Intensity-Modulated Radiotherapy versus Three-Dimensional Conformal Radiotherapy in Definitive Chemoradiotherapy for Cervical Esophageal Squamous Cell Carcinoma: Comparison of Survival Outcomes and Toxicities

Nai-Bin Chen; Bo Qiu; Jun Zhang; Meng-Yun Qiang; Yu-Jia Zhu; Bin Wang; Jin-Yu Guo; Ling-Zhi Cai; Shao-Min Huang; Meng-Zhong Liu; Qun Li; Yong-Hong Hu; Qi-Wen Li; Hui Liu

doi:10.4143/crt.2018.624

Articles

Page Path: HOME > Cancer Res Treat > Volume 52(1); 2020 > Article

Original Article Intensity-Modulated Radiotherapy versus Three-Dimensional Conformal Radiotherapy in Definitive Chemoradiotherapy for Cervical Esophageal Squamous Cell Carcinoma: Comparison of Survival Outcomes and Toxicities: Nai-Bin Chen, MD^1,2,3, Bo Qiu, PhD^1,2,3, Jun Zhang, MD^1,2,3, Meng-Yun Qiang, MD^1,2,3, Yu-Jia Zhu, PhD^1,2,3, Bin Wang, MD^1,2,3, Jin-Yu Guo, BS^1,2,3, Ling-Zhi Cai, BS^1,2,3, Shao-Min Huang, MD^1,2,3, Meng-Zhong Liu, PhD^1,2,3, Qun Li, PhD^1,2,3, Yong-Hong Hu, PhD^1,2,3, Qi-Wen Li, PhD^1,2,3, Hui Liu, PhD^1,2,3; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2020;52(1):31-40.
DOI: https://doi.org/10.4143/crt.2018.624
Published online: April 30, 2019

¹Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China

²State Key Laboratory of Oncology in South China, Guangzhou, China

³Collaborative Innovation Center for Cancer Medicine, Guangzhou, China

Correspondence: Hui Liu, PhD Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, Guangdong 510060, P. R. China
Tel: 86-2087343031 Fax: 86-2087343492 E-mail: liuhuisysucc@sina.com.

Co-correspondence: Qi-Wen Li, PhD Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, Guangdong 510060, P. R. China
Tel: 86-13660775270 Fax: 86-2087343492 E-mail: liqw@sysucc.org.cn.

Co-correspondence: Yong-Hong Hu, PhD Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, Guangdong 510060, P. R. China
Tel: 86-2087343385 Fax: 86-2087343492 E-mail: huyh@sysucc.org.cn.

^*Nai-Bin Chen and Bo Qiu contributed equally to this work.

• Received: November 14, 2018 • Accepted: April 29, 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

9,938 Views
256 Download
22 Web of Science
19 Crossref
26 Scopus

prev next

Full Article

Download PDF

Abstract

Purpose
The purpose of this study was to compare the survival and toxicities in cervical esophageal squamous cell carcinoma (CESCC) treated by concurrent chemoradiothrapy with either three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) techniques.
Materials and Methods
A total of 112 consecutive CESCC patients were retrospectively reviewed. 3D-CRT and IMRT groups had been analyzed by propensity score matching method, with sex, age, Karnofsky performance status, induction chemotherapy, and tumor stage well matched. The Kaplan-Meier method and Cox proportional hazards model were used for overall survival (OS) and progression-free survival (PFS). Toxicities were compared between two groups by Fisher exact test.
Results
With a median follow-up time of 34.9 months, the 3-year OS (p=0.927) and PFS (p=0.859) rate was 49.6% and 45.8% in 3D-CRT group, compared with 54.4% and 42.8% in IMRT group. The rates of grade ≥ 3 esophagitis, grade ≥ 2 pneumonitis, esophageal stricture, and hemorrhage were comparable between two groups, while the rate of tracheostomy dependence was much higher in IMRT group than 3D-CRT group (14.3% vs.1.8%, p=0.032). Radiotherapy technique (hazard ratio [HR], 0.09; 95% confidence interval [CI], 0.01 to 0.79) and pretreatment hoarseness (HR, 0.12; 95% CI 0.02 to 0.70) were independently prognostic of tracheostomy dependence.
Conclusion
No survival benefits had been observed while comparing IMRT versus 3D-CRT in CESCC patients. IMRT with fraction dose escalation and pretreatment hoarseness were considered to be associated with a higher risk for tracheostomy dependence. Radiation dose escalation beyond 60 Gy should be taken into account carefully when using IMRT with hypofractionated regimen.
Key words: Cervical esophageal squamous cell carcinoma, Conformal radiotherapy, Intensity-modulated radiotherapy, Survival, Tracheostomy dependence

Introduction

Cervical esophageal squamous carcinoma (CESCC) is a relatively rare malignancy, accounting for less than 5% of all esophageal cancers [1]. Historically, surgical resection has been the mainstay of treatment for CESCC, which requires the removal of the larynx, hypopharynx, and esophagus, and deprives these patients of speech and swallowing. As the notion of organ preservation has been introduced and due to the rapid developments in concurrent chemoradiotherapy (CCRT), physicians and patients predisposed to accept the non-aggressive therapy, hoping to improve functional outcomes after therapy. Prior works [2-13] have documented promising overall survival (OS) and functional preservation with definitive CCRT in CESCC patients.

Three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) are the most effective and commonly used techniques in esophageal cancer. Although recent studies failed to demonstrate the survival benefit of IMRT based definitive CCRT in esophageal cancer [14,15], IMRT does show a greater advantage in target coverage, dose inhomogeneity, and reducing toxicities to normal organs compared to 3D-CRT [16-19]. With the dosimetric advantage of IMRT technique, hypofractionated radiation therapy for various cancers has been comprehensively studied, which shortens the treatment time and intensifies the dose. Several randomized trials demonstrated that dose-escalated, moderately hypofractionated IMRT improves local control in prostate cancer, lung cancer and breast cancer [20-22]. Since previous data suggested that esophageal cancer patients could not benefit from high dose radiation [3], fraction dose escalation (hypofrationated IMRT) started to attract attention especially for CESCC patients.

Since definitive CCRT is an essential treatment option for CESCC, we believed the technique of dose delivery should be well investigated. To our best knowledge, data comparing IMRT with 3D-CRT for CESCC are still limited. Therefore, current study was designed to compare the survival outcomes and toxicities between CESCC patients treated with definitive 3D-CRT and IMRT with concurrent chemotherapy. A propensity score matching (PSM) approach wad used to reduce bias introduced by the non-random treatment assignment, by matching patients with similar clinical stages and other baseline characteristics.

