|Year : 2014 | Volume
| Issue : 2 | Page : 337-341
Treatment outcomes after intraluminal brachytherapy following definitive chemoradiotherapy in patients with esophageal cancer
Krishna Sharan1, Donald Jerard Fernandes1, PU Prakash Saxena1, Sourjya Banerjee1, Brijesh Sathian2
1 Department of Radiotherapy, Shirdi Saibaba Cancer Hospital and Research Centre, Manipal, Karnataka, India
2 Department of Community Medicine, Manipal College of Medical Sciences, Pokhara, Nepal, India
|Date of Web Publication||14-Jul-2014|
Department of Radiotherapy and Oncology, Shirdi Saibaba Cancer Hospital and Research Centre, Manipal, Karnataka-576 104
Source of Support: None, Conflict of Interest: None
Aims and Objectives: To report the results of treatment with intraluminal brachytherapy (ILRT) after concurrent chemoradiotherapy for esophageal carcinoma with respect to disease free survival (DFS), dysphagia free interval (DFI), and complications of treatment.
Materials and Methods: The study retrospectively analyzed the records of 26 eligible patients with nonmetastatic carcinoma of the esophagus treated with definitive chemoradiotherapy followed by ILRT between 2008 and 2011. The DFS and DFI were estimated and factors likely to influence them were analyzed.
Results: Nineteen (73%) patients were males. The mean age at presentation was 60 years (range: 47-90 years). All the patients had squamous cell carcinomas. Following treatment, the median DFS was 12.7 months (range: 0-27 months). Sixteen patients (61.5%) had local control of their disease, while one had residual disease at completion of treatment. Other than three patients who were not evaluated for recurrent dysphagia, six (23.1%) had proven local recurrence on follow-up. The estimated mean DFI was 13.8 months (range: 0-27 months). One patient died of tracheoesophageal fistula following treatment. On statistical analysis, only the location of tumor was prognostically significant, with lower third tumors performing worse. Other probable predictors of poor outcome included large volume (> 40 cc), tumor length (> 6 cm), and eccentric location.
Conclusion: ILRT boost following concurrent chemoradiotherapy is well tolerated and potentially improves outcomes. It might be beneficial in selected patients with esophageal carcinoma. Further studies are required to identify its role in definitive treatment.
结果：19例（73%）为男性。发病时的平均年龄在60岁（范围：47~90岁）。所有的病人都为鳞状细胞癌。治疗后，中位DFS 12.7个月（0~27个月）。16例患者（61.5%）得到局部控制，其中1例治疗结束后仍有残留病灶。除3例未进行复发性吞咽困难的评估，其余16例患者中6例（23.1%）局部复发，平均DFI约在 13.8个月（范围：0~27个月）。一例病人死于食管气管瘘的治疗。统计分析结果表明，肿瘤部位与肿瘤位置对预后有显著影响：体积＞40 CC、肿瘤直径＞6cm、肿瘤位于食管下1/3段的患者预后较差。
Keywords: Concurrent chemoradiotherapy, esophageal cancer, intraluminal brachytherapy
|How to cite this article:|
Sharan K, Fernandes DJ, Prakash Saxena P U, Banerjee S, Sathian B. Treatment outcomes after intraluminal brachytherapy following definitive chemoradiotherapy in patients with esophageal cancer. J Can Res Ther 2014;10:337-41
|How to cite this URL:|
Sharan K, Fernandes DJ, Prakash Saxena P U, Banerjee S, Sathian B. Treatment outcomes after intraluminal brachytherapy following definitive chemoradiotherapy in patients with esophageal cancer. J Can Res Ther [serial online] 2014 [cited 2020 Jul 3];10:337-41. Available from: http://www.cancerjournal.net/text.asp?2014/10/2/337/136623
| > Introduction|| |
Carcinoma of the esophagus is known to have a high prevalence in Asia, including India. According to a report that analyzed the combined data from cancer registries across the country, esophageal cancer is reported to be the second most common cancer among males and the fourth most common cancer among females. 
Unfortunately, the disease is asymptomatic at early stages, and locally advanced disease at presentation is the rule. Thus, despite developments that have taken place in the treatment of esophageal carcinoma, the outcomes remain poor. Surgery is the preferred primary treatment for operable patients. However, a substantial number of patients are unfit for surgery. Concurrent chemoradiotherapy is the present accepted standard of care for patients who are not operable.
