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

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

Intersphincteric resection for low rectal cancer: the risk is functional rather than oncological. A 25-year experience from Bordeaux.

AIM: There are few data evaluating the long-term outcomes of intersphincteric resection (ISR), especially the impact of inclusion of more juxtapositioned and intra-anal tumours on oncological and functional outcomes. We compared the oncological and functional results of patients treated by total mesorectal excision and ISR for low rectal cancer over a 25-year period. METHOD: This is a retrospective study from a single institution evaluating results of ISR over three periods: 1990-1998, 1999-2006 and 2007-2014. Patients treated by partial or total ISR, with or without neoadjuvant chemoradiotherapy, for low rectal cancer (≤ 6 cm from the anal verge) were included. We compared postoperative morbidity, quality of surgery and oncological and functional outcomes in the time periods studied. RESULTS: Of 813 patients operated on for low rectal cancer, 303 had ISR. Tumour stage did not differ; however, the distance of the tumour from the anorectal junction decreased from 1 to 0 cm (P < 0.001) and the distal resection margin shortened from 25 to 10 mm (P < 0.001) from 1990 to 2014. The postoperative morbidity and quality of surgery did not change significantly over time. The 5-year local recurrence (4.3% vs 5.9% vs 3.5%; P = 0.741) and disease-free survival (72% vs 71% vs 75%; P = 0.918) did not differ between the three time periods. Functional results improved during the last period; however, overall 42% of patients experienced major bowel dysfunction. CONCLUSION: Pushing the envelope of sphincter-saving resection in ultra-low rectal cancer reaching or invading the anal sphincter did not compromise oncological and functional outcomes. The main limitation of the ISR procedure appears to be functional rather than oncological, suggesting that bowel rehabilitation programmes should be developed.

Delayed coloanal anastomosis: an alternative option for restorative rectal cancer surgery after high-dose pelvic radiotherapy for prostate cancer.

AIM: Restorative total mesorectal excision (TME) for rectal cancer after high-dose pelvic radiotherapy for prostate cancer has been reported to provide an unacceptable rate of pelvic sepsis. In a previous publication we proposed that delayed coloanal anastomosis (DCAA) should be performed in this situation. The present study aimed to assess the feasibility and outcomes of this strategy. METHOD: Between 2000 and 2018, 1094 men were operated on for rectal cancer in our institution. All men with T2/T3 mid and low rectal cancer with preoperative radiotherapy and restorative TME were considered for this study (n = 416). Patients with external-beam high-dose radiotherapy (EBHRT) for prostate cancer (70-78 Gy) were identified and compared with patients with conventional long-course chemoradiotherapy (CRT) followed by TME. We compared our already published historical cohort (2000-2012), including arm A (CRT + TME; n = 236) and arm B (EBHRT + TME; n = 12), with our early cohort (2013-2018), including arm C (CRT + TME; n = 158) and arm D (EBHRT + TME-DCAA; n = 10). The end-points were morbidity, pelvic sepsis, reoperation rate and quality of the specimen. RESULTS: Overall morbidity was not significantly different between groups. Pelvic sepsis decreased from 50% (arm B) to 10% (arm D) with the use of DCAA (P = 0.074), and was similar between arms A, C and D. Quality of the specimen was not significantly different between the four groups. CONCLUSION: Our results suggest that TME with DCAA in patients with previous EBHRT is feasible, with the same postoperative pelvic sepsis rate as conventional CRT.

Late toxicities and clinical outcome at 5 years of the ACCORD 12/0405-PRODIGE 02 trial comparing two neoadjuvant chemoradiotherapy regimens for intermediate-risk rectal cancer.

