Evolving paradigms in locally advanced rectal cancer: the means justify the ends

The methodical study of locally advanced rectal cancer over 5 decades has culminated in improvements in therapeutic options and patient outcomes (1). In the 1980s and 1990s in the United States, the studies of rectal cancer in the era predating total mesorectal excision (TME) employed a surgery-first approach that necessitated the use of adjuvant combined-modality therapy because of high risks of both local and distant recurrences (2). These early studies provided vital knowledge about the roles of chemotherapy and radiation therapy (RT) in the adjuvant setting for T3/T4 and/or node-positive rectal cancer; they also established chemoradiation as a standard of care in improving systemic disease control and local control postoperatively (3-7). In Europe, another contemporaneous therapeutic option consisted of preoperative short-course RT (5 Gy × 5 fractions) that enhanced overall survival rates without systemic therapy (8,9), suggesting the importance of a preoperative approach in the control of rectal cancer. In the mid-2000s, the German CAO/ARO/AIO-94 Rectal Cancer study compared preoperative with postoperative chemoradiation with total mesorectal excision and established preoperative therapy as a standard of care for locally advanced rectal cancer by reducing local recurrence rates and improving the toxicity profile compared to postoperative chemoradiation (10). Notably, the rates of sphincter preservation by tumor downstaging increased with preoperative chemoradiation therapy and highlighted the potential role of neoadjuvant therapy (10). Although preoperative chemoradiation became the standard of care, the development of new, effective systemic therapies in this era allowed the delivery of postoperative chemotherapy—namely, leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX) (11). In the postoperative setting, chemotherapeutic delays during recuperation from surgery or other logistical delays resulted in lower survival rates (12). Therefore, the addition of chemotherapy to the preoperative setting along with chemoradiation provided a logical approach to the management of locally advanced rectal cancer. Several early studies evaluated the sequencing of chemoradiation, with chemotherapy in the preoperative setting, known as total neoadjuvant therapy, addressing the feasibility of this approach and the further refinement of downstaging (11,13). Habr-Gama et al. (14) also demonstrated that a subset of patients with complete responses (CRs) to chemoradiation could forgo surgery safely. This nonsurgical approach allowed for close monitoring with salvage rectal surgery in the event of an intraluminal local recurrence. With the potential for nonoperative management and intensified preoperative therapy, this approach ushered in a series of trials that evaluated total neoadjuvant therapy approaches, studying chemotherapy intensity along with short-course RT and long course chemoradiation (11,15,16). The continued optimization of total neoadjuvant therapy (TNT) to increase response rates and, in turn, rates of nonoperative management is an area of ongoing development. An additional landmark event in the treatment of rectal cancer was the presentation of the PROSPECT (Preoperative Radiation Or Selective Preoperative Radiation and Evaluation before Chemotherapy and TME) study at the 2023 American Society of Clinical Oncology annual meeting. This massive effort, involving an 1194-patient noninferiority study, demonstrated that patients treated with neoadjuvant chemotherapy for a planned sphincter-sparing surgery and responding with shrinkage of at least 20% do not need radiation to achieve equivalent disease-free survival (DFS) and overall survival (17). This approach may benefit those who are seeking fertility preservation with early-stage tumors (T2 node-positive disease, T3 node-negative disease, or T3 node-positive disease, with ≤3 lymph nodes measuring <10 mm and a negative circumferential radial margin on initial imaging). In the era of TNT, where there is an opportunity for nonoperative management, TNT may be effective for this group of patients who have low-volume disease (18) and may be favored during shared decision making. In this issue of the Journal, we find 2 additional important works by Pesantez et al. (19) and Kennecke et al (20). Pesantez et al. evaluates the addition of aflibercept in the TNT setting for rectal cancer. Kennecke et al. presents a consensus review of clinical trial design in rectal cancer from an expert panel convened by the National Cancer Institute Rectal-Anal Task Force. Pesantez et al. (19) present Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD)-1402, a phase 2 randomized trial of total neoadjuvant therapy with or without aflibercept, an antiangiogenic agent, in rectal cancer with 3-year results. This collaborative effort from Spain found that the addition of aflibercept