Illustration showing colorectal cancer
Credit: Mohammed Haneefa Nizamudeen/Getty Images

Researchers from Aarhus University Hospital in Denmark have shown that the rate of colorectal cancer (CRC) recurrence has decreased to such a large degree since 2004 that changes in surveillance strategies may be warranted.

The decreases were observed across all disease stages and, by 2019, recurrence rates were particularly low (<7%) for patients with stage I cancers that had been detected by screening.

“Due to this difference in the pattern of recurrence for patients with stage I disease, less intensive surveillance, or even no surveillance, may be noninferior to current guidelines—especially when also considering health-related quality of life, late sequelae, and cost-effectiveness,” writes Jesper Nors, from the departments of Molecular Medicine, Clinical Medicine, and Surgery, and co-authors in JAMA Oncology.

The researchers explain that although surgery is intended to be curative treatment, approximately 20% of patients experience disease recurrence. Therefore, all patients with stages I to III CRC are offered postoperative surveillance for five years.

New treatment and screening strategies implemented over the past two decades have been associated with improved survival among people with CRC but, Nors et al say their impact on recurrence is less well-known.

To address this, they reviewed data from 34,166 patients (median age 70 years, 54% men) with stages I to III CRC in the Danish Colorectal Cancer Group Database who underwent primary surgery between 2004 and 2019. Of these, 9,135 had their surgery between 2004 and 2008, 9,780 between 2009 and 2013, and 15,251 between 2014 and 2019.

Overall, 7,027 (20.6%) patients developed recurrence during the five-year, post-surgery surveillance period. However, the risk for recurrence was a significant 41% lower in the 2014–2019 period than in the 2004–2008 period at cumulative incidences of 15.8% versus 26.9%. The incidence was 22.2% between 2009 and 2013.

For colon cancer, the 5-year incidence of recurrence decreased from 16.3% in the 2004–2008 period to 6.8% in 2014–2019 for stage I disease, from 21.9% to 11.6% for stage II disease, and from 35.3% to 24.6% for stage III disease.

The pattern was similar for rectal cancer, with decreases from 19.9% to 9.5% for stage I, from 25.8% to 18.4% for stage II, and from 38.7% to 28.8% for stage III disease.

Speaking to Inside Precision Medicine, Jesper Nors, and lead investigator Claus Lindbjerg Andersen, group leader and director of the National Danish ctDNA Research Center, say the reduced risk for recurrence over time was not unexpected. “We know that colorectal cancer recurrence is the main risk factor of CRC-related death following curative-intended treatment, and Danish and international data has documented a decreasing mortality over the past decades. Consequently, we expected that the risk of recurrence had decreased as well.” They add that “the combined impact of all the initiatives that have been implemented in management of CRC has been positive on the risk of recurrence. And we were delighted that our findings were consistent among both colon and rectum cancers and for stage I, II, and III disease.”

The study also revealed that the proportion of diagnosed colorectal cancer recurrences was highest in the first three years after surgery in all three calendar periods and increased over time, with 80% of cases diagnosed within three years in 2004–2008 compared with 85.4% in 2014–2019.

In addition, patients with stage III disease had a significantly shorter time from surgery to recurrence than those with stage I disease.

“Our study shows that the time to recurrence is different between UICC stages, as stage III patients had shorter times to recurrence,” say Nors and Lindbjerg Andersen. “This suggests that stage III patients may benefit from intensive surveillance in the early period following curative-intended surgery.” They are currently awaiting results from their national randomized trial, IMPROVE-IT2, which is investigating if circulating tumor DNA guided post-operative surveillance of stage III CRC patients could result in earlier detection of recurrent disease.

In 2014, a population-wide CRC screening program was implemented in Denmark, which led to a shift toward a higher proportion of stage I CRC cases being detected during this period. Between 2014 and 2019 period, 43.6% of patients with stage I CRC, 20.5% of those with stage II CRC, and 22.5% of those with stage III CRC were diagnosed through screening, and Nors et al point out that the 5-year recurrence rates during this period were lower among patients with screening-detected CRC vs nonscreening-detected CRC. Specifically, the recurrence rate was 6.5% for screening-detected stage I CRC versus 8.9% for nonscreening-detected stage I CRC. For stage II disease the corresponding rates were 10.1% and 14.1%, and for stage III disease they were 21.7% and 27.1%.

However, further analysis showed that the recurrence rates among people with nonscreening-detected CRC were still lower in 2014–2019 than in earlier periods, suggesting that initiatives other than screening that were implemented in this period also had implications for recurrence risk. A shift towards treatment of CRC at specialized centers may be one of the main drivers behind the improved outcomes in these patients, Nors and Lindbjerg Andersen suggest.

Discussing the current standardized approach to surveillance, the researchers point out that “a substantial amount” of recurrences are detected when they become symptomatic rather than through surveillance. They also say that “we spend more resources per recurrence today than we did 20 years ago simply because the risk of recurrence has decreased.” Taken together, this causes them to “question the value of the surveillance protocol in patients at low risk of recurrence.” Instead, Nors and Lindbjerg Andersen suggest “investigating whether shifting some of the resources from surveillance to a focus on late sequelae may be of better value to these patients in terms of improved quality of life.”

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