The safety and efficacy of total mesorectal excision (TME) surgery following dose-escalation: Surgical outcomes from the organ preservation in early rectal adenocarcinoma (OPERA) trial, a European multicentre phase 3 randomised trial (NCT02505750).

Nonsurgical treatment with chemoradiotherapy for rectal cancer is gaining interest as it avoids total mesorectal excision (TME) surgery and stoma. The OPERA trial aims to evaluate whether dose escalation with contact X-ray brachytherapy (CXB) boost improves organ preservation compared to external beam radiotherapy (EBRT) boost. It has been suggested that dose escalation adversely affects surgical outcomes and therefore we report outcomes following TME in OPERA at 36 months. OPERA is a European multicentre phase 3 trial (NCT02505750) which randomises patients with cT2-3a-b, cN0-1, M0 to EBCRT (45 Gy in 25 fractions over 5 weeks with oral capecitabine 825 mg/m2 ) followed by EBRT boost (9 Gy in 5 fractions over 5 days) versus EBCRT followed by CXB boost (90 Gy in 3 fractions over 4 weeks). Patients were assessed at 14, 20 and 24 weeks from the start of treatment. Watch and wait management was adopted for patients who achieved a clinical complete response (cCR) at 24 weeks following treatment. Either local excision (LE) or TME surgery was offered for residual disease or local regrowth, according to patient and surgeon preference. Surgical morbidity and mortality were recorded prospectively. Between July 2015 and June 2020, 148 patients were randomised of which 141 were evaluable in March 2022. At median follow-up of 38.2 months (range: 34.2-42.5), surgery was performed for 66 (47%) patients. A total of 27 (20%) patients had local excision and 39 (29%) had TME surgery, 22/39 (56%) underwent anterior resection and 17/39 (44%) underwent abdominoperineal excision of the rectum. The R0 resection rate was 87%. There were no deaths, and six patients (15%) had Clavien-Dindo IIIb complications. Whilst there was a statistically significant decrease in the TME rate following CXB boost (HR 0.38, 95% CI: 0.19-0.74, p = 0.00419) there was no difference in surgical outcomes between patients who received EBRT and CXB boost. Dose escalation can facilitate nonsurgical treatment for cT2-3 rectal cancer patients who are fit but wish to avoid TME surgery and stoma. If TME surgery is required, then it can be performed safely and effectively.

Sun Myint A ，Rao C ，Barbet N ，Thamphya B ，Pace-Loscos T ，Schiappa R ，Magné N ，Martel-Lafay I ，Mineur L ，Deberne M ，Zilli T ，Dhadda A ，Gerard JP ... -  《-》

Neoadjuvant chemoradiotherapy with radiation dose escalation with contact x-ray brachytherapy boost or external beam radiotherapy boost for organ preservation in early cT2-cT3 rectal adenocarcinoma (OPERA): a phase 3, randomised controlled trial.

