Assessing the UNICANCER-PRODIGE 23 trial through the lens of nonoperative management

Introduction

The incidence of rectal cancer in the United States has continued to climb, with notable acceleration among younger patients (20–49 years) (1). Previously, the standard management for patients with locally advanced rectal cancer (LARC) was neoadjuvant chemoradiation, total mesorectal excision (TME), and adjuvant chemotherapy as indicated (2). More recent treatment strategies favor adding preoperative chemotherapy as part of a total neoadjuvant therapy (TNT) approach (3). While chemoradiation offers excellent local control (4,5), neoadjuvant chemotherapy acts on the tumor with intact vasculature, intervenes early on micrometastases, and improves chemotherapy compliance (6,7). However, few phase III studies of TNT have demonstrated a clear survival benefit. As such, the UNICANCER-PRODIGE 23 trial aimed to assess the effects of FOLFIRINOX-based TNT on oncologic outcomes (8,9).

Since the publication of UNICANCER-PRODIGE 23, LARC treatment has evolved to include selective nonoperative management (2). In this approach, after completion of TNT, patients with no residual tumor on exam, endoscopy, or imaging are designated as having a clinical complete response (cCR). These patients may be managed by a “watch-and-wait” (WW) strategy, undergoing active surveillance rather than surgical management (10). This commentary aims to summarize the findings of the UNICANCER-PRODIGE 23 trial and describe the implications of these results in the context of nonoperative management.

Methods

The UNICANCER-PRODIGE 23 trial (NCT01804790) was a multicenter, open-label, phase III randomized control trial conducted across 35 French healthcare centers. Patients aged 18–75 years with a diagnosis of cT3 or cT4 LARC were eligible. Patients were required to have a WHO ECOG status of 0 or 1. Patients with distant metastatic or unresectable disease were excluded, as well as patients with prior pelvic radiation or chemotherapy. Patients with hematologic derangements, kidney dysfunction, ischemic cardiac disease, symptomatic inflammatory bowel disorders, and pre-existing peripheral neuropathy were also excluded. Patients were enrolled from 06/05/2012 to 06/26/2017. The 3-year data cut off was 01/14/2020.

Randomization was stratified by center, extent of tumor, and disease stage. The experimental arm received 6 cycles of neoadjuvant FOLFIRINOX and subsequent chemoradiation, while the standard arm received neoadjuvant chemoradiation alone. Chemoradiation was administered over 5 weeks in 25 fractions of 2 Gy with oral capecitabine and was planned 1–3 weeks after FOLFIRINOX for the experimental group. Surgery was planned 6–8 weeks after chemoradiation for both groups. Notably, this study mandated surgical management with TME without an option for WW. Finally, adjuvant chemotherapy was standardized and administered regardless of treatment response: the experimental arm received 6 cycles of FOLFOX or 3 months of twice-daily capecitabine, and the standard arm received 12 cycles of FOLFOX or 6 months of twice-daily capecitabine. This design ensured equivalent doses and approximately the same total duration of chemotherapy for each treatment group. Figure 1 shows a schematic of study design.

Figure 1 UNICANCER-PRODIGE 23 trial design. In this trial, patients were randomized to an experimental arm receiving neoadjuvant chemotherapy or a control arm receiving standard-of-care treatment. Randomization was stratified by center, extent of tumor, and disease stage to mitigate selection bias. This schematic depicts the study design including the approximate timelines and treatments administered in each arm of the trial. ECOG, Eastern Cooperative Oncology Group; FOLFIRINOX, triplet regimen of fluorouracil, leucovorin, oxaliplatin, and irinotecan; LARC, locally advanced rectal cancer; mFOLFOX, modified FOLFOX; TME, total mesorectal excision.

