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.

[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.

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 remnant tooth in an edentulous patient.

OBJECTIVES: We describe a case of an unusual remnant tooth located in the paranasal sinus in a head and neck cancer patient. CASE REPORT: A 72-year patient with a history of T3N2aM0 oropharyngeal cancer treated with chemoradiation came for systematic post-therapeutic multidetector-CT reformation (MDCT) examination. MDCT scan multi planar reformation revealed a well-limited high-density mass in his maxillary sinus, which proved to be a remnant molar tooth. Physical examination and CT imaging were performed at 26 months. Local malignancy, fungal ball and persistent oroantral fistula were ruled out. CONCLUSION: The physio-pathogenesis of oroantral fistula (OAF) and causes of intra sinusal tooth as well as therapy are discussed in this article.

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.

[Feasibility and efficacy of cyberknife radiotherapy for lung cancer: early results]. / Analyse de la toxicité précoce des traitements par Cyberknife des cancers pulmonaires et résultats préliminaires.

PURPOSE: High-dose robotic stereotactic irradiation can be achieved with high precision using the CyberknifeM system equipped with the Synchrony respiratory tracking device. Cyberknife irradiation can overcome some limitations of conventional radiotherapy including errors due to breathing motion and patient setup. High dose levels are of interest for tumours that have shown a dose-response relationship including lung tumours. We reviewed the treatments and outcomes for the first French patients with lung tumours treated at the Cyberknife centre of Nice. PATIENTS AND METHODS: Thirty four patients were treated between November 2006 and November 2007 at the Cyberknife centre of Nice, Centre Lacassagne, France. Thirty had untreated primary lung cancer, 4 had colorectal metastasis to the lung. We evaluated the feasibility and reliability of fiducial placement, toxicity and early outcomes. Objective tumour response was assessed on thoracic CT scan every three months. RESULTS: There was no grade 3-4 toxicity. Toxicity (11%) mainly consisted of grade 1-2 asthenia. Crude overall tumour response rate was 96% for all assessable patients and 91% at 3 and 6 months, respectively. The use of one fiducial ensured minimal toxicity (no grade III pneumothorax) while allowing reliable tumour tracking as shown by the low infield failure rate (no geographic miss). Diagnostic procedure was performed during fiducial placement when required. CONCLUSION: Early toxicity and tumour control rates from this population suggest that the use of a unique fiducial for a Cyberknife treatment was safe and effective for the treatment of selected primary and secondary lung tumours. This strategy is corroborated by similar control rates in the literature. Longer follow-up are awaited.

[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.

State of the art and recent advance in the treatment of resectable nonmetastatic rectal cancer.

INTRODUCTION: Standard treatment is achieving good local control for rectal cancer. Innovative approach is aiming at increasing conservative treatment. METHODOLOGY: Strong evidence relies on randomized trials. Phase I and II trials are the method to evaluate advances. RESULTS: Preoperative radiotherapy with concurrent chemotherapy is the standard treatment for most of the T3 (4) tumors. To increase conservative treatment innovative neoadjuvant treatment achieving complete clinical response is a promising approach. CONCLUSION: Well-conducted clinical trials are improving the standard treatments and are evaluating new hypotheses.

French experience with contact X-ray endocavitary radiation for early rectal cancer.

This paper is an overview of the French experience with contact X-ray radiation for rectal cancer. The analysis was mainly carried out on 50 years of experience in Lyon or since 1980 in the Centre Hospitalier Universitaire Lyon Sud. The results obtained in Dijon and Nancy are also reported. In early rectal cancer, contact X-ray radiation can play an important role in three different situations: (1) small T1 less than 2 cm: adjuvant contact X-ray radiotherapy after local excision; (2) T2 N0 or large T1: first-line contact X-ray radiotherapy combined with external beam radiotherapy (+/- chemotherapy) followed by surgery (anterior resection or local excision); (3) early T3 N0 in frail patients: the same approach as for T2 N0 with, in case of clinical complete response, local excision or follow-up.

[Robotic radiotherapy for prostate cancer with CyberKnife]. / Radiothérapie robotisée des cancers de prostate par CyberKnife.

After 3D conformal radiation therapy without and with modulated intensity, image-guided radiation therapy represents a new technological step. Should prostate cancer treatment using radiotherapy with the CyberKnife robotic system be considered as a new treatment and then investigated through classical clinical research procedure rather than a technical improvement of an already validated treatment? After a general presentation of the CyberKnife , the authors focused on prostate cancer treatment assuming that, according to dosimetric and biological considerations, the treatment by robotic system appears comparable to high dose rate brachytherapy. For prostate cancer treatment are discussed: biological rational for hypofractionated treatment, high dose rate brachytherapy boost and interest of dose escalation. A comparison is presented between CyberKnife and other validated treatment for prostate cancer (radical prostatectomy, 3D conformal radiation therapy and low and high dose rate brachytherapy). In summary, CyberKnife treatment could be considered as a technical improvement of an already validated treatment in order to deliver a prostate boost after pelvic or peri-prostatic area irradiation. However, the clinical, biological and economical results must be precisely analyzed and could be assessed in the frame of a National Observatory based on shared therapeutic program.

[CyberKnife robotic stereotactic radiotherapy: technical aspects and medical indications]. / Radiothérapie stéréotaxique robotisée par CyberKnife : aspects techniques et indications.

In 2006, 3 sites have been selected by the Institut national of cancer (Lille, Nancy et Nice) to evaluate a radiotherapy robot, the CyberKnife. This machine, able to track mobile tumours in real time, gives new possibilities in the field of extra cranial stereotactic radiotherapy. Functionalities and medico economical issues of the machine will be evaluated during 2 years on the 3 sites.

[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.

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.

[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.

[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.

[Radiotherapy in primary cerebral lymphoma]. / Radiothérapie des lymphomes primitifs du système nerveux central.

Primary cerebral lymphoma is a rare disease with an unfavorable prognosis. Whole brain radiotherapy has been the standard treatment, but neither the optimal radiation fields nor optimal dose level of the regimen are as yet firmly established. From this review of the literature, it seems that the whole brain must be treated, and a boost to the area of the primary site must be discussed. With regard to dose, the radiation dose-response relationship is not clearly proven. Yet, a minimum dose of 40 Gy is necessary, and the maximum dose is set at 50 Gy because of late neurological sequelae. Because of the poor prognosis of this disease and the risk of late sequelaes, other avenues have been explored. Chemotherapy has been studied, seem to have a survival advantage and combinations of radiotherapy and chemotherapy, especially with high-dose methotrexate. Because primary cerebral lymphoma is an uncommon disease, randomized clinical trials that compare radiotherapy alone to chemotherapy plus radiotherapy may not be feasible. Finally, even if chemotherapy seems to have a survival advantage, the regimen of chemotherapy is still a matter of debate.