Abstract
Background/Aim: To compare clinical outcomes following intensified total neoadjuvant therapy (TNT) and intensified neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). Patients and Methods: Of the 79 patients with LARC admitted to our department, 51 received intensified neoadjuvant CRT (CRT group) and 28 received intensified TNT (TNT group). Intensified TNT was defined as multi-agent chemotherapy, including FOLFOXIRI regimen plus bevacizumab (mutated Ras-BRAF) or panitumumab/cetuximab (wild-type Ras-BRAF) followed by oxaliplatin-5-fluorouracil-based CRT and surgery. Kaplan–Meier and Log rank test were used for survival analysis. Survival rates of the two groups were compared using propensity score matching. Results: Data from 28 TNT patients and 28 CRT patients were analyzed after a 1:1 propensity matching with replacement. Kaplan–Meier curve showed that overall survival (OS), disease-free survival (DFS) and distant metastasis-free survival (DMFS) rates with TNT were comparable to those with CRT. The 5-year DMFS rates for TNT and CRT were 61.5% versus 63.0% (p=0.82), respectively. In the TNT group, 32.1% patients (n=9) achieved pathological complete response (pCR), whereas 21.4% patients (n=6) achieved pCR with CRT (p=0.37). Conclusion: Intensified TNT and CRT resulted in similar survival outcomes, while intensified TNT led to higher pCR, albeit not statistically significant.
Rectal cancer remains a deadly disease with an estimated 732,210 new cases and 339,022 deaths worldwide in 2020 (1). Despite important advances in combination therapies, including surgery, radiotherapy (RT) and chemotherapy (CHT), the rate of distant metastasis continues to remain high (>30%) in locally advanced rectal cancer (LARC) (2). Several small phase II trials have tested the effectiveness of total neoadjuvant therapy (TNT) in patients with LARC and two randomized phase III trials seem to add evidence to reinforce its efficacy over standard conventional treatment, including neoadjuvant chemoradiotherapy (CRT) followed by surgery and adjuvant CHT (3-14). To verify whether TNT was associated with improved survival outcomes compared to standard trimodal approach in LARC management, we investigated the long-term outcomes of LARC patients who were treated with intensified TNT or conventional trimodal approach in our institution. Treatment outcomes between the two groups were compared using propensity score matching in order to minimize biases and produce more robust results.
Patients and Methods
Patient selection. Patients with newly diagnosed histologically proven adenocarcinoma of the rectum, staged as high-risk tumors (clinically cT3-4 and/or cN+ and/or circumferential resection margin involvement) receiving intensified TNT at our institution were included in a phase II trial (ethical committee number 88569-140/5638) and clinical data were prospectively recorded (12). To perform a comparative analysis, a group of LARC patients treated with conventional trimodal approach were selected from our institutional database (ethical committee number 6452-0712/2021).
Independently of treatment, all cases were assessed by a multidisciplinary team including medical oncologist, radiation oncologist, surgical oncologist, pathologist and radiologist. Patients underwent physical examination and were staged using pelvic magnetic resonance imaging with diffusion-weighted imaging (DW-MRI) and computed tomography (CT) of chest, abdomen and pelvis. Signed written informed consent was obtained from each patient.
Treatment. Treatment details and response assessment were previously described (11, 14-17). Briefly, the standard approach consisted of concomitant 5-fluorouracil (5-FU) and oxaliplatin (OXP) plus RT, followed by surgery 7-9 weeks later and adjuvant CHT (14, 15). Whereas the intensified TNT regimen included target-based FOLFOXIRI (5-FU, leucovorin, OXP and irinotecan) prior to CRT and surgical approach (11). Two weeks from the end of the last IC cycle and 6 weeks after the end of neoadjuvant CRT, the assessment of local clinical response was performed by pelvic DW-MRI, according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (17-20).
Follow-up program. Clinical assessment was carried out every 3 weeks during the IC period, whereas during CRT patients were evaluated daily. Toxicity was (re)scored according to the Common Terminology Criteria for Adverse Events, Version 5.0 (21). After treatment, all patients were monitored at three-month intervals for the first 2 years and every 6 months thereafter in order to evaluate toxicities and detect potentially locoregional recurrence or distant metastasis.