BACKGROUND: Outcome of intermediate risk rectal cancer may be improved by the addition of oxaliplatin during 5-fluoruracil concomitant neoadjuvant chemoradiotherapy. The purpose of this study is to analyze the main clinical results of the ACCORD12 trial (NCT00227747) in rectal cancer after 5 years of follow-up. PATIENTS AND METHODS: Inclusion criteria were as follows: rectal adenocarcinoma accessible to digital examination staged T3-T4 Nx M0 (or T2 Nx distal anterior rectum). Two neoadjuvant chemoradiotherapy regimens were randomized: CAP45 (RT 45 Gy + capecitabine) and CAPOX50 (RT 50 Gy + capecitabine and oxaliplatin). Main end point was sterilization of the operative specimen. Acute and late toxicities were prospectively analyzed with dedicated questionnaires. RESULTS: Between November 2005 and July 2008, 598 patients were included in the trial. After a median follow-up of 60.2 months, there was no difference between treatment arms in multivariate analysis either for disease-free survival or overall survival (OS) [P = 0.9, hazard ratio (HR)=1.02; 95% confidence interval (CI), 0.76-1.36 and P = 0.3, HR = 0.87; 95% CI, 0.66-1.15, respectively]. There was also no difference of local control in univariate analysis (P = 0.7, HR = 0.92; 95% CI, 0.51-1.66). Late toxicities were acceptable with 1.6% G3 anal incontinence, and <1% G3 diarrhea, G3 rectal bleeding, G3 stenosis, G3-4 pain, G3 urinary incontinence, G3 urinary retention and G3 skeletal toxicity. There was a slight increase of erectile dysfunction over time with a 63% rate of erectile dysfunction at 5 years. There was no significant statistical difference for these toxicities between treatment arms. CONCLUSIONS: The CAPOX50 regimen did not improve local control, disease-free survival and overall survival in the ACCORD12 trial. Late toxicities did not differ between treatment arms.

[Prospective longitudinal study on the evolution of autobiographical memory in patients irradiated for benign skull base tumour]. / Étude prospective longitudinale sur l'évolution de la mémoire autobiographique de patients irradiés pour une tumeur bénigne de la base du crâne.

PURPOSE: Cranial irradiation can lead to long-term neurological complications, in particular memory disorders. The aim of this prospective study is to evaluate the impact of irradiation of benign skull base tumours located near the hippocampi on autobiographical memory. PATIENTS AND METHODS: From 2016 to 2019, patients with cavernous sinus meningioma or pituitary adenoma treated with normofractionated irradiation were included. Patients underwent full neuropsychological assessment at baseline, 1year and 2years post-treatment. Neuropsychological tests were converted to Z-Score for comparability. RESULTS: Twelve of the 19 patients included had a complete neuropsychological evaluation at 2years and were analysed. On the "TEMPau" test, no significant difference in autobiographical memory was found at 2years, regardless of the period of autobiographical memory. The mean hippocampal dose had no impact on the variation in autobiographical memory. There was no significant cognitive impairment in the other domains assessed, such as attention, anterograde memory, working memory and executive functions. Autobiographical memory was independent of these other cognitive domains, which justifies its specific study. CONCLUSION: Radiotherapy to the skull base for a benign pathology does not lead to significant cognitive impairment. Longer follow-up would be needed to confirm these results.

Radiation therapy of the primary tumour and/or metastases of digestive metastatic cancers.

Metastatic gastrointestinal cancer is not an uncommon situation, especially for pancreatic, gastric, and colorectal cancers. In this setting, few data are available on the impact of the treatment of the primary tumour. Oligometastatic disease is associated with longer survival in comparison with more advanced disease. Metastasis-directed therapy, such as stereotactic body radiotherapy, seems related to better outcomes, but the level of evidence is low. In most tumour locations, prospective data are very scarce and inclusion in ongoing trials is strongly recommended.

[Informed consent in radiotherapy care]. / Consentement aux soins en radiothérapie.

Obtaining consent to care requires the radiation oncologist to provide loyal information and to ensure that the patient understands it. Proof of such an approach rests with the practitioner. The French Society for Radiation Oncology (SFRO) does not recommend the signature of a consent form by the patient but recommends that the radiation oncologist be able to provide all the elements demonstrating the reality of a complete information circuit.

Practice-changing clinical trials in radiation oncology for gastrointestinal malignancies in 2021-2023.