to upfront modified FOLFOX improved pathologic CR to 22.6% compared with FOLFOX alone (13.8%). Aflibercept, an anti–vascular endothelial growth factor decoy receptor agent, did not improve overall survival, DFS, local relapse, or distant metastases, however. Diagnostic biopsy specimens centrally assessed using immunohistochemistry-based consensus molecular subtypes can predict intrinsic chemosensitivity. Here, pathologic CR was achieved in 27.5% of consensus molecular subtypes 2/3 epithelial subtypes compared with none of the mesenchymal subtypes (consensus molecular subtype 4). Similarly, prior studies suggested that consensus molecular subtype 4 tumors are resistant to neoadjuvant therapy (21). This work suggests that a risk-stratification approach by molecular subtype may be a promising method for future study to individualize patient management. One of the earliest endpoints that can be evaluated in rectal cancer trials is pathologic CR, which is assessed at the time of surgery by the complete disappearance of tumor. The comparable correlate for nonoperative management is the evaluation of clinical CR, which is evaluated 4 to 12 weeks after completion of therapy. It is likely that clinical CR will be higher than pathologic CR because of the limitations of restaging by endoscopy with biopsies and radiographic assessment. In contrast, local recurrence or DFS evaluate long-term endpoints. Local recurrence refers to rectal, regional lymph node, or pelvic recurrences, which in modern series is often under 5%. DFS assesses both intrapelvic and extrapelvic disease progression after curative therapy. This study shows that the backbone of total neoadjuvant therapy can serve as the platform for adding novel agents to rectal cancer studies. Currently, the National Institutes of Health National Clinical Trials Network studies led by NRG Oncology and using the total neoadjuvant therapy platform, have reported on the use of pembrolizumab and veliparib in this context (22). Other approaches may add novel agents to chemoradiation, as well. In the National Cancer Institute consensus review by Kennecke et al. (20), the invited participants of US cooperative-group physicians answered 82 questions about RT and neoadjuvant therapy, patient perceptions and rectal cancer populations, and design elements studied using a Delphi analytical approach. Consensus was accomplished in determining that 1) the control arm for clinical trials of total neoadjuvant therapy should incorporate long-course chemoradiation with either induction or consolidation chemotherapy or short-course RT followed by chemotherapy; 2) the inclusion of patients with T3N0 disease in these studies, given the benefits of total neoadjuvant therapy and the limitations of assessing clinical lymph node positivity; 3) better risk stratification with the use of circulating tumor DNA, imaging, and genomic features was felt to be an area of continued need to tailor therapies well; and 4) continuing to support patient participation in clinical trials and integration of patient preferences in future studies. Separating patients with early-stage tumors, vulnerable populations, and young patients for their own studies was recommended, also. The group recommended novel endpoints, including 3-year sphincter preservation rate and 3-year ostomy-free survival, with secondary endpoints of R0 resection rates and clinical and pathologic CR for upcoming trials. Also, challenges with data management in the nonoperative management setting were discussed. This comprehensive work will help guide future phase 2 and 3 clinical trial design to advance the field through integration of novel therapeutics into an already-successful treatment strategy. In summary, important improvements in rectal cancer therapy accomplish improved cure rates for locally advanced rectal cancers by incorporating advancing surgical and radiation techniques as well as intensified neoadjuvant chemotherapies. Total neoadjuvant therapy provides an invaluable platform for drug development in rectal cancer. Owing to the stepwise study of this disease, future work will help individualize care based on novel molecular features, imaging, and biomarkers such as circulating tumor DNA. We look forward to future studies using a total neoadjuvant therapy backbone that will continue to build on the gains made in rectal cancer therapy and allow a solid platform to incorporate novel agents that can improve pathologic CR rates and overall survival. No new data were generated or analyzed for this editorial. Salma K. Jabbour, MD (Conceptualization; Writing—original draft; Writing—review & editing), Howard S. Hochster, MD (Conceptualization; Writing—original draft; Writing—review & editing). No funding was used for this editorial. Howard S. Hochster, a JNCI deputy editor, and Salma K. Jabbour, a JNCI associate editor, were not involved in the editorial review of the manuscript or decision to publish the editorial.