Organ preservation after reaching clinical complete response on neoadjuvant therapy is gaining interest for rectal cancers, although the role of radiation dose escalation is still not known. We aimed to determine whether a contact x-ray brachytherapy boost, following or preceding neoadjuvant chemoradiotherapy, increases the probability of 3-year organ preservation for patients with early rectal cancers. OPERA was a multicentre, open-label, phase 3 randomised controlled trial done at 17 cancer centres that included operable patients, aged 18 years or older, with cT2, cT3a, or cT3b adenocarcinoma of low-mid rectum, tumours of less than 5 cm in diameter, and cN0 or cN1 smaller than 8 mm. All patients received neoadjuvant chemoradiotherapy and 45 Gy external beam radiotherapy in 25 fractions over 5 weeks with concurrent oral capecitabine (825 mg/m2 twice a day). Patients were randomly assigned (1:1) to receive a boost of external beam radiotherapy at 9 Gy in five fractions (group A) or a boost with contact x-ray brachytherapy (90 Gy in three fractions; group B). Randomisation was done centrally using an independent web-based system and stratified by trial centre, tumour classification (cT2 vs cT3a or cT3b), tumour distance from rectum (<6 cm from anal verge vs ≥6 cm), and tumour diameter (<3 cm vs ≥3 cm). Treatment in group B was stratified by tumour diameter, with the contact x-ray brachytherapy boost given before neoadjuvant chemoradiotherapy in patients with tumours smaller than 3 cm. The primary outcome was organ preservation at 3 years, analysed in the modified intention-to-treat population. This study was registered with ClinicalTrials.gov, NCT02505750, and is ongoing. Between June 14, 2015, and June 26, 2020, 148 patients were assessed for eligibility and were randomly assigned to group A (n=74) or group B (n=74). Seven patients withdrew their consent (five in group A and two in group B). 141 patients were included in the primary efficacy analysis, including 69 assigned to group A (29 with tumours <3 cm in diameter and 40 with tumours ≥3 cm) and 72 assigned to group B (32 with tumours <3 cm and 40 with tumours ≥3 cm). After a median follow-up of 38·2 months (IQR 34·2-42·5), the 3-year organ preservation rate was 59% (95% CI 48-72) in group A versus 81% (72-91) in group B (hazard ratio [HR] 0·36, 95% CI 0·19-0·70; p=0·0026). For patients with tumours less than 3 cm in diameter, 3-year organ preservation rates were 63% (95% CI 47-84) in group A versus 97% (91-100) in group B (HR 0·07, 95% CI 0·01-0·57; p=0·012). For patients with tumours of 3 cm or larger, 3-year organ preservation rates were 55% (95% CI 41-74) in group A versus 68% (54-85) in group B (HR 0·54, 95% CI 0·26-1·10; p=0·11). 21 (30%) patients in group A and 30 (42%) in group B had an early grade 2-3 adverse event (p=1·0). The most common early grade 2-3 adverse events were proctitis (four [6%] in group A, nine [13%] in group B) and radiation dermatitis (seven [10%] in group A, two [3%] in group B). The main late side-effect was grade 1-2 rectal bleeding due to telangiectasia, which was more frequent in group B (37 [63%] of 59) than in group A (five [12%] of 43; p<0·0001) and subsided after 3 years. Neoadjuvant chemoradiotherapy with a contact x-ray brachytherapy boost significantly improved the 3-year organ preservation rate, particularly for patients with tumours smaller than 3 cm who were treated with contact x-ray brachytherapy first, compared with neoadjuvant chemoradiotherapy with a boost via external beam radiotherapy. This approach could be discussed and offered to operable patients with early cT2-cT3 disease who are keen to avoid surgery and seek organ preservation. The French Programme Hospitalier de Recherche Cinique.

Gerard JP ，Barbet N ，Schiappa R ，Magné N ，Martel I ，Mineur L ，Deberne M ，Zilli T ，Dhadda A ，Myint AS ，ICONE group ... -  《The Lancet Gastroenterology &amp; Hepatology》

Dose Escalation Using Contact X-ray Brachytherapy After External Beam Radiotherapy as Nonsurgical Treatment Option for Rectal Cancer: Outcomes From a Single-Center Experience.