Since the INT01-23 report suggested that higher doses of radiotherapy administered concurrently with chemotherapy provided no additional advantage, 50-50.4 Gy in conventional fraction remains the standard radiotherapy regimen. More recently though, higher radiotherapy dose is being increasingly reported to improve the outcomes in esophageal cancer. ,,,,,,
Radiotherapy dose escalation can be done either with external beam radiotherapy (EBRT) or using intraluminal brachytherapy (ILRT). ILRT in esophageal cancer offers an advantage of higher doses to the tumor while sparing the normal tissues and has been studied in combination with external radiotherapy-for both curative and palliative intents-by many researchers around the world. ,,,
The added advantage of brachytherapy however remains unclear. In this study, we present the long-term results of patients treated with concurrent chemoradiotherapy followed by ILRT for esophageal carcinoma, specifically on local and distant control rates, relief from dysphagia, and complications following treatment.
| > Materials and methods|| |
The study retrospectively looked into the records of the patients who received the above mentioned treatment between the years 2008 and 2011. Patients with esophageal carcinoma treated with ILRT following concurrent chemoradiotherapy with a curative intent were included into the study. Patients with tumors in the cervical or gastroesophageal junction, which preclude ILRT, were excluded from the study. Patients with evidence of mediastinal adenopathy or multiple/skip lesions and with metastatic disease at presentation were also excluded from the study. Similarly, patients not planned for concurrent chemotherapy and those with recurrent disease being planned for palliative ILRT were excluded.
EBRT was delivered using 3-D conformal radiotherapy technique on a linear accelerator. The initial phase of EBRT treated gross tumor volume (GTV) with a 5 cm craniocaudal margin and 1.5 cm radial margin, to 36 Gy/20#/4 weeks, using anterior and posterior opposed fields. Thereafter, the plan was changed to three-field technique (one anterior and two posterior oblique beams) to deliver additional 14.4 Gy/8# to GTV with 2.5 cm cranial and caudal margins and 1 cm radial margin.
Concurrent chemotherapy was planned for all the patients while they received external radiotherapy, with weekly cisplatin 40 mg/m 2 for a total of six courses. Chemotherapy was withheld if the patient developed any chemotherapy related toxicity such as nephrotoxicity or hematological toxicity, and restarted if/once the patient improved. No patient received concurrent chemotherapy along with brachytherapy.
Two weeks after completion of EBRT, the patients were planned for two settings of high dose rate (HDR) ILRT, delivered 1 week apart. Barium swallow was done 2 days prior to completion of EBRT to identify any residual filling defect, and the superior and inferior borders of length to be treated by ILRT were marked on the patient's chest to facilitate the ILRT planning. In patients with free flow of barium, the location of the tumor was identified using the initial endoscopic and planning computed tomography (CT) findings. A dose of 4 Gy to 1 cm from the central axis was planned for each setting. The treatment was delivered on a MicroSelectron HDR remote after-loading system (Nucleotron, Netherlands) with a 6 mm external diameter applicator. A 2 cm cranial and caudal margin was added to the superior and inferior borders of the GTV, providing that the total length treated did not exceed 10 cm.
After completion of treatment, the patients were followed-up. No adjuvant chemotherapy was given to any patient. On follow-up, endoscopy was done only if the patient had symptoms of recurrent dysphagia.The radiotherapy treatment data was collected from the radiotherapy records of the patient. The initial length, volume, eccentricity, etc., of the gross tumor at presentation was identified from the planning CT images on the treatment planning system (PrecisePLAN, version 2.16, Elekta). The other relevant data was collected from the medical records of the patient. The outcome parameters were calculated from the date of completion of treatment. The date of recurrence if any and the site of recurrence were recorded, along with any details of the patient having developed complications. The date and status at last follow-up were noted.The data collected was analyzed using Excel 2003, R 2.8.0 Statistical Package for the Social Sciences (SPSS) for Windows Version 16.0 (SPSS Inc; Chicago, IL, USA) and EPI Info 3.5.1 Windows Version. Kaplan-Meier survival curves were obtained, and the patient and tumor variables were correlated with outcomes using log-rank test. P < 0.05 was considered as statistically significant.
| > Results|| |
Fifty-one patients were treated with ILRT for esophageal cancer at our institute between 2008 and 2011. Of these, 26 patients were identified to satisfy the eligibility criteria. The patient and tumor characteristics are given in [Table 1]. Twenty-one patients (81%) completed the planned course of treatment. Seventeen patients (65%) received at least four cycles of concurrent chemotherapy. The median follow-up duration of the study was 9.7 months.
