Abstract
Objective:
To evaluate outcomes and toxicity profiles after re-irradiation in patients with pelvic recurrence of anorectal cancer.
Methods:
25 anorectal cancer patients who received re-irradiation for pelvic recurrence between 2005 and 2015 were included. For initial treatment, all patients underwent surgical resection and preoperative or postoperative radiotherapy.
Results:
The median follow-up duration was 21.5 months (range, 2.9–84.4). After a median of 43.3 months (range, 11.7–218.5), patients received re-irradiation with a median dose of 45 Gy (range, 36–60). The equivalent dose in 2 Gy fractions (EQD2) of re-irradiation—calculated using α/β = 10 Gy—ranged from 34.5 to 84.0 Gy (median, 46.4). Surgical resection was performed for 11 patients, and 14 patients received concurrent chemotherapy with re-irradiation. The 3-year local progression-free survival was 29.7%. The 3-year overall survival was 49.7%. Concurrent chemotherapy with re-irradiation and re-irradiation doses >50 Gy EQD2α/β=10 were significant prognostic factors for local progression free survival and overall survival according to multivariate analysis. 90% (9 of 10) of patients with symptoms had improvement after re-irradiation. Among 23 patients available for evaluation of late toxicity, 12 developed late toxicities. There were no Grade 4 late toxicities, and 6 patients had Grade 3 late toxicities (small bowel obstruction, bowel perforation and fistula).
Conclusion:
Re-irradiation for pelvic recurrence of anorectal cancer improved symptoms of patients but the rate of late toxicity was high. Further investigation for patient selection is required.
Advances in knowledge:
Re-irradiation could be considered as a possible option for pelvic recurrence of anorectal cancer in selected patients.
Introduction
Although multimodality treatment of rectal cancer consists of total mesorectal excision (TME) and preoperative or postoperative concurrent chemoradiotherapy improves outcomes, about 5–10% of patients still experience local recurrence.1–3 Locally recurrent rectal cancer not only affects prognosis, but it also decreases quality of life.4 Although a standard treatment for locally recurrent rectal cancer is not established, surgical resection with negative margin is considered the primary curative treatment.5–7 However, radical resection is not possible in most patients, and it can be accompanied by substantial complications.8 Radiotherapy is a potential alternative local treatment modality in patients with unresectable disease. However, with increased use of radiotherapy as a part of initial multimodality treatment, most patients with local recurrence of rectal cancer have previously undergone irradiation to the pelvis. Historically, re-irradiation has been discouraged because of concerns about late toxicity of normal tissues and because few data regarding re-irradiation were available. Recently, a few studies have tested the efficacy and safety of re-irradiation for rectal cancer. Mohiuddin et al demonstrated the feasibility of re-irradiation followed by surgical resection in selected patients with locally recurrent rectal cancer.9 Lingraeddy et al reported the outcomes of palliative re-irradiation for recurrent rectal cancer.10 They showed effective symptom palliation after re-irradiation and a reduced rate of late complications with hyperfractionated treatment. In a Phase II prospective study, Valentini et al reported the outcomes of hyperfractionated re-irradiation with acceptable toxicities.11
In this study, we evaluate the treatment outcomes and toxicities of re-irradiation for pelvic recurrence of anorectal cancer patients previously treated with radiotherapy.
Methods and materials
Between 2005 and 2015, patients with adenocarcinoma of the rectum or anus undergoing re-irradiation for pelvic recurrence were identified. The inclusion criteria were as follows: (1) histologically confirmed adenocarcinoma of anus or rectum; (2) initial pre- or post-operative radiotherapy; (3) initial curative surgical resection; (4) no initial distant metastases; (5) re-irradiation for pelvic recurrence; (6) completion of planned radiotherapy. The medical records of the patients were reviewed with approval by the institutional review board.
Acute and late toxicities were graded using the Common Terminology Criteria for Adverse Events v. 4.0. Local progression was defined as any recurrence or progression in the re-irradiation field. Local progression free survival (LPFS) and overall survival (OS) were calculated from the first day of re-irradiation. The actuarial survival rates were estimated using the Kaplan–Meier method, and the difference of survival curves were verified with the log-rank test. Variables found to be statistically significant or marginally significant on univariate analysis were analyzed by multivariate analysis with the Cox proportional-hazards model. All statistical analyses were performed with SPSS, v. 18.0.1 (SPSS Inc. Chicago, IL).