To review the outcomes of rectal cancer patients treated with a nonsurgical approach using contact x-ray brachytherapy (CXB) when suspicious residual disease (≤3 cm) was present after external beam chemoradiation therapy/radiation therapy (EBCRT/EBRT). Outcome data for rectal cancer patients referred to our institution from 2003 to 2012 were retrieved from an institutional database. These patients were referred after initial local multidisciplinary team discussion because they were not suitable for, or had refused, surgery. All selected patients received a CXB boost after EBCRT/EBRT. Most patients received a total of 90 Gy of CXB delivered in 3 fractions over 4 weeks. The median follow-up period was 2.5 years (range 1.2-8.3). Of 345 consecutive patients with rectal cancer referred to us, 83 with suspicious residual disease (≤3 cm) after EBCRT/EBRT were identified for a CXB boost. Their median age was 72 years (range 36-87), and 58 (69.9%) were men. The initial tumor stages were cT2 (n = 28) and cT3 (n = 55), and 54.2% were node positive. A clinical complete response (cCR) was achieved in 53 patients (63.8%) after the CXB boost that followed EBCRT/EBRT. Of these 53 patients, 7 (13.2%) developed a relapse after achieving a cCR, and the 6 patients (11.6%) with nonmetastatic regrowth underwent salvage surgery (100%). At the end of the study period, 69 of 83 patients (83.1%) were cancer free. Our data suggest that a CXB boost for selected patients with suspicious residual disease (≤3 cm) after EBCRT/EBRT can be offered as an alternative to radical surgery. In our series, patients with a sustained cCR had a low rate of local regrowth, and those with nonmetastatic regrowth could be salvaged successfully. This approach could provide an alternative treatment option for elderly or comorbid patients who are not suitable for surgery and those with rectal cancer who wish to avoid surgery.

Sun Myint A ，Smith FM ，Gollins S ，Wong H ，Rao C ，Whitmarsh K ，Sripadam R ，Rooney P ，Hershman M ，Pritchard DM ... -  《-》

'Folfirinox' chemotherapy combined with contact x-ray brachytherapy 50kVp and 'CAP50' chemoradiotherapy aiming at organ preservation for selected intermediate distal-middle cT2-T3 rectal cancers: A feasibility study.

The standard treatment of T2-T3 rectal adenocarcinoma is radical proctectomy by total mesorectal excision often combined with some neoadjuvant treatment. To reduce morbidity of this surgery, organ preservation strategy using various combination of radiotherapy, chemotherapy and local excision is gaining interest. Some randomized trials have proven the feasibility of such approaches. The OPERA trial demonstrated, for T2 T3<5cm diameter low-middle rectum, that a contact X-ray brachytherapy boost of 90Gy in three fractions over 4 weeks was able to achieve a planned organ preservation in 81% of patients at 3years with 97% success for tumour smaller than 3cm treated with contact X-ray brachytherapy boost first. To try to expand organ preservation to larger tumours we set up a feasibility trial in T2-T3 tumours using total neoadjuvant treatment and a contact X-ray brachytherapy boost. The trial was approved by the institutional review board of Nice. Inclusion criteria were operable patients, 75years or less, adenocarcinoma of the low-middle rectum staged T2c-T3N0 larger than 3.5cm and less than 6cm in diameter or T2-T3N1 less than 6cm in diameter. Treatment started in all cases with neoadjuvant chemotherapy associating 5-fluoro-uracile, irinotecan and oxaliplatin ('folfirinox' regimen, four to six cycles). In case of good tumour response after four cycles, a contact X-ray brachytherapy boost (delivering 90Gy in three fractions) was given followed by chemoradiotherapy (external beam radiotherapy delivering 50Gy, with concurrent capecitabine). After six cycles if only a partial response (tumour still larger than 3cm) was seen, chemoradiotherapy was given and contact X-ray brachytherapy boost was delivered after that. At the end of this total neoadjuvant treatment a watch and wait strategy was decided in case of clinical complete response or radical proctectomy by total mesorectal excision for partial response. Between July 2019 and October 2022, 14 patients were included; median age was 66years (range: 51-77years), there were nine male and five female, two T2 N1 tumours, seven T3N0, and five T3N1, all were M0. Median tumour diameter was 40mm (range: 11-50mm); three tumours had a circumferential extension greater than 50%. Seven patients received four folfirinox cycles and seven had six cycles. Contact X-ray brachytherapy boost was given during folfirinox chemotherapy before chemoradiotherapy in 11 patients (and after in three). The tolerance was good, with no grade 4-5 toxicity. The main grade 3 early toxicity was in relation with the folfirinox regimen. A clinical complete response was seen in 12 patients at the end of the total neoadjuvant treatment (85%). All these patients are alive and have preserved their rectum with a mean follow-up time of 17.8months (range: 6-48months) and a good bowel function (low anterior rectal resection syndrome score below 30). The main contact X-ray brachytherapy boost toxicity was radiation ulceration in three patients that usually healed within 6 months, sometimes necessitating hyperbaric oxygen. The preliminary results of this feasibility study show that early tolerance of these intensive total neoadjuvant treatment is compatible with an acceptable toxicity. The high rate of organ preservation in this intermediate group of T2-T3 tumours is encouraging and is a good argument to start the next randomized TRESOR trial that will aim at achieving a 65% of 3-year survival with organ preservation in this intermediate tumour group.