One month after completion of treatment, two patients had residual disease, identified on evaluation for persistent dysphagia. On follow-up, four patients presented with local failure only, two with both local failure and regional/distant failure; five presented with metastatic recurrence alone. All the three patients suspected to have local recurrence due to complaints of recurrent dysphagia, but not evaluated for the same, were proven to have metastatic recurrent disease.
The median disease free survival (DFS) for all the patients was 12.7 months (range: 0-27 months). Thirteen patients (50%) did not have any recurrent dysphagia at the last follow-up; five (19.2%) had persistent mild dysphagia following treatment, out of which one had residual disease, two had benign strictures and one was eventually proven to have recurrent disease. Eight patients (30.8%) had recurrent dysphagia. Of these, one (12.5%) had stricture, five (62.5%) had local recurrence, and the other two were not evaluated. Median dysphagia free interval (DFI) was 8.5 months (range: 0-27 months), with an estimated mean DFI of 13.8 months. The Kaplan-Meier curves for DFS and time to local failure are shown in [Figure 1] and [Figure 2], respectively. Out of the 23 evaluable patient for local recurrence, 16 (61.5%) had local control of their disease at last follow-up.
The treatment was well tolerated by the patients. One patient developed tracheoesophageal fistula within months of completion of treatment, and expired shortly thereafter due to aspiration pneumonitis. No other grade 3 or higher toxicity was recorded on follow-up.
The variables affecting the DFS and DFI are shown in [Table 2]. Older age group, male gender, eccentric tumors, tumors with large volume (> 40 cc) and length (≥ 6 cm) and tumors located in the distal third of esophagus performed poorly. However, except for tumor location, none of the other factors reached statistical significance.
| > Discussion|| |
Treatment outcomes continue to be poor in esophageal cancer. In an attempt to improve the results, various techniques have been tried, including increasing the dose of radiation, performing a curative surgery after a course of chemoradiotherapy, addition of ILRT boost, accelerated hyperfractionated boost administration, etc.
The INT01-23 was an important report that suggested no benefit with higher doses of radiation in esophageal cancer; on the contrary, the data even seemed to suggest poorer outcomes among patients assigned to higher dose arm.  Considering that the local/regional distant control rates and toxicities were similar between the two arms, the increased death rate in the higher dose arm remains unexplained. More recent reports however seem to question the assumption that radiotherapy response rates in esophageal cancer plateau by 50 Gy. , A meta-analysis on the pathological complete response (pCR) rates following definitive chemoradiotherapy suggested higher rates of pCR with higher doses of radiotherapy. However, only three of the 26 studies in this 'published data' meta-analysis used doses higher than 50 Gy.  Similarly, Zhang et al.,  reported that the patients who received a dose of 54 Gy or higher with concurrent chemotherapy had a significantly better locoregional control, disease free survival, and overall survival.
This study is an attempt to report our experience with ILRT boost following concurrent chemoradiotherapy in esophageal cancers. There are a few trials that have reported on the use of ILRT following concurrent chemoradiotherapy. RTOG 92-07 was designed to study if there was an additional benefit of adding brachytherapy to the concurrent chemoradiotherapy regimen. After the initial dose of 15 Gy in three fractions of HDR brachytherapy led to significant increase in the incidence of fistulae, the protocol was modified to deliver a dose of 10 Gy in two settings. Persistence of disease was observed in 19% of the patients. However, the 1-year survival rate was reported as 49%. The incidence of fistulae post-treatment continued to be high at 12%, and the authors urged caution in the use of brachytherapy boost to concurrent chemoradiotherapy. Higher doses of ILRT were used; also, concurrent chemotherapy was administered at the time of brachytherapy. 
Since the RTOG 92-07 report, there have been several reports on improved outcomes with concurrent chemotherapy followed by ILRT in esophageal carcinoma. ,, Calais et al.,  reported a local control rate of 74% at 1-year and a 3-year survival rate of 27% following treatment with concurrent chemoradiotherapy followed by brachytherapy, with a good retained swallowing score for 75% of the patients. Khurana et al.,  reported in their study that the patients receiving chemoradiotherapy followed by ILRT had the highest median survival of 14.5 months, compared to EBRT alone (9 months), EBRT with ILRT (10 months), and concurrent chemoradiotherapy (11 months). The authors, however cautioned that the results could have been confounded by bias, as fitter patients were more likely to receive aggressive regimens. A more recent study by Vuong et al.,  reported on their experience with combining ILRT with external radiotherapy. Of the 70 patients, 53 received concurrent chemotherapy along with external radiotherapy. The median survival was reported to be 21 months, with a very good local control rate of 75%. Fifty-seven percentage of the patients had no recurrent dysphagia. Only one patient developed fistula. Notably, in this study a much higher dose of radiation was delivered. After 50 Gy of EBRT with concurrent chemotherapy, additional 20 Gy in 5# (dose prescribed 1 cm from the mid-dwell position) of HDR brachytherapy was administered.
