The impact of intensity‐modulated radiotherapy in conjunction with chemotherapy on proximal pT3N0 rectal cancer patients after total mesorectum excision

Abstract Background This study aimed to ascertain if the incorporation of intensity‐modulated radiotherapy (IMRT) with chemotherapy (CTx) offered any advantages for patients diagnosed with stage pT3N0 rectal cancer located in the proximal (upper) region following a complete total mesorectum excision (TME). Methods We retrospectively examined medical records of stage II/III rectal cancer patients who had undergone CTx or concurrent chemoradiation (CCRT) with IMRT after a successful TME. We juxtaposed a variety of survival outcomes across two patient cohorts. Each outcome was further classified according to Gunderson's risk stratification between proximal and distal (middle and low) rectal cancer patients, and we evaluated the factors associated with each outcome. Results The median follow‐up duration was 4.9 years. Our research comprised 236 rectal adenocarcinoma patients treated at our institution between 2007 and 2019. They received either the CTx (n = 135) or the CCRT (n = 101) with 10‐year locoregional recurrence‐free survival (LRRFS) of 90.1% and 96.1%, respectively (p = 0.163). However, after performing multivariate adjustments, a pattern emerged hinting at a better LRRFS for the CCRT group (p = 0.052). Perforation had a strong correlation with locoregional recurrence. No significant differences were observed in other survival between the two treatment arms and their respective subgroups. The CCRT group witnessed significantly higher immediate and chronic complications with p = 0.007 and 0.009, respectively. The CCRT group had two secondary cancer‐related fatalities (2%, one attributed to IMRT), and another reported by the CTx group (1%). The sole classified locoregional recurrence within the cohort of 37 individuals treated with CTx for proximal pT3N0 rectal cancer was, in fact, the development of sigmoid colon cancer. Conclusion The results suggest that for patients with proximal pT3N0 rectal cancer post‐TME, IMRT is better when not combined with CTx, except in highly perilous scenarios or those involving perforation.

tively (p = 0.163).However, after performing multivariate adjustments, a pattern emerged hinting at a better LRRFS for the CCRT group (p = 0.052).Perforation had a strong correlation with locoregional recurrence.No significant differences were observed in other survival between the two treatment arms and their respective subgroups.The CCRT group witnessed significantly higher immediate and chronic complications with p = 0.007 and 0.009, respectively.The CCRT group had two secondary cancer-related fatalities (2%, one attributed to IMRT), and another reported by the CTx group (1%).The sole classified locoregional recurrence within the cohort of 37 individuals treated with CTx for proximal pT3N0 rectal cancer was, in fact, the development of sigmoid colon cancer.

