Organ Preservation Rates Research Articles

Implications of recent neoadjuvant clinical trials on the future practice of radiotherapy in locally advanced rectal cancer.

Over the last two decades, the standard treatment for locally advanced rectal cancer (LARC) has been neoadjuvant chemoradiotherapy plus total mesorectal excision followed by adjuvant chemotherapy. Total neoadjuvant treatment (TNT) and immunotherapy are two major issues in the treatment of LARC. In the two latest phase III randomized controlled trials (RAPIDO and PRODIGE23), the TNT approach achieved higher rates of pathologic complete response and distant metastasis-free survival than conventional chemoradiotherapy. Phase I/II clinical trials have reported promising response rates to neoadjuvant (chemo)-radiotherapy combined with immunotherapy. Accordingly, the treatment paradigm for LARC is shifting toward methods that increase the oncologic outcomes and organ preservation rate. However, despite the progress of these combined modality treatment strategies for LARC, the radiotherapy details in clinical trials have not changed significantly. To guide future radiotherapy for LARC with clinical and radiobiological evidence, this study reviewed recent neoadjuvant clinical trials evaluating TNT and immunotherapy from a radiation oncologist's perspective.

Do nonoperative modality (NOM) treatments of rectal cancer compromise the chance of cure? Final surgical salvage results from OPERA phase 3 randomised trial (NCT02505750).

6 Background: Watch and wait strategy without surgery for rectal cancer is gaining popularity as it avoids a stoma. We set up an OPERA trial to evaluate the role of radiation dose escalation using Contact X-ray brachytherapy [CXB] (Papillon). We report on the final surgical salvage results for local failures of non-surgical approach. Methods: OPERA is a European phase 3 randomised trial between (Arm A-standard arm)EBCRT 45Gy/25/5weeks with oral capecitabine 825mg/m2 and EBRT boost of 9Gy/5/5 days randomised against experimental arm (Arm B) EBCRT followed by CXB boost (90 Gy/3/4 weeks). Patients were assessed at 14, 20 and 24 weeks. Watch & wait policy was adopted for patients with cCR and surgery (TME or local excision) offered for residual disease or recurrence after cCR. Results: From July 2015 –June 2020, 148 patients were randomised of which 141 were evaluable. Median age was 68 years and 88 (61%) patients were males. There were 69 patients in Arm A (standard of care with EBRT boost) and 72 patients in Arm B (experimental with CXB boost). All patients received the protocol stratified radiation dose. Median follow-up was 38.2 months (95% CI:34.2-42.5). Clinical complete response (cCR) was observed in 44/69 (64%) in Arm A and 66/72 (92%) in Arm B at 24 weeks (p< 0.001). Surgery was carried out in 66/141 (47%) with suspected residual tumour or local regrowth after achieving cCR. Total 39/66 (59%) patients had TME surgery. Local excision was carried out in 27 /49(41%). Our primary endpoint of organ preservation (OP) rate was 59% (95% CI: 48-72) in Arm A vs. 81% (95% CI: 72-91) in Arm B (HR 0.36, 95% CI: 0.19-0.70; P= 0.0026). When comparing A1(<3cm) vs. B1(<3cm), OP rate was 63% vs. 97% respectively (HR: 0.072, 95% CI 0.0093-0.57; P= 0.0123]). Overall TME free overall survival was 57% for Arm A and 79% for Arm B (HR 0.37,95% CI 0.2-0.71; P=0.0026). Conclusions: OPERA data at 38 months suggest that non-surgical treatment for cT2-cT3a-b rectal cancer is feasible and those who needed surgery for local failures can be salvaged without compromising their chance of cure. There is significant improvement in OP rate for rectal cancer <3cm to start with CXB followed by EBCRT. This option should be discussed with patients wishing to avoid surgery and a stoma as an initial treatment. Clinical trial information: NCT02505750 . [Table: see text]

Outcome of Concurrent Chemoradiation after Induction Chemotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma - A Prospective Study among Patients Attending a Tertiary Care Center in Kerala, India

BACKGROUND
 Concurrent chemoradiation (CCRT) is the standard of care for locally advanced head and neck squamous cell carcinoma (LAHNSCC). In settings with considerable waiting period for radiation, institutional protocols advocate induction chemotherapy before CCRT. This study aimed to assess the outcome of concurrent chemoradiation after induction of chemotherapy among patients with LAHNSCC attending a tertiary care radiotherapy center in Kerala, India.
 METHODS
 Patients with non-metastatic LAHNSCC (stage 111 and 1V) with good performance score of 0-1 who received induction chemotherapy (with docetaxel 75mg/m2and cisplatin 75 mg/m2, day 1 and 5-fluorouracil 750 mg/m2, day 1 and 2 as infusion every 3 weeks for 3 cycles) followed by CCRT (with concurrent cisplatin 40 mg/m2 weekly) were selected for the study. CCRT was administered only to those patients who showed more than 30 % response to induction chemotherapy. They were followed up for 24 months. The primary end point was the clinical response assessed by ENT evaluation 8 weeks after the completion of CCRT.
 RESULTS
 117 patients with LAHNSCC were enrolled. Four patients (3.4 %) dropped out after induction therapy. Out of 113 patients who initiated concurrent chemo radiation, two patients (1.7 %) dropped out while on CCRT, two patients (1.7 %) were intolerant to CCRT and two patients (1.7 %) left soon after CCRT. 107 patients were available for follow up after treatment completion. Acute toxicities were noticed in 9 (7.7 %) while on induction treatment. Mucositis occurred in 1 (0.9 %), haematological toxicities in 4 (3.4 %), gastrointestinal toxicities in 2 (1.7 %) and fatigue and malaise in 2 (1.7 %). In patients who underwent concurrent chemo radiation, 53 (49.03 %) had acute mucosal, skin, GIT and haematological toxicities. On treatment completion, 82 patients (70.1 %) had complete response, 24 (20.5 %) had partial response and one (0.9 %) had stable disease. During the follow up period of 24 months, locoregional failure (relapse) was noted in 15 patients (12.8 %) while 61 patients (52.1 %) remained disease free. Organ preservation rate was 53.4 % for laryngeal primaries. 4 patients (3.4 %) developed distant metastases during the follow up.
 CONCLUSIONS
 Induction chemotherapy with docetaxel containing regime followed by concurrent chemoradiation was associated with good clinical response and acceptable toxicity profile.