Results
Among 27 patients referred for re-irradiation during the accrual period, 2 patients were excluded from the analysis. One patient was off re-irradiation after one fraction due to the bleeding from the pre-existing rectovaginal fistula. The other patient initially refused planned surgical resection after pre-operative concurrent chemoradiotherapy (CCRT). Patient underwent palliative surgical resection after tumor regrowth. Thus, 25 patients were analyzed in this study.
Patient characteristics and initial treatment
The patient and treatment characteristics at initial treatment are summarized in Table 1. Among the 25 patients included, 24 had rectal cancer and 1 had anal cancer. The median age at diagnosis was 50 years (range, 31–75) and 15 patients (60.0%) were male. The median radiation dose was 50.4 Gy (range, 50.4–59.4). 21 patients (84.0%) received concurrent chemotherapy during radiotherapy.
Table 1.
Patient and treatment characteristics at initial treatment
| Characteristics | n | % | |
| Age, year | Median (range) | 50 (31–75) | |
| Gender | Male | 15 | 60.0 |
| Female | 10 | 40.0 | |
| Types of surgery | Low anterior resection | 16 | 64.0 |
| Abdominoperineal resection | 9 | 36.0 | |
| Resection margin status | Negative | 20 | 80.0 |
| Positive | 4 | 16.0 | |
| N/A | 1 | 4.0 | |
| Aim of RT | Preoperative | 12 | 48.0 |
| Postoperative | 13 | 52.0 | |
| RT dose, Gy | Median (range) | 50.4 (50.4–59.4) | |
| CCRT | Yes | 21 | 84.0 |
| No | 4 | 16.0 | |
| CCRT regimen | 5-fluorouracil | 11 | 52.4 |
| Capecitabine | 8 | 38.1 | |
| 5-fluorouracil + leucovorin | 2 | 9.5 | |
CCRT, concurrent chemoradiotherapy; N/A, not available;RT, radiotherapy.
Re-irradiation
The patient and treatment characteristics at re-irradiation are summarized in Table 2. The median age was 57 years (range, 34–81), and seven patients had synchronous extrapelvic metastases at re-irradiation. The locations of recurrent tumors were as follows: anastomosis site or tumor bed in nine patients, pelvic side-wall in five patients, regional lymph node in five patients and presacral area in five patients. Two patients had recurrences in anastomosis site with regional lymph node or abdominal wall involvement. Surgical resection was performed in 11 patients, and of these patients, pelvic exenteration was performed in 4 patients, Hartmann's operation in 1, and abdominoperineal resection in 1 patient. The median interval between two courses of radiotherapy was 43.3 months (range, 11.7–218.5). The aim of re-irradiation was salvage in 6 patients, pre- or postoperative in 9 patients, and palliative in 10 patients. Four patients received pre-operative radiotherapy, five received post-operative adjuvant radiotherapy, and two patients received re-radiotherapy after surgery as salvage or palliative therapy, respectively. 18 patients were treated with three-dimensional conformal radiotherapy (3D-CRT), 5 with intensity-modulated radiotherapy (IMRT), 1 with stereotactic body radiotherapy (SBRT), and 1 patient received initial 3D-CRT followed by an IMRT boost. The radiation doses ranged from 36 to 60 Gy, with a median of 45 Gy. Because patients received re-irradiation at diverse fractionation schedules, the radiation dose was converted to the equivalent dose in 2 Gy fractions (EQD2) using α/β of 10 Gy. The median EQD2α/β=10 of re-irradiation was 46.4 Gy (range, 34.5–84.0). The total summated dose of initial and re-irradiation EQD2 with α/β of 3 Gy had a median of 92.5 Gy (range, 80.1–199.8). The target volume of re-irradiation was the recurrent tumor or tumor bed plus a 5–10 mm margin in 22 patients, the whole pelvis followed by boost to the gross tumor in two patients, and lymphatic chains in two patients. The median clinical target volume was 191.1 cc (range, 8.6–777.3). 19 patients were irradiated in once-daily fractionation (QD), and 6 in twice a day fractionation (BID). Concurrent chemotherapy was administered in 15 patients and all received 5-fluorouracil-based chemotherapy.
Table 2.
