Lessons from FOWARC: moving towards the more precise use of radiation therapy in the era of total neoadjuvant therapy

Advances in the delivery of neoadjuvant therapy have revolutionized the management of locally advanced rectal cancer over the past decade (1-3), yet the optimization of therapeutic strategies remains an evolving domain. Within the context of total neoadjuvant therapy (TNT), variations in chemotherapy intensity, radiation dose and/or fractionation, as well as use of radiosensitizing adjuncts are important variables that may improve tumor response and long-term outcomes (4). With the emergence of watch-and-wait (WW) management, there is a growing appreciation for the diverse range of clinical responses, shedding light on the tumor heterogeneity of rectal cancer. Therefore, the assumption that all rectal cancer patients benefit from a singular treatment paradigm is potentially misguided and underscores the demand for precision oncology based on distinct clinicopathologic features, in order to minimize overtreatment or undertreatment. The FOWARC trial (NCT01211210) pioneered discussions on treatment de-intensification by comparing neoadjuvant chemoradiotherapy to chemotherapy alone and questioning of the role of radiotherapy in the preoperative setting. Although trial enrollment completed nearly a decade ago, a recently published post-hoc analysis from FOWARC questions the benefit of radiotherapy for early-onset rectal cancer, offering relevant insights for contemporary discussions on rectal cancer treatment strategies.

In brief, FOWARC was a phase III study in China that randomized stage II/III rectal cancer patients 1:1:1 to three treatment arms, comprising of two arms with neoadjuvant chemoradiotherapy (5-fluoruracil or mFOLFOX6 concurrently administered with 46.0–50.4 Gy/23–25 fractions) and one arm with neoadjuvant mFOLFOX6 alone (5,6). Following completion of neoadjuvant therapy with a seven-to-eight-week recovery interval, all patients underwent total mesorectal excision followed by adjuvant chemotherapy, with a primary endpoint of 3-year disease-free survival (DFS). Although mFOLFOX6-radiotherapy achieved superior pathologic complete response (pCR) and downstaging rates compared to fluorouracil-radiotherapy and mFOLFOX6 alone, there was no difference in estimated 3-year DFS or overall survival (Table 1). Additionally, patients in the two radiotherapy treatment arms experienced greater toxicities, post-operative complications, and worsened long-term anorectal function, including an increased daily defecation frequency, higher Wexner scores, and more frequent liquid and solid incontinence (Table 1). Thus, in absence of improved long-term oncologic outcomes and at the cost of heightened complications, the benefit of neoadjuvant radiotherapy warranted further investigation. These data served as a preface for PROSPECT (NCT01515787) which demonstrated noninferiority between neoadjuvant chemotherapy and chemoradiotherapy with respect to 5-year DFS among patients eligible for sphincter-preserving surgery (7). Taken together, pelvic radiation may be reasonably omitted for a subset of rectal cancer patients pursuant of surgical intent, fortifying the concept of treatment de-intensification. However, broad application of these findings should be approached with caution, as key tumor features such as extramural venous invasion (EMVI), lateral lymph node status, cT3 subclassifications, and microsatellite status were not explicitly reported by either study. Moreover, PROSPECT excluded patients with T4 tumors, N2 nodal involvement, and threatened radial margins (7). Given the recent literature supporting long-term survival benefits with TNT (8), there should be greater caution in omitting radiation for cases with high-risk features.

With the recognition that rectal cancer incidence is rapidly rising among young adults (9) and concerns about a prevailing provider bias to overtreat this patient population, the investigators of FOWARC recently conducted a post-hoc analysis (10) of treatment response stratified by patient age. Patients were dichotomized by age at diagnosis into early onset (i.e., less than 50 years old; n=150) or late onset (i.e., 50 years old or greater; n=266) cohorts, both exhibiting similar clinicopathologic characteristics. The authors conducted a univariate Cox screen to investigate associations between individual characteristics and survival outcomes by cohort. Although the Forest Plots suggest mild heterogeneity in prognostic factors between early- and late-onset cohorts, the authors did not provide statistical evidence to support significance (10). The early- and late-onset cohorts were subdivided with respect to whether they received radiation as a component of their neoadjuvant therapy. Greater proportions of pCR and tumor downgrading (tumor regression grade 0–1) were achieved among patients who received radiation compared to those who did not. However, the odds ratio (OR) for achieving pCR following radiation was lower in the early-onset cohort [OR =3.75; 95% confidence interval (CI): 1.37–10.27; P=0.010] compared to the late-onset cohort (OR =5.33; 95% CI: 1.83–15.58; P=0.002). A similar discrepancy in OR was observed with respect to tumor downgrading between early-onset (OR =3.03; 95% CI: 1.52–6.02; P=0.002) and late-onset (OR =3.65; 95% CI: 2.13–6.26; P<0.001) cohorts, suggesting that favorable tumor response to radiation was less pronounced in younger rectal cancer patients. Although comprehensive toxicity data were not provided, higher complication rates were noted following radiation in both cohorts. The hazard ratio (HR) was more prominent in the early-onset patients (HR =11.35; 95% CI: 1.46–88.31; P=0.02) than the late-onset patients (HR =5.80; 95% CI: 2.32–14.49; P<0.001). Finally, receipt of radiation did not confer improvement in overall survival (early-onset, HR =1.37, 95% CI: 0.49–3.87, P=0.56; late-onset, HR =0.86, 95% CI: 0.47–1.56, P=0.61) or DFS (early-onset, HR =1.05, 95% CI: 0.58–1.90, P=0.87; late-onset, HR =0.99, 95% CI: 0.47–1.56, P=0.61) in either cohort. The authors concluded that chemoradiotherapy may not be superior to chemotherapy alone in the context of early-onset rectal cancer, suggesting the need for alternative neoadjuvant strategies for this patient population.

