Watch and Wait Approach in LARC Patients Achieves Complete Response After TNT

In the Global Cancer Movement, hosted by OncoDaily, Amil Družić, oncology and radiotherapy resident at the Oncology Clinical Center, University of Sarajevo, explores the evolution of rectal cancer care. The virtual event, held from December 6-8, 2024, highlights the advancements that have reshaped cancer management, prioritizing organ preservation and improving patient outcomes.

Amil Družić introduces the session on the Global Cancer Movement, focusing on challenging the status quo in colorectal cancer. He mentions his role as an oncology and radiotherapy resident at the Oncology Clinical Center, University of Sarajevo, and his position as a sub-investigator for the International Watch and Wait Database Registry at his site. The discussion centers around organ preservation strategies in locally advanced and early rectal cancer, specifically exploring the watch-and-wait approach.

The presentation begins with a historical overview of rectal cancer management, highlighting key milestones. In 1908, William Ernest Miles introduced abdominal perineal resection, which, despite being a surgical breakthrough, left patients with permanent colostomies and reduced quality of life. In the 1940s, Dixon’s anterior resection allowed sphincter preservation in upper and middle rectal tumors. The 1970s and 1980s saw the introduction of low anterior resection and total mesorectal excision (TME) by Dr. Bill Held, which became the gold standard due to its significant reduction in local recurrence rates. From the 1990s to 2000s, multimodal treatment trials, such as the Swedish and German rectal cancer trials, demonstrated the benefits of preoperative chemotherapy in reducing recurrence and preserving sphincter function, with pathological complete responses achieved in 15-20% of patients.

In 2004, Dr. Angelita Heber-Gamal pioneered the watch-and-wait approach, which allowed patients who achieved a clinical complete response after chemotherapy to avoid surgery, improving their quality of life. The 2010s saw the introduction of total neoadjuvant therapy (TNT) to address micrometastatic disease earlier. Trials such as Polish II, RAPIDO, PRODIGE, and CAO-ARO-AIO established TNT as a standard for locally advanced rectal cancer, further improving clinical and pathological complete response rates and enabling organ preservation in selected patients. Between 2020 and 2024, the OPERA trial integrated TNT with the watch-and-wait approach, achieving improved organ preservation rates and confirming the safety and efficiency of this method.

Družić then explains the watch-and-wait approach in detail. It is a non-operative management strategy for patients who achieve a clinical complete response after neoadjuvant therapy, emphasizing organ preservation and quality of life. Unlike traditional surgical methods, this approach requires regular and close monitoring through digital rectal examinations, endoscopy, and advanced imaging techniques such as MRI to ensure early detection of tumor regrowth. The key advantage is the avoidance of surgery-related complications, such as permanent colostomy and functional impairments. However, the approach demands strict adherence to follow-up protocols, making patient compliance critical.

Not all patients qualify for the watch-and-wait strategy. Suitable candidates include those with locally advanced rectal cancer who have undergone neoadjuvant therapy and achieved a clinical complete response confirmed through a combination of diagnostic tools. These patients must also demonstrate strong commitment to follow-up care, with no evidence of distant metastases or extra-mesorectal disease. The approach is especially beneficial for low-rectal tumors, as rectal preservation significantly impacts the patient’s quality of life. Since the risk of tumor regrowth is highest within the first two years, intensive monitoring is required.

A complete clinical response, the foundation of organ-preserving strategies, is defined as the absence of detectable cancer following neoadjuvant therapy. Assessment relies on three key tools: digital rectal examination, endoscopy, and high-resolution MRI. The concept was first introduced by Dr. Angelita Heber-Gamal in 2004, showing that patients achieving a clinical complete response could safely avoid surgery. A normal mucosal appearance on endoscopy, the absence of residual tumor signals on MRI, and strict evaluation criteria are crucial to ensure accurate identification and prevent over-treatment or under-treatment.