Patient and treatment characteristics at re-irradiation
| Characteristics | n | % | |
| Age, year | Median (range) | 57 (34–81) | |
| Extrapelvic metastasis | Yes | 7 | 28.0 |
| No | 18 | 72.0 | |
| Surgery | Yes | 11 | 44.0 |
| No | 14 | 56.0 | |
| Types of surgery | Debulking/excision | 4 | 36.4 |
| Pelvic exenteration | 4 | 36.4 | |
| Hartmann's operation | 1 | 9.1 | |
| Abdominoperineal resection | 1 | 9.1 | |
| Lymph node dissection | 1 | 9.1 | |
| Interval between RT, month | Median (range) | 43.3 (11.7–218.5) | |
| Aim of RT | Salvage | 6 | 24.0 |
| Preoperative | 4 | 16.0 | |
| Postoperative | 5 | 20.0 | |
| Palliative | 10 | 40.0 | |
| RT modality | 3D-CRT | 18 | 72.0 |
| IMRT | 5 | 20.0 | |
| SBRT | 1 | 4.0 | |
| 3D + IMRT | 1 | 4.0 | |
| RT dose, Gy | Median (range) | 45.0 (36.0–60.0) | |
| RT dose, EQD2, Gy (α/β = 10 Gy) | Median (range) | 46.4 (34.5–84.0) | |
| Total cumulative dose, EQD2, Gy (α/β = 3 Gy) | Median (range) | 92.5 (80.1–199.8) | |
| RT schedule | QD | 19 | 76.0 |
| BID | 6 | 24.0 | |
| Chemotherapy | Before re-RT | 10 | 40.0 |
| CCRT | 14 | 56.0 | |
| After re-RT | 16 | 36.0 | |
| CCRT regimen | Capecitabine | 9 | 64.3 |
| 5-fluorouracil | 2 | 14.3 | |
| XELOX | 1 | 7.1 | |
| FOLFOX | 1 | 7.1 | |
| 5-fluorouracil + leucovorin | 1 | 7.1 | |
BID, twice a day fractionation; CCRT, concurrent chemoradiotherapy; 3D-CRT, three dimensional conformal radiotherapy;EQD2, equivalent dose in 2 Gy fractions; FOLFOX, leucovorin + 5-FU + oxaliplatin; IMRT, intensity modulated radiotherapy; QD, once-daily fractionation;RT, radiotherapy; Re-RT, re-irradiation; SBRT, stereotactic body radiotherapy; XELOX, capecitabine + oxaliplatin.
Pelvic control
The median follow-up was 21.5 months (range, 2.9–84.4). One patient was lost to follow-up after re-irradiation, and the treatment outcome could not be evaluated. Among 24 patients with available follow-up data, 13 patients (54.2%) developed local recurrence with 2-year and 3-year LPFS of 44.6 and 29.7%, respectively (Figure 1A). The results of the univariate and multivariate analyses for local control are summarized in Table 3. Surgical resection for recurrent lesions was not associated with LPFS (p = 0.717). The time interval between two courses of radiotherapy and concurrent chemotherapy with re-irradiation showed marginally significant associations with LPFS (p = 0.050 and p = 0.057, respectively). Re-irradiation doses >50 Gy EQD2α/β=10 were associated with improved LPFS (3-year LPFS 58.3% vs 0.00%, p = 0.007). Most patients with re-irradiation intervals ≤ 36 months (6 of 8, 75.0%) received less than 50 Gy EQD2α/β=10, while more patients with re-irradiation intervals > 36 months (10 of 17, 58.8%) received more than 50 Gy EQD2α/β=10, although this difference was not statistically significant. On multivariate analysis, CCRT at recurrence and re-irradiation dose remained significant predictors of LPFS (p = 0.001, Figure 2).
Figure 1.
Local progression-free survival (A) and overall survival (B)
Table 3.