Feasibility study of a Response Surveillance Program in locally advanced mid and low rectal cancer to increase organ preservation.

Assessment of tumor response in rectal cancer after neoadjuvant treatment by MRI (Tumour Regression Grade, TRG 1-5) is well standardized. The overall timing and method of defining complete response (cCR) remain controversial. The aim of this work was to evaluate the feasibility of a defined Response Surveillance Program (RSP) to increase organ preservation for locally advanced rectal cancer after neoadjuvant treatment. A standardized program of clinical (CR), radiological (RR) and metabolic (MR) assessment of tumor response is defined over a 6 month period from completion of NACRT with formal assessment performed every 2 months (M). Patients with TRG1-3at M2 and TRG1-2at M4 continue in the program up to M6 assessment. Patients managed with this protocol from 2016 to 2020 were analyzed. The primary endpoint was rectal preservation rate. Secondary endpoints included disease-free survival and overall survival at 3 years. 314 potentially suitable patients were enrolled in the RSP and 50 patients completed the six month program and were successfully enrolled into watch and wait. Fourteen (28%) were T2 tumor stage, 27 (54%) T3 and nine (18%) were T4. During watch and wait, patients with locoregional recurrence (n=11) were treated with local excision (n=3), endocavitary radiotherapy (n=1), TME (n=5) and APR (n=2). With a median follow-up of 32 months, the rectal preservation rate was 88%, with a 3-year disease-free survival of 67% and an overall survival of 98%. This study validates the feasibility of the practical implementation of a Response Surveillance Program to increase organ preservation rates without compromising oncological outcomes in rectal cancer.

STAR-TREC: An International Three-arm Multicentre, Partially Randomised Controlled Trial Incorporating an External Pilot

AimOrgan saving treatment for early-stage rectal cancer can reduce patient reported side effects compared to standard total mesorectal excision (TME) and preserve quality of life (QOL). An optimal strategy for achieving organ preservation and longer-term oncological outcomes are unknown, thus there is a need for high quality trials. MethodCan we Save the rectum by watchful waiting or TransAnal surgery following (chemo)Radiotherapy versus Total mesorectal excision for early REctal Cancer (STAR-TREC) is an international 3-arm multi-centre, partially randomised controlled trial incorporating an external pilot. In phase III, patients with cT1-3b N0 tumours, ≤40mm in diameter, who prefer organ preservation are randomised 1:1 between mesorectal long course chemoradiation versus mesorectal short course radiotherapy, with selective transanal microsurgery. Patients preferring radical surgery receive TME. STAR-TREC aims to recruit 380 patients to organ preservation and 120 to TME surgery. The primary outcome is the rate of organ preservation at 30 months. Secondary clinician reported outcomes include acute treatment-related toxicity, rate of non-operative management, non-regrowth pelvic tumour control at 36 months, non-regrowth disease free survival at 36 months, and overall survival at 60 months and patient reported toxicity, health related QOL at baseline, 12 and 24 months. Exploratory biomarker research uses circulating tumour DNA to predict response and relapse. DiscussionSTAR-TREC will prospectively evaluate contrasting therapeutic strategies and implement new measures including a smaller mesorectal target volume, 2-step response assessment and non-operative management for complete response. The trial will yield important information to guide routine management of patients with early-stage rectal cancer.

Modified DCF (Docetaxel, Cisplatin and 5-fluorouracil) chemotherapy is effective for the treatment of advanced rectal squamous cell carcinoma.

Advanced rectal squamous cell carcinoma (rSCC) is a very rare and aggressive entity, and the best initial management is crucial for long survival as well as organ preservation and quality of life. Whereas local diseases are treated with chemo-radiotherapy and salvage surgery, data are scarce on how to treat more advanced diseases, and the role of induction chemotherapy is unknown. We retrospectively analyzed all consecutive patients with advanced rSCC and treated with modified DCF (docetaxel, cisplatin, 5-fluorouracil; mDCF) regimen, from January 2014 and December 2021 in two French centers. Exploratory endpoints were efficacy (overall survival, recurrence-free survival, response rate, organ preservation rate) and safety. Nine patients with locally advanced or metastatic diseases received a mDCF regimen and were included for analysis. The median age was 62.0 years, 7 patients (77.8%) were women, and all eight available tumors were positive for HPV, mostly (85.7%) to genotype 16. With a median follow-up of 33.1 months, 77.8% of patients were still alive and disease-free, and the median overall survival was not reached at six years. The objective response rate was 87.5% after mDCF, and the complete response rate was 25.0% after mDCF and was increased to 75.0% after chemoradiotherapy. Only one patient underwent surgery on the primary tumor, with a complete pathological response. The median mDCF cycle was eight over eight scheduled, and all patients received the complete dose of radiotherapy without interruptions. Induction mDCF chemotherapy followed by chemoradiotherapy is safe and highly effective in patients with advanced rSCC, and should be considered as an option in metastatic stage or locally advanced disease with an organ-preservation strategy.

