Abstract
Background
Despite absence of level 1 evidence on the long-term oncological safety of non-operative management for rectal cancer (watch and wait), increased implementation has occurred globally over the past decades. In Sweden, a pan-national prospective non-randomized study was initiated in 2017 to assess its implementation.
Method
Patients with biopsy-proven rectal cancer receiving neoadjuvant therapy according to national guidelines in whom a clinical complete response was detected at reassessment were eligible for inclusion following informed consent. Only patients with an opportunistic watch-and-wait approach were included. Inclusion and follow-up, according to the study protocol, was managed at the participating study centres. The primary outcome measure of the study is 3-year disease-free survival. Here, the secondary short-term outcomes local regrowth rate, distant metastasis rate and outcomes after surgery for regrowth, at 6 months follow-up, are reported.
Results
Between January 2017 and February 2023, 211 patients with a clinical complete response were included in the study. Thirty-three (16%) patients developed suspicious regrowth within 6 months of inclusion. Thirty-two of 33 patients had abdominal resectional surgery for regrowth. The curative intention rate was 94% for patients with regrowth. Three patients (1.4%) developed distant metastases within 6 months of inclusion.
Conclusion
This Swedish national study on watch and wait reports regrowth rates after 6 months are in line with previous reports in the literature. Nearly all patients with early regrowth could be treated with salvage surgery and curative intent.
This prospective multicentre observational study included patients who, following neoadjuvant treatment for rectal cancer, obtained a clinical complete response and were followed in a watch-and-wait programme. Two hundred and eleven patients were included, and this article presents short-term outcomes at 6 months. Thirty-three patients (16%) developed local regrowth, and 31 patients were salvaged with curative intent.
Introduction
Previous studies have reported that 6–28% of patients with rectal cancer receiving neoadjuvant treatment with an interval to surgical resection have a pathological complete response (pCR), that is, no remaining tumour on histopathologic examination1–4. A clinical complete response (cCR) refers to the absence of detectable tumour on radiological, clinical, and endoscopic examination following neoadjuvant treatment but before surgical resection. Patients who obtain a cCR are potential candidates for non-operative management (NOM).
NOM for rectal cancer, also referred to as watch and wait (W&W), was first described over two decades ago5. Two important concerns after cCR are local regrowth and metastatic disease. In an observational multicentre study from 2018, comprising 880 patients from the International Watch and Wait Database (IWWD), 2-year local regrowth rate was 25% and 5-year disease-specific survival was 94%6. In the randomized controlled OPRA trial on chemoradiotherapy with addition of either induction chemotherapy or consolidation chemotherapy, local regrowth rate in patients managed by NOM was 40% and 27% respectively, depending on neoadjuvant treatment arm7. A 2018 systematic review and meta-analysis of 17 mainly retrospective observational studies, comprising 692 patients, reported a 3-year pooled local regrowth rate of 22% and pooled 3-year regrowth-free survival rate of 89%8.
The overall aim of the Swedish ‘Watch and Wait’ (WoW) study was to investigate whether a W&W strategy could be safely adopted for selected patients, regarding oncological outcomes and functional results. The aim of this report is to present short-term results at 6 months.
Methods
The WoW study is a prospective non-randomized study. Seven university hospitals in Sweden, along with one regional hospital, constituted the study centres. At each study centre, a limited number of surgeons (one to three) were responsible for assessment, inclusion, and follow-up of patients. The WoW study was registered at clinicaltrials.gov (NCT03125343) and the study protocol is available as Supplementary Material. The reporting of the study complies with the STROBE Statement9, and a completed STROBE checklist is included (Supplementary Material).
Study population
Patients were recruited between January 2017 and February 2023. Eligibility criteria were biopsy-proven rectal adenocarcinoma, age older than 18 years, curative intent, no distant metastasis at diagnosis and neoadjuvant therapy with an interval to planned abdominal surgical resection. Decision on neoadjuvant treatment was at the discretion of the colorectal multidisciplinary tumour board (MDT) at each participating hospital, in accordance with the Swedish national guidelines (Confederation of Regional Cancer Centres in Sweden)10.