Statistical analysis. Standard descriptive statistics were used to evaluate the distribution of each factor. Continuous variables are reported as means±standard deviation (SD) and categorical variables as frequencies and percentages. Based on treatment approach, patients were divided into i) TNT group and ii) standard CRT group. Data were compared using non-parametric Fisher exact test for qualitative data and Student t-test for quantitative data. Survival curves were generated using the Kaplan–Meier method and were compared by the log-rank test. Overall survival (OS), disease-free survival (DFS) and distant metastasis-free survival (DMFS) were calculated from the date of diagnosis to the first event, including date of the last follow-up or death (OS) and/or relapse (DFS) and/or distant metastasis (DMFS). Pathological complete response (pCR) was defined as the absence of any residual tumor cells detected in the operative specimen, including the primary tumor area, the whole mesorectal fat, and the resected lymph nodes. As we aimed to define the utility of the TNT to improve distant control, the primary outcome focused on DMFS.
Considering that LARC patients were not randomly assigned to receive IC (TNT group) or neoadjuvant CRT alone (CRT group), a propensity score-matching analysis was used to reduce the effect of treatment selection bias and simulate the effects of randomization. Propensity-score matching was performed using a 1:1 nearest-neighbor method. Balance was assessed using mean standardized differences. CRT patients were matched with TNT patients based on several factors, including age (≤65 versus >65), gender (male versus female), primary tumor distance from anal verge (>8 cm versus 6-8 cm versus ≤5 cm), dimension of primary lesion (≤5 cm versus >5 cm), cT stage, cN stage. All reported p-values are two-sided, and p-values lower than 0.05 were considered significant. Statistical analysis was carried out using R-Studio 0.98.1091 software (Boston, MA, USA).
Results
Patient characteristics. In total 79 patients with LARC were identified. Patient and tumor characteristics are summarized in Table I. Most of the patients (n=2, 91.1%) had regional lymph node involvement at diagnosis. Based on treatment approach, the entire cohort was divided in conventional CRT group (n=51) and TNT group (n=28).
Patients and tumor characteristics.
Non-matched data analysis. Median follow-up was 39 months (range=12-82 months) for the entire cohort, 26 months (range=12-43 months) for the CRT group and 62 months (range=44-82 months) for the TNT group. In total 14 (17.7%) patients died, 11 (21.6%) in CRT group and 3 (10.7%) patients in TNT group. The 2-year OS was 90.0% (95%CI=0.776-0.957) in CRT group and 92.6% (95%CI=0.734-0.981) in TNT group. The 5-year OS was 70.5% (95%CI=0.520-0.830) in CRT group and 81.0% (95%CI=0.446-0.946) in TNT group. OS details are presented in Figure 1. Two-year DFS rates were 70.9% and 75.0% for CRT patients and TNT patients, respectively. Five-year DFS rates were 55.3% for CRT patients and 44.4% for TNT patients (Figure 2). No significant differences were found between the CRT and TNT groups with respect to OS (p=0.19) and DFS (p=0.96).
Overall survival according to treatment approach (standard CRT versus TNT). (A) Non-matched data. (B) Matched data. CRT: Chemoradiotherapy; TNT: total neoadjuvant therapy.
Disease-free survival according to treatment approach (standard CRT versus TNT). (A) Non-matched data. (B) Matched data. CRT: Chemoradiotherapy; TNT: total neoadjuvant therapy.
Twenty-eight events (distant metastasis or death) were observed, 19 (67.9%) in the CRT group and 9 (32.1%) in the TNT group, leading to a 2-year and 5-year DMFS of 70.9% (95%CI=0.557-0.817) and 55.3% (95%CI=0.380-0.696) versus 78.6% (95%CI=0.584-0.898) and 61.5% (95%CI=0.361-0.793), respectively (p=0.42). DMFS curves according to treatment group are shown in Figure 3.
Distant metastasis-free survival according to treatment approach (standard CRT versus TNT). (A) Non-matched data. (B) Matched data. CRT: Chemoradiotherapy; TNT: total neoadjuvant therapy.
Matched data analysis. After propensity score matching, patient characteristics were well balanced between the two groups, indicating an adequate algorithm procedure (Table I).
