INTRODUCTION
Most patients with colorectal cancer without distant metastases are treated with surgical excision at initial diagnosis. However, radiotherapy (RT) still plays an important role, in combination with surgery and chemotherapy, in multimodal treatment for patients with rectal cancer. In particular, according to the current National Comprehensive Cancer Network (NCCN) guidelines, for patients with advanced stage rectal cancer (T3–4 or N1–2), neoadjuvant chemoradiotherapy before surgery is recommended to achieve the best results [
1].
Performing a total-mesorectal excision (TME) significantly was reported to reduce the local recurrence rate in patients with rectal cancer [
2]. According to studies that were completed before the TME was commonly used for rectal-cancer treatment [
3,
4,
5,
6], up to 33% of patients experienced local recurrence, even after curative surgery. However, local recurrence occurs in 4%.10% of patients in the era of the TME [
2,
7]. As a result, the role of RT tends to be diminishing compared to that in the pre-TME era.
Surgical treatment is considered a mainstay of treatment for recurrent rectal cancer [
5]. According to a report by Palmer et al. [
8], the 5-year survival rate was 57% in patients treated with a curative resection. In addition, Bouchard and Efron [
7] reported that patients with recurrence who were successfully managed with combined surgery and chemoradiotherapy showed better survival, with a 5-year OS rate of up to 35%, compared to those who were treated without surgical treatment. For patients who did not receive surgery for their recurrent rectal cancer, the reported 5-year overall survival (OS) rate was as low as <5% when treated with supportive care or palliative treatment [
9]. However, only half of all patients are reported to be able to be treated with reoperation owing to tumor extension into or fixation to other pelvic structures [
10]. Moreover, an R0 resection can only be achieved in less than one-third of the patients treated with reoperation [
10].
In this study, we aimed to evaluate the efficacy of salvage RT in treating patients with loco-regionally recurrent colorectal cancer. As data about RT for the treatment of recurrent colorectal cancer are still lacking [
11], this study could provide new information in this field. The primary endpoint of this study was the progression-free survival (PFS) after salvage RT for the treatment of recurrent disease. In addition, we sought to determine the prognostic factors related to treatment failure after a salvage RT for the treatment of recurrent colorectal cancer. We also tried to determine the effect of radiation dose escalation on the RT outcomes.
METHODS
Patients
We retrospectively evaluated 22 patients who were clinically diagnosed with loco-regional relapses of colorectal cancer (confirmed using radiology and/or pathology) without distant metastases. All 22 patients with recurrent colorectal cancer were treated with salvage RT without surgery between June 2008 and to October 2014 at Busan Paik Hospital and Haeundae Paik Hospital. At the time of the diagnosis of recurrence, all patients were evaluated with computed tomography (CT); among them, 20 (90.9%) received positron emission tomography (PET) to confirm recurrence. Pathological confirmation (biopsy) was performed in the other 2 patients who experienced relapses. This study was approved by the institutional review board of Inje University Busan Paik Hospital.
Treatment
None of the patients received any surgical resection for recurrence. Chemotherapy was performed according to the physician's preference. Combined chemotherapy with 5-fluorouracil, capecitabine, tegafur, oxaliplatin, and doxifluridine was used simultaneously with RT for salvage treatment. Sequential chemotherapy with the FOLFOX (Folinic acid, Fluorouracil, and Oxaliplatin) regimen, irinotecan, and capecitabine was administered after RT. For RT, all patients underwent CT simulation. All patients received 3-dimensional conformal RT, except for 2 patients who were treated with intensity-modulated radiotherapy (IMRT) for reirradiation. For RT, a 6- to 10-MV energy was used. Irradiation was performed with a daily dose of 1.8–2 Gy with a margin of 1–3 cm from the beam to the tumor. The margin of the reduced field was defined as 0.3–0.8 cm of the gross tumor. The decision to use radiation dose escalation was made depending on physician's preference and the distance of the tumor from critical organs including the vagina, bladder, and anus, among others. The history of previous RT also influenced the decision making for dose-escalated RT.
Follow-up
Follow-up imaging using CT or PET was performed from 2 to 4 times in the year after treatment. Loco-regional failure was defined as intrapelvic failure (residual tumor regrowth), and distant failure was defined as extrapelvic recurrence. Loco-regional control (LRC) was defined as the time interval from the start of RT for recurrent disease to loco-regional failure. PFS was defined as the time from the start of RT to progression. OS was defined as the time interval from the start of RT to the date of death or last follow-up. Radiation-induced toxicity was reported by using the Common Terminology Criteria for adverse events v.4.03. The symptoms were assessed and recorded at every follow-up visit. Late toxicity was defined as symptoms occurring more than 6 months after salvage RT.