Reassessment MRI of the pelvis and thoraco-abdominal CT were performed 2–8 weeks after termination of neoadjuvant treatment, depending on type of neoadjuvant treatment. In patients receiving short-course radiotherapy (SCRT), that is a daily dose of 5 Gray (Gy) for 5 consecutive days, or chemoradiotherapy (CRT; 1.8–2 Gy × 25), reassessment was performed 6–8 weeks after termination of radiotherapy. During the study period, the use of CRT declined whereas the use of SCRT followed by 4–6 cycles of full-dose systemic chemotherapy increased. In patients receiving chemotherapy after radiotherapy (consolidation chemotherapy), reassessment was performed 2–4 weeks after completion of chemotherapy. At the MDT following reassessment radiology, for patients in whom a cCR potentially was achieved, referral for study inclusion was encouraged.
Inclusion
Prior to study inclusion, oral and written consent was obtained. The flow chart for inclusion was updated and translated to English Jan 2nd 2023 (Supplementary Material).
Diagnosis of clinical complete response
Eligibility assessment included a review of the MR images by a radiologist at a study centre, providing structured reporting of MRI tumour regression grade (mrTRG) using T2- and diffusion-weighted images. The mrTRG was modified based on previously described mrTRG using T2-weighted images only11. A detailed description of the radiological assessment criteria was included in the study protocol by one of the authors (LB) (Supplementary Material).
Prior to inclusion, examination at a study centre by a local investigator was mandatory. White light flexible endoscopy and/or rectoscopy was performed on all patients, and digital rectal examination (DRE) was performed irrespective of tumour height at baseline. Patients assessed as having an insufficient response were referred to the local hospital for surgery with no further follow-up in the study. Endoscopic criteria for cCR were in accordance with those reported previously12. In short, a homogenous flat white scar with telangiectasia was considered a cCR. All patients with a cCR who fulfilled eligibility criteria and consented to participate were included in the study.
For near clinical complete response (ncCR), no widely accepted endoscopic criteria or definition exist13. Discrete persisting mucosal abnormalities, for example redness of the scar, residual fibrin slough in a flat superficial ulcer, symmetrical minimal elevation around the edges of the scar, or small nodules were considered an ncCR, if residual tumour was not primarily suspected. The presence of more pronounced mucosal irregularity, ulcer, residual nodules, or exophytic mass was assessed as a sign of residual cancer.
Patients with an ncCR at first evaluation according to MRI or endoscopy could be included and have a repeat MRI, DRE, and endoscopy after 4 weeks. If a cCR was obtained at this second evaluation, the patient entered the follow-up schedule. If an ncCR was still present, patients could either be referred for resection surgery or one additional repeat MRI, DRE, and endoscopy after 4 weeks. Unless all criteria for a cCR were fulfilled at the third evaluation, the patient was recommended and referred for surgery. Local excision or brachytherapy was not part of the study protocol.
Radiological examinations were allowed to be performed at the local hospital but were re-evaluated at the study centre responsible for follow-up.
Follow-up
Patients assessed as having a cCR according to both MRI and endoscopy entered a predefined follow-up schedule including MRI, DRE, endoscopy, and serum level of carcinoembryonic antigen (CEA) every 3 months for 2 years, every 6 months for an additional 3 years, and then yearly for 5 years with a planned total follow-up time of 10 years.
In accordance with the national guidelines for follow-up of operated rectal cancer patients, the study follow-up also included a thoraco-abdominal CT scan at 1 and 3 years, and a complete colonoscopy at 3 years following the diagnosis of rectal cancer.
The start of follow-up was the date of inclusion in the study as cCR. Patients with an ncCR that became cCR started follow-up on the date of a cCR. The decision to choose the date of cCR as start of follow-up was in accordance with the study protocol stating that the first follow-up exam should be performed 3 months after inclusion as cCR. The flowchart for follow-up is available in the study protocol (Supplementary Material).
Study endpoints
The primary endpoint of the WoW study is 3-year disease-free survival, which will be reported after completion of long-term follow-up for all patients. The study reports the secondary short-term endpoints tumour regrowth rate, distant metastasis rate, and outcomes after surgery for regrowth, within 6 months of inclusion.