With a median follow up of 37 months (range=16-82 months), 7 (12.5%) patients died, 4 (14.3%) in the CRT-matched group and 3 (10.7%) in the TNT-matched group. Overall, 18 DMFS events, 9 (32.1%) in the CRT group and 9 (32.1%) in the TNT group, were observed. No significant differences were found between the two groups (CRT versus TNT) in the estimated 2-year and 5-year survival rates. Details of survival endpoints between treatment groups are described in Table II, Figure 1, Figure 2 and Figure 3.
Survival rates in the matched data.
The association between pCR and survival was studied. pCR was achieved in 15 cases (26.8%), 6 (21.4%) in the CRT group and 9 (32.1%) in the TNT group (p=0.37). pCR was associated with increased DMFS (p=0.087). The DMFS curves according to pCR and treatment approach are shown in Figure 4. In pCR patients, no significant survival difference was demonstrated between intensified CRT and intensified TNT (hazard ratio HR=0.30; 95%CI=0.07-1.30), although a trend of DMFS benefits at 2 and 5 years of +5.6% was found in favor of the TNT group.
Distant metastasis-free survival according to treatment approach (standard CRT versus TNT) and pCR. CRT: Chemoradiotherapy; TNT: total neoadjuvant therapy; pCR: pathological complete response.
Subgroup analysis stratified by the distance between the tumor and the anal verge showed that a lower rectal location (≤ 8 cm) reduced the risk of distant metastasis. A higher (>8 cm) distance from anal verge of primary tumor was strongly associated with worst DMFS (HR=4.69; 95%CI=1.83-12.02; p=0.001), leading to a 2-year DMFS of 41.7% (>8 cm), 81.0% (6-8 cm) and 95.7% (≤6 cm) and a 5-year DMFS of 33.3% (>8 cm), 61.3% (6-8 cm) and 77.3% (≤6 cm), respectively.
DMFS was also significantly worst for the two treatment strategies (CRT versus TNT) in tumor lesions >8 cm from anal verge compared lower LARC (p<0.001) (Figure 5).
Distant metastasis-free survival according to treatment approach (standard CRT versus TNT) and tumor distance from anal verge. CRT: Chemoradiotherapy; TNT: total neoadjuvant therapy.
Overall, treatment-related acute toxicities were easily tolerated. Severe neutropenia was recorded in 39.3% of TNT patients (n=11), whereas there was no evidence in CRT group (p<0.01). Severe diarrhea occurred in 3 TNT cases (10.7%) and 4 CRT cases (14.3%) (p=0.68).
Discussion
To the best of our knowledge, we here present the first study that compares intensified TNT sequence and conventional trimodal approach with intensified neoadjuvant CRT followed by total mesorectal excision and adjuvant CHT in LARC patients. IC included FOLFOXIRI regimen plus a targeted agent based on Ras-BRAF status – bevacizumab (mutated Ras-BRAF) or panitumumab/cetuximab (wild-type Ras-BRAF) –, as per a phase II trial (12). Whereas, according to our previous studies (15, 16), the CRT regimen was intensified by adding OXP to standard concurrent 5-FU in both groups. We used propensity score matching to minimize effects of selection bias between treatment strategies by balancing characteristics of patients receiving intensified TNT and CRT. Although not powered to draw any comparative conclusions, our results reveal that the TNT strategy has OS, DFS, DMFS and pCR rates similar to those of neoadjuvant CRT alone. But we must notice that the pCR rate of 32.1% in the TNT group was slightly higher than that reported in the TNT randomized phase III trials (27.8%-28.4%) (23), meaning that intensification of TNT and CRT potentially increase the proportion of patients who probably do not require surgery. The main limitation of this study is related to the retrospective nature of intensified CRT patients, limiting toxicity quality data. However, the survival outcomes of interest were rigorously collected from both TNT and CRT groups. One unanticipated finding was that DMFS decreased as the distance from the anal margin increased (HR=4.69; 95%CI=1.83-12.02; p=0.001). This may be explained by the anatomic factors as the intestine leaves the peritoneal double bag approximately midway through the rectum (22). One could expect that patients with high LARC, who were shown to have the highest risk of distant metastasis and/or death, would be the ones who benefit most from the intensified TNT regimen compared with those with the intensified CRT therapy. Strikingly, this is not the case, probably because of the small number of patients. The absence of interaction between tumor location and treatment strategy prevents from defining a specific population that would not benefit from intensified TNT. Yet, the distance from anal verge is an important factor that should be taken into consideration for DMFS. Surely, despite attempts to control for inherent biases using propensity matching, our results should be considered hypothesis-generating and indicative rather than definitive in scope.
