Total neoadjuvant treatment to increase the clinical complete response rate for distal locally advanced rectal cancer (TESS): A study protocol of a prospective, open‐label, multicenter, single‐arm, phase 2 trial

Abstract Background Standard treatment of locally advanced rectal cancer (LARC) was neoadjuvant chemoradiotherapy (CRT), followed by total mesorectal excision (TME). Total neoadjuvant treatment (TNT), a new concept, attempts to deliver both systemic chemotherapy and neoadjuvant CRT prior to surgery. Patients treated with neoadjuvant chemotherapy were more likely to show higher tumor regression. The objective of this trial was to increase complete clinical rate (cCR) for LARC patients by optimizing tumor response, using TNT regimen as compared to conventional chemoradiotherapy. TESS, a prospective, open‐label, multicenter, single‐arm, phase 2 study, is underway. Methods Main inclusion criteria include cT3‐4aNany or cT1‐4aN+ rectal adenocarcinoma aged 18‐70y; Eastern Cooperative Oncology Group (ECOG) performance 0–1; location ≤5 cm from anal verge. Ninety‐eight patients will receive 2 cycles of neoadjuvant chemotherapy Capeox (capecitabine + oxaliplatin) before, during, and after radiotherapy 50Gy/25 fractions, before TME (or other treatment decisions, such as Watch and Wait strategy) and adjuvant chemotherapy capecitabine 2 cycles. Primary endpoint is the cCR rate. Secondary endpoints include ratio of sphincter preservation strategy; pathological complete response rate and tumor regression grade distribution; local recurrence or metastasis; disease‐free survival; locoregional recurrence‐free survival; acute toxicity; surgical complications; long‐term anal function; late toxicity; adverse effect, ECOG standard score, and quality of life. Adverse events are graded per Common Terminology Criteria for Adverse Events V5.0. Acute toxicity will be monitored during antitumor treatment, and late toxicity will be monitored for 3 years from the end of the first course of antitumor treatment. Discussion The TESS trial aims to explore a new TNT strategy, which is expected to increase the rate of cCR and sphincter preservation rate. This study will provide new options and evidence for a new sandwich TNT strategy in patients with distal LARC.


| BACKGROUND
Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) with or without adjuvant chemotherapy is the standard treatment for locally advanced rectal cancer (LARC). The standard treatment has been reported to reduce local recurrence for LARC patients. However, there was no improvement in the distant metastasis. 1 Additionally, TME surgery may lead to urinary and sexual function impairment due primarily to the removal of the rectum. Thus, perioperative treatment strategies are developed to decrease surgical morbidity and improve quality of life in surviving patients, such as the changing sequences of chemotherapy and radiotherapy and prolonging the interval between surgery and radiotherapy. 2,3 Total neoadjuvant treatment (TNT), a new concept, shifts all or part of adjuvant chemotherapy to the neoadjuvant phase. Two TNT paradigms have emerged: neoadjuvant induction chemotherapy followed by CRT (NeoCT-CRT) and CRT followed by neoadjuvant consolidation chemotherapy (CRT-NeoCT). Many trials assessing TNT have shown obvious advantages in increased treatment compliance along with improved tumor response. 4,5 Findings from a study of 628 patients treated at Memorial Sloan-Kettering Cancer Center (MSKCC) demonstrated that patients in the TNT arm received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose compared with chemoradiotherapy and planned adjuvant chemotherapy arm. And this trial also found improved tumor responses: 36% of patients in TNT arm had either pathologic complete response (pCR) or clinical complete response (cCR) compared with chemoradiotherapy and planned adjuvant chemotherapy arm (21%). 6 RAPIDO and PRODIGE-23 trials showed that TNT strategy could increase the pCR rate and reduce the risk of distant metastasis. [7][8][9][10] And for patients with a cCR after neoadjuvant CRT, National Comprehensive Cancer Network (NCCN) guidelines suggest "Watch and Wait (W&W)" strategy. 11 It is widely acknowledged that "W&W" strategy offers the potential to avoid surgery-associated morbidity and bowel, urinary, and sexual dysfunction that can permanently impair the patient's quality of life.
The lengthening of the interval between CRT and TME has been reported to achieve more pCR. 2,12 Recent trials showed that the surgical interval of 10 weeks would attain the best pCR rates without impacting survival outcomes. 13 The addition of chemotherapy in the surgical interval may have greater tumor response, even achieving higher cCR rates and providing potential for the W&W strategy. So, the surgery can be avoided to reduce the risks of postoperative complications. However, the longer surgical interval in "CRT-NeoCT" TNT model may aggravate pelvic fibrosis and edema making it more difficult to ensure the integrity of surgical resection of the mesorectum, thereby increasing the difficulty of TME surgery and reducing the quality of surgery. [14][15][16][17] The efficacy and safety of double-drugs oxaliplatinbased concurrent neoadjuvant chemoradiotherapy is still under debate. [18][19][20][21] However, based on our center's during, and after radiotherapy 50Gy/25 fractions, before TME (or other treatment decisions, such as Watch and Wait strategy) and adjuvant chemotherapy capecitabine 2 cycles. Primary endpoint is the cCR rate. Secondary endpoints include ratio of sphincter preservation strategy; pathological complete response rate and tumor regression grade distribution; local recurrence or metastasis; disease-free survival; locoregional recurrence-free survival; acute toxicity; surgical complications; long-term anal function; late toxicity; adverse effect, ECOG standard score, and quality of life. Adverse events are graded per Common Terminology Criteria for Adverse Events V5.0. Acute toxicity will be monitored during antitumor treatment, and late toxicity will be monitored for 3 years from the end of the first course of antitumor treatment.

