In the Dutch TME trial [4] non-irradiated patients with a positive CRM had a LR risk of 23.3 %, whereas those who received radiation showed a drop in LR risk to 15.5 % (p = 0.16). The MRC-CR07 trial [6] showed a LR rate of 13.8 % in patients receiving NA SCRT with 5 × 5 Gy and a LR rate of 20.7 % in patients receiving postoperative CT-LCRT.

Several Northern European randomized clinical trials (RCT) studies have demonstrated a significant reduction in the LR rate after SCRT (Table 46.1). There exists a controversy concerning optimal treatment for the different stages of rectal cancer and prioritization of treatment modalities. In Northern Europe, SCRT is the standard of care for most stage II and III rectal cancer patients. CT-LCRT is reserved for more advanced cases with positive CRM. On the other hand, in America and southern Europe, patients are treated with NA LCRT (LCRT, 45–50 Gy) in combination with chemotherapy (CT). Furthermore, as both the EORTC 22921 [7] and FFCD 9203 [8] studies demonstrated that the addition of CT to preoperative LCRT is beneficial to LC in locally advanced tumors (T3–4), patients are now treated with CT-LCRT, followed by TME S.

Two published RCT were conducted comparing SCRT to CT-LCRT: The Polish trial with 312 patients [9] and the Australian trial [10] with 326 patients. Both studies had a similar design and sample size was calculated to demonstrate a difference of 15 % in the rate of sphincter preservation (SPS) and 10 % in LR, respectively. Both trials showed higher rates of early radiation toxicity in the CT-LCRT arm when compared with the SCRT group; grade III to IV acute toxicity rates were 18 % versus 3 % (P = 0.001) in the Polish trial and 28 % versus 1.9 % (P = 0.001) in the Australian study. In the Polish trial, the SPS rate did not differ between the groups: 61 % in the SCRT group and 58 % in the CT-LCRT (P = 0.57). In this trial, the LR rate was slightly lower in the SCRT group than in the CT-LCRT group (10.6 % vs. 15.6 % (P = 102 .21), whereas the opposite tendency was seen in the Australian study at 7.5 % versus 4.4 % (P = 0.24). In this latter trial, a difference was observed in the group of tumors below 5 cm, with 6 out of 48 patients in the CT-LCRT arms. One out of thirty-one patients after SCRT although not statistically significant. Additionally, no increase in late toxicity rates was seen in the SCRT irradiation group compared with the CT-LCRT group. In the Polish study, severe late toxicity was observed in 10.1 % of patients after SCRT and in 7.1 % of patients after CT-LCRT compared to 5.8 % of patients after SCRT vs. 8.2 % of patients after CT-LCRT (p = 0.53) in the Australian trial.

There are four out of five contemporary RCT studies testing the oxaliplatin based chemotherapy regimen published: STAR-0145 [11], ACCORD 12/0405-Prodige 246 [12], NSABP R-0447 [13] and the German trial CAO/ARO/AIO-0448 [14], which compared standard NA 5-Fluorouracil (5-FU) based CT and LCRT (CT-RT) to oxaliplatin and 5-FU CT and NA LCRT. Patients with T3 or T4 rectal cancer were recruited sequentially. All but the CAO/ARO/AIO-0448 [14] reported higher morbidity without any improvement in early endpoints such as pathological complete response (pCR) rate.

TMES now provides optimal tumor bed resection together with the perirectal nodes within the mesorectal fascia but it is not addressing the pelvic nodes. The Dutch CKVO 95–04 study [4, 5] is unique, having an arm with more than 908 patients treated with TME alone. In this trial, 36 % of patients had positive nodes and the LR rate was 10.9 % after a median follow up of 6 years. Most of the recurrences were located below the S2–3 interspace [15] in patients with negative nodes and negative CRM therefore, consistent with the Swedish experience reporting on the level of S1–S2 interspace [16]. The addition of radiation therapy reduced mostly the perineal, anastomotic leakage as well as the lateral recurrence.