| INTRODUCTION
The standard course of treatment for locally advanced rectal cancer (LARC), as suggested by the National Comprehensive Cancer Network (NCCN) guidelines, typically involves preoperative chemotherapy (CTx) and radiotherapy (RT), followed by surgery. 1 Despite this, numerous randomized studies have been unable to demonstrate a significant improvement in overall survival (OS) or disease progression-free survival (DFS) when combining preoperative CTx with RT as opposed to adjuvant postoperative CTx and RT.3][4] Other investigations have suggested that postoperative concurrent chemoradiation (CCRT) achieves 3-5-year OS and DFS comparable to the standard treatment.At the same time, intensity-modulated radiotherapy (IMRT) noticeably reduces complications and side effects. 5Based on this evidence, upfront surgery has become a viable treatment choice for LARC patients at our hospital.
Whether or not to supplement CTx with RT after surgery is pivotal yet challenging for rectal cancer patients.Pelvic relapse rates of approximately 25% have been observed in patients showing pathological evidence of extramural tumor invasion (pT3/4) or lymph node (LN) involvement (pN+). 6,7To boost locoregional control, adjuvant RT is generally prescribed alongside CTx for these patients. 76][17] Cancers above the anterior peritoneal reflection (in the proximal or upper rectum) tend to recur less frequently, and the benefit of adjuvant RT for such patients remains debatable. 18,19Gunderson and colleagues have stratified patients with T3/4 or N+ according to their risk levels, which are intermediate risk (pT1N1, pT2N1, and pT3N0), moderately high risk (pT3N1, pT4N0, pT1N2, and pT2N2), and high risk (pT3N2, pT4N1, and pT4N2). 16][22] In 2020, the NCCN guidelines introduced the option of standalone adjuvant chemotherapy for patients with margin-negative proximal pT3N0 cancer. 1 However, adjuvant CCRT remains an available treatment option for these patients after low anterior resection (LAR).Nonetheless, sufficient evidence must be provided to make informed decisions about the groups of patients that should receive RT.The potential benefits of tumor control must be cautiously balanced against the harmful effects of RT toxicity.Recent changes in NCCN guidelines have led to increased use of IMRT due to its potential to reduce toxicity. 1owever, as of now, there have not been any large-scale randomized clinical trials that assess the use of adjuvant IMRT after TME in patients with upper rectum tumors from each risk category.In this study, we aim to assess if integrating IMRT postoperative chemotherapy (CTx) regimen benefits patients with pT3N0 upper rectal cancer.We plan to employ a meticulous research approach involving a retrospective review of patient records.In addition, we will compare treatment outcomes and potential complications between both groups to evaluate the impact of IMRT.Essential aspects under examination include survival rates, recurrence rates, and side effects experienced by patients.This comprehensive approach will enable us to offer solid evidence on the merits and potential drawbacks of IMRT integration in treating pT3N0 upper rectal cancer patients, thereby aiding in informed decision-making and enhancing treatment strategies.
| 21211 FANG et al. at our institution between January 2007 and December 2019.All the patients were pathologically confirmed to have stage T3/4 or N+ adenocarcinoma and had undergone TME surgery.Our study's inclusion criteria were as follows: patients aged 20 or older with good performance scores (Eastern Cooperative Oncology Group [ECOG] ≤3); diagnosed as pathologically stage II/III; and had sufficient circumferential resection margin (CRM) (≥1 mm), distal margin (≥1 cm), and retrieved ≥12 LNs.Exclusion criteria included: a secondary cancer diagnosis concurrent with or before the rectal cancer diagnosis, tumors situated 16 cm or more above the anal verge (AAV); tumors in the sigmoid-rectal junction without definitive rectal invasion as determined by imaging studies or intraoperatively; a history of significant pelvic surgery or radiation therapy (RT); administration of an unclear RT regimen at doses between 18 and 36 Gy; the final RT date being >180 days postsurgery; and suspected recurrence before RT initiation, as suggested by postoperative images.
The patient's primary physicians were responsible for determining treatment, with most patients under the surveillance and review of a tumor team, which included colorectal surgeons, medical oncologists, diagnostic radiologists, nuclear medicine physicians, and radiation oncologists.Pretreatment evaluations consisted of physical examination, fiberoptic colonoscopy, contrast-enhanced computed tomography (CT), or magnetic resonance imaging of the pelvis (which covered the area between the diaphragm and the proximal femoral region), chest X-ray or CT, abdomen ultrasonography, and a standard radionuclide bone scan.Positron emission tomography/CT was optional.

| Surgical procedure
All patients had undergone a radical proctectomy with TME before adjuvant therapy.The choice between LAR and abdominoperineal resection (APR) was at the surgeons' discretion.Patients were informed about their treatment options, and, in some cases, the decision to undergo adjuvant RT was left to them.Two treatment pathways were created: an adjuvant CCRT arm and an adjuvant CTx arm.

| Radiation therapy and chemotherapy
The RT procedure followed established protocols from previous studies. 23Briefly, the main component of CTx was fluorouracil, administered intravenously or orally.Combination regimens like FOLFOX (folinic acid, fluorouracil, and oxaliplatin) and FOLFIRI (folinic acid, fluorouracil, and irinotecan) were used.Generally, stage III patients were treated with FOLFOX, while stage II patients were given a fluorouracil + leucovorin or oral tegafur-uracil + folinic acid regimen.Oxaliplatin and irinotecan were occasionally used.All patients who underwent irradiation received CCRT.Adjuvant CTx was sometimes administered before CCRT in patients with a high risk of distant metastasis.