Statistics
For statistical analyses, IBM SPSS ver. 18.0 (IBM Co., Armonk, NY, USA) was used. Fisher exact tests were used to determine the clinical factors related to treatment failure. Actuarial LRC, PFS, and OS rates were estimated by using the Kaplan-Meier method. Log-rank tests were used to compare clinical variables. The Cox proportional-regression hazard model was used to assess independent prognostic factors for survival. Statistical significance was defined as P < 0.05.
DISCUSSION
In this study, we evaluated the clinical outcomes of RT for treating patients with loco-regional recurrent colorectal cancer. Patients receiving salvage RT had better LRC and PFS compared to those receiving only symptom palliation without RT. In particular, the patients who received RT for the first time for treatment of their recurrence showed better PFS and OS than those treated with reirradiation. Therefore, RT can be a possible treatment option for patients who are not suited for curative surgery. In addition, dose escalation (≥70 Gy) showed a benefit in PFS.
Higher radiation doses (≥70 Gy) are generally required to cure gross tumors. A dose of 70 Gy is known to control gross tumors in most cancers with epithelial origins; it can also be applied to recurrent colorectal tumors according to the results of this study. However, most dose-volume parameters showed that rectal doses ≥60 Gy are associated with Radiation Therapy Oncology Group grade ≥2 rectal toxicity [
13]. In addition, more than 20% of the rectal volume receiving >70 Gy is considered to be highly associated with toxicity [
13]. Therefore, radiation-induced toxicity should be monitored in patients who receive dose-escalation.
Recently, Koom et al. [
14] showed the efficacy (treatment outcome) and safety (radiation toxicity) of reirradiation; both longer PFS (median, 16 months) and a higher grades 3–4 late toxicity rate (36%) were observed in reirradiation cases. In addition, they argued that dose escalation might improve LRC in patients who received reirradiation. Although our study showed a worse prognosis in patients with LRC among the patients who were treated with reirradiation, RT for salvage treatment in patients with recurrent colorectal cancer seems to be effective, especially in those who are not able to receive salvage surgery. Moreover, dose escalation seems to be effective for improving clinical outcomes in patients treated with RT.
The reduced rate of distant failure and the improved PFS in patients who received high dose RT (≥70 Gy) may be related to the abscopal effect; local RT inhibits distant, untreated tumors through immunologic mediation [
15]. In this regard, further biological studies can be helpful to determine the clear mechanism underlying this phenomenon.
Salvage RT resulted in good LRC and PFS in this study (2-year LRC rate, 74.6% and PFS rate, 45.1%;
Fig. 2), especially in patients without prior irradiation at initial treatment (2-year PFS rate, 64.3%). Three patients (13.6%, ranges of radiation dose for recurrent disease 45–74 Gy) who were enrolled in this study survived for more than 3 years after RT for recurrent disease. This result is better than that obtained in a Swedish study by Palmer et al. [
8]; in that study, the patients who received only symptom palliation without chemotherapy and/or RT at the time of recurrence showed no survival at the 3-year follow-up. Moreover, Lee et al. [
16] previously reported improved clinical outcomes after chemoradiotherapy in patients with locally recurrent rectal cancer (the 5-year loco-regional relapse-free survival rate was 66.4%, and the OS rate was 48.9%). Active salvage RT, even without curative resection, seems to be effective and better than supportive care or palliative therapy for this patient population [
8].
In contrast to previous reports about the prognostic factors of operable, recurrent colorectal cancer [
12], the tumor site (lateral or posterior) was not a determining factor for prognosis in patients treated with RT. In contrast to the results of another study with a multidisciplinary approach [
17], the interval of recurrence was not a significant prognostic factor in this study. This may be one of the specific features of RT outcomes. However, drawing conclusions is difficult because the negative results may have been affected by the relatively small sample size of this study
This study has several limitations. First, the follow-up period was relatively short (median, 24.9 months). Moreover, it was designed as a retrospective study and included a relatively small number of patients (n = 22) because of the rarity of the condition. Nevertheless, we showed an improved PFS in patients treated with high-dose radiation. A large-scale, long-term follow-up study should be undertaken to clarify the effect of salvage RT.
For future studies of RT for the treatment of patients with colorectal cancer recurrence, preoperative RT combined with reoperation [
18] might be an interesting topic. Symptom evaluation may also be an important issue, although we could not deal with the effect of pain palliation caused by salvage RT in this study owing to the lack of access to medical records. Dose escalation using an IMRT technique also seems to be a promising avenue of research [
19]. Attempts at dose escalation using IMRT to improve local control and reduce the rate of radiation toxicity should be continued. In addition, the use of stereotactic body RT for the treatment of patients with oligo-recurrence in the pelvis may be another treatment option [
20], and it should be evaluated further.
In conclusion, salvage RT for the treatment of patients with locally-recurrent colorectal cancer can be offered when surgery is not possible, especially in patients who did not receive prior RT as an initial treatment. Furthermore, dose escalation seems to have a potential benefit for the treatment outcome. Further evaluation is required to assess the effect of RT for the treatment of patients with recurrent colorectal cancer.