Skipping Surgery in Rectal Cancer: Better or Worse?

Liam Davenport

July 17, 2019

BARCELONA — Can patients with rectal cancer skip surgery?

Skipping surgery is better for quality of life because it avoids placement of a permanent colostomy, as well as other potential complications, such as coloanal anastomosis, which can lead to fecal incontinence.

In an ideal world, rectal cancer patients who achieve a complete clinical response following neoadjuvant chemoradiotherapy (nCRT) would be assigned to a watch-and-wait strategy rather than undergo total mesorectal excision (TME) immediately, say experts.

But does the watch-and-wait approach lead to worse outcomes with respect to cancer recurrence and survival? These are some of the questions about a watch-and-wait strategy, which is not standard of care, as became clear from a debate on the topic here at the World Conference on Gastrointestinal Cancer (WCGC) 2019.

Rodrigo Perez, MD, PhD, from the Angelita and Joaquim Gama Institute, Hospital Beneficência Portuguesa de São Paulo, Brazil, argued that watch and wait is a reasonable option for patients who experience complete clinical response after nCRT, especially for patients with early-stage disease in the absence of local regrowth.

However, Albert Wolthuis, MD, PhD, from the University Hospital Leuven, University Hospital Gasthuisberg Leuven, Belgium, said that although he is in favor of the watch-and-wait approach, there is no consensus as to what constitutes a complete clinical response.

This issue is complicated further by questions over how to restage disease, as well as over the nature of the watch-and-wait strategy and the practical issues of how best to follow these patients.

What to Do When Patient Responds to nCRT?

Perez started the debate by asking: "What should we do with our next patient who develops, by chance, by accident, a complete clinical response following chemoradiation therapy?"

He characterized complete clinical response as coming about "by accident" because "these patients would have to undergo chemoradiation therapy anyway" before undergoing surgery for locally advanced disease.

He explained that a complete clinical response is determined in three ways:

  • A digital rectal examination (DRE) that shows the rectal mucosa to be smooth and firm, with no irregularities;

  • Endoscopic assessment that shows whitening of the mucosa, with a clear scar and no mass or ulceration of the rectum and no stenosis; and

  • Radiologic assessment that reveals no residual disease within the mesorectal envelope, as well as a significant response in the primary tumor, as demonstrated by very low signal intensity on MRI.

Perez said, however, that, in their hands, positron-emission tomography (PET)/CT is the best predictor of a complete clinical response, as shown by a decrease in total lesion glycolysis (TLG) — a combination of standardized uptake value and metabolic tumor volume.

"Whenever you have a 90% reduction in TLG, this is the best predictor of a complete clinical response," he said.

He went on to say that the best approach is to combine clinical assessment, endoscopy, and MRI with diffusion-weighted MRI (DWI).

However, Perez emphasized that it should be borne in mind that "not all patients achieve a complete clinical response at the same time."

One study demonstrated that 37% of patients with rectal cancer who achieved a complete response did so within 10 to 16 weeks of completing nCRT, but for the others, it took more than 16 weeks.

Surgery Is Difficult and Not Always Successful

Another issue is that TME is a difficult procedure and is not always accomplished successfully. The ACOSOG Z6051 trial showed that a successful resection is achieved in approximately 82% of cases with laparoscopic surgery. The success rate increases to 87% with an open procedure.

In addition, patients may be left with debilitating complications. Morbidity rates are high, at 38% overall, with 20% of patients developing urinary dysfunction, 20% developing fecal incontinence, 15% experiencing sexual dysfunction, and more than half needing at least a temporary stoma.

Some patients don't make it through the surgery: mortality rates are 2% to 3%.

There is also the possibility that surgery will not remove all the tumor. Recurrence rates range from 8% to 40%.

In view of all these possibilities, Perez questioned whether radical surgery is suitable for all patients.