Univariate and multivariate analysis for local progression-free survival
| Univariate | Multivariate | |||||
| Variables | n a (%) | 3-year LPFS (%) | p | p | HR (95% CI) | |
| Initial surgery | Sphincter saving surgery | 16 (66.7) | 24.9 | 0.468 | ||
| Abdominoperineal resection | 8 (33.3) | 40.0 | ||||
| Initial RT dose | ≤50.4 Gy | 15 (62.5) | 32.3 | 0.434 | ||
| >50.4 Gy | 9 (37.5) | 31.7 | ||||
| Initial CCRT | No | 4 (16.7) | 0.00 | 0.948 | ||
| Yes | 20 (83.3) | 33.6 | ||||
| Aim of initial RT | Preoperative | 11 (45.8) | 30.3 | 0.532 | ||
| Postoperative | 13 (54.2) | 33.0 | ||||
| Surgery at recurrence | No | 13 (54.2) | 30.0 | 0.717 | ||
| Yes | 11 (45.8) | 32.7 | ||||
| Interval between RT | ≤36 mo | 8 (33.3) | 0.00 | 0.050 | 0.317 | |
| >36 mo | 16 (66.7) | 53.3 | ||||
| Extrapelvic metastases at re-RT | No | 18 (75.0) | 35.2 | 0.489 | ||
| Yes | 6 (25.0) | 0.00 | ||||
| CCRT at re-RT | No | 10 (41.7) | 0.00 | 0.057 | 0.001 | 5.802 (1.434–23.474) |
| Yes | 14 (58.3) | 42.1 | ||||
| Re-RT aim | Salvage, adjuvant b | 15 (62.5) | 37.7 | 0.681 | ||
| Palliative | 9 (37.5) | 20.8 | ||||
| Re-RT dose, EQD2 (α/β = 10) | ≤50 Gy | 12 (50.0) | 0.00 | 0.007 | 0.001 | 8.422 (1.955–36.282) |
| >50 Gy | 12 (50.0) | 58.3 | ||||
| Re-RT modality | 3D-CRT c | 18 (75.0) | 42.5 | 0.186 | ||
| IMRT, SBRT | 6 (25.0) | 0.00 | ||||
| Re-RT schedule | QD | 18 (75.0) | 50.2 | 0.091 | ||
| BID | 6 (25.0) | 0.00 | ||||
LPFS, local progression-free survival; HR, hazard ratio; CI, confidence interval; RT, radiotherapy; Re-RT, re-irradiation; CCRT, concurrent chemoradiotherapy; EQD2, equivalent dose in 2 Gy fractions; 3D-CRT, three dimensional conformal radiotherapy; IMRT, intensity modulated radiotherapy; SBRT, stereotactic body radiotherapy; QD, once-daily fractionation; BID, twice a day fractionation.
One patient lost to follow-up after re-irradiation was excluded.
Preoperative and postoperative.
One patient received 3-D CRT followed by IMRT boost.
Figure 2.
Local progression-free survival according to re-irradiation dose. reRT, re-irradiation; CCRT, concurrent chemoradiotherapy; EQD2, equivalent dose in 2 Gy fractions.
Overall survival
Among 25 patients, there were 18 deaths and 2-year and 3-year OS rates were 54.6 and 49.7%, respectively (Figure 1B). For OS, extrapelvic metastases at recurrence, CCRT at recurrence, the aim of re-irradiation, and the dose of re-irradiation showed significant associations in univariate analysis (Table 4). Patients with extrapelvic metastasis had poorer survival than those without metastasis (3-year OS 14.3% vs 63.5%, p < 0.001), and patients treated with CCRT showed better survival than those who did not (3-year OS 82.5% vs 9.1%, p < 0.001). The 3-year OS was 62.0% in patients treated with aim of neoadjuvant or adjuvant (pre- or postoperative) salvage and 30.0% for patients who received palliative re-irradiation (p = 0.018). There was a tendency toward improved survival with re-irradiation doses >50 Gy EQD2α/β=10 compared with ≤50 Gy EQD2α/β=10 (3-year OS 58.3% vs 42.2%, p = 0.044). On multivariate analysis, CCRT at recurrence and re-irradiation dose were independent prognostic factors for OS (Figure 3A and B). Most patients without extrapelvic metastasis received concurrent chemotherapy (14 of 18, 77.8%), while none of the patients with extrapelvic metastasis received concurrent chemotherapy (0 of 7, 0%). 12 of 14 patients who received CCRT were treated with salvage, preoperative, or postoperative aims.
Table 4.
