Watch your steps, especially when changing treatment for locally advanced rectal cancer

Treatment for rectal cancer has evolved over the last decades. After the introduction of low-dose radiotherapy (RT) prior to surgery, local control rates improved, although the effect on survival was not convincing [1–3]. From Sweden a series of studies have investigated the effects from shortcourse preoperative RT (SCRT) [4]. With the seminal publication on the results from total mesorectal excision (TME) trial, the first data indicated that surgery could yield 3.7% local recurrence rate without RT [5]. Norway was one of the first countries to accept the new TME surgery and arranged TME training courses for rectal cancer surgeons. Motivated by the lack of survival effect from preoperative RT alone, TME was initially implemented without additional treatments. Local recurrence rates improved from 25-30% to 14.5%, but remained higher than the target level around 5% [6]. Soon, it became evident that the distance from tumour to the mesorectal fascia (CRM or MRF) evaluated in the operation specimen was a strong prognostic factor [7,8]. With the introduction of magnetic resonance imaging (MRI) it became possible to measure this distance preoperatively [9]. A minimal MRF or CRM distance of 1–2mm by MRI is now accepted as an indication for preoperative RT. The changing treatment guidelines and patterns have translated results to better outcomes, which is demonstrated in new data from The Norwegian Cancer Registry that now show local recurrence rates of 4%–5% compared to 25%–30% before the introduction of TME [6]. Distant spread remains the predominant clinical challenge with distant metastases reduced from 25% to 20% for all operable rectal cancer patients with or without preoperative RT in Norway. Treatment of rectal cancer is constantly evolving. There is consensus that organ preservation represents a paradigm shift in the management of early rectal cancer [10–13]. In this issue of Acta Oncologica, two previously published studies using different preoperative RT scheduled have been re-analysed [14]. Three schedules were used: SCRT alone before surgery or SCRT followed by three courses of de Gramont chemotherapy (CT) with delayed surgery, and conventional preoperative chemo RT (CRT) with 50Gy given by 2Gy per fraction over 5weeks, combined with 5-fluorouracil and leukovorin (Nordic schedule). The authors motivate the investigation with concern for a potentially inferior treatment using SCRT with respect to complete clinical response. Heterogeneity in treatment with the different regimens and potential bias in patient selection may be related to treatment choice at the discretion of the participating institutions in the observational studies presented. Especially the SCRT alone group included many early stages. The study revealed no significant differences in complete clinical response in relation to RT schedule. Although the authors conclude that the data did not demonstrate superiority of CRT over delayed SCRT or SCRTþCT and underline that this is hypothesis generating, the study is underpowered to demonstrate superiority. Demonstration of potential superiority would require randomised data with comparable groups. Hence, the data presented document that SCRT can lead to a complete clinical and/or pathological complete response and lend further support to the watch and wait strategy [15,16]. The authors presented complete response data separately for the earliest tumours, defined as less than 4 cm length and less than 50% of the rectal circumference. Among 152 patients in this group complete clinical response rates for SCRT, SCRTþCT, and CRT were 26%, 38% and 45%, respectively. It is not obvious that these three regimens are equal based on this small sample. In a recent large register study 764 patients treated with SCRT were compared with 5070 patients treated with CRT. Pathological complete response rates were 9.3 vs. 17.5% [17]. Whether clinical or pathological complete response represent ideal surrogate endpoints remains unclear [10,18]. These endpoints are linked to favourable outcomes using disease-free survival or cancer-specific survival. However, in a study 17% of the patients with pathological complete response in the primary tumour had viable cells in harvested lymph nodes indicating increased risk of pelvic recurrence if the nodes were not removed [19]. In the study by Pietrzak L et al. [14] the primary endpoint is local regrowth with death of any cause handled as a competing risk. The authors apply a Gray test to avoid the inherited overestimation using Kaplan–Maier calculations. Also, the definition of time to surgery from day one of radiation start to date of decision of clinical complete response may influence relevant endpoints.