Great Debates: Surgery or Watch and Wait After Total Neoadjuvant Therapy for Rectal Cancer

Watch and Wait After Total Neoadjuvant Therapy for Rectal Cancer

The traditional management of locally advanced rectal cancer (LARC) consists of neoadjuvant chemoradiotherapy, total mesorectal excision (TME), and postoperative systemic chemotherapy. ¹ While this approach improves outcomes of patients with rectal cancer as compared to surgery alone, survivors of this regimen may continue to suffer from morbidity associated with the surgery, namely, permanent colostomy, body image distortion, and postoperative complications such as urinary and sexual dysfunction. ² Total Neoadjuvant Therapy (TNT)involves a full course of radiation and systemic chemotherapy prior to surgical resection as opposed to lower radiosensitizing chemotherapy doses that were used as neoadjuvant chemotherapy in past protocols.^3,4 It has been associated with higher rates of disease-free survival (DFS) (hazard ratio [HR] .69, 95% confidence interval [CI] .49-.097; P = .034) and pathologic complete response (pCR) (27.8% for TNT vs 12.1% for standard therapy), and lower rates of disease-related treatment failure (HR .75, 95% CI .60-.95; P = .019) and distant metastasis (HR .69, 95% CI .54-.90; P = .0048) than non-TNT regimens.^3,4 Increased survival is mostly attributable to the completion of the entire course of systemic chemotherapy prior to the potentially morbid surgery. Historical data has failed to show improved survival with surgery alone without chemotherapy or radiation.^5,6 Multiple studies have therefore investigated “watch and wait” (W&W) for patients who achieve a clinical complete response (cCR) or near-complete response after TNT vs a traditional approach of definitive surgical resection following TNT.

Habr-Gama et al ⁷ reported long-term results of 71 patients treated with a W&W strategy after neoadjuvant chemoradiotherapy resulting in a cCR. 5- and 10-year disease-free survival (DFS) was 92% and 86%, respectively, and overall survival (OS) was 100% after a mean follow-up period of 57.3 months. The OnCoRe project was a UK-based propensity-score matched cohort analysis of matched 109 patients monitored with W&W after achieving a cCR vs surgical resection who were followed up for a median of 33 months. ⁸ A P-value of less than .01 was used to indicate statistical significance. Results showed no difference in 3-year non-regrowth DFS (88% [95% CI 75-94] in W&W vs 78% [95% CI 63-87] in surgical resection; P = .043) or 3-year OS (96% [88-98] vs 87 [77-93]; P = .024) between the matched groups. ⁸ These results would have been significant if a P-value of <.05 was used as was the case in the other studies.

Several reviews support the W&W approach. Sammour et al ⁹ critically appraised 15 studies with a total of 575 patients treated with W&W after cCR and a mean follow-up of 39.4 months; DFS and OS were 82.7% and 91.7%, respectively. Another systematic review and meta-analysis of 23 studies with a total of 867 patients and a median follow-up of 12-68 months showed no significant difference between the W&W group and the surgery group in terms of DFS, OS, or cancer-specific mortality (HR of .56, 95% CI 0 20-1·60; HR 3.91, 95% CI .57-26.72; and RR .58, 95% CI .06-5.84, respectively). ¹⁰

The Organ Preservation in Rectal Adenocarcinoma (OPRA) trial, a prospective, randomized, nonblinded, multicenter, phase II clinical trial, included 324 patients who received TNT and had a different design compared to other studies and, therefore, different results. ¹¹ All patients received TNT; however, one group received induction chemotherapy followed by chemoradiotherapy and the other received chemoradiotherapy followed by consolidation chemotherapy. In all, 225 patients achieved a cCR or near-complete response and were offered W&W. The primary end point for the study was DFS, and the secondary end point was organ preservation or, in other words, survival without TME. The proportion of patients who preserved their rectum was 60% (95% CI, 52 to 68) in the consolidation group and 47% (95% CI, 39 to 56) in the induction group (P = .02). ¹¹ In summary, approximately half of the study population after 3 years required surgical intervention, or conversely, half of the patients were disease free and preserved their rectum at 3 years.

