A retrospective study of californium-252 neutron brachytherapy combined with EBRT versus 3D-CRT in the treatment of esophageal squamous cell cancer
© Wang et al. 2015
Received: 29 May 2015
Accepted: 13 October 2015
Published: 24 October 2015
We conducted a retrospective analysis on 884 patients who were diagnosed with esophageal squamous cell carcinoma (ESCC) and treated with either the neutron brachytherapy in combination with external beam radiotherapy (NBT + EBRT) or 3-dimensional conformal radiation therapy (3D-CRT) to determine the differences in efficacy and morbidity between the two treatment groups.
The 884 ESCC patients treated with either NBT + EBRT or 3D-CRT between 2002 and 2012 were retrospectively reviewed and analyzed. Multivariable Cox regression was used to compare oncologic outcomes of the two groups of patients in the context of other clinically relevant variables. The acute and chronic toxicities associated with the two groups were compared using Fisher exact and log-rank tests, respectively.
Among the 884 patients, 545 received NBT + EBRT and 339 received 3D-CRT (i.e. EBRT-only). The age range is 39–95 years (median 66). The follow-up time range is 3–145 months (median 32). The analysis shows that the NBT + EBRT group has higher overall survival rate and local control rate than that of the 3D-CRT group. The acute toxicity effects were acceptable for both groups of patients with the NBT + EBRT group showing higher rates of leukopenia and thrombocytopenia and the 3D-CRT group showing higher rates on fistula and massive bleeding.
The patients treated with NBT + EBRT showed better oncologic outcomes than those treated with 3D-CRT. The toxicity effects were acceptable for both groups with the NBT + EBRT group showing higher rates on the acute effects and the 3D-CRT group showing higher rates on the late effects.
KeywordsEsophageal squamous cell carcinoma (ESCC) Neutron brachytherapy (NBT) High-LET Relative biological effectiveness (RBE)
Worldwide, an estimated 482,000 new esophageal cancer cases were diagnosed and approximately 407,000 deaths occurred in 2008 . The management of localized esophageal cancers has shifted from surgery or radiation single modality approaches to the trimodality. The current trimodality approach combining chemotherapy, radiation therapy, and surgery, has shown improved survival rates . However, there are patients that either cannot tolerate or decide not to undergo surgery. For these individuals, concurrent chemoradiotherapy (CCRT) is the standard approach.
In recent years, two radiotherapy modalities have become widely used in China to treat esophageal cancers: the neutron brachytherapy in combination with conventional external beam radiotherapy (NBT + EBRT) and the 3-dimensional conformal radiotherapy (3D-CRT). Currently there are no prospective, randomized trials comparing the efficacy of the two modalities for the treatment of esophageal cancer. The choice between the two modalities is not trivial, and their characteristics can have bearing on both disease control and adverse effects . Generally speaking, 3D-CRT tends to treat lymph nodes adjacent to the target with relatively high doses, whereas EBRT tends to cover farther regional nodes with lower doses [4, 5]. Because the radiation dose of NBT is highly localized, the NBT + EBRT has a benefit of sculpting away high-dose regions from normal tissues, e.g. the heart and lungs. In addition to clinical considerations, there are also substantial differences between NBT + EBRT and 3D-CRT (i.e. EBRT-only) in terms of the allocations of time, labor, and health care costs. Accordingly, we conducted a retrospective study on patients of esophageal squamous cell carcinoma (ESCC) who were treated with either NBT + EBRT or 3D-CRT to determine the differences in efficacy and morbidity of the two modalities.
The characteristics of patients of the two treatment groups (EBRT + NBT and 3D-CRT) and the univariate analysis of the clinical outcome
EBRT + NBT (%)
5y OS (%)
5y LC (%)
Group 1: NBT + EBRT
Group 2: 3D-CRT (i.e. EBRT-only)
For the patients treated with 3D-CRT, simulation CT scanning was first performed with the CT Brilliance Scanner (Philips Medical Systems, the Netherlands) and with the use of intravenous contrast. All patients were immobilized in a supine position (with thermoplastic on the chest) when simulation and radiotherapy was performed. The scanned area was from the angulus mandibulae to the bottom of the L1 vertebral body. These images were transferred to a 3-D treatment planning system. The clinical target volume (CTV) in this study was re-created using a 3-cm margin in the proximal and distal direction (following the course of the esophagus) beyond the barium esophagram, endoscopic examination and the gross tumor volume (GTV) defined by a 0.5-cm margin in the lateral and anteroposterior directions of the CT scan. Finally, the planning treatment volume (PTV) was defined by including additional 1-cm proximal and distal margins and 0.5-cm radial margin based on the CTV. The prescribed radiation doses were delivered by 6-MV X-rays from a linear accelerator (Elekta Precise Linear Accelerator, Sweden). For each patient the PTV was covered by at least 95 % isodose surface, and 95 % of the PTV received the 56–60 Gy of the prescribed dose with 2 Gy/fraction/day and 5 days per week.