Materials and Methods

1. Patient and clinical data

From January 1, 2000, to September 30, 2016, a total of 138 consecutive patients with CESCC who were treated at the Department of Radiation Oncology, Sun Yat-sen University Cancer Center were retrospectively reviewed. To be included in our study, patients had to meet the following criteria: pathologically confirmed CESSC; treated with definitive radiotherapy with concurrent chemotherapy; without a history of prior radiotherapy; and Karnofsky performance status (KPS) ≥ 70. Surgical therapy was not allowed to be used. Patients with metastasis upper mediastinal lymph nodes (M1 lymph/stage IV) were included. Each patient underwent a physical examination, laboratory tests, electrocardiogram, lung function test, barium contrast study, endoscopy, and computed tomography (CT) scan of the neck, chest, and upper abdomen. Clinical data collected from each patient included age, sex, KPS, smoking or alcohol-abusing history, primary esophageal tumor location, tumor stage, T and N category of primary tumor, total radiation dose, fraction dose, radiotherapy technique, concurrent chemotherapy regimen, pretreatment hoarseness, pretreatment vocal cord paralysis, tracheostomy dependence after treatment, therapeutic toxicities, and tumor progression. Tumor stage was classified using the TNM staging system proposed by the American Joint Committee on Cancer (6th edition).

2. Treatment

All patients received external beam radiation, either 3D-CRT or IMRT, using a 6-8 MV photon beam, with concurrent chemotherapy. During radiotherapy, immobilization, simulation, and treatment planning were performed according to the standard protocol in our department for patients with cervical esophageal carcinoma [23]. The gross tumor volume (GTV) was defined as visible primary tumors (GTV-T) and involved lymph nodes (GTV-N) on endoscopy, CT and/or positron emission tomography (PET) scans. The criteria of lymph node positivity included: short-axis size ≥ 10 mm, or an infiltrative margin, or central necrosis on pretreatment CT scan, reported positive on the pretreatment PET scan, or biopsy positive. The clinical target volume (CTV) included GTV-T with a 3-cm proximal and distal margin, GTV-N and elective nodal regions, including bilateral levels II-IV of the cervical lymph node area and supraclavicular fossa. The planning target volume (PTV) 1 and PTV2 was defined as a 0.5 cm margin added to GTV and CTV, respectively. The radiation doses of 60-70 Gy to PTV1 and 46-54 Gy to PTV2 were delivered in 28-35 fractions, with 5 fractions per week.

Concurrent chemotherapy regimens consisted either of a single agent such as 5-fluorouracil or platinum, or of double agents combined with taxane and platinum (TP) or platinum and 5-fluorouracil (PF).

3. Follow-up and treatment response assessments

The beginning of the follow-up period was defined as the date of diagnosis. All patients were evaluated weekly during therapy, and then underwent a neck and chest or upper abdomen CT scan every 3 months, and an upper digestive tract endoscopy every 6 months for the first 2 years after completion of CCRT, and subsequently every 6 months thereafter until tumor progression. Bone scans were administered when patients were suspected to have bone metastasis. PET scans were performed in patients with suspected systemic progression. The date of last follow-up was January 1, 2018. Treatment response, OS, and progression-free survival (PFS) were recorded. The responses to CCRT were assessed 2 months after radiotherapy by an independent radiation oncologist according to Response Evaluation Criteria in Solid Tumors ver. 1.1. OS was calculated from the diagnosis of CESCC until death or last follow-up. PFS was defined as the time from diagnosis to tumor recurrence, or death, or last follow-up. OS and PFS were used as measures of survival outcomes. Acute and late toxicities were collected retrospectively and then presented according to The National Cancer Institute Common Toxicity Criteria (ver. 4.0).

4. Statistical analysis

We matched patients in the 3D-CRT and IMRT groups by propensity score with a caliper of 0.1 in a 1:1 ratio, using the PSM method with five covariates including sex, age, KPS, induction chemotherapy, and tumor stage. Means, frequencies, and percentage were calculated to describe the data. Continuous variables, such as age, total radiation dose, fraction dose, D5 of PTV1, GTV volume, Dmean of larynx and so on, were normalized as the sample median and then analyzed as nominal categorical variables. Comparisons of categorical variables between groups were first performed by Fisher exact test, and then the variables that reached a p-value < 0.1 were further evaluated in a multivariate analysis using Logistic regression model. The Kaplan-Meier method was used to produce survival curves. The 3-year, 5-year OS and PFS were estimated. OS and PFS were first compared in univariate analysis by using the two-sided logrank test. Then the Cox proportional hazards model was used to test independent prognostic factors of OS and PFS. All statistical analyses were performed using SPSS ver. 24.0 software (IBM Corp., Armonk, NY), and differences were considered significant at a p-value < 0.05.

5. Ethical statement

Our study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center, and the approval number was YB2017-080. As this was a retrospective analysis of routine clinical data, a waiver of the requirement for individual informed consent was granted by our institutional ethics committee.

Results

1. Baseline characteristics

A total of 112 of the included 138 consecutive patients were divided into the 3D-CRT and IMRT groups based on the above-mentioned PSM procedure. Patient sex, age, KPS, induction chemotherapy, and tumor stage were well matched (p > 0.1). The demographic and clinical characteristics of the cohort are listed in Table 1. The median age was 59 years, range from 18 to 81. Most patients (102/112, 77%) had stages II and III disease and the rest 10 patients had stages IV disease. As for T category, 21 patients had T1-2 lesion, and 89 had T3-4 lesion. In our group, 9.8% (11/112) patients had pretreatment hoarseness, and the incidence of pretreatment vocal cord paralysis was 6.3% (7/112). The median radiation dose was 62 Gy (range, 60 to 70 Gy) in 30-35 fractions. The dosimetric parameters were listed in Table 2. The median fraction dose, Dmean of GTV, V5 of the lungs, V20 of the lungs, Dmean of the lungs, Dmax of the spinal cord, D5 of PTV1 and Dmean of larynx in the 3D-CRT group vs. IMRT group was 200 cGy vs. 213 cGy (p < 0.001, Fisher exact test), 6,123 cGy vs. 6,290 cGy (p=0.001), 38.0 vs. 50.2 (p=0.032), 18.7 vs. 21.8 (p=0.479), 958 cGy vs. 1,101 cGy (p=0.156), 4,917 cGy vs. 4,344 cGy (p < 0.001), 6,394 cGy vs. 6,745 cGy (p=0.007), and 5,779 cGy vs. 6,045 cGy (p=0.227), respectively. Most patients (93/112, 83%) received double agents chemotherapy regimens, and the remaining adopted single-agent regimens. Part of patients (27/112, 24%) underwent induction chemotherapy before definitive CCRT.

