Need for adjuvant chemotherapy after colon cancer surgery – has it decreased?

Colorectal cancer (CRC) is the third most common cancer worldwide. Increased screening, early awareness, and improved treatment mainly explain decreasing mortality, despite rising incidence. One of the treatments for colon cancer contributing to improved survival is adjuvant chemotherapy. Its effect, at least in stage III, appears in many randomized trials [1]. Its effect is less well established in stage II, however, although is considered sufficient to motivate treatment when risk factors are present for recurrence. The decision as to the importance of risk factors varies between guidelines [2–4]. For stage II patients, tumour depth pT4 has been a predominant factor indicating higher risk for recurrence, but also perineural or vascular invasion, obstruction or perforation have frequently been associated with worse outcome, as is a low number of sampled lymph nodes. Microsatellite instability confers less recurrence risk [1,5]. In this issue of Acta Oncologica, Nozawa et al. [6] report pT4 to be the most important factor indicating higher risk for recurrence in stage II. In this Japanese study of 384 CRC patients treated in 2005–2014, approximately 10% received adjuvant chemotherapy. The study’s strength is their sufficient lymph node yield for the majority of patients (85%). Their reporting of possible loss of follow-up, confounders, patient selection and hence, generalizability, however, leaves questions unanswered. They present results for CRC patients, of whom 74% had colon cancer. In addition to pT4, preoperative carbohydrate antigen 19-9 (CA 19-9), which plays a significant role in pancreatic cancer, was of independent prognostic value. Preoperative carcinoembryonic antigen (CEA) did not influence prognosis. In a preceding issue of Acta Oncologica, Hoshino et al. [7] similarly found the pronounced influence of infiltration depth. Their study created a nomogram to predict the probability of recurrence in stage II CRC, not separating colon and rectal cancer. Their nomogram had a bootstrapped concordance index of 0.64; 5-year recurrence-free survival (RFS) was 83%. For a male patient aged 64 with a pT3N0 tumour in the right colon, without perineural or vascular invasion, and with a preoperative CEA level of 5.0, and 15 investigated lymph nodes, the nomogram predicted 5-year freedom from recurrence at 93%. Interestingly, Weiser et al., 8 years earlier, created for stage I to III colon cancer another nomogram for the same fictive patient; it showed 5-year freedom from recurrence to be 85% [8]. Reasons for this difference are several. The Weiser et al. study based its results on a specialized single-centre institution in 1990–2000. Patients were mostly elective, and hence none had perforation or obstruction, which restricts generalization of its results. Both omitted data on emergency surgery, and on mismatch repair status [7,8]. In the two Japanese trials, risk for recurrence within the first 5 years for stage II patients was, overall, 13% [6] and 14% [7]. Adjuvant chemotherapy has influenced these seemingly low recurrence rates, but was given to few individuals, only 10% [6] and 25% [7]. This reflects a limited need for adjuvant therapy for all stage II patients today in Japan at centres having apparently high-quality surgery and pathology. In one systematic review aiming to describe recurrence risks in patients undergoing surgery during the past 10–15 years, with modern staging and surgery, 5-year disease-specific survival (DSS) for stage II colon cancer patients was about 83% [9]; the corresponding figure for stage III was 64%. Few studies, however, reported details on quality of care or on recurrence rates. Disease-free survival (DFS) and RFS are appropriate endpoints for clinical trials [10], when a need exists to balance gains (fewer recurrences) and negative consequences (toxicity including toxic deaths and second malignancies). These endpoints fail, however, to measure well the need for adjuvant therapy. Inclusion of endpoints other than recurrence, DFS (all deaths and second malignancies), and RFS (all deaths) overestimate that need. Cancerspecific survival (CSS) may underestimate the need for adjuvant therapy, since some recurrences are curable. Time to tumour recurrence (TTR), including recurrences of and death from the same cancer, seems the most appropriate measure, but was rarely reported [9]. Deciding on adjuvant therapy depends on differences between characteristics (like pT3 or pT4), and also on absolute risk for recurrence. Most studies exploring risk factors for recurrence do not report absolute risks. Knowledge of absolute risks facilitates dialogue with the patient as to whether the possible gain is sufficiently large to consider adjuvant treatment. Shared decision-making between doctor and patient, according to a Dutch study on adjuvant treatment of CRC, is rare [11,12]. Following trials showing gains from adjuvant therapy, major improvements have occurred in surgery, pathology, and staging. Absolute recurrence risk is presently lower, overall and at each stage (taking into account also stage migration), with the extent of improvement unclear