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).

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: The French Programme Hospitalier de Recherche Cinique.

Reproducibility of surface-based deep inspiration breath-hold technique for lung stereotactic body radiotherapy on a closed-bore gantry linac.

Background and purpose: Tumor motion and delivery efficiency are two main challenges of lung stereotactic body radiotherapy (SBRT). The present work implemented the deep inspiration breath hold technique (DIBH) with surface guided radiation therapy (SGRT) on closed-bore linacs and investigated the correlation between SGRT data and internal target position. Materials and methods: Thirteen lung SBRT patients treated in DIBH using a closed-bore gantry linac and a ring-mounted SGRT system were retrospectively analysed. Visual coaching was used to achieve DIBH with a ± 1 mm threshold window in the anterior-posterior direction. Three kV-CBCTs were added to the treatment workflow and examined offline to verify intra-fraction tumor position. Surface-based DIBH was analysed using SGRT treatment reports and an in-house python script. Data from 73 treatment sessions and 175 kV-CBCTs were studied. Correlations between target and surface positions were studied with Linear Mixed Models. Results: Median intra-fraction tumor motion was 0.8 mm (range: 0.7-1.3 mm) in the anterior-posterior direction, 1.2 mm (range: 1-1.7 mm) in the superior-inferior direction, and 1 mm (range: 0.7-1.1 mm) in the left-right direction, with rotations of <1° (range: 0.6°-1.1°) degree in all three directions. Planned target volumes and healthy lung volumes receiving 12.5 Gy and 13.5 Gy were reduced on average by 67% and 54%, respectively. Conclusions: Lung SBRT in DIBH with the ring-mounted SGRT system proved reproducible. The surface monitoring provided by SGRT was found to be a reliable surrogate for internal target motion. Moreover, the implementation of DIBH technique helped reduce target volumes and lung doses.

Targeted Radiotherapy Using Contact X-ray Brachytherapy 50 kV.

Rectal adenocarcinoma is a quite radioresistant tumor. In order to achieve non-operative management (NOM) radiotherapy plays a major role. Targeted radiotherapy aiming at high precision 3D radiotherapy uses stereotactic image-guided external beam radiotherapy machines. To further safely increase the tumor dose, endocavitary brachytherapy (ECB) is an original approach. There are two different ways to perform such an ECB: contact X-ray brachytherapy (CXB) using a 50 kV X-ray generator with an X-ray tube positioned under eye guidance into the rectal cavity and high-dose-rate brachytherapy (HDRB) using iridium-192 sources positioned into the rectal cavity under image guidance. This study focused on CXB. CXB uses a small mobile generator that produces 50 kV X-rays with limited penetration. This technique is well adapted to accessible tumors of limited size and especially needs a high dose rate (≥15 Gy/minutes) for rectal tumors. It is performed on an ambulatory basis. A total dose between 80−110 Gy is delivered in 3−4 fractions over 3 to 6 weeks into a small volume (5 cm3). CXB was pioneered in the 1970s by Papillon using the Philips RT 50TM. Since 2009, the Papillon P50TM has been used in 11 institutions in Europe. The OPERA Phase III trial tested the hypothesis that a CXB boost (90 Gy/3 fr) compared to an EBRT boost (9 Gy/5 fr) for T2−T3 ab < 5 cm and N0−N1 < 8 mm will increase the 3-year organ preservation (OP) rate when combined with 45 Gy/5 weeks with concomitant capecitabine. Out of more than 300 patients with tumors < 3 cm (1962−1992), Papillon reported a long-term local control close to 85%. Similar results were published in Europe and USA at that time. The Lyon R96-2 Phase III trial (2004) demonstrated that, when combined with preoperative EBRT, a CXB boost (90 Gy/3 fr) significantly increased the rate of clinical complete response (cCR) and sphincter preservation, with some patients having OP at 10 years. With more than 2000 patients treated in Europe (2010−2020) using the Papillon 50TM, organ preservation appears possible in close to 80% of cases in selected early T2−T3. The OPERA trial closed after 141 inclusions (2015−2020) after an independent data monitoring committee recommendation because of promising results. At the 2-year follow-up (blinded data), the rate of cCR and OP were 77% and 72%, respectively, for the 141 tumors, and for T < 3 cm (61 pts), they were 86% and 85%, respectively, with good bowel function. The final results should be available in 2022. Organ preservation using NOM appears to be a promising approach for rectal cancer. A CXB boost with chemoradiotherapy in selected early T2−T3 could become an attractive option to achieve a planned OP. This approach should be proposed to well-informed patients after discussion in an MDT.

Commissioning and performance testing of the first prototype of AlignRT InBore™ a Halcyon™ and Ethos™-dedicated surface guided radiation therapy platform.

PURPOSE: To commission and assess the performance of AlignRT InBore™, a Halcyon™ and Ethos™-dedicated Surface Guided Radiation Therapy (SGRT) platform which combines ceiling-mounted cameras for patient setup and bore-mounted cameras for in-bore tracking. METHODS: To check the potential impact of InBore™ cameras on dose delivery, 16 SRS, H&N, breast and pelvis patients' quality assurance (QA) treatment plans were measured with/without AlignRT InBore™ and using ArcCHECK® and SRS MapCHECK®. Impact on image quality was determined using Catphan® 540 phantom and considering all available MV and CBCT protocols (head, breast, chest and pelvis). The stability, accuracy and overall performance of AlignRT InBore™ was assessed using an MV Cube and anthropomorphic phantoms. RESULTS: Comparison of 2D dose distributions with/without AlignRT InBore™ showed no impact on treatment delivery for all 16 QA checks (p-value > 0.25). 2D and CBCT images showed no artefacts or change in the contrast-to-noise ratio, resolution and noise values measured with Catphan® 540. Anti-collision sensors were unaffected by the bore-mounted cameras. Additionally, AlignRT InBore™ cameras allowed for motion detection with sub-0.5 mm accuracy and sub-0.4 mm stability with surface coverage of >50 × 60 × 35 cc. Accurate transition (sub-0.3 mm) from virtual to treatment isocentres was achieved. Finally, Halcyon™ rotations during CBCT and beam delivery resulted in limited camera vibrations with translation uncertainty <0.5 mm in left-right and anterior-posterior directions and <0.1 mm in head-feet direction. CONCLUSION: AlignRT InBore™ provides SGRT setup and intrafraction monitoring capabilities with a performance comparable to standard SGRT solutions while having no adverse effect on Halcyon™.

