Neoadjuvant chemotherapy prior to preoperative chemoradiation or radiation in rectal cancer: should we be more cautious?

Abstract

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 l...

A Phase II Study of Additional Four-Week Chemotherapy With Capecitabine During the Resting Periods After Six-Week Neoadjuvant Chemoradiotherapy in Patients With Locally Advanced Rectal Cancer

“…Distant micrometastases could remain despite sterilization of tumor cells around the tumor's origin in the pelvis. Neoadjuvant chemotherapy has theoretical advantages over the potential to eradicate early distant micrometastases, which may already exist at initial diagnosis or may grow during preoperative treatment [ 29 ]. Although the resting period is essential when preparing for surgery, it could be considered as a delay of definite surgery and as a vacancy of treatment.…”

The multidisciplinary management of rectal cancer

“…Studies on patients who obtain a complete clinical response after neoadjuvant chemoradiotherapy show that increasing cT stage was associated with increased risk of local regrowth (random-effects hazard ratio per cT stage: 1•40, 95% CI: 1•00-1•94; P= 0•048). 2-year cumulative incidence of local regrowth was 19% (95% CI: 13-28) for stage cT2 tumours and 31% (95% CI: [26][27][28][29][30][31][32][33][34][35][36][37] for cT3 tumours 22 . Local recurrence-free survival has also been shown to be significantly better for patients with cT2 tumours than those with cT3 tumours at 1 year after neoadjuvant chemoradiotherapy (96% versus 69%; P=0.009), with a lower baseline T stage serving as an independent predictor of improved local recurrencefree survival at 1 year (OR=0.09 95% CI: 0.01-0.81; P=0.03) 23 .…”

“…Once the treatment decision is made for a patient with rectal cancer to have neoadjuvant therapy, three evidence-based approaches are currently supported: longcourse chemoradiotherapy; induction chemotherapy followed by long-course chemoradiotherapy; and short-course radiotherapy with increasing use of regimens where all chemotherapy is delivered upfront (total neoadjuvant treatment) and consolidation approaches (delivering chemotherapy after chemoradiotherapy completion and before surgery) 10,11,[36][37][38] to sterilize the mesorectal fat before surgery and the regimen does not include chemotherapy. Patients receive 5 Gy per day for 5 days total, then typically proceed to surgery within 1-2 weeks.…”

Current debate in the oncologic management of rectal cancer

“…Despite the controversial results of the EORTC 22921, there remains substantial interest in the use of systemic chemotherapy, both as adjuvant therapy and as CRT, to decrease distant metastatic disease and improve survival[ 20 ]. The theoretical advantages of systemic chemotherapy include eradicating distant micrometastases and providing ideal systemic treatment prior to a large and potential debilitating surgery (and thus a less fit patient)[ 21 ].…”