2. Survival outcomes

With a median follow-up of 34.9 months (range, 2.1 to 183.6 months), our analysis demonstrated a median estimated OS of 36.0 months in the 3D-CRT group, 45.6 months in the IMRT group and 41.4 months in the whole group. The 3-year and 5-year OS rate was 49.6% and 45.6% in the 3D-CRT group, compared with 54.4% and 43.8% in the IMRT group (p=0.927, log-rank). The median estimated PFS was 30.2, 25.2, and 27.5 months in the 3D-CRT, IMRT, and the whole group, respectively. And the 3-year and 5-year PFS rate was 45.8% and 32.1% in the 3D-CRT group, vs. 42.8% and 32.1% in the IMRT group (p=0.859, log-rank) (Fig. 1). There was no statistically significant difference observed in OS and PFS between the 3D-CRT group and the IMRT group.

3. Prognostic factors

Univariate Kaplan-Meier survival analysis found that sex (p=0.088) and tumor stage (p=0.053) were significantly associated with OS (Table 3). Multivariate Cox proportional hazards model identified none of them reached statistical significance (Table 4). Similarly, univariate analysis of factors influencing PFS showed that sex (p=0.058), concurrent chemotherapy regimen (p=0.034), induction chemotherapy (p=0.054) and tumor stage (p < 0.001) were statistically significant variables. Only sex remained independently related to PFS in multivariable analysis (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.36 to 0.99).

4. Toxicities

The most commonly documented therapeutic toxicity was radiation esophagitis, and most patients (60/112, 53.6%) had grade 3 esophagitis. Seventeen percent of patients (19/112) had esophageal stricture and required dilatation, with 12 in the 3-dimensional radiotherapy (3D-RT) group and seven in the IMRT group. Other observed toxicities were mostly grade 1 or 2, including radiation pneumonitis and gastrointestinal toxicity. There were both one reported case of life-threatening hemorrhage in the 3D-CRT group and the IMRT group. However, none of these toxicities reached statistical significance between the 3D-RT group and the IMRT group (Table 5). No patient developed acute grade 4 toxicity, and there were no treatment-related deaths.

Moreover, we observed that 8.0% of patients (9/112) developed dyspnea and required tracheostomy within 6 months after cessation of therapy, without any evidence of tumor progression or second primary tumor. Univariate analysis indicated that radiotherapy (RT) technique (p=0.032), fraction dose (p=0.091), pretreatment hoarseness (p=0.043), and pretreatment vocal cord paralysis (p=0.098) were significantly related to tracheostomy dependence (Table 6). IMRT, fraction dose more than 206 cGy, pretreatment hoarseness, and pretreatment vocal cord paralysis were risk factors for tracheostomy dependence. Since fraction dose was significantly associated with RT technique (p < 0.001), and pretreatment vocal cord paralysis was significantly associated with pretreatment hoarseness (p < 0.001), we excluded fraction dose and pretreatment vocal cord paralysis from multivariate analysis, then the other two variables reached p < 0.1 in univariate analysis were further analyzed by using a Logistic regression model. RT technique (HR, 0.09; 95% CI, 0.01 to 0.79) and pretreatment hoarseness (HR, 0.12; 95% CI, 0.02 to 0.70) were independently prognostic of tracheostomy dependence (Table 7).

Discussion

Although dosimetric studies [16-19] reported that IMRT was better than 3D-CRT with respect to improved target coverage and conformality, the clinical benefits of IMRT have not been well established. To our knowledge, this is the first study to compare the survival outcomes and toxicities of CESCC between the 3D-CRT and the IMRT group using PSM approach with the largest sample size. Our study indicated OS and PFS were comparable between the 3D-CRT and IMRT groups. The 3-year and 5-year OS rate was 49.6% and 45.6% in the 3D-CRT group, while 54.4% and 43.8% in the IMRT group (p=0.927, log-rank). The 3-year and 5-year PFS rate was 45.8% and 32.1% in the 3D-CRT group, vs. 42.8% and 32.1% in the IMRT group (p=0.859, log-rank).

Advances in radiotherapy technique in treatment planning and radiation delivery, such as simultaneous integrated boosting IMRT, could allow the optimization of target volume coverage, which theoretically resulted in better survival outcomes. However, the published data failed to support the significant advantage of IMRT in survival. Yang et al. [24] reported that OS and failure-free survival (FFS) were not significantly different between the IMRT and 3D-CRT group, with the 2-year OS and FFS for the 3D-CRT vs. IMRT group was 53.6% vs. 55.6% (p=0.965), and 49.5% vs. 56.7% (p=0.998), respectively. Similarly, there was no statistically significant difference observed in OS, local FFS, and regional FFS between the IMRT group and two-dimensional conformal radiotherapy group in the study conducted by Cao et al. [25]. A recent published data from Japan [26] showed that IMRT achieved a significantly better 3-year OS than 3D-CRT (81.6% vs. 57.2%, p=0.037). They found that the sufficient salvage rate was higher in IMRT than 3D-CRT group when locoregional recurrence was presented, which contributed to the difference in OS. There was yet no statistical difference in locoregional control or PFS between these two groups. Similarly to most of the previous studies, our study did not support the survival advantage of IMRT compared with 3D-CRT. In our study, the Dmean of GTV was higher in IMRT group (6,290 cGy vs. 6,123 cGy, p=0.001). It suggests that there was no more dose-response relationship in dose ranges over 50 Gy, as indicated by series of Radiation Therapy Oncology Group studies [2,3].

IMRT could achieve well-demonstrated sparing of organs at risk, such as lungs and spinal cord, reducing both acute and late toxicities. However, our analysis showed that the rates of observed toxicities, including pneumonitis, esophagitis, esophageal stricture, gastrointestinal reaction, and life-threatening hemorrhage were comparable between the 3D-CRT group and the IMRT group. Detailed dosimetric study showed similar V20 and mean dose of the lungs between two groups, a relatively lower Dmax of spinal cord and a higher V5 of the lungs in the IMRT group. These results indicated that both 3D-CRT and IMRT could be delivered safely without obvious toxicities when the total dose did not exceed 70 Gy.

Within 6 months after CCRT, nine patients (8%, 9/112) developed dyspnea and required tracheostomy. All of the nine patients got partial remission after therapy and did not show any evidence of tumor progression at the time of tracheostomy. Few published reports had recorded and analyzed this complication. Gkika et al. [13] reported one patient (1.8%, 1/55) with CESCC underwent tracheostomy during definitive CCRT because of inability to breathe, who had got a paralysis of the recurrent laryngeal nerve before treatment. In Tong’s study [4], two patients (9.5%, 2/21) treated with up-front CCRT had bilateral vocal cord palsy requiring permanent tracheostomy. Staton et al. [27] reviewed 45 patients with advanced laryngeal cancer at 6 months after CCRT, and they found that the rate of tracheostomy dependence was 44% in patients with baseline vocal fold fixation versus 6% in patients without fixation. The authors attributed tracheostomy dependence to radiation-related bilateral recurrent laryngeal nerve paralysis, which results in bilateral vocal cord fixation. Similarly, in our cohort, pretreatment hoarseness was an independent risk factor for tracheostomy dependence during or after CCRT. As a result, it is urgent to call for close surveillance in those with pretreatment hoarseness or vocal cord paralysis during and 6 months after therapy. Our results showed a significantly higher rate of tracheostomy in IMRT group than that in 3D-CRT group (14.3% vs. 1.8%, p=0.032). Most IMRT plans in our cohort utilize the SIB technique with the median fraction dose to GTV of 213 cGy. For patients with CESSC, recurrent laryngeal nerves are always located in the proximity of GTV, which inevitably received a fraction dose more than 200 cGy when treated with IMRT. Therefore, we inferred that IMRT with fraction dose escalation (hypofractionated IMRT) might lead to a higher rate for tracheostomy dependence. Hypofractionated IMRT scheme should be carefully defined especially with concurrent chemotherapy in case of severe adverse events.