Družić highlights the significance of the landmark 2004 study by Dr. Heber-Gamal, published in the Annals of Surgery, which revolutionized rectal cancer management. The study demonstrated that stage 0 rectal cancer patients who achieved a complete response after chemoradiation could be safely managed without surgery, showing no significant difference in survival compared to those who underwent surgery. It underscored the potential of non-operative management in preserving quality of life and minimizing the morbidity associated with rectal surgery. This study was among the 100 most cited works in surgery, reflecting its impact on the field.

MRI characteristics play a crucial role in assessing a complete clinical response. A complete radiologic response is indicated by the absence of residual tumor signals, with the rectal wall appearing normal or as a thin scar. Features such as low T2 signal intensity and the absence of diffusion restriction confirm the absence of viable tumor cells, distinguishing true response from post-treatment changes. High-resolution pelvic MRI with diffusion-weighted imaging is essential for accurate assessment.

Endoscopic evaluation is another key component in determining a complete response, providing direct visualization of the rectal mucosa. A flat, wide scar at the tumor site with no ulceration or nodularity is indicative of successful healing. Telangiectasia may be present due to the effects of radiotherapy. The combination of endoscopic findings with MRI and digital rectal examination ensures a comprehensive evaluation.

The watch-and-wait surveillance protocol, based on the International Watch and Wait Database guidelines, involves intensive follow-up, particularly in the first two years when the risk of recurrence is highest. Digital rectal examinations are performed every three months, with regular endoscopy and pelvic MRI, and CT scans every six months to monitor for distant metastases. Follow-ups gradually decrease to annual intervals after five years.

Družić also references the latest NCCN guidelines, which endorse the watch-and-wait approach for patients achieving a complete or near-complete clinical response after neoadjuvant therapy. The guidelines emphasize the importance of organ preservation and quality of life while ensuring rigorous follow-up protocols for safety.

The session then transitions to a discussion of TNT trials, such as the Polish II, RAPIDO, PRODIGE, STELLAR, and ongoing trials like BEYOND. The Polish II trial compared short-course radiotherapy with consolidation chemoradiotherapy to long-course chemoradiation, showing benefits in overall survival and lower toxicity, despite no significant difference in resection rates.

The RAPIDO trial, a phase III study, aimed to address the high risk of distant metastasis by comparing short-course radiotherapy followed by total neoadjuvant therapy to standard long-course chemoradiation. The experimental arm demonstrated improved disease-related failure rates and higher pathological complete response rates.

The PRODIGE-23 trial examined the integration of FOLFIRINOX chemotherapy with TNT, demonstrating superior pathological complete response rates and improved three-year disease-free survival compared to conventional approaches. Comparisons between RAPIDO and PRODIGE-23 highlighted differences in local regional failure rates, with PRODIGE-23 showing better pelvic control due to its prolonged targeted approach.

The session then discusses the CAO-ARO-AIO-12 trial, a multicenter randomized phase II study conducted across 18 centers in Germany, which aimed to further refine TNT strategies and optimize treatment outcomes for locally advanced rectal cancer.

In the consolidation chemotherapy group, the treatment protocol consisted of chemoradiotherapy followed by three cycles of FOLFIRINOX, culminating in total mesorectal excision. Key interventions included intensity-modulated radiotherapy at a dosage of 50.4 gray in 28 fractions, concurrent chemotherapy, and surgery scheduled 123 days after the initiation of treatment. While non-operative management for clinical complete response was not part of the protocol, 10 patients opted to refuse surgery and were managed accordingly.

The pathological response observed in this trial underscored the significant impact of treatment sequencing. In the consolidation chemotherapy group, where chemoradiotherapy was followed by consolidation chemotherapy, pathological complete response (pCR) was achieved in 25% of patients compared to 70% in the induction chemotherapy group.

These findings suggest that administering chemotherapy after chemoradiotherapy not only enhances local control but also contributes to an improved overall tumor response. The higher pCR rates in the consolidation group point to the synergistic effect of prolonged systemic chemotherapy exposure alongside the localized tumor-killing effects of radiation, which enables more thorough eradication of tumor cells.

