Neoadjuvant chemotherapy (NACT) is a term originally used to describe the administration of
chemotherapy preoperatively before surgery. The original rationale for administering NACT or so-called
induction chemotherapy to shrink or downstage a locally advanced tumour, and thereby facilitate more effective local treatment with surgery or
radiotherapy, has been extended with the introduction of more effective combinations of
chemotherapy to include reducing the risks of metastatic disease. It seems logical that survival could be lengthened, or organ preservation rates increased in resectable tumours by NACT. In
rectal cancer NACT is being increasingly used in locally advanced and nonmetastatic unresectable tumours. Randomised studies in advanced
colorectal cancer show high response rates to combination cytotoxic
therapy. This evidence of efficacy coupled with the introduction of novel
molecular targeted therapies (such as
Bevacizumab and
Cetuximab), and long waiting times for
radiotherapy have rekindled an interest in delivering NACT in locally advanced
rectal cancer. In contrast, this enthusiasm is currently waning in other sites such as head and neck and
nasopharynx cancer where traditionally NACT has been used. So, is NACT in
rectal cancer a real advance or just history repeating itself? In this review, we aimed to explore the advantages and disadvantages of the separate approaches of neoadjuvant, concurrent and
consolidation chemotherapy in locally advanced
rectal cancer, drawing on theoretical principles, preclinical studies and clinical experience both in
rectal cancer and other disease sites.
Neoadjuvant chemotherapy may improve outcome in terms of disease-free or overall survival in selected groups in some disease sites, but this strategy has not been shown to be associated with better outcomes than postoperative
adjuvant chemotherapy. In particular, there is insufficient data in
rectal cancer. The evidence for benefit is strongest when NACT is administered before surgical resection. In contrast, the data in favour of NACT before radiation or chemoradiation (CRT) is inconclusive, despite the suggestion that response to
induction chemotherapy can predict response to subsequent
radiotherapy. The observation that spectacular responses to
chemotherapy before radical
radiotherapy did not result in improved survival, was noted 25 years ago. However, multiple trials in
head and neck cancer,
nasopharyngeal cancer,
non-small-cell lung cancer,
small-cell lung cancer and
cervical cancer do not support the routine use of NACT either as an alternative, or as additional benefit to CRT. The addition of NACT does not appear to enhance local control over concurrent CRT or
radiotherapy alone.
Neoadjuvant chemotherapy before CRT or radiation should be used with caution, and only in the context of clinical trials. The evidence base suggests that concurrent CRT with early positioning of
radiotherapy appears the best option for patients with locally advanced
rectal cancer and in all disease sites where radiation is the primary local
therapy.