| Follow-up
Post-treatment, patients were followed up at 3-month intervals.Radiological studies and fiberoptic colonoscopy were also performed every 3-6 months or in longer interval depending on clinical indications.Signs of possible recurrence were investigated through tumor markers.
Recurrent lesions close to the anastomosis site were classified as local recurrence, and other lesions within the RT planned target volume were classified as regional recurrence (RR).

| Statistical analysis
Collected demographic and clinical variables included sex, age, and tumor location.Histological variables comprised perineural invasion (PNI); lymphovascular invasion (LVI); surgical margins, including the CRM; and nodal invasion and retrieval status.Medical records were also examined for treatment complications, with the second cancer induction during follow-up considered a related side effect.Side effects were categorized using the Common Terminology Criteria for Adverse Events (CTCAE) (v.5.0).Tumor deposit data, post the publication of the eighth edition of the American Joint Committee on Cancer staging manual in 2017, were available.A comprehensive list of variables measured is provided in Table 1.
Primary endpoints were DFS, with secondary endpoints being OS, local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), LRRFS, and distant metastasis-free survival (DMFS).For the CCRT arm, survival duration was calculated from the end of RT until either death or the last follow-up.The Kaplan-Meier method was used for creating survival curves, and the differences between the curves were compared using logrank tests.A Cox proportional hazard regression model was used to calculate hazard ratios and the corresponding 95% confidence interval.If the survival curves on a Kaplan-Meier plot intersect, we verify it using Schoenfeld residuals to test the assumption of proportional hazards.
Chi-square or independent t-tests (or Fisher's exact test for small cell sizes) were used to compare differences between groups for categorical and continuous variables.All tests were two-sided, with p values <0.05 deemed significant.All statistical analyses were conducted using R software, version 4.1.2(R Foundation for Statistical Computing, Vienna, Austria).
Following the analysis of the two arms of the whole cohort, a subgroup survival analysis was performed for proximal and distal (middle and low) rectal cancer patients.Tumors located below the level of peritoneal reflection or 10 cm AAV were defined as distal (which included middle and low region, defined as >5 cm and ≤5 cm AAV, respectively) rectal cancer; all others were classified as proximal. 24 3 |RESULTS likelihood of not undergoing RT was observed in patients with fewer involved lymph nodes, older age (p < 0.001), and proximal tumors location (p = 0.001).However, no significant discrepancies were found in other variables between the two groups.The median duration of follow-up was 4.9 years, with an interquartile range of 2.4-7.5 years.Among these, 88 were diagnosed with pT3N0 rectal cancer (26 in the CCRT group and 62 in the CTx group which included 37 proximal-located cases), with the details shown in Table S1.

| Effectiveness of treatments
No statistically significant differences were identified in any of the survival outcomes (OS, DFS, LRFS, RRFS, LRRFS, and DMFS) between the treatment groups, either for the whole group (Figure 1A-F) comparisons.The same trends were observed when comparing distal and proximal subgroups, and risk-stratified subgroups (Figures S1-S14A-F).Table S2 includes details of the 12 cases of recurrence, which comprised both local and regional cases.The 10-year LRRFS for the two arms of the entire cohort were 90.1% for the CTx arm and 96.1% for the CCRT arm, with no statistically significant difference (p = 0.163; Figure 1F).However, after performing multivariate adjustments, the CCRT group exhibited a nonsignificant tendency toward better locoregional control after multivariate adjustments (p = 0.052; Table 2).Table 3 provide the frequency, location of the first recurrence, and of initial salvage treatment modality for local and regional recurrences and distant failures, respectively, for an entire cohort of patients with rectal cancer.Of total 236 patients, 54 (22.9%) had distant lesions, primarily located in the lung, liver, and bone.More specifically, 13 cases were from the proximal rectum and 12 from distal region in the CTx arm, whereas in the CCRT arm, nine cases were from the proximal region and 20 from distal region (Tables S3 and S4).
In the 44 proximal pT3N0 rectal cancer patients (37 undergoing CTx and seven receiving CCRT), RR was observed in one CTx patient, diagnosed with sigmoid colon cancer located 40 cm from the anal verge.Among the 44 distal pT3N0 patients (25 CTx, 19 CCRT), two CTx patients experienced local recurrence, with one having simultaneous RR.For all 88 pT3N0 patients, no cases of isolated RR were reported in the CCRT group.(Figures S12-S14A-F).