Quality-of-life outcomes in older patients with early-stage rectal cancer receiving organ-preserving treatment with hypofractionated short-course radiotherapy followed by transanal endoscopic microsurgery (TREC): non-randomised registry of patients unsuitable for total mesorectal excision

Older patients with early-stage rectal cancer are under-represented in clinical trials and, therefore, little high-quality data are available to guide treatment in this patient population. The TREC trial was a randomised, open-label feasibility study conducted at 21 centres across the UK that compared organ preservation through short-course radiotherapy (SCRT; 25 Gy in five fractions) plus transanal endoscopic microsurgery (TEM) with standard total mesorectal excision in adults with stage T1-2 rectal adenocarcinoma (maximum diameter ≤30 mm) and no lymph node involvement or metastasis. TREC incorporated a non-randomised registry offering organ preservation to patients who were considered unsuitable for total mesorectal excision by the local colorectal cancer multidisciplinary team. Organ preservation was achieved in 56 (92%) of 61 non-randomised registry patients with local recurrence-free survival of 91% (95% CI 84-99) at 3 years. Here, we report acute and long-term patient-reported outcomes from this non-randomised registry group. Patients considered by the local colorectal cancer multidisciplinary team to be at high risk of complications from total mesorectal excision on the basis of frailty, comorbidities, and older age were included in a non-randomised registry to receive organ-preserving treatment. These patients were invited to complete questionnaires on patient-reported outcomes (the European Organisation for Research and Treatment of Cancer Quality of Life [EORTC-QLQ] questionnaire core module [QLQ-C30] and colorectal cancer module [QLQ-CR29], the Colorectal Functional Outcome [COREFO] questionnaire, and EuroQol-5 Dimensions-3 Level [EQ-5D-3L]) at baseline and at months 3, 6, 12, 24, and 36 postoperatively. To aid interpretation, data from patients in the non-randomised registry were compared with data from those patients in the TREC trial who had been randomly assigned to organ-preserving therapy, and an additional reference cohort of aged-matched controls from the UK general population. This study is registered with the ISRCTN registry, ISRCTN14422743, and is closed. Between July 21, 2011, and July 15, 2015, 88 patients were enrolled onto the TREC study to undergo organ preservation, of whom 27 (31%) were randomly allocated to organ-preserving therapy and 61 (69%) were added to the non-randomised registry for organ-preserving therapy. Non-randomised patients were older than randomised patients (median age 74 years [IQR 67-80] vs 65 years [61-71]). Organ-preserving treatment was well tolerated among patients in the non-randomised registry, with mild worsening of fatigue; quality of life; physical, social, and role functioning; and bowel function 3 months postoperatively compared with baseline values. By 6-12 months, most scores had returned to baseline values, and were indistinguishable from data from the reference cohort. Only mild symptoms of faecal incontinence and urgency, equivalent to less than one episode per week, persisted at 36 months among patients in both groups. The SCRT and TEM organ-preservation approach was well tolerated in older and frailer patients, showed good rates of organ preservation, and was associated with low rates of acute and long-term toxicity, with minimal effects on quality of life and functional status. Our findings support the adoption of this approach for patients considered to be at high risk from radical surgery. Cancer Research UK.

Chemoradiation and consolidation chemotherapy for rectal cancer provides a high rate of organ preservation with a very good long-term oncological outcome: a single-center cohort series

AimTo report long-term oncological outcomes and organ preservation rate with a chemoradiotherapy-consolidation chemotherapy (CRT-CNCT) treatment for locally advanced rectal cancer (LARC).MethodRetrospective analysis of prospectively maintained database was performed. Oncological outcomes of mid-low LARC patients (n=60) were analyzed after a follow-up of 63 (50–83) months. Patients with clinical complete response (cCR) were treated with the watch-and-wait (WW) protocol. Patients who could not achieve cCR were treated with total mesorectal excision (TME) or local excision (LE).ResultsThirty-nine (65%) patients who achieved cCR were treated with the WW protocol. TME was performed in 15 (25%) patients and LE was performed in 6 (10%) patients. During the follow-up period, 10 (25.6%) patients in the WW group had regrowth (RG) and 3 (7.7%) had distant metastasis (DM). Five-year overall survival (OS) and disease-free survival (DFS) were 90.1% and 71.6%, respectively, in the WW group. Five-year OS and DFS were 94.9% (95% CI: 88–100%) and 80% (95% CI: 55.2–100%), respectively, in the RG group. For all patients (n=60), 5-year TME-free DFS was 57.3% (95% CI: 44.3–70.2%) and organ preservation-adapted DFS was 77.5% (95% CI: 66.4–88.4%). For the WW group (n=39), 5-year TME-free DFS was 77.5% (95% CI: 63.2–91.8%) and organ preservation-adapted DFS was 85.0% (95% CI: 72.3–97.8%).ConclusionCRT-CNCT provides cCR as high as 2/3 of LARC patients. Regrowths, developed during follow-up, can be successfully salvaged without causing oncological disadvantage if strict surveillance is performed.