Clinical and tumour characteristics
Demographic and clinical characteristics at baseline and follow up were registered prospectively in an electronical case report form (eCRF). Co-morbidity was measured using the Adult Co-morbidity Evaluation-2714. Local study investigators at each study centre had access to their own data, but not to data entered at the other sites. The study secretariate had access to all data and monitored safety by regular checks of the cumulative regrowth rate in the database. Adherence to the follow-up schedule and that prospective registration was performed were also checked regularly.
Study participants responded to questionnaires on quality of life (QoL) and functional outcomes at predetermined time points and this will be reported separately.
Statistical analysis
Results are presented as crude rates and no further statistical analysis was performed. The calculation of sample size in the WoW study was based on the primary end-point 3-year disease-free survival. Patients with a cCR were assumed to represent a selected group with a more favourable prognosis, given an excellent response to neoadjuvant treatment. For patients with rectal cancer treated with surgery, approximately 10–20% could be anticipated to develop distant metastases during the first 3 years15. In a RCT, an improvement of disease-free survival at 3 years from 80% to 90% could be estimated in the W&W group. This would require 199 patients in each group with a significance level of 5% and a power of 80%. As this was a prospective non-randomized non-controlled study, the aim was to include and evaluate 200 patients with cCR.
Ethical approval
The study was approved by the Regional Ethical Review Board (Dnr 566–16) and the Swedish Ethical Review Authority (Dnr 2023–05262–02).
Results
In total, 254 patients were evaluated, of whom 149 had a cCR and 105 an ncCR. Among patients with an ncCR, 29 were assessed as having an insufficient response after repeated evaluations and surgery was recommended. A total of 225 patients were identified with a cCR. Fourteen patients were excluded due to distant metastases at diagnosis (n = 13) and squamous cell carcinoma in the diagnostic biopsy (n = 1), and the remaining 211 patients were included in the study (Fig. 1). The median time from end of neoadjuvant treatment to start of follow-up was 75 days. Demographic and clinical characteristics for the total study population, patients with regrowth within 6 months and patients with sustained cCR are presented in Table 1.
Fig. 1.
Flowchart of study population
Closed circle, clinical complete response; open circle, near clinical complete response.
Table 1.
Demographics, tumour stage and neoadjuvant treatment for the total study population, patients with regrowth within 6 months and patients with sustained clinical complete response (cCR)
| Total | Regrowth | cCR | |
|---|---|---|---|
| Number of patients | 211 | 33 (16) | 178 (84) |
| Sex | |||
| Female | 86 | 12 | 74 |
| Male | 125 | 21 | 104 |
| Age (years), median (range) | 66 (30–89) | 67 (36–79) | 66 (30–89) |
| BMI (kg/m2), median | 25.7 | 25 | 26 |
| Tumour height (cm), median (range) | 5 (0–14) | 6 (1–13) | 5 (0–14) |
| Tumour length on MRI (cm), median (range) | 4 (1–11) | 4 (1–9) | 4 (1–11) |
| Co-morbidity (ACE-27) | |||
| 0 | 87 (41) | 13 (39) | 74 (42) |
| 1 | 72 (34) | 11 (33) | 61 (34) |
| 2 | 29 (14) | 6 (18) | 23 (13) |
| 3 | 23 (11) | 3 (9) | 20 (11) |
| Clinical T | |||
| 1 | 1 (0.5) | 0 (0) | 1 (1) |
| 2 | 53 (25) | 5 (15) | 48 (27) |
| 3 | 114 (54) | 17 (52) | 97 (54) |
| 4 | 43 (20) | 11 (33) | 32 (18) |
| Clinical N | |||
| 0 | 57 (27) | 8 (24) | 49 (28) |
| 1 | 93 (44) | 14 (42) | 79 (44) |
| 2 | 61 (29) | 11 (33) | 50 (28) |
| Clinical UICC stage | |||
| I | 28 (13) | 3 (9) | 25 (14) |
| II | 29 (14) | 5 (15) | 24 (13) |
| III | 154 (73) | 25 (76) | 129 (72) |
| Neoadjuvant treatment | |||
| SCRT | 64 (30) | 5 (15) | 59 (33) |
| SCRT + chemo* | 131 (62) | 25 (76) | 106 (60) |
| CRT | 14 (7) | 3 (9) | 11 (6) |
| Other** | 2 (1) | 0 (0) | 2 (1) |
Values are n or n (%) unless otherwise indicated. ACE-27, Adult Comorbidity Evaluation-27; SCRT, short-course radiotherapy; CRT, chemoradiotherapy; UICC, Union for International Cancer Control. *Any regimen of neoadjuvant chemotherapy. **One patient received 78 Gy due to synchronous prostate cancer and one patient had long-course radiotherapy only.
