Do patients with rectal cancer who have responded optimally to chemoradiation need to undergo surgery as well? The answer to that is up for grabs, with strong viewpoints on both sides of the coin.
Experts arguing against surgery are urging that patients can be followed with "a wait and see" approach, but experts for surgery argue that this places patients at unnecessary risk for relapse.
The two sides of this debate are outlined in a pair of articles published online in the December 22 in JAMA Oncology.
Yes to Surgery
In the article outlining the case for surgery, Heidi Nelson, MD, Nikolaos Machairas, MD, and Axel Grothey, MD, all from the Mayo Clinic, Rochester, Minnesota, argue that it is still "premature to practice selective withdrawal of surgery based on the curative contribution of surgery, the lack of reliable predictive biomarkers, and the scarcity of solid evidence in support of this practice."
Thus far, the existing evidence does not support withholding surgery, they write. Prior to the 1990 consensus recommendation of radiation and chemotherapy, the authors point out, the overall 5-year survival rate for surgery alone was 58%.
They also point out that a recent Cochrane review (Cochrane Database Syst Rev. 2007;2:CD002102) estimated that the addition of radiation conferred only a 2% absolute survival advantage and modest improvements in local pelvic control. In addition, 10-year survival rates are about 17% from primary radiation therapy.
"Because the curative contribution of surgery is substantial, the predictive certainty that surgery can safely be withheld should be highly accurate, and the evidence in favor of a change in practice should be significant before this practice is recommended outside of clinical trials," write Dr Nelson and colleagues.
The current evidence supporting the use of chemoradiation therapy (CRT) alone is limited. Only been a few small single-institution pilot studies have been conducted, with the number of participants ranging from 6 to 129, for a total of roughly 425 patients who have been studied worldwide with observation after complete response to CRT, they point out.
The rates of local failure rates have ranged from as low as 0% to as high as 60%, with similar variation seen for distant failure rates (0% to 17%). Importantly, long-term outcomes data for this intervention are limited, and the data that are available have not been reported with respect to intent to treat or with comparable controls.
One example they highlight is a study that included 122 patients with clinical complete response to CRT who were then observed without their having undergone surgery (J Gastrointest Surg. 2006;10:1319-1328). Of this group, however, only 99 patients with no evidence of disease after 1 year of observation were reported in the 5-year survival analysis; the remaining 23 patients were omitted. This subgroup received salvage therapy with unspecified long-term outcomes.
It is also unclear how many of these patients were eligible for or would have derived a benefit from salvage therapy, the authors point out. There is dramatic variation in the observation literature ― salvage therapy appears possible in 0% to 100% of patients.
There is also a lack of long-term data to determine whether salvage therapy performed at the time of tumor recurrence is as effective as surgery performed at the time of maximum radiation impact, when the tumor is at its nadir.
Given the "limitations of existing information and based on the current paradigm for how we establish best practices, the individualized approach to patients with apparent complete response to CRT should be considered experimental and not ready for routine clinical practice," the authors conclude.
"Patients and physicians who wish to advance the individualized practice of rectal cancer care are encouraged to do so through participation in clinical trials," the authors add. They note three currently open trials are evaluating individualizing the care of patients with rectal cancer – the National Cancer Institute’s PROSPECT Trial (NCT01515787), a Brazilian trial (NCT02052921), and a US trial headed by the Memorial Sloan Kettering Cancer Center (NCT02008656).
No to Surgery
In the article outlining the case against surgery, John Monson, MBBCh, MD, of the Florida Medical Group, Orlando, and Reza Arsalanizadeh, MD, of the North West Deanery, Manchester, England, refute the idea that surgery is necessary for every patient who responds well to CRT.
There is a significant patient cohort who achieve a complete clinical response following CRT, and traditionally, these patients would still undergo radical rectal excision "and be congratulated when the subsequent pathologic results revealed no residual tumor," they write.
But for some patients, this sequence of events appears "problematic," and the appropriateness of a surgical intervention with such high morbidity has been taken to task. Thus, the "issue of watch and wait strategy as opposed to radical surgery in this group has been heavily debated in the literature," the authors note.
That rectal cancer surgery is associated with high morbidity and impairment of quality of life is "simply undeniable," the authors argue. As an example, the risk for anastomotic leak following anterior resection can reach up to 12%, and sexual and bowel dysfunction is a clinically significant problem and is exacerbated in patients who have received neoadjuvant treatment. In addition, the 30-day mortality following radical rectal cancer surgery can reach 10%.
In the past, they point out, local resection or simple observation was reserved for "the frailest of the frail patients" for whom radical surgery was considered "impossibly risky."
No longer is that the case, and increasingly, younger and younger patients are asking to avoid the real possibility of a lifetime of impotence or incontinence or living with a stoma," they emphasize. "These individuals ask a very simple question: tell me why you are proposing to remove my normal rectum?"
As an alternative to surgery, they support the idea of a "watch and wait" approach after chemoradiation, reserving surgery as a salvage treatment. In their article, Dr Monson and Dr Arsalanizadeh cite evidence supporting this approach.
The first series in which a watch-and-wait policy was employed in rectal cancer patients who were treated with CRT occurred in 1998 (J Gastrointest Surg. 2006;10:1319-1328). In a cohort of 118 patients, 36 had a complete clinical response after CRT, and 30 did not go on to have surgery. Eight patients subsequently developed local recurrence during the follow-up period and required salvage surgery, but survival and recurrence rates in the rest of the patients were similar to those in the surgery group.
Other institutions, the authros note, have reported similar findings, such as Memorial Sloan Kettering Cancer Center in New York City, which reported a case series of 32 patients with complete clinical response (Ann Surg. 2012;256:965-972). After 28 months of follow-up, they found no difference in rates of overall and disease-free survival in this group, as compared with 57 patients who underwent total mesorectal excision and had a pathologic complete response.
In the face of these "compelling data," it is not surprising that there are now several ongoing studies regarding the watch-and-wait strategy, they comment. These trials are attempting to address some of the remaining unanswered questions, including clarifying the ideal induction schedule, how to best identify complete responders, and the most appropriate and accurate protocol for follow-up and observation, they write.
Although the data are limited and immature, "the evidence that some patients do not need to undergo a radical resection is frankly undeniable," they conclude. "A watch-and-wait policy is feasible and seems to be safe for most candidates."
The ideal would be to compare watch and wait with standard total mesorectal excision in a randomized clinical trial with clear long-term oncologic and functional outcome measures. But such a trial seems unlikely, the authors point out, considering the morbidity and mortality associated with the surgical procedure and the comparable oncologic and survival outcomes that have already been reported with observation.
"It simply must be admitted that a universal policy of radical surgery in complete responders is no longer justified," they add.
The authors have disclosed no relevant financial relationships.
JAMA Oncol. Published online December 22, 2016