Mitrea D ，Barbet N ，Pacé-Loscos T ，Scouarnec C ，Ben-Dhia S ，Baron D ，Mineur L ，Évesque L ，Durand-Labrunie J ，Gérard JP ，Baudin G ，Doyen J ... -  《-》

Short-term outcomes of chemoradiotherapy and local excision versus total mesorectal excision in T2-T3ab,N0,M0 rectal cancer: a multicentre randomised, controlled, phase III trial (the TAU-TEM study).

The standard treatment of T2-T3ab,N0,M0 rectal cancers is total mesorectal excision (TME) due to the high recurrence rates recorded with local excision. Initial reports of the combination of pre-operative chemoradiotherapy (CRT) and transanal endoscopic microsurgery (TEM) have shown reductions in local recurrence. The TAU-TEM study aims to demonstrate the non-inferiority of local recurrence and the improvement in morbidity achieved with CRT-TEM compared with TME. Here we describe morbidity rates and pathological outcomes. This was a prospective, multicentre, randomised controlled non-inferiority trial including patients with rectal adenocarcinoma staged as T2-T3ab,N0,M0. Patients were randomised to the CRT-TEM or the TME group. Patients included, tolerance of CRT and its adverse effects, surgical complications (Clavien-Dindo and Comprehensive Complication Index classifications) and pathological results (complete response in the CRT-TEM group) were recorded in both groups. Patients attended follow-up controls for local and systemic relapse. NCT01308190. From July 2010 to October 2021, 173 patients from 17 Spanish hospitals were included (CRT-TEM: 86, TME: 87). Eleven were excluded after randomisation (CRT-TEM: 5, TME: 6). Modified intention-to-treat analysis thus included 81 patients in each group. There was no mortality after CRT. In the CRT-TEM group, one patient abandoned CRT, 1/81 (1.2%). The CRT-related morbidity rate was 29.6% (24/81). Post-operative morbidity was 17/82 (20.7%) in the CRT-TEM group and 41/81 (50.6%) in the TME group (P < 0.001, 95% confidence interval 42.9% to 16.7%). One patient died in each group (1.2%). Of the 81 patients in the CRT-TEM group who received the allocated treatment, 67 (82.7%) underwent organ preservation. Pathological complete response in the CRT-TEM group was 44.3% (35/79). In the TME group, pN1 were found in 17/81 (21%). CRT-TEM treatment obtains high pathological complete response rates (44.3%) and a high CRT compliance rate (98.8%). Post-operative complications and hospitalisation rates were significantly lower than those in the TME group. We await the results of the follow-up regarding cancer outcomes and quality of life.

Serra-Aracil X ，Pericay C ，Badia-Closa J ，Golda T ，Biondo S ，Hernández P ，Targarona E ，Borda-Arrizabalaga N ，Reina A ，Delgado S ，Vallribera F ，Caro A ，Gallego-Plazas J ，Pascual M ，Álvarez-Laso C ，Guadalajara-Labajo HG ，Mora-Lopez L ... -  《-》