Discussion:
The TESS trial aims to explore a new TNT strategy, which is expected to increase the rate of cCR and sphincter preservation rate. This study will provide new options and evidence for a new sandwich TNT strategy in patients with distal LARC.

K E Y W O R D S
clinical trials, neoadjuvant chemotherapy, rectal cancer, surgical oncology experience in clinical practice and several prospective clinical trials, it has been shown to significantly increase tumor response and to be well tolerated in LARC patients. 3,[22][23][24] The FOWARC study also demonstrated that the combination of oxaliplatin and fluorouracil with longcourse radiotherapy was acceptably tolerated and resulted in a higher pCR rate compared with single-agent fluorouracil plus radiotherapy. 25 Thus, our study designs a new sandwich model of TNT, in which 2 cycles of Capeox are added before, during, and after radiotherapy, followed by TME (or other treatment decisions, such as W&W strategy) and adjuvant chemotherapy capecitabine 2 cycles. This sandwich TNT model with double-drugs before, during, and after radiotherapy would be more compact. And we assess whether it increases the cCR rate and how to influence the proportion of various sphincter preservation strategies in patients with LARC compared with conventional neoadjuvant chemoradiotherapy.

| Study overview
This study is a prospective, multicenter, single-arm, phase 2 clinical trial, comparing a new sandwich TNT regimen to conventional chemoradiotherapy in the cCR rate of patients with LARC. Our study aimed to increase the cCR rate for LARC patients who are unable or not sure to undergo sphincter-preserving surgery at initial diagnosis. The study design is shown in Figure 1. The primary endpoint is the cCR rate. This study is conducted in full conformance with the principles of the Declaration of Helsinki.

| Screening of eligibility criteria
Eligible patients are screened by the investigators at each participating center. All patients are required to have a complete workup of LARC within 2 weeks before the treatments, including medical history review, the collection of personal data, currently taken medications and treatments, physical examination (height, weight, vital signs, anorectal digital examination, lymph node examination, and physical examination of the chest and abdomen), neurological examination, routine blood tests, urinal test, routine biochemistry, Eastern Cooperative Oncology Group (ECOG) performance score, biopsy pathology, CT and MRI of the chest/abdomen, pelvic MRI and endoscopic ultrasonography or transrectal color Doppler ultrasoundguided electronic colonoscopy.

| Inclusion criteria
Patients eligible for inclusion in this study should meet all the following criteria:

| Sample size
After the amendment, the primary endpoint was changed from the sphincter preservation rate to the cCR rate, and therefore, the corresponding sample size was changed. Based on the results of a retrospective study in our center, the cCR rate after CRT for LARC patients was known to be 17%. Thus, we assume that the new sandwich TNT model would show a 13% improvement in cCR rate compared with the history control (17%-30%). Based on the superiority design, one-sided proportion test and log-rank test with αerror of 0.025 and a power of 80% are conducted for the primary endpoint: the cCR rate. Allowing for a drop-out rate of 10%, a total of 98 patients will need to be enrolled, eventually.

