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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 5  |  Page : 82-88

The efficacy and safety of simultaneous integrated boost intensity-modulated radiation therapy for esophageal squamous cell carcinoma in Chinese population: A single institution experience


Department of Radiation Oncology, Zhejiang Key Laboratory of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China

Date of Web Publication7-Oct-2016

Correspondence Address:
Ming Chen
Department of Radiation Oncology, Zhejiang Cancer Hospital, No. 38, Guangji Road, Gongshu District, Hangzhou 310022
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.191640

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 > Abstract 


Purpose: To evaluate the clinical efficacy and toxicity of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) in patients with esophageal squamous cell carcinoma (ESCC) in Chinese population.
Patients and Methods: Patients with ESCC, who received SIB-IMRT from September 2011 to January 2013 were retrospectively analyzed. The SIB-IMRT plans were designed to deliver primary gross tumor volume at 60–64.4 Gy in 28–30 fractions, and planning target volume at 50.4–56 Gy in 28–30 fractions. Treatment-related toxicities were estimated based on Common Terminology Criteria for Adverse Events version 4.0, and tumor response after the treatment was estimated according to Response Evaluation Criteria in Solid Tumors version 1.0. Overall survival (OS), locoregional progression-free survival (LPFS), and progression-free survival (PFS) were estimated with Kaplan–Meier.
Results: All patients completed definitive radiotherapy, 54 (78.3%) received combined chemotherapy, of which 31 (44.9%) were concurrent chemoradiotherapy and 23 (33.3%) were sequential chemotherapy. The objective response rate is 82.6% (56/69), with complete response 11 (15.9%), partial response 45 (65.2%), stable disease 8 (11.6%), and progressive disease 5 (7.2%). The 1-, 2- and 3-year LPFS was 74.4%, 57.8%, and 55.6%, respectively. The 1-, 2- and 3-year PFS was 62.3%, 41.0%, and 34.2%, respectively, and the 1-, 2-, and 3-year OS was 73.8%, 57.4%, and 41.0%, respectively, with a median OS of 27.1 months (4.5–54.9 m). For those who received concurrent chemotherapy, the 1-, 2-, and 3-year OS was 75.9%, 69.0%, and 55.2%, respectively, better than those who had sequential chemotherapy or radiotherapy alone (χ2 = 3.115, P = 0.078). Radiation esophagitis occurred in 63.8% and 14.5% with Grade 2 and 3, respectively. No patients occurred ≥ Grade 3 radiation pneumonia.
Conclusions: It is safe and effective using SIB-IMRT technology to treat patients with ESCC. More prospective clinical studies should be needed.

Keywords: Esophageal carcinoma, integrated boost intensity-modulated radiotherapy, overall survival


How to cite this article:
Xu Y, Wang Z, Liu G, Zheng X, Wang Y, Feng W, Lai X, Zhou X, Li P, Ma H, Wang J, Hu X, Chen M. The efficacy and safety of simultaneous integrated boost intensity-modulated radiation therapy for esophageal squamous cell carcinoma in Chinese population: A single institution experience. J Can Res Ther 2016;12:82-8

How to cite this URL:
Xu Y, Wang Z, Liu G, Zheng X, Wang Y, Feng W, Lai X, Zhou X, Li P, Ma H, Wang J, Hu X, Chen M. The efficacy and safety of simultaneous integrated boost intensity-modulated radiation therapy for esophageal squamous cell carcinoma in Chinese population: A single institution experience. J Can Res Ther [serial online] 2016 [cited 2018 Nov 16];12:82-8. Available from: http://www.cancerjournal.net/text.asp?2016/12/5/82/191640




 > Introduction Top


Esophageal carcinoma (EC) is one of the most fatal cancers in the world, and China is one of the high-incidence areas of all time. The overall 5-year survival rate for all EC patients is not better than 20%.[1] Different from the western countries, esophageal squamous cell carcinoma (ESCC) accounts for 95% of all Chinese EC patients.[2] According to the results of Radiation Therapy Oncology Group (RTOG) 85-01, concurrent chemoradiotherapy is established as a standard treatment option to treat inoperable locally advanced EC, and chemotherapy based on cisplatin has also been confirmed as a standard concurrent regimen.[3]