Gastrointestinal cancers are one of the most frequent cancers and a leading cause of cancer deaths worldwide. We provide an overview of the most important practice-changing trials that were either published or presented at the international scientific meetings in 2021-2023. Highlights included reports on three phase III trials (CONCORDE/PRODIGE 26, ARTDECO, and a study by Xu et al.) that evaluated dose escalation in the definitive setting for locally advanced oesophageal cancers, as well as two phase III trials that evaluated the role of chemotherapy (neo-AEGIS) and targeted therapy (NRG/RTOG 1010) in the neoadjuvant setting for adenocarcinoma oesophageal cancers or gastroesophageal junction cancer. CheckMate 577 evaluated nivolumab in patients who had residual pathological disease after neoadjuvant chemoradiation followed by complete resection. The use of radiation therapy for borderline and locally advanced pancreatic cancer is also discussed (SMART and CONKO-007 trials). Stereotactic body radiation therapy followed by sorafenib was compared to sorafenib alone in patients with hepatocellular carcinoma in the NRG/RTOG 1112 study. New options in the management of rectal cancer are emerging such as total neoadjuvant treatment (PRODIGE 23, RAPIDO, PROSPECT), organ preservation (OPRA, OPERA), and the role of immunotherapy in patients with DNA mismatch-repair deficient/microsatellite instability. Finally, preliminary results of the ACT 4 trial that evaluated de-escalation in anal cancer are presented.

[Anal cancer: Focus on current treatment and future perspective]. / Prise en charge des cancers du canal anal : mise au point et perspectives futures.

Anal cancer is considered a rare tumor, accounting for 6 % of digestive cancers and about 2000 new cases per year in France. It is mostly diagnosed at a localized stage. For many years, the standard of care for patients with localized disease is an association with radiotherapy and chemotherapy including Mitomycin C and 5-Fluorouracil. There weren't any major changes in the therapeutic management of these tumors despite several phase III studies. However, there is an improvement in patient prognostic. This can be explained by imaging progress, using magnetic resonance imaging and positron emission tomography-computed tomography, permitting better staging and evaluation of disease. Moreover, irradiation modalities changed because of the development of Intensity Modulated Radiotherapy. Actual research focuses on a more personalized strategy according to tumoral stages. Patients with early-stage tumors are potentially over-treated with a risk of chronic digestive toxicities. Several studies are interested in irradiation de-escalation for these patients. On the other hand, treatment results for patients with advanced tumoral stages are disappointing. It seems relevant to propose a therapeutic intensification for these patients, such as dose escalation, association with new therapies like immunotherapy or induction chemotherapy using taxans given promising results at the metastatic stage.

[Impact of IMRT for neoadjuvant rectal cancer?] / Quel apport de la modulation d'intensité pour la radiothérapie des cancers du rectum ?

The standard management of locally advanced rectal tumors as cT3-T4 and/or N0/N1 is based on preoperative treatment combining radiotherapy of 45 to 50Gy and chemotherapy based on 5-fluorouracil. Intensity-modulated radiotherapy has already shown its interest compared to conformal radiotherapy in other locations, like in pelvic cancer. The role of intensity-modulated radiotherapy in the pre/postoperative treatment of rectal cancers is not a standard of care. Published studies showed its feasibility with the objective of less toxicity with equivalent efficacy.

[Organ preservation for rectal cancer: What are the arguments in favor of radiotherapy?] / Préservation d'organe dans les cancers du rectum : quels arguments en faveur de la radiothérapie ?

Standard care for rectal cancers relies on both tumor (location relative to the sphincter, T and N stage, sphincter involvement) and patients characteristics. Radical surgery (total mesorectal excision) following short-course radiotherapy (RT) or standard chemo-radiotherapy, associated with induction or consolidation chemotherapy (total neoadjuvant treatment), remains the cornerstone of locally advanced rectal cancer (T3cd, T4 and/or N+) treatment. Nevertheless, for early stages, this radical resection could be avoided in favor of conservative approaches combining RT (external, contact, brachytherapy) with or without chemotherapy (concurrent, induction or consolidative), or even be limited, for good responders, to a local excision with view of organ-preservation strategies. This conservative approach could also be offered selectively to patients with complete clinical response after the induction sequence, irrespective of initial tumor characteristics. The Watch and Wait strategy relies on clinical, endoscopic and radiological evaluations, as well as sustained surveillance. Ongoing studies aim to improve response rates, either with chemotherapy intensification, or RT boost dose escalation with brachytherapy or contact-therapy.