A few other reports too suggest a benefit of incremental radiotherapy dose on outcomes. ,,, In our study, the median DFS following completion of treatment was 12.7 months, with a 61.5% local control rate, which can be considered at par with other reports.
At least theoretically, brachytherapy is likely to benefit less bulky and superficial tumors which it can better address. There are studies which seem to suggest this being true in practice. ,, In our study, the treatment outcomes appeared to be poorer with larger volume and longer tumors, as well as eccentric tumors. However, none of these associations were statistically significant, likely due to the small sample size. Also, all the measured tumor parameters are prior to EBRT; measurements taken prior to ILRT would be more relevant.
The treatment was very well tolerated in our study, with only one patient developing fistula following treatment. The dysphagia-free interval was also good, with an estimated mean DFI of 13 months. Complications following the use of ILRT with chemoradiotherapy have been varyingly reported by different investigators. While Montravadi et al.,  reported no patient developing fistula post treatment, Sharma et al.,  on the other hand reported a 12% incidence of fistula formation and 29% incidence of post-treatment esophageal ulcers. Notably, the patients in this study were administered chemotherapy just prior to ILRT.  Significantly fewer incidences of strictures was seen when ILRT dose was reduced from 20 to 15 Gy (24% vs 8%). The retrospective report on factors affecting the development of strictures following treatment of esophageal carcinoma also found highest complication rates among patients receiving concurrent chemoradiotherapy followed by brachytherapy.  Forty-one percentage of the patients under this subgroup were reported to develop strictures. However, as with RTOG 92-07, concurrent chemotherapy was used in most patients along with brachytherapy.
It is believed that higher dose per fraction, concurrent use of chemotherapy and dose delivered to the esophageal mucosa are important factors in determining complications following ILRT. Using a lower dose per fraction, delivered with a catheter with a larger external luminal diameter (1 cm or higher), with no chemotherapy concurrently administered with brachytherapy are likely to render the procedure much safer. The protocol we followed adhered to all these factors, except for the use of large diameter applicator, and was quiet well tolerated.
This report has its limitations. Most importantly, the study constituted of small number of patients, with a short follow-up. No patient underwent an endoscopic ultrasonography, so accurate T-staging was not possible in most patients. Concurrent 5-FU was not given to any patients. Cisplatin-5-FU combination is the accepted concurrent chemotherapy regimen presently. A re-evaluation CT of thorax prior to ILRT would have been a better measure of the tumor parameters that could affect the results of ILRT, such as tumor thickness and tumor length. In this study, no routine imaging or endoscopy was performed on follow-up, and consequently DFS and LR were based on symptoms/clinical findings, which may have led to underestimation of tumor recurrence.
| > Conclusion|| |
The scope for radiotherapy dose escalation in definitive chemoradiotherapy in esophageal cancer remains unanswered. Adequately sized and well-planned randomized control studies comparing the standard radiotherapy dose of 50 Gy to higher doses administered either by external beam technique or brachytherapy are required.
In our study, the addition of brachytherapy was found to be relatively safe, with low incidence of severe complications. Moreover, the observed long-term dysphagia-free interval was also good. Brachytherapy could be the best method of radiotherapy dose escalation at least in a subset of patients that have responded well to the initial concurrent chemoradiotherapy and may have the potential to improve on treatment outcomes in esophageal cancer. Further studies are required to identify its role in the definitive treatment of esophageal cancers.
