|Year : 2023 | Volume
| Issue : 1 | Page : 28-32
Comparative Study between conventional EBRT alone and EBRT followed by intraluminal brachytherapy in local advanced cancer esophagus
Kapil Kumar Soni1, Vansh Arora2, Amita Chaudhary3, HS Kumar2, Rajendra Kumar Tanwar1, Neeti Sharma2, Shankar Lal Jakhar1, Bhuvanesh Narayan Purohit1
1 Department of Radiotherapy, GMC, Kota, Rajasthan, India
2 Department of Radiotherapy, SPMC Bikaner, Rajasthan, India
3 District Hospital, Solan, India
|Date of Submission||10-Oct-2021|
|Date of Decision||29-May-2022|
|Date of Acceptance||30-May-2022|
|Date of Web Publication||31-Dec-2022|
Drl Bhuvanesh Narayan Purohit
Department of Radiotherapy, GMC, Kota, Rajasthan
Source of Support: None, Conflict of Interest: None
Aim: The purpose of this study is to compare local tumor control, dysphagia-free survival, and complication in patients with locally advanced carcinoma esophagus using external beam radiotherapy (EBRT) alone (Arm A) and EBRT followed by intraluminal brachytherapy (ILBT) (Arm B). Materials and Methods: A total of 50 histopathologically proven patients of locally advanced unresectable cancer esophagus were taken for the study from March 2019 to February 2020 and were divided into two arms, 25 patients each. Arm A was treated by standard concurrent chemotherapy–radiotherapy (CTRT) alone (a total dose of 50 Gray (Gy) in 25 fractions (fr), 2 Gy/fr administered daily 5 days per week with weekly injection cisplatin 40 mg/m2) and Arm B received 44 Gy through two definitive radiation therapies along with computed tomography followed by ILBT (5 Gy/fr; 2 fr 1 week apart). Assessment was done weekly during RT and 3 and 6 months post treatment for local control of disease and dysphagia-free survival and complication. Results: The local tumor control was observed 80% and 84% at 6 months in Arm A and Arm B, respectively (P = 0.82). Six-month dysphagia-free survival was 52% versus 68% (P = 0.248) and stricture formation was found 16% and 24% (P = 0.479) in Arm A and Arm B, respectively. Conclusion: This study shows comparable results of CTRT-ILBT over CTRT alone in locally advanced esophageal cancer patients.
Keywords: Chemotherapy–radiotherapy, dysphagia, external beam radiotherapy, esophagus, high-dose rate, intraluminal brachytherapy
|How to cite this article:|
Soni KK, Arora V, Chaudhary A, Kumar H S, Tanwar RK, Sharma N, Jakhar SL, Purohit BN. Comparative Study between conventional EBRT alone and EBRT followed by intraluminal brachytherapy in local advanced cancer esophagus. J Radiat Cancer Res 2023;14:28-32
|How to cite this URL:|
Soni KK, Arora V, Chaudhary A, Kumar H S, Tanwar RK, Sharma N, Jakhar SL, Purohit BN. Comparative Study between conventional EBRT alone and EBRT followed by intraluminal brachytherapy in local advanced cancer esophagus. J Radiat Cancer Res [serial online] 2023 [cited 2023 Mar 23];14:28-32. Available from: https://www.journalrcr.org/text.asp?2023/14/1/28/366506
| Introduction|| |
Esophageal cancer is the ninth most common cancer with an annual incidence of 604,100 new cases worldwide. It has been reported that in countries with higher Human Development Index, there is a relatively higher incidence of adenocarcinoma (ADC) of the esophagus than in other parts of the world.
In our institute, there is a continuously rising trend in the number of esophagus cancer patients. In 2017–2018, total 518 patients (M – 284 and F – 234); in 2018–2019, total 609 patients (M – 329 and F – 280); and in 2019–2020, total 710 patients (M – 381 and F – 329) were registered with carcinoma esophagus.
Esophageal cancer prevails among both men and women. Squamous cell carcinoma (SCC) accounts for up to 80% of these cancers, although ADC is on the increase due to changing lifestyles.