Finally, the International Watch and Wait database, a registry of patients from 60 centers across 15 countries with the largest number of patients treated with the W&W strategy, demonstrated similar outcomes. A registry report of 880 patients with a median follow-up of 3.3 years revealed a 5-year DFS of 94% and OS of 85%. ¹² A more recent report compared outcomes in patients with complete response at first reassessment to those with a complete response at a later reassessment (had a near-cCR at first reassessment). ¹³ The 5-year OS was 92.2% (CI 88.8 to 95.7) for patients with a cCR at first reassessment and 86.0% (79.8-92.7) % for those with a cCR at later reassessment (P = .497). The 5-year organ preservation rates were 72.0% (67.8-76.6) and 74.0% (69.2 to 79.2), respectively (P = .499). ¹³

Surgery After Total Neoadjuvant Therapy for Rectal Cancer

While there is growing interest in adopting W&W approach in patients who achieved cCR after TNT, surgery with TME remains the current standard of care. In the two decades since the landmark study by Habr-Gama et al, ⁷ there is no level I evidence to support the W&W approach. Evidence so far is largely limited to observational studies. There was only one RCT, the recently published OPRA trial. ¹¹ However, major drawbacks included short-term follow-up of 3 years, and that the trial was designed to compare patients assigned to different sequences of TNT (induction chemotherapy followed by neoadjuvant chemoradiotherapy, vs neoadjuvant chemoradiotherapy followed by consolidation chemotherapy), rather than W&W approach vs TME approach.

The evidence supporting the W&W approach is also marred by significant heterogeneity in data quality, mainly due to inadequate staging techniques or insufficient clinical data. A wide range of TNT strategies have been described in studies evaluating W&W approach, with variable time course and sequence of radiotherapy and different chemotherapy regimens. Considerable disparities exist in terms of methods of assessment to define cCR, and the rigor of subsequent follow-up, further adding to the problem of lack of standardization. A significant proportion of the cases included in retrospective studies are patients who refused surgery, even though surgery was not contraindicated. Studies are also skewed towards distal tumors. Patients with proximal tumors are excluded from some clinical trials due to difficulty of performing digital rectal examination (DRE), resulting in a lack of long-term outcome data especially in proximal tumor. The International Watch and Wait Database ¹² aims to provide the strongest available evidence; however, the database includes a heterogenous group of patients, stages, assessments, and monitoring protocols that may lead to inaccuracies of results.

The safety of W&W strategy therefore must be interpreted with caution, as observational studies and retrospective studies are prone to selection bias, information bias, and confounding factors.

Watch and Wait After Total Neoadjuvant Therapy for Rectal Cancer

Major concerns about the W&W approach are regional and distant recurrence. Habr-Gama et al ⁷ reported an overall regional recurrence of 7% in the W&W group and all were salvaged by either surgery or chemotherapy. The study did not report any cancer-related death in the W&W group. Additionally, there was no difference in recurrence and mortality rate, and DFS between the surgical vs W&W groups. Sammour et al’s ⁹ review revealed a pooled regrowth rate of 21.3% after more than 3 years of follow-up with salvage in >90% of patients and a lower colostomy rate in the W&W group even after salvage surgery than the resection group . The systematic review and meta-analysis by Dossa et al ¹⁰ similarly reported a 2-year regrowth rate of 15.7% with 95.4% undergoing salvage surgery, respectively. The OPRA trial showed similar DFS for patients who underwent TME after restaging following TNT, and for those who underwent TME after a period of W&W and developed regrowth. ¹¹

Those patients who developed regrowth and eventually needed surgery in the W&W group were able to preserve their rectum for a longer period of time than their counterparts who underwent early surgery. And in those patients who did develop regional recurrence, salvage surgery was possible in over 90% of cases. ¹¹ The OnCoRe project showed a 3-year colostomy-free survival of 74% in the W&W vs 47% in the TME group (P < .0001). ⁸ The true benefit to organ preservation, even if temporary, is that it can prevent or delay the morbidity of definitive surgical resection without negative influence on cancer-related recurrence or death.

