No Operation After Short-Course Radiotherapy Followed By Consolidation Chemotherapy in Locally Advanced Rectal Cancer (NOAHS-ARC): Study Protocol for a Prospective, Phase II Trial

doi:10.21203/rs.3.rs-4713792/v1

Download PDF

Study protocol

No Operation After Short-Course Radiotherapy Followed By Consolidation Chemotherapy in Locally Advanced Rectal Cancer (NOAHS-ARC): Study Protocol for a Prospective, Phase II Trial

https://doi.org/10.21203/rs.3.rs-4713792/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Background

The landscape of locally advanced rectal cancer treatment has shifted over the past decade with the introduction of total neoadjuvant therapy (TNT), enhancing tumor response and oncologic outcomes. Consequently, the concept of organ preservation by means of a watch-and-wait (W&W) strategy has emerged as a viable option for select patients who demonstrate clinical complete responses (cCR) to TNT, thereby limiting the morbidity associated with multimodal treatment. Although there is increasingly robust evidence supporting the notion of organ preservation, the optimal treatment strategy and predictors of treatment response remain outstanding questions. Rectal cancer incidence is expected to rise sharply in developing countries, and the disease is already recognized as a significant public health issue in Chile. Prior to NOAHS-ARC, TNT-based treatment protocols and W&W programs had yet to be implemented in the country.

Methods

This is a single arm, multicenter phase II prospective trial accruing in Santiago, Chile. Patients with histologically proven rectal adenocarcinoma (< 7cm from anal verge) and stage II or III disease will be recruited and consented. Protocol treatment comprises induction short-course radiotherapy (25 Gy in 5 Gy fractions) followed by consolidation chemotherapy (FOLFOX x9 cycles or CAPOX x6 cycles). Patients will undergo response assessment four to eight weeks following completion of chemotherapy. Patients achieving cCR will be offered W&W management while those with incomplete clinical responses (iCR) will undergo total mesorectal exicision (TME). The primary endpoint is rate of complete tumor response, defined as the sum of pathologic complete responses (pCR) and sustained (> 1 year) cCR, which will be compared to the pCR rate of a historical cohort of patients treated with neoadjuvant chemoradiation alone. Accrual of 73 patients is anticipated assuming an estimated combined pCR/sustained cCR rate of 30%. Quality of life measures and functional bowel, urinary, and sexual outcomes will be studied. Additionally, a biorepository of longitudinally archived tissue and plasma samples will be established, in conjunction with serial endoscopic and MRI images.

Discussion

NOAHS-ARC aims to contribute to the ongoing dialogue on organ preservation while also pioneering the first standardized TNT protocol and W&W program in Chile. Additional emphasis on functional outcomes and meticulous data collection for exploratory research endeavors aim to improve patient care both locally and globally.

Trial Registration:

ClinicalTrials.gov identifier: NCT04864067. Registered April 28, 2021.

Organ preservation

watch-and-wait

nonoperative management

short-course radiotherapy

total neoadjuvant therapy

locally advanced rectal cancer

Colorectal cancer (CRC) is the third most common cancer globally, comprising approximately 10% of all oncologic diagnoses annually [1]. Although CRC incidence is greater in developed countries [2], developing countries are anticipated to experience a sharp rise in disease incidence, with an estimated 396,000 new cases per year in Latin America alone by 2030 [3]. In Chile, population studies have reported annual percent increases of up to 4.1% since 1997 [4] and an actuarial 5-year survival rate of 43.2% from 2009–2018 [5], rendering it a major public health issue. Consequently, CRC has been included in Garantias Explícitas de Salud (Explicit Guarantees in Health Programme; GES), which provides Chileans with access to affordable and expedited healthcare for prespecified diseases.

