Survival outcomes were considerably better in patients with locally advanced rectal cancer who had surgery within 8 weeks after not responding to upfront chemoradiation, when compared with patients who had surgery later.
In fact, the difference in time when the surgery was performed was small, around 3 weeks. Patients in the shorter interval group had a median wait time of 7 weeks, whereas for those in the longer interval group it was 10.6 weeks.
But that small difference in timing made a big difference to the survival outcomes.
At 5 years, 72% of those in the shorter interval group were alive and free of disease compared with 59.6% of patients in the longer interval group (P < .001).
At 10 years, the overall survival (OS) rates were 58.8% vs 40.1% (P < .001).
“Time is quite everything in oncology,” senior author Angelo Restivo, MD, University of Cagliari, Cagliari, Italy told Medscape Medical News.
“There is a direct relationship between time and worse outcomes in oncology so the longer you wait, the worse the outcome [although] the magnitude of the difference in disease-free and overall survival [between the longer and shorter wait interval groups] was a real surprise,” he admitted.
The study was published online September 29 in JAMA Surgery.
Neoadjuvant Protocol
The study was conducted in patients with stage II to III locally advanced rectal cancer who had undergone the neoadjuvant chemotherapy protocol followed by total mesorectal excision (TME) in one of 12 Italian high-volume referral centers.
Only patients with a minimum follow-up of 5 years were considered for analysis. In all, 1064 patients were included in the analysis.
All patients underwent long-course chemoradiation therapy given over 5 weeks in 25 fractions of 1.8 Gy per day. Patients were then divided into two groups based on the interval between the time they ended chemoradiation and the actual time of surgery.
As the authors point out, a waiting period of at least 8 weeks is felt to be necessary to optimize treatment effects from chemoradiation and to increase the rate of responders, but there was some variation in the actual time that patients waited for surgery.
“Our data showed that patients who had surgery after 8 weeks had a linear worsening of survival for each additional month of waiting,” the researchers report.
“The magnitude of the detrimental effect of delaying surgical resection in these patients, in terms of OS…is clinically relevant — reaching almost a 20% difference at 10 years —and [was] somehow unexpected,” say the researchers.
“A longer interval also correlated with a significantly higher cumulative incidence of local recurrence, at both 5 and 10 years],” the authors note.
At 10 years, DFS rates were 53.9% of those in the shorter interval group vs 36.2% for those in the longer interval group (P < .001).
In addition, surgical outcomes were also significantly worse among patients who had a wait time in excess of 8 weeks than they were for those who had a wait time of less than 8 weeks.
Table. Surgical outcomes: shorter vs longer interval groups
| Wait time >8 weeks |
Wait time <8 weeks |
Odds ratio | P value | |
|---|---|---|---|---|
| Abdominal perineal resections | 33.2% | 21.9% | 1.71 | < .001 |
| Positive margins | 1.7% | 0.5% | 3.6 | .04 |
| 30-day morbidity | 19.6% | 14.8% | 1.4 | .04 |
| Surgical Complications | 15.1% | 10% | 1.6 | .01 |
Response to Neoadjuvant Therapy
The main reason for delaying surgery is waiting to see if the patient responds to neoadjuvant chemoradiation therapy. About 15%-20% of patients experience a good or even a complete response to neoadjuvant treatment, but there is no way to tell beforehand which patients will — and which ones will not — respond, Restivo commented.
“Of course it would be much better if we had something that would tell us if patients will respond to this treatment, but right now we have nothing,” he stressed. Thus, it is widely accepted that patients should wait up to 12 weeks after receiving chemoradiation before proceeding to surgery, based on evidence that tumor response to upfront treatment should have reached its maximum effect by then.
If patients are fortunate enough to achieve a pathological complete response, they may not only enjoy a survival advantage but they may also be suitable for an organ-sparing strategy and avoid radical surgery altogether: For this lucky minority, delaying surgical resection might be a good option, as the authors point out.
However, they comment that “our study shows that extending this time in the search for more pathologic responses occurs at the expense of a worse outcome in most patients (almost 75% in our series) who will not achieve the desired pathologic response.”
Until prospective studies confirm these retrospective findings, Restivo recommended that surgeons play it safe and perform the surgery as soon as possible in patients who do not respond or who respond poorly to upfront chemoradiation.
Unnecessary Delays
Asked to comment on the findings, George Chang, MD, chair ad interim of the Department of Colon and Rectal Surgery at the University of Texas MD Anderson Cancer Center in Houston, said it should always be the goal to avoid unnecessary delays to surgery for patients with cancer. “However, for patients with rectal cancer following neoadjuvant radiation treatment, a longer interval from completion of radiation to surgery can increase the rate achieving the desired outcome of better treatment response,” he wrote in an email to Medscape Medical News.
Chang, who was not involved in the research, also pointed out that study investigators performed a retrospective analysis to assess if a longer wait time was associated with survival. “While the findings are provocative, there were notable differences between the two groups that could have contributed to the poorer outcome [for the longer interval group],” he noted.
In addition, patients who achieved a major response were excluded, thus potentially biasing the longer interval group to poorer responders who are known to have worse prognosis, Chang said. “These findings emphasize the need to better understand factors associated with treatment response and long term outcomes.”
The authors have disclosed no relevant financial relationships. Chang declares that he has been a scientific advisory consultant to Medicaroid, Johnson and Johnson, and Exact Science.
JAMA Surg. Published online September 29, 2021. Abstract, Editorial
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