by univariate (Log Rank tests) and multivariate (Cox models) analyses. RESULTS: A total of 149 patients (102 men and 47 women; mean age=61.3±12.1 years) were included in the study. Five-year overall, cause-specific and locoregional disease-free survivals were 55%, 68% and 71%, respectively. Age, comorbidity and tumour size (histological evaluation) were significantly correlated with overall survival (P<0.05). Age, tumour size, bone invasion and surgical margins were significantly correlated with locoregional disease-free survival (P<0.05). CONCLUSION: The main prognostic factors identified in this study were clinical (age and comorbidity) and histological (pathological tumour size, bone invasion and surgical margins).

[Adenoid cystic carcinoma of the head and neck: a retrospective series of 169 cases]. / Carcinomes adénoïdes kystiques ORL : étude rétrospective multicentrique de 169 cas.

PURPOSE: Adenoid cystic carcinoma represents 1% of head and neck cancers. Adenoid cystic carcinomas are slow growing tumours with high potential for local recurrence. Treatment usually associates radiotherapy and surgery, but the role of radiotherapy remains unclear. We report a retrospective multicentric study of the management and prognostic factors of 169 adenoid cystic carcinomas of head and neck. PATIENTS AND METHODS: Between 1982 and 2010, 169 patients with adenoid cystic carcinoma of the head and neck were referred to the Cercle des oncologues radiothérapeutes du Sud departments of radiotherapy either for primary untreated tumour (n=135) or for a recurrence of previously treated tumour (n=34). The site of adenoid cystic carcinoma was: parotid gland (n=48, 28.4%), minor salivary gland (n=35, 20.7%), submandibular gland (n=22, 13%), sinus cavities (n=22, 13%), other (n=42, 24.9%). Tumour stages were: T1 (12.4%); T2 (14.2%); T3 (12.4%); T4 (41.4%) and Tx (19.5%). Lymph node involvement was 13% and distant metastasis 8.9%. For adenoid cystic carcinomas of the parotid gland, major nerve involvement was evaluated. Preferential site of metastasis was the lung (87.5%). Treatments were: surgery alone (n=27), surgery and adjuvant radiotherapy (n=89), surgery and adjuvant chemoradiotherapy (n=12), exclusive chemoradiotherapy (n=13), exclusive radiotherapy (n=14), other associations (n=5) and no treatment (n=7). Radiotherapy was delivered through photons (n=119), neutrons (n=6), both (n=4). Two patients had a brachytherapy boost. Median prescribed doses to T and N were respectively 65 Gy and 50 Gy for the 119 photons treated patients. RESULTS: Mean follow-up was 58 months (range 1-250 months). As of December 1, 2010, 83 patients were alive with no evolutive disease (49%), 35 alive and had recurred, 18 had uncontrolled evolutive disease, 28 had died of adenoid cystic carcinoma and 5 of intercurrent disease. Overall survival and disease free survival were respectively 72% and 72% at 5 years, 53% and 32% at 10 years; 5 and 10-year freedom from local recurrence were 81% and 52% respectively. Nerve involvement was found in 17/48 parotid gland adenoid cystic carcinomas. The Cox model including all patients, showed that surgery (P<0.001), surgical margins (P=0.015), nerve involvement (P=0.0079), length of radiotherapy (P=0.018), and tumour location (P=0.041) were associated with disease free survival. CONCLUSION: In this large series of adenoid cystic carcinoma of head and neck with a majority of T3-T4 tumours, 10-year survivals were achieved for 50% of patients. Radiotherapy did not impact survival.

[Induction chemotherapy for head and neck epidermoid carcinomas]. / Chimiothérapie d'induction des carcinomes épidermoïdes de la tête et du cou.