Although population statistics specifically pertaining to rectal cancer in Chile are scarce, the rectum generally comprises one third of all colorectal malignancies [6]. Locally advanced rectal cancer (LARC), defined as stage II (T3-4, N0) and stage III (T any, N1 or greater) disease, has historically been treated in Chile with a multimodal approach of neoadjuvant long-course chemoradiotherapy (LCRT) followed by total mesorectal excision (TME) and adjuvant chemotherapy. Over the past decade, there has been an international shift in the treatment paradigm of LARC toward total neoadjuvant therapy (TNT) which entails the delivery of systemic chemotherapy and pelvic radiotherapy prior to surgical resection. The adoption of this treatment approach has been supported by both retrospective and prospective studies demonstrating superior treatment responses [7–10] with pathologic complete responses (pCR) achieved in over a quarter of patients [9–10]. Consequently, the need for radical surgery has been questioned, as TME is associated with significant complications in about 30% of patients, including long-term impacts on bowel, sexual, and urinary function [11]. Indeed, the concept of rectal preservation by means of watch-and-wait (W&W) management is increasingly accepted worldwide as mounting retrospective and prospective evidence supports its efficacy and oncologic safety in appropriately selected patients who achieve a clinical complete response (cCR) [12–16]. Recently published 5-year data from the OPRA trial (NCT02008656) demonstrates that organ preservation is achievable in approximately 50% of patients without compromising oncologic outcomes [16]. Moreover, the treatment sequence of induction chemoradiotherapy followed by consolidation chemotherapy achieved superior organ preservation compared to the inverse sequence. At present day, several randomized control trials are accruing worldwide such as the Janus Rectal Cancer Trial (NCT05610163) in the United States, the ENSEMBLE trial (NCT05646511) in Japan, the ACO/ARO/AIO 18.4 trial (NCT02363374) in Germany, and CCHOWW trial (NCT05000697) in Brazil to further elucidate treatment regimens that optimally facilitate organ preservation.

Given that the demonstration of the safety and feasibility of W&W is an iterative process, the importance of multiple prospective studies cannot be understated. Herein, we report on the details of the Chilean single arm, phase II trial, No Operation After Short-Course Radiotherapy Followed By Consolidation Chemotherapy in Locally Advanced Rectal Cancer (NOAHS-ARC, NCT04864067), hypothesizing that the utilization of induction short-course radiotherapy (SCRT) followed by consolidation chemotherapy as an investigational TNT paradigm will achieve superior treatment response (sustained cCR > 1 year or pCR) compared to a historical cohort treated with neoadjuvant LCRT alone. This represents an essential inquiry, as most organ preservation studies to date have been conducted in the context of LCRT. Although SCRT has been demonstrated to be noninferior to LCRT in multiple prospective studies which entailed surgical resection [26–34], concerns remain regarding the risk of local regrowth following SCRT in the context of organ preservation and TNT approaches [35]. Given that SCRT is fundamentally delivered as 25 Gy in 5 Gy fractions, (as opposed to 45-50.4 Gy in 1.8 Gy fractions with LCRT), SCRT may provide practical yet effective treatment for many Chileans who have limited access to healthcare, such as rural communities or public hospitals. Moreover, treatment response is recognized as a prognostic indicator of long-term outcomes [36–37], but molecular drivers of treatment response remain undefined and the early identification of responders versus non-responders remains an unmet need. Our aim is to assess the efficacy of a standardized SCRT-based TNT model in enhancing treatment response (i.e., pCR/sustained cCR) and to develop a biorepository to identify predictors of response using patient-derived tissue and plasma specimens obtained longitudinally.

Trial Design and Setting

The NOAHS-ARC trial is a prospective, single arm phase II trial based in Santiago, Chile, sponsored by Agencia Nacional de Investigación y Desarrollo (FONDECYT #11201291, trial PI and Chair, F.F. Quezada-Díaz). Patients with locally advanced rectal cancer are recruited from three tertiary hospitals within the Health Service Network. All patients are treated with TNT with the potential for W&W management versus TME, based on clinical response at time of reassessment (Fig. 1). ClinicalTrials.gov identifier: NCT04864067.

Patient Selection

Patients with biopsy proven stage II (T3-4, N0) and stage III (T any, N1 or greater) adenocarcinoma of the middle/lower rectum (< 7cm from anal verge, palpable by digital rectal exam, DRE) will be recruited and consented (Table 1). At time of baseline assessment, all patients will undergo a comprehensive evaluation including DRE, flexible sigmoidoscopy with endoscopic biopsies, rectal MRI, staging CT chest/abdomen/pelvis and bloodwork (Fig. 2). Exclusion criteria include tumors > 7cm from anal verge, evidence of metastatic disease at diagnosis, anticipated need for pelvic exenteration, age less than 18 years, ECOG > 1, contraindication to radiotherapy or chemotherapy, prior pelvic radiation, active pregnancy or breastfeeding, and failure to follow-up or consent. Comorbidities including untreated coronary artery disease or recent acute coronary syndrome within 12 months, congestive heart failure, and peripheral neuropathy are also grounds for trial exclusion. Additional exclusionary criteria include baseline laboratory values of hemoglobin < 8g/dL, white blood cell count < 4000/L, platelets < 100,000/L, creatinine clearance < 50mL/min, and total bilirubin > 5mg/dL. All trial candidates are discussed by a Disease Management Team prior to inclusion.