| Treatment side effects
Patients in the CCRT group exhibited significantly more grade ≥3 side effects, both acute and chronic (p < 0.001 and = 0.009, respectively; Table 4).Additionally, this trend was observed in the 88 pT3N0 patients, particularly for complications like diarrhea (p = 0.041; Table S5).Second cancers were reported in nine cases (five in the CTx arm and four in the CCRT arm).However, more cancer-related deaths occurred in the CCRT arm (two deaths, 2%) than in the CTx arm (one death, 1%).

| Prognostic factors
Both univariate and multivariate Cox regression analyses were performed using data from the entire cohort.The significant risk factors for both OS and DFS, older age, the ratio of positive LNs, and perforation were consistently significant.Tumor size and the ratio of positive LNs were found to be consistently statistically significant factors affecting DMFS (Tables S6-S8).In contrast only perforation were consistently significant factor, whereas multivariate analyses the absence of RT (p = 0.052) exhibited a trend concerning LRRFS (Table 2).However, two factors, namely upper tumor location and LVI, exhibited significant violations of the proportional hazard assumption (Table S9).Consequently, we attempted stratification of these two factors.The subsequent separate Cox test results revealed no RT (p = 0.038), older age (p = 0.012), and perforation (p = 0.001) to be significant factors for LRRFS in the multivariate Cox regression analyses (Table S10).No other parameters, including sex, T stage, comorbidities, serum carcinoembryonic antigen levels, or ECOG performance scores, showed a consistently significant relationship with outcomes.

| DISCUSSION
In our cohort of patients who had undergone comprehensive TMEs, we identified similar oncological results in those treated postoperatively with CTx and CCRT, including the pT3N0 upper rectal cancer subgroup (Figures 1A-F).Among the 44 upper rectal pT3N0 cases, we observed nearly equivalent survival outcomes, especially in LRFS, RRFS, and LRRFS (Figures S13A-F).
The risk of locoregional recurrence (LRR) due to complete TME was less than 10%, indicated by the LRRFS for the CTx group.Hence, further improvement with postoperative treatment is challenging. 25,26The only instance of LRR among the 37 cases of upper rectal pT3N0 patients who received CTx was likely a diathesis and would not have been preventable by adding RT to CTx.Older patients were less likely to choose CCRT, and our data showed advanced age significantly linked with lower OS, which could have led to an overestimation of OS in the CCRT arm.
The CCRT arm displayed a higher incidence of severe, long-term complications and acute side effects.The RTinduced Malignant Mixed Müllerian Tumor (MMMT) caused a fatality 7 years after RT was performed, 27 showing that using RT for locoregional control carries long-term survival risks.The cancer induction risk from RT complications seen in the cohort can be reasonably extended to the pT3N0 group, as their RT volumes and doses were virtually identical.Despite the limited number of cases, based on our findings and NCCN guidelines, we suggest that CTx alone is the more appropriate treatment option for upper rectal pT3N0 cancer following adequate TME.][14]17,[28][29][30][31] However, perforation was the most significant risk factor (Table 2 and Table S10).Perforation itself can directly disrupt the mesorectal fascial envelope, challenging locoregional control.Later, two out of eight perforation cases in our cohort (25%) developed LRR, even though five of them had received adjuvant CCRT.This rate is consistent with surgical outcomes before the era of TME. 6,7Although perforation does not necessarily indicate a tumor beyond pT3N0, it negatively impacts tumor control and should be considered when deciding on RT treatment in these patients. 10,28Additionally, in our results, older age was significant for LRR (Table 2 and Table S10).Nevertheless, we could not find any other strong reasons to determine whether or not to pursue RT.Therefore, further investigations are warranted.
Although our study and previous ones have relatively small sample sizes, assessing recurrence risk in upper rectal pT3N0 patients should consider the variables correlated with recurrence unless other evidence argues against using RT in a particular case.While adjuvant RT does not seem to provide additional benefits over CTx alone, it could be appropriate for pT3N0 upper rectal cancer patients with perforated tumors or an extremely high risk of LRR.In cases where RT is necessary, minimizing the toxicity of postoperative CCRT is essential.This study explored the potential benefits of postoperative CCRT by comparing it with CTx alone in different risk strata, including patients with proximal or distal rectal cancer.Despite the limitations of this study, which include a limited number of cases and potential selection bias due to the nonrandomized study design, our analyses found no evidence to support concurrent treatment of rectal adenocarcinoma with RT alongside postoperative CTx.
There was at least a noticeable trend toward better LRRFS in the CCRT arm of the study cohort, mildly supporting the current NCCN recommendation of adjuvant CCRT for patients with distal pT3 or pT4 or pN+ cancers.Future investigations should confirm our results.
Given the continued evolution of perioperative RT and recent notable results using upfront surgery, 1,5 further research on the use of postoperative CCRT after upfront TME in larger patient cohorts and subgroup analyses based on tumor locations and risk stratification of patients with LARC is warranted.