Although there was a significant improvement in local/regional control and overall survival (OS) with radiation plus chemotherapy compared with radiotherapy alone, the incidence of local/regional failure and local/regional persistence of disease was 47%. RTOG 94-05 was undertaken to investigate whether high-dose radiation (64.8 Gy) could achieve better results than standard-dose (50.4 Gy). For the 218 eligible patients, there was no significant difference in median survival (13.0 vs. 18.1 months), 2-year survival (31% vs. 40%), or local/regional failure, and local/regional persistence of disease (56% vs. 52%) between the high-dose and standard-dose arms. The higher radiation dose did not increase survival or local/regional control.[4]

However, the radiation technique used in RTOG 94-05 was two-dimensional conformal radiotherapy (2D-CRT) with a sequential boost for dose escalation. The margins for radiation volumes were significantly larger than those used in the current clinical study, which caused higher doses to the normal lungs, heart, and esophagus and would have increased the incidence of toxicity. Some researches have shown that the implementation of intensity-modulated radiation therapy (IMRT) can provide additional flexibility to modify dose distributions and improve normal tissue sparing.[5]

The simultaneous integrated boost SIB-IMRT technique can offer the advantage of delivering a higher dose to the primary tumor; simultaneously conventional lower doses are used to treat subclinical lesions or elective node regions. We hypothesized that SIB-IMRT technique could be used to selectively escalate the radiation dose to the gross tumor volume and improve the local control rate. In recent years, we have treated 69 cases of inoperable locally advanced ESCC with this technique, and we now perform a retrospective analysis of these cases, to investigate the efficacy and safety of SIB-IMRT on ESCC, and to provide evidence for the launch of further clinical studies.


 > Patients and Methods Top


Patients

All 69 cases involved were ESCC confirmed by histopathology or cytology in our hospital from September 2011 to January 2013. Eligibility criteria were as follows: (1) medically inoperable or patient refusal; (2) clinical stage from IIA to IVB according to the American Joint Committee on Cancer (AJCC 2002 edition); (3) age ≥18 years; (4) Karnofsky Performance Status of at least 70; (5) no any prior anticancer therapy; (6) target lesions can be measured according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria; (8) no serious system dysfunction and immunodeficiency; (9) adequate organ function including the following: hemoglobin ≥9 g/dL, white blood cell count ≥3 × 109/L, neutrophils (absolute neutrophil count) ≥1.5 × 109/L, platelet count ≥100 × 109/L, serum bilirubin <1.5 × the upper limit of normal (ULN), Glutamic oxaloacetic transaminase and glutamic pyruvic transaminase ≤2.5 × ULN, and creatinine ≤1.5 × ULN; (10) life expectancy of more than 3 months. All patients provided written informed consent to participate before treatment. Among 69 cases, 14 cases were accompanied with hypertension, 5 cases of diabetes, 3 cases of coronary heart disease, and 1 case of hepatitis B. About 43 cases had a history of smoking. The clinical characteristics are shown in [Table 1].
Table 1: Patient characteristics

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Pretreatment evaluations

Routine pretreatment evaluations included physical examination, complete blood cell count and biochemistry, esophageal barium X-ray, endoscopy of the upper gastrointestinal tract and biopsy of primary tumor, and computed tomography (CT) of neck, chest, and upper abdomen.18 F-fluorodeoxyglucose positron emission tomography (PET) was optional. All patients were clinical-staged based on the AJCC TNM classification of malignant tumors (2002).

