Prime Time for Watch and Wait in Rectal Cancer or More Wait and See?

What is the innovation?

A watch-and-wait (WW) approach in rectal cancer patients after a clinical complete response (cCR) to neoadjuvant therapy (NAT) is the innovation^1–3. cCR means no rectal tumor is found by digital exam, endoscopy, and MRI. The WW approach is non-standard, and gives the patient an opportunity to preserve the rectum and avoid surgery. WW has become more widespread as a cCR can occur in ~30% of patients treated with a total neoadjuvant therapy (TNT) approach⁴ (giving all therapy prior to rectal resection) and can occur in some patients receiving CRT alone, thereby leading to increased patient demand.

What are the key advantages over existing approaches?

Rectal cancer remains a complex disease to treat given multimodal care, including neoadjuvant chemoradiation (CRT), rectal resection (total mesorectal excision (TME)) and adjuvant chemotherapy. Some have opted to give all CRT and chemotherapy before surgery⁵ (e.g., TNT) addressing the micrometastatic niche immediately while improving chemotherapeutic regimen compliance. After neoadjuvant therapy, standard treatment is to proceed to TME, which places patients at risk for bowel, bladder, or sexual dysfunction as well as a stoma and other potential post-surgical complications (e.g., anastomotic leak). For patients with no clinical evidence of residual tumor, WW offers significant advantages including avoiding TME and maintaining excellent quality of life⁶. cCR is of course different than no pathologic evidence of tumor (pathologic complete response (pCR)), but clearly a pathological assessment can only be made after TME. The potential downside is that WW patients who do not have sustained complete tumor response are at risk for developing local regrowth^2,3, and thus require delayed TME and face increased metastasis risk³ and oncologic outcome compromise.

How will this affect clinical care?

Patients electing WW must undergo strict surveillance for at least five years. Patients are observed for 8–12 weeks post-NAT to determine tumor response. For patients managed ‘off-protocol’ by WW at MSK, an agreement is made between the surgeon and the disease management team to proceed with this non-standard approach, accepting the inherent risks of local regrowth, possible need for salvage surgery, and potential local and/or distant failure³. The surveillance strategy used for those who achieve a cCR after NAT is shown in Figure 1. Patients who cannot handle uncertainty or return for follow-up visits will not be good WW candidates. TME is the best option for those who want to be absolutely certain there is no remaining cancer in the rectum.

Figure 1: Surveillance Strategy for Off-protocol WW patients.

Shown is a surveillance strategy utilized in patients followed after cCR off-protocol. The surveillance includes endoscopy, digital rectal exam and MRI-rectum for the follow-up of patients after they achieve a cCR. In addition, regular CEA checks and axial CT imaging is completed. Suggested intervals are shown. An alternative regimen used by some includes 3 monthly intervals in year 1, extending to 4 monthly intervals in year 2 after cCR is declared for endoscopy, digital exam and MRI-rectum and then extending the intervals to every 6 months for years 3–5.

Is there evidence supporting the benefits of the innovation?

Habr-Gama demonstrated that WW in selected patients, with a sustained cCR, compared to pCR patients who underwent TME that there were no differences in overall survival between the groups, that deferral of surgery was safe in the cCR group, and that local regrowths could be salvaged with R0 TME¹. These original findings have been supported by work recently described in an international WW database analysis². Nonetheless, WW is an alternative treatment strategy. The supporting data is based mainly on institutional case series with the exception of one prospective observational study⁷. Our work, evaluating 113 patients achieving a cCR after NAT, reflects the largest North American WW assessment and demonstrated four key points³. First, cCR patients accepted WW and were willing to take risk in order to preserve their rectum. Second, we observed a high rate of rectal preservation (79% at 5-years) in those achieving a cCR. Third, WW with careful surveillance and timely surgical salvage after local regrowth detection obtained local control in >90% of the salvage surgery patients and >98% overall. Fourth, distant metastases developed in 8% of WW patients. This metastatic progression rate is comparable to that reported for patients undergoing TME and found to have pCR (6%)⁸, is similar to WW patients in other series (8–9%)², and is superior to rectal cancer patients in recent randomized trials (20–25%)⁹.

What are the barriers to implementing this innovation more broadly?

A main barrier to broad WW implementation is lack of expertise with the surveillance strategies including knowledge of the clinical appearance of cCR by endoscopy, and dedicated radiologists who can assess and reliably interpret MRI-rectum findings after NAT. Challenges to patient adherence include travel for surveillance exams, life interruption and anxiety related to surveillance. Another barrier in the community is lack of insurance coverage for interval endoscopy and MRI since there is not a solid WW endorsement by the NCCN. Other hurdles to broad implementation include non-uniform response definitions regarding cCR, surveillance protocol variations, multiple NAT regimens used, and short follow-up in the retrospective studies to date. It is unclear if a WW approach could be accomplished safely in all community-based settings as most studies to date have occurred in large, tertiary-care centers. Finally, refining patient selection and lowering local regrowth rates would improve acceptance and make this approach more generalizable.

In what time frame will this innovation likely be applied routinely?

The Organ Preservation in Rectal Adenocarcinoma (OPRA) phase II trial is evaluating 3-year disease-free survival in rectal cancer patients treated with CRT plus induction or consolidation chemotherapy and TME or WW¹⁰. In OPRA, MRI-staged clinical stage II or III rectal cancer patients amenable to TME are randomized to systemic chemotherapy in an induction approach (pre-CRT) or a consolidation approach (post-CRT). The decision for TME or WW is based on three-tiered tumor response assessment¹⁰. TME is required if residual tumor remains; if no tumor is detected, then WW is employed. OPRA will reveal whether implementation of WW using a TNT approach will affect overall oncologic outcome compared to standard treatment. OPRA will illuminate the best way to get patients to cCR; however, given that it is a phase II trial, the findings must be validated in an adequately powered phase III trial. Therefore, it will be 3–4 years before additional level I, prospective data will be available to validate this approach.