Study design
The study is a prospective, single-center, single-arm phase II clinical trial to evaluate the combination of preoperative (re)irradiation, chemotherapy and immunotherapy in locally recurrent rectal cancer. The enrolled patients will receive 25-40Gy/5Fx irradiation or 15-30Gy/5Fx reirradiation (pelvic radiation history), 6 cycles of toripalimab and CAPOX, and followed by multidisciplinary team (MDT) for decision: radical surgery, sustained treatment until resectable or exit. Te study algorithm is presented in Fig. 1.
Trial organization, ethics approval, drug supply and insurance
This trial is principal-investigator initiated by the Department of Radiation Oncology, Fudan University Shanghai Cancer Center. The study protocol was approved by the Ethics Committee of FUSCC (Approval Number: 2210263-18). All patients provide written informed consent before recruitment.
Primary endpoint
R0 resection rate: the proportion of patients who achieve R0 resection of pelvic recurrent tumour after preoperative therapy. R0 resection is defined as microscopic margin-negative resection.
Secondary endpoints
The objective response rate (ORR) is the percentage of patients with objective response in the irradiated local recurrence or metastatic lesions. Objective response is defined as complete response (CR) or partial response (PR) per response evaluation criteria (RECIST v1.1) and the immune related response criteria (iRECIST) after treatment.
Progression-free survival (PFS) is calculated from the date of start treatment until the date of local recurrence progression or distant metastases or censored at last follow-up or death.
Overall survival (OS) is calculated from the date of start treatment until the date of death from any cause or censored at last follow-up.
Treatment safety.
Inclusion Criteria:
• Aged 18–75, regardless of gender.
• Histologically or cytologically or iconography confirmed locally recurrent rectal cancer with or without distant metastasis (UICC 8th version).
• No prior chemotherapy or radiotherapy within 6 month.
• Distant metastasis lesions are resectable by MDT evaluation.
• ECOG performance status 0–1.
• Has an investigator determined life expectancy of at least 24 weeks.
• Demonstrate adequate organ function (bone marrow, liver, kidney and clotting function) within 7 days before the first administration without using blood products or hematopoietic stimulating factors.
• Non pregnant or lactating patients. Effective contraceptive methods should be used during the study and within 6 months of the last administration.
• Fully informed and willing to provide written informed consent for the trial.
Exclusion Criteria:
• Neutrophil < 1.5×10^9/L, PLT < 100×10^9/L (PLT < 80×10^9/L in patients with liver metastasis), or Hb < 90g/L; blood transfusion within 2 weeks before enrollment is not allowed to meet the enrollment criteria.
• TBIL > 1.5 ULN, or TBIL > 2.5 ULN in patients with liver metastasis.
• AST or ALT > 2.5 ULN, or ALT and / or AST > 5 ULN in patients with liver metastasis.
• Cr > 1.5 ULN, or creatinine clearance < 50ml / min (calculated according to Cockcroft Gault formula).
• APTT > 1.5 ULN, PT > 1.5 ULN (subject to the normal value of the clinical trial research center).
• Serious electrolyte abnormalities.
• Urinary protein ≥ 2+, or 24-hour urine protein ≥ 1.0g/24h.
• Uncontrolled hypertension: SBP > 140mmHg or DBP > 90mmHg.
• The presence of gastrointestinal diseases such as gastric or duodenal active ulcers, ulcerative colitis or unresected tumours with active bleeding; or other conditions likely to cause gastrointestinal bleeding or perforation; or unhealed gastrointestinal perforation or gastrointestinal fistula after surgical treatment.
• A history of arterial thrombosis or deep vein thrombosis within 6 months; a history of bleeding or evidence of bleeding tendency within 2 months.
• A history of heart disease within 6 months (including congestive heart failure, acute myocardial infarction, severe/unstable angina, coronary artery bypass grafting, cardiac insufficiency ≥ NYHA grade 2 and LVEF < 50%).
• Uncontrolled malignant pleural effusion, ascites, or pericardial effusion.
• History of anti-PD-1, PD-L1, PD-L2, CTLA-4 or any other specific T cell co-stimulation or checkpoint pathway targeted therapy.
• Receiving anti-VEGF or anti-EGFR therapy within 4 weeks.
• The presence of a clinically detectable second primary malignancy, or history of other malignancies within 5 years excluding adequately treated non-melanoma skin cancer, carcinoma in situ of cervix and superficial bladder tumour (non-invasive tumour, or carcinoma in situ, or T1).
• A history of liver disease including, but not limited to HBV infection or HBV DNA positive(≥ 1×10^4/ml), HCV infection or HCV DNA positive(≥ 1×10^3/ml) and liver cirrhosis.
•Pregnant or lactating women or women who may be pregnant have a positive pregnancy test before the first medication; Or the female participants themselves and their partners who were unwilling to implement strict contraception during the study period.
•The investigator considers that the subject is not suitable to participate in this clinical study due to any clinical or laboratory abnormalities or compliance problems.
