Induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as neoadjuvant treatment for locally recurrent rectal cancer: study protocol of a multicentre, open-label, parallel-arms, randomized controlled study (PelvEx II)

Abstract Background A resection with clear margins (R0 resection) is the most important prognostic factor in patients with locally recurrent rectal cancer (LRRC). However, this is achieved in only 60 per cent of patients. The aim of this study is to investigate whether the addition of induction chemotherapy to neoadjuvant chemo(re)irradiation improves the R0 resection rate in LRRC. Methods This multicentre, international, open-label, phase III, parallel-arms study will enrol 364 patients with resectable LRRC after previous partial or total mesorectal resection without synchronous distant metastases or recent chemo- and/or radiotherapy treatment. Patients will be randomized to receive either induction chemotherapy (three 3-week cycles of CAPOX (capecitabine, oxaliplatin), four 2-week cycles of FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) or FOLFORI (5-fluorouracil, leucovorin, irinotecan)) followed by neoadjuvant chemoradiotherapy and surgery (experimental arm) or neoadjuvant chemoradiotherapy and surgery alone (control arm). Tumours will be restaged using MRI and, in the experimental arm, a further cycle of CAPOX or two cycles of FOLFOX/FOLFIRI will be administered before chemoradiotherapy in case of stable or responsive disease. The radiotherapy dose will be 25 × 2.0 Gy or 28 × 1.8 Gy in radiotherapy-naive patients, and 15 × 2.0 Gy in previously irradiated patients. The concomitant chemotherapy agent will be capecitabine administered twice daily at a dose of 825 mg/m2 on radiotherapy days. The primary endpoint of the study is the R0 resection rate. Secondary endpoints are long-term oncological outcomes, radiological and pathological response, toxicity, postoperative complications, costs, and quality of life. Discussion This trial protocol describes the PelvEx II study. PelvEx II, designed as a multicentre, open-label, phase III, parallel-arms study, is the first randomized study to compare induction chemotherapy followed by neoadjuvant chemo(re)irradiation and surgery with neoadjuvant chemo(re)irradiation and surgery alone in patients with locally recurrent rectal cancer, with the aim of improving the number of R0 resections.


Introduction
Locally recurrent rectal cancer (LRRC) occurs in 6-10 per cent of patients who undergo intentionally curative surgery for primary rectal cancer 1,2 . To cure patients with LRRC, achieving a resection with clear resection margins (R0 resection) is imperative [2][3][4][5][6][7][8] . When an R0 resection is achieved, 5-year overall survival rates vary between 48 and 58 per cent, whereas a resection without clear resection margins (R1/2 resection) results in a 5-year survival rate of only 10-18 per cent. Moreover, incomplete resections are associated with 5-year local re-recurrence rates of 70-80 per cent, and often result in severe morbidity, poor quality of life, and/or death 5,6,[9][10][11][12][13] . Unfortunately, the attempt to achieve an R0 resection often fails because of challenging anatomy due to previous surgery, the presence of fibrosis as a result of previous radiotherapy, and the involvement of other structures such as adjacent organs, pelvic sidewall, and sacrum. To increase the chance of achieving an R0 resection, neoadjuvant treatment with chemoradiotherapy is considered the standard of care in many institutions 14 . In patients who received pelvic radiotherapy previously, reirradiation with a dose of 30 Gy has been proven to be safe and effective 3,15 . Despite the use of neoadjuvant chemo(re)irradiation, R0 resections are achieved in only 60 per cent of patients 16,17 . Therefore, there is ongoing research to optimize the treatment strategy for patients with LRRC.

Potential benefits and disadvantages of induction chemotherapy
Induction chemotherapy in addition to neoadjuvant chemo(re)irradiation has the potential to induce more local tumour downstaging than can be achieved with chemoradiotherapy alone owing to the supplementary effect of the induction chemotherapy, and possibly also the synergistic effect of induction chemotherapy and chemoradiotherapy 18 . Improved local downstaging may subsequently increase the R0 resection rate, which has been identified as the main prognostic factor for overall survival [6][7][8] . When local downstaging is excellent, a pathologic complete response (pCR) can be achieved, which is a predictive variable for survival in patients with LRRC 19 .
With improved local downstaging, the proportion of patients with a pCR may also increase. Alongside the local effect, induction chemotherapy may also have the potential to eradicate micrometastases 20 . The addition of induction chemotherapy also has potential drawbacks. First, induction chemotherapy is associated with toxicity 21 . Second, chemotherapy-induced morbidity could delay, reduce or prevent subsequent treatment with chemoradiotherapy and surgery. Third, when chemoradiotherapy is preceded by induction chemotherapy, the toxicity of chemoradiotherapy may be increased. Finally, the prolonged and intensified neoadjuvant course may influence the patient's performance status and may have a negative effect on surgical morbidity and mortality rates. Furthermore, prolonged neoadjuvant treatment may increase the risk of disease progression and secondary unresectability.