The primary endpoint was 3-year disease-free survival (DFS) from the time of randomization to the first cancer-related event, secondary cancer, or death from any cause. It was hypothesized that 3-year DFS would improve with neoadjuvant FOLFIRINOX treatment compared to the standard-of-care. Important secondary endpoints included overall survival (OS), metastasis-free survival (MFS), locoregional and distant metastatic recurrence rates, and pathologic complete response (pCR) rate. These outcomes were hypothesized to be improved or preserved in the neoadjuvant FOLFIRINOX group. Finally, data on adverse events, surgical morbidity, and quality-of-life were also collected. Similar endpoints were examined at 5- and 7-year follow-up. Data cutoff for 7-year analysis was 01/09/2023.

Results

The UNICANCER-PRODIGE 23 trial enrolled a total of 461 patients, 231 in the neoadjuvant arm and 230 in the standard arm. Median age was 61 years in the neoadjuvant arm and 62 years in the standard arm. Individuals over 65 years accounted for 32% of patients in the neoadjuvant group and 37% in the standard group. Most patients were cT3 or cT4 (97%, 445/461), and 90% (415/461) had clinical lymph node involvement. These characteristics were well-matched between the two treatment arms. Median follow-up was 46.5 months (47.7 months in the neoadjuvant group and 45.7 months in the standard group).

Three-year DFS was 76% for the neoadjuvant FOLFIRINOX arm and 69% for the standard treatment arm (P=0.03). In both groups, the most common DFS event was distant metastasis. Three-year MFS was 79% in the neoadjuvant group and 72% in the standard group (P=0.02). Locoregional recurrence was 4% (10/231) in the neoadjuvant group and 6% (13/230) in the standard group (P=0.56). Finally, 3-year OS was 91% in the neoadjuvant arm and 88% in the standard arm (P=0.08).

Within the neoadjuvant group, 90% (207/231) of patients completed 6 cycles of FOLFIRINOX. Subsequently, 95% (219/231) of patients in the neoadjuvant group and 99% (227/230) in the standard group completed chemoradiation (P=0.02). The rate of surgery was 92% (213/231) in the neoadjuvant group and 95% (218/230) in the standard group. The R0 resection rate was 95% (201/211) in the neoadjuvant group and 94% (202/214) in the standard group (P=0.63). There were no significant differences in post-operative morbidity (P=0.66), serious adverse events (P=0.11), or 30-day post-operative mortality (P=0.06) between groups. Importantly, there were significantly fewer grade 4 and 5 post-operative complications in the neoadjuvant group (1%) compared with the standard group (5%, P=0.04), and 60-day post-operative mortality was significantly lower in the neoadjuvant group (0%) compared with the standard group (3%, P=0.03). Finally, the rate of pCR was 28% (59/212) for the neoadjuvant group and 12% (26/215) for the standard group (P<0.001). Two patients refused surgery after neoadjuvant therapy and continued to be in remission at 59.5 and 62.1 months of follow-up, respectively.

Adjuvant chemotherapy was completed by 77% of patients (160/207) in the neoadjuvant arm and 79% of patients (158/201) in the standard arm (P=0.75). The most common reasons for omission of adjuvant therapy were investigator decision and post-operative complications, without significant differences between groups (P=0.57). Serious adverse events occurred in 11% of the neoadjuvant group and 23% of the standard group (P=0.005). Though treatment arms were designed to receive an equivalent dose of chemotherapy, the neoadjuvant group received a greater cumulative dose of oxaliplatin due to the higher rate of adverse events in the standard group (P=0.009).

At 5-year follow-up, DFS was 73% for the neoadjuvant group and 66% for the standard group (P=0.03), with a survival difference of 4.3 months. At 7-year follow-up, DFS was 68% for the neoadjuvant group and 63% (P=0.048) for the standard group, with a survival difference of 5.7 months. Five-year MFS was 82% in the neoadjuvant group and 74% in the standard group. Seven-year MFS was 79% in the neoadjuvant group and 72% in the standard group (P=0.02), with a survival difference of 6.1 months. Conversely, the rate of local recurrence at 7 years remained low at 5% in the neoadjuvant group and 8% in the standard group. Finally, 5-year OS was 87% in the neoadjuvant group and 80% in the standard group (P=0.03), with a survival difference of 2.8 months. At 7 years, OS was 82% in the neoadjuvant group and 76% in the standard group (P=0.03), with a survival difference of 4.4 months. Table 1 summarizes oncologic outcomes by timepoint.