• Serious mental abnormalities.
• The diameter of brain metastasis is greater than 3cm or the total volume is greater than 30cc.
• Clinical or radiological evidence of spinal cord compression, or tumours within 3 mm of the spinal cord on MRI.
Treatment plan
The general preoperative treatment regimen consists of six cycles of toripalimab and CAPOX (Capecitabine: 1000mg/m2 d1-14 q3w, Oxaliplatin: 130 mg/m^2 d1 q3w). Radiotherapy of pelvic recurrence depends on whether the patients have previous pelvic radiotherapy. In irradiation-naive patients, short course irradiation is delivered with a cumulative dose of 25–40 Gy in 5 fractions. In patients with pelvic radiation, reirradiation consists of 15–30 Gy in 5 fractions. Previous radiation therapy plan and dose volume histogram will be reviewed for relevant dose metrics. The dose prescription is escalated until the maximum pre-defined organ at risk (OAR) constraints are met. OARs delineate include small and large bowel, bladder, cauda-equina, and sacral plexus or roots. Individual dose constraints for all patients are calculated retrospectively based on national consensus OAR constraints for volumes of 10 cm3 or less[37] and fixed 15% annual tissue recovery post-previous radiotherapy using the following formula[22]. OARs are assumed to receive full previous prescription doses.
EQD2 1=\(D1\left(d1+ \frac{{\alpha }}{{\beta }}\right)/\left(2+ \frac{{\alpha }}{{\beta }}\right)\)
EQD2 2=\(D2\left(d2+ \frac{{\alpha }}{{\beta }}\right)/\left(2+ \frac{{\alpha }}{{\beta }}\right)\)
TRF = 0.15 \(\times\) years post \(–\)radiotherapy
Re-irradiation Constraint = EQD21 \(–(\)EQD22 \(\times\) (1\(–\) TRF))
After finishing six cycles of immunotherapy and (re)irradiation, preoperative evaluation will be discussed during the MDT meeting in our center, to determine whether they were suitable resection candidates. In case of a no evidence of disease (NED) state could be achieved, surgery is considered for pelvic recurrence and/or distant metastases. In case of a radiological partial or stable response to the preoperative therapy, immuno-chemotherapy is sustained until suitable for surgery. In case of a radiological progressive response, exit is recommended.
Synchronous metastases are treated during the waiting time between chemo(re)radiotherapy and surgery or after surgery. All metastasis sites will receive stereotactic ablative radiotherapy (SABR). Other treatment consisted of local resection, microwave ablation and radiofrequency ablation.
A total of one-year toripalimab is scheduled including perioperative treatment and postoperative maintenance treatment. The dose is 240mg intravenously every three weeks.
Efficacy, safety and toxicity evaluation
Patients will receive regular examinations at the following time points: baseline, every 3 cycles (9 weeks) of immunotherapy, at the end of the whole preoperative therapy (before surgery) and at every visit during the follow-up. The radiological evaluation is based on pelvic MRI/CT, abdominopelvic MRI/CT and chest CT with or without the addition of FDG-PET. Imaging efficacy is evaluated based on the response evaluation criteria in solid tumours (RECIST v.1.1) and immune response evaluation criteria in solid tumours (iRECIST). Adverse events will be assessed according to the Common Terminology Criteria for Adverse Event (CTCAE) v5.0. Quality of life will be evaluated at the end of the whole preoperative therapy and at every two visits during the follow-up using the EORTC QLQ-C30 and EORTC QLQ-CR29 scales. Bowel function will be evaluated using the Wexner score[38] and LARS score [39].
Sample size
In this study, the reference R0 resection rate is 40% (invalid response rate, P0), and we assume that our treatment group can achieve a R0 resection rate of 57% (alternative response rate, P1). The null hypothesis (H0): the R0 resection rate of our treatment group is not better than that reference, that is, P1-P0 ≤ 0. The alternative hypothesis (H1): the R0 resection rate of our treatment group can be increased by 17% compared with reference, that is, P1-P0 = 17%.
One side test is adopted, and if the error rate of type I (α) is set to 0.05, then 66 patients need to be enrolled, which can ensure that the test efciency (1-β) reaches 80%. When the dropout rate is set to 13%, 75 patients are needed. The ORR, PFS, OS, safety and tolerability will be analyzed.
Follow‑up
Patients will be scheduled for follow-up every three months after surgery for at least two years, every six months for the third to the fifth year after surgery, and then every 12months for life.
The follow-up contents include the physical examination, especially DRE (if possible), tumour marker examination, and radiological examination (pelvic MRI/CT, abdominopelvic MRI/CT and chest CT). Colonoscopy (if possible) will be performed every 6 months.
Statistics
Median follow-up is ascertained by reverse censoring on death. The cumulative probabilities of PFS, OS will be calculated using the Kaplan-Meier method. All analyses were performed using R studio.