While emphasizing the need to individualize treatment strategies is a valid conclusion, the strength of these findings is inherently limited by the post-hoc study design. The age stratification provides an interesting framework to analyze outcomes; however, concluding that age alone is responsible for the observed outcomes would be overly simplistic. Concerns regarding the underappreciated interplay between genetic, environmental, and lifestyle factors in early-onset disease have previously been raised (11). Moreover, while various short-term and long-term outcomes were scrutinized, the absence of quality-of-life comparisons is a notable limitation. With PROSPECT’s demonstration of improved sexual function in the FOLFOX arm compared to the chemoradiation arm (12), it could be theorized that age-dependent changes in sexual activity may influence a patient’s willingness to undergo radiation.

Given that FOWARC predated the publication of sentinel prospective studies on TNT (2,3) and organ preservation (13,14), it was not designed with the intention of organ preservation, although the included study subjects would likely have met pretreatment inclusion criteria for modern-day organ preservation protocols. Therefore, interpretation of FOWARC-derived publications must acknowledge that evidence on neoadjuvant treatment strategies and organ preservation has evolved considerably since the trial enrollment was completed. For example, FOWARC utilized a neoadjuvant approach in which chemotherapy was given concurrently with radiation, with a recommendation for adjuvant chemotherapy following mandatory surgery. It did not employ a true TNT paradigm in which (chemo)radiotherapy and chemotherapy are administered in separate induction and consolidation treatment blocks in the preoperative setting (1). In contrast, the OPRA trial (NCT02008656) investigated a true TNT approach and associated oncologic outcomes with tumor response endpoints (13,14). Although clear survival benefits had not been demonstrated until very recently (8), previously recognized merits of a TNT approach include improved chemotherapy compliance, control of early micrometastatic disease, and enhanced primary tumor response (1-3,15). Subsequently, OPRA demonstrated how TNT can facilitate organ preservation by obviating the need for surgery in well-selected patients (13,14). While quality-of-life data have yet to be published from the OPRA study, prior literature has shown functional outcome benefits with a WW strategy compared to total mesorectal excision (16,17). Moreover, literature (including OPRA) suggests that the sequence of TNT may be consequential for organ preservation, as regimens which utilize induction (chemo)radiation followed by consolidation chemotherapy have demonstrated superior organ preservation rates relative to the inverse sequence (13,14,18). Finally, OPRA has laid the foundation for ongoing organ preservation trials around the world which are designed to investigate the nuances of a TNT framework (Table S1). For the many young and active patients who seek the quality-of-life benefits associated with organ preservation, currently available evidence supports a TNT paradigm with induction (chemo)radiation and consolidation chemotherapy, with the caveat that the appropriate intensity of these modalities remain under investigation. Alternatively, a subset of patients may express an unwavering desire to proceed with surgery during shared decision-making discussions, for whom FOWARC suggests that de-intensification of neoadjuvant chemoradiotherapy by means of radiation omission does not compromise long-term outcomes.

Cai and colleagues’ post-hoc analysis suggests that not all patients derive equal short-term benefits from neoadjuvant chemoradiotherapy, reinforcing the principle that rectal cancer is not a homogenous entity. This highlights the urgent need for early stratification of patients based on predicted treatment response. To date, the most informative predictor of treatment response is mismatch repair protein (MMR) status, which broadly divides treatment strategies into TNT or immune-checkpoint inhibitor (ICI) based approaches for MMR proficient (pMMR) and MMR deficient (dMMR) rectal cancers, respectively. Early-onset rectal cancers have a greater propensity for dMMR status (19,20), the treatment of which with dostarlimab-based ICI has demonstrated promising preliminary results (21). In this context, it is worth noting that FOWARC did not assess MMR status, as the trial was conducted prior to universal screening of this biomarker. While purely speculative, a subset of FOWARC patients in the early-onset cohort may have had occult dMMR rectal cancers which could have been more effectively treated with immunotherapy, potentially explaining the observed differences in tumor response described by the post-hoc analysis. Nevertheless, dMMR rectal cancers account for a minority of all rectal cancers, with an estimated 5–10% prevalence (20,21). This underscores the importance of devising a clinically relevant biomarker to stratify between pMMR rectal cancers at time of initial diagnosis. In this regard, circulating tumor DNA (ctDNA) has shown promise in the realm of select solid tumor malignancies (22,23). Beyond the early prognostication of neoadjuvant treatment response, ctDNA may also be informative for surveillance of minimal residual disease and guiding adjuvant treatment decisions (24). Despite much anticipation, several challenges must be addressed prior to widespread implementation of ctDNA in the management of rectal cancer. Relevant barriers at present day include a lack of standardization in methods of sample collection and assay performance, as well as a paucity of prospective data validating the clinical utility of a ctDNA assay. Notably, The Janus Rectal Cancer Trial and ENSEMBLE are among the current trials designed with exploratory objectives to evaluate ctDNA kinetics during treatment and surveillance, with correlation to oncologic outcomes (Table S1). As validated ctDNA data are generated from thoughtfully designed clinical trials, assay standardization and collection protocols are expected to improve.

