Rectal cancer: preoperative versus postoperative irradiation as a component of adjuvant treatment

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Abstract

The search for improved disease control and survival for resectable but high-risk rectal cancers has led to studies that combine all 3 modalities. For surgically resected, high-risk rectal cancers, postoperative chemoradiation has been shown to improve both disease control (local and distant) and survival (disease free and overall) and was recommended as standard adjuvant treatment at the 1990 National Institute of Health Colorectal Cancer Consensus Conference. Three randomized studies showed improved overall survival (OS) and local control for patients treated with postoperative irradiation and chemotherapy when compared with surgery alone or surgery plus irradiation control arms. These include 2 US trials, Gastrointestinal Tumor Study Group and Mayo/North Central Cancer Treatment Group (NCCTG) and a Norway trial. Although most preoperative external beam radiation trials show reductions in local relapse with the addition of preoperative EBRT to resection, only the large Swedish trial of ∼1,100 patients showed a survival improvement when compared with a surgery alone control arm for resectable primary rectal cancers. In a recent pooled analysis of 3 postoperative adjuvant rectal cancer trials (NCCTG 794751, NCCTG 864751, and GI Intergroup 0114) survival and disease relapse were dependent on both TN and NT stage of disease (N substage within T stage and T substage within N stage). Even among N2 patients (4 or more positive nodes), T substage influenced 5-year OS (T1-2, 69%; T3, 48%; and T4, 38%; P < .001). Ongoing randomized trials are being conducted for patients with high-risk, resectable primary rectal cancers. The intent is to help define optimal combinations of postoperative chemoradiation (US GI Intergroup), to test sequencing issues of preoperative versus postoperative chemoradiation (Germany trial), and to determine if concurrent and maintenance 5-FU and leucovorin add to the benefits found with preoperative irradiation (European Organization for Research and Treatment of Cancer). For subsequent trials, it may be preferable to perform separate studies, or a planned statistical analysis, for different risk groups of patients (low, intermediate, moderately high, and high), as defined in the rectal cancer pooled analysis.

Section snippets

Preoperative vs postoperative irradiation

When both surgery and radiation are indicated in an adjuvant setting, differences of opinion exist regarding the preferred sequence of each modality. Potential advantages of preoperative irradiation (± concurrent and maintenance chemotherapy) include the damaging effect on cells that may be spread locally or distantly at the time of resection and downstaging of lesions in an attempt to improve the rate of sphincter preservation. The major advantage of postoperative irradiation (± concurrent and

Results and prognosis

Results will be presented as a function of disease presentation and whether complete surgical resection is feasible for primary lesions. For lesions that appear to be high-risk but resectable with negative margins, results in adjuvant trials of both preoperative and postoperative irradiation will be discussed (single v combined modality).

Trial design and results of pertinent randomized studies will be presented with a focus on 3 independent scientific endpoints identified at the 1990 National

Complications and therapeutic ratio

An optimal therapeutic ratio between local control and complications is achieved only with close interaction between the surgeon and the radiation oncologist and the use of sophisticated radiation techniques.37, 38, 39, 40 In the Massachusetts General Hospital postoperative rectal adjuvant series that used shaped multiple-field irradiation techniques, bladder distention, and so on, the incidence of small bowel obstruction requiring operative intervention was the same in patients receiving

Summary and future directions for adjuvant therapy

The impact of pre- and postoperative irradiation ± chemotherapy on both disease-relapse and survival in major randomized adjuvant rectal cancer trials is summarized in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9.

Single-modality rectal adjuvants

Neither irradiation nor chemotherapy as single adjuvant modalities achieve all suggested criterion of efficacy except for the large Swedish preoperative irradiation trial.21 Adjuvant irradiation reduces the rate of local relapse in both prospective nonrandomized as well as randomized preoperative and postoperative trials, but this has not translated into an improvement in OS in most series because of a lack of impact on distant metastases. The only published trial in which single-modality

Combined modality rectal adjuvants

Only combined modality postoperative adjuvant treatment has consistently shown efficacy in all scientific endpoints as noted in 2 prospectively randomized US trials (GTSG 717524, 25 and Mayo/NCCTG 79-47-5126) and a third trial from Norway27). In both of the US studies, bolus 5-FU was administered during irradiation, and patients received additional chemotherapy either after irradiation plus 5-FU (GTSG) or both before and after (Mayo/NCCTG) the combined modality segment of treatment. In the

Sequencing of systemic chemotherapy and concurrent chemoradiation

A delay in concurrent chemoradiation to allow the delivery of 2 cycles of systemic chemotherapy has been the routine in most phase III rectal adjuvant postoperative chemoradiation trials in the United States, starting with Mayo/NCCTG 794751.26 However, the improvement in 4-year DFS found in the phase III trial from Seoul, Korea, suggests that we may need to reevaluate the sequencing of systemic chemotherapy and chemoradiation in subsequent postoperative adjuvant chemoradiation trials. It would

Results by TN stage and treatment method (rectal cancer-pooled analyses): future implications

In the initial pooled analysis of 2,551 eligible patients who received postoperative adjuvant treatment,35 OS and DFS were dependent on both TN stage Table 3, Table 4 and NT stage Table 5, Table 6. Even among N2 patients, T stage influenced 5-year OS (T1-2, 69%; T3, 48%; T4, 38%; P < .001) (Table 5). Three risk groups of patients were defined: (1) intermediate, T3N0 and T1-2N1; (2) moderately high, T4N0, T1-2N2, and T3N1; and (3) high, T3N2, T4N1, and T4N2. For Group 1, 5-year OS rates were 74%

Clinical investigations and treatment algorithms

Future trials need to continue to define optimal combinations of chemo-radiation (what drugs, route and timing of delivery, sequencing of irradiation and chemotherapy, etc.) and to determine whether some patients can be spared the most aggressive treatment combinations (i.e., limited T3N0 and T1-2 N1 lesions). There is a need to evaluate which drug(s) and what method of administration should be used during irradiation to enhance its effect and which drugs are necessary to alter systemic

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