Toxicity assessment and follow-up
The patients were examined weekly during the course of treatment. Weekly blood tests were obtained, and any indication of treatment-related complications was recorded. All adverse events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 3.0 . The patients usually underwent follow-up examinations every 3–6 months after the completion of treatment. Tumor response and nodal disease were evaluated with repeated CT scans, barium swallow studies, and endoscopy.
Patients were grouped according to different radiotherapy regimes. Pearson’s chi-square test was used to assess the relationship between frequency data. The overall survival (OS) time was calculated from the date of consultation until death or the last follow-up. Local and regional failure was defined as persistent and/or the recurrence of primary tumor and regional lymph nodes. Time to first failure, time to local failure, and time to any distant metastases were calculated from the date of consultation. The OS rate and the local control (LC) rate were estimated using the Kaplan-Meier method. Nine factors were included for the univariate analysis of OS and LC, like gender, age, Karnofsky performance score (KPS), tumor location, tumor length, T stage, N stage, AJCC stage, and radiation dose. The log-rank test was used to assess the survival differences between groups. Data were analyzed using SPSS software (version 20.0, SPSS Inc., Chicago, IL, USA).
Patient characteristics and treatments
Table 1 shows the characteristics of the patients according to the two different treatment modalities. As shown, there were 583 men and 301 women whose ages range between 36 and 93 years (median 66). The patients were divided into two age groups (≤65 and > 65) because an elder (or a senior citizen) in China is defined as one whose age is greater than 65. Among the 884 patients, 512 had a KPS of 90–100 and 372 had a KPS of 80. As to the tumor location, 329 patients occurred in the upper section of the esophagus, 442 occurred in the middle section, and 113 occurred in the lower section. The tumor lengths range from 3 to 10 cm with the median of 6 cm. In the TNM classification, T1 was found in 32 patients, T2 in 163, T3 in 305 and T4 in 384; N0 in 461 patients and N1 in 423.
Univariate and multivariate analysis of OS and LC rates
Multivariate cox regression analysis of overall survival (OS) rate and local control (LC) rate of the patients
HR (95 % CI)
HR (95 % CI)
Tumor length (≤5 cm vs >5 cm)
T stage (T1 + T2 vs T3 + T4)
N stage (N0 vs N1)
AJCC Stage (I + II vs III)
Treatment modality (3D–CRT vs NBT + EBRT)
Subgroup analyses on OS and LC rates
The 5-year local control (LC) rate and overall survival (OS) rate for the early-stage (I + II) and advanced stage (III) patients of the two treatment groups (EBRT + NBT and 3D-CRT)
EBRT + NBT
Stage I + II
n = 237
n = 126
n = 308
n = 213
n = 545
n = 339
Toxicity and pattern of failure
As of the last date of follow-up (March 31, 2013), in the EBRT + NBT group the total number of failures (including local recurrences, remote metastasis, and deaths) were 326(59.8 %). There were 195 recurrences (35.7 %), among which 170 (31.2 %) were in-field recurrences and 25 (4.6 %) were out-of-field recurrences. Among the 25 out-of-field recurrences, ten occurred in the supraclavicular lymph nodes and 15 occurred in the intra-abdominal lymph nodes. A total of 86 cases (15.8 %) of remote metastasis were found, among which the number of metastasis to the lung, liver, bone, brain and others (including more than one organ metastasis) were 23, 14, 14, 5 and 30, respectively. A total of 36 deaths (6.6 %) were found to be the results of fistula and hematemesis. A total of 45 deaths (8.2 %) were found to be caused by reasons other than the original cancer and the radiation treatment.
In the 3D-CRT group, the total number of failures (including local recurrences, remote metastasis, and deaths) were 219 (64.6 %). There are 139 recurrences (41.0 %), among which 124(39.5 %) were in-field recurrences and 15 (4.4 %) were out-of-field recurrences. Among the 15 out-of-field recurrences, 4 occurred in the supraclavicular lymph nodes and 11 occurred in the intra-abdominal lymph nodes. A total of 41 cases (12.1 %) of remote metastasis were found, among which the number of metastasis to the lung, liver, bone, brain and others (including more than one organ metastasis) were 14, 8, 3, 3 and 13, respectively. A total of 18 deaths (5.3 %) were found to be the results of fistula and hematemesis. Four patients died of second cancer. A total of 35 deaths (10.3 %) were found to be caused by reasons other than the original cancer and the radiation treatment.