| Randomization process
This study uses a single-arm design; thus, no randomization is performed.

| Neoadjuvant chemotherapy
Neoadjuvant chemotherapy consisted of 6 cycles of Capeox (Oxaliplatin (130 mg/m 2 ) as a 3-h IV infusion on day 1, followed by capecitabine (1000 mg/m 2 ) twice daily for 14 days every 3 weeks). In the third and fourth cycles of chemotherapy, patients receive oxaliplatin (100 mg/m 2 ) and capecitabine (1000 mg/m 2 ) concurrently with radiotherapy.

| Radiotherapy
Patients receive radiotherapy in 25 fractions of 2.0 Gy up to 50.0 Gy. Intensity-modulated radiation therapy is conducted for the primary tumor, regional lymph nodes, and clinical target volume. The dose to gross tumor volume (GTV) and involved lymph nodes (GTVnd) is 50 Gy in 25 fractions, and the dose to clinical target volume (CTV) is 45 Gy in 25 fractions.

| Surgery
For other patients who did not assessed as cCR, the surgical treatment modality, including local excision (LE), intersphincteric resection (ISR), and low anterior resection (LAR), abdominal-perineal resection (APR) should be determined after multidisciplinary team discussion. APR and LAR will be undertaken following principles of TME and tumor-free for patients who are appropriate for undergoing resection. Surgical resection is performed 2-4 weeks after the end of preoperative treatment. The rectal resection will be performed by experienced professors with respect to colorectal cancer.

| Adjuvant chemotherapy
The use of two courses of capecitabine is recommended 21 days after R0 resection. In patients with positive margins confirmed by pathological examination, postoperative adjuvant chemoradiotherapy should be proposed. Clinicians could make an individualized treatment based on pathological results.

| Nonoperative therapy
Patients with cCR will be observed under the "W&W" strategy. cCR was defined according to the guideline of Chinese Society of Clinical Oncology (CSCO) colorectal cancer 2018. V1, including (1) digital rectal examination: normal; (2) white and flat mucosal scars under the endoscope, accompanied by peripheral capillary telangiectasia, without signs of malignant ulcers or nodules; and (3) high-resolution MRI in T2 shows completely dark, without moderate intensity signals and lymph nodes; in DW phase, no tumor signal for B800-B1000 and/or, in ADC shows little or no signal, and intestinal wall linear signals in the tumor area.

| Follow-up
All patients will be followed up as per protocol until 1.5 years (for the primary endpoint, not for others). For patients undergoing surgery, follow-up will perform every 3 months within the first 3 years and every 6 months after 3 years up to 5 years, and annually thereafter. Follow-up examination mainly consisted of physical examination, digital rectal examination, tumor markers detection, and ultrasonography. Enhanced pelvic MRI and contrastenhanced chest-abdomen CT should perform at least once a year. PET-CT should be conducted if necessary. The patients who received "W&W" strategy should be more intensive followed up. Endoscope and pelvic MRI should be carried out in each follow-up. Transrectal color Doppler ultrasound will also be conducted if necessary.

| Study endpoints
Through investigator meetings, the primary endpoint was changed from the sphincter preservation rate to the cCR rate. Sphincter-preserving strategies for LARC patients include sphincter-preserving surgeries and the "W&W" strategy. However, serious postoperative complications, such as leaks or obstruction, may occur. The "W&W" strategy may be more appropriate for LARC patients with cCR after TNT to avoid surgery. For this reason, a new primary endpoint was formulated: the cCR rate. The change to this new endpoint was approved by the Ethical Committee of Sun Yat-sen University Cancer Center (December 27, 2020) and amended on clini caltr ial.gov accordingly (January 23, 2022). Secondary endpoints are ratio of sphincter preservation strategy, pathologic response of specimens after surgery according to the Tumor Regression Grading (TRG) system, local recurrence or metastasis, locoregional recurrence-free survival (LRFS), disease-free survival (DFS), acute toxicity, surgical complications, long-term anal function, late toxicity, adverse events, ECOG performance score, and quality of life. Diagnosis of recurrence or progression can be made only when the clinical and laboratory findings meet at least one of the following criteria objective radiological recurrence or progression on radiological imaging (ultrasound, CT scan, MRI scan, and PET-CT scan as indicated by the clinical picture), positive cytology or biopsy (in case of ascites, anastomotic recurrence, doubt on radiological imaging). LRFS is defined as the time interval from the randomization to the date of local relapse. DFS is calculated from the date of randomization to the date of disease recurrence, the appearance of new colorectal cancer or death. Acute and chronic toxicity will be recorded in the case report form (CRF). The grade of any adverse event will be recorded by the International Common Terminology Criteria for Adverse Events (CTCAE), V5.0. 26