Watch and Wait in Rectal Cancer After a Complete Response to Chemoradiotherapy – Is It Safe and Are We Doing Enough?

AimsTo summarise current understanding and the associated outcomes of the watch and wait approach after a clinical complete response (cCR) of rectal cancer to chemoradiotherapy. Materials and methodsA contemporary and comprehensive literature review was carried out using focused searches of the MEDLINE and Google Scholar databases. ResultsThe watch and wait approach is now an established and oncologically safe option for patients who develop a cCR. Long-term survival is equivalent to primary rectal resection and quality of life outcomes are demonstrably superior. The tumour regrowth rate of 25–33% is higher than local recurrence rates after total mesenteric excision. Therefore, intensive surveillance protocols are required to enable early salvage surgery. Salvage is feasible in more than 84% of cases, with equivalent survival outcomes to primary resection. DiscussionCurrent evidence focuses on patients with locally advanced disease, but there are superior rates of cCR and organ preservation in earlier stages of rectal cancer. A shift towards planning for cCR and maximising cCR rates is the logical next step for rectal preservation. Emerging evidence attempts to predict those who will achieve a complete response and allow more tailored management plans, and earlier cancers may represent the optimal targets.

The Role of Contact X-Ray Brachytherapy in Early Rectal Cancer – Who, when and How?

The National Institute for Health and Care Excellence (NICE) has recommended the use of contact X-ray brachytherapy (CXB) for rectal cancer patients who are not suitable for surgery. At present, patients with early rectal cancer who wish to avoid major surgery and a stoma are not usually offered CXB as an alternative treatment option to surgery. The main reason for this has been a lack of large, randomised trial evidence, hence NICE encouraged provision of this evidence in their recommendation. In 2015, the OPERA (Organ Preservation in Early rectal Adenocarcinoma) trial was set up and the 3-year organ-preservation results were presented at the American Society of Clinical Oncology (ASCO) meeting in Chicago on 4 June 2022. We are now awaiting full publication of the OPERA results. Most rectal cancer patients who are not suitable for surgery are currently offered external beam radiotherapy (EBRT) with or without chemotherapy after the multidisciplinary discussions. Clinical complete response (cCR) rates vary between 20 and 50% after EBRT. Those who achieve cCR usually adopt a ‘watch and wait’ policy, but patients who have residual disease are often not offered any additional treatment. We hypothesised that dose escalation with a CXB boost could achieve a higher cCR and therefore lead to improved organ-preservation rates. This was the rationale behind the OPERA trial, which randomised patients between standard of care [EBRT with chemotherapy (EBCRT)] followed by an EBRT boost against EBCRT with a CXB boost to evaluate the role of CXB in dose escalation. In 1993, the first CXB centre was established in the UK at Clatterbridge Cancer Centre. There are now four centres offering CXB in the UK and 10 centres in Europe. Patients should be provided with full information during the consent discussion and offered all the treatment options that are available, so that they can share in decision making and be empowered to make treatment decisions of their choice after proper fully informed consent. Randomised trial evidence of the role of dose escalation with CXB from the OPERA trial, when published, will help in consenting patients who are keen to avoid surgery. We hope this review will help to provide some information about who should be offered CXB, when this modality should be offered and how this is delivered.

Short-Course Radiotherapy Based Total Neoadjuvant Therapy Combined with Toripalimab for Locally Advanced Rectal Cancer: Preliminary Findings from a Randomized, Prospective, Multicenter, Double-Arm, Phase II Trial (TORCH)

<h3>Purpose/Objective(s)</h3> For patients with locally advanced rectal cancer (LARC), the standard treatment is neoadjuvant chemoradiotherapy combined with curative surgery. Total neoadjuvant therapy (TNT) has been used to increase rates of complete response and organ preservation, and achieve early control of distant metastasis. Recently, hypofractionated radiotherapy shows better synergistic effects in combination with PD-1/PD-L1 antibodies than conventional fractionated radiotherapy. Thus, the combination of short-course radiotherapy (SCRT) based TNT and immunotherapy is likely to further improve both tumor response and prognosis for LARC patients. <h3>Materials/Methods</h3> TORCH is a randomized, prospective, multicenter, double-arm, phase II trial. 130 LARC (T3-4/N+M0, distance from anus ≤10cm) patients will be treated with TNT approach and assigned to the consolidation arm (A) and induction arm (B). Arm A will receive SCRT (25 Gy/5Fx), followed by 6 cycles of Toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Arm B will first receive 2 cycles of ToriCAPOX, then receive SCRT, followed by 4 cycles of ToriCAPOX. Both groups will receive curative surgery or W&W strategy. The primary endpoint is the rate of complete response (CR, pCR plus cCR). The secondary endpoints include the grade 3-4 acute adverse effects (AE) rate, 3-year DFS rate, 3-year OS rate, etc. The "pick the winner" method is used to investigate the better regimen. <h3>Results</h3> Up to February 20, 2022, 81 patients have been recruited in the trial. A total of 16 patients (all MSS; arm A: 7, arm B: 9) have completed all neoadjuvant therapy. Most of them showed high risk factors of recurrence, including lower location (≤5cm, 14/16), deeper primary lesion invasion (cT4/MRF+, 7/16) and more positive lymph nodes (cN2, 9/16). Finally, 5 patients (arm A: 1, arm B: 4) achieved cCR and decided to adopt W&W strategy. 11 patients received surgery (Dixon: 6, Miles: 5) and the pathological results showed 8 cases of pCR (arm A: 4, arm B: 4), one near-pCR (arm A) and two non-pCR (arm A: 1, arm B: 1). Thus, the CR rate was amazingly high (CR rate: 81.25%, 13/16; pCR rate: 72.73%, 8/11). Even 6 patients who were evaluated as ycT3/N+/MRF+/EMVI+ before surgery was still demonstrated to be pCR after strict pathological examination. The only grade 3 AE was thrombocytopenia (37.50%, 6/16). And no grade 4 AE was observed. <h3>Conclusion</h3> SCRT base TNT combined with Toripalimab have achieved surprisingly excellent CR rate and good tolerance in LARC patients (in our cohort), which has the potential to improve organ preservation rate. In the future, this ongoing trial will demonstrate this efficacy and compare the two arms by larger sample size.