Current evidence
Induction chemotherapy, whether or not combined with neoadjuvant chemoradiotherapy, is increasingly being used in the treatment of LRRC, although evidence for this approach is lacking 22 . Several retrospective studies and phase II clinical trials [23][24][25][26] performed to investigate the role of induction chemotherapy in patients with primary locally advanced rectal cancer (LARC) have reported high R0 resection rates. However, other studies [27][28][29] , including comparative studies, did not demonstrate superior R0 resection rates after the addition of induction chemotherapy to neoadjuvant treatment.
Several studies investigating this treatment regimen in LARC used pCR as the primary endpoint. As in the studies focusing on R0 resection rate, the results were mixed. Some studies described promising pCR rates, whereas others found no effect of adding induction chemotherapy with regard to the pCR rate [30][31][32][33][34] . Regardless of the effect of this treatment on the R0 resection or pCR rate, induction chemotherapy seemed feasible, with high rates of compliance with the chemotherapy as well as with the subsequent chemoradiotherapy, and acceptable toxicity and postoperative morbidity 28,33,35 .
The available literature regarding induction chemotherapy in addition to chemoradiotherapy for patients with LRRC is limited; currently only three retrospective studies 19,36,37 have been published. The first study 36 , which focused on patients with lateral local recurrence, reported a high R0 resection rate of 85 per cent in a subgroup of 13 patients who were treated with induction chemotherapy followed by chemoradiotherapy. In the second and third studies 19,37 , 58 and 132 patients respectively underwent induction chemotherapy followed by chemo(re)irradiation. Both studies reported promising pCR rates of 17 per cent, but the R0 resection rates did not appear to have improved. However, in both studies induction chemotherapy was initially administered to patients with unresectable disease or prognostically unfavourable characteristics, which may have had a negative impact on the R0 resection rate.

Rationale for the study
Although the real benefit provided by the addition of induction chemotherapy to chemoradiotherapy and surgery for LRRC has not yet been established, its use is nevertheless increasing 22 .
This study will randomize patients with LRRC to receive either induction chemotherapy followed by chemoradiotherapy and surgery (experimental arm) or chemoradiotherapy and surgery alone (control arm). As R0 resection is the single most important prognostic factor for survival in patients with LRRC, the main hypothesis to be tested will be an increase in the R0 resection rate in the experimental arm compared with the control arm.

Study design and setting
This is a multicentre, international, open-label, phase III, parallel-arms study that will randomize eligible patients in a 1 : 1 ratio to receive either induction chemotherapy followed by neoadjuvant chemoradiotherapy and surgery (experimental arm) or neoadjuvant chemoradiotherapy and surgery alone (control arm). The study is registered with ClinicalTrials.gov (NCT04389086), including the list of centres enrolling for the trial. Surgical treatments will be limited to centres that perform at least 10 resections of LRRC per year (expert centres). Induction chemotherapy and chemoradiotherapy will be administered in expert centres and selected non-expert centres. This is protocol version 4.0, dated 10 December 2020.

Participants
Patients aged 18 years or older, with resectable histopathologically or clinically proven LRRC after previous partial or total mesorectal resection, with a WHO performance status of 1 or less will be eligible for study participation. Patients with distant metastases at the time of randomization or in the previous 6 months, those who have undergone chemotherapy and/or radiotherapy in the past 6 months, patients with any contraindication to chemotherapy and/or radiotherapy and/or surgery, and those with concurrent malignancies that interfere with the planned study treatment or the prognosis of resected LRRC, will be excluded.

Recruitment
Participants will be identified either by physicians in expert centres, or by physicians in non-expert centres who then refer the patients to an expert centre. All eligible patients will be reviewed in a multidisciplinary team (MDT) meeting in an expert centre to assess whether the patient meets the inclusion and exclusion criteria. The multicentre, international involvement in this study will ensure adequate participant enrolment to reach the targeted sample size.