Univariate and multivariate analysis for overall survival
| Univariate | Multivariate | |||||
| Variables | n (%) | 3-year OS (%) | p | p | HR (95% CI) | |
| Initial surgery | Sphincter saving surgery | 16 (64.0) | 45.1 | 0.623 | ||
| Abdominoperineal resection | 9 (36.0) | 55.6 | ||||
| Initial RT dose | ≤50.4 Gy | 16 (64.0) | 45.1 | 0.623 | ||
| >50.4 Gy | 9 (36.0) | 55.6 | ||||
| Initial CCRT | No | 4 (16.0) | 25.0 | 0.102 | ||
| Yes | 21 (84.0) | 55.4 | ||||
| Aim of initial RT | Preoperative | 12 (48.0) | 36.5 | 0.605 | ||
| Postoperative | 13 (52.0) | 60.6 | ||||
| Surgery at recurrence | No | 14 (56.0) | 41.7 | 0.129 | ||
| Yes | 11 (44.0) | 58.9 | ||||
| Interval between RT | ≤36 mo | 8 (32.0) | 72.9 | 0.734 | ||
| >36 mo | 17 (68.0) | 39.2 | ||||
| Extrapelvic metastases at re-RT | No | 18 (72.0) | 63.5 | <0.001 | 0.543 | |
| Yes | 7 (28.0) | 14.3 | ||||
| CCRT at re-RT | No | 11 (44.0) | 9.1 | <0.001 | <0.001 | 41.278 (7.015–242.878) |
| Yes | 14 (56.0) | 82.5 | ||||
| Re-RT aim | Salvage, adjuvant a | 15 (60.0) | 62.0 | 0.018 | 0.158 | |
| Palliative | 10 (40.0) | 30.0 | ||||
| Re-RT dose, EQD2 (α/β = 10) | ≤50 Gy | 13 (52.0) | 42.2 | 0.061 | 0.010 | 4.757 (1.452–15.588) |
| >50 Gy | 12 (48.0) | 58.3 | ||||
| Re-RT modality | 3D-CRT b | 19 (76.0) | 56.0 | 0.156 | ||
| IMRT, SBRT | 6 (24.0) | 33.3 | ||||
| Re-RT schedule | QD | 19 (76.0) | 40.5 | 0.779 | ||
| BID | 6 (24.0) | 80.0 | ||||
OS, overall survival; HR, hazard ratio; CI, confidence interval; RT, radiotherapy; CCRT, concurrent chemoradiotherapy; Re-RT, re-irradiation; EQD2, equivalent dose in 2 Gy fractions; 3D-CRT, three dimensional conformal radiotherapy; IMRT, intensity modulated radiotherapy; SBRT, stereotactic body radiotherapy; QD, once-daily fractionation; BID, twice a day fractionation.
Preoperative and postoperative.
One patient received 3-D CRT followed by IMRT boost.
Figure 3.
Overall survival rate according to re-irradiation dose (A) and CCRT at re-irradiation (B). reRT, re-irradiation; CCRT, concurrent chemoradiotherapy; EQD2, equivalent dose in 2 Gy fractions.
Symptoms and toxicity
Of the 25 patients, 10 had clinical symptoms related to recurrent lesions before re-irradiation. Nine patients had pelvic or lower extremity pain, and one patient had lower extremity paresthesia. The symptoms improved in 9 of 10 patients (90.0%) and stayed stable in one patient (10.0%) during or after re-irradiation.
All 25 patients completed re-irradiation as planned, and no patients had any acute complications. Late complications could not be evaluated in 2 patients because one was lost to follow-up after re-irradiation, and 1 died within 3 months after re-irradiation. Among 23 patients with available data, 12 patients (52.2%) experienced late toxicities (Table 5). Grade 3 toxicities developed in six patients, and the actuarial 3-year rate of Grade 3 toxicity was 52.5%. Among the Grade 3 fistula cases, there were two enterovaginal fistulas, two enterocutaneous fistulas, one vesicocutaneous fistula, and for one patient the fistula location was not specified. No clinical or treatment factor was associated with Grade 3 late toxicities.
Table 5.
Late toxicities after re-irradiation (n = 23) by CTCAE criteria v. 4.0
| n (%) | ||||
| Adverse effect | Grade 1 | Grade 2 | Grade 3 | Grade 4 |
| Small bowel obstruction | 2 (8.3) | 0 | 1 a (4.2) | 0 |
| Bowel perforation | 0 | 0 | 2 b (8.3) | 0 |
| Rectal bleeding | 1 (4.2) | 0 | 0 | 0 |
| Ileus | 1 (4.2) | 0 | 0 | 0 |
| Fistula | 2 (8.3) | 0 | 6 (25.0) | 0 |
CTCAE, common terminology criteria for adverse events.
One patient had both Grade 3 small bowel obstruction and fistula.
Two patients had both Grade 3 bowel perforation and fistula.
Discussion
In this study, we evaluated the treatment outcomes of re-irradiation to the pelvis in patients with recurrent rectal cancer who were previously treated with radiotherapy. The actuarial 3-year LPFS and OS were 29.7 and 49.7%, respectively. Concurrent chemotherapy with re-irradiation and re-irradiation dose were significant prognostic factors for LPFS and OS in multivariate analysis.