The major concern in watchful waiting after cCR is patient adherence to follow-up. The current national recommendations are for history, physical exam, and CEA every 3-6 months for 2 years and then every 6 months for a total of 5 years. ¹⁴ Computerized tomography of the chest, abdomen, and pelvis is also needed every 6-12 months for 5 years, in addition to a colonoscopy 1 year after surgery. ¹⁴ As with many clinical considerations, patient selection is critical for appropriate adherence to watchful waiting. In fact, a parallel can be drawn between the time and diligence spent in the preoperative evaluation in consideration for TME with the appropriateness of candidate selection in W&W.

Surgery After Total Neoadjuvant Therapy for Rectal Cancer

The most feared complication of watchful waiting is local regrowth, and possible progression to lymph node spread and metastatic disease. Local regrowth is the reappearance of primary tumors within the rectal wall, the mesorectum, or within the pelvic compartment after achieving cCR. Risk of local regrowth varies widely from different studies from 2.8% to 30.4%, and rate of salvage surgery varies significantly as well (80%-100%).^10,15 This wide range of figures and significant inconsistencies undermine the evidence supporting the W&W approach and underscore the inherent uncertainties in patient selection and surveillance protocols.

In patients who develop tumor regrowth, the majority are amenable to salvage surgery. However, salvage surgery is riskier and more challenging, possibly due to the side effect of pelvic fibrosis after radiation. As such, salvage surgery has lower rates of sphincter-preservation than patients proceeding straight to TME, with a significant proportion of patients requiring abdominal perineal resection.^16,17 Furthermore, some studies report 5-year survivals of 63.3% in patients who undergo salvage surgery, substantially lower than the 85%-92.9% reported in upfront surgery. ¹⁸

Another major concern of the W&W approach is the lack of international consensus on follow-up protocols and patient adherence to follow-up. Considering the risk of local regrowth is higher within the first 3 years after achieving cCR, recommended surveillance is more intense during the first 3 years of follow-up. Most research centers adopt follow-up protocols consisting of frequent digital rectal examination (DRE), endoscopy, and MRI every 8-12 weeks during the first 3 years; however, there is a lack of consensus of a safe follow-up protocol. Furthermore, in real-world clinical settings outside of specialized research centers, it is impractical to expect patients to adhere to such cumbersome and costly follow-up. Insurance approval and other logistic problems may delay MRI and endoscopy, potentially resulting in delay in detection of tumor regrowth.

Additionally, surveillance strategies may not detect all cases of tumor regrowth, as DRE, endoscopy, and MRI have inherent limitations. Endoscopic signs of rectal tumor remission—defined as complete elimination of rectal tumor and replacement with a flat, regular, whitish scar—are not always present in patients with pathological complete response (pCR), occurring only in 25%-75% of cases. ¹⁵ Similarly, certain mucosal abnormalities (eg, flat, regular ulcerations) are common in patients with complete remission. ¹⁹ In a pooled analysis, cCR was associated with pCR in only 30% of patients. ²⁰ According to a meta-analysis on MRI in detecting complete response, MRI has a pooled accuracy of 75%, sensitivity and specificity of 95% and 31%, respectively, and positive predictive value of 83% and negative predictive value of 47%. These findings suggest that MRI may be more useful to rule out complete response rather than to confirm it. ²¹ Even in clinical trial settings, only 71%-94% of patients received MRI on follow-up. ²² In real-world scenarios, significantly fewer patients could realistically afford and tolerate frequent MRI in follow-up.

Watch and Wait After Total Neoadjuvant Therapy for Rectal Cancer

The data in support of watch and wait after total neoadjuvant therapy in those with clinical complete response shows no difference in disease-free survival, regional recurrence, distant recurrence, or disease-related mortality. Moreover, patients who undergo W&W with organ preservation are not subject to the morbidity associated with definitive surgical resection. Importantly, patient selection and adherence to surveillance protocols should be heavily considered when electing to proceed with W&W.

Surgery After Total Neoadjuvant Therapy for Rectal Cancer

The adoption of the W&W approach in rectal cancer management represents a paradigm shift with significant implications for patient care. While the W&W approach is an attractive alternative to radical surgery, its implementation requires careful consideration of the associated risks and challenges. The lack of level I evidence to support W&W approach must be emphasized while long-term safety is concerned. Considering the limitations of W&W approach in surveillance and risks of salvage surgery, the current standard of care of rectal cancer after TNT remains surgery.