Tumour regrowth
Thirty-three of 211 patients (16%) developed signs of local tumour regrowth within 6 months of inclusion in the study. Thirty-two of these 33 patients with regrowth underwent resectional surgery. One patient with regrowth had a microsatellite unstable tumour and received immunotherapy (outside study protocol) and was therefore not operated. Thirty of 32 patients resected on suspicion of regrowth had remaining tumour cells in the resected specimen, and in two patients the histopathology revealed ypT0N0. The actual tumour regrowth rate, including the patient treated with immunotherapy, was 31/211 (15%).
Outcomes after surgery for regrowth
Surgical and oncological outcomes for patients with regrowth or metastasis are shown in Table 2. Resectional surgery for suspected regrowth included abdominoperineal resection (n = 16), sphincter-sparing total mesorectal excision (n = 13), Hartmann´s procedure (n = 2), and anterior resection with partial mesorectal excision (n = 1). Excluding the patient who received immunotherapy and one patient with unresected suspected pulmonary metastasis, 31 of 33 (94%) patients with regrowth were resected with curative intent. All but three of the 30 (90%) patients with resected confirmed regrowth had a circumferential resection margin >1 mm, here defined as a negative resection margin.
Table 2.
Oncological outcomes for patients with suspected tumour regrowth or distant metastasis within 6 months from inclusion in study
| Oncological outcomes | Total (%) |
|---|---|
| Regrowth ≤ 6 months | 33/211 (16) |
| Surgery for regrowth ≤ 6 months | 32 (15) |
| Immunotherapy for regrowth ≤ 6 months | 1 (0.5) |
| Surgically treated patients | |
| Abdominoperineal resection | 16 (50) |
| Hartmann procedure (TME) | 2 (6) |
| Anterior resection (TME) | 13 (41) |
| Anterior resection (PME) | 1 (3) |
| Pathological T | |
| 0 | 2 (6) |
| 1 | 2 (6) |
| 2 | 12 (38) |
| 3 | 16 (50) |
| 4 | 0 (0) |
| Pathological N | |
| 0 | 24 (75) |
| 1–2 | 8 (25) |
| CRM | |
| n.a./pCR* | 2 (6) |
| >1 mm | 27 (84) |
| ≤1 mm | 3 (9) |
| Distant metastasis ≤ 6 months | 3/211 (1.4) |
| Surgery for distant metastasis | 2 (1) |
| Treatment intention | |
| Curative | 31 (94) |
| Palliative** | 2 (6) |
Values are n or n (%). n.a./pCR, not applicable/ pathological complete response; PME, partial mesorectal excision; TME, total mesorectal excision; CRM, circumferential resection margin. *Two patients had ypT0N0. **One patient treated with immunotherapy, and one patient with multiple small, suspected lung metastases, not accessible for surgical removal.
Distant metastasis
Distant metastasis within 6 months of inclusion was detected in three patients (1.4%). During the same follow-up time, that is 6 months, two of these three patients also had regrowth detected. The patient without synchronous regrowth had a pulmonary metastasis radically removed, one patient with regrowth and a solitary lung metastasis underwent surgery for both regrowth and the pulmonary metastasis, and in one patient surgery was undertaken for regrowth while the suspected pulmonary metastases were scheduled for continued follow-up.
Discussion
In this Swedish national prospective study of W&W after neoadjuvant (chemo)radiotherapy for rectal cancer, the local tumour regrowth rate was 15% at 6 months follow-up. Only three of 211 patients developed distant metastasis within 6 months of inclusion, and 94% of patients with early regrowth were treated with curative intent, indicating that W&W may be a safe treatment option in selected patients.