After initial studies, which reported acceptable toxicities with low re-irradiation doses of about 30 Gy in hyperfractionations,9,10 most studies then used radiation doses of 30–40 Gy using hyperfractionation schedules.11–15 In those studies, re-irradiation dose did not affect the local control rate of recurrent lesions, while they reported improved local control with surgical resection.13–15 In our study, re-irradiation dose exceeding 50 Gy EQD2α/β=10 was a significant prognostic factor, and surgical resection did not improve LPFS. These results might suggest the possibility that the re-irradiation doses of 30–40 Gy in previous studies were not sufficient to control recurrent lesions. In a recent study by Koom et al, infield progression-free survival was significantly increased with re-irradiation doses exceeding 50 Gy EQD2α/β=10, which was compatible with our results.16 Additionally, re-irradiation dose was a significant predictor of OS in our study. In a study by Mohiuddin et al, re-irradiation dose was not associated with local control but significantly associated with overall survival, and they recommended 50–55 Gy of re-irradiation in patients whose intervals to re-irradiation were more than 36 months.12 Susko et al also found a longer overall survival in patients who received more than 32 Gy than those who received less than 32 Gy, although the difference was not statistically significant.15 In rectal cancer, improved local control often translates into improved survival, and multimodality treatment with TME has been a standard treatment to improve local control. 2,17,18 Although there are little data regarding the association of local control and overall survival in patients with recurrent disease, there are possibilities that improved local control by sufficient doses of re-irradiation prolonged the survival of patients in our study. Therefore, higher dose of re-irradiation, more than 50 Gy EQD2α/β=10 in current analysis, might provide more durable local control of recurred rectal cancer and consequently, improve overall survival. Further studies to evaluate the efficacy of high-dose re-irradiation in large numbers of patients are needed.
The time interval between the two courses of radiotherapy was associated with LPFS with marginal statistical significance in univariate analysis, but this was not significant in multivariate analysis. In general, because of concerns about toxicity, patients with short re-treatment intervals tend to receive lower doses of re-irradiation than those with longer intervals. In our study, although this finding was not statistically significant, patients with longer re-irradiation intervals tended to receive higher doses of re-irradiation than those with short intervals. Mohiuddin et al reported the long-term results of re-irradiation with concurrent chemotherapy in 103 patients with recurrent rectal cancer.12 They used different radiation doses and fractionation schedules depending on the interval between initial treatment and recurrence, and they made dose recommendations based on the interval to re-irradiation. Therefore, the time interval might be an important consideration when determining re-irradiation doses.
Concurrent chemotherapy with re-irradiation was another significant predictor for local control and overall survival. CCRT at recurrence was a marginally significant factor in univariate analysis for LPFS, but in multivariate analysis, it remained a statistically significant factor. In univariate analysis for OS, synchronous extrapelvic metastasis and aim of re-irradiation were significant factors, but lost their significance in multivariate analysis, while CCRT was a strong prognostic factor in both univariate and multivariate analysis. In our study, most patients with extrapelvic metastasis were treated with a palliative aim and did not receive CCRT. Because treatment decisions were made based on the patients’ general condition and disease status, CCRT itself might have reflected all of the other clinical factors considered in the analysis.
In our study, late toxicities were frequent relative to previous studies, which have reported 10–20% incidence rates for Grade three late toxicities.10,12,13 However, these previous studies used much lower re-irradiation doses than our study. A study by Koom et al, which used similar radiation doses to our study—with a median dose of 50 Gy (range, 30–66 Gy)—reported a Grade three late toxicity rate of 36%, which is comparable to our study16 . They also found that the location of recurrent tumors was associated with late toxicity. Therefore, increased re-irradiation dose is associated with higher rates of late toxicity, and careful patient selection depending tumor location could reduce the rate of late toxicity.
Two studies have reported outcomes of re-irradiation using IMRT. Cai et al 19 treated 22 patients with 39 Gy in 30 fractionations, twice a day, and reported a low late toxicity rate, with 2 cases of chronic severe diarrhea (9.1%), one small bowel obstruction (4.5%), and 2 cases of dysuria (9.1%). Youssef et al reported an even lower frequency of late toxicity 20. They prescribed 39 Gy in 26 fractionations, BID, or 27–40 Gy in 15–22 fractionations, QD, and reported only one patient (3.2%) with Grade 3 late toxicity (sacral insufficiency fracture). Although these two studies with IMRT also used low doses of re-irradiation similar to previous studies, the toxicity rates were much lower than those studies.10,12,13 In a study by Abusaris et al21, 27 patients were retreated with SBRT for abdominal or pelvic lesions; their prescribed doses were higher than those of other studies, ranging from 24 to 150 Gy EQD2α/β=10, and they reported favorable outcomes. The toxicity rate was low and no grade ≥3 acute or late toxicity was observed. In a recent systematic review by Murray et al 22, SBRT was suggested as a feasible treatment option for previously irradiated patients with recurrent pelvic disease. Although the treatment modality did not affect the treatment outcome or toxicity rate in our study, using more precise radiation techniques, such as IMRT or SBRT, can be beneficial for re-irradiation by delivering higher radiation doses while minimizing the radiation exposure to adjacent normal tissues. Further studies involving larger sample sizes and using diverse radiation doses are needed to validate this.