The standard treatment for head and neck inoperable squamous cell carcinoma is an association of radiotherapy and platinum. However, only one patient out of three remains alive five years after diagnosis. The interest in induction chemotherapy was renewed by the introduction of taxanes combined with cisplatinum and 5-fluoro-uracile. The triple association taxane-cisplatinum-5-fluoro-uracile yielded improved survival when compared to cisplatinum-5-fluoro-uracile. Wider use of taxane-cisplatinum-5-fluoro-uracile is limited by its toxicity and the lack of randomized comparison with a concomitant chemoradiotherapy scheme including optimal doses of platinum. Until the results of new phase III trials are published, the choice between induction chemotherapy followed by concomitant chemoradiotherapy or concomitant chemoradiotherapy alone has to be made on an individualized basis, taking into account the patient's medical condition, the ability of the medical team to deal with intensive treatment regimens, and the clinical/pathological characteristics of the tumour.

Head and neck free-flap reconstruction in the elderly.

OBJECTIVE: To evaluate the reliability of free-flap head and neck reconstruction in the elderly. MATERIAL AND METHODS: All patients who underwent free-flap head and neck reconstruction in our institution between 2000 and 2010 were included in this retrospective study. In all, 418 patients (301 men and 117 women) were enrolled, including 95 patients aged 70 years or older (mean age=60.2±11.6 years). The impact of age on free-flap failure and local and general complication rates was assessed on univariate and multivariate analysis. RESULTS: Advanced age had no impact on free-flap failure and local complications rate but was correlated with a higher risk of general complications (multivariate analysis: P=0.007). A high level of comorbidity also had a significant impact on the general complications rate (multivariate analysis: P=0.001). Patients who underwent circular total pharyngolaryngectomy showed elevated risk of free-flap failure (P=0.005) and local complications (P=0.001) on multivariate analysis. CONCLUSION: Free-flap reconstruction of the head and neck is safe and reliable in the elderly. Nevertheless, meticulous patient selection, mainly based on the level of comorbidity, is necessary.

[Total pharyngolaryngectomy in the 21st century: indications, oncologic and functional outcomes]. / Les pharyngo-laryngectomies totales au 21ème siècle : indications, résultats carcinologiques et fonctionnels.

INTRODUCTION: The development of laryngeal preservation protocols has considerably modified the indications for total (pharyngo-)laryngectomy (TPL). The objectives of our study are to analyze the current indications for TPL and to evaluate the oncologic and functional outcomes after TPL and their predictive factors. METHODS: All patients who underwent TPL for squamous cell carcinoma of the larynx or hypopharynx, at our institution, between 2000 and 2009, were included in this retrospective study. Predictive factors of oncologic and functional outcomes were assessed in univariate and multivariate analyzes. RESULTS: A total of 130 patients were enrolled in our study including 119 men and 11 women, with a mean age of 65.9 years. TPL was realized for salvage in 65 patients. Extra-laryngeal tumor extension (n = 42) was the main indication for TPL in the 65 remaining patients. Overall survival was 49 and 41% at 3 and 5 years respectively. In multivariate analysis, primary tumor site (hypopharynx in comparison to larynx; p = 0.04) has a significant pejorative impact on overall survival. Oral alimentation (no enteral nutrition) was recovered successfully by 94% of the patients. In multivariate analysis, primary tumor site (hypopharynx) has a significant pejorative impact on functional results (deglutition: p < 0.0001; phonation: p = 0.03). CONCLUSION: Primary tumor site is one of the main predictive factor of oncologic and functional outcomes after TPL.

[Reirradiation of spine and lung tumor with CyberKnife]. / Réirradiation des tumeurs du rachis et du poumon par CyberKnife).

We present the results of two retrospective studies, one regarding reirradiation of spinal tumours and the second, concerning lung tumours. In the first case, primary or secondary tumours were located in or in contact with the vertebrae and spinal cord. The first irradiation has given a full dose to the spinal cord. In the second case, primary or secondary lung tumours have already been treated by irradiation alone or by radiochemotherapy. No grade 3 or 4 early toxicity has been found. Preliminary clinical results are encouraging. The use of CyberKnife represents a major therapeutic advance in the management of irradiated spinal or lung lesions. The possibility of sparing organs at risk and increasing the dose in the tumour target volume are the main advantages.