The ‘Watch and Wait’ Strategy in Rectal Cancer: Weighing the Pros and Cons

1. Introduction

Treatment for locally advanced rectal cancer has changed significantly over the last few decades, primarily as a result of the use of radiation therapy and neoadjuvant chemotherapy.

In the past, the rectum and its lymphatic and vascular components were surgically removed in order to treat nonmetastatic rectal cancer (1). However, there was a notable shift toward neoadjuvant chemoradiotherapy starting in the 1990s and continuing into the 2000s. Benefits of this approach included improved surgical resection results, disease downstaging, and tumor size reduction. During physical tests, endoscopic procedures, and MRI scans, doctors observed the complete response of the tumor in multiple cases. Many of these individuals subsequently had total mesorectal excisions (TMEs), but the results showed a pathological complete response (pCR) (2)

2. W&W definition

A noninvasive therapy strategy aimed at protecting organs and preventing surgical complications is the watch-and-wait (W&W) method. Patients with locally advanced rectal cancer who show an exceptional clinical response after neoadjuvant therapy are treated with this strategy (3–4).

These patients are monitored closely by active surveillance rather than having rectal cancer surgery right away. Patients can keep their rectum thanks to the W&W technique, which has demonstrated disease-free survival rates comparable to those of traditional treatments.

• Patients who achieve a complete clinical response (cCR) following neoadjuvant therapy during the evaluation of tumor response or post-local excision,
• Patients who present with local clinical CR and M1, and
• Patients exhibiting a clinical near CR to neoadjuvant therapy for whom the decision was made to postpone surgery and extend the observation duration are all eligible for the International Watch & Wait Database (IWWD) protocol (5).

Near complete response (near CR) refers to a clinical state where residual abnormalities are minimal and may include small irregularities or slight mucosal changes that do not fulfill criteria for complete clinical response but suggest substantial tumor regression. This category includes patients with near-complete endoscopic, digital, and radiologic findings, who may convert to a complete response on further observation.

3. CR (complete response) definition and timing

Endoscopic findings of a flat, white scar with telangiectasia but without ulceration or nodularity, along with classic findings in the digital rectal examination, define complete response. MRI findings of a dark T2 signal and no lymph nodes visible on T2-weighted MRI are also supportive of CR findings (6).

Timing of reassessments for CR is dissimilar in each study. For instance, the OPRA trial reassessed 8 ± 4 weeks after neoadjuvant treatment. Patients who have achieved CR by 12 weeks from the onset of neoadjuvant treatment are eligible for entry into the IWWD protocol. It also encompasses patients with near CR who eventually attain clinical CR by 24 weeks in the IWWD program (7-13).

Although there is no consensus on an optimal reevaluation time, it varies from 4 to 20 weeks depending on the series. It is essential to avoid early evaluations that could potentially be misinterpreted as an incomplete response.

4. Pros

W&W’s advantages are mostly related to economic efficiency and quality of life. For locally advanced rectal cancer, neoadjuvant treatment has typically been followed by rectal resection surgery. However, severe resection often results in poor functional outcomes and a reduced quality of life, especially for those with low rectal cancer. Total mesorectal excision (TME) frequently results in significant morbidity, affecting a patient’s health in several ways. Issues with urine and sexual function, gastrointestinal problems, and negative body image are common. Additionally, abdominoperineal resection may be necessary for individuals with very low rectal tumors, which would result in a permanent colostomy and severely impair their quality of life (14-15).

Current clinical research emphasizes the W&W method’s superior cost-effectiveness, organ-preservation rates, and life quality compared to initial TME. Following neoadjuvant chemoradiotherapy (nCRT), patients who achieve complete clinical response (cCR) can avoid surgery without sacrificing their prognosis. Studies showing that patients who match cCR criteria have statistically comparable outcomes with or without surgical intervention lend support to this approach. For example, a large multicenter study by van der Valk et al. (IWWD) reported a 5-year overall survival of 84.7% and a 5-year disease-specific survival of 93.8% in the W&W group. Although direct comparisons with patients who underwent surgery after clinical complete response (cCR) are limited, the survival of W&W patients with sustained cCR was 87.9%, which falls within the 85–90% range of 5-year survival rates reported for patients achieving pathological complete response (pCR) after TME in multiple studies (e.g., Maas et al., 2011; other meta-analyses). These data suggest that for patients achieving sustained cCR, the W&W strategy does not compromise oncologic outcomes while avoiding the morbidity associated with surgery (7, 28).