Pathological complete response serves as a crucial endpoint in rectal cancer management, correlating with better survival outcomes and supporting non-operative management strategies for selected patients. The trial demonstrated comparable three-year disease-free survival rates of 73% in both groups, with no significant differences. Local regional recurrence rates were low at 6% for group A and 5% for group B, further reinforcing the efficacy of the total neoadjuvant therapy (TNT) approach in achieving robust local control.

Distant metastasis rates were slightly lower in group B (16%) compared to group A (18%), but the difference did not reach statistical significance. Similarly, overall survival rates at three years were high, with 92% in group A and 91% in group B, highlighting that both TNT strategies yield strong oncologic outcomes. However, the consolidation-first strategy may be particularly beneficial in maximizing response and facilitating watch-and-wait strategies for patients aiming to preserve their rectum and quality of life.

The OPRA trial, a pivotal study in organ preservation, was designed to evaluate the effectiveness of two distinct TNT sequences in patients with stage II-III rectal adenocarcinoma. The trial compared induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy followed by consolidation chemotherapy. Eligibility criteria included tumors located within 12 cm of the anal verge, no distant metastasis, and suitability for TNT and surgical resection. A total of 324 patients were randomized equally between the two arms.

The TNT sequences were assessed for their impact on disease-free survival and organ preservation. Following treatment, patients were restaged using digital rectal examination, endoscopy, and MRI. Those achieving clinical complete response were offered a watch-and-wait approach, while those with incomplete response underwent total mesorectal excision. The trial’s rigorous design incorporated a structured surveillance program to ensure close follow-up and early detection of tumor regrowth.

The OPRA trial introduced a three-tier clinical response assessment, categorizing patients into complete clinical response, near-complete response, and incomplete response based on post-treatment evaluations. Complete responders were managed with watch-and-wait, near-complete responders were evaluated for surveillance or surgical intervention, and incomplete responders were directed toward surgery.

Pathological response analysis revealed higher clinical complete response rates in the chemoradiotherapy followed by consolidation chemotherapy arm (53%) compared to the induction chemotherapy followed by chemoradiotherapy arm (51%). Tumor regrowth rates during watch-and-wait were 27% and 40%, respectively, favoring the chemoradiotherapy-first approach for better tumor control and organ preservation.

Long-term analysis showed that tumor regrowth predominantly occurred within the first two years, emphasizing the need for close surveillance. Distance-free survival rates remained similar between the groups, confirming the efficacy of salvage therapies in maintaining disease control.

A recent meta-analysis published in the Journal of the American Medical Association in 2024 provided robust evidence supporting different TNT strategies, with a focus on achieving pCR. Long-course chemoradiotherapy followed by consolidation chemotherapy emerged as the most effective regimen, with a relative risk of 1.96 and a number needed to treat of 7.5. This sequence demonstrated superior local control, a critical factor in organ preservation.

Additionally, the DOSTARLIMAB trial in mismatch repair-deficient rectal cancer brought groundbreaking results, achieving a 100% clinical complete response rate with no tumor evidence on imaging, endoscopy, or biopsy. This trial marks a paradigm shift in treatment, potentially eliminating the need for surgery and reducing morbidity.

The OPERA trial, published in The Lancet Gastroenterology and Hepatology, further provided insights into organ preservation strategies for early-stage rectal cancer. It compared external beam radiotherapy boosts versus contact x-ray brachytherapy (Papillon therapy), with the latter achieving higher organ preservation rates (81% vs. 59%). The five-year update confirmed the long-term benefits of contact x-ray brachytherapy, especially for tumors under three centimeters, with preservation rates reaching 93%.

Future directions include trials evaluating the efficacy of N-FOLFIRINOX against standard regimens and exploring circulating tumor DNA kinetics to refine treatment approaches. Additionally, the International Watch-and-Wait Database, established in 2014, continues to provide valuable data supporting the safety and efficacy of non-operative management in rectal cancer.

Recent updates from the NCI have highlighted ongoing efforts to optimize TNT strategies and personalize treatment based on molecular profiling. Emerging biomarkers such as ctDNA and tumor microenvironment analysis hold promise in guiding treatment decisions and improving patient outcomes.