Elsevier

Cancer Treatment Reviews

Volume 28, Issue 4, August 2002, Pages 181-188
Cancer Treatment Reviews

ANTI TUMOUR TREATMENT
Adjuvant therapy of resectable rectal cancer

https://doi.org/10.1016/S0305-7372(02)00037-3Get rights and content

Abstract

The two conventional treatments for clinically resectable rectal cancer are surgery followed by postoperative combined modality therapy and preoperative combined modality therapy followed by surgery and postoperative chemotherapy. Preoperative therapy (most commonly combined modality therapy) has gained acceptance as a standard adjuvant therapy. The potential advantages of the preoperative approach include decreased tumor seeding, less acute toxicity, increased radiosensitivity due to more oxygenated cells, and enhanced sphincter preservation. There are a number of new chemotherapeutic agents that have been developed for the treatment of patients with colorectal cancer. Phase I/II trials examining the use of new chemotherapeutic agents in combination with pelvic radiation therapy are in progress.

Introduction

There are two conventional treatments for clinically resectable rectal cancer. The first is surgery and, if the tumor is T3 and/or N1–2, this is followed by postoperative combined modality therapy (1). If the tumor on ultrasound assessment is classified as T3 or clinically staged as T4 then preoperative combined modality therapy followed by surgery and postoperative chemotherapy is the alternative approach (2).

Section snippets

Postoperative therapy

The NCI Consensus Conference concluded in 1990 that combined modality therapy was the standard postoperative adjuvant treatment for patients with T3 and/or N1–2 disease (1). Pelvic radiation therapy decreases local recurrence but does not improve survival. As would be predicted, randomized data do not reveal a survival advantage of pelvic radiation plus elective para-aortic and liver radiation versus pelvic radiation alone (3).

For patients treated with postoperative combined modality therapy

Are there patients who do not require postoperative adjuvant therapy?

There are retrospective data that suggest that there may be a subset of patients with T3N0 disease who do not require adjuvant therapy, as well as some patients with Stage I disease that should be considered for adjuvant therapy. Retrospective trials examining patients at both the MGH (17) and MSKCC (18) have identified favorable subsets of patients with T3N0 disease who, following surgery alone, had a 10-year actuarial local recurrence rate of <10%. These results need to be confirmed in a

Preoperative therapy

Preoperative therapy (most commonly combined modality therapy) has gained acceptance as a standard adjuvant therapy. The potential advantages of the preoperative approach include decreased tumor seeding, less acute toxicity, increased radiosensitivity due to more oxygenated cells, and enhanced sphincter preservation (2). The primary disadvantage of preoperative radiation therapy is the possible over treatment of patients with either early stage (T1–2N0) or undetected metastatic disease.

Sphincter function

Sphincter preservation without good function is of questionable benefit. In a series of 73 patients who underwent surgery, Grumann and associates reported that the 23 patients who underwent an APR had a more favorable quality of life compared with the 50 who underwent a low anterior resection (36).

Although preoperative combined modality therapy may adversely effect sphincter function, the impact is probably less than postoperative combined modality therapy (37). In four of the seven

Randomized trials

Three randomized trials of preoperative versus postoperative combined modality therapy for clinically resectable, T3 rectal cancer have been developed. Two are from the United States (INT 0147, NSABP R0-3) and one from Germany (CAO/ARO/AIO 94). All three use conventional doses and techniques of radiation therapy and concurrent 5-FU based chemotherapy and require a preoperative clinical assessment declaring the type of operation required. Unfortunately, low accrual has resulted in early closure

Response of the primary tumor

Although some series show no correlation (38), most series suggest that there is improved outcome with increasing pathologic response to preoperative therapy [39], [40], [41], [42]. Analysis of biopsies examining selected molecular markers such as c-K-ras (43), thymidylate synthase (44), p27kip1 (45), p53 [46], [47], [48], apoptosis [49], [50], and Ki-67 (51) have had varying success in helping to select patients who may best respond to preoperative therapy.

In one series the value of radical

The impact of total mesorectal excision on adjuvant therapy

Some physicians contend that adjuvant therapy is not necessary if patients undergo resection with a TME. In one series, TME, which involves sharp dissection around the integral mesentery of the hind gut, decreased the local recurrence rate to 5% (57). These data must be interpreted with caution for a number of reasons. First is selection bias. TME allows the identification and exclusion of patients with more advanced disease as compared with patients treated in the adjuvant trials in which more

Alternative radiation therapy approaches

Various fractionation strategies have evolved with the goal of enhancing tumor cell damage by radiation without augmenting normal tissue injury. The major limitation of accelerated hyperfractionation is acute normal tissue toxicity. However, late effects should be the same as or, more likely, less than in conventional fractionation schemes.

There are limited data on the use of twice a day (BID) radiation therapy in the pelvis. In a phase I/II trial from the RTOG, 54 patients with advanced

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