Organ preservation in rectal cancer : neoadjuvant therapy and response assessment

Treatment of rectal cancer has significantly changed in the past decades. The implementation of TME, MRI-based staging and preoperative radiotherapy have significantly improved local control. Moreover, the addition of chemotherapy to radiotherapy, known as total neoadjuvant treatment (TNT) has led to an increase in complete response rates. Patients with a clinical complete (cCR) or near clinical complete response (ncCR) at re-assessment can decide to follow a Watch & Wait (W&W) surveillance program and potentially avoid surgical morbidity and colostomy. For these reasons, response assessment after neoadjuvant treatment is getting a prominent role in the management of rectal cancer. Information on clinical and pathological findings, including long-term outcomes, after neoadjuvant treatment are needed for further improvement of rectal cancer care. In this thesis, different aspects of organ preservation are explored, aiming to provide knowledge to guide assessment of response to neoadjuvant treatment and support subsequent multidisciplinary decision- making.

Paper I. A total of 1010 patients from the International Watch & Wait Database (IWWD) were divided into two groups: 608 achieved a cCR at their first reassessment, and 402 achieved a cCR at a later reassessment based on MRI and endoscopy. At a median follow-up of 2.6 and 2.9 years respectively, no significant difference in organ preservation, distant metastasis, or overall survival (OS) were found.

Paper II. The aim of this study was to investigate changes in neoadjuvant treatment and its impact on pathological, and overall, complete response rates on a population-based level. Between 2009 and 2020, 10,232 Swedish patients with stage I-III rectal cancer treated with neoadjuvant therapy were analysed. Over this period, the pCR rate remained similar around 3.9% while the overall complete response rate (including both pCR and cCR) increased significantly from 3.0% to 9.6% (p < 0.001). Both changes in neoadjuvant therapy and the start of the national Watch & Wait (WoW) study presumably contributed to these changes.

Paper III. This substudy from the RAPIDO trial compared patients with a pCR in the TNT arm vs. patients with a pCR in the standard-of-care (chemoradiation, CRT) arm. TNT in the form of short-course radiotherapy followed by systemic chemotherapy resulted in doubled pCR rates compared to chemoradiation (CRT) (28% vs. 14%, p<0.001) in patients with high-risk locally advanced rectal cancer (LARC). For patients who achieved a pCR, 5-year oncological outcomes are favourable and similar between the two groups. We found characteristics associated with pCR to be the EXP treatment, normal CEA, and small tumour size. Within the protocolized treatment times, we did not find an association between prolonging the overall treatment time (OTT) and increasing pCR rates.

Paper IV. Here we describe the development and evaluation of a web-based educational course designed to support clinicians in implementing the W&W strategy. It focuses on standardizing response assessment and multidisciplinary decision-making to address variability in clinical practice. A feasibility study will be conducted to assess the practicality and effectiveness of the course in real- world clinical settings.

List of scientific papers

I. Watch and wait after neoadjuvant treatment in rectal cancer: comparison of outcomes in patients with and without a complete response at first reassessment in the International Watch & Wait Database (IWWD). Temmink SJD, Peeters KCMJ, Bahadoer RR, Kranenbarg EM, Roodvoets AGH, Melenhorst J, Burger JWA, Wolthuis A, Renehan AG, Figueiredo NL, Pares O, Martling A, Perez RO, Beets GL, van de Velde CJH, Nilsson PJ, Consortium IWWDI. Br J Surg. 2023;110(6): 676-684. https://doi.org/10.1093/bjs/znad051

II. Complete response rates in rectal cancer: Temporal changes over a decade in a population-based nationwide cohort. Temmink SJD, Martling A, Angenete E, Nilsson PJ. Eur J Surg Oncol. 2023;49(11): 106991. https://doi.org/10.1016/j.ejso.2023.106991

III. Oncological outcomes after a pathological complete response following total neoadjuvant therapy or chemoradiotherapy for high-risk locally advanced rectal cancer in the RAPIDO trial. Zwart WH, Temmink SJD, Hospers GAP, Marijnen CAM, Putter H, Nagtegaal ID, Blomqvist L, Kranenbarg EM, Roodvoets AGH, Martling A, van de Velde CJH, Glimelius B, Peeters KCMJ, van Etten B, Nilsson PJ, investigators C. Eur J Cancer. 2024;204: 114044. https://doi.org/10.1016/j.ejca.2024.114044

IV. Watch and Wait in rectal cancer: development of a virtual webcourse. Temmink SJD, Szczegielniak S, Halldorsson K, Blomqvist L, Martling A, Nilsson PJ. [Manuscript]