This retrospective study has several limitations, such as selection bias and relatively small number of patients which might affect the results of our study, and it was a single-institution experience. Larger multi-center prospective trials are warranted to validate our results.

No survival benefits had been observed while comparing IMRT versus 3D-CRT in CESCC patients. Sex was the only independent prognostic factor for PFS. IMRT with fraction dose escalation (hypofractionated IMRT) was considered to be associated with a higher risk for tracheostomy dependence within 6 months after definitive CCRT, and patients with pretreatment hoarseness or vocal cord paralysis should be under close surveillance for dyspnea. Radiation dose escalation beyond 60 Gy should be taken into account carefully when using IMRT with hypofractionated regimen. Prospective studies are warranted to verify presented results.

NOTES

Conflict of interest relevant to this article was not reported.

Acknowledgements

Our study was supported by Guangdong Esophageal Cancer Institute Science and Technology Program (M201505).

Fig. 1.

Overall survival (OS) (A) and progression-free survival (PFS) (B) between the three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) groups. There was no statistically significant difference observed in OS (p=0.927, log-rank) and PFS (p=0.859, log-rank) between the 3D-CRT group and the IMRT group.

Table 1.

Demographic and clinical characteristics of the matched patients

Characteristic	3D-CRT (n=56)	IMRT (n=56)	p-value
Sex
Male	38 (67.9)	38 (67.9)	> 0.999
Female	18 (32.1)	18 (32.1)
Age (yr)
Median (range)	60.5 (37-81)	58 (18-75)	0.706
KPS
90-100	36 (64.3)	35 (62.5)	> 0.999
70-80	20 (35.7)	21 (37.5)
Weight loss (%)
≥ 10	6 (10.7)	4 (7.1)	0.521
< 10	43 (76.8)	47 (83.9)
Pretreatment hoarseness
Yes	6 (10.7)	5 (8.9)	> 0.999
No	50 (89.3)	51 (91.1)
Pretreatment vocal cord paralysis
Yes	4 (7.1)	3 (5.4)	> 0.999
No	52 (92.9)	53 (94.6)
T category of primary tumor
T1-2	9 (16.1)	12 (21.4)	0.472
T3-4	47 (83.9)	42 (75.0)
Tumor stage
II	12 (21.4)	12 (21.4)	0.131
III	36 (64.3)	42 (75.0)
IV	8 (14.3)	2 (3.6)
Hypopharyngeal extension
Yes	1 (1.8)	16 (28.6)	< 0.001
No	55 (98.2)	40 (71.4)
Induction chemotherapy
Yes	11 (19.6)	16 (28.6)	0.377
No	45 (80.4)	40 (71.4)
Concurrent chemotherapy regimen
Single agent	9 (16.1)	10 (17.9)	> 0.999
Double agents	47 (83.9)	46 (82.1)

3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; KPS, Karnofsky performance status.

Table 2.

Dosimetric parameters

	3D-CRT	IMRT	p-value
Total radiation dose (Gy)	60 (60-70)	63.9 (60-70)	0.037
Fraction dose (cGy)	200 (165-232)	213 (180-229)	< 0.001
Dmean of GTV (cGy)	6,123 (5,939-6,321)	6,290 (5,921-6,455)	0.001
V5 of the lungs (%)	38.0 (18.4-61.9)	50.2 (11.8-88.5)	0.032
V20 of the lungs (%)	18.7 (6.1-31.6)	21.8 (5.5-32.8)	0.479
Dmean of the lungs (cGy)	958 (488-1,617)	1,101 (298-1,658)	0.156
Dmax of the spinal cord (cGy)	4,917 (4,030-5,148)	4,344 (1,052-4,752)	< 0.001
D5 of PTV1 (cGy)	6,394 (6,150-7,033)	6,745 (6,351-7,711)	0.007
Dmean of larynx (cGy)	5,779 (707-6,658)	6,045 (780-6,902)	0.227
GTV volume (cm³)	43.4 (6.8-165.0)	42.3 (4.4-252.0)	> 0.999

Values are presented as median (range). 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; GTV, gross tumor volume; PTV, planning target volume.

Table 3.

Univariate analysis of prognostic factors for OS and PFS

Factor	3-Year OS (%)	p-value	3-Year PFS (%)	p-value
Sex
Male	46.4	0.088	41.3	0.058
Female	63.9		51.2
Age (yr)
< 59	55.8	0.550	49.9	0.343
≥ 59	48.2		38.9
KPS
90-100	54.4	0.661	45.8	0.890
70-80	52.8		41.6
Weight loss (%)
≥ 10	36.0	0.636	30.5	0.922
< 10	55.4		44.9
Pretreatment hoarseness
Yes	45.5	0.584	40.9	0.849
No	52.7		44.8
Pretreatment vocal cord paralysis
Yes	42.9	0.650	51.4	0.508
No	52.6		44.0
T category of primary tumor
T1-2	61.9	0.622	51.8	0.846
T3-4	50.1		43.2
Tumor stage
II	61.3	0.053	49.8	< 0.001
III	53.3		47.0
IV	20.0		10.0
Hypopharyngeal extension
Yes	63.0	0.289	35.9	0.894
No	50.1		45.8
Concurrent chemotherapy regimen
Single agent	47.4	0.462	26.6	0.034
Double agents	52.9		48.0
Induction chemotherapy
Yes	40.7	0.113	26.5	0.054
No	55.7		49.8
Radiotherapy technique
3D-CRT	49.6	0.927	45.8	0.859
IMRT	54.4		42.8
Total radiation dose (Gy)
< 62	55.2	0.928	43.2	0.580
≥ 62	49.0		45.8
Fraction dose (cGy)
≤ 206	52.6	0.664	44.0	0.701
> 206	51.3		45.3
GTV volume (cm³)
≤ 43.2	50.9	0.988	48.0	0.453
> 43.2	47.1		30.3

OS, overall survival; PFS, progression-free survival; KPS, Karnofsky performance status; 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; GTV, gross tumor volume.

Table 4.