The primary treatment for localized esophageal cancer is radical excision, but in majority of cases, the tumor is in advanced stage and already involves in the esophageal wall. The current standard of care for inoperable esophageal cancer is concurrent chemoradiation with 50.4 Gy by 1.8-Gy/fr radiotherapy and cisplatin/5-FU-based chemotherapy. Radiotherapy has conventionally played a major role, both as an adjunct and as an alternative to surgical approach, but is hampered by the fact that despite the inherent radiosensitivity of these tumors, locally curative doses are difficult to achieve because of the proximity to vital organs such as lungs, heart, and spinal cord. Unsurprisingly, therefore, local failure is frequently observed as a result of underdosage of the tumor site.
Intraluminal brachytherapy (ILBT) is an elegant method to achieve high doses to the esophageal wall with spatial precision. High-dose-rate-ILBT (HDR-ILBT) offers a simple, inexpensive method of conformal radiation therapy in this context of dose escalation with minimum morbidity. HDR-ILBT allows the escalation of dose to the esophagus while protecting dose-limiting structure which is not possible even with the most conformal method of external beam radiotherapy (EBRT). In the definitive chemoradiation treatment of carcinoma esophagus, the role of brachytherapy remains unclear and investigational. Most of the studies are single-center experiences and done in a palliative setting to relieve dysphagia. HDR-ILBT is feasible, effective, better tolerated, and safe, but patient compliance is needed. The key to further improvement in the treatment result, therefore, appears to lie in increasing the biological response with the optimal use of combined modality treatment, namely radiation only or chemoradiation followed by ILBT. ILBT, due to its rapid dose falloff and ability to deliver a high dose to the intraluminal disease, is used for local boost. Because of shorter treatment time, better patients' compliance, and ease of administration, HDR brachytherapy is preferred.
| Materials and Methods|| |
This was a randomized prospective study conducted at a regional cancer center in India. A total of 50 patients of locally advanced unresectable SCC esophagus were taken for the study from March 2019 to February 2020. All patients were histopathologically proven cases, involving upper and middle thoracic esophagus with age between 18 and 70 years, tumor size equal or <10 cm, European Cooperative Oncology Group (ECOG) performance status (0–2) [Table 1], no prior treatment of malignancy, and normal baseline organ functions (complete blood count, renal function test, liver function test, and others). Patients with ADC, disease involving cervical and lower esophagus, presence of distant metastases, evidence of second malignancies, or associated comorbid diseases were excluded from this study.
Complete clinical history including tobacco and alcohol, performance status, orodental hygiene, nutritional status, and anemia was evaluated. To assess spread of the disease investigations such as barium swallow, upper GI endoscopy ,contrast enhanced computed tomography (CECT) were done. Ultrasonography (USG) abdomen was done to rule out liver metastasis. Approval from the institutional ethical committee and informed written consent from patients were taken.
All patients in both Arm A and Arm B received weekly cisplatin (40 mg/m2) with EBRT and were administered premedication with antiemetics: injection ondansetron, injection pheniramine maleate, injection dexamethasone, injection ranitidine, injection KCl, injection MgSO4, and injection mannitol with 3-l fluid over 12-h duration.
Patients were given radiotherapy by telecobalt machine using parallel opposed and posterior oblique field technique. The target volume included initial tumor volume consisting of primary tumor, involved lymph nodes, and possible site of subclinical disease.
Patients (in the study group) receiving concurrent chemoradiation were accessed 2 weeks after completion of chemotherapy–radiotherapy (CTRT) for local disease response and fitness for HDR. Treatment response was assessed by upper gastrointestinal endoscopy (UGIE), barium swallow, and USG neck. Hematological and renal function tests were evaluated weekly during treatment. Patients with anemia or poor general condition received fresh packed cell volume and buildup therapy. Symptomatic treatment was given in patients suffering from side effects of chemotherapy. Patients were followed and evaluated for dysphagia at 1, 3, and 6 months. A barium swallow was done at months 1, 3, and 6. UGIE was done at 3 months for disease assessment, and biopsy was taken when indicated. CECT of chest and abdomen was obtained if any clinical suspicion of either local recurrence or metastasis. Toxicity was graded as per RTOG/EORTC criteria.