In North America, the definition of clinical target volume for the treatment of rectal cancer has been based on consensus by a panel of experts [17] to include coverage of the tumor bed, entire mesorectum and perirectal, presacraland internal iliac nodes which is supported by the patterns of local recurrence literature. It is imperative to note that the majority of these data were derived before the implementation of quality imaging such as pelvic MRI and the introduction of TMES.

If the value of radiation therapy is now well-established, cumulative data on long-term toxicities associated with external beam (EBRT) raise concerns. In a meta-analysis, Camma et al. [18] reported an increased risk of septic complications in irradiated patients compared to non-irradiated patients: 21 % vs. 15.2 % (p ≤ 0.001). Moreover, there was an increased risk of overall complications in the irradiated group: 21 % vs. 5.2 % (p < 0.003). Postoperative adverse events were also higher in the radiation treatment group: 57.4 % vs. 42.3 % (p < 0.02). Finally, irradiated patients had a 15 % higher risk of death from vascular or infectious causes compared to non-irradiated patients (p = 0.02). The Cochrane Database Systematic Review in 2007 by Wong et al. [19], assessing the effect of preoperative RT vs. surgery alone for rectal cancer patients confirmed the benefits of preoperative RT in reducing LR (HR 0.71, 95 % CI 0.64–0.78) with borderline significance with respect to cancer specific and overall survival (OS) (HR 0.93, 95 % CI 0.87–1.0). Late toxicities including pelvic fractures, venothrombosis events, intestinal obstruction, postoperative fistula, cardiovascular death, bowel obstruction, anal sphincter and sexual dysfunction were all increased.

Thus, if neoadjuvant EBRT has been effective in decreasing local recurrence, the number of patients requiring treatment will need to be weighed against the substantial morbidity risks and long-term side effects related to EBRT. Reducing treatment volumes to the level of S1/S2 might be the most effective and simple means to improve therapeutic index.

The majority of patients with rectal cancer are doing well with current management but there are less favorable cases with positive CRM or recurrent tumors after previous pelvis radiation therapy that remains a clinical management challenge. There are other radiation modalities, apart from EBRT, that could be considered.

The likelihood of achieving tumor down staging and/or R0 improves as a function of dose. Wiltshire et al. [20], who investigated the value of dose escalation with 5-FU CT in a phase II trial for patients with operable rectal cancer. The three dose levels were 40 Gy in 20 fractions, 46 Gy in 23 fractions and 50 Gy in 25 fractions and included 46, 52 and 36 patients, respectively. The pCR rates were 15 %, 23 % and 33 % (p = 0.07) respectively and the 2-year relapse free survival was 72, 90 and 89 % respectively (p = 0.02). In Lyon RCT study R96–0256 [21] NA RT alone using 39 Gy in 13 fractions was compared to the same RT with boost (85 Gy in 3 fractions) using contact X-ray for 88 patients with low rectal cancer. A significant improvement in pCR rate was seen in the contact X-ray boost arm, (2 % vs. 24 %), along with a complete or near complete sterilization of the operative specimen (34 % vs. 57 %) resulting in a significant increase in SPS in the boost group (44 % vs. 76 %, p = 0.04). At a median follow up time of 152 months, although there was no difference in OS and LC, however, the rate of colostomy free survival was 37 % vs. 71 % (p = 0.001) in favor of the boost arm. Using modern preoperative staging imaging, Jakobsen et al. [22] conducted a recent RCT trial on T3–4 tumors with dose escalation, comparing CT-LCRT delivering 50.4 Gy in 28 fractions vs. a dose escalation to 60 Gy with the same regimen (50.4 Gy/28) and high dose rate endorectal brachytherapy (HDREBT) as boost modality to deliver 10 Gy. A negative CRM rate of 90 % vs. 99 % respectively was observed (p = 0.03) for T3 tumors only in favor of the boost arm.