Multivariate analysis of prognostic factors for OS and PFS

Survival outcome	HR	95% CI for HR	p-value
OS
Sex	0.65	0.38-1.11	0.114
Tumor stage	1.52	0.93-2.51	0.098
PFS
Sex	0.60	0.36-0.99	0.049
Tumor stage	1.52	0.87-2.65	0.140
Concurrent chemotherapy regimen	0.59	0.31-1.12	0.106
Induction chemotherapy	1.40	0.82-2.37	0.216

OS, overall survival; PFS, progression-free survival; HR, hazard ratio; CI, confidence interval.

Table 5.

Univariate analysis of therapeutic toxicities between 3D-CRT and IMRT

Toxicity	The whole group (n=112)	3D-CRT (n=56)	IMRT (n=56)	p-value
Grade ≥ 3 esophagitis	60 (53.6)	32 (57.1)	28 (50.0)	0.570
Grade ≥ 2 pneumonitis	8 (7.1)	3 (5.4)	5 (8.9)	0.716
Esophageal stricture	19 (17.0)	12 (21.4)	7 (12.5)	0.314
Life-threatening hemorrhage	2 (1.8)	1 (1.8)	1 (1.8)	> 0.999
Tracheostomy	9 (8.0)	1 (1.8)	8 (14.3)	0.032

3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy.

Table 6.

Univariate analysis of prognostic factors for tracheostomy dependence

Factor	Incidence (%)	p-value
Sex
Male	9.2	0.716
Female	5.6
Age (yr)
≤ 59	9.1	0.740
> 59	7.0
KPS
90-100	7.0	0.722
70-80	9.8
Weight loss (%)
≥ 10	0.0	> 0.999
< 10	7.8
Pretreatment hoarseness
Yes	27.3	0.043
No	5.9
Pretreatment vocal cord paralysis
Yes	28.5	0.098
No	6.7
T category of primary tumor
T1-2	0.0	0.349
T3-4	9.0
Tumor stage
II	8.3	0.616
III	9.0
IV	0.0
Hypopharyngeal extension
Yes	11.8	0.624
No	7.4
Concurrent chemotherapy regimen
Single agent	5.3	> 0.999
Double agents	8.6
Induction chemotherapy
Yes	3.7	0.685
No	9.4
Radiotherapy technique
3D-CRT	1.8	0.032
IMRT	14.3
Total radiation dose (Gy)
< 62	3.7	0.164
≥ 62	12.1
Fraction dose (cGy)
< 206	3.5	0.091
≥ 206	12.7
PTV1 D5 (cGy)
≤ 6,542	5.7	0.428
> 6,542	11.8
GTV volume (cm³)
≤ 43.2	11.4	0.673
> 43.2	5.9
Dmean of larynx (cGy)
≤ 5,908	8.6	> 0.999
> 5,908	8.8

KPS, Karnofsky performance status; 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; PTV, planning target volume; GTV, gross tumor volume.

Table 7.

Multivariate analysis of prognostic factors for tracheostomy dependence

Factor	HR	95% CI for HR	p-value
Radiotherapy technique	0.09	0.01-0.79	0.030
Pretreatment hoarseness	0.12	0.02-0.70	0.018

HR, hazard ratio; CI, confidence interval.

REFERENCES

1. Mendenhall WM, Sombeck MD, Parsons JT, Kasper ME, Stringer SP, Vogel SB. Management of cervical esophageal carcinoma. Semin Radiat Oncol. 1994;4:179–91. Article PubMed
2. Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr, Al-Sarraf M, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA. 1999;281:1623–7. Article PubMed
3. Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 2002;20:1167–74. Article PubMed
4. Tong DK, Law S, Kwong DL, Wei WI, Ng RW, Wong KH. Current management of cervical esophageal cancer. World J Surg. 2011;35:600–7. Article PubMed PDF
5. Kim HJ, Suh YG, Lee YC, Lee SK, Shin SK, Cho BC, et al. Dose-response relationship between radiation dose and locoregional control in patients with stage II-III esophageal cancer treated with definitive chemoradiotherapy. Cancer Res Treat. 2017;49:669–77. Article PubMed PDF
6. Grass GD, Cooper SL, Armeson K, Garrett-Mayer E, Sharma A. Cervical esophageal cancer: a population-based study. Head Neck. 2015;37:808–14. Article PubMed
7. Yamada K, Murakami M, Okamoto Y, Okuno Y, Nakajima T, Kusumi F, et al. Treatment results of radiotherapy for carcinoma of the cervical esophagus. Acta Oncol. 2006;45:1120–5. Article PubMed
8. Wang S, Liao Z, Chen Y, Chang JY, Jeter M, Guerrero T, et al. Esophageal cancer located at the neck and upper thorax treated with concurrent chemoradiation: a single-institution experience. J Thorac Oncol. 2006;1:252–9. Article PubMed
9. Huang SH, Lockwood G, Brierley J, Cummings B, Kim J, Wong R, et al. Effect of concurrent high-dose cisplatin chemotherapy and conformal radiotherapy on cervical esophageal cancer survival. Int J Radiat Oncol Biol Phys. 2008;71:735–40. Article PubMed
10. Zhang P, Xi M, Zhao L, Qiu B, Liu H, Hu YH, et al. Clinical efficacy and failure pattern in patients with cervical esophageal cancer treated with definitive chemoradiotherapy. Radiother Oncol. 2015;116:257–61. Article PubMed
11. Cao C, Luo J, Gao L, Xu G, Yi J, Huang X, et al. Definitive radiotherapy for cervical esophageal cancer. Head Neck. 2015;37:151–5. Article PubMed