Planned organ preservation for early T2-3 rectal adenocarcinoma: A French, multicentre study.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) and watch-and-wait policy as reported by Habr-Gama are references for organ preservation in rectal cancer. To increase the clinical complete response (cCR) and reduce the local recurrence rates, we report a retrospective analysis of a prospective cohort of selected T2-3 tumours treated in three French institutions using contact X-ray brachytherapy (CXB) with nCRT. METHODS: Tumour selection was based on digital rectal examination (DRE), rigid rectoscopy, magnetic resonance imaging (MRI) and/or endorectal ultrasound. Adenocarcinoma T2-3 < 5 cm largest diameter, M0 were treated, all with organ preservation intent. CXB delivering 90 Gy/3 fractions/4 weeks was combined with CRT (capecitabine 50). Strict evaluation of tumour response using DRE and rectoscopy ± MRI was performed at regular interval with prolonged surveillance. FINDINGS: Between 2002 and 2016, 74 consecutive patients were treated (median age: 74 years. T2: 45 and T3: 29). A cCR or near-cCR (mainly rectal wall ulceration) was noted at week 14 in 71 patients (95%). A local excision was performed in 13 patients. Of three partial responses (PRs), one salvage anterior resection was performed. With a median follow-up of 3 years, local recurrence (mainly in the rectal wall) was seen in seven patients. The 3-year local recurrence rate was 10%, and the cancer-specific survival, 88%. Two patients underwent radical proctectomy for PR or local recurrence and 96% preserved their rectum. Grade III acute toxicity was recorded in five patients. Rectal bleeding was the main late toxicity (grade III in 12%). Bowel function was scored as good or excellent in 85% of patients. INTERPRETATION: Combining CXB and nCRT in selected early T2-T3 rectal cancers may safely provide a high rate of cCR, organ preservation, and good bowel function with a risk of local recurrence below 15%. Such an approach could be offered to operable patients as a planned option for organ preservation.

Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatin-containing regimen: the Lyon R0-04 phase II trial.

PURPOSE: The combination of radiation, fluorouracil, and oxaliplatin in locally advanced rectal cancer has been shown to be feasible in a phase I trial. The purpose of this phase II trial was to assess tolerance and efficacy of this regimen in a preoperative setting. PATIENTS AND METHODS: Between May 2000 and October 2001, 40 operable patients were entered onto the study. Radiotherapy was delivered with a three-field technique to a dose of 50 Gy over 5 weeks with a concomitant boost approach. Two cycles of chemotherapy were given synchronously on weeks 1 and 5, with oxaliplatin 130 mg/m(2) on day 1 followed by 5-day continuous infusion of fluorouracil 350 mg/m(2) and L-folinic acid 100 mg/m(2). Surgery was planned 5 weeks later. RESULTS: All patients completed treatment without modification except one who experienced grade 3/4 toxicity. Grade 3 toxicity was seen in seven patients. Surgery was performed in all patients after a mean interval time of 5 weeks. An objective clinical response was seen in 30 patients (75%). Sphincter-saving surgery was possible in 26 patients. No postoperative deaths occurred. In four patients (10%), a reoperation was necessary (anastomotic fistula, n = 2; pelvic abscess, n = 2). In six cases the operative specimen was sterilized (15%), and in 12 cases (30%), only few residual cells were detected. CONCLUSION: Such a combined preoperative chemoradiotherapy and oxaliplatin-containing regimen is well tolerated with no increase in surgical toxicity. The good response rate observed warrants its use in further clinical trials.

Improved sphincter preservation in low rectal cancer with high-dose preoperative radiotherapy: the lyon R96-02 randomized trial.

PURPOSE: The potential advantage of high-dose preoperative radiotherapy to increase tumor response and improve the chance of sphincter preservation for low rectal cancer remains controversial. The aim of this trial was to evaluate the role of escalating the dose of preoperative radiation to increase sphincter-saving procedures. PATIENTS AND METHODS: Patients with rectal carcinoma located in the lower rectum, staged T2 or T3, Nx, or M0 with endorectal sonography, and not involving more than two-thirds circumference, were randomly assigned to one of two groups: preoperative external-beam radiotherapy (EBRT; 39 Gy in 13 fractions over 17 days) versus the same EBRT with boost (85 Gy in three fractions) using endocavitary contact x-ray. RESULTS: Between 1996 and 2001, 88 patients were enrolled onto the study. A significant improvement was seen in favor of the contact x-ray boost for complete clinical response (24% v 2%) and for a complete or near-complete sterilization of the operative specimen (57% v 34%). A significant increase in sphincter preservation was observed in the boost group (76% v 44%; P =.004). At a median follow-up of 35 months, there was no difference in morbidity, local relapse, and 2-year overall survival. CONCLUSION: A dose escalation with endocavitary irradiation provides increased tumor response and sphincter preservation with no detrimental effect on treatment toxicity and early clinical outcome.