| CONCLUSION
Our research indicates that patients with upper rectal cancer categorized as pT3N0, who have undergone a thorough TME and received adjuvant CTx, may not necessitate the application of postoperative IMRT.This conclusion stems from the comparable oncological outcomes observed in patients treated with CTx alone or combined with RT in our study cohort.It is particularly true without specific risk factors, such as perforation or an extremely high likelihood of LRR.Our study emphasizes the importance of further research to validate these findings and to establish more definitive guidelines for the postoperative management of pT3N0 upper rectal cancer patients.

ACKNOWLEDGMENTS
All authors contributed to the study and provided more than general help.The authors deeply appreciate the manuscript preparation assistance from Chao-Yu Hsu.T A B L E 4 Side effects in a cohort of rectal adenocarcinoma patients treated with chemotherapy alone or chemotherapy and intensity-modulated radiotherapy after total mesorectum excision.Side effects were classified using the Common Terminology Criteria for Adverse Events (CTCAE) (v.5.0).

F I G U R E 1
Kaplan-Meier plots, including the number at risk, depict the outcomes of 236 patients with stage II and III rectal adenocarcinoma (CCRT: 101; CTx: 135) who underwent postoperative treatment with either chemotherapy alone or concurrent chemoradiation (A) Overall survival; (B) Disease progression-free survival; (C) Local relapse-free survival; (D) Regional relapse-free survival; (E) Distant metastasis-free survival; (F) Locoregional relapse-free survival.RT, radiotherapy; CCRT, concurrent chemoradiation; CTx, chemotherapy.

Table 1
presents the demographic and clinical traits of the two patient groups diagnosed with rectal cancer.Our study included 236 rectal adenocarcinoma patients (101 receiving CCRT and 135 receiving CTx).A significant Clinical and demographic characteristics of the patients in our cohort with rectal cancer.
Abbreviations: APR: abdominoperineal resection; LAR: low anterior resection; LVI: lymphovascular invasion; PNI: perineural invasion; LN: lymph node; CTx: chemotherapy; CCRT: concurrent chemoradiation; IV: intravenous; CEA: initial serum carcinoembryonic antigen level; pN stage: pathological nodal stage; ECOG: initial Eastern Cooperative Oncology Group Performance Status score.a mean ± standard deviation.T A B L E 1 Univariate and multivariate Cox regression analyses of locoregional relapse-free survival in a cohort of rectal adenocarcinoma patients.: APR, abdominoperineal resection; CCRT, concurrent chemoradiation; CEA, initial serum carcinoembryonic antigen level; CI, confidence interval; CRM, circumferential resection margin; CTx, chemotherapy; ECOG score, initial Eastern Cooperative Oncology Group Performance Status score; HR, hazard ratio; IV, intravenous; LAR, low anterior resection; LN, lymph node.Locoregional and distant relapses in whole cohort patients.Recurrence frequency, site of the first recurrence, and the first salvage treatment modality are shown.