Survival benefit of re-irradiation in esophageal Cancer patients with Locoregional recurrence: a propensity score-matched analysis

In the current study, we retrospectively examined 87 consecutive ESCC patients with locoregional recurrence who were admitted to Fujian Cancer Hospital between June 2000 and June 2014. All included patients met the following criteria: a) pathological confirmation of primary ESCC at initial diagnosis; b) a history of initial radiation; c) histological and/or PET-CT confirmation of locoregional recurrence including regional lymph node recurrence only (LN) or primary failure with/without regional lymph node recurrence (PF); d) no evidence of esophageal perforation or ulcer; and e) adequate liver, kidney, and bone marrow functioning with a Karnofsky performance status (KPS) score ≥ 70. The exclusion criteria were as follows: a) history of other malignancies; b) distant metastases; and c) confirmation of recurrence within 3 months of initial treatment.

Clinical staging at first diagnosis was determined by chest computed tomography (CT) and barium esophagram and/or endoscopic ultrasound (EUS). Re-staging of initial ESCC was done according to the 8th edition of American Joint Committee on Cancer (AJCC). The current study was approved by the Ethics Committee of Fujian Medical University Cancer Hospital, Fuzhou, China (KT2018–006-01). Because this was a retrospective study involving patient medical records, the requirement of patients’ consent was waived.

For initial treatment, 11 (12.6%) patients received radical resection with adjuvant radio (chemo) therapy (median dose = 52 Gy, range 40–56 Gy). Thirty-nine (44.8%) and 37 (42.6%) patients received CRT and RT, respectively. Among the 43 (49.4%) cases initially treated with chemotherapy (median of 3 cycles, range 1–6 cycles), 30 (34.5%) received cisplatin and paclitaxel, whereas the remaining 13 (14.9%) received cisplatin or oxaliplatin.

Patients were treated with 6- or 10-MV linear accelerators for initial radiotherapy with 1.8–2.2 Gy/fraction and 5 fractions/week. Initial RT was conventional two-dimensional (36.8%) or conformal three-dimensional (63.2%) RT with a median dose of 62 Gy (range 40–76 Gy). The median dose of re-RT was 50 Gy (ranged 21–70 Gy) with 2Gy (range 1.8–4 Gy) per fraction. Intensity-modulated RT (56.4%; 22/39) and conformal three-dimensional RT (43.6%; 17/39) were employed for re-RT. Among the 39 patients treated with re-RT, 19 patients (48.7%) received concomitant chemotherapy, of which 6 received cisplatin, 4 received 5-flurouracil (5-FU), and 9 received cisplatin combined with 5-FU. The remaining 20 (51.3%) patients received RT alone.

The biological effectiveness of radiation schedule was calculated by the biologically effective dose (BED) formula: BED = n × d (1 + d/(α/β)), d for the dose per fraction (Gy) and n for the number of fractions. Assuming an α/β ratio of 10 Gy for ESCC (BED₁₀) [12]. For re-RT patients, the cumulative dose was calculated.

For patients without re-RT, 7 (8.0%) patients received chemotherapy alone with cisplatin combined with 5-FU, whereas 3 (3.4%) patients underwent salvage total esophagectomy with gastric pull-through. The remaining 38 (43.7%) patients received supportive care including esophageal stenting, dilation or percutaneous endoscopic gastrostomy to relieve dysphagia.

The primary endpoint was OS, which was defined as the time duration from recurrence diagnosis to death or last follow-up. The recurrence-free interval (RFI) was defined as the time interval from the end of initial treatment to the recurrence diagnosis. According to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, toxicities recorded in the patients’ medical records were retrospectively graded [13]. Tracheoesophageal fistula (TEF), pericardial/pleural effusion, and radiation pneumonitis (RP) were recorded.

All statistical tests were performed using SPSS version 22.0 (IBM Corporation, Armonk, NY, USA). The propensity score matching ratio was set to 1:1 to minimize differences due to age, gender, primary tumor location, and initial clinical stage. Chi-square (χ²) and Fisher’s exact tests were applied to compare unmatched background factors. Survival curves were constructed and compared by the Kaplan-Meier method and log-rank tests. The Cox regression model was employed for the univariate analysis and multivariate analysis. P-values < 0.05 were considered statistically significant.

The patient characteristics are summarized in Table 1. The median age was 62 years (range 39–86 years), and the study population included 65 (74.7%) males and 22 (25.3%) females. Considering KPS at recurrence diagnosis, 32 (36.8%) of patients were 70–80, while 55 (63.2%) were ≥ 80. Eight (9.2%) patients had stage I disease, 18 (20.7%) had stage II, and 61 (70.1%) had stage III at the initial diagnosis. The primary tumor location was the upper thoracic esophagus in 34 (39.1%) patients and the middle and lower thoracic esophagus in 53 (60.9%) patients. The median RFI was 16 months (range 3–168 months), and the RFI was ≤12 months in 38 (43.7%) patients and > 12 months in 49 (56.3%) patients. The failure pattern of 62 (71.3%) patients was primary recurrence, 14 (16.1%) cases of regional LN recurrence alone and 11 (12.6%) cases of combined sites. All patients were divided into two groups, 14 patients with regional LN recurrence and the remaining 73 patients with PF. For re-RT patients, 36 of 39 cases received in-field re-irradiation, while the other three cases experienced out-field locoregional failure.