There is also a consideration of what the patients themselves prefer. A recent survey of more than 160 colorectal surgical resection patients found that the number one concern among patients was to avoid having a permanent stoma, a fear that was rated as more important than being cured of cancer.

The risk for definitive stoma formation after low and ultra-low anterior resection for rectal cancer rises from 11% at 1 year to 22% at 10 years.

Moreover, patients who undergo rectal cancer treatment and surgery face a significant risk of being subsequently unable to work; 23% receive a disability pension a median of 6 years after surgery, vs 10% of the general population.

Watch-and-Wait Strategy

An alternative to surgery is to employ a watch-and-wait strategy for such patients .

This, Perez said, would include monitoring every 1 to 2 months with endoscopic rectal ultrasound, MRI, and PET/CT, as well as with a blood test to measure carcinoembryonic antigen levels.

There is always the risk for a cancer recurrence.

A systematic review of 692 patients from seventeen studies by Mit Dattani, MBChB, FRCS, and colleagues suggested that 22% of rectal cancer patients who achieve a complete clinical response after nCRT experience local regrowth at 3 years.

The rate of local regrowth depends on the stage of the tumor at baseline; 96% of cT2 rectal patients remain disease free at 1 year after a complete clinical response. The rate falls to 69% among those with cT3/4 disease at baseline.

These statistics were echoed in findings from a 2018 study published in the Lancet indicating that each increase in cT stage at baseline is associated with a 10% increase in the risk for local regrowth at 2 years.

Perez said that if a recurrence does occur after a complete clinical response with nCRT, research suggests that 90% of cases have an endoluminal component and that 93% of cases are salvagable.

Crucially, delaying surgery does not result in "oncologic compromise." A retrospective analysis of 250 patients revealed no difference in either disease-free or overall survival between those who underwent surgery within 12 weeks of nCRT and those who waited longer.

The systematic review by Dattani and colleagues also suggested that there is no increase in the incidence of metastases in patients who undergo watch and wait. The overall rate of metastases is 8% to 12%.

Perez noted that the analysis showed that the incidence of distant metastases depended on whether or not patients experienced local regrowth during watch and wait. The rate was 36% among those with local regrowth and 1% among those without.

These statistics are reflected in a decrease in overall survival at 1 year among patients who experienced local regrowth or recurrence during watch and wait vs those who remained relapse free.

Perez suggested that these patients did not in fact experience a complete clinical response after nCRT; rather, for these patients, the response was incomplete.

Encouragingly, Dattani and colleagues showed in their systematic review that for patients who were assigned to watch and wait, the 3-year overall survival rate was 93.5%, even without adjuvant chemotherapy.

In contrast, a study by Monique Maas, MD, and colleagues indicated that for patients who had a pathologic complete response after undergoing nCRT and surgery, the overall survival rate at 3 years was 90.1%. In that study, 40% of patients underwent adjuvant chemotherapy.

Opportunity for Organ Preservation

Perez said that, taken together, the evidence suggests that watch and wait offers an opportunity for organ preservation in advanced and early-stage disease.

Patients with low-risk features could therefore be given nCRT, and if they have a complete clinical response, they could be spared surgery.

The response could be enhanced by increasing the amount of chemotherapy and radiotherapy given to patients and by using extended nCRT regimens.

He concluded by quoting the old surgical adage: "A good surgeon knows how to operate, a better surgeon knows when to operate, but perhaps the best surgeon knows when not to operate."

Perhaps the best surgeon knows when not to operate. Dr Rodrigo Perez

During the post-presentation debate, Perez said that currently, the question of whether or not to utilize watch and wait hinges on the assessment of whether or not the patient has experienced a complete clinical response to chemoradiotherapy.

"So far, we have been able to come up with a predictor of poor response to chemoradiation therapy," he said, but he added that "the predictor of good responses is a little bit tricky."