Local tumour regrowth during follow-up in a W&W programme has been reported to occur in 22–40% of patients6–8,16. Previous studies indicate that most regrowth occurs within the first 2 years, and that the risk of regrowth declines with longer follow-up17. The long-term results from this prospectively registered cohort remain to be seen.
Although assessment of cCR and inclusion in WoW was limited to selected study centres, the 15% rate of early regrowth is a good indicator of the challenges associated with determining cCR. Despite having all MRI examinations re-evaluated at the study centres and dedicated teams doing the clinical examinations, it is likely that some patients were incorrectly assessed as having cCR. This underlines the importance of further training and education prior to the more widespread adoption of W&W.
Contrary to some other reports on W&W, this cohort only includes opportunistic W&W of patients with an indication for neoadjuvant therapy according to national guidelines. Consequently, cT3–T4 tumours comprised almost 75% of the study cohort. Tumour stage has previously been reported to be a risk factor for tumour regrowth17. However, the regrowth rate at 6 months in the WoW study reported here appears similar to earlier data from the UK16. The rate will increase with longer follow-up, and how the long-term regrowth rate compares to previously published results is yet to be seen.
One important aspect of implementing a W&W strategy is oncological safety. This relates both to the possibility of salvage treatment in case of tumour regrowth, but also to the risk that regrowth potentially induces a worse long-term oncological outcome. Furthermore, response assessment in non-operative management of rectal cancer remains one of the main challenges18. The term ncCR has been used to describe a good clinical response to neoadjuvant treatment, but with some residual MRI or clinical findings incompatible with cCR. A widely accepted definition of what constitutes an ncCR is lacking, as reported in a recent review of the literature13. Incorrectly assigning a cCR when residual cancer in fact remains posts a high risk of distant metastasis and poor oncological outcomes, illustrated by the implementation of watch and wait in Norway19. On the other hand, data from the International Watch & Wait Database (IWWD) have shown that oncological outcomes are similar between those who achieve a cCR at the first reassessment compared to those with a later cCR20. Improving response assessment after neoadjuvant treatment remains an important issue.
All included patients with suspected regrowth within 6 months had salvage total mesorectal excision (TME) surgery, except one patient treated with immunotherapy. Even though results indicate that immunotherapy can produce high rates of cCR in microsatellite unstable rectal cancers21, the evidence was unavailable at the time of study design, and immunotherapy was not part of the study protocol. In addition, local excision or brachytherapy was not part of the study protocol in the present study, and TME was considered the gold standard for salvage surgery.
Although salvage surgery for regrowth seems to provide high rates of local disease control, the impact on distant metastases is less clear. In the 2018 publication from the IWWD, the proportion of patients with distant metastasis was 18% among patients with local regrowth compared to 5% for patients with a sustained cCR6. In a recent publication from the same database, local regrowth was reported to be an independent risk factor of distant metastasis22. As per the present study, these studies were observational in design with the possible biases that follow, and a strictly causal interpretation is impossible.
A strength of this study is the prospective registration and controlled national setting, providing complete data on study participants with high validity. Further strengths are the multicentre design, increasing generalizability; neoadjuvant treatment according to national guidelines, reflecting clinical everyday practice and decreasing inclusion bias; and lastly the relatively large study population. Additionally, although not reported in the present study, the patient-reported data on health-related QoL, bowel, urinary and sexual function will provide a valuable patient perspective on the outcomes after W&W.
The major limitation is the observational design paired with short follow-up and a limited number of events. Randomizing patients with a cCR to surgical resection or W&W would be the optimal design to elucidate outcomes after NOM versus surgery. However, when the WoW study was designed it was perceived that randomization would not be feasible, as the W&W concept has gained public attention over time, and patient preference would likely influence the willingness to participate in a randomized trial in a negative way. A final limitation is the incomplete registration of patients with an ncCR who did not achieve a cCR.
Supplementary Material
Contributor Information
Daniel Rydbeck, Department of Surgery, SSORG—Scandinavian Surgical Outcomes Research Group, Institute of Clinical Sciences, Sahlgrenska Academy University of Gothenburg, Gothenburg, Sweden; Department of Surgery, Region Västra Götaland, Sahlgrenska Universitetssjukhuset, Gothenburg, Sweden.
Najia Azhar, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden; Department of Surgery, Skåne University Hospital, Malmö, Sweden.
