Rethinking Rectal Cancer End Points: pCR Not a Survival Surrogate

A comprehensive systematic review and meta-analysis, encompassing 25 randomized clinical trials and nearly 12,000 patients, has found no trial-level association between pathologic complete response (pCR) and long-term survival outcomes—specifically overall survival (OS) and disease-free survival (DFS)—in rectal cancer.¹

“Our study’s findings suggest a recommendation against using pCR as a [surrogate end point] for neoadjuvant therapies in rectal cancer until conclusive trial-level evidence of its association with long-term outcomes is firmly established,” authors wrote in the study published in JAMA Network.

This significant finding challenges the increasing reliance on pCR as a surrogate end point in clinical trials for neoadjuvant therapies in this disease setting. The study suggests that while pCR remains an important indicator of response to neoadjuvant treatment, its use as a primary surrogate for survival should be reevaluated.

The Growing Role of Surrogate End Points in Oncology

Clinical trial design often leverages surrogate end points to accelerate drug development and approval processes, particularly in oncology where measuring OS can be time-consuming and costly.² pCR, defined as the absence of viable tumor in the resected specimen following neoadjuvant therapy, has emerged as a widely adopted surrogate end point. The US FDA has supported its use for accelerated approval in certain contexts, including breast cancer. However, the validity of pCR as a reliable surrogate for long-term survival benefits at the trial level has been a subject of ongoing debate across various cancer types.

While patient-level analyses have often shown an association between pCR and improved survival in rectal cancer, this new meta-analysis specifically investigated the trial-level association. This distinction is crucial because a strong patient-level correlation does not always translate to a trial-level association, a paradox that has previously raised concerns in the medical community regarding the broad adoption of pCR as a surrogate marker.

Key Findings: No Trial-Level Correlation

The meta-analysis, which screened studies from PubMed, EMBASE, and Cochrane databases up to January 3, 2024, included randomized clinical trials evaluating various neoadjuvant therapies in patients with rectal cancer who underwent subsequent surgical resection.¹ The primary objective was to assess the correlation between pCR rates and both OS and DFS at the trial level.

Of the 3363 records identified, 25 randomized clinical trials with a total of 11,882 patients met the stringent inclusion criteria. The researchers performed weighted linear regression to assess the correlation. The results were unequivocal and showed on meta-regression analysis, pCR was not correlated with OS (β = 0.37; 95% CI, −0.98 to 1.71; P =.57). Similarly, pCR was not correlated with DFS (β = −0.84; 95% CI, −2.55 to 0.87; P =.32).

These findings remained consistent even after sensitivity analyses that excluded studies with a high risk of bias or those contributing significantly to heterogeneity. Subgroup analyses, including those excluding studies with only neoadjuvant radiation therapy or those where patients did not undergo curative resection in survival analyses, also yielded similar null results.

Implications for Clinical Trial Design and Regulatory Approval

The absence of a trial-level association between pCR and long-term survival in rectal cancer has significant implications for future clinical trial design and regulatory considerations. Relying solely on pCR as a primary surrogate end point could potentially lead to the approval of treatments that do not ultimately confer a true survival benefit, or conversely, the premature abandonment of therapies that may have long-term efficacy.

Previous meta-analyses focusing on rectal cancer had primarily explored patient-level associations, often concluding that pCR was linked to improved OS. However, this study's robust methodology, including the use of relative differences in odds ratios for pCR and hazard ratios for survival curves, provides a more accurate reflection of how survival end points are reported in clinical trials and strengthens the argument against pCR as a reliable trial-level surrogate. The authors also highlight that their meta-analysis nearly doubled the number of trials included in a previous meta-analysis that similarly questioned pCR's surrogacy, reinforcing their conclusions.

Why the Discrepancy?

The study authors explore several reasons why pCR may not translate to a trial-level survival benefit. Pathologic complete response assesses the effect of therapy on the primary tumor but may not fully capture the impact on micrometastatic disease, which can still lead to distant recurrence and impact survival. Furthermore, effective neoadjuvant therapies might improve long-term outcomes without necessarily achieving a complete pathologic response. The influence of subsequent adjuvant therapies, often given to patients who do not achieve pCR, could also dilute the association between pCR and survival outcomes.

Future Directions and Open Questions

The current paradigm for treating locally advanced rectal cancer increasingly favors total neoadjuvant therapy (TNT). While this meta-analysis included some TNT therapy trials (eg, PRODIGE 23 [NCT01518349], RAPIDO [NCT01558921]), the limited number of such studies prevented a dedicated subgroup analysis of TNT regimens. Further research is warranted to understand the utility of pCR in the context of TNT, particularly as these regimens have shown improvements in DFS in some trials.

For patients undergoing a "watch and wait" approach, where organ preservation is a goal, pCR remains a crucial marker for determining the feasibility of nonoperative management. However, in these scenarios, other surrogate end points like complete clinical response or circulating tumor DNA minimal residual disease might become more relevant for predicting long-term outcomes.

This study underscores the critical need for continued vigilance in validating surrogate end points. While surrogate end points offer an expedited path for drug development, their true value hinges on their consistent and reliable correlation with definitive long-term clinical benefits. Moving forward, oncology clinical trials for rectal cancer should consider definitive survival endpoints as the gold standard or rigorously validate any proposed surrogates at both patient and trial levels before broad adoption for regulatory approval.

REFERENCES:

1. Sugumar K, Lie JJ, Stucky CC, et al. Pathologic Complete Response and Survival in Rectal Cancer: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2025 Jul 1;8(7):e2521197. doi: 10.1001/jamanetworkopen.2025.21197.

2. Pavic M, Wolfer A, Li Q, et al. Regulatory Challenges: Is a Surrogate End Point Instead of Overall Survival Enough for Regulatory Approval of (Neo)Adjuvant Cancer Treatment? The Swissmedic Perspective. J Clin Oncol. 2023 Nov 10;41(32):4973-4975. doi: 10.1200/JCO.23.01442. Epub 2023 Sep 21.