For planning of HDR-ILBT, we need to deliver a source in esophageal lumen near the tumor. Here, we used Eckert and Ziegler BEBIG machine with cobalt 60 radioactive source and, for delivery, applicator which can be of different sizes. Here, we used a LLA1200-20 applicator which has a diameter of 8 mm and we are prescribing a 100% dose at 1 cm from the center of applicator to the prescribed length of esophagus. For this, we defined dwell points in longitudinal direction, and the distance between each dwell point was 5 mm. Wire with radio-opaque beads was used to locate the tumor length to be treated.
| Results|| |
The median age of patients was 59 years in Arm A and 52 years in Arm B. All patients were ECOG 1 or 2, with mostly having disease in middle thoracic esophagus and size >6 cm. The maximum incidence of dysphagia after treatment was observed at 1 month in both the arms, 68% and 76% for Arm A and Arm B, respectively (X2 = 0.11; P = 0.74, not significant). Dysphagia was seen in 48% and 40% of patients at 3 months and in 36% and 24% of patients at 6-month follow-up in Arm A and Arm B, respectively [Table 2] (X2 = 0.6; P = 0.43, not significant).
|Table 2: Prevalence of dysphagia and stricture formation at 6-month follow-up|
Click here to view
Overall survival at 6 months
In Arm A, three patients died (12%) after completion of treatment (after 4 and 5 months of treatment completion). In Arm B, two patients died (08%) after completion of treatment (one after 2 months of treatment completion and the other after 3 months of treatment). Nutritional deficiencies and infections were the primary reasons of death in both the arms. However, this difference was not significant (X2 = 0.04; P = 0.84).
The stricture formation was high in 24% in Arm B as a patient received brachytherapy and was low in Arm A, 16% [Table 2] (X2 = 0.4; P = 0.527, not significant). All strictures were negative for malignant cells on endoscopic biopsies and cytology. No tracheoesophageal fistulae were seen in the study, but ulceration was present in four patients in Arm B and two patients in Arm A which were managed by sucralfate suspension. Patients improved both symptomatically and endoscopically.
Local control (LC) rates were 80% and 84% in Arm A and Arm B, respectively, after a median follow-up of 6 months [Table 3] (X2 = 0.048; P = 0.82, not significant). Three patients in Arm A and two patients in Arm B were not on regular follow-up.
|Table 3: Evaluation of brachytherapy in carcinoma esophagus as a boost in different clinical trials|
Click here to view
| Discussion|| |
In this study, a total of 50 patients, histopathologically proven cases of locally advanced stage carcinoma esophagus, were enrolled and randomized in two Arms A and B with 25 patients each treated with EBRT up to dose 50 Gy in Arm A and up to dose 44 Gy followed by 10 Gy by brachytherapy in 5 Gy each weekly session in Arm B. All the patients showed good response to CTRT. Across both the schedules, dysphagia was initially high in both the arms but subsided as time lapsed. Dysphagia-free survival was found better in EBRT followed by the ILBT arm, but P value is nonsignificant, which might be due to the small sample size and shorter duration of follow-up.
LC rates were 80% and 84% in Arm A and Arm B, respectively, after a median follow-up of 6 months, but those differences were not statistically significant. These results were comparable with previous studies [Table 3]. In RTOG 92-07 trial, patients were treated with 50-Gy EBRT followed by 2# of brachytherapy with 5 Gy/# and LC rate was noted as 73%. A study by Calais et al., in which 60-Gy conventional external radiation was given concurrent with cisplatin, 5-fluorouracil, and mitomycin followed by two sessions of ILBT 5 Gy each, reported LC rates of 74% at 1 year. This suggests that chemoradiation schedules with brachytherapy boost are feasible but require a careful selection of patients with a good Karnofsky performance status, along with a need of further studies to standardize HDR-ILBT schedules with chemoradiation protocols.
Stricture formation was the most common complication found and it was slightly high in Arm B, 16% versus 24% in Arm A and Arm B, respectively (P = 0.4404, not significant). In their study, Kapoor et al. treated 86 patients with 35 Gray (Gy) EBRT followed by 6 Gy/# (2#) and 4.67 Gy (3#) in two different arms. They experienced LC 67.6% in the 6-Gy/# arm and 89% in the 4.67-Gy/# arm. Murakami et al. treated 62 patients with 60 Gray (Gy) EBRT followed by 12-Gy/# (2#). They experienced LC 45% after 3 years. Tamaki et al. in their study found that after EBRT and brachytherapy with 10 Gy, LC was 49% after 5 years and overall survival was 31%–84%. Gaspar et al. present sufficient clinical data to guide safe practice. Based on the clinical data available, the American Brachytherapy Society has drawn up as a set of guidelines to help in the selection of patients who are likely to benefit from an ILBT boost. They found a 49% overall survival at 1 year. Kumar et al. observe that EBRT doses in the range of 50–55 Gy followed by a dose of 10–12-Gy ILBT were optimal with respect to complications and LC in the radiotherapeutic management of esophageal cancer. They concluded with 38% LC and 39% overall survival at 1 year. Rosenblatt et al. recommended the addition of EBRT to standard high-dose-rate brachytherapy (HDRBT). With the encouraging results of their trial, they concluded that the combination of EBRT to standard HDRBT results in symptom improvement, is well tolerated, and is relatively safe. In longitudinal regression analyses, scores for dysphagia, odynophagia, regurgitation, chest pain, and performance status were all significantly improved. In contrast, weight, toxicities, and overall survival were not different between the study arms.
