In the treatment of locally advanced rectal cancer, neoadjuvant radiochemotherapy with total mesorectal excision (TME) significantly reduces local recurrence. Local recurrence of rectal cancer (LRRC) occurs in 5–10% of patients [1–4]. LRRC represents an important clinical challenge, with significant symptoms (severe pain, rectal bleeding, discharge, and change in bowel habits), poor quality of life, and poor survival [5]. In 40–60% of patients, LRRC is the only manifestation of disease; in the remaining patients, distant metastases are detected within a median of 6 months after the diagnosis of the LRRC [6]. Prognosis is poor, with a 5-year overall survival (OS) rate of ~9%, which increases to ~57% after potentially curative (R0) surgery. Radical surgery is the only option to control this disease [7, 8]. However, curative R0 resection can be achieved in only about 20–30% of all patients with LRRC [1]. In addition, it is important to select patients carefully for radical surgery due to high postoperative morbidity (15–68%) [9–12] and mortality [13–16] rates. Radiotherapy is an effective approach for relieving symptoms and improving local control (LC) in patients with LRRC.

Following surgery, in patients with LRRC who had no previous radiotherapy, radiochemotherapy (50–60 Gy over 5–6 weeks) alone is usually given for palliation or as preoperative treatment before surgical salvage [17]. High-dose (50 Gy) preoperative radiochemotherapy is also feasible, with low perioperative mortality and acceptable morbidity rates, although morbidity is higher than with radiotherapy alone [17, 18]. Preoperative treatment may also influence resectability, and it has been reported that up to 80% of patients with recurrent tumor initially not suitable for curative surgery can be converted to resectable status after high-dose preoperative radiochemotherapy [18]. In patients with LRRC who previously received radiotherapy, reirradiation is often not recommended because of the extremely high risk of late toxicity. Although data regarding reirradiation outcomes are scarce, several recent observations and trials have demonstrated the safety and efficacy of reirradiation in patients with LRRC who previously underwent irradiation [19–23]. After a conventional pre-or postoperative dose (50 Gy in 5 weeks or 25 Gy in 1 week), reirradiation appears to be possible for short-term palliation and potentially for cure if surgical resectability is possible. A dose of 30 Gy in 3 weeks is likely to be safe, even with chemotherapy, if the small bowel can be excluded from the field. If the tissue volume to be reirradiated is small, it may be possible to give doses up to ~40 Gy without risking severe toxicity [22].

Mohiuddin et al. concluded that high doses of reirradiation could be delivered with acceptable risks without prohibitive long-term side effects and that surgical salvage and long-term survival of patients were possible [19]. A reirradiation dose up to 50–55 Gy was recommended if the interval between initial radiotherapy and radiotherapy for recurrence was >36 months [19]. Some authors suggested that reirradiation with hyperfractionated radiotherapy is a valid treatment option with an acceptable risk for late toxicity as well as good palliation [20, 21]. Valentini et al. [20] reported results from a multicenter phase II study of preoperative reirradiation with a hyperfractionated scheme in 59 patients with LRRC treated twice daily with 1.2-Gy fractions, for a cumulative dose of 40.8 Gy and with concurrent continuous 5-fluorouracil (5-FU) infusion. The authors concluded that hyperfractionated radiochemotherapy was associated with a low rate of acute toxicity and an acceptable incidence of late complications, with excellent pain control. The overall response rate was 44.1% (complete response [CR] 8.5%; partial response [PR] 35.6%) and 5-year OS was 39%. Radical R0 resection was performed in ~15–35% of patients after reirradiation with 30–40 Gy, regardless of fractionation scheme. The remaining patients could not receive curative surgery after radiotherapy (30–40 Gy), and their 2-year LC rate was ~30–45% [20, 21].

Other retrospective studies of reirradiation for LRRC showed late severe toxicity (grade 3–4) was significantly increased in patients who received surgery after reirradiation (53% vs. 15% in those not undergoing surgery) or who had an axial or anterior tumor [21–23]. Indeed, tumor location is important in determining the appropriate treatment modality (i.e., surgery or reirradiation) and reirradiation dose for local tumor control. Therefore, careful patient selection is highly important to minimize late severe toxicity. Reirradiation at a dose equivalent 2 Gy (EQD2) exceeding 50 Gy (considering an a/b10) may improve infield tumor control [23].

Accelerated hyperfractionated intensity-modulated radiation therapy (IMRT) would seem to provide excellent symptom palliation and good local response, with acceptable toxicity profiles, in patients with LRRC and previous pelvic irradiation [24]. Reirradiation toxicity is correlated with many factors: previous radiation and reirradiation volumes, dose to small intestine exposed to the radiation field, reirradiation dose, reirradiation fractionation, total cumulative dose, and interval between initial radiotherapy and reirradiation. Local control in patients with advanced and recurrent rectal cancer is related to irradiation dose. However, the total dose deliverable by external beam radiotherapy (EBRT) is limited by toxicity to adjacent organs, such as small bowel and bladder.

Intraoperative radiation therapy (IORT), with its precise delivery of high-dose radiation to the tumor bed and concomitant possibility of protecting surrounding normal tissues, avoids the problem of regrowth of possible remaining cancer cells [22]. IORT can be delivered using various methods, such as intraoperative electron-beam radiotherapy (IOERT) or high-dose-rate brachytherapy (HDR-IORT), but there are no significant differences in outcome related to the method of administration. IOERT, through electron energies, allows treatment to a depth of >1 cm, with quick delivery of the radiation. HDR-IORT with flexible template can treat all surfaces with the highest dose at the area at risk, albeit with longer treatment time [25–29]. There is no clear difference in complication profile between IOERT and HDR-IORT: overall complication rate (short- and long-term complications) attributable to IORT-containing treatment regimens ranges from 15 to 59%, and the most frequently reported morbidities are wound-related problems, gastrointestinal complications, ureteric obstruction, and neuropathy. IORT dose used for cases of LRRC is variable and ranges from 7.5 to 30 Gy, with no obvious trend toward a higher incidence of complications according to studies that routinely delivered higher radiation fractions [30].

In the first pooled analysis of the effect of IORT on long-term oncological outcome in LRRC, IORT was administered as a component of multimodality treatment, including EBRT with or without concurrent chemotherapy and surgery, making it difficult to draw definitive inferences about its independent contribution. In addition, reirradiation with hyperfractionated EBRT after previous pelvic radiotherapy is a source of further heterogeneity [30]. The results of this analysis indicate that the use of IORT for LRRC is associated with improved LC following resection and that the benefits are primarily seen among patients with microscopic (R1) resection margins. IORT may also lead to improved LC and survival, with a modest but significant effect on disease-free survival. Patient selection, the ideal zone of irradiation, radiation dosing, and optimal ratio of EBRT to IORT remain open questions regarding the use of IORT [30].