| Statistical analysis
Continuous measures will be compared using the t test. Chi-square test will be utilized to compare categorical variables. Survival analysis will be estimated using the Kaplan-Meier (log-rank) test. The Cox proportional hazards model will be employed to identify the prognostic factors. The significance level is p < 0.05. The analysis will be performed with SPSS statistical software or R. Counts and percentage will be used to describe enumeration data, and the quantitative data will be described using means and 95% confidence.

| DISCUSSION
At present, most researches of TNT treatment focused on improving pCR and survival. [7][8][9] Our meta-analysis showed that TNT strategy could increase the rate of pCR (OR = 1.77, 95% CI: 1.28-2.45, p = 0.0005) and reduce the risk of distant metastasis (HR = 0.81, 95% CI: 0.68-0.95, p = 0.012). 10 The three-drug combination regimen also had well treatment adherence and tolerance, according to the PRODIGE 23 trial. 9 Despite the exponential increase in pCR rates in some studies, [7][8][9] there was no improvement in organ preservation rates, as the study design did not aim to improve anal retention or avoidance of surgery. Further treatment optimization should be attentively directed toward improving organ preservation and quality of life in LARC.
The results of Organ Preservation in Rectal Adenocarcinoma (OPRA) trial showed a higher sphincter preservation rate in both induction group (NeoCT-CRT) and the consolidation group (CRT-NeoCT; 43% vs. 58%, p = 0.007), compared with standard neoadjuvant chemoradiotherapy (historical controls). There was no significant difference in toxicity between the induction group and the consolidation group, and there was no significant difference in DFS (77% vs. 78%, p = 0.63) and DMFS (82% vs. 84%, p = 0.83). 27 Another prospective, single-arm study, with cCR as the primary endpoint, includes cT3 or any cT1 cN+ or cT2 cN+ rectal cancer patients, now in progress. 28 Similarly, the CAO/ARO/AIO-12 trial showed that NeoCT-CRT strategy has a higher pCR rate compared with CRT-NeoCT strategy (17% vs. 25%) and the long-term evaluations have not been reported. 29 Due to the limited data, there is no consensus on which treatment is better for "NeoCT-CRT" or "CRT-NeoCT." This study is currently the first investigation of the new sandwich TNT model of NeoCT-CRT-NeoCT. This model with 2 cycles of Capeox before, during, and after radiotherapy was a complete TNT paradigm. The time from the completion of radiotherapy to the evaluation of 8-10 weeks is appropriate, which can avoid the serious fibrosis caused by the long operation interval. 2,30,31 In addition, two courses of chemotherapy during this period will consolidate the therapeutic effect effectively.
In fact, the assession criterion for cCR is still under discussion. We evaluate cCR by digital rectal examination, endoscope examination, and rectal MRI examination included T2WI and DWI sequences, according to CSCO guidelines. 32 Although ESMO guidelines recommend the negative multipoint biopsy as an assessment criterion for cCR, 33 its ideal evaluated timing and value remains controversial. 34,35 Therefore, rectal biopsy is not mandatory for cCR in our study.
The TESS trial is designed with the aim of improving cCR and the sphincter preservation rate without compromising survival in distal LARC patients. In the TESS trial, we are exploring a completely new sandwich TNT paradigm, "NeoCT-CRT-NeoCT." Patients will receive two cycles of neoadjuvant chemotherapy Capeox before, during, and after long-course radiotherapy, and two cycles of adjuvant chemotherapy of capecitabine. This is expected to be an effective and safe treatment with better quality of life. The exploration of TNT versus standard chemoradiation will provide a new treatment option and evidence for the distant LARC.