Clinical applications of high dose rate endorectal brachytherapy for patients with rectal cancer.

With the establishment of total mesorectal excision for the treatment of rectal cancer, local recurrence rates have significantly decreased. The addition of preoperative external beam irradiation further reduces this risk to less than 6%. As the local treatment becomes successful and more widely used, the associated treatment-related toxicity is becoming clinically important. If 4 to 6% of the patients are to benefit from neo-adjuvant therapy before total mesorectal excision, the acute and the long-term toxicity burden must be reasonable. With the introduction of better-quality imaging for tumour visualization and treatment planning, a new-targeted radiation treatment was introduced with high dose rate endorectal brachytherapy. The treatment concept was tested in phase I and II studies first in the preoperative setting, then as a boost after external beam radiation therapy as a dose escalation study to achieve higher tumour local control in a radical treatment setting with no surgery. High dose rate endorectal brachytherapy is safe and effective in achieving high tumour regression rate and was well tolerated. It is presently explored in a phase III dose escalation study in the non-operative management of patients with operable rectal cancer.

Radiotherapy for cancers of the oesophagus, cardia and stomach.

We present the updated recommendations of the French society for radiation oncology on radiotherapy of oesophageal cancer. Oesophageal cancer still remains a malignant tumour with a poor prognosis. Surgery remains the standard treatment for localized cancers, regardless of histology. For locally advanced stages, surgery remains a standard for adenocarcinomas after neoadjuvant treatment with chemotherapy or chemoradiotherapy. However, it is a therapeutic option after initial chemoradiotherapy for stage III squamous cell carcinomas, given the increased morbidity and mortality with a multimodal treatment, which results in an equivalent overall survival with or without surgery. Preoperative or exclusive chemoradiotherapy should be delivered according to validated regimens with an effective total dose (50Gy), if surgery is not planned or if the tumour is deemed resectable before chemoradiotherapy. Intensity-modulated radiotherapy significantly reduces irradiation of the lungs and heart and may reduce the morbidity of this treatment, especially in combination with surgery. In case of exclusive chemoradiotherapy, dose escalation beyond 50Gy is not currently recommended. Some technical considerations still remain questionable, such as the place of prophylactic lymph node irradiation, adaptive radiotherapy, evaluation of response during and after chemoradiotherapy and the value of proton therapy.

Radiation therapy of pancreatic cancers.

We present the update of the recommendations of the French society of oncological radiotherapy on radiotherapy of pancreatic tumors. Currently, the use of radiation therapy for patients with pancreatic cancer is subject to discussion. In the adjuvant setting, the standard treatment is six months of chemotherapy with 5-fluorouracile, irinotecan and oxaliplatin. Chemoradiation may improve the survival of patients with incompletely resected tumours (R1). This remains to be confirmed by a prospective trial. Neoadjuvant chemoradiation is a promising treatment especially for patients with borderline resectable tumours. For patients with locally advanced tumours, there is no standard. An induction chemotherapy followed by chemoradiation for non progressive patients reduces the rate of local relapse. Whereas in the first trials of chemoradiation large fields were used, the treated volumes have been reduced to improve tolerance. Tumour movements induced by breathing should be taken in account. Intensity modulated radiation therapy allows a reduction of doses to the organs at risk. Whereas widely used, this technique has poor evidence-based recommendation. Stereotactic body radiation therapy is also being studied, as a neoadjuvant or exclusive treatment.

Radiotherapy of anal canal cancer.

We present the update of the recommendations of the French society for radiation oncology on external radiotherapy and brachytherapy of anal canal carcinoma. The following guidelines are presented: indications, treatment procedure, as well as dose and dose-constraints objectives, immediate postoperative management, post-treatment evaluation, and long-term follow-up.

[Stereotactic radiotherapy of non-tumoral brain pathologies: Arteriovenous malformations and trigeminal neuralgias]. / Radiothérapie stéréotaxique des affections cérébrales non tumorales : malformations artérioveineuses et névralgies trigéminales.