There have been few clinical trials using brachytherapy as boost and reporting data on the feasibility, tumor control, and associated toxicities. [Table 3] gives an overview of selected clinical trials on ILBT following chemoradiation.
Thus, we can conclude that ILBT with EBRT is optimal with respect to complications and LC in the radiotherapeutic management of locally advanced esophageal cancer.
| Summary and Conclusion|| |
The present study was conducted with the aim to compare local tumor control, dysphagia-free survival (DyFS), and complication (stricture formation) in between EBRT alone with dose 50 Gy (Arm A) and HDR ILBT (5 Gy/# in two fractions weekly) following EBRT dose of 44 Gy (Arm B) with weekly cisplatin in locally advanced carcinoma esophagus. On assessment and result evaluation, the results in respect of LC, DyFS rate were slightly better in the ILBT arm at 3 months, 6 months, but not statistically significant. The stricture formation rate was also slightly higher in EBRT followed by the ILBT arm.
In patients with unresectable carcinoma esophagus, concurrent chemoradiation followed by an ILBT boost is feasible with an acceptable toxicity profile and good LC rates with increased risk of complications are seen. This is a small sample size study to conclude the results. Further prospective clinical studies with a large number of patients and longer follow-up are required to define dose schedules.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bray F, Jemal A, Grey N, Ferlay J, Forman D. Global cancer transitions according to the Human Development Index (20082030): A population-based study. Lancet Oncol 2012;13:790-801.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
Hareyama M, Nishio M, Kagami Y, Narimatsu N, Saito A, Sakurai T. Intracavitary brachytherapy combined with external-beam irradiation for squamous cell carcinoma of the thoracic esophagus. Int J Radiat Oncol Biol Phys 1992;24:235-40.
Gaspar LE, Winter K, Kocha WI, Coia LR, Herskovic A, Graham M. A phase I/II study of external beam radiation, brachytherapy, and concurrent chemotherapy for patients with localized carcinoma of the esophagus (Radiation Therapy Oncology Group Study 9207): Final report. Cancer 2000;88:988-95.
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.
Kapoor R, Bansal A, Kochhar R, Kumar P, Sharma SC. Effectiveness of two high-dose-rate intraluminal brachytherapy schedules for symptom palliation in carcinoma esophagus: A tertiary care center experience. Indian J Palliat Care 2012;18:34-9. [Full text]
Murakami Y, Nagata Y, Nishibuchi I, Kimura T, Kenjo M, Kaneyasu Y, et al.
Long-term outcomes of intraluminal brachytherapy in combination with external beam radiotherapy for superficial esophageal cancer. Int J Clin Oncol 2012;17:263-71.
Tamaki T, Ishikawa H, Takahashi T, Tamaki Y, Kitamoto Y, Okamoto M, et al.
Comparison of efficacy and safety of low-dose-rate vs. high-dose-rate intraluminal brachytherapy boost in patients with superficial esophageal cancer. Brachytherapy 2012;11:130-6.
Kumar MU, Swamy K, Supe SS, Anantha N. Influence of intraluminal brachytherapy dose on complications in the treatment of esophageal cancer. Int J Radiat Oncol Biol Phys 1993;27:1069-72.
Rosenblatt E, Jones G, Sur RK, Donde B, Salvajoli JV, Ghosh-Laskar S, et al.
Adding external beam to intra-luminal brachytherapy improves palliation in obstructive squamous cell oesophageal cancer: A prospective multi-centre randomized trial of the International Atomic Energy Agency. Radiother Oncol 2010;97:488-94.
[Table 1], [Table 2], [Table 3]