Table 1

Eligibility Criteria
Inclusion criteria
• Histologically confirmed rectal adenocarcinoma • Mismatch repair proficient • Stage II (T3-4, N-) or III (any T, N+) based on MRI • Tumor < 7cm from anal verge (palpable) • No prior history of rectal cancer • Age > 18 years
Exclusion criteria
• Stage IV disease at diagnosis • Tumor > 7cm from anal verge (not palpable) • Indication for pelvic exenteration • ECOG > 1 • Recurrent rectal cancer • Contraindication to radiotherapy • Contraindication to chemotherapy • Contraindication to MRI (i.e., pacemakers) • Untreated coronary artery disease • Acute coronary syndrome within the past 12 months • Congestive heart failure • Peripheral neuropathy • Pregnancy or breastfeeding • Baseline hemoglobin < 8g/dL • Baseline white blood cell count < 4000/L • Baseline platelets < 100,000/L • Baseline creatinine clearance < 50mL/min • Baseline total bilirubin < 5mg/dL • Inability to consent or follow-up

Intervention/Treatment

After informed consent is obtained, protocol therapy will be initiated with induction SCRT, delivered as 25 Gy in five 5 Gy fractions. 7 to 14 days following the completion of SCRT, consolidation systemic chemotherapy will begin with either 9 cycles of FOLFOX (Oxaliplatin 85 mg/m2 + 5 Fluorouracil bolus of 400 mg/ m2 + Leucovorin 400 mg/ m2 + 5-Fluorouracil infusion of 2400 mg/m2 in 46 h every 14 days) OR 6 cycles of CAPOX (Capecitabine 1000 mg/m2 every 12 h for 14 days + Oxaliplatin 130 mg/m2 on day 1, every 21 days). Treatment toxicity will be monitored and classified according to CTCAE version 5.0 [38]. Prior to each chemotherapy cycle, patients will undergo bloodwork including a complete blood cell count, renal function panel, and hepatic function panel.

In addition to the baseline tumor assessment, all patients will undergo re-evaluation by a colorectal surgeon during the middle of TNT (9 weeks after initiation of chemotherapy) and upon completion of TNT (4 weeks after chemotherapy completion). At each of the three timepoints, patients will be evaluated with DRE, flexible sigmoidoscopy with biopsy, rectal MRI, and bloodwork. CT chest/abdomen/pelvis will be performed at baseline and post-TNT. Four to eight weeks following TNT completion, a response assessment will be performed by two independent evaluators (PI and surgical staff) and described according to the Memorial Sloan Kettering Regression Schema [39]. In the event of discrepant assessments, the opinion of a third evaluator will be rendered. Patients demonstrating an incomplete clinical response (iCR) will undergo TME. Patients with a cCR will be offered nonoperative management with a W&W strategy or TME. Patients with a near complete response (nCR) will be offered re-evaluation in 4 weeks, after which cCR or iCR will be assigned. Surgical specimens will be processed in a standardized manner and tumor regression grade will be assessed using the American College of Pathologist Scale (REF) [40].

Follow-Up

All patients will be followed for at least two years regardless of whether they were managed with TME or W&W (Fig. 3). TME patients will be followed with: (a) clinical exam every four months for two years, (b) CEA and CBC every four months for two years, (c) CT chest/abdomen/pelvis at 12 and 24 months and (d) complete colonoscopy at 12- and 24-months postoperatively. W&W patients will be followed with: (a) clinical exam with DRE every four months for two years (b) flexible sigmoidoscopy every four months for two years, (c) CBC and CEA every four months for two years; (d) CT chest/abdomen/pelvis annually for two years, (e) rectal MRI every six months for two years and (f) complete colonoscopy annually for two years. Local regrowth, defined as any endoscopic or MRI evidence of pelvic tumor recurrence on W&W surveillance following the confirmation of cCR, will require a recommendation for TME. Sustained cCR will be defined as the absence of local regrowth for at least one year following the completion of TNT.