Lastly, the UNICANCER-PRODIGE 23 trial demonstrated benefits in quality-of-life for patients in the neoadjuvant arm. Encouragingly, 86% of patients in both groups had sphincter-preserving surgery, and 85.5% in both groups were stoma-free at seven years. However, the neoadjuvant group showed significant improvement in tumor-related functional scores and symptoms during FOLFIRINOX chemotherapy (such as pain, bleeding, incontinence, embarrassment, and anxiety) (11).

Discussion

Demonstrating improved oncologic outcomes with the evolution of rectal cancer therapies is essential to changing clinical practice. For example, the Swedish Rectal Cancer Trial published in 2005 demonstrated a survival benefit with preoperative radiation, providing evidence to shift radiotherapy to the neoadjuvant setting (12). Similarly, the German CAO/ARO/AIO-04 study published in 2015 demonstrated improved DFS with the addition of oxaliplatin to neoadjuvant chemoradiation (13). In contrast, the 2016 Polish II study which initially demonstrated an OS benefit for short-course radiotherapy with FOLFOX over long-course radiotherapy alone recently reported that survival benefits were not durable on long-term follow-up (14). In this context, the UNICANCER-PRODIGE 23 trial was one of the first phase III trials to demonstrate that TNT with neoadjuvant FOLFIRINOX led to a significantly improved DFS at three, five, and seven years when compared to standard-of-care therapy (8). Further, outcomes such as OS and MFS were also significantly improved in the neoadjuvant arm (9). Local recurrence rates remained low in both groups, suggesting that the addition of neoadjuvant chemotherapy did not compromise locoregional control. Treatment toxicity, post-operative morbidity and mortality, and quality-of-life were also improved in the neoadjuvant group. Thus, the UNICANCER-PRODIGE 23 trial demonstrated that TNT with neoadjuvant FOLFIRINOX was safe with durable improvements in oncologic outcomes for LARC patients who underwent surgery. It is important to note that because nearly all patients in the trial had surgical resection (with an R0 rate of over 94%) and standardized adjuvant chemotherapy, these results and conclusions cannot be directly compared to those of trials centered around nonoperative management. Rather, the UNICANCER-PRODIGE 23 study can inform the interpretation of subsequent trials and influence the design of the next generation of rectal cancer clinical trials focused on nonoperative management.

One such trial was the Organ Preservation in Patients with Rectal Adenocarcinoma (OPRA) trial (NCT02008656) which studied the impact of TNT when used with a selective WW approach (15). Two different TNT regimens were investigated: one arm received induction FOLFOX followed by chemoradiation, while the other arm underwent chemoradiation followed by consolidation FOLFOX. Patients with a cCR were managed with WW surveillance. Patients with a near complete response (nCR) were observed for an additional 8 weeks before re-assessing tumor response. Finally, patients with an incomplete response (iCR) or failure to evolve from an nCR to cCR underwent TME. Important endpoints in OPRA included DFS, organ preservation rate (defined as TME-free survival), and tumor regrowth rate. Three-year DFS in OPRA was 76% across both treatment arms, which was comparable to the three-year DFS of the neoadjuvant arm in the UNICANCER-PRODIGE 23 trial (77%). Demonstrating that survival outcomes were not substantially compromised (even with the selective omission of surgery) strengthened the argument for safe nonoperative management in OPRA and supported the paradigm shift toward selective WW.