Stereotactic radiotherapy and radiosurgery allow delivery of high irradiation doses in a limited volume. These techniques are specially adapted to brain and nervous pathologies. Indication are not only cancers and tumors but also non tumor tissues such as arteriovenous malformations. In some case purpose of stereotactic radiotherapy is solely functional, for example for trigeminal neuralgia. We detail the questions that raise treatment of these non-tumor pathologies. These pathologies imply a multidisciplinary approach that associate radiation oncologists, neuro-radiologist and neurosurgeons.

Rectal cancer radiotherapy.

We present the updated recommendations of the French society of oncological radiotherapy for rectal cancer radiotherapy. The standard treatment for locally advanced rectal cancer consists in chemoradiotherapy followed by radical surgery with total mesorectal resection and adjuvant chemotherapy according to nodal status. Although this strategy efficiently reduced local recurrences rates below 5% in expert centres, functional sequelae could not be avoided resulting in 20 to 30% morbidity rates. The early introduction of neoadjuvant chemotherapy has proven beneficial in recent trials, in terms of recurrence free and metastasis free survivals. Complete pathological responses were obtained in 15% of tumours treated by chemoradiation, even reaching up to 30% of tumours when neoadjuvant chemotherapy is associated to chemoradiotherapy. These good results question the relevance of systematic radical surgery in good responders. Personalized therapeutic strategies are now possible by improved imaging modalities with circumferential margin assessed by magnetic resonance imaging, by intensity modulated radiotherapy and by refining surgical techniques, and contribute to morbidity reduction. Keeping the same objectives, ongoing trials are now evaluating therapeutic de-escalation strategies, in particular rectal preservation for good responders after neoadjuvant treatment, or radiotherapy omission in selected cases (Greccar 12, Opera, Norad).

Can mesorectal lymph node excision be avoided in rectal cancer surgery?

Rectal excision is the standard in rectal cancer treatment. The morbidity of rectal excision, together with the low rate of positive lymph nodes in patients with a good response after radiochemotherapy, raises the challenging concept of organ preservation. Patients with a complete response can benefit from a nonoperative strategy based on a strict follow up. Those with a complete or subcomplete response can be treated by local excision. Limitations in accurately assessing a complete response by conventional and modern imaging modalities suggest that local excision is more appropriate for the majority of patients when organ preservation is being considered. The encouraging results of retrospective series of local excision in downstaged clinical T2/T3 low rectal cancer after radiochemotherapy, however, need to be confirmed by the ongoing multicentre phase II United States and phase III French trials before routinely proposing organ preservation in patients with a good response.

[Rectal cancer: Towards personalized medicine]. / Cancer du rectum : vers une prise en charge personnalisée.

The standard of care for patients with locally advanced rectal cancer has recently changed and is now based on the concept of total neoadjuvant therapy with the association of radiotherapy and systemic chemotherapy before radical surgery. The addition of noeadjuvant systemic chemotherapy before or after radiotherapy during preoperative course significantly decreased the risk of distant metastases and prolonged disease-free survival after surgery. The risk of recurrence varies among patients and the standard management associating chemotherapy, radiotherapy and surgery may expose many patients to overtreatment and can negatively affect quality of life. In this setting, several ongoing trials evaluate the possibility of less aggressive individually tailored approach based on omission of one of three treatments. In particular, NORAD and PROSPECT trials evaluate whether irradiation could be safely omitted in patients who are good responders to induction chemotherapy and have locally advanced primarily resectable tumor with large predictive circumferential resection margin. In the other hand, the total neoadjuvant therapy had significantly improved the pathological complete response rate, up to 30%, leading the concept of non-operative management and organ-preserving strategies. The phase III GRECCAR 12 study has therefore evaluated the potential benefit of intensification of neoadjuvant chemotherapy whereas OPERA and MORPHEUS trials assessed radiotherapy dose escalation by contact X-ray or brachytherapy for organ-preserving strategies. To date, total neoadjuvant therapy following by radical surgery remains the standard of care but probably less aggressive approach with omission of radiotherapy or surgery will become a new standard in selected patients in next future.