Lennart Blomqvist, Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Sweden; Department of Radiation Physics/Nuclear Medicine, Karolinska University Hospital, Stockholm, Sweden.
Abbas Chabok, Centre for Clinical Research, Region Västmanland, Uppsala University, Uppsala, Sweden; Department of Surgery, Västmanland Hospital, Västerås, Sweden.
Joakim Folkesson, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Department of Surgery, Uppsala University Hospital, Uppsala, Sweden.
Anders Gerdin, Department of Surgery, Umeå University Hospital, Umeå, Sweden; Department of Diagnostics and Intervention Surgery, Umeå University, Umeå, Sweden.
Linda Hermus, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Surgery, Linköping University Hospital, Linköping, Sweden.
Peter Matthiessen, Department of Surgery, Faculty of Medicine and Health Sciences, Örebro University, Örebro, Sweden; Department of Surgery, Örebro University Hospital, Örebro, Sweden.
Anna Martling, Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Sweden; Department of Pelvic Cancer, Karolinska University Hospital, Stockholm, Sweden.
Per J Nilsson, Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Sweden; Department of Pelvic Cancer, Karolinska University Hospital, Stockholm, Sweden.
Eva Angenete, Department of Surgery, SSORG—Scandinavian Surgical Outcomes Research Group, Institute of Clinical Sciences, Sahlgrenska Academy University of Gothenburg, Gothenburg, Sweden; Department of Surgery, Region Västra Götaland, Sahlgrenska Universitetssjukhuset, Gothenburg, Sweden.
Author contributions
Daniel Rydbeck (Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing—original draft), Najia Azhar (Investigation, Writing—review & editing), Lennart Blomqvist (Conceptualization, Methodology, Writing—review & editing), Abbas Chabok (Investigation, Writing—review & editing), Joakim Folkesson (Investigation, Writing—review & editing), Anders Gerdin (Investigation, Writing—review & editing), Linda Hermus (Investigation, Writing—review & editing), Anna Martling (Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Supervision, Writing—review & editing), Peter Matthiessen (Investigation, Writing—review & editing), Per Nilsson (Investigation, Project administration, Supervision, Writing—review & editing), and Eva Angenete (Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing—review & editing)
Funding
Grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement ALFGBG-716581, ALFGBG-965084, The Swedish Cancer Society CAN2016/509, 19 0333 Pj, 22 2265 Pj, The Swedish Research Council VR: 2017-01103, VR: 2021-01025, Lions Cancer Fund West, Mary von Sydow's Foundation, The Healthcare Board, Region Västra Götaland VGFOUREG-733162, VGFOUREG-855161 and VGFOUREG-931675.
Disclosure
The authors declare no conflict of interest.
Supplementary material
Supplementary Material is available at BJS Open online.
Data availability
The participants of this study did not give written consent for their data to be shared publicly, so due to the sensitive nature of the research supporting data are not available.
References
- 1. 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;11:835–844 [DOI] [PubMed] [Google Scholar]
- 2. Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM 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 [DOI] [PubMed] [Google Scholar]
- 3. Conroy T, Bosset JF, Etienne PL, Rio E, François É, 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;22:702–715 [DOI] [PubMed] [Google Scholar]
- 4. Temmink SJD, Martling A, Angenete E, Nilsson PJ. Complete response rates in rectal cancer: temporal changes over a decade in a population-based nationwide cohort. Eur J Surg Oncol 2023;49:106991. [DOI] [PubMed] [Google Scholar]
- 5. Habr-Gama A, de Souza PM, Ribeiro UJr, Nadalin W, Gansl R, Sousa AHJR et al. Low rectal cancer: impact of radiation and chemotherapy on surgical treatment. Dis Colon Rectum 1998;41:1087–1096 [DOI] [PubMed] [Google Scholar]
- 6. 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 (London, England) 2018;391:2537–2545 [DOI] [PubMed] [Google Scholar]