Importantly, patients in OPRA who underwent TNT and had an incomplete response or had a cCR followed by regrowth were managed with TME. Three-year DFS did not differ significantly between patients who underwent immediate TME after TNT (75%) versus salvage TME after regrowth (72%, P=0.40) (15). Again, this was comparable to the three-year DFS seen in UNICANCER-PRODIGE 23 (77%). Thus, the benefits of TNT followed by surgery seen in UNICANCER-PRODIGE 23 were relevant to high-risk patients, even within a clinical trial that integrated nonoperative management. Building on this finding, the OPRA trial demonstrated that delayed TME after regrowth did not negatively affect DFS, giving patients an opportunity to pursue nonoperative management with the option of safe salvage surgery.

The UNICANCER-PRODIGE 23 trial showed a significant improvement in pCR rates in the neoadjuvant FOLFIRINOX arm (28%) compared with the standard arm (12%, P<0.0001) (8). The neoadjuvant group also had increased tumor regression with fewer metastatic regional lymph nodes. Further, two patients who refused surgery after TNT demonstrated continued complete clinical remission at last follow-up. The utilization of FOLFIRINOX (a triplet regimen) in the experimental arm clearly played a role in improved tumor response, as prior studies using doublet regimens have failed to demonstrate increased pCR rates (16).

It should be noted that the complete response rate (specifically pCR) seen in UNICANCER-PRODIGE 23 is lower than the rates of complete response (specifically cCR) seen in contemporary trials (3,15). Prior work has demonstrated that increased time from the end of neoadjuvant chemoradiation (combined with cycles of FOLFOX) to surgery was directly correlated with increasing pCR rates without compromising oncologic or surgical outcomes (17). Along similar lines, the OPRA trial granted patients with a near complete tumor response an additional eight weeks after restaging for maximal tumor response evolution, resulting in higher rates of patients eligible for WW surveillance (74%) and achieving organ preservation at 3 years (47%). In contrast, in UNICANCER-PRODIGE 23, patients went directly to surgery, which did not allow additional time for tumor response and could explain the discrepancy between response rates. Importantly, clinical tumor response prior to tumor resection was not evaluated in the UNICANCER-PRODIGE 23 trial at all, representing a missed opportunity to determine the correlation of clinical tumor response to pathologic tumor response after neoadjuvant FOLFIRINOX, to identify near complete and complete responders, or to provide additional time for tumor response evolution in a subset of patients to further improve response rates.

Another explanation for the discrepancy between pCR and cCR rates is the difficulty in ascertaining a cCR consistently and accurately with the available diagnostic modalities (18). It is well known that digital rectal exam alone grossly underestimates pCR rates, and even in the OPRA trial when investigators thought there was persistent tumor, the final pathology demonstrated a pCR in approximately 8–9% of cases (15). Because restaging after TNT is a cornerstone of the nonoperative approach, tools such as the Memorial Sloan Kettering Tumor Regression Schema have been employed to standardize the assessment of tumor response (10), highlighting another important opportunity for the improvement of future clinical trials.

A unique strength of the UNICANCER-PRODIGE 23 study was its approach to adjuvant chemotherapy. While most contemporary studies administered adjuvant chemotherapy at institutional discretion, the UNICANCER-PRODIGE 23 trial required adjuvant therapy for each treatment arm. This standardized regimen of systemic therapy employed after surgical resection may have contributed to the improved survival outcomes seen in this trial. However, a related limitation of the UNICANCER-PRODGE 23 study is the potential overtreatment of lower-risk patients, as there are conflicting conclusions regarding which patients may benefit most from adjuvant chemotherapy (19). Further, this standardization may limit the applicability of UNICANCER-PRODIGE 23 to future trials as adjuvant chemotherapy and its benefits may be rendered moot in the context of TNT with selective nonoperative management.

In summary, demonstrating improved oncologic outcomes and pCR rates in UNICANCER-PRODIGE 23 helped to solidify the safety and efficacy of TNT in the context of operative management, setting the stage for the next generation of rectal cancer clinical trials. Taken together, the findings of UNCANCER-PRODIGE 23 and OPRA are now being actively integrated into the design of ongoing rectal cancer trials with a focus on nonoperative management (20,21).