Additionally, with a 2-year local recurrence-free rate of 97.8%, almost 97% of patients who experience local recurrence following W&W can have successful salvage radical surgery (16).

W&W patients had better overall bowel function, particularly in terms of urgency, soilage, and fecal incontinence, according to a retrospective case-control study that compared them to patients who had anal sphincter-preserving surgery (17).

Another study found that 41 people treated with the watch-and-wait (W&W) strategy had better sexual and urinary tract function and fewer problems with defecation than 41 similar individuals who got chemoradiation followed by surgery (18).

The W&W approach significantly boosts the rate of anus preservation, helps avert surgical complications, and guarantees a better quality of life for patients.

5. Cons

Despite its advantages, the watch-and-wait (W&W) technique should be used carefully because of certain significant drawbacks. When compared to total mesorectal excision (TME), it may lead to worse outcomes, higher rates of recurrence, and more metastases (19). Studies show that the W&W cohort has a higher local recurrence rate than the TME group (OR=8.54, 95% CI 3.52–20.71, P<0.001).

A significant consequence here is that irradiated tissue heals more slowly and often develops infections with greater frequency, along with other problems. Moreover, local recurrence is difficult to distinguish from scar tissue of a fibrotic type in follow-up. A longer duration could be subject to distant metastasis, local tumor advancement, and the need for remedial surgery. Also, studies revealed that the leading type of failure among the survivors of W&W is distant metastasis and the overgrowth of the local tumor. Approximately 88% of local recurrences are found within the first two years since the start of W&W. Thus, it is a high-risk period that requires close observation (20).

Radiotherapy can cause some partial functional abnormalities of the anus, and the cCR rate after neoadjuvant chemoradiotherapy is still relatively low.

Despite the potential for local regrowth, salvage surgery is usually successful for most patients. However, the frequency of distant metastasis is consistently higher in those who have local regrowth than in those who do not (36% vs. 1%; p < 0.001) (21). Compared to regular monitoring after conventional therapy, the W&W technique necessitates a more stringent follow-up protocol, which comes with a significant cost.

Sexual and bowel dysfunctions are common in people using the watch-and-wait approach. According to a thorough research evaluating the outcomes of people who followed the W&W approach, almost 25% of them experienced significant gastrointestinal problems. Additionally, erectile dysfunction was observed by nearly 30% of men (22).

The patient’s commitment to preserving organ function and the expertise of a multidisciplinary team are crucial for the success of the W&W approach in rectal cancer. Several regulatory issues, including the lack of uniform standards for multimodal treatment and illness monitoring, slow down the implementation of W&W, which makes it challenging to compare results, share best practices, and carry out multicenter research.

Therefore, developing novel and clinically significant quality metrics is essential. These metrics should include patient-reported outcomes, appropriate patient selection, managing chemoradiation side effects, the number and timing of salvage surgeries, and compliance with monitoring procedures.

Healthcare organizations may be discouraged from adopting W&W procedures due to concerns about potential legal repercussions if a patient is not adequately monitored or if disease progression occurs during the process.

Furthermore, financial incentives may not align with the existing reimbursement paradigm, which would make these institutions less motivated as fewer proctectomies are performed and more regular endoscopic and imaging exams are required. It can be challenging from a logistical standpoint to ensure patients adhere to strict monitoring guidelines.

In the first year, only 50.5% of patients met the baseline surveillance criteria, and in the second year, only 34% did. Therefore, to ensure the W&W methodology’s success, a high degree of commitment from patients and medical personnel is needed (23)

6. Future perspectives

One important yet challenging part of treating rectal cancer is predicting the tumor’s reaction to neoadjuvant therapy. Although many patients benefit from preoperative chemoradiotherapy (nCRT), especially those who achieve complete clinical response (cCR), it is still difficult to select the target group beforehand in order to reduce overtreatment of non-responders.

Numerous biomarkers, including single molecular markers like HER-2, PI3K, and MSI molecular phenotypes, have been identified in recent research as potential predictors of sensitivity to nCRT (24-25).