Functional and Quality of Life Measures

Patients will be asked to complete multiple validated questionnaires throughout the treatment course, including at baseline, time of TNT completion, and at 6-, 12- and 24-months post-TNT. To evaluate bowel function, the Low Anterior Resection Syndrome (LARS) Score will be used, which has previously been validated in the Chilean population [41]. To assess sexual function, the IIEF-5 score FSFI score will be used for males and females, respectively. Both scores have been translated and adapted to Chilean population. Urinary function will be assessed with the IPPS score (male and female) at baseline, time of TNT completion and 6 months post-TNT. Quality-of-life (QoL) evaluation will be conducted using the EORTC QLQ-C30 version 3.0 questionnaire (Chilean Spanish Version).

Primary and Secondary Outcomes

The primary outcome of NOAHS-ARC is the rate of complete response, defined as the combined number of cases with pCR and sustained ( > = 1 year) cCR. The rate of complete response will be compared to the pCR rate reported from a historical cohort of patients treated with neoadjuvant chemoradiotherapy followed by TME. A secondary outcome is the assessment quality of life and functional outcomes between W&W and TME patients, using standardized evaluations with validated questionnaires, as described previously. Additionally secondary outcomes measures include the incidence of adverse events during treatment, which will also be compared to the historical cohort.

Data Collection and Management

All data collected during the trial will be stored in a de-identified and encrypted database. Upon obtaining informed consent, tissue and blood specimens will be collected longitudinally during the treatment course to establish a biorepository for future correlative and translational analyses (Fig. 4). Endoscopic tissue biopsy specimens will be fixed in paraformaldehyde, rinsed, and placed in ethanol before being set in paraffin blocks and stored at 4ºC. Histologic slides will be prepared for pathologic assessment, including baseline analysis for MMR protein expression using immunohistochemistry. Peripheral blood specimens will be collected for standard laboratory monitoring including complete blood count (Beckman Coulter LH780, California, USA) and CEA immunoassay (Roche Analytics E170, Basel, Switzerland). An additional 3mL peripheral blood sample will be collected in EDTA tubes and centrifuged to isolate plasma, which will be stored at -80ºC for future circulating tumor DNA (ctDNA) analysis.

Next generation targeted sequencing techniques such as MSK-IMPACT will be used to analyze key genetic regions of cancer-related genes, aiding in the evaluation of targeted therapies and mutations associated with treatment response. Whole exome sequencing (WES) will be utilized as a complementary analysis for broad genetic evaluation beyond those assessed by MSK-IMPACT, potentially identifying new genetic markers relevant to cancer treatment and patient outcomes. Sequencing may be undertaken using plasma or paraffin-embedded tissue samples.

Additionally, an imaging repository will be established using endoscopic photographs/videos and MRI obtained longitudinally during the treatment course. Endoscopic images will be collected via the Exera III capture system (Olympus, Tokyo, Japan). MRI images are obtained via Philips Achieva 1.5 T MRI. An exploratory objective is to correlate and validate the findings of the prospectively banked tissue and plasma specimens with radiographic, pathologic, and clinical outcomes in collaboration with our translational partners (PBR and JJS) to identify potential predictors of treatment response.

Statistical Methods

For the sample size calculation, a pCR rate of 12% was used based on historical data. Using a previously reported design and estimated combined pCR/sustained cCR rate of 30%, a target accrual of 73 patients will be required to achieve statistical significance with β power of 80% and error of 10%. An interim analysis will be performed at 50% of expected accrual for safety and data analysis. For comparison purposes, patients will be categorized as responders (i.e., pCR/sustained cCR) or non-responders (i.e., non-pCR/non-sustained cCR). Parametric or non-parametric tests will be used for continuous variables, while Chi-square and Fischer exact tests will be used for categorical variables. Group analyses will assume a 5% α-error level, utilizing STATA Software for the analysis.

The NOAHS-ARC trial adds to the ongoing global dialogue around the optimization of total neoadjuvant treatment strategies while addressing the growing challenge of rectal cancer in Chile, with recognition of the profound impact that rectal cancer can have on an individual patient’s quality of life and the economic strain on the individual and the collective healthcare system. Our comprehensive study is a pioneering initiative in Chile, aimed to develop and implement the first standardized TNT protocol in Chile and introduce a dedicated W&W program which promises to enhance patient outcomes by deferring radical surgery for well-selected candidates.