Recursive Partitioning Analysis to Define Prognostic Groups Using a Large Single Institution Experience of Multimodality Radiation Therapy for Bladder Cancer

<h3>Purpose/Objective(s)</h3> We analyzed a cohort of patients who received definitive trimodality therapy (TMT) for bladder cancer at a single high-volume institution. We hypothesized that a recursive partitioning analysis (RPA) including patient and tumor characteristics would allow stratification of patients into clinically meaningful prognostic groups for local recurrence. <h3>Materials/Methods</h3> A retrospective cohort analysis was performed for bladder cancer patients treated with definitive radiation or chemoradiation therapy from 2006 to 2021 at our institution. We assessed overall and disease-free survival for the cohort and as a function of clinical and pathologic features. We performed an RPA for multivariate decision tree analysis to associate outcomes with individual clinical and pathologic variables. <h3>Results</h3> 175 patients were identified who were treated with definitive radiation (28%) or chemoradiation (72%) and had adequate follow-up data for analysis. Median follow up time was 23 months (Median age=78 [IQR 71-84], 77% male). While Grade 1-2 toxicities were common, Grade ≥3 toxicities were rare and there were no treatment related deaths. Cumulative 2yr and 5yr CSS were 79% and 61%, respectively. Radical cystectomy (RCx) eligible patients (35%) had a significantly longer OS after bladder sparing therapy compared to RCx ineligible patients (5y OS 54% vs 29%, Log-Rank p=0.003), however no difference in cancer specific survival was seen between groups (5y CSS 61% vs 58%, Log-Rank p = 0.851). Tumor size greater than 5cm did not correlate with risk of recurrence (Log-Rank p=0.194). The most common site of recurrence in the cohort was distant (35%), followed by locoregional (19%) and bladder only (6%). Nine patients (5%) underwent salvage cystectomy (7 for invasive local recurrence) after initial definitive radiation therapy. Using RPA and decision tree analysis, the presence of CIS and older age at treatment were the strongest predictors of local recurrence. The RPA results confirmed no significant association between tumor size and risk of local recurrence. <h3>Conclusion</h3> Multimodality bladder preservation had CSS comparable to modern surgical series and high rates of functional organ preservation. Cystectomy candidacy was a strong predictor of overall survival but not cancer specific survival, suggesting group level mismatches in competing risks of death. Extensive CIS was associated with increased risk of local failure, but tumor size may not be a reliable predictor of treatment response. RPA prognostic groups were generated which may be used to guide clinical decision making and improve patient selection for bladder preservation.

Reduction of Tumor Length by >50%, Post Neoadjuvant Chemoradiation as a Predictor for Complete Response and Organ Preservation in Rectal Cancer

<h3>Purpose/Objective(s)</h3> 20-30% of the locally advanced rectal cancer patients undergoing neoadjuvant chemoradiation (NACRT) have complete response (CR) and are suitable for wait and watch approach. This tumor response can be enhanced by radiotherapy dose escalation such as brachytherapy which is typically given at the end of NACRT. However, there is no data so as to which patients are likely to benefit by brachytherapy to achieve CR. We aimed to identify decrease in tumor length following CTRT, as predictor of CR, and eventual organ preservation. <h3>Materials/Methods</h3> Patients diagnosed with T2-T4, N0-N2 distal rectal cancer treated from December 2017 to March 2021 were retrospectively reviewed. All were treated with radiation dose of 50 Gray (Gy) in 25 fractions (#) with concurrent capecitabine. All patients received escalated dose of radiation by high dose rate endorectal brachytherapy of 8-12 Gy in 2-3 #s within 2 to 3 weeks post CTRT. Baseline tumor length (MRI) and residual tumor length after CTRT during brachytherapy (assessed with planning MRI) were compared for response. Statistical analysis was done to determine decrease in tumor length as predictor of CR. <h3>Results</h3> One hundred patients records were reviewed. Disease and treatment characteristics are provided in table 1. Median length of tumor at baseline was 4.9 cm (3.8-6 cm). 39 patients had >50% decrement in tumor length (median length 3 cm) from baseline post CTRT, whereas 61 patients had <50% response. Out of 39 patients with>50% response, 26 patients achieved CR (66.7%) while 13 patients had partial or no response (33.3%), while out of 61 patients with <50% decrease in tumor length, 27 achieved CR (44.2%) and 34 had partial or no response (55.8%). The patients who had >50% reduction in tumor length had higher probability of achieving CR than the patients with <50% reduction (66% vs 44% p=0.029). <h3>Conclusion</h3> Response assessment at the end of CTRT with respect to decrease in length of tumor may predict CR and thus can lead to better selection of patients for escalated radiation dose via endorectal brachytherapy leading to higher rate of organ preservation.