12. Zhao L, Zhou Y, Mu Y, Chai G, Xiao F, Tan L, et al. Patterns of failure and clinical outcomes of definitive radiotherapy for cervical esophageal cancer. Oncotarget. 2017;8:21852–60. Article PubMed PMC
13. Gkika E, Gauler T, Eberhardt W, Stahl M, Stuschke M, Pottgen C. Long-term results of definitive radiochemotherapy in locally advanced cancers of the cervical esophagus. Dis Esophagus. 2014;27:678–84. Article PubMed PDF
14. Freilich J, Hoffe SE, Almhanna K, Dinwoodie W, Yue B, Fulp W, et al. Comparative outcomes for three-dimensional conformal versus intensity-modulated radiation therapy for esophageal cancer. Dis Esophagus. 2015;28:352–7. Article PubMed PDF
15. Haefner MF, Lang K, Verma V, Koerber SA, Uhlmann L, Debus J, et al. Intensity-modulated versus 3-dimensional conformal radiotherapy in the definitive treatment of esophageal cancer: comparison of outcomes and acute toxicity. Radiat Oncol. 2017;12:131.Article PubMed PMC PDF
16. Nicolini G, Ghosh-Laskar S, Shrivastava SK, Banerjee S, Chaudhary S, Agarwal JP, et al. Volumetric modulation arc radiotherapy with flattening filter-free beams compared with static gantry IMRT and 3D conformal radiotherapy for advanced esophageal cancer: a feasibility study. Int J Radiat Oncol Biol Phys. 2012;84:553–60. Article PubMed
17. Zhang WZ, Chen JZ, Li DR, Chen ZJ, Guo H, Zhuang TT, et al. Simultaneous modulated accelerated radiation therapy for esophageal cancer: a feasibility study. World J Gastroenterol. 2014;20:13973–80. Article PubMed PMC
18. Fenkell L, Kaminsky I, Breen S, Huang S, Van Prooijen M, Ringash J. Dosimetric comparison of IMRT vs. 3D conformal radiotherapy in the treatment of cancer of the cervical esophagus. Radiother Oncol. 2008;89:287–91. Article PubMed
19. Gao M, Li Q, Ning Z, Gu W, Huang J, Mu J, et al. Dosimetric comparison between step-shoot intensity-modulated radiotherapy and volumetric-modulated arc therapy for upper thoracic and cervical esophageal carcinoma. Med Dosim. 2016;41:131–5. Article PubMed
20. Hoffman KE, Voong KR, Levy LB, Allen PK, Choi S, Schlembach PJ, et al. Randomized trial of hypofractionated, dose-escalated, intensity-modulated radiation therapy (IMRT) versus conventionally fractionated IMRT for localized prostate cancer. J Clin Oncol. 2018;36:2943–9. Article PubMed PMC
21. Kim JO, Chu KP, Fairchild A, Ghosh S, Butts C, Chu Q, et al. Dose-escalated hypofractionated intensity-modulated radiation therapy with concurrent chemotherapy for inoperable or unresectable non-small cell lung cancer. Am J Clin Oncol. 2017;40:294–9. Article PubMed
22. Freedman GM, Anderson PR, Bleicher RJ, Litwin S, Li T, Swaby RF, et al. Five-year local control in a phase II study of hypofractionated intensity modulated radiation therapy with an incorporated boost for early stage breast cancer. Int J Radiat Oncol Biol Phys. 2012;84:888–93. Article PubMed PMC
23. Li QQ, Liu MZ, Hu YH, Liu H, He ZY, Lin HX. Definitive concomitant chemoradiotherapy with docetaxel and cisplatin in squamous esophageal carcinoma. Dis Esophagus. 2010;23:253–9. Article PubMed PDF
24. Yang H, Feng C, Cai BN, Yang J, Liu HX, Ma L. Comparison of three-dimensional conformal radiation therapy, intensity-modulated radiation therapy, and volumetric-modulated arc therapy in the treatment of cervical esophageal carcinoma. Dis Esophagus. 2017;30:1–8. Article
25. Cao C, Luo J, Gao L, Xu G, Yi J, Huang X, et al. Definitive intensity-modulated radiotherapy compared with definitive conventional radiotherapy in cervical oesophageal squamous cell carcinoma. Radiol Med. 2015;120:603–10. Article PubMed PDF
26. Ito M, Kodaira T, Tachibana H, Tomita N, Makita C, Koide Y, et al. Clinical results of definitive chemoradiotherapy for cervical esophageal cancer: comparison of failure pattern and toxicities between intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy. Head Neck. 2017;39:2406–15. Article PubMed
27. Staton J, Robbins KT, Newman L, Samant S, Sebelik M, Vieira F. Factors predictive of poor functional outcome after chemoradiation for advanced laryngeal cancer. Otolaryngol Head Neck Surg. 2002;127:43–7. Article PubMed

