Neoadjuvant therapy for rectal cancer
Neoadjuvant treatment with radiation (with or without chemotherapy), followed by surgery, is current practice for managing most mid-low rectal cancers that are staged preoperatively as at least T3 and/or at least N1 (i.e. Stage II or III), in individuals well enough to tolerate it.
The timing of treatment preoperatively rather than postoperatively is based on the results of the CAO/ARO/AIO-94 study, a seminal 2004 phase III randomised controlled trial (RCT) comparing preoperative (neoadjuvant) with postoperative (adjuvant) chemoradiation, which reported a significant improvement in local control in favour of neoadjuvant chemoradiation. This finding changed practice at the time.
Both neoadjuvant long-course chemoradiation and short-course radiation treatment alone are delivered with the primary aim of reducing the risk of local recurrence. Neoadjuvant therapy can also achieve downsizing of the tumour, attain pathological complete response, and enable sphincter preservation surgery. However, there is not enough time for tumour downsizing with short-course radiation treatment followed by immediate surgery.
Both short-course radiation treatment and long-course chemoradiation emerged as recommended management options following trials investigating either strategy that recruited simultaneously and were conducted in parallel over several years during the 1980s and 1990s. Geographic preferences have emerged: for chemoradiation in the USA and Mediterranean Europe, and for radiation treatment in Scandinavia and Northern Europe. Recent RCTs comparing chemoradiation and radiation treatment have not shown any clear advantage for one strategy over the other.
Determining suitability for neoadjuvant therapy[edit source]
It is important to make the distinction between upper (high) rectal cancers and/or rectosigmoid cancers, and the mid–low cancers that lie within the true pelvis. This is crucial as upper cancers do not require treatment with neoadjuvant therapy, and overall management (including adjuvant therapy) should follow that of colon cancers. The somewhat common approximation of upper versus lower rectal cancer being situated above or below the peritoneal reflection is not accurate for each and every patient, and should not be used alone to distinguish between upper and lower rectal cancers for the purposes of deciding management. The key neoadjuvant rectal cancer trials defined rectal cancer by the number of centimetres from the anal verge; but the studies included a variety of upper limits, usually ranging between 15-16cm; and most participants’ tumours were in fact situated <10cm from the anal verge. The decision regarding whether a rectal cancer – based on its location – requires neoadjuvant treatment relies on expert and accurate multidisciplinary input in particular from the radiologist and surgical endoscopist.
It is also important to acknowledge the heterogeneity in rectal cancers staged as Stage II (T3-4 N0). Patients with T4 tumours (AJCC/UICC stage IIB and IIC disease) should always undergo neoadjuvant treatment where feasible. Within the Stage IIA (T3N0) T3 MRI staging, a tumour may be considered ‘early T3’ or ‘late T3’, or somewhere in between, depending on the distance of extension in millimetres in the axial plane beyond the muscularis propria. On this basis, T3 disease has been subdivided into T3a-d disease in some literature, T3a being <1mm, T3b 1-5mm, T3c 5-15mm and T3d >15mm extension. A simpler subdivision has used T3a as ≤5mm and T3b as >5mm extension. Notably, although the depth of T3 extension has been shown to be a prognostic factor for recurrence, the current American Joint Committee on Cancer (AJCC) 8th Edition TNM staging system does not include subdivisions of T3 disease. The Royal College of Pathologists of Australasia Structured Pathology Reporting of Colorectal Cancer Protocol notes that in lieu of providing a formal T3a-d classification, the distance of invasion in millimetres may be provided in the pathology report as an alternative; although this is not prescriptive.
Within radiological (MRI) reporting, considerable variability has been documented as to whether T3 distance in millimetres is routinely formally reported. Accurate MRI staging is critical in determining T stage, and depth of extension through muscularis propria for T3 disease. It is acknowledged that accuracy, especially when distinguishing between T2 and early T3 disease, is challenging but may not impact on management.
European ESMO guidelines note that ‘early cT3’ (<1mm extension) rectal cancers could be appropriate for primary TME surgery without neoadjuvant therapy. The St Gallen EORTC conference consensus recommendations in 2016 also indicated primary TME surgery without neoadjuvant therapy as an option for early low-risk rectal cancers, including cT3a (<1mm extension) disease. However, the US NCCN guidelines do not distinguish between T3 tumours and recommend neoadjuvant therapy for all T3 disease. Ultimately a high level of confidence in the MRI staging is crucial as this directly influences management strategy. As millimetres can mean the difference between primary surgery or neoadjuvant therapy, careful multidisciplinary review and discussion is essential.
For clinical stage I (cT1-2, N0, M0) rectal cancer, if there is a high level of confidence in the preoperative staging evaluation of node negative disease, surgery alone without neoadjuvant treatment is the preferred approach. If subsequent histopathological evaluation unexpectedly results in upstaging (pT3 or N1-2 disease) or there are several high-risk features (such as positive margins or lymphovascular invasion), then adjuvant therapy should be considered on an individual case-by-case basis. An ASTRO 2016 Clinical Practice Statement utilised a systematic review and expert opinion to formulate recommendations for appropriate customisation of radiation treatment for stage II and III rectal cancer. It noted several acceptable options for medically inoperable patients or those who refused surgery, including definitive radiation treatment or chemoradiation. This guidance could be extended to patients with stage I disease.
In patients who refuse or who are unable to tolerate surgery, definitive radiation treatment with or without chemotherapy may be considered as a potentially curative approach. There are no randomised controlled trial data to support this.
Accurate determination of suitability for neoadjuvant therapy is based on careful preoperative location and staging assessments, and requires optimal quality of care from each aspect of the multidisciplinary team’s assessment.
Chapter subsections[edit source]
Please see sections:
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