Still Have to Consider Radical Surgery

In opposition to this point of view in the debate, Wolthuis began by saying that his "disclosure is that I do believe in watchful waiting after a complete response has been achieved, but I will give you some food for thought on why I think we still have to consider radical surgery in this debate.

"We cannot deny," he continued, "the fact that although TME optimizes local control rates, it's still a difficult and dangerous operation with major morbidity and mortality, with the need for stomas and also a significant impact on the quality of life of our patients."

He emphasized that watch-and-wait strategies "are not standard of care."

For Wolthuis, radical surgery remains the "cornerstone" of achieving a cure in rectal cancer. He noted that "a noncurable local situation is unacceptable."

He pointed to data from his own group that show that among more than 300 rectal cancer patients who underwent nCRT followed by TME, the 5-year cancer-related survival rate was 98%, and the 5-year disease-free survival rate was 91%.

He said it is important that any follow-up be carried out by the same surgeon and that the quality of DRE assessment depends on the surgeon's experience.

Wolthuis also feels that the best prognosis is indicated not by a complete clinical response following nCRT but by a pathologic complete response.

The question then becomes how to assess that.

This is not as straightforward as it sounds, because there are questions as to the accuracy of restaging modalities as well as to the role of biopsy and the significance of residual mucosal abnormalities, he explained.

There is also ongoing debate over the assessment interval, when to assess patients, what to do during the interval, and the impact on outcomes.

Finally, there are questions concerning patient follow-up, including when, how, and by whom it should be performed.

What Constitutes a Complete Response?

Although certain core features characterize a complete clinical response, in the literature, there is a high degree of heterogeneity as to the definitions of response, Wolthius commented.

Moreover, there is wide variation in opinions among clinicians about what should be done after achieving a complete clinical response, and those opinions evolve over time.

Even the selection of rectal cancer patients to undergo nCRT depends on what the clinician is trying to achieve, Wolthuis noted.

The decision depends on whether the aim is to improve the local control rate, achieve a margin-negative resection, perform sphincter-saving surgery, or to induce a complete clinical response.

The type of nCRT also has to be selected, as do the restaging modalities. In addition, Wolthuis said that there is "no reliable test to predict pathologic complete response."

Not only that, but retrospective data showed that even among expert MRI readers, when it comes to assessing response on DWI to nCRT in rectal cancer, diagnostic accuracy is less than perfect.

Morever, combining all available modalities does not yield a positive predictive value greater than 80%, at a sensitivity of 75% and a specificity of 94%.

Wolthuis pointed out that there is no "exact correlation" between complete clinical response and pathologic complete response in terms of local regrowth and the presence of fibrosis vs residual tumors.

Better Outcomes After Surgery

Although salvage surgery after a period of watching and waiting is considered feasible and safe, it is associated with a higher local recurrence rate, at 3%, vs 0% with TME performed immediately after nCRT.

One study that compared the two strategies showed worse outcomes. For rectal cancer patients who were assigned to watch and wait after experiencing a complete clinical response, the 5-year disease-free survival rate was 75%, vs 92% for those who underwent TME and who had a pathologic complete response.

Citing a study by Perez's team that showed that local recurrence occurred in more than 50% of patients within 12 months of an initial complete clinical response, Wolthius asked: "Could all of these patients have been saved by upfront TME?"

After reviewing a series of studies of salvage surgery after watch and wait for rectal cancer after nCRT, he concluded that the majority of patients "can be salvaged," but that there is "insufficient evidence" on the oncologic safety of the approach.

He concluded that TME "remains the gold standard to cure patients, but assessment of complete clinical response is unreliable at present."

Consequently, "patient selection for watch-and-wait strategies and for a watch-and-wait approach is key, and the local regrowth has worse outcomes," he said.

Wolthuis also quoted an old surgical adage: "When in doubt, it definitely has to come out."

The participants have disclosed no relevant financial relationships.

World Conference on Gastrointestinal Cancer (WCGC) 2019: Presented July 5, 2019.

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