Figure & Data

REFERENCES

Citations

Citations to this article as recorded by

Surgical Outcomes for Cervical Esophageal Cancer: A Retrospective Cohort Study
Chang Yuan, Zhichao Liu, Bin Li, Yuxin Yang, Kaiyuan Zhu, Boyao Yu, Cong Qi, Chenyang Jing, Xinyi Fan, Zhigang Li, Chunguang Li
World Journal of Surgery.2025; 49(9): 2560. CrossRef
IL-15 signaling via cis- and trans-presentation to progenitor-exhausted CD8+ T cells enhances radio-immunotherapy efficacy in ESCC
Yi You, Linrui Gao, Shijia Li, Hui Huang, Tierun Wang, Zongchang Nie, Jian Zhou, Xiaoxue Ma, Jiarui Li, Hongyu Bie, Tian Zhang, Xi Chen, Qingsong Pang, Ping Wang, Cihui Yan, Wencheng Zhang
Journal of Nanobiotechnology.2025;[Epub] CrossRef
Current and future on definitive concurrent chemoradiotherapy for inoperable locally advanced esophageal squamous cell carcinoma
Renxian Xie, Qingxin Cai, Tong Chen, Hongxin Huang, Chuangzhen Chen
Frontiers in Oncology.2024;[Epub] CrossRef
Tumor-Derived Exosomal miR-143-3p Induces Macrophage M2 Polarization to Cause Radiation Resistance in Locally Advanced Esophageal Squamous Cell Carcinoma
Lin-Rui Gao, Jiajun Zhang, Ning Huang, Wei Deng, Wenjie Ni, Zefen Xiao, Mei Liu
International Journal of Molecular Sciences.2024; 25(11): 6082. CrossRef
Dose escalation in radical radio(chemo)therapy for cervical and upper thoracic esophageal cancer with 3DCRT/IMRT (ChC&UES): a multicenter retrospective study
Xiao-Han Zhao, Wen-Cheng Zhang, Xin Wang, Jun-Qiang Chen, Yuan-Ji Xu, Kuai-Le Zhao, Wei Huang, Pu-Dong Qian, Ya-Tian Liu, Xiao-Lin Ge, Xiao-Jie Xia, Chen-Gang Weng, Chun-Yue Gai, He-Song Wang, Hong-Mei Gao, Wen-Bin Shen, Shu-Chai Zhu
Radiation Oncology.2024;[Epub] CrossRef
Oncological outcomes of squamous cell carcinoma of the cervical esophagus treated with definitive (chemo-)radiotherapy: a systematic review and meta-analysis
Armando De Virgilio, Andrea Costantino, Bianca Maria Festa, Giuseppe Mercante, Davide Franceschini, Ciro Franzese, Marta Scorsetti, Andrea Marrari, Raffaele Cavina, Salvatore Marano, Carlo Castoro, Giuseppe Spriano
Journal of Cancer Research and Clinical Oncology.2023; 149(3): 1029. CrossRef
Effect of preoperative radiotherapy on the prognosis of patients with stage cTxN0M0 esophageal squamous cell carcinoma: propensity score matching analysis based on SEER database
Zixian Jin, Jiajing Sun, Jian Zhang, Jianfei Shen, Bo Zhang
Frontiers in Surgery.2023;[Epub] CrossRef
Paclitaxel and cisplatin combined with concurrent involved-field irradiation in definitive chemoradiotherapy for locally advanced esophageal squamous cell carcinoma: a phase II clinical trial
Hui Li, Ying Fang, Dayong Gu, Mingyu Du, Zhi Zhang, Lei Sun, Guoren Zhou, Jinjun Ye
Radiation Oncology.2022;[Epub] CrossRef
A Retrospective Study of Chemotherapy and 3D-Image-Guided Afterloading Intracavitary Radiotherapy in Locally Advanced Cervical Cancer
Xiaojun Li, Cunlian An, Chunlan Feng, Jieren Sun, Huixiang Lu, Xiaodong Yang, Kaiping Wang, Ruimei Wang, Zhongjie Shi
Journal of Oncology.2022; 2022: 1. CrossRef
Intensity modulated radiotherapy might be effective for locally advanced esophageal carcinosarcoma: A single center’s experience and review of literature
Siran Yang, Wenqing Wang, Nan Bi, Zongmei Zhou, Qinfu Feng, Zefen Xiao, Dongfu Chen, Jun Liang, Jima Lu, Jianyang Wang, Xin Wang, Jingbo Wang, Yong Yang, Ningning Lu, Hongxing Zhang, Luhua Wang
Medicine.2022; 101(42): e31215. CrossRef
Outcome of chemoradiotherapy using intensity-modulated radiation therapy for cervical esophageal cancer: a single institute experience
Masahiro Inada, Yasumasa Nishimura, Kazuki Ishikawa, Takuya Uehara, Yutaro Wada, Yasuo Oguma, Hiroshi Doi, Kiyoshi Nakamatsu
Esophagus.2021; 18(3): 638. CrossRef
Radiation-induced acute injury of intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy in induction chemotherapy followed by concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma: a prospective cohor
Zexin Yao, Bing Zhang, Jialin Huang, Lei Shi, Biao Cheng
Scientific Reports.2021;[Epub] CrossRef
Correlation between the γ passing rates of IMRT plans and the volumes of air cavities and bony structures in head and neck cancer
Zhengwen Shen, Xia Tan, Shi Li, Xiumei Tian, Huanli Luo, Ying Wang, Fu Jin
Radiation Oncology.2021;[Epub] CrossRef
Rehabilitation Nursing Intervention Can Improve Dysphagia and Quality of Life of Patients Undergoing Radiotherapy for Esophageal Cancer
Xiange Zeng, Ling Li, Wenjing Wang, Lihui Zhu, Alamgeer Yuchi
Journal of Oncology.2021; 2021: 1. CrossRef
Late Toxicities, Failure Patterns, Local Tumor Control, and Survival of Esophageal Squamous Cell Carcinoma Patients After Chemoradiotherapy With a Simultaneous Integrated Boost: A 5-Year Phase II Study
Chuangzhen Chen, Jianzhou Chen, Ting Luo, Siyan Wang, Hong Guo, Chengbing Zeng, Yanxuan Wu, Weitong Liu, Ruihong Huang, Tiantian Zhai, Zhijian Chen, Derui Li
Frontiers in Oncology.2021;[Epub] CrossRef
Conformal radiation therapy versus volumetric arc therapy in high dose concurrent chemoradiotherapy for carcinoma esophagus
Tapas Kumar Dora, Jayashree Deshmukh, Abhishek Chatterjee, Alok Goel, Subhadeep Bose, Avtar Singh, Amit Saini, Shefali Pahwa, Sarbani Ghosh Laskar, Jai Prakash Agarwal, Shyam Kishore Shrivastava, Rakesh Kapoor
Cancer Research, Statistics, and Treatment.2021; 4(3): 456. CrossRef
Propensity score-based comparison of survival and radiation pneumonitis after definitive chemoradiation for esophageal cancer: Intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy
Kaiqi Lan, Jinhan Zhu, Jun Zhang, Sha Zhou, Yadi Yang, Zizhen Feng, Li Zhang, Shi Wang, Mian Xi
Radiotherapy and Oncology.2020; 149: 228. CrossRef
LINC00473 contributes to the radioresistance of esophageal squamous cell carcinoma by regulating microRNA‑497‑5p and cell division cycle 25A
Wei‑Hua Liu, Han‑Yong Qiao, Jian Xu, Wei‑Qing Wang, Yi‑Lei Wu, Xia Wu
International Journal of Molecular Medicine.2020; 46(2): 571. CrossRef
A multicenter prospective phase III clinical randomized study of simultaneous integrated boost intensity-modulated radiotherapy with or without concurrent chemotherapy in patients with esophageal cancer: 3JECROG P-02 study protocol
Lin-rui Gao, Xin Wang, Weiming Han, Wei Deng, Chen Li, Xiaomin Wang, Yidian Zhao, Wenjie Ni, Xiao Chang, Zongmei Zhou, Lei Deng, Wenqing Wang, Wenyang Liu, Jun Liang, Tao Zhang, Nan Bi, Jianyang Wang, Yirui Zhai, Qinfu Feng, Jima Lv, Ling Li, Zefen Xiao
BMC Cancer.2020;[Epub] CrossRef

PubReader
ePub Link

Cite

CITE: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

Intensity-Modulated Radiotherapy versus Three-Dimensional Conformal Radiotherapy in Definitive Chemoradiotherapy for Cervical Esophageal Squamous Cell Carcinoma: Comparison of Survival Outcomes and Toxicities

Cancer Res Treat. 2020;52(1):31-40. Published online April 30, 2019

DOI: https://doi.org/10.4143/crt.2018.624

XML Download

Abstract
Introduction
Materials and Methods
Results
Discussion
NOTES
REFERENCES

Fig. 1. Overall survival (OS) (A) and progression-free survival (PFS) (B) between the three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) groups. There was no statistically significant difference observed in OS (p=0.927, log-rank) and PFS (p=0.859, log-rank) between the 3D-CRT group and the IMRT group.

Fig. 1.