Interventions
Eligible patients who have signed informed consent will be randomized by the coordinating investigator in a 1 : 1 ratio using a software randomization program (ALEA Clinical; FormsVision, Abcoude, the Netherlands). Patients will be stratified for previous chemotherapy, previous radiotherapy, and expert centre. After randomization, the treating surgical oncologist will refer the patient to the medical oncologist (experimental arm) or radiation oncologist (control arm).
The study flow chart is shown in Fig. 1, and study interventions and timelines for patients allocated to the experimental and control arms in Tables 1 and 2 respectively.

Induction chemotherapy
Patients allocated to the experimental arm will start treatment with induction chemotherapy within 4 weeks after randomization. Induction chemotherapy will consist of either three 3- After three cycles of CAPOX or four cycles of FOLFOX or FOLFIRI, pelvic MRI will be performed for local restaging, and high-dose thoracoabdominal CT for restaging of possible distant metastases. Restaging imaging will be discussed during a dedicated MDT meeting in one of the expert centres. If a patient develops distant metastases or local disease becomes unresectable, best palliative treatment will be offered according to the standard of care. If a patient has progressive local disease, but surgery is still considered feasible, no further systemic therapy will be administered and patients will start treatment with chemoradiotherapy. If a patient has stable or responsive disease, induction chemotherapy will be continued with either one 3-week cycle of CAPOX or two 2-week cycles of FOLFOX or FOLFIRI.

Chemoradiotherapy
Patients in the experimental arm will start chemoradiotherapy within 3-5 weeks after the first day of the last cycle of chemotherapy. Patients in the control arm will start chemoradiotherapy within 4 weeks after randomization. The radiotherapy dose will depend on whether the patient received radiotherapy previously. In radiotherapy-naive patients, full-course radiotherapy will consist of 25 Â 2.0 Gy or 28 Â 1.8 Gy radiotherapy. In patients with a history of radiotherapy, the radiotherapy dose will consist of 15 Â 2.0 Gy. The target volume will be defined by the gross, clinical, and planning target volumes (GTV, CTV and PTV respectively), and will be similar for radiotherapy-naive and previously irradiated patients. The GTV contains all macroscopic visible tumour, the CTV includes the GTV with a margin of 1 cm, without adjustment of the CTV towards other organs, and the PTV includes the CTV with a margin that can be determined according to local policy. Concomitant chemotherapy will comprise capecitabine, administered orally at a dose of 825 mg/m 2 twice daily on radiotherapy days. In the event of unacceptable toxicity caused by capecitabine during induction chemotherapy, concomitant tegafur/gimeracil/oteracil administered orally at a dose of 25 mg/m 2 twice daily on radiotherapy days may be prescribed at the physician's discretion.

Restaging
Four to 6 weeks after the last day of radiotherapy, pelvic MRI will be performed for local restaging and high-dose thoracoabdominal CT for restaging of possible distant metastases. Restaging imaging will be discussed during a dedicated MDT meeting in one of ý ý ¶ * 4 to 6 weeks after finishing chemoradiotherapy; † after finishing chemoradiotherapy and before surgery; ‡ 3 months after surgery; § 6-monthly; ¶ 3 and 12 months after surgery; # 3-monthly; ** yearly. CEA, carcinoembryonic antigen. the expert centres. In the event of distant metastases or unresectable local disease, best palliative treatment will be offered. Patients with resectable disease will undergo surgery.

Surgery
Surgery will be performed by experienced surgical oncologists within 10-14 weeks after completion of chemoradiotherapy. The type of surgery will depend on the location of the recurrence and involvement of adjacent structures, and will be left to the discretion of the surgeon. When deemed necessary and feasible by the surgeon and radiation oncologist, intraoperative radiotherapy may be administered by either intraoperative electron beam radiotherapy or high-dose-rate intraoperative brachytherapy 38,39 .

Follow-up
Patients will be followed up at 3,6,9,12,15,18,21,24,27,30,33,36,42,48,54, and 60 months after surgery. At each follow-up point, a blood sample will be taken to determine the level of carcinoembryonic antigen (CEA). If the CEA level increases compared with the previous CEA level or the level rises above 5.0 mg/l during follow-up, high-dose thoracoabdominal CT will be performed. At 6,12,18,24,30,36,48, and 60 months after surgery, high-dose thoracoabdominal CT will be performed regardless of the CEA level.