Considering that we proposed a more demanding experimental treatment with both intensified TNT and CRT strategies, some questions remain open. First, is triplet CHT plus targeted agent really required? Based on the efficacy demonstrated in colon metastatic setting (response rate up to 69%) (24), we hypothesize that intensified TNT would be superior to OXP-based doublet or FOLFOXIRI alone in terms of distant control. Actually, until now, the addition of a targeted agent to triplet CHT combination has not been tested in LARC. We suggest that both the addition of targeted agent to FOLFOXIRI and the intensified neoadjuvant CRT approach had a crucial role in our pCR results. In this context, the second question concerns concomitant CHT scheme to RT. In fact, despite addition of OXP to standard 5FU-based CRT is related to significantly lower rate of distant failures (0.76, 95%CI=0.60-0.97; p=0.03), treatment intensification in the neo-adjuvant CRT setting does not represent routine clinical practice in LARC management (2, 25). We selected the OXP-5FU, rather than 5-FU, as the concomitant CHT regimen to RT for two key reasons. First, based on our institution experience, the regimen has substantial efficacy in LARC disease, especially in terms of pCR (24%) and survival rates (5-year OS=76.4% and 5-year DFS=74.5%) (15). Second, these effective benefits were not reached at the price of increased toxicity. OXP cumulative dose (up to 300 mg) was not linked to higher incidence of neurologic symptoms – late sensory neuropathy was recorded in only 6% of cases (16). Then a major issue is whether the systemic and local benefits of intensified TNT are sufficient to allow better distant disease control by themselves with or without intensified CRT.
Recently, two randomized phase III clinical trials have reported on the use of TNT for LARC patients (12, 13). The UNICANCER-PRODIGE 23 trial incorporates FOLFOXIRI followed by CRT, surgery and adjuvant FOLFOX CHT, whereas the RAPIDO trial a short course RT followed by FOLFOX regimen in the neoadjuvant setting (13, 14). Despite difficulty of both data interpretation and critical comparison – different primary end-points, heterogeneity of treatment strategies – TNT will likely reflect the new standard of care. But the definition of the optimal TNT approach cannot be resolved. Probably, in the near future, an ongoing trial (NCT03854799) might add to the confusion, as different concomitant treatments are tested.
Considering that, at present, the high risk of distant metastasis remains the main cause of treatment failure and death in LARC, a comprehensive and more effective treatment modality is needed for these patients. Identifying predictive biomarkers and gene expression profiling for patients who are more likely to benefit from TNT is a current need. Beyond TNM stage disease at diagnosis, additional risk factors – such as MRI assessments of circumferential resection margin involvement, extramural vascular invasion, lateral lymph nodes and intersphinteric plane involvement – that could help to refine patient stratification should be considered in the decision-making process. Our intensified TNT and CRT approach could be considered for selected patients with high-risk tumors. Surely, this assumption should be confirmed by randomized clinical trials and this propensity score matching analysis could serve as an initiating impulse to design it.
Conclusion
Although intensified TNT is not superior to intensified CRT in terms of survival outcomes and pCR rates, its precise role compared with intensified CRT in the management of LARC remains to be defined. Given the higher chances of pCR, the added value of intensified TNT remains to be established especially in high-risk LARC patients.
Footnotes
Authors’ Contributions
FDF, DM, VT, EC designed and supervised the study. FT, FI, SC, VP collected data. FDF did the statistical analyses and wrote the draft, with revisions from the other Authors.
Conflicts of Interest
All Authors have no conflicts of interest to disclose in relation to this study.
- Received December 11, 2021.
- Revision received December 30, 2021.
- Accepted December 31, 2021.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
