How to Select for Preoperative Short-course Radiotherapy, While Considering Long-course Chemoradiotherapy or Immediate Surgery, and Who Benefits?

European Oncology & Haematology, 2014;10(1):17–24

Abstract:

The management of patients with locally advanced rectal cancer (LARC) has evolved with the aim of reducing local recurrence and improving survival. Current practice has developed from refinements in surgical technique, the availability of different types of preoperative imaging, the selective or blanket use of neoadjuvant treatment (usually radiation) and sophisticated efforts exploring multimodality treatments to achieve organ preservation. Both short-course preoperative radiotherapy (SCPRT) and long-course chemoradiation (CRT) are considered standard neoadjuvant strategies, which are advocated in different parts of the world. New techniques in the delivery of radiotherapy, such as intensity-modulated radiotherapy (IMRT), may allow more precise dosing to the target volume (tumour and/or locoregional lymph nodes) and limit radiation doses to critical normal structures; however, current schedules of SCPRT and CRT impact on late function, and if they do not improve survival in resectable cancers, can they be omitted in selected cases?

Keywords: Rectal adenocarcinoma, neoadjuvant radiation, chemoradiation, chemotherapy, short-course preoperative radiation, long-course chemoradiation
Disclosure: Rob Glynne-Jones has received honoraria for lectures and advisory boards and has been supported in attending international meetings in the last five years by Eli Lilly, Merck, Pfizer, Sanofi-Aventis and Roche. He has received unrestricted grants for research from Merck-Serono, Sanofi-Aventis and Roche. He is principal investigator of a randomised phase II neoadjuvant chemotherapy study in the UK called BACCHUS. David Tan, Brendan J Moran and Vicky Goh have no conflicts of interest to declare. No funding was received for the publication of this article.
Received: February 01, 2014 Accepted May 12, 2014 Citation European Oncology & Haematology, 2014;10(1):17–24
Correspondence: Rob Glynne-Jones, Mount Vernon Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN, UK. E: rob.glynnejones@nhs.net

In patients with locally advanced rectal cancer (LARC), not involving the mesorectal fascia (MRF), surgery with total mesorectal excision (TME) is the standard of care. Prior to the TME era, high rates of local recurrence (LR) were observed after radical surgery, and 10–40 % of patients required a permanent stoma, even for tumours arising in the mid/upper rectum. In the 1990s, randomised trials1–3 established shortcourse preoperative pelvic radiotherapy (SCPRT) using 5 x 5 Gy as a component of the curative treatment of resectable and early rectal cancers. These historical trials reported LR rates of 20–30 % after surgery alone, reflecting the suboptimal surgical practice at the time.

Two subsequent trials examined whether SCPRT simply compensated for poor surgical technique, i.e. whether SCPRT still reduced LR if TME was performed. By then, it was recognised that the risk of LR, after a potentially curative resection, is mainly explained by microscopic tumour cells within 1 mm of the circumferential resection margin (CRM).4 Hence, in the control group in the event of a histopathological involved CRM, postoperative RT or chemoradiotherapy was intended in the Dutch TME study5 and CR07 trial,6 respectively. Both trials confirmed a reduction in LR, but overall survival (OS) was not improved, and the risk of metastases predominated over LR.5–8

During the same period, the strategy of postoperative fluorouracil (5FU)-based chemoradiation (CRT) for patients with stage II or III rectal cancer9 was extrapolated to the preoperative setting. Randomised trials of preoperative 5FU-based CRT demonstrated an improvement in locoregional control,10–12 but not disease-free survival (DFS) or OS. However, in more advanced unresectable/borderline cases, CRT improved resectability and DFS.13 The German trial also led to the recognition that preoperative CRT is more effective and less morbid than postoperative CRT.10 With the benefit of preoperative imaging (computed tomography [CT], transrectal ultrasound and magnetic resonance imaging [MRI]) to stage and define the ease of resectability, neoadjuvant CRT has been widely extended, particularly when the CRM is predicted to be compromised.

Hence, different strategies for treating LARC have developed independently in different countries, shaped by local experts and regional biases based on the results of individual national trials. Both SCPRT and long-course CRT are considered standard strategies, which are fervently advocated in highly polarised arguments. Sometimes there are perverse incentives in terms of reimbursement that partly drive these selections.

Ideally, we should individualise available treatments, based on clinical, imaging and molecular characteristics. This strategy could select patients more likely to respond to RT/chemotherapy/targeted agents or could spare patients from treatment that may not be needed, or is unlikely to be effective. Imaging can accurately determine the local disease extent and the presence of metastatic disease. The prospective multicentre MERCURY trial established that MRI measured extramural primary tumour extent was equivalent to measurement in the resection specimen.14 MRI can also identify macroscopic extramural vascular invasion and a CRM at risk (<1 mm).

There has been a long-standing debate on whether to improve surgical quality or utilise RT.15 The majority of LRs historically reflected inadequate mesorectal resection,16 which is a common finding on postoperative MRI after partial mesorectal excision.17 Currently, optimal quality-controlled surgery, in terms of TME in the trial setting, can be associated with LR rates of less than 10 %, whether patients receive RT or not.7 Factors that compromise the performance of good-quality TME are well recognised and include patient- and disease-related aspects and the surgeon’s case volume.18

This review attempts to evaluate the individual advantages relating to SCPRT or long-course CRT. The question as to whether there is a group of patients who do not need RT because the benefit is so marginal is also addressed. It represents an individualised approach to the use of radiation therapy, with speculation on future applications and developments.

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Keywords: Rectal adenocarcinoma, neoadjuvant radiation, chemoradiation, chemotherapy, short-course preoperative radiation, long-course chemoradiation