Questionnaires
All participants will be asked to provide separate informed consent to receive validated quality of life questionnaires (European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-CR29; EuroQol EQ-5D-5L TM (EuroQoL Group, Rotterdam, the Netherlands)). Patients will receive questionnaires at inclusion, and 3 and 12 months after surgery either by mail or digitally, according to their own preference.

Translational research
All participants will be asked to provide separate informed consent for collection of blood samples and/or tumour tissue for future translational research. If patients give such consent, an additional 20 ml blood will be drawn during regular blood draws before the start of induction chemotherapy (experimental arm only), before chemoradiotherapy, before surgery, 3 months after surgery, and once a year during 3 years of follow-up, resulting in seven samples per patient in the experimental arm and six per patient in the control arm. Tumour tissue will be collected by the pathologist, fresh frozen and stored until further use.

Central multidisciplinary team meetings
During the study inclusion period, a monthly central MDT meeting will be organized for quality control. All newly included patients will be discussed during this meeting, which has been designed as a teleconference. In addition, eligible patients will be discussed in the event of uncertainty about whether they meet the inclusion and/or exclusion criteria. Patients who are under treatment at the time of the central MDT meeting, or who have completed treatment, will be discussed only if there are remarkable findings, such as progression of disease resulting in unresectability.

Outcomes
The primary outcome of the study is the proportion of patients with a clear resection margin. A resection margin is considered clear (R0), if there are no tumour cells in any of the resection surfaces as determined by microscopy (resection margin more than 0 mm).

Secondary outcomes are:
• 3-and 5-year local re-recurrence-free survival, defined as the interval between surgery and local re-recurrence; • 3-and 5-year progression-free survival, defined as the interval between randomization and progression of local recurrence, local re-recurrence, distant metastases or death; • 3-and 5-year metastasis-free survival, defined as the interval between randomization and development of distant metastases; • 3-and 5-year disease-free survival, defined as the interval between surgery and local re-recurrence, distant metastases or death; • 3-and 5-year overall survival, defined as the interval between randomization and death; • pathological response, graded according to the Mandard grading system 40 ; • radiological response, scored according to the magnetic resonance tumour regression grade (mrTRG); • compliance rate with induction chemotherapy (i.e., the number of patients receiving CAPOX, FOLFOX or FOLFIRI as initial regimen will be tabulated, and dose modification and reason will be summarized for each regimen); • toxicity of induction chemotherapy, scored from day 1 of the first cycle of induction chemotherapy until 1 month after the final administration, and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0; • compliance rate with chemoradiotherapy, calculated as the total radiotherapy dose received divided by the total planned dose; • toxicity of chemoradiotherapy, scored from start of radiotherapy until 3 months after the final dose of radiotherapy, and graded according to CTCAE version 5.0; • number of patients undergoing surgery; • surgical characteristics (e.g., type of resection, ostomy, use of intraoperative radiotherapy, blood loss, duration of operation, intraoperative complications); • major surgical morbidity rate scored from the date of surgery to 3 months after surgery, and graded according to the Clavien-Dindo classification 41 ; • quality of life, assessed with EQ-5D-5L TM , QLQ-C30 and QLQ-CR29 questionnaires at inclusion, and at 3 and 12 months after surgery; and • cost-effectiveness and cost-utility, based on Dutch costing guidelines for healthcare, the case report forms, and the EQ-5D-5L TM questionnaire.

Sample size
Currently, an R0 resection is achieved in approximately 60 per cent of patients undergoing surgery after treatment with neoadjuvant chemoradiotherapy 16,17 . However, 25 per cent of patients who start neoadjuvant chemotherapy are not eligible for surgery owing to progressive disease: local progression, distant progression, or death from progression 12 . This means that an R0 resection is obtained in only 45 per cent of patients (75 per cent of 60 per cent) who start with intentionally curative treatment. The study hypothesis is that there will be a 15 per cent increase in the R0 resection rate (from 45 to 60 per cent) for patients in the experimental arm. A v 2 test with a 5 per cent two-sided significance level indicated that the study would have 80 per cent power to detect a significant difference of 15 per cent between the two groups (given that the percentage in the control group is 45 per cent) when the sample size in each group is 173 patients. With an expected dropout of 5 per cent, the total requirement was calculated as 364 patients.