For re-RT patients, the median BED₁₀ of 74.11 Gy (range 48–86.32 Gy) and 60 Gy (range 25.41–84.87 Gy) were delivered in the initial radiation and re-RT, respectively. The median cumulative BED₁₀ was 135.53 Gy (range 96–168 Gy). The median Dmax of spinal cord was 25 Gy (range 9–39 Gy), the median V20 of the total lung and V30 of the heart was 10% (range 0–24%) and 9% (range 0–25%), respectively.

The median follow-up was 87 months (range 2–206 months). The follow-up rate was 96.6% (84/87). One patient without re-RT and 7 patients with re-RT remained alive at the last follow-up. For re-RT, 82.1% (32/39) patients were dead at last follow up, among which, 84.4% (27/32) patients were cancer-related death. After re-RT, 89.7% (35/39) suffered from failure, with 24 (68.6%) cases of distant metastasis alone, 5 (14.3%) cases of local failure alone and 6 (17.1%) cases of both. The median survival time (MST) was 10 months (range 1–85 months). The median RFI was 16 months (range 3–168 months). Fifty-two (59.8%) patients were diagnosed with recurrence within 2 years after initial treatment (Fig. 1).

Significant differences in the clinical stage of initial cancer were observed for patients with re-RT (n = 39) and without re-RT (n = 48) before matching (P = 0.003) (Table 2). A nearest neighbor and 1:1 matching algorithm was applied within a default caliper (0.2) [14]. After matching, baseline covariates of the clinicopathological characteristics were corrected, with characteristics being evenly distributed between the re-RT group (n = 33) and the non-re-RT group (n = 33, all P > 0.1).

The results of univariate and multivariate analyses for OS are summarized in Table 3. LN recurrence alone and re-RT were associated with better OS (P = 0.006 and P < 0.001) by Cox univariate analysis. The 1-, 3-, and 5-year OS rates in the LN group were 84.62%, 30.77%, and 23.01%, respectively, and the 1-, 3-, and 5-year OS rates in the PF group were 37.86%, 10.29%, and 2.57%, respectively. The MST in the LN group was 23 months, whereas the MST in the PF group was 9 months (P = 0.004, Fig. 2a). The 1-, 3-, and 5-year OS rates in the re-RT group were 67.94%, 22.89%, and 13.08%, respectively, and the 1-, 3-, and 5-year OS rates for patients without re-RT were 28.52%, 6.58%, and 2.19%, respectively. Their MSTs were 21 months and 8 months, respectively (P < 0.001, Fig. 2b).

Initial clinical stage (I + II vs. III), failure pattern (LN vs. PF), re-RT (with vs. without), and chemotherapy for both courses of treatment (with vs. without) were possible prognostic factors in the Cox multivariate model. The failure pattern and re-RT were independent prognostic factors for OS (P = 0.040 and P = 0.015, respectively). However, no statistical difference in OS was observed between the re-RT alone and re-RT with concomitant chemotherapy groups (18 vs. 19, P = 0.70, Fig. 3) in the subgroup analysis.

In the matched cohort, failure pattern and re-RT were independently associated with OS for recurrent ESCC (P = 0.025 and P = 0.002, respectively; Table 4). For the two failure patterns (LN vs. PF), the comparative 1-, 3-, and 5-year OS rates were 75.00% vs. 29.49%, 37.50% vs. 9.53%, and 37.50% vs. 0%, respectively. The MSTs in the LN and PF groups were 28 months and 6 months, respectively (P = 0.004, Fig. 2c). For treatment with re-RT or no re-RT (with or without), the comparative 1-, 3-, and 5-year OS rates were 62.38% vs. 9.93%, 23.71% vs. 3.31%, and 15.81% vs. 0%, respectively. The MSTs in the re-RT and without re-RT groups were 23 months and 5 months, respectively (P < 0.001, Fig. 2d).

In the re-RT and non-re-RT groups of the matched cohort, 9.09% (3/33) and 3.03% (1/33) of cases experienced TEF, 15.15% (5/33) and 3.03% (1/33) of cases experienced pericardial/pleural effusion (P = 0.613 and P = 0.197, respectively). The rates of grade 3 RP were 24.24% (8/33) and 6.06% (2/33) in the re-RT and non-re-RT groups, respectively (P = 0.039). No case of grade 5 RP was observed. The median age of the 10 patients who developed RP was 61 years (range 43–83 years). The radiation doses for primary RT in 2 patients not treated with re-RT were 63 Gy and 70 Gy. The median doses for primary RT and re-RT in the other eight patients were 62.2 Gy (range 41–64 Gy) and 50.3 Gy (range 36–60 Gy), respectively. No significant correlation was found between RP and the V20 of the total lungs in re-RT (P = 0.25). No treatment-related deaths were recorded.