A Meta-analysis of Total Neoadjuvant Therapies Combining Chemoradiotherapy with Induction or Consolidated Chemotherapy for Locally Advanced Rectal Cancer.

Total neoadjuvant therapy (TNT) combining chemoradiotherapy (CRT) with chemotherapy (CT) was a novel pre-surgical approach to cancer treatment. This meta-analysis aimed to compare the clinical outcomes between neoadjuvant CRT (nCRT) with induction CT and nCRT with consolidated CT in locally advanced rectal cancer (LARC) patients. In July 2022, a literature search was conducted using the following public databases: PubMed, MEDLINE, Embase, the Cochrane Library, and Web of Science, retrieved all relevant articles comparing nCRT-combining induction CT with nCRT-combining-consolidated CT treatments for LARC patients. Four eligible studies were identified, including a total of 995 LARC patients: 473 in the nCRT with consolidated CT group and 522 in the nCRT with induction CT group. The organ preservation (OP) rate of the nCRT with consolidated CT group was higher than that of the nCRT with induction CT group (RR [relative risk]: 1.53; 95% CI (confidence interval): 1.09-2.14). The pathological complete response (PCR, RR: 1.22; 95% CI 0.37-2.17), the 3-year disease-free survival (DFS, RR 1.02; 95% CI 0.71-1.46), the local recurrence (LR, RR 0.98; 95% CI 0.52-1.85), rates of R0 resection (RR 0.74; 95% CI 0.55-1.10), compliance (RR 0.52; 95% CI 0.12-2.26), and grade 3--4 toxicities (RR 0.78; 95% CI 0.57-1.06) were all similar between the two groups. In this meta-analysis of TNT regimens for rectal cancer, consolidative CT following nCRT was associated with similar PCR, 3-year DFS, LR, R0 resection, compliance, and grade 3-4 toxicities compared to induction CT prior to nCRT but a higher rate of organ preservation.

The Evolving Landscape of Immunotherapy in Locally Advanced Rectal Cancer Patients

Simple SummaryAt the last 2022 annual ASCO meeting, impressive results of anti-PD1 activity in clinical stage 2 and 3 microsatellite instable rectal cancer patients have been published. Moreover, a growing number of studies assessed the synergism between neoadjuvant (chemo)radiotherapy and immunotherapy in microsatellite stable localized rectal cancer patients. Major findings of immunotherapy activity and efficacy in localized rectal cancer, according to microsatellite status, are discussed in this commentary.Standard treatments of localized rectal cancer are surgery or the multimodal approach with neoadjuvant treatments (chemo-radiotherapy, short-course radiotherapy, induction, or consolidation chemotherapy) followed by surgery. In metastatic colorectal cancer (mCRC), immune checkpoint inhibitors (ICIs) are now the first choice in patients with a deficient mismatch repair system/microsatellite instability (dMMR/MSI-H) and are being explored in combination with chemotherapy to rewire the immune system against malignant cells in subjects with proficient mismatch repair system/microsatellite low (pMMR/MSI-L) cancers, with promising signals of efficacy. Recently, some efforts have been made to translate ICIs in earlier stages of CRC, including localized rectal cancer, with breakthrough efficacy and an organ preservation rate of mono-immunotherapy in dMMR/MSI-H patients and promising anti-tumor activity of immunotherapy plus neoadjuvant (chemo)radiotherapy in pMMR/MSI-L subjects. Here, we present the rationale, results, and limitations of the most remarkable trials assessing ICIs in dMMR/MSI-H and pMMR/MSI-L localized rectal cancer patients, at the same time highlighting the most promising research perspectives that have followed these studies.

Intentional Watch and Wait or Organ Preservation Surgery Following Neoadjuvant Chemoradiotherapy Plus Consolidation CAPEOX for MRI-defined Low-risk Rectal Cancer: Findings From a Prospective Phase 2 Trial (PKUCH-R01 Trial, NCT02860234).

To assess the efficacy and safety of intentional watch and wait (W&W) and organ preservation surgery following neoadjuvant chemoradiotherapy plus consolidation CAPEOX in magnetic resonance imaging (MRI)-defined low-risk rectal cancer. Clinical T2/early T3 rectal cancers can achieve high yield pathological complete response (ypCR) rates after chemoradiotherapy; thus, an intentional W&W or organ preservation strategy for good clinical responders in these subgroups can be further tested. This prospective, single-arm, phase 2 trial enrolled patients with low-risk MRI prestaged rectal cancers, who concurrently received chemoradiation, followed by four 3-weekly cycles of CAPEOX regimen. Following reassessment, clinical complete response (cCR) or near-cCR patients underwent W&W/organ preservation surgery; the primary endpoint was a 3-year organ preservation rate. Of the 64 participants, 58 completed treatment, with 6.4% and 33.9% grade 3 to 4 toxicities in the radiotherapy and consolidation CAPEOX phases, respectively, during a median 39.5-month follow-up. Initial cCR, and non-cCR occurred in 33, 13, and 18 patients, respectively. Of the 31 cCR and 7 near-cCR cases managed by W&W, local regrowth occurred in 7; of these, 6 received salvage surgery. The estimated 2-year local regrowth rates were 12.9% [95% confidence interval (CI): 1.1%-24.7%] in cCR and 42.9% (95% CI: 6.2%-79.6%) in near-cCR cases, respectively. Eight patients received local excision, including 2 with regrowth salvage. Lung metastases occurred in 3 patients and multiple metastasis occurred in 1 patient; no local recurrence occurred. The estimated 3-year organ preservation rate was 67.2% (95% CI: 55.6%-78.8%). The estimated 3-year cancer-specific survival, non-regrowth disease-free survival, and stoma-free survival were 96.6% (95% CI: 92.1%-100%), 92.2% (95% CI: 85.5%-98.9%), and 82.7% (95% CI: 73.5%-91.9%), respectively. Chemoradiotherapy plus consolidation CAPEOX for MRI-defined low-risk rectal cancer can lead to high rates of organ preservation through intentional W&W or local excision. The oncologic safety of this strategy should be further tested.