Statistical methods
Demographics, patient, and tumour characteristics will be presented for each treatment arm. Continuous data will be reported as mean (standard deviation) or median (interquartile range or 95 per cent confidence interval), depending on the distribution. Categorical data will be reported as count with percentage. All statistical tests will be two-sided and P < 0.050 will be classified as statistically significant. Patients initially randomized but considered ineligible afterwards, based on information that should have been available before randomization, will be excluded from all analyses.
Analysis of the primary endpoint of this study, the proportion of patients with an R0 resection, will be based on the intentionto-treat principle using Fisher's exact test. In addition, a per-protocol analysis will be performed as a sensitivity analysis.
All survival curves will be constructed according to the Kaplan-Meier method, and the log rank test will be used to compare treatment arms, adjusting for stratification factors at randomisation (previous radiotherapy, previous systemic therapy, and expert centre). In addition, hazard ratios will be calculated using a Cox proportional hazards regression model, adjusting for stratification factors. Metastasis-free survival, progression-free survival, and overall survival will be based on the intention-totreat group. Local re-recurrence free survival and disease-free survival analyses will include only patients who underwent surgery.
Data on surgical characteristics, histopathological characteristics, and major surgical morbidity will be presented by treatment arm, and will be derived only for patients who underwent surgery. The number of patients undergoing surgery will be analysed in the intention-to-treat population. Comparison between treatment arms will be done by means of Fisher's exact test.
The absolute and relative incidence of toxicities related to the administration of induction chemotherapy or chemoradiotherapy will be presented by treatment arm, and analysed in all patients who received at least one dose of neoadjuvant chemotherapy (experimental arm) or chemoradiotherapy (control arm). Comparison between treatment arms will be done by means of Fisher's exact test.
Comparison of health-related quality of life between the two treatment arms at baseline and over time will be performed by means of a random-effects regression model and will be based on the intention-to-treat group.
Incremental cost-effectiveness and cost-utility ratios will be calculated for the extra costs per additional surviving patient and the extra costs per additional quality-adjusted life year respectively. Non-parametric bootstrapping, drawing samples of the same size as the original samples and with replacement, will be applied to generate 95 per cent confidence intervals for (differences in) costs and health outcomes. Cost-effectiveness planes will be displayed and cost-effectiveness acceptability curves drawn for willingness-to-pay values up to e100 000.

Data collection and management
A central study database (Netherlands Comprehensive Cancer Institute (IKNL), Utrecht, the Netherlands) with an electronic case report form will be used to record all data required to address the primary and secondary objectives. Local data management will be undertaken by the IKNL or an in-hospital qualified local data management team. Questionnaires will be collected centrally by the coordinating investigators and recorded using an ISO 27001-certified information security system (Research Manager, Deventer, Netherlands).

Data safety monitoring board
A central data safety monitoring board (DSMB), consisting of a medical oncologist, a surgical oncologist, and a statistician, has been assigned to monitor the safety of study participants, and to protect the validity and credibility of the study. Members of the DMSB are independent and have no competing interest. After 100 patients have undergone surgery, the DSMB will review the safety data. Inclusion will be continued during interim analysis. At the interim analysis, the number of patients who cannot complete the full course of chemoradiotherapy and the number of patients with major postoperative morbidity (Clavien-Dindo grade at least III) will be tabulated and discussed. Examining these safety and logistical aspects will not affect the total sample size or the actual a level at final analysis. After the interim analysis, the DSMB will recommend to the trial steering committee (TSC) whether the study should be continued or terminated. Should the TSC decide not to fully implement the advice of the DSMB, it must explain to the medical ethical committee why (part of) the advice of the DSMB will not be followed.

Harms
All serious adverse events (SAEs) or suspected unexpected serious adverse events (SUSARs) will be reported by the physician to the study coordinator within 24 h and without undue delay after obtaining knowledge of the event. The coordinating investigator will report SAEs through the web portal ToetsingOnline (https:// www.toetsingonline.nl) to the medical ethical committee that approved the protocol. The time window for recording SAEs and SUSARs is from randomization until 3 months after surgery, or 1 month after the last day of neoadjuvant treatment for patients with progressive disease who did not undergo surgery. SAEs and SUSARs will be followed up until resolved or until a stable situation has been reached.

Auditing
The study will be monitored by independent qualified monitors. The monitoring plan is based on the assessment that the study carries a moderate risk for the participants.