Furthermore, noninvasive liquid biopsy tests have become proper instruments for predicting and tracking W&W results.

To improve the accuracy of response predictions, Wang et al. have suggested integrating baseline levels of circulating tumor DNA (ctDNA) with MRI tumor regression grade (mrTRG) (26). A ctDNA and mrTRG-based algorithm demonstrated remarkable predictive accuracy (27). Additionally, Shin et al. and Bibault et al. have created models that use deep learning and radiomics to forecast pathologic complete response (pCR) after neoadjuvant therapy.

The results of the W&W strategy could be further enhanced by the development of reliable techniques for predicting pCR.

7. Authors’ opinion

The “watch and wait” (W&W) approach for locally advanced rectal cancer has some good points but needs to be looked into critically due to several significant issues. One of the key benefits of the W&W approach is improving patients’ quality of life. Patients can avoid surgical consequences such as bowel dysfunction and body image changes. Patients who value their quality of life during and after treatment may find preservation of body integrity very appealing.

However, compared to patients who undergo complete mesorectal excision (TME), W&W has a higher risk of metastasis and local recurrence, which is one of the most significant problems. This discrepancy raises doubts about the long-term effectiveness of W&W. Besides making treatment decisions more complicated, the possibility of metastasis may require more aggressive and possibly fatal measures. The risk of disease progression may outweigh any apparent benefit for patients who may initially respond well to neoadjuvant therapy.

Furthermore, patients and healthcare providers may find the W&W approach’s logistic requirements unmanageable. Patient fatigue and burden on resources may result from the need for frequent and intense monitoring. Many patients may not be able to adhere to the strict follow-up schedules required, increasing the risk of missed opportunities for timely intervention.

Another point to consider is the W&W approach’s psychological impact. Patients may experience severe stress and anxiety if they have to live with a non-surgical management plan. Their overall quality of life may be affected by the ongoing concern about tumor growth and the delay of treatment.

Inconsistent patient management is due to the lack of standard guidelines on how to apply the W&W approach. Without specific protocols, there may be considerable differences in the quality of care provided by different institutions, which may result in different patient outcomes. This inconsistency makes it harder to evaluate the W&W approach and raises ethical questions regarding equitable access to care.

Moreover, lastly, we cannot ignore the legal implications of W&W. Clinicians may not fully adopt W&W due to the fear of lawsuits, which could limit its implementation and potentially compromise patient care.

In summary, W&W has many good points, but some substantial risks and challenges need to be taken into account. There are real issues to be addressed, including higher recurrence rates, logistic difficulties, psychological effects, the lack of a defined procedure, and legal implications.

8. Conclusion

The “watch and wait” (W&W) strategy for locally advanced rectal cancer offers significant benefits, including organ preservation and improved quality of life, with survival rates comparable to traditional surgical interventions. However, it carries risks such as higher recurrence rates, potential metastasis, and challenges related to intensive surveillance and the psychological impact on patients. Further research is needed to refine patient selection and optimize follow-up protocols. Ultimately, the W&W approach should be applied on a case-by-case basis, carefully weighing the risks and benefits for each patient.

STATEMENTS

Authors’ Contributions: LM conceived the idea for this article. YD drafted the initial manuscript. ZB and YD contributed to the development of the main arguments and critically revised the content for intellectual depth and clarity. All authors reviewed and approved the final version of the manuscript.

Consent for Publication: As the corresponding author, I confirm that the manuscript has been read and approved for submission by all named authors.

Conflict of Interest: The authors declare no conflict of interest.

Funding Sources: None.

Acknowledgments: The authors would like to thank the staff of the Radiotherapy Department for their support and the colleagues who contributed indirectly through discussions and feedback during manuscript preparation.

ABBREVIATIONS

cCR – complete clinical response

CR – complete response

ctDNA – circulating tumor DNA

IWWD – International Watch & Wait Database

MRI – Magnetic Resonance Imaging

mrTRG – MRI tumor regression grade

nCRT – neoadjuvant chemoradiotherapy

pCR – pathological complete response

PI3K – Phosphoinositide 3-kinase

TME – total mesorectal excision

W&W – watch-and-wait

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