Future directions

The UNICANCER-PRODIGE 23 trial importantly utilized FOLFIRINOX in its experimental arm with improvements in pCR rates, prompting further study of FOLFIRINOX as a neoadjuvant agent. For example, the NORAD01-GRECCAR16 trial (NCT03875781) is a multicenter, randomized phase III trial investigating the effects of neoadjuvant FOLFIRINOX without preoperative chemoradiation. Patients with cT3N0 or cT1-3N+ tumors were eligible for this study. Designed as a noninferiority study, the experimental arm will be treated with modified FOLFIRINOX alone and compared to the control arm receiving chemoradiation (with capecitabine) (20). Subsequently, both arms will undergo surgery. The primary endpoint is 3-year progression-free survival (PFS), with the hypothesis that neoadjuvant modified FOLFIRINOX will be non-inferior to chemoradiation. Interestingly, pathologic treatment response will be evaluated in both arms after completing neoadjuvant treatment and before surgery. However, the collection of data on clinical tumor response is unaddressed, and it appears that all patients will undergo surgical resection in 6–8 weeks regardless of pathologic findings. While the further evaluation of FOLFIRINOX as a neoadjuvant therapy is promising, a contemporary rectal cancer trial without the option for WW surveillance may have limited applications in the shifting treatment paradigm of rectal cancer and preclude patients from the benefits of organ preservation.

In contrast, based on the findings of the UNICANCER-PRODIGE 23 and OPRA trials, the currently recruiting Janus Rectal Cancer Trial seeks to further characterize the effects of chemotherapy intensification with FOLFIRINOX in the nonoperative setting by measuring its effects on tumor response rates (22). The Janus Rectal Cancer Trial (NCT05610163) was originally designed as a randomized phase II study comparing neoadjuvant triplet chemotherapy to neoadjuvant doublet chemotherapy after long-course chemoradiation. The primary endpoint for the phase II trial is cCR, hypothesizing that modified FOLFIRINOX will show a higher cCR rate than FOLFOX. Patients will be restaged 8–12 weeks after treatment completion and enter WW or undergo surgery based upon clinical tumor response. Secondary outcomes for the phase II trial include OS, organ preservation time, and treatment toxicity. The trial was recently approved to advance to a seamless phase II/III design (460 of 760 patients enrolled as of 9/30/2024). Three-year DFS is the primary endpoint for the phase III trial, hypothesizing that triplet versus doublet chemotherapy after long-course chemoradiation will improve DFS (22). Similar trials to support the triplet chemotherapy approach are ongoing. For example, the ENSEMBLE trial is evaluating the superiority of triplet chemotherapy over doublet chemotherapy followed by short-course radiation therapy in the setting of nonoperative management (23).

In conclusion, the UNICANCER-PRODIGE 23 trial newly demonstrated that TNT with FOLFIRINOX improved oncologic outcomes such as DFS, MFS, and OS and increased the rates of pCR without increasing treatment toxicity, operative risk, or local treatment failure. Integrating these findings into the current landscape of nonoperative management for rectal cancer treatment can inform the design of current and future trials investigating neoadjuvant chemotherapy intensification and TNT with selective WW surveillance.

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-24-218/prf

Funding: This work was supported by Memorial Sloan Kettering Institutional Grant (No. P30CA008748, to J.J.S.); National Institutes of Health (NIH) Training Grant (No. T32CA009501-31A1, to W.Z. and A.B.); NIH Grant (No. R37CA248289, to J.J.S.); Wasserman Colorectal Research Fund; and Department of Surgery and Colorectal Service at MSK. The funders had no role in the writing, review, or final revision of this work.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-218/coif). W.Z. and A.B. report funding support from NIH Training Grant (No. T32CA009501-31A1). J.J.S. reports funding support from Memorial Sloan Kettering Institutional Grant (No. P30CA008748) and National Institutes of Health (NIH) Grant (No. R37CA248289); travel support for fellow education from Intuitive Surgical; and has 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 GlaxoSmithKline. The authors have no other 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.

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