Radiation therapy

All patients underwent CT simulation in the supine position; enhanced scanning was performed with large diameter spiral CT simulator (GE LightSpeed RT, USA), with patients in quiet breathing conditions, with CT images obtained at 5 mm thickness throughout the entire neck, thorax, and upper abdomen. When the scanned images were transmitted to the Philips Pinnacle 9.2 three-dimensional (3D) treatment planning system, GTV, primary gross tumor volume (PGTV), clinical target volume (CTV), planning target volume (PTV), and normal organs at risk were delineated layer by layer. The gross tumor volume (GTV) includes primary tumors (GTV-T) and lymph node metastasis (GTV-N). GTV-T included all esophageal tumors, which were found by CT scan, esophageal barium, endoscopy, endoscopic ultrasonography, and PET/CT. The definitions of GTV-N (to meet one) were as follows: nodes >1.0 cm in the shortest axis in the intrathoracic and intra-abdominal region and >0.5 cm beside the recurrent nerve on CT scans or with a high standardized uptake value - max of 18 F-deoxyglucose avid on PET/CT images.[6],[7],[8] CTV-T was defined as 3 cm superoinferior margins and a 0.6 cm lateral margin from the GTV-T. We recommended CTV-N should include cervical and upper mediastinal nodes for lesions in the upper thoracic esophagus. Upper, middle/lower mediastinal, and abdominal nodal regions should be involved in the middle thoracic EC. For lesions in the lower thoracic esophagus, the CTV-N should cover the middle, lower mediastinal and abdominal lymph nodes regions. The PTV was generated by adding a uniform 5 mm margin around the CTV (CTV-T + CTV-N). PGTV was defined by GTV plus 1 cm margin. Prescription dose was defined as 95% of the receiving dose of PTV and PGTV, with the difference of internal target dose uniformity <5%, and internal target maximum dose point ≤110%. Lung V20 (i.e., percentage of the total lung volume receiving ≤20 Gy) was generally required to be <28% and was changed appropriately (not exceeding 34%) according to patient's physical conditions and comprehensive treatment model. Mean lung dose (MLD) <17%, spinal cord maximum dose <45 Gy, esophageal V50 <50%, mean heart dose (MHD) ≤30 Gy, and heart V40 <50% were other demands to meet. Radiation was performed with linear accelerator 6MV-X. A representative SIB-IMRT planning image, with contours and dose-volume histogram, is shown in [Figure 1].
Figure 1: Isodose curves of a representative simultaneously integrated boost intensity-modulated radiotherapy plan for a patient with esophageal squamous cell carcinoma, displayed on the axial, coronal, and sagittal planes through the primary tumor. Dose-volume histograms for the relevant structures. Green shading indicates the gross tumor volume (primary tumor bed and involved nodes, primary gross tumor volume), blue shading indicates the planning tumor volume, the yellow line outlines the planning target volume around primary gross tumor volume (61.6 Gy/28 fractions), and the red line area indicates the planning target volume around planning target volume (50.4 Gy/28 fractions)

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Follow-up

The treatment response was estimated according to the RECIST (version 1.0) by barium esophagram, CT scan of chest and upper abdomen 1 month after the treatment. After the first evaluation, follow-up should be performed every 3 months over the first 2 years and every 6 months thereafter. Each visit included medical history, physical examination, complete blood count, chest and upper abdomen CT, brain magnetic resonance imaging/CT, and bone scan (if necessary). If esophageal recurrence was suspected by barium esophagram or CT scan, endoscopy, and biopsy should be used for confirmation. Treatment-related toxicities were scored according to the Common Terminology Criteria for Adverse Events version 4.0.

Statistical analysis

The primary endpoint of this study was locoregional progression-free survival (LPFS). Secondary end points included treatment-related toxicity, objective response, OS, and progression-free survival (PFS). LPFS was calculated from the 1st day of treatment to local or regional recurrence, death or last follow-up time. OS was calculated from the 1st day of treatment to death or last follow-up time, and PFS was calculated from the 1st day of treatment to progress, death or last follow-up time. All data were processed using SPSS 16.0 (Statistical Package for Social Sciences, SPSS Inc., Chicago, IL, USA, 2007) statistical software. Chi-square test was used for comparisons among the efficacy of the groups, whereas Kaplan–Meier method was used for survival analysis. P</i> 0.05 was considered to be statistically significant.


 > Results Top


Radiotherapy plan evaluation

All patients completed the radiotherapy plan. Ten (14.5%) patients received 56.0 Gy (in 28 fractions of 2.0 Gy/fraction) to PTV and 64.4 Gy (in 28 fractions at 2.3 Gy/fraction) to the PGTV. Forty-three (62.3%) patients received 50.4 Gy (in 28 fractions of 1.8 Gy/fraction) to PTV and 61.6 Gy (in 28 fractions at 2.2 Gy/fraction) to the PGTV. Another 16 (23.2%) received 54.0 Gy (in 30 fractions of 1.8 Gy/fraction) to PTV and 60.0 Gy (in 30 fractions at 2.0 Gy/fraction) to the PGTV. The median MLD was 13.4 Gy (range 9.7–16.2 Gy), V20 was 22.6% (range 14.1–28.8%), median MHD was 22.5 Gy (range 10.6–29.2 Gy), and median spinal cord maximum dose was 39.6 Gy (range 35.9–44.3 Gy).

Chemotherapy

Among all 69 patients, 54 received combined chemotherapy, of which 31 were concurrent chemoradiotherapy and 23 were sequential chemotherapy. The regimens included 8 cases of single S-1, 3 cases of paclitaxel plus cisplatin, 7 cases of docetaxel plus cisplatin, and another 36 cases of cisplatin combined with fluorouracil. The number of chemotherapy cycles was ranged from one to six, with a median of four cycles.