The objectives of the study are multifaceted and ambitious. Foremost, we seek to evaluate the efficacy, safety, and feasibility of a TNT paradigm in the Chilean population. This will serve as a proof of concept, demonstrating the viability and potential for wider adoption and replication of TNT strategies. Given the findings of prior prospective investigations [8–10], we anticipate that our TNT protocol will increase complete response (i.e., pCR and sustained cCR) rates relative to the pCR rate of the historical standard of neoadjuvant chemoradiation alone followed by resection. Furthermore, this study represents one of the first prospective investigations on the oncologic safety and efficacy of SCRT-based TNT in the framework of organ preservation. It will be important to regard our results in the context of additional ongoing prospective trials evaluating SCRT and organ preservation, such as ENSEMBLE (NCT05646511) investigating SCRT with randomization to doublet (CAPOX) or triplet (CAPOXIRI) chemotherapy and ACO/ARO/AIO-18.1 (NCT02363374) randomizing patients to SCRT- and LCRT-based TNT regimens. The current study can serve as a platform for future studies in our unique population where optimization of response and appropriate selection for non-responders will be essential.

Moreover, the study aims to deepen the understanding of the broader impact that rectal cancer can have on each individual patient, particularly how the disease and associated treatments affect patient-reported quality of life. This includes examining the psychological and physical burdens placed on patients and the healthcare infrastructure. Differences in functional and QoL outcomes between patients treated with nonoperative management and TME will be compared longitudinally using previously validated questionnaires, with the hypothesis that nonoperative management will yield improved patient-reported outcomes compared to those patients managed by total mesorectal excision. By closely monitoring compliance and toxicity associated with the protocol treatment, our goal is to develop methods for early detection and prevention of treatment-related adverse effects, mitigating the morbidity associated with the treatment of LARC.

Furthermore, the establishment of a biorepository in our public hospital represents a critical step towards facilitating future research efforts. An exploratory objective of NOAHS-ARC entails the identification of predictive markers of treatment response, which remains a critically unmet need. Given the heterogeneity of treatment responses observed in rectal cancer, we believe that a sensitive biomarker requires the integration of multi-modal datapoints. To that end, we aim to leverage tissue specimens, plasma specimens, endoscopic images and MRI images collected longitudinally during the trial, along with histopathologic slides and patient-specific molecular profiling data. These datapoints will serve as critical inputs for future integrated analyses using artificial intelligence (AI), which has demonstrated promise in revolutionizing oncologic care and delivering targeted therapies [42–45]. Moreover, the repository of tissue specimens may be harnessed to derive rectal cancer organoids, which serve as invaluable platforms for translational research [46]. Research efforts employing AI and organoids may indeed uncover clinical markers or molecular drivers of treatment response, thereby enhancing the selection of patients who will benefit most from treatment intensification or de-intensification strategies and optimization of outcomes. Finally, although the role of ctDNA has been explored for a range of solid malignancies, in the context of rectal cancer, it has yet to be implemented into routine clinical practice. We hypothesize that plasma-based ctDNA analysis may correlate with treatment response and detect disease relapse with a high degree of sensitivity. To that end, we will explore the feasibility of developing a surveillance protocol using ctDNA to monitor for local regrowth/recurrence and determining whether ctDNA can detect local regrowth/recurrence prior to imaging/endoscopic assessments.

In conclusion, NOAHS-ARC is a prospective study which not only seeks to introduce a novel and potentially transformative treatment protocol for LARC in the Chilean population, but also aims to lay the groundwork for future advances in the delivery of precision oncologic care. Through extensive longitudinal assessments, consideration for functional and QoL outcomes, and endeavors to identify predictive markers of treatment response, this trial embodies a holistic approach to addressing rectal cancer while seeking to contribute to future scientific progress in our understanding of the biology and underlying features of treatment response in rectal cancer.

Trial Status

The NOAHS-ARC trial opened for accrual on June 9, 2021 with an estimated study completion date of May 30, 2025. As of February 1, 2024, 43 patients had been enrolled.

CAPOX capecitabine, oxaliplatin

CAPOXIRI capecitabine, oxaliplatin, irinotecan

CEA carcinoembryonic antigen

cCR clinical complete response

CRC colorectal cancer

CT computed tomography

CTCAE Common Terminology Criteria for Adverse Events

DRE igital rectal exam

ECOG Eastern Cooperative Oncology Group

FOLFOX 5-fluorouracil, leucovorin, oxaliplatin

iCR clinical incomplete response

LARC locally advanced rectal cancer

LCRT long-course chemoradiotherapy

MRI magnetic resonance imaging

nCR clinical near complete response

pCR pathologic complete response

SCRT short-course radiotherapy

TME total mesorectal excision

TNT total neoadjuvant therapy

W&W watch-and-wait

Acknowledgements

Not applicable.