- 7. 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;40:2546–2556 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Dattani M, Heald RJ, Goussous G, Broadhurst J, Julião S, Habr-Gama GP et al. Oncological and survival outcomes in watch and wait patients with a clinical complete response after neoadjuvant chemoradiotherapy for rectal cancer: a systematic review and pooled analysis. Ann Surg 2018;268:955–967 [DOI] [PubMed] [Google Scholar]
- 9. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening The Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 2008;61:344–349 [DOI] [PubMed] [Google Scholar]
- 10.Regional Cancer Centres in Sweden. National clinical cancer care guidelines [Internet]. Stockholm (Swe): Regional Cancer Centres in Sweden; 2023 [updated 2023; cited 2024 Mar 4]. Available from: https://cancercentrum.se/samverkan/regional-cancer-centres/knowledge-based-healthcare/national-clinical-cancer-care-guidelines/
- 11. Patel UB, Brown G, Rutten H, West N, Sebag-Montefiore D, Glynne-Jones R et al. Comparison of magnetic resonance imaging and histopathological response to chemoradiotherapy in locally advanced rectal cancer. Ann Surg Oncol 2012;19:2842–2852 [DOI] [PubMed] [Google Scholar]
- 12. Habr-Gama A, Perez RO, Wynn G, Marks J, Kessler H, Gama-Rodrigues J. Complete clinical response after neoadjuvant chemoradiation therapy for distal rectal cancer: characterization of clinical and endoscopic findings for standardization. Dis Colon Rectum 2010;53:1692–1698 [DOI] [PubMed] [Google Scholar]
- 13. Custers PA, Geubels BM, Beets GL, Lambregts DMJ, van Leerdam ME, van Triest B et al. Defining near-complete response following (chemo)radiotherapy for rectal cancer: systematic review. Br J Surg 2022;110:43–49 [DOI] [PubMed] [Google Scholar]
- 14. Kallogjeri D, Gaynor SM, Piccirillo ML, Jean RA, Spitznagel ELJR, Piccirillo JF. Comparison of comorbidity collection methods. J Am Coll Surg 2014;219:245–255 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Nors J, Iversen LH, Erichsen R, Gotschalck KA, Andersen CL. Incidence of recurrence and time to recurrence in stage I to III colorectal cancer: a nationwide Danish cohort study. JAMA Oncol 2024;10:54–62 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Renehan AG, Malcomson L, Emsley R, Gollins S, Maw A, Myint AS 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;17:174–183 [DOI] [PubMed] [Google Scholar]
- 17. Fernandez LM, São Julião GP, Figueiredo NL, Beets GL, van der Valk MJM, Bahadoer RR et al. Conditional recurrence-free survival of clinical complete responders managed by watch and wait after neoadjuvant chemoradiotherapy for rectal cancer in the International Watch & Wait Database: a retrospective, international, multicentre registry study. Lancet Oncol 2021;22:43–50 [DOI] [PubMed] [Google Scholar]
- 18. Kimura C, Crowder SE, Kin C. Is it really gone? Assessing response to neoadjuvant therapy in rectal cancer. J Gastrointest Cancer 2022;54:703–711 [DOI] [PubMed] [Google Scholar]
- 19.Helsetilsynet. Avgjørelse i tilsynssak om Norwait-studien – helsepersonell med brudd på kravet til faglig forsvarlighet [Internet]. Oslo (No): Helsetilsynet; 2022 [updated 2022; cited 2024 Jan 24]. Available from: https://www.helsetilsynet.no/tilsyn/tilsynssaker/2022/avgjoerelse-i-tilsynssak-om-norwait-studien-helsepersonell-med-brudd-paa-kravet-til-faglig-forsvarlighet/
- 20. Temmink SJD, Peeters K, Bahadoer RR, Kranenbarg EM, Roodvoets AGH, Melenhorst J et al. 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). Br J Surg 2023;110:676–684 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M et al. JR. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med 2022;386:2363–2376 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Fernandez LM, São Julião GP, Renehan AG, Beets GL, Papoila AL, Vailati BB et al. The risk of distant metastases in patients with clinical complete response managed by watch and wait after neoadjuvant therapy for rectal cancer: the influence of local regrowth in the International Watch and Wait Database. Dis Colon Rectum 2023;66:41–49 [DOI] [PubMed] [Google Scholar]
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Supplementary Materials
Data Availability Statement
The participants of this study did not give written consent for their data to be shared publicly, so due to the sensitive nature of the research supporting data are not available.