Neoadjuvant Chemotherapy Alone for Early-Stage Rectal Cancer: An Evolving Paradigm?

https://doi.org/10.1016/j.semradonc.2011.02.005Get rights and content

Current management of early-stage rectal cancer comprises combinations of surgery, radiotherapy, and chemotherapy, with the presence or absence of several validated high-risk features determining which treatment modalities will be used and the order of administration. In high-risk individuals, most centers have adopted neoadjuvant combined chemotherapy and radiotherapy followed by surgery as the initial approach. However, long-term toxicity, limited survival gains, and high rates of distant failure have called this approach into question, with early data suggesting that neoadjuvant chemotherapy alone may be feasible in selected patient groups. This review discusses the current data and feasibility of managing early stage rectal cancer with neoadjuvant chemotherapy before surgical resection.

Section snippets

Selection of Patients for Multimodality Therapy

The universal implementation of total mesorectal excision (TME) and neoadjuvant hypofractionated (short-course) radiotherapy (SCRT) or long-course chemoradiation (CRT) have reduced local recurrence rates from 25% to 40% to under 10%.3, 4, 5, 6 However, multimodality management increases toxicity and has not consistently translated to improved survival, with only the Swedish Rectal Cancer Trial showing a survival benefit after SCRT in the pre-TME era.7, 8 With 5-year survival rates greater than

Neoadjuvant Radiotherapy

The dominant pattern of local recurrence after rectal cancer surgery and its devastating impact have led to neoadjuvant radiotherapy becoming a standard of care. The treatment of local recurrence remains a management challenge, and outcomes are extremely poor. The neoadjuvant treatment strategy offers several advantages, allowing for preoperative downstaging of the primary tumor, thus increasing the likelihood of an R0 resection and/or sphincter-preserving surgery; improves radiosensitivity by

Long-Term Impact of Radiotherapy

The toxicity of pelvic radiotherapy for rectal cancer can be problematic. Although acute side effects and surgical complications are only marginally increased with the addition of preoperative radiotherapy to surgery,23 the impact of neoadjuvant SCRT on long-term toxicities has been established in large randomized trials. The Dutch Colorectal Cancer Group found that compared with those who underwent TME alone, irradiated patients experienced significantly higher rates of fecal incontinence (62%

Adjuvant Chemotherapy

Distant failure rates remain as high as 36% with neoadjuvant CRT alone,20 heavily contributing to the lack of survival benefit of this approach. Therefore, intensification of the systemic component of management is needed, and chemotherapy without radiotherapy has only been evaluated in the adjuvant setting. Several studies have shown a survival benefit with adjuvant chemotherapy.26, 27, 28, 29 In a pooled analysis of 5 phase III trials, OS was significantly improved by adjuvant chemotherapy

Neoadjuvant Chemotherapy Plus Chemoradiotherapy

Despite the efficacy of postoperative chemotherapy, only 40% to 60% is administered at full dose, most commonly because of toxicity.20, 32, 36 Thus, several phase II studies have incorporated chemotherapy into preoperative management in high-risk patients. At our institution in a single-arm phase II study, Chau et al37 administered 12 weeks of 5-FU plus mitomycin C (MMC) before CRT and postoperatively to 36 patients with locally advanced tumors (at least T3 disease on digital rectal examination

Targeted Therapy

Blockade of both VEGF and EGFR with monoclonal antibodies has proven efficacy in advanced colorectal cancer.41, 42, 43, 44, 45, 46 Bevacizumab, a VEGF antibody, has been incorporated into neoadjuvant CRT with variable toxicity and pCR rates (0%-32%), but reports so far are limited to small numbers and no firm conclusions regarding its additional benefit can be made at present.47, 48, 49 Two recent studies have added bevacizumab to neoadjuvant chemotherapy, before CRT, again with small numbers.

Conclusions

Three notions remain clear; first, all locally advanced rectal tumors do not behave in the same manner. Second, multimodality treatment, particularly neoadjuvant therapy, improves outcomes, and third, reductions in local recurrence do not obviously confer a survival benefit. Because of the strong prognostic value of CRM involvement, extramural spread, higher nodal stage, and low tumor position in T3-T4 tumors, along with the improved outcomes with an R0 resection in high-risk groups, patients

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    Supported by the National Health Service Funding to the National Institute for Health Research Biomedical Research Centre.

    David Cunningham received funding from Roche, Amgen, and Merck Serono and is on the Advisory Board for Roche and Amgen; and Ian Chau received funding from Novartis, Roche, and Merck Serono and is on the Advisory Boards of Imclone, Novartis and Merck.

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