| > References|| |
|1.||Gajalakshmi V, Swaminathan R, Shanta V. An independent survey to assess completeness of registration: Population Based Cancer Registry, Chennai, India. Asian Pac J Cancer Prev 2001;2:179-83. |
|2.||Vuong T, Szego P, David M, Evans M, Parent J, Mayrand S, et al. The safety and usefulness of high-dose-rate endoluminal brachytherapy as a boost in the treatment of patients with esophageal cancer with external beam radiation with or without chemotherapy. Int J Radiat Oncol Biol Phys 2005;63:758-64. |
|3.||Staar S, Mueller RP, Achterrath W. Intensified treatment for inoperable esophagus cancer: Simultaneous radiochemotherapy combined with HDR intraluminal brachytherapy. Results of a phase II trial. Proc ASCO 1993;12:223. |
|4.||Montravadi RV, Gates JO, Bajpai D, Crawford JN, Trenkner JD, Trenkner DA. Combined chemotherapy and external radiation therapy plus intraluminal boost with high dose rate brachytherapy for carcinoma of the esophagus. Endocuriether Hyperthermia Oncol 1995;11:223-33. |
|5.||Chatani M, Matayoshi Y, Masaki N. Radiation therapy for the esophageal carcinoma: External irradiation versus high dose rate intraluminal irradiation. Strahlenter Onkol 1992;168:328-32. |
|6.||Fietkau R, Grabenbauer GG, Sauer R. Radiotherapy of esophageal cancer. Results following radiotherapy alone and simultaneous radiochemotherapy and intracavitary irradiation. Strahlenther Onkol 1994;170:69-78. |
|7.||Khurana R, Dimri K, Lal P, Rastogi N, Joseph K, Das M, et al. Factors influencing the development of ulcers and strictures in carcinoma of the esophagus treated with radiotherapy with or without concurrent chemotherapy. J Cancer Res Ther 2007;3:2-7. |
|8.||Scepanovic D, Pobijakova M, Lukacko P, Masar M, Dolinska Z, Masarykova A. Combined external beam radiotherapy and intraluminal brachytherapy in the treatment of esophageal cancer. Radiother Oncol 2012;103 Suppl 2:S153. |
|9.||Gaspar LE, Qian C, Kocha WI, Coia LR, Herskovic A, Graham M. A phase I/II study of external beam radiation, brachytherapy and concurrent chemotherapy in localized cancer of the esophagus (RTOG 92-07): Preliminary toxicity report. Int J Radiat Oncol Biol Phys 1997;37:593-9. |
|10.||Sur RK, Donde B, Levin VC, Mannell A. Fractionated high dose rate intraluminal brachytherapy in palliation of advanced esophageal cancer. Int J Radiat Oncol Biol Phys 1998;40:447-53. |
|11.||Yorozu A, Dokiya T, Oki Y, Suzuki T. Curative radiotherapy with high-dose-rate brachytherapy boost for localized esophageal carcinoma: Dose-effect relationship of brachytherapy with the balloon type applicator system. Radiother Oncol 1999;51:133-9. |
|12.||Muijs CT, Beukema JC, Mul VE, Plukker JT, Sijtsema NM, Langendijk JA. External beam radiotherapy combined with intraluminal brachytherapy in esophageal carcinoma. Radiother Oncol 2012;102:303-8. |
|13.||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. |
|14.||Geh JI, Bond SJ, Bentzen SM, Glynne-Jones R. Systematic overview of preoperative (neoadjuvant) chemoradiotherapy trials in oesophageal cancer: Evidence of a radiation and chemotherapy dose response. Radiother Oncol 2006;78:236-44. |
|15.||Zhang Z, Liao Z, Jin J, Ajani J, Chang JY, Jeter M, et al. Dose-response relationship in locoregional control for patients with stage II-III Esophageal cancer treated with concurrent chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys 2005;61:656-64. |
|16.||Calais G, Dorval E, Louisot P, Bourlier P, Klein V, Chapet S, et al. Radiotherapy with high dose rate brachytherapy boost and concomitant chemotherapy for Stages IIB and III esophageal carcinoma: Results of a pilot study. Int J Radiat Oncol Biol Phys 1997;38:769-75. |
|17.||Nishimura Y, Okuno Y, Ono K, Mitsumori M, Nagata Y, Hiraoka M. External beam radiation therapy with or without high-dose-rate intraluminal brachytherapy for patients with superficial esophageal carcinoma. Cancer 1999;86:220-8. |
|18.||Okawa T, Dokiya T, Nishio M, Hishikawa Y, Morita K. Multi-institutional randomized trial of external radiotherapy with and without intraluminal brachytherapy for esophageal cancer in Japan. Japanese Society of Therapeutic Radiology and Oncology (JASTRO) Study Group. Int J Radiat Oncol Biol Phys 1999;45:623-8. |
|19.||Sharma V, Agarwal J, Dinshaw K, Nehru RM, Mohandas M, Deshpande R, et al. Late esophageal toxicity using a combination of external beam radiation, intraluminal brachytherapy and 5-fluorouracil infusion in carcinoma of the esophagus. Dis Esophagus 2000;13:219-25. |
[Figure 1], [Figure 2]
[Table 1], [Table 2]