The National Surgical Adjuvant Breast and Bowel Project (NSABP) R-01 trial randomised 574 patients with histologically staged Dukes B and C rectal cancer following a curative resection to three groups: a control group receiving no further treatment; postoperative radiation therapy alone; and postoperative chemotherapy consisting of semustine, vincristine, and 5-FU (MOF) [4]. The dose of radiation was 46–47 Gy, or 51–53 Gy for those patients intended to receive a perineal boost.

Postoperative chemotherapy significantly improved DFS (p = 0.006). with a borderline improvement in OS (p = 0.05) from chemotherapy. Only males benefitted from chemotherapy in terms of DFS and OS, and women actually achieved worse OS (which did not reflect treatment associated deaths). Postoperative radiotherapy decreased local regional failure to 16 % versus 25 % in the control group and 21 % in the chemotherapy group (p = 0.06 for the comparison with the control group). Radiation itself did not confer any significant benefit in terms of DFS or OS for either males or females.

The Gastrointestinal Tumor Study Group (GITSG) trial evaluated the benefit of the respective roles of radiation, chemotherapy, or combined modality therapy (chemoradiation) in the treatment of locally advanced rectal cancer [2]. After curative surgery 202 patients were randomized into four different groups: a control group receiving no further treatment; adjuvant chemotherapy only with semustine and 5-fluorouracil; adjuvant radiotherapy only at doses of 40–48 Gy, and finally a combination of chemotherapy and radiotherapy. After 80 months follow-up. significantly better DFS was observed in the combination therapy arm compared to resection alone, although there was no significant difference in OS in four groups 55 % recurred in the surgery alone control arm versus 46 % in the chemotherapy alone arm, 48 % in the radiation alone arm, and 33 % with combined CRT (p = 0.04). The comparison between the control arm and CRT was even more significant (p = 0.009). The long-term follow-up results of this study confirmed a significantly improved overall survival in the combination treatment group compared to surgery alone group [23].

The North Central Cancer Treatment Group (NCCTG) trial (protocol 79-47-51) evaluated a short chemotherapy regimen combined concurrently with a higher dose of radiation and the same higher-dose radiation regimen alone [3]. After curative surgery 209 patients were randomised to receive postoperative radiation therapy alone to a dose of 45 Gy plus a 5.4 Gy boost or postoperative semustine and 5-FU chemotherapy combined with the same radiation regimen. Patients randomised to CRT started treatment radiation after two cycles of chemotherapy, followed by two further cycles of chemotherapy. After a median follow-up time of over 7 years, the estimated 5-year recurrence rate in the radiation arm was 63 % compared with 42 % in the CRT arm. The CRT arm reduced overall recurrence by 34 % compared to the radiation alone arm (P < 0.003). The addition of chemotherapy to radiation reduced both local recurrence (25 % versus 13 % P < 0.02) and distant metastases (43 % versus 29.5 % P < 0.003). OS was also significantly improved (p = 0.025). CRT increased the acute toxicity in terms of nausea, vomiting, diarrhea, stomatitis, leukopenia, and thrombocytopenia. It should also be noted that a subsequent publication highlighted that there was a significant increase in severe diarrhoea (≥Grade 3) in the CRT arm (22 vs. 4 %, p = 0.001) and this was more marked in patients who underwent a low anterior resection compared with those who had an APER (p = 0.006) [24]. There was no significant increase in late morbidity in the CRT arm. In the light of this evidence, the National Institute of Health Consensus Conference in 1990 [25] recommended post-operative chemoradiation as the standard of care in the United States for curatively resected rectal cancer.

The NSABP R-02 trial evaluated whether adding radiation to chemotherapy was better than chemotherapy alone in terms of postoperative adjuvant therapy of Dukes B and C rectal cancers [26]. A radiation dose of 45 Gy with a 5.4 Gy boost was used. In the light of the NSABP R-01 results, male patients were randomised to one of four postoperative treatment groups: (1) 5-FU plus leucovorin (LV), (2) 5-FU plus LV plus radiation, (3) MOF chemotherapy, and (4) MOF chemotherapy plus radiation. Female patients were randomly assigned to 5-FU plus LV or 5-FU plus LV plus radiation The chemotherapy during radiation therapy for both combined modality arms involved bolus infusions of 5-FU during the first 3 and last 3 days of radiation therapy.

The results of NSABP R-02 supported the previous results of the NSABP R-01 study, where postoperative radiation therapy resulted in decreased locoregional recurrence, but not in improved DFS or OS. In NSABP R-02 radiation therapy added to chemotherapy again reduced the cumulative incidence of locoregional recurrence as a first event (8 % versus 13 % at 5 years) compared to chemotherapy alone (HR = 0.57), but had no impact on DFS, or OS. Males treated with 5-FU plus LV compared with MOF experienced significantly better DFS (55 % versus 47 % at 5 years), but not OS (65 % compared with 62 % at 5 years).

A randomised trial of postoperative 5FU based chemoradiation against surgery alone in Dukes B and C rectal cancer to a dose of 46 Gy demonstrated a significant improvement in local control, disease free survival and overall survival for postoperative chemoradiation [27]. Other randomised trials comparing postoperative radiotherapy with surgery alone [28, 29] showed some benefit in local control but no survival benefit. The small EORTC trial randomised only 172 patients and did not show any benefit in OS or local control from postoperative irradiation [30] following resection of locally advanced rectal carcinoma (Dukes B and C).

Many of these studies have been criticised because the design delayed the use of fully adequate systemic doses of 5FU until after the completion of the chemoradiation phase.

Subsequent successive studies in the postoperative setting have attempted to improve outcomes by modifying and intensifying the concurrent chemotherapy component. This strategy has been associated with only marginal success.