Treatment toxicity and the sites of first failure for the two patient groups (EBRT + NBT and 3D-CRT)
EBRT + NBT (n = 545)
3D-CRT (n = 339)
Acute toxicity (Events of grade ≥2)
Number of patients (%)
197 (36.1 %)
122 36.0 %)
30 (5.5 %)
10 (2.9 %)
425 (78.0 %)
209 (61.7 %)
282 (51.7 %)
165 (48.7 %)
54 (9.9 %)
8 (2.4 %)
33 (6.1 %)
47 (13.9 %)
27 (5.0 %)
20 (5.9 %)
The sites of first failure in the whole group
195 (35.7 %)
139 (41.0 %)
170 (31.2 %)
124 (36.6 %)
25 (4.6 %)
15 (4.4 %)
86 (15.8 %)
41 (12.1 %)
23 (4.2 %)
14 (4.1 %)
14 (2.6 %)
8 (2.4 %)
14 (2.6 %)
3 (0.9 %)
5 (1.0 %)
3 (0.9 %)
≥2 metastasis sites
30 (5.5 %)
13 (3.8 %)
Not otherwise specified (disease of heart head blood-vessel, pneumonia, second tumor)
36 (6.6 %)
35 (6.4 %)
While esophageal cancer radiotherapy technology has progressed from 2-D CRT to 3-D CRT, and to intensity-modulated radiotherapy (IMRT), the local recurrence rates remain unchanged at about 50 % [5, 7]. Myles et. al. reported long term outcomes of 3D-CRT vs. IMRT with concurrent chemotherapy for the treatment of esophageal cancer . They showed that the 5 year OS rate and median survival time for IMRT (42.2 % and 36 months) were significantly higher than that for 3D-CRT (31.3 % and 24 months) with p = 0.001. However, there were no differences in the 5 year LC rate and distant metastasis free survival between the two groups. Xiao et. al. reported that 3D-CRT can achieve ideal dose distribution of providing good coverage to the target volumes and at the same sparing the normal tissues when compared with the conventional and enlarged field radiotherapy techniques . Other authors reported that the patients treated with 3D-CRT have better OS and LC than that of conventional radiotherapy alone in many types of cancer [10, 11]. In this study, we found that NBT + EBRT produced better clinical outcomes than those of 3D-CRT.
We believe that there are at least two factors making the NBT + EBRT more effective than 3D-CRT in treating the localized ESCC. The first factor has to do with the high-LET nature of fission neutrons of NBT. These neutrons are known to be much more effective (than the low-LET x-ray) in killing the hypoxic tumor cells in locally advanced cancer. The second factor has to do with the water being an effective neutron attenuator and that it can be conveniently injected into the source applicator during treatment to reduce the neutron dose to the nearby normal tissue. Because there is a significant difference in the elasticity between normal tissue and tumor tissue, one can inject water into the source applicator to effectively push away the nearby normal tissue while still keep the tumor tissue close to the source .
In terms of radiation related toxicity effects, this study shows that the NBT + EBRT group showed significantly higher rates of leukopenia and thrombocytopenia (P < 0.001 and P < 0.001) than that of the 3D-CRT group. But the 3D-CRT group showed a higher rate of esophageal fistulas. The above differences between the two groups likely have to do with the differences in their radiation dose distributions of which the 3D-CRT has a more uniform dose over the entire target/tumor volume and the NBT gives an increased dose for the inner part of the tumor volume.
For long-term survivors from primary cancer, second primary malignancies (SPMs) are among the most serious late adverse effects after radiotherapy. Samerdokiene et. al. recently reported a study on SPMs of 662 long-term survivors with invasive cervical cancer . Among these patients, 375 were treated with NBT and 287 were treated with high-dose-rate (HDR) 60Co brachytherapy. The study reported that no significant difference in rates or distribution of SPMs was found (21/375 vs 14/287; P = 0.68). Our study did not include SPMs as most of the esophageal cancer patients had not survived long enough to develop SPMs.
An obvious limitation of the reported results is that they were based on the retrospective study in which the patients were not randomly assigned. As such, many factors (e.g. patients’ income level and social status, etc.) may cause bias of the results.
In this cohort of patients with ESCC treated with NBT + EBRT were associated with better oncologic outcomes than those of 3D-CRT. NBT + EBRT were associated with a higher rate of acute irradiation toxicity. 3D-CRT has the higher rate of late toxicity esophageal fistulas.
Ethical standards statement
All patients included in this study gave their informed consents before treatment in accordance with the Declaration of Helsinki. The informed consents were also approved by the respected Ethics Committees of Changzhi Cancer Hospital and Sichuan Cancer Hospital.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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