There were some limitations in our study. Our sample was small and heterogeneous, with a diversity of systemic disease statuses and tumor locations. Therefore, the treatments for recurrent pelvic lesions were also heterogeneous, consisting of surgery, chemotherapy, and radiotherapy, and the contribution of each treatment modality to the outcome and toxicity could not be disentangled. Additionally, as this was a retrospective study, the toxicities could have been underestimated due to incomplete medical records. Higher re-irradiation dose was related with improved result in current analysis. Because the radiation doses and schedules were decided depending on the disease extent and patient performance, the improved outcome may have resulted from patient selection rather than the employed dose. However, despite these limitations, current analysis suggested the possible role of re-irradiation to improve the prognosis of patients with recurrent rectal cancer and the needs for further investigations to find the subset of patients who may benefit from re-irradiation without late toxicities.
Conclusions
Re-irradiation could be considered as a treatment option for patients with recurrent anorectal cancer, and improved the related symptoms effectively. The late toxicity rate is high, so patients should be well informed about the risks, and all appropriate measures should be undertaken to minimize re-irradiation toxicity.
Footnotes
Acknowledgements: This work wassupported by the Soonchunhyang University Research Fund.
Park Y and Kim K contributed equally to this work
Contributor Information
Younghee Park, Email: yh810530@daum.net.
Kyubo Kim, Email: kyubokim.ro@gmail.com.
Hae Jin Park, Email: haejinpark@hanyang.ac.kr.
Seung-Yong Jeong, Email: syjeong@snu.ac.kr.
Kyu Joo Park, Email: kjparkmd@plaza.snu.ac.kr.
Sae-Won Han, Email: saewonhan@medimail.co.kr.
Tae-You Kim, Email: kimty@snu.ac.kr.
Eui Kyu Chie, Email: ekchie93@snu.ac.kr.
REFERENCES
- 1. Bouchard P , Efron J . Management of recurrent rectal cancer . Ann Surg Oncol 2010. ; 17 : 1343 – 56 . doi: 10.1245/s10434-009-0861-2 [DOI] [PubMed] [Google Scholar]
- 2. van Gijn W , Marijnen CAM , Nagtegaal ID , Kranenbarg EM-K , Putter H , Wiggers T , et al. . Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled Tme trial . Lancet Oncol 2011. ; 12 : 575 – 82 . doi: 10.1016/S1470-2045(11)70097-3 [DOI] [PubMed] [Google Scholar]
- 3. Sebag-Montefiore D , Stephens RJ , Steele R , Monson J , Grieve R , Khanna S , et al. . Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial . The Lancet 2009. ; 373 : 811 – 20 . doi: 10.1016/S0140-6736(09)60484-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Camilleri-Brennan J , Steele RJ . The impact of recurrent rectal cancer on quality of life . Eur J Surg Oncol 2001. ; 27 : 349 – 53 . doi: 10.1053/ejso.2001.1115 [DOI] [PubMed] [Google Scholar]
- 5. Westberg K , Palmer G , Hjern F , Johansson H , Holm T , Martling A . Management and prognosis of locally recurrent rectal cancer - A national population-based study . Eur J Surg Oncol 2018. ; 44 : 100 – 7 . doi: 10.1016/j.ejso.2017.11.013 [DOI] [PubMed] [Google Scholar]
- 6. Caricato M , Borzomati D , Ausania F , Valeri S , Rosignoli A , Coppola R . Prognostic factors after surgery for locally recurrent rectal cancer: an overview . Eur J Surg Oncol 2006. ; 32 : 126 – 32 . doi: 10.1016/j.ejso.2005.11.001 [DOI] [PubMed] [Google Scholar]
- 7. Wells BJ , Stotland P , Ko MA , Al-Sukhni W , Wunder J , Ferguson P , et al. . Results of an aggressive approach to resection of locally recurrent rectal cancer . Ann Surg Oncol 2007. ; 14 : 390 – 5 . doi: 10.1245/s10434-006-9119-4 [DOI] [PubMed] [Google Scholar]
- 8. Boyle KM , Sagar PM , Chalmers AG , Sebag-Montefiore D , Cairns A , Eardley I . Surgery for locally recurrent rectal cancer . Dis Colon Rectum 2005. ; 48 : 929 – 37 . doi: 10.1007/s10350-004-0909-0 [DOI] [PubMed] [Google Scholar]
