Recurrence Risk after Radical Colorectal Cancer Surgery-Less Than before, But How High Is It?

Abstract

Adjuvant chemotherapy aims at eradicating tumour cells sometimes present after radical surgery for a colorectal cancer (CRC) and thereby diminish the recurrence rate and prolong time to recurrence (TTR). Remaining tumour cells will lead to recurrent disease that is usually fatal. Adjuvant therapy is administered based upon the estimated recurrence risk, which in turn defines the need for this treatment. This systematic overview aims at describing whether the need has decreased since trials showing that adjuvant chemotherapy provides benefits in colon cancer were performed decades ago. Thanks to other improvements than the administration of adjuvant chemotherapy, such as better staging, improved surgery, the use of radiotherapy and more careful pathology, recurrence risks have decreased. Methodological difficulties including intertrial comparisons decades apart and the present selective use of adjuvant therapy prevent an accurate estimate of the magnitude of the decreased need. Furthermore, most trials do not report recurrence rates or TTR, only disease-free and overall survival (DFS/OS). Fewer colon cancer patients, particularly in stage II but also in stage III, today display a sufficient need for adjuvant treatment considering the burden of treatment, especially when oxaliplatin is added. In rectal cancer, neo-adjuvant treatment will be increasingly used, diminishing the need for adjuvant treatment.

Keywords: adjuvant treatment; chemotherapy; colon cancer; colorectal cancer; rectal cancer; recurrence risk; systematic overview.

Figure 1

Colorectal cancer recurrence risks by tumor location and stage. Kaplan Meier event plot split by diagnosis and stage. Outcome is recurrence after radical surgery in a Swedish population-based cohort diagnosed between 2010–2017 with minimum 2 years follow-up.

Figure 2

Time to recurrence (TTR) or freedom from (crude) recurrence (FFR) in surgically operated nonmetastatic colorectal cancer patients according to when the first patient was operated. Improvements with time were seen when all trials were included (right panel) and in the different types of trials as presented in the six Tables. The numbers in each filled point refer to the reference number as provided in the tables and reference list. Individual points are coloured by distribution of colon vs rectal cancer and shapes represents stage mix in each study. Linear regression for the trend, weighted by number of cases in the studies, are presented for each panel and for the total with the equation, R² and p-value presented for each panel. In the left panel (CRC T1–2), TTR/FFR are from the untreated control group in randomized (chiefly) colon cancer trials. The best results are seen in a recent Japanese study in stage II [48], in a trial [90] including only low-risk stage II patients, and in [46], mainly including patients with stage II where the doctor was uncertain about the benefit of adjuvant therapy. In the second left panel (rectal T3) a marked improvement is seen from the two older US trials [92,94] reporting improved results after adjuvant chemotherapy/chemoradiotherapy. No apparent improvement has been observed since then. However, the trial with the best results [97] was initiated at an early stage but included most patients between 2008–2011 and included “intermediate risk” tumours as opposed to “locally advanced tumours” in most of the other trials (although most of the tumours anyhow belonged to an intermediate risk group). One of the most recent trials [177] included only patients at high risk for relapse. Also [100] included only high-risk patients. In these trials preoperative chemoradiotherapy was given to all and adjuvant chemotherapy to some. Two of the older trials [95,96] had worse results despite including less advanced (most cT3 and not cT4) tumours. In the middle chart (CRC T4–5), being a systematic review of all randomized surveillance and laparoscopic trials, a clear improvement with time is seen. However, adjuvant therapy was provided to more patients in the recent trials than in the older trials, explaining some of the improvement. The two studies with the best results used the circumferential mesorectal technique, CME, potentially explaining few recurrences. In the second chart to the right (CRC T6), including recent patient series, the results are apparently better than in the older trials. Few recurrences were seen in an early trial from Erlangen [138], where the surgical quality was “at a high level”. No adjuvant therapy was provided, further emphasizing the good results. Besides this trial, there still appears to be an improvement with time, but the studies are heterogenous and many factors may lie behind this improvement.