Cancer of the Rectum: Neoadjuvant Therapy

Introduction

In the era of total mesorectal excision (TME) surgery, preoperative radiotherapy (RT) reduces local recurrence (LR) and can be administered either as long-course RT (LCRT) with a 5-fluorouracil (5-FU)–based regimen or as short-course RT (SCRT). For patients with a positive circumferential resection margin (CRM) at TME, tumor downstaging is highly desirable. In these circumstances, SCRT is not as effective as LCRT in preventing LR. To reduce radiation-related toxicity, field adjustments and new targeted radiation modalities should be explored.

Radiation therapy was initially introduced as part of the treatment regimen of rectal cancer to improve local control in conjunction with surgery for patients with locally advanced disease. During the past two decades, neoadjuvant (NA) therapy has evolved significantly, not only through its application in serial randomized clinical trials (RCTs) but also as a result of advances in technology that include introduction of computerized imaging techniques. Currently, the treatment of patients with rectal cancer centers around a TME along with NA therapy. Locally advanced rectal cancers are those that are stage III and some that are stage II with extensive local tumor spread. Such patients are treated with similar strategies based on National Comprehensive Cancer Network recommendations ( http://www.nccn.org/clinical.asp ). However, in the era of modern tumor imaging, rectal magnetic resonance imaging (MRI) in particular facilitates the precise estimation of involvement of the CRM, which is the most important factor predicting LR and systemic disease. The Mercury Trial investigators reported that for patients with a positive CRM on preoperative MRI, the risks of LR and systemic spread were significantly higher than for patients with a negative CRM.

Radiotherapy Trials

Surgery remains the cornerstone of rectal cancer treatment for locally advanced (T3/T4) tumors. To further improve local control (LC) in rectal cancer, NA RT has been added to surgical treatment. The benefit of NA SCRT was first shown by the Swedish Rectal Cancer Group in the pre-TME era. After a median follow-up of 5 years, the LR risk was 11% in the group that underwent radiation and 27% in the group that did not undergo radiation, and the overall survival (OS) rates were 58% and 48%, respectively. In spite of these excellent results, the role of RT was questioned after the introduction of TME. In a Dutch TME study, the benefit of SCRT followed by immediate TME was demonstrated, with a 10-year LR rate of 11% for patients treated with TME alone versus 5% for patients treated with SCRT followed by TME. In the MRC-CR07 study, which has a comparable design, patients with resectable rectal cancer were randomized between NA SCRT followed immediately by surgery versus surgery alone. The patients in the group that underwent surgery alone received postoperative chemotherapy (CT)-LCRT when the CRM was involved. The LR rate was 5% in the patients receiving NA SCRT and 12% in patients undergoing surgery alone ( P <.001), demonstrating that selective postoperative CT-LCRT is not able to provide the same results as preoperative treatment.

It has been established that NA RT (either SCRT alone or CT-LCRT) provides significantly better local control than does postoperative CT-LCRT, and LR rates are significantly improved in patients receiving NA SCRT. In this study, the benefits of NA SCRT were observed at all tumor levels, including upper third tumors, and were significant even for patients with specimens obtained within the mesorectal plane. Thus far no survival benefit has been demonstrated for patients who received RT and underwent surgery with the TME technique. In the Dutch TME trial, NA SCRT had no effect on OS or cancer-specific survival when all randomized patients were included in the analyses. However, in patients with a negative CRM who underwent surgery, RT significantly improved cancer-specific survival. Unfortunately, this benefit was offset by an increase in other causes of death, resulting in an equal OS rate compared with the group that underwent surgery only. A subgroup analysis demonstrated that for patients with TNM stage III cancer who had a negative CRM, 10-year survival was 50% in the NA SCRT group versus 40% in the surgery-alone group ( P = .032). In most studies, the LR rate was reduced from greater than 10% for patients treated with surgery only to 5% for patients treated with NA RT and surgery.

NA RT, in conjunction with TME, improves local control but does not improve OS.

Role of Circumferential Resection Margin

In the Dutch TME trial, patients with a positive CRM who had not undergone RT had an LR rate of 23.3%, whereas those who received RT showed a drop in LR to 15.5% ( P = .16). The MRC-CR07 trial showed an LR of 13.8% in patients receiving NA SCRT with 5 × 5 Gy and an LR of 20.7% in patients receiving postoperative CT-LCRT.

In patients with a positive CRM, NA SCRT is not as effective in reducing LR.

Multimodality Treatment Approaches

Several Northern European RCTs have demonstrated a significant reduction in the LR rate after SCRT. Optimal treatment for the different stages of rectal cancer and prioritization of treatment modalities are controversial. In Northern Europe, SCRT is the standard of care for most patients with stage II and III rectal cancer, whereas CT-LCRT is reserved for more advanced cases with a positive CRM. On the other hand, in America and southern Europe, most patients are treated with NA LCRT (LCRT, 45 to 50 Gy) in combination with CT. Furthermore, because the EORTC-22921 and FFCD-9203 studies demonstrated that the addition of CT to preoperative LCRT enhances local control in locally advanced (T3/T4) tumors, with this finding recently confirmed by a recent Cochrane review, patients are now treated with CT-LCRT, followed by TME.