- 9. Mohiuddin M , Marks GM , Lingareddy V , Marks J . Curative surgical resection following reirradiation for recurrent rectal cancer . Int J Radiat Oncol Biol Phys 1997. ; 39 : 643 – 9 . doi: 10.1016/S0360-3016(97)00340-4 [DOI] [PubMed] [Google Scholar]
- 10. Lingareddy V , Ahmad NR , Mohiuddin M . Palliative reirradiation for recurrent rectal cancer . Int J Radiat Oncol Biol Phys 1997. ; 38 : 785 – 90 . doi: 10.1016/S0360-3016(97)00058-8 [DOI] [PubMed] [Google Scholar]
- 11. Valentini V , Morganti AG , Gambacorta MA , Mohiuddin M , Doglietto GB , Coco C , et al. . Preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: a multicentric phase II study . Int J Radiat Oncol Biol Phys 2006. ; 64 : 1129 – 39 . doi: 10.1016/j.ijrobp.2005.09.017 [DOI] [PubMed] [Google Scholar]
- 12. Mohiuddin M , Marks G , Marks J . Long-term results of reirradiation for patients with recurrent rectal carcinoma . Cancer 2002. ; 95 : 1144 – 50 . doi: 10.1002/cncr.10799 [DOI] [PubMed] [Google Scholar]
- 13. Das P , Delclos ME , Skibber JM , Rodriguez-Bigas MA , Feig BW , Chang GJ , et al. . Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation . Int J Radiat Oncol Biol Phys 2010. ; 77 : 60 – 5 . doi: 10.1016/j.ijrobp.2009.04.056 [DOI] [PubMed] [Google Scholar]
- 14. Tao R , Tsai CJ , Jensen G , Eng C , Kopetz S , Overman MJ , et al. . Hyperfractionated accelerated reirradiation for rectal cancer: an analysis of outcomes and toxicity . Radiother Oncol 2017. ; 122 : 146 – 51 . doi: 10.1016/j.radonc.2016.12.015 [DOI] [PubMed] [Google Scholar]
- 15. Susko M , Lee J , Salama J , Thomas S , Uronis H , Hsu D , et al. . The use of re-irradiation in locally recurrent, non-metastatic rectal cancer . Ann Surg Oncol 2016. ; 23 : 3609 – 15 . doi: 10.1245/s10434-016-5250-z [DOI] [PubMed] [Google Scholar]
- 16. Koom WS , Choi Y , Shim SJ , Cha J , Seong J , Kim NK , et al. . Reirradiation to the pelvis for recurrent rectal cancer . J Surg Oncol 2012. ; 105 : 637 – 42 . [DOI] [PubMed] [Google Scholar]
- 17. Bernstein TE , Endreseth BH , Romundstad P , Wibe A . Norwegian Colorectal Cancer Registry . Improved local control of rectal cancer reduces distant metastases . Colorectal Dis 2012. ; 14 : e668 – 78 . doi: 10.1111/j.1463-1318.2012.03089.x [DOI] [PubMed] [Google Scholar]
- 18. Kodner IJ , Shemesh EI , Fry RD , Walz BJ , Myerson R , Fleshman JW , et al. . Preoperative irradiation for rectal cancer. Improved local control and long-term survival . Ann Surg 1989. ; 209 : 194 – 9 . [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Cai G , Zhu J , Hu W , Zhang Z . Accelerated hyperfractionated intensity-modulated radiotherapy for recurrent/unresectable rectal cancer in patients with previous pelvic irradiation: results of a phase II study . Radiat Oncol 2014. ; 9 : 278 : 278 . [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Youssef FF , Parikh PJ , DeWees TA , Mutch MG , Tan BR , Grigsby PW , et al. . Efficacy and toxicity of rectal cancer reirradiation using IMRT for patients who have received prior pelvic radiation therapy . Adv Radiat Oncol 2016. ; 1 : 94 – 100 . doi: 10.1016/j.adro.2016.02.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Abusaris H , Hoogeman M , Nuyttens JJ . Re-irradiation: outcome, cumulative dose and toxicity in patients retreated with stereotactic radiotherapy in the abdominal or pelvic region . Technol Cancer Res Treat 2012. ; 11 : 591 – 7 . [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Murray LJ , Lilley J , Hawkins MA , Henry AM , Dickinson P , Sebag-Montefiore D . Pelvic re-irradiation using stereotactic ablative radiotherapy (SABR): a systematic review . Radiother Oncol 2017. ; 125 : 213 – 22 . [DOI] [PubMed] [Google Scholar]