Treatment response evaluation

One month after treatment ended, enhanced CT was performed for the evaluation of efficacy. Of the 69 patients, objective response rate was 82.6%, with 11 cases of complete response (15.9%), 45 cases of partial response (65.2%), 8 cases of stable disease (11.6%), and 5 cases of progressive disease (7.2%).

Survival

Except 8 patients lost follow-up, the median follow-up for 61 patients was 25.7 months, with a range of 3.1–50.7 months. Up to the latest follow-up, 20 patients were alive and free of recurrence, 4 were alive with progression, and 37 were dead. Of the 37 deaths, 36 were related to esophageal cancer, and 1 for nontumor-related death (heart disease). The 1-, 2-, and 3-year LPFS was 74.4%, 57.8%, and 55.6%, respectively. For all patients, the 1-, 2- and 3-year PFS was 62.3%, 41.0%, and 34.2%, respectively, with a median PFS of 17.9 months (1.1–54.9 months) (95% confidence interval [CI] 8.3–27.6 months) [Figure 2]. Moreover, the 1-, 2-, and 3-year OS was 73.8%, 57.4%, and 41.0%, respectively, with a median OS of 27.1 months (4.5–54.9 months) (95% CI 19.7–34.5 months). For those who received concurrent chemotherapy, the 1-, 2-, and 3-year OS was 75.9%, 69.0%, and 55.2%, respectively, better than those who had sequential chemotherapy or radiotherapy alone (χ2 = 3.115, P = 0.078) [Figure 3].
Figure 2: Kaplan–Meier estimates of progression-free survival and locoregional progression-free survival for all patients

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Figure 3: Kaplan–Meier estimates of overall survival for all patients, and overall survival for patients treated with concurrent chemoradiotherapy and those treated with sequential radiochemotherapy or radiotherapy alone

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Toxicity

No patient experienced Grade 5 toxicity. The toxicities for all patients were presented in detail [Table 2]. The most common radiation-associated toxicity was radiation esophagitis, occurring in 63.8% and 14.5% of all patients with Grade 2 and 3, respectively. No patients occurred more than Grade 3 radiation pneumonia. Grade 1 and two pneumonitis occurred in 11 (15.9%) and 3 (4.3%) cases, respectively. More than Grade 3 hematologic toxicities, which were caused mainly by chemotherapy, included 17 (24.6%) of leukopenia, 16 (23.1%) of neutropenia, 1 (1.4%) of anemia, and 4 (5.7%) of thrombocytopenia. After the corresponding treatment such as granulocyte colony-stimulating factor or recombinant human interleukin, all patients fully recovered from hematologic toxicities.
Table 2: Treatment-related toxicity

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Failure patterns

Of all 61 followed up patients, a total of 40 cases (65.6%) had disease progression, among which 19 cases (31.1%) were local or regional relapse, 15 cases (24.6%) were distant metastasis, and 6 cases (9.8%) remain were developed local relapse and metastasis simultaneously. In 25 patients who developed relapse, 18 (72.0%) were relapse within the field of PGTV, 3 (12.0%) within the field of PTV, and 4 (16.0%) outside the PTV field. Of all 21 metastasis patients, 10 (47.6%) were lung metastasis, 5 (23.8%) were abdominal lymph node metastasis, 4 (19.0%) were hepatic metastasis, 1 (4.8%) were bone metastasis, and 1 (%) were brain metastasis.


 > Discussion Top


Moderate hypofractionation by SIB-IMRT has gained interest as a means of radiotherapy acceleration because of the convenience of single daily fractions and no need to generate separate boost plans.[9] From a radiobiologic standpoint, acceleration based on SIB-IMRT may be advantageous with respect to counteracting the effects of accelerated tumor repopulation. Whereas conventional fractionation schedules delay acceleration for several days, it is implicit to SIB-IMRT that dose acceleration is present from treatment inception, thus eliminating the possibility that accelerated tumor repopulation is not temporally matched to accelerated fractionation.

