Hot TopicAdjuvant chemotherapy for rectal cancer: Current evidence and recommendations for clinical practice
Introduction
Rectal cancer is the 8th most common tumour and the 9th leading cause of cancer-related deaths worldwide [1]. While substantial heterogeneity exists with regard to the anatomical landmarks used for the definition of these tumours, rectal cancers account for approximately 40% of all colorectal malignancies overall. Of note, they are the most common colorectal tumour in people <50 years, and incidence in this population is on the rise [2], [3].
While 310,394 individuals were estimated to have died of rectal cancer worldwide in 2018 [1], survival outcomes have substantially improved over the past decades. According to statistics from the Surveillance, Epidemiology, and End Results Program (SEER), 5-year relative survival rates for all-stage rectal cancer patients in the US increased from 59.8% in 1986–1992 to 66.7% in 2007–2013 [4]. Taking into account the risk of stage migration bias, this improvement is especially noticeable for patients with stage III disease, the 5-year relative survival rates in this group being 54.9% and 70.3%, respectively.
The improved outcome over time of non-metastatic rectal cancer patients is to be largely attributed to a number of factors including advances and standardisation of pathological examination, imaging techniques, neoadjuvant treatments and surgical procedures, as well as routine implementation of a multidisciplinary decision-making approach [5], [6], [7], [8]. Furthermore, the increased ability to stratify tumours at baseline according to their prognosis has allowed optimising the use of available therapies with resulting maximisation of outcome for high-risk patients and reduction of unnecessary treatment-related toxicities for low-risk patients [9].
The mainstay of treatment for non-metastatic rectal cancer is surgery according to the technique of total mesorectal excision (TME) [10]. In patients with locally advanced tumours (as defined, depending on the risk classification system, by ≥ T3/N + stage or additional risk factors such as tumour location, depth of mesorectal invasion, extramural vascular invasion, mesorectal fascia threatening/involvement and lateral node invasion) neoadjuvant (chemo)radiotherapy is also routinely delivered to reduce the risk of local tumour recurrence [11], [12], [13], [14], [15], [16]. While both surgery and neoadjuvant (chemo)radiotherapy are established therapies for locally advanced tumours, the role of adjuvant chemotherapy in this setting is still highly debated with substantial variation in practice among healthcare providers.
This review article aims to analyse the role of adjuvant chemotherapy in rectal cancer, to critically appraise the available data, and to provide physicians with some guidance regarding management options and treatment decisions.
Section snippets
Why is adjuvant chemotherapy attractive in rectal cancer?
Pelvic recurrence has historically been a major cause of treatment failure and morbidity in rectal cancer patients undergoing surgical resection especially for locally advanced tumours. In studies conducted in the 1970s and 1980s, 15% to 40% of patients were reported to have experienced local tumour recurrence [17], [18], [19]. Beyond the obvious impact on survival, this also had important implications in terms of quality of life as locally recurring patients frequently suffered a number of
Adjuvant chemotherapy versus observation after surgery alone
Before the routine implementation of a multimodal treatment approach including neoadjuvant (chemo)radiotherapy, a number of adjuvant chemotherapy randomised trials were conducted both in Western countries and in Japan [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46]. The results of these trials are largely ambigous and influenced by notable heterogeneity with regard to some key variables such as sample size, type of patients included
How to make sense of the available evidence?
The results of these studies suggest overall that, in contrast to colon cancer, the role of adjuvant chemotherapy in the modern management of rectal cancer remains controversial. This conclusion, however, sharply contrasts with the longstanding common belief that data from colon cancer adjuvant trials should be extrapolated to inform treatment decisions for rectal cancer. How can this discrepancy be explained? Why does adjuvant chemotherapy work in colon cancer but may not work in rectal cancer?
Clinical guidelines recommendations and real-world data
The uncertainty regarding the role of adjuvant chemotherapy in rectal cancer is largely reflected by the variegated recommendations from national and international clinical guidelines.
While most guidelines ultimately suggest or recommend using adjuvant chemotherapy, substantial differences still exist across them especially with regards to the strength of the recommendation and the criteria for patient selection. According to the ESMO guidelines it is reasonable to discuss with patients risks
Who are the patients who may benefit most from adjuvant chemotherapy?
In this complex scenario, the question as to whether there are subgroups of patients who could benefit from adjuvant chemotherapy and how these should be identified has become increasingly relevant.
TNM stage is the strongest and most commonly used risk factor in rectal cancer. The routine use of pre-operative (chemo)radiotherapy for locally advanced tumours (i.e., ≥T3 or N+) as defined by pelvic MRI, however, adds significant complexity to the interpretation and use of tumour stage as a
Recommendations for clinical practice
The suboptimal quality of the completed trials and the results of the same make adjuvant chemotherapy in rectal cancer one of the most controversial topics in modern clinical oncology. It is clear though that no strong recommendation can be made for its regular use, and physicians should refrain from using data from colon cancer trials to guide management choices in routine practice. This approach can be no longer justified in the evidence-based era. Instead, a risk-adapted decisional algorithm
Future perspectives and conclusions
After decades of clinical research, the exact role of adjuvant chemotherapy in the modern multimodal management of rectal cancer remains an unsolved puzzle. Furthermore, early closure of most clinical trials suggests that no solution is likely to be found unless novel and more appealing study designs are proposed to re-engage physicians and patients and to revive their interest in this clinical question.
A game changer could certainly be the analysis of circulating tumour (ct)DNA. While the
Declaration of Competing Interest
The Authors do not have any conflict of interest to disclose.
References (101)
- et al.
Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm. Stockholm Colorectal cancer study group, Basingstoke bowel cancer research project
Lancet
(2000) - et al.
Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial
Lancet
(2009) - et al.
The impact of recurrent rectal cancer on quality of life
Eur J Surg Oncol
(2001) - et al.
Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicenter, randomized controlled TME trial
Lancet Oncol
(2011) - et al.
Adjuvant chemotherapy in cancer of the colon and rectum: demonstration of effectiveness of prolonged 5-FU chemotherapy in a prospectively controlled, randomized trial
Surg Clin North Am
(1981) Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study
Lancet
(2007)- et al.
Adjuvant postoperative radiotherapy and chemotherapy in rectal carcinoma: a review of the Gastrointestinal Tumor Study Group experience
Radiother Oncol
(1988) - et al.
No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): Long term results of a randomized trial (I-CNR-RT)
Radiother Oncol
(2014) - et al.
Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study
Lancet Oncol
(2014) - et al.
Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial
Ann Oncol
(2015)