Research ethics approval
This study was approved by the Medical Research Ethics Committees United, Nieuwegein, the Netherlands (R20.035), the Dutch Competent Authority (Centrale Commissie Mensgebonden Onderzoek, The Hague, the Netherlands; NL73593.100. 20), and all institutional review boards of the participating study centres. The study will be submitted to the competent authorities, central ethical committees, and institutional review boards of the participating international centres.

Protocol amendments
All substantial amendments will be notified to the (principal) investigators, institutional review boards of all study centres, the medical ethical committee, the competent authority, and trial registries.

Consent and assent
Informed consent will be obtained by the treating physician in one of the expert centres. Patients will be allowed to provide separate permission for the collection of blood and/or tissue samples for translational research, and for receiving quality of life questionnaires.

Confidentiality
Individual patient information obtained as a result of this study is considered confidential and its handling will conform with the Dutch Personal Data Protection Act (AVG). Patients' confidentiality will be ensured by use of study numbers.

Declaration of interests
The investigators declare no financial or other competing interests.

Access to data
Access to the final data set is reserved for the central data manager, study statistician, coordinating investigator, and trial steering committee. There are no contractual agreements that limit this access.

Ancillary and post-study care
The study has no provision for ancillary or post-study care.

Dissemination policy
The results of this study will be dispersed by publishing the results in international peer-reviewed journals and by offering an abstract to international (surgical) oncological congresses. Any publication, abstract or presentation based on patients included in this study must be approved by the trial steering committee and coordinating investigator. The principal manuscript resulting from this study will be published by group authorship (PelvEx Collaborative).

Discussion
This randomised controlled trial will investigate the role of induction chemotherapy in patients with LRRC. The results of this study will demonstrate whether or not induction chemotherapy has additional value in the treatment of patients with non-metastasized resectable LRRC with regard to the R0 resection rate; this group of patients has had a poor prognosis so far.
The rationale for R0 resection as the primary outcome in this study was based on the fact that R0 resection is the most important prognostic factor for survival in patients undergoing surgery for LRRC. Ultimately, an increase in R0 resection rate should lead to an improvement in local re-recurrence-free and overall survival. Because of the relatively rarity of LRRC as a result of improvements in the treatment of primary rectal cancer, and the fact that approximately 50 per cent of patients with LRRC will not be eligible for inclusion in this study owing to distant metastases or unresectable local disease, survival parameters could not be used as the primary outcome, as power calculations showed that the sample size would be unfeasible 42,43 .
The rationale for the induction chemotherapy regimen chosen in this study is based on studies in (metastatic) colorectal cancer. In those first-line studies [44][45][46][47] , doublet therapy led to better response rates and improved survival compared with monotherapy. Results of triplet therapy among patients with metastatic colorectal cancer have been conflicting 48,49 . In addition, although higher response rates have been observed for triple therapy compared with doublet therapy in patients with right-sided metastatic colorectal cancer, this has not been observed in patients with left-sided disease 50,51 . Moreover, triplet therapy is associated with more toxicity, and in patients with LRRC, in particular, toxicity of treatment is considered a major limitation often precluding curative treatment 52 . Therefore, doublet therapy is the treatment regimen of choice. As doublet therapy with capecitabine and oxaliplatin (CAPOX), 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX), and 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) have similar efficacy, all are incorporated in the present study protocol 46,53,54 .
There are three other ongoing trials investigating the optimal treatment for patients with LRRC. The French GRECCAR15 study (Chemotherapy Followed by Pelvic Reirradiation Versus Chemotherapy Alone as Pre-operative Treatment for Locally Recurrent Rectal Cancer; NCT03879109) is randomizing between induction chemotherapy, chemoreirradiation, and surgery versus induction chemotherapy and surgery in previously irradiated patients. The primary outcome measure is the R0 resection rate. The Japanese JCOG1801 study (Surgery Plus Chemo Versus Chemoradiotherapy Followed by Surgery Plus Chemo for Locally Recurrent Rectal Cancer; NCT04288999) is randomizing between surgery followed by adjuvant chemotherapy versus neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy (CAPOX/FOLFOX) in radiotherapy-naive patients, with local recurrence-free survival as the primary outcome measure. The Chinese NARC study (Efficacy and Safety Study of Neoadjuvant in Treating Patients With Resectable Local Recurrent Rectal Cancer; NCT01271192) is randomizing between surgery followed by adjuvant chemotherapy versus neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy, with overall survival as the primary outcome measure. The results of these studies will be actively monitored to assess whether their results have any implications for the present study protocol.