Contact x-ray brachytherapy (Papillon) in addition to chemoradiotherapy to improve organ preservation in early cT2-T3 rectal adenocarcinoma: The 3-year results of OPERA randomized trial (NCT02505750).

3512 Background: The OPERA trial was testing the hypothesis that Contact x-ray brachytherapy (CXB) 50 kV boost will increase the rectal preservation rate in early T2-T3ab rectal adenocarcinoma. We present the 3 years clinical results. Methods: Inclusion criteria were: Age &gt; 18 years, PS: 0-1, adenocarcinoma, distal - middle rectum, cT2-T3ab cN0-N1 &lt; 8mm staged using MRI, M0. Stratification: T &lt; vs ≥ 3 cm diameter. Control arm (A) was chemoradiotherapy (CRT) 45Gy/ 5 weeks with concurrent chemotherapy (Capecitabine 825 mg / m2) and external beam radiotherapy boost (9Gy/ 5 fr/ 1 week). Experimental arm used the same CRT (Cape 45) but the boost used CXB (90 Gy/ 3 fr/ 4 weeks). CXB was given first (B1) for tumor &lt; 3 cm and after cap 45 (B2) for tumor ≥ 3 cm. Response assessment was made at week 14 after treatment start using palpation, endoscopy and MRI. A new assessment could be made at week 20 and 24 with a second MRI.TME was recommended in case of Partial response, Watch&amp; Wait in case of clinical complete response (cCR). Bowel function measurement used LARS score. Main end- point was: Rate of organ preservation at 3 years. The hypothesis (in 2014) was 20% arm A vs 40% arm B (HR:0.53). Results: Between 5-2015 and 6-2020, 144 patients were included (France 96, UK 44, Switzerland 4). The analysis was made in 01-2022 with a median Follow-up time of 34 months. Treatment compliance was good in ≥ 90% of patients. Table gives main patients characteristics and clinical outcome. At three years the OP rate (Kaplan Meier estimate) was respectively arm A vs B: 60% vs 81% (HR 0.34 [95% CI 0.19 – 0.73]; p= 0.005). At three years OP for group A1 and B1 were: 65% vs 97% (HR 0.081 [95% CI 0.01-0.64]; p= 0.02). Conclusions: A CXB boost, when combined with chemoradiotherapy, increases the rate of organ preservation in early rectal adenocarcinoma. Starting with CXB in T &lt; 3 cm appears as an attractive option. A B A1 (T &lt; 3cm) B1 (T &lt; 3cm) N° patient 71 73 30 32 Median age 68 69 69 70 Gender M/F 45/26 43/30 18/12 18/14 T2/T3 45/26 47/26 25/5 29/3 Distal/middle 53/18 53/20 21/9 27/5 cCR (W 14-24) 61% 90% p &lt; 0.001 70% 94% p = 0.027 TME 26 12 8 1 Death 2 2 1 0 LARS &lt; 30 80% 83% 87% 86%.

The clinical efficacy and safety of neoadjuvant chemoradiation therapy with immunotherapy for the organ preservation of ultra low rectal cancer: A single arm and open label exploratory study.

e15603 Background: Neoadjuvant chemoradiotherapy (nCRT) not only could bring tumor downsizing and downstaging but also could achieve clinical complete response (cCR) or pathological complete response (pCR). Although immunotherapy benefits MSI-H/dMMR rectal cancer patients, little response is observed in MSS/pMMR patients. Several clinical trials including VOLTAGE trial demonstrated that a combination of PD-1 inhibitor and nCRT could result in a promising pathological response even in MSS/pMMR patients. But the elucidation regarding organ preservation after treatment is lacking. Watch and Wait (W&amp;W) is an effective strategy in rectal cancer patients showing cCR after nCRT to preserve organs. This study was designed to explore the efficacy, safety, and organ preservation rate of a combination of nCRT and PD-1 inhibitor(sintilimab) in MSS/pMMR patients with ultra-low rectal cancers. Methods: This was a single-arm, phase II trial. Patients with ultra-low rectal cancer that was confirmed as MSS/pMMR T1-3aN0-1M0 and received 50 Gy (25×2 Gy) chemoradiotherapy and 2 cycles of sintilimab, followed by 6 cycles of capecitabine or CAPOX regimen plus 2 cycles of sintilimab as consolidation therapy. Patients with cCR were managed using the W&amp;W strategy, patients with ncCR were given local excision. The primary outcome was cCR rate and secondary outcomes were anal preservation rate, organ preservation rate, tumor regression grade (TRG), and safety profile. Results: From 2021 January to 2021 December, a total of 23 patients were enrolled. The median age was 55 y (range; 38 to 75). Male patients were 61%. cT2 was 56.5% (13/23), cT3 was 43.5% (10/23), cN0 was 69.6% (16/23), and cN1 was 30.4% (7/23). All patients completed 50Gy chemoradiotherapy. Nineteen patients received 4 cycles of sintilimab treatment, 3 patients received 3 cycles of sintilimab, and 1 patient received 1 cycle of sintilimab. cCR was 43.5% (10/23), ncCR was 26.1% (6/23), and cPR was 30.4% (7/23). The anal preservation rate was not assessed in 1 patient due to cerebral ischemic stroke. The anal preservation rate was 95.5% (21/22), rectal preservation rate was 59.1% (13/22). Ten patients underwent surgery. Among them, two patients achieved pCR, and the major pathologic response rate (TRG0-1) was 60.0% (6/10). The overall CR(cCR+pCR) rate was 52.2% (12/23). Grade 3/4 treatment-related adverse events occurred in 17.4% (4/23) of patients. No unexpected adverse events or deaths were observed. Conclusions: Given the favorable tolerability and encouraging cCR rate, nCRT plus sintilimab could be a feasible and safe option for patients with pMMR/MSS, ultra-low rectal cancer who have a strong desire to preserve the anus. Based on these results, a prospective, randomized, controlled, multicenter, phase III study is currently in progress (NCT05215379). Clinical trial information: ChiCTR2100042785.