Public Disclosure and Publication Policy

PBR received research funding (2019) and serves as a consultant for EMD Serono (2018-present), receives research funding from XRAD Therapeutics (2022-present), is a consultant for Faeth Therapeutics (2022-present), is a consultant for Natera (2022-present), and is a volunteer on the advisory board for the HPV Alliance and Anal Cancer Foundation non-profit organizations.

JJS received travel support for fellow education from Intuitive Surgical (August 2015). He also served as a clinical advisor for Guardant Health (March 2019) and as a clinical advisor for Foundation Medicine (April 2022). He served as a consultant and speaker for Johnson and Johnson (May 2022). And he serves as a clinical advisor and consultant for GlaxoSmithKline (2023-24).

Authors Contributions

Protocol creation, protocol writing, manuscript conception, design and drafting: FQD, AB, JJS

Review, critical assessment of the protocol and writing of the manuscript: FQD, AB, PBR , JLE, NC, LDF, EM, JJS, GC.

Funding

This trial was funded by Agencia Nacional de Investigacion and Fondo Nacional de Desarrollo Científico y Tecnológico (ANID + FONDECYT) #11201291.

AB is supported by an NCI Surgical Oncology T32 Research Training Grant [5T32 CA 9501-34]. PBR is supported by an NIH/NCI grant [K08 CA255574]. JJS is supported by an NIH/NCI grant [R37 CA248289].

Availability of Data and Materials

Not applicable.

Ethics Approval and consent to participate

This study was approved by Comite Etico Cientifico Servicio Salud Metropolitano Sur Oriente. All patients provided written consent prior to participating in the trial.

Consent for publication

Not applicable.