The study demonstrated that local recurrence after chemoradiotherapy with a radiation dose of 50.4 Gy for unresectable esophageal cancer mostly develops in the region of GTV.[10] Although dose escalation has been shown to improve local control and OS in patients with some solid tumors, caution should be warranted in using this concept to esophageal cancer.[11] For the esophagus is adjacent to the lung and heart, great care must be taken to ensure that improvements in local control are not achieved at the cost of greater morbidity. Meanwhile, even though we found that the GTV was the most common site of initial failure, the patients also experienced high rates of distant metastasis; thus, efforts to increase local control may not necessarily transform improved survival. James compared the dose–volume constraints to critical structures of a traditional 2D-CRT plan, a modern-day IMRT plan, and a dose-escalated SIB-IMRT plan.[12] The results showed that 50.4 Gy IMRT plan was associated with significant reductions in mean cardiac, pulmonary, and hepatic doses relative to the 50.4 Gy 2D-CRT plan. The 64.8 Gy SIB-IMRT plan produced a 28% increase in GTV dose and comparable normal tissue doses as the 50.4 Gy IMRT plan; compared with the 50.4 Gy 2D-CRT plan, the 64.8 Gy SIB-IMRT produced significant dose reductions to all critical structures (heart, lung, liver, and spinal cord). Another study demonstrated that SIB-IMRT significantly reduced normal organs doses compared with a sequential boost using 3D-CRT.[13]

In the present study, we first applied SIB-IMRT that delivered PGTV at 60–64.4 Gy in 28–30 fractions and PTV at 50.4–56 Gy in 28–30 fractions at the same time. The dose could be escalated in a single plan for the whole treatment plan, but still met dose constraints to critical normal structures such as the lung, spinal cord, and heart. We achieved favorable results, with 1-, 2-, and 3-year LPFS, PFS, and OS were 74.4%, 57.8%, 55.6%, 62.3%, 41.0%, 34.2%, and 73.8%, 57.4%, and 41.0%, respectively. Meanwhile, radiation-related toxicity was acceptable including Grade 3 esophagitis rate of 14.5%. Of note, the sample size of our study was still small.

Concurrent chemoradiotherapy is the standard treatment for esophageal cancer. However, it is less used because of the high risk of severe toxicity in China. Age is a vital factor when we determine whether to use concurrent chemoradiotherapy for EC because we found that elderly patients were easier to cause substantial morbidity from therapy and subsequent deterioration in treatment outcomes, which is consistent with some results from other institutions as well.[14],[15],[16],[17] In our present study, 15 patients received radiotherapy alone, mainly caused by older age (11 among 15 older than 70). Of all 16 patients older than 70 in our study, 4 patients received concurrent chemoradiotherapy with single S-1, 1 patient received radiotherapy followed by chemotherapy, which caused Grade 4 hematologic toxicity and had to discontinue the chemotherapy. Our studies also suggested that for those who received concurrent chemotherapy, OS was really better than those who had sequential chemotherapy or radiotherapy alone (χ2 = 3.115, P = 0.078). There was no significant difference mainly caused by the small size.

Versteijne reported the pattern of locoregional recurrence of 184 patients with inoperable or unresectable esophageal cancer.[18] After a mean follow-up of 22.8 months, 41% had locoregional recurrence. The 3-year locoregional recurrence-free rate was 45%. The majority of these patients failed at the site of the primary tumor (86%). The majority of locoregional recurrences occurred within 12 months, nearly all within 24 months. In our study, at a median follow-up time of 25.7 months, 19 (31.1%) had experienced local or regional failure, 15 (24.6%) had distant metastasis, and 6 (9.8%) had local and distant failure simultaneously. In 25 local failure patients, 72.0% was in the field of PGTV and 12.0% in the field of PTV. Local failure rate was less than previous reports, which suggested 90% local failure was within the GTV.[18],[19] However, our follow-up time was still short, longer follow-up is needed.

The present study truly had some deficiency, mainly the small size of enrolled patients, the heterogeneity of the patient selection, and low proportion of concurrent chemoradiotherapy. At the other hand, PET/CT scanning was rarely used for pretreatment staging and the evaluation of recurrence, which means that some metastatic sites may have been missed, and the location of relapses in relation to the PGTV and PTV could not be accurately identified. Burmeister reported that PET/CT scanning exclude an extra 10% of patients for definitive chemoradiation by detecting distant metastases, compared with CT scans for staging esophageal cancer.[20] The sensitivity for detecting lymph nodes and distant metastatic disease is higher compared with combined use of CT and endoscopic ultrasound.

To sum up, application of SIB-IMRT in the treatment of ESCC has favorable efficacy and fine safety and demonstrated an encouraging outcome in patients with ESCC. Further randomized studies should be carried out to establish whether this technique could lead to improved long-term clinical outcomes.

Financial support and sponsorship

The present study was supported in part by a grant from Zhejiang Medical Science and Technology Foundation (Grant No: 2016146486).

Conflicts of interest

There are no conflicts of interest.

 
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