Short-course radiotherapy combined with CAPOX and toripalimab for the total neoadjuvant therapy of locally advanced rectal cancer: Preliminary findings from a randomized, prospective, multicenter, double-arm, phase II trial (TORCH).

e15602 Background: For patients with locally advanced rectal cancer (LARC), the standard treatment is neoadjuvant chemoradiotherapy combined with curative surgery. Total neoadjuvant therapy (TNT) has been used to increase rates of complete response and organ preservation, and achieve early control of distant metastasis. Recently, hypofractionated radiotherapy shows better synergistic effects in combination with PD-1/PD-L1 antibodies than conventional fractionated radiotherapy, as well as less impact on peripheral lymphocytes and more abscopal effects. Thus, the combination of immunotherapy and short-course radiotherapy (SCRT) based TNT is likely to further improve both tumor response and prognosis for LARC patients. Methods: TORCH is a randomized, prospective, multicentre, double-arm, phase II trial. 130 LARC (T3-4/N+M0, distance from anus ≤10cm) patients will be treated with TNT approach and assigned to the consolidation arm (A) and induction arm (B). Arm A will receive SCRT (25Gy/5Fx), followed by 6 cycles of Toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Arm B will first receive 2 cycles of ToriCAPOX, then receive SCRT, followed by 4 cycles of ToriCAPOX. Both groups will receive curative surgery or W&amp;W strategy. The primary endpoint is the rate of complete response (CR, pCR plus cCR). The secondary endpoints include the grade 3-4 acute adverse effects (AE) rate, 3-year DFS rate, 3-year OS rate, etc. The “pick the winner” method is used to investigate the better regimen. Results: Up to Jan 20th 2022, 67 patients have been recruited in the trial (arm A: 35; arm B: 32). A total of 11 patients (all MSS) have completed all neoadjuvant therapy. Most of them showed high risk factors of recurrence, including lower location (≤5cm, 10/11), deeper primary lesion invasion (cT4/MRF+, 6/11) and more positive lymph nodes (cN2, 6/11). Finally, 2 patients (both arm B) achieved cCR and received W&amp;W strategy. 9 patients received surgery and the pathological results showed 7 cases of pCR (arm A:3; arm B: 4), one near-pCR (arm A) and one non-pCR (arm A). Thus, the CR rate was amazingly high (CR rate: 81.8%, 9/11; pCR rate: 77.8%, 7/9). Even 5 patients who were evaluated as ycT3/N+/MRF+/EMVI+ before surgery was still demonstrated to be pCR after strict pathological examination. The only grade 3 AE was thrombocytopenia (4/11). And no grade 4 AE was observed. Conclusions: SCRT base TNT approach combined with Toripalimab have achieved surprisingly excellent CR rate and good tolerance in LARC patients (in our cohort), which has great clinical value in improving organ preservation. In the future, this ongoing trial will demonstrate this efficacy and compare the two arms by larger sample size. Clinical trial information: NCT04518280.

Organ preservation in rectal cancer: review of contemporary management.

Organ preservation as a successful management for rectal cancer is an evolving field. Refinement of neoadjuvant therapies and extended interval to response assessment has improved tumour downstaging and cCR rates. This was a narrative review of the current evidence for all aspects of organ preservation in rectal cancer management, together with a review of the future direction of this field. Patients can be selected for organ preservation opportunistically, based on an unexpectedly good tumour response, or selectively, based on baseline tumour characteristics that predict organ preservation as a viable treatment strategy. Escalation in oncological therapy and increasing the time interval from completion of neaodjuvant therapy to tumour assessment may further increase tumour downstaging and complete response rates. The addition of local excision to oncological therapy can further improve organ preservation rates. Cancer outcomes in organ preservation are comparable to those of total mesorectal excision, with low regrowth rates reported in patients who achieve a complete response to neoadjuvant therapy. Successful organ preservation aims to achieve non-inferior oncological outcomes together with improved functionality and survivorship. Future research should establish consensus of follow-up protocols, and define criteria for oncological and functional success to facilitate patient-centred decision-making. Modern neoadjuvant therapy for rectal cancer and increasing the interval to tumour response increases the number of patients who can be managed successfully with organ preservation in rectal cancer, both as an opportunistic event and as a planned treatment strategy.