Competing Interests

The author(s) declare that they have no competing interests.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209–249. Available from https://doi.org/10.3322/caac.21660.
Lu B, Li N, Luo C, Cai J, Lu M, Zhang Y, et al. Colorectal cancer incidence and mortality: the current status, temporal trends and their attributable risk factors in 60 countries in 2000–2019. Chin Med J. 2021; 134(16):1941–1951. Available from https://doi.org/10.1097/CM9.0000000000001619.
Arnold M, Sierra M, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017; 66(4): 683–691. Available from https://doi.org/10. 1136/gutjnl-2015-310912.
Sierra MS, Forman D. Burden of colorectal cancer in Central and South America. Cancer Epidemiol. 2016; 44 Suppl 1:S74-S81. Available from doi: 10.1016/j.canep.2016.03.010.
Mondschein S. Estay C, Subiare F, Yankovic N, Von Muhlenbrock C, Berger Z. Colorectal cancer trends in Chile: an observational study. Lancet Oncol. 2022; 23 (S33); Available from DOI: https://doi.org/10.1016/S1470-2045(22)00432-6.
Siegel RL, Wagle ND, Cercek, A, Smith RA, Jemal A. Colorectal cancer statistics. 2023. CA A Cancer J. Clin. 2023; 73: 233–254.
Cercek A, Roxburgh CSD, Strombom P, Smith JJ, Temple LKF, Nash GM, et al. Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer. JAMA Oncol. 2018; 4(6): e180071.
Jin J, Tang Y, Hu C, Jiang LM, Jiang J, Li N, et al. Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR). J Clin Oncol. 2022;40(15):1681–92.
Conroy T, Bosset JF, Etienne PL, Rio E, François E, Mesgouez-Nebout N, et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021; 22(5):702-715.
Bahadoer RR, Dijkstra ER, van Etten B Marijnen CAM, Putter H, Meershoek-Klein Kranenbarg E, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): A randomised, open-label, phase 3 trial. Lancet Oncol. 2021; 22:29–42.
Downing A, Glaser AW, Finan PJ, Wright P, Thomas JD, Gilbert A, et al. Functional Outcomes and Health-Related Quality of Life After Curative Treatment for Rectal Cancer: A Population Level Study in England. Int J Radiat Oncol Biol Phys. 2019; 103(5):1132–42.
Habr-Gama A, Perez RO, Nadalin W, Sabbaga J, Ribeiro U, Silva e Sousa AH, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg. 2004; 240(4):711-7.
van der Valk MJM, Hilling DE, Bastiaannet E, Meershoek-Klein Kranenbarg E, Beets GL, Figueiredo NL, et al. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet. 2018; 391: 2537-2545.
Smith JJ, Strombom P, Chow OS, Roxburgh CS, Lynn P, Eaton A, et al. Assessment of a Watch-and-Wait Strategy for Rectal Cancer in Patients With a Complete Response After Neoadjuvant Therapy. JAMA Oncol. 2019; 5(4): e185896.
Garcia-Aguilar J, Patil S, Gollub MJ, Kim JK, Yuval JB, Thompson HM, et al. Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy. J Clin Oncol. 2022; 40(23): 2546-2556.
Verheij FS, Omer DM, Williams H, Buckley JT, Lin ST, Qin LX, et al. Long-Term Results of Organ Preservation in Patients with Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial. J Clin Oncol. 2023; 42(5): 500-506 doi: 10.1200/JCO.23.01208. Epub ahead of print.
Maas M, Beets-Tan RGH, Lambregts DMJ, Lammering G, Nelemans PJ, Engelen SME et al. Wait-and-See policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Onc. 2011; 29(35): 4633–4640.
Appelt AL, Ploen J, Harling H, Jensen FS, Jensen LH, Jorgensen JCR, et al: High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: A prospective observational study. Lancet Oncol. 2015; 16(8):919-927.
Renehan AG, Malcomson L, Emsley R, Gollins S, Maw A, Sun Myint A, et al. Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis. Lancet Oncol. 2016; 17(2): 174–183.
Jimenez-Rodriguez RM, Quezada-Diaz F, Hameed I, Kalabin A, Patil S, Smith JJ, et al. Organ Preservation in Patients with Rectal Cancer Treated with Total Neoadjuvant Therapy. Dis Colon Rectum. 2021; 64(12): 1463-1470.
Gerard JP, Barbet N, Schiappa R, Magne N, Martel I, Mineur L, et al. 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. Lancet Gastroenterol Hepatol. 2023; 8(4): 356-367.
Garant A, Vasilevsky CA, Boutros M, Khosrow-Khavar F, Kavan P, et al. MORPHEUS Phase II-III Study: A Pre-Planned Interim Safety Analysis and Preliminary Results. Cancers. 2022; 14(15): 3665.
Chin RI, Roy A, Pedersen KS, Huang Y, Hunt SR, Glasgow SC, et al. Clinical Complete Response in Patients With Rectal Adenocarcinoma Treated With Short-Course Radiation Therapy and Nonoperative Management. Int J Radiat Oncol Biol Phys. 2022; 112(3):715-725.
Kim H, Pedersen K, Olsen JR, Mutch MG, Chin RI, Glasgow SC, et al. Non-operative rectal cancer management with short course radiation followed by chemotherapy: a nonrandomized control trial. Clin Colorectal Cancer. 2021;20: e185–e193.
Nilsson PJ, Ahlberg M, Kordnejad S, Holm T, Martling A. Organ preservation following short-course radiotherapy for rectal cancer. BJS Open. 2021(5): Available from doi: 10.1093/bjsopen/zrab093.
Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg. 2006; 93: 1215–1223.
Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Krynski J, et al; Polish Colorectal Study Group. Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol. 2016;27: 834–842.
Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group Trial 01.04. J Clin Oncol. 2012; 30:3827–3833.
Erlandsson J, Holm T, Pettersson D, Berglund A, Cedermark B, Radu C, et al. Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial. Lancet Oncol. 2017;18:336–346.
Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Meershoek-Klein Kranenbarg E, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): A randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:29–42.
Jin J, Tang Y, Hu C, Jiang LM, Jiang J, Li N, et al. Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR). J Clin Oncol. 2022; 40(15): 1681-1682.
Thakur N, Seam RK, Gupta MK, Gupta M, Fotedar V, Vats S, et al. A prospective observational study comparing long-course conventional neoadjuvant chemoradiotherapy with short-course radiotherapy followed by consolidation chemotherapy with delayed surgery in locally advanced rectal cancer. South Asian J Cancer. 2020;9:80–5.
Aghili M, Khalili N, Khalili N, Babaei M, Farhan F, Haddad P, et al. Short-course versus long-course neoadjuvant chemoradiotherapy in patients with rectal cancer: preliminary results of a randomized controlled trial. Radiat Oncol J. 2020;38:119–28.
Chakrabarti D, Rajan S, Akhtar N, Qayoom S, Gupta S, Verma M, et al. Short-course radiotherapy with consolidation chemotherapy versus conventionally fractionated long-course chemoradiotherapy for locally advanced rectal cancer: randomized clinical trial. Br J Surg. 2021; Available from https:// doi.org/10.1093/bjs/znab020.
Romesser PB, Park BK, Nemirovsky D, Alvarez J, Omer DM, Sarkar R, et al. Organ preservation and total neoadjuvant therapy for rectal cancer: Investigating long-course chemoradiation versus short-course radiation therapy. J Clin Oncol. 2023; 41(4): 10-10. Available from https://doi.org/10.1200/JCO.2023.41.4_suppl.10.
Maas M, Nelemans PJ, Valentini V, Das P, Rodel C, Kuo LJ, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol, 2010; 11(9): 835-44.
Park IJ, You YN, Agarwal A, Skibber JM, Rodriguez-Bigas MA, Eng C, et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol. 2012; 30(15): 1770-6.
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Published: November 27, 2017. US Department of Health and Human Services, National Institutes of Health, National Cancer Institute.
Smith JJ, Chow OS, Gollub MJ, Nash GM, Temple LK, Weiser MR, et al: Organ preservation in rectal adenocarcinoma: A phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total mesorectal excision or nonoperative management. BMC Cancer. 2015; 15:767.
Ryan R, Gibbons D, Hyland JMP, Treanor D, White A, Mulcahy HE, et al. Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology. 2005 Aug;47(2):141–6.
Lopez SN, Carrillo K, Sanguineti MA, Azolas RM, Diaz MB, Bocic G, et al. Adaptacion transcultural del cuestionario acerca de la funcion intestinal (LARS Score) para su aplicacion en pacientes operados de cancer de recto medio y bajo. Revista chilena de cirugia. 2017;69:44–48.
Luchini C, Pea A, Scarpa A. Artificial Intelligence in Oncology: current applications and future perspectives. Br J Cancer. 2022; 126(1): 4-9.
Mansur A, Saleem Z, Elhakim T, Daye D. Role of artificial intelligence in risk prediction, prognostication, and therapy response assessment in colorectal cancer: current state and future directions. Front Oncol. 2023; 13: DOI: 1065402.
Foersch S, Glasner C, Woerl AC, Eckstein M, Wagner DC, Schulz S, et al. Multistain deep learning for prediction of prognosis and therapy response in colorectal cancer. Nat Med. 2023; 29(2): 430-439.
Wang A, Ding R, Zhang J, Zhang B, Huang X, Zhou H. Machine Learning of Histomorphological Features Predict Response to Neoadjuvant Therapy in Locally Advanced Rectal Cancer. J Gastroint Surg. 2023; 27(1): 162-165.
Ganesh K, Wu C, O’Rourke KP, Szeglin BC, Zheng Y, Gabriel Sauve CE, et al. A rectal cancer organoid platform to study individual responses to chemoradiation. Nat Med. 2019; 25(10): 1607-1614.
Tie J, Cohen JD, Wang Y, et al. Circulating tumor DNA analysis informing adjuvant chemotherapy in locally advanced rectal cancer: The randomized AGITG DYNAMIC-Rectal study. J Clin Oncol. 2024; 42, 12-12.