Characteristic	3D-CRT (n=56)	IMRT (n=56)	p-value
Sex
Male	38 (67.9)	38 (67.9)	> 0.999
Female	18 (32.1)	18 (32.1)
Age (yr)
Median (range)	60.5 (37-81)	58 (18-75)	0.706
KPS
90-100	36 (64.3)	35 (62.5)	> 0.999
70-80	20 (35.7)	21 (37.5)
Weight loss (%)
≥ 10	6 (10.7)	4 (7.1)	0.521
< 10	43 (76.8)	47 (83.9)
Pretreatment hoarseness
Yes	6 (10.7)	5 (8.9)	> 0.999
No	50 (89.3)	51 (91.1)
Pretreatment vocal cord paralysis
Yes	4 (7.1)	3 (5.4)	> 0.999
No	52 (92.9)	53 (94.6)
T category of primary tumor
T1-2	9 (16.1)	12 (21.4)	0.472
T3-4	47 (83.9)	42 (75.0)
Tumor stage
II	12 (21.4)	12 (21.4)	0.131
III	36 (64.3)	42 (75.0)
IV	8 (14.3)	2 (3.6)
Hypopharyngeal extension
Yes	1 (1.8)	16 (28.6)	< 0.001
No	55 (98.2)	40 (71.4)
Induction chemotherapy
Yes	11 (19.6)	16 (28.6)	0.377
No	45 (80.4)	40 (71.4)
Concurrent chemotherapy regimen
Single agent	9 (16.1)	10 (17.9)	> 0.999
Double agents	47 (83.9)	46 (82.1)

	3D-CRT	IMRT	p-value
Total radiation dose (Gy)	60 (60-70)	63.9 (60-70)	0.037
Fraction dose (cGy)	200 (165-232)	213 (180-229)	< 0.001
Dmean of GTV (cGy)	6,123 (5,939-6,321)	6,290 (5,921-6,455)	0.001
V5 of the lungs (%)	38.0 (18.4-61.9)	50.2 (11.8-88.5)	0.032
V20 of the lungs (%)	18.7 (6.1-31.6)	21.8 (5.5-32.8)	0.479
Dmean of the lungs (cGy)	958 (488-1,617)	1,101 (298-1,658)	0.156
Dmax of the spinal cord (cGy)	4,917 (4,030-5,148)	4,344 (1,052-4,752)	< 0.001
D5 of PTV1 (cGy)	6,394 (6,150-7,033)	6,745 (6,351-7,711)	0.007
Dmean of larynx (cGy)	5,779 (707-6,658)	6,045 (780-6,902)	0.227
GTV volume (cm³)	43.4 (6.8-165.0)	42.3 (4.4-252.0)	> 0.999

Factor	3-Year OS (%)	p-value	3-Year PFS (%)	p-value
Sex
Male	46.4	0.088	41.3	0.058
Female	63.9		51.2
Age (yr)
< 59	55.8	0.550	49.9	0.343
≥ 59	48.2		38.9
KPS
90-100	54.4	0.661	45.8	0.890
70-80	52.8		41.6
Weight loss (%)
≥ 10	36.0	0.636	30.5	0.922
< 10	55.4		44.9
Pretreatment hoarseness
Yes	45.5	0.584	40.9	0.849
No	52.7		44.8
Pretreatment vocal cord paralysis
Yes	42.9	0.650	51.4	0.508
No	52.6		44.0
T category of primary tumor
T1-2	61.9	0.622	51.8	0.846
T3-4	50.1		43.2
Tumor stage
II	61.3	0.053	49.8	< 0.001
III	53.3		47.0
IV	20.0		10.0
Hypopharyngeal extension
Yes	63.0	0.289	35.9	0.894
No	50.1		45.8
Concurrent chemotherapy regimen
Single agent	47.4	0.462	26.6	0.034
Double agents	52.9		48.0
Induction chemotherapy
Yes	40.7	0.113	26.5	0.054
No	55.7		49.8
Radiotherapy technique
3D-CRT	49.6	0.927	45.8	0.859
IMRT	54.4		42.8
Total radiation dose (Gy)
< 62	55.2	0.928	43.2	0.580
≥ 62	49.0		45.8
Fraction dose (cGy)
≤ 206	52.6	0.664	44.0	0.701
> 206	51.3		45.3
GTV volume (cm³)
≤ 43.2	50.9	0.988	48.0	0.453
> 43.2	47.1		30.3

Survival outcome	HR	95% CI for HR	p-value
OS
Sex	0.65	0.38-1.11	0.114
Tumor stage	1.52	0.93-2.51	0.098
PFS
Sex	0.60	0.36-0.99	0.049
Tumor stage	1.52	0.87-2.65	0.140
Concurrent chemotherapy regimen	0.59	0.31-1.12	0.106
Induction chemotherapy	1.40	0.82-2.37	0.216

Toxicity	The whole group (n=112)	3D-CRT (n=56)	IMRT (n=56)	p-value
Grade ≥ 3 esophagitis	60 (53.6)	32 (57.1)	28 (50.0)	0.570
Grade ≥ 2 pneumonitis	8 (7.1)	3 (5.4)	5 (8.9)	0.716
Esophageal stricture	19 (17.0)	12 (21.4)	7 (12.5)	0.314
Life-threatening hemorrhage	2 (1.8)	1 (1.8)	1 (1.8)	> 0.999
Tracheostomy	9 (8.0)	1 (1.8)	8 (14.3)	0.032

Factor	Incidence (%)	p-value
Sex
Male	9.2	0.716
Female	5.6
Age (yr)
≤ 59	9.1	0.740
> 59	7.0
KPS
90-100	7.0	0.722
70-80	9.8
Weight loss (%)
≥ 10	0.0	> 0.999
< 10	7.8
Pretreatment hoarseness
Yes	27.3	0.043
No	5.9
Pretreatment vocal cord paralysis
Yes	28.5	0.098
No	6.7
T category of primary tumor
T1-2	0.0	0.349
T3-4	9.0
Tumor stage
II	8.3	0.616
III	9.0
IV	0.0
Hypopharyngeal extension
Yes	11.8	0.624
No	7.4
Concurrent chemotherapy regimen
Single agent	5.3	> 0.999
Double agents	8.6
Induction chemotherapy
Yes	3.7	0.685
No	9.4
Radiotherapy technique
3D-CRT	1.8	0.032
IMRT	14.3
Total radiation dose (Gy)
< 62	3.7	0.164
≥ 62	12.1
Fraction dose (cGy)
< 206	3.5	0.091
≥ 206	12.7
PTV1 D5 (cGy)
≤ 6,542	5.7	0.428
> 6,542	11.8
GTV volume (cm³)
≤ 43.2	11.4	0.673
> 43.2	5.9
Dmean of larynx (cGy)
≤ 5,908	8.6	> 0.999
> 5,908	8.8

Factor	HR	95% CI for HR	p-value
Radiotherapy technique	0.09	0.01-0.79	0.030
Pretreatment hoarseness	0.12	0.02-0.70	0.018

Table 1. Demographic and clinical characteristics of the matched patients

3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; KPS, Karnofsky performance status.

Table 2. Dosimetric parameters

Values are presented as median (range). 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; GTV, gross tumor volume; PTV, planning target volume.

Table 3. Univariate analysis of prognostic factors for OS and PFS

Table 4. Multivariate analysis of prognostic factors for OS and PFS

OS, overall survival; PFS, progression-free survival; HR, hazard ratio; CI, confidence interval.

Table 5. Univariate analysis of therapeutic toxicities between 3D-CRT and IMRT

3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy.

Table 6. Univariate analysis of prognostic factors for tracheostomy dependence

KPS, Karnofsky performance status; 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; PTV, planning target volume; GTV, gross tumor volume.

Table 7. Multivariate analysis of prognostic factors for tracheostomy dependence