The programmed cell death ligand 1 (PD-L1) combined positive score (CPS) may be another compelling biomarker for predicting treatment response in the context of pMMR rectal cancer, as recently described by Xiao and colleagues (25). In their phase II trial, pMMR rectal cancer patients were randomized to neoadjuvant chemoradiotherapy with or without programmed cell death protein 1 (PD-1) antibody sintilimab. While the study design initially mandated surgery for all enrolled patients, it was amended to be permissive of organ preservation near the end of trial randomization, the timing of which coincided with the publication of the 3-year OPRA results (13). Adjuvant chemotherapy was recommended following surgery or achievement of clinical complete response. Notably, the combination therapy of sintilimab and CAPOX (capecitabine, oxaliplatin) given concurrently with 50 Gy/25 fractions achieved a greater complete response (CR) rate (i.e., the sum of clinical complete response and pathologic complete response) relative to the control arm of CAPOX with 50 Gy/25 fractions [CR rate: 44.8% (95% CI: 32.6–57.0%) versus 26.9% (95% CI: 16.0–37.8%), respectively] with comparable toxicity (25). This translated into a response ratio of 1.667 (95% CI: 1.035–2.683), suggesting that radiation and immunotherapy may induce a synergistic effect which potentiates tumor response. Although promising, it remains unclear whether all patients benefit equally from a synergistic approach. To that end, the investigators conducted an exploratory analysis by performing immunohistochemical staining on pre-treatment tumor specimens to determine the CPS, defined as the measure of PD-L1 staining cells relative to all viable tumor cells per high-powered field. While several CPS cutoffs were assessed, the synergistic effect was most evident with tumors which exhibited CPS ≥2. Thus, certain pMMR rectal cancers which meet a PD-L1 expression threshold may achieve an augmented response with combination immunotherapy and radiation. In light of these novel findings, it may be speculated that a subset of FOWARC patients could have experienced enhanced tumor responses from immunotherapy-intensified radiotherapy. However, survival endpoints from Xiao et al. have yet to be reached, thus the implications for long-term outcomes cannot be discerned at this time. These results may inspire additional investigations on potential biomarkers for treatment response, but broader validation and correlation with oncologic outcomes is paramount.

The treatment schemas for FOWARC and Xiao et al. provide interesting insights into the selective modulation of chemoradiation regimens in the context of a non-TNT paradigm. Both studies suggest that tumor regression can be enriched by intensification of radiosensitizing agents for a subset of patients, though long-term survival benefits are not supported. With growing demand for organ preservation options and a recently reported 5- and 7-year survival benefit in the TNT arm of the updated UNICANCER PRODIGE 23 trial results (8), radiotherapy is anticipated to remain a cornerstone in the management of locally advanced rectal cancer. Although only 3-year survival have been reported from FOWARC, its findings are comparable to those of PRODIGE-23, suggesting that radiation de-escalation is a viable option for patients who either decline organ preservation, are intolerant of radiation-related adverse events, or have inherently radioresistant tumors. However, caution is advised when considering the omission of radiation in the setting of high-risk features such as T4 and/or N2 disease, lateral lymph node involvement, EMVI, and encroached radial margins. Early predictors of radiation efficacy have yet to be identified; however, integrating genomic and transcriptomic data with clinical and radiographic information using artificial intelligence-based approaches may hold promise for improving treatment precision (4). The exploration and validation of versatile biomarkers of treatment response should a priority in ongoing and future clinical trials, as this will likely facilitate the personalization of rectal cancer therapies.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-219/prf

Funding: This work was supported by National Institutes of Health (NIH) Grant (No. T32CA009501-31A1, to A.B. and W.Z.; No. R37-CA248289-01, to J.J.S.), and Memorial Sloan Kettering Institutional Grant (No. P30CA008748, to J.J.S.). The sponsors did not play a role in the writing of this report.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-219/coif). J.J.S. received travel support for fellow education from Intuitive Surgical, and served as a clinical advisor for Guardant Health and Foundation Medicine, a consultant and speaker for Johnson and Johnson, and a clinical advisor and consultant for GlaskoSmithKline. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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