Competing interest reported. PBR received research funding (2019) and serves as a consultant for EMD Serono (2018-present), receives research funding from XRAD Therapeutics (2022-present), is a consultant for Faeth Therapeutics (2022-present), is a consultant for Natera (2022-present), and is a volunteer on the advisory board for the HPV Alliance and Anal Cancer Foundation non-profit organizations. JJS received travel support for fellow education from Intuitive Surgical (August 2015). He also served as a clinical advisor for Guardant Health (March 2019) and as a clinical advisor for Foundation Medicine (April 2022). He served as a consultant and speaker for Johnson and Johnson (May 2022). And he serves as a clinical advisor and consultant for GlaxoSmithKline (2023-24).

Download PDF

Editor assigned by journal
10 Jul, 2024
Submission checks completed at journal
10 Jul, 2024
First submitted to journal
09 Jul, 2024

You are reading this latest preprint version

No Operation After Short-Course Radiotherapy Followed By Consolidation Chemotherapy in Locally Advanced Rectal Cancer (NOAHS-ARC): Study Protocol for a Prospective, Phase II Trial

Status:

Version 1

Abstract

Background

Methods

Discussion

Trial Registration:

Figures

Introduction

Methods

Trial Design and Setting

Patient Selection

Intervention/Treatment

Follow-Up

Functional and Quality of Life Measures

Primary and Secondary Outcomes

Data Collection and Management

Statistical Methods

Discussion

Trial Status

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1