Intraluminal brachytherapy boost following external beam radiotherapy with concurrent chemotherapy of oesophagus carcinoma: Results of a prospective observational study

Intraluminal brachytherapy boost following external beam radiotherapy with concurrent chemotherapy of oesophagus carcinoma: Results of a prospective observational study

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Intraluminal brachytherapy boost following external beam radiotherapy with concurrent chemotherapy of oesophagus carcinoma: Results of a prospective observational study Curiethérapie endoluminale après chimioradiothérapie externe concomitante pour un carcinome de l’œsophage : résultats d’une étude prospective d’observation P. Nag , O.P. Gurjar ∗ , V. Bhandari , K.L. Gupta , P. Bagdare , H. Goyal Roentgen-SAIMS Radiation Oncology Centre, Sri Aurobindo Institute of Medical Sciences, 453555 Indore, Madhya Pradesh, India

a r t i c l e

i n f o

Article history: Received 24 July 2017 Accepted 19 September 2017 Keywords: Intraluminal brachytherapy Oesophagus Toxicity

a b s t r a c t Purpose. – The main objective of our study is to evaluate response and toxicity profile in patients receiving external beam radiotherapy with concurrent chemotherapy followed by intraluminal brachytherapy boost for a carcinoma of the oesophagus. Material and methods. – Twenty patients with biopsy-proven carcinoma of the oesophagus received external beam radiotherapy (50 Gy in 25 fractions) with concurrent chemotherapy (cisplatin: 40 mg/m2 ). After a gap of two to three weeks, intraluminal brachytherapy (10 Gy in two fractions each 1 week apart by a high dose rate 60 Co source) was given. Response was evaluated at 1 month and at 1 year of completion of treatment. In addition, acute and chronic toxicity was evaluated at 1 month and 6 months of treatment. Results. – Complete response were seen in 80% of patients and partial response in 20% at 1 month. Moreover, there were 65% complete response, 10% local recurrences, 15% patients showed local control with distant metastasis and 10% patients died at 1 year. Grade 1, grade 2 and grade 3 oesophagitis were seen in 10%, 70% and 20% of patients respectively. Stricture was seen in 40% of patients and fistula in 10% of patients. There was no spinal cord, cardiac and nephrotoxicity found. Conclusions. – With the concept that high tumoricidal dose for adequate tumor control achieved by intraluminal brachytherapy as a mean of dose escalation, while sparing surrounding normal tissue and potentially improving therapeutic ratio, external beam radiotherapy followed by intraluminal brachytherapy could be a better choice for oesophagus carcinoma. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Published by Elsevier Masson SAS. All © 2018 Societ rights reserved.

r é s u m é Mots clés : Curiethérapie de haut débit de dose Cobalt 60 Curiethérapie endoluminale Œsophage Toxicité

Objectif de l’étude. – L’objectif principal de l’étude était d’évaluer le profil de réponse et de toxicité chez les patients recevant une radiothérapie externe avec une chimiothérapie concomitante suivie d’une curiethérapie endoluminale pour un cancer de l’œsophage. Matériel et méthodes. – Vingt patients ont rec¸u une radiothérapie externe de 50 Gy en 25 fractions et une chimiothérapie concomitante de 40 mg/m2 par semaine, puis deux à trois semaines plus tard une curiethérapie endoluminale par une source de cobalt 60 de 10 Gy en deux fractions espacées d’une semaine. La réponse a été évaluée à 1 mois et 1 an après l’achèvement du traitement. La toxicité aiguë et chronique a également été évaluée à 1 mois et 6 mois de traitement. Résultats. – Une réponse complète a été observée chez 80 % des patients et une réponse partielle chez 20 % à 1 mois. Il y a eu 65 % de réponses complètes, 10 % de récidives locales, 15 % des patients étaient en situation de contrôle local avec une métastase à distance et 10 % de patients sont décédés à 1 an. Une œsophagite de grade 1, de grade 2 et de grade 3 a été observée chez respectivement 10 %, 70 % et 20 % des patients la première année. Une sténose a été observée chez 40 % des patients et une fistule chez 10 %. Il n’y pas eu de toxicité spinale, cardiaque et rénale.

∗ Corresponding author. E-mail address: [email protected] (O.P. Gurjar). https://doi.org/10.1016/j.canrad.2017.09.008 ´ e´ franc¸aise de radiotherapie ´ 1278-3218/© 2018 Societ oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Nag P, et al. Intraluminal brachytherapy boost following external beam radiotherapy with concurrent chemotherapy of oesophagus carcinoma: Results of a prospective observational study. Cancer Radiother (2017), https://doi.org/10.1016/j.canrad.2017.09.008

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Conclusions. – En réalisant une escalade de dose tout épargnant relativement les tissus sains avoisinants, une chimioradiothérapie suivie de curiethérapie pourrait s’avérer être le meilleur choix pour le cancer de l’œsophage. ´ e´ franc¸aise de radiotherapie ´ © 2018 Societ oncologique (SFRO). Publie´ par Elsevier Masson SAS. Tous ´ ´ droits reserv es.

1. Introduction Oesophageal cancer is the third most common cancer of the digestive tract and the seventh leading cause of cancer-related deaths worldwide [1]. Multidisciplinary treatment have been tried, which includes surgery, concurrent chemoradiation, external beam radiotherapy followed by high dose rate intraluminal brachytheray in such patients to improve prognosis, however the results of the treatment of carcinoma of oesophagus have been poor despite advances in various treatment modalities [2]. Historical series of external beam radiation therapy alone report 5-year survival rates of 0–10%. Low survival rate followed initial radiotherapy alone could be due to loco regional persistence or recurrence of tumor, which is seen in as high as 85% of cases [3]. The combination of radiotherapy and concurrent chemotherapy with cisplatin and fluorouracil has led to long-term survival in approximately 20 to 30% of patients, an outcome similar to that associated with surgery alone but with an increased rate of local recurrence 77% when radiation therapy alone is used [4]. The above considerations have resulted in attempts to apply higher doses of radiation to the tumor but this lead to increased risk of late treatment related toxicity and 77% when radiation therapy alone is used. Endooesophageal brachytherapy makes it possible to use high doses of radiation to the tumor itself with concurrent protection of the adjoining healthy tissues due to rapid fall in dose with square in distance from the centre of the dose. The aim of brachytherapy is to reduce dysphagia, diminish pain and bleeding as well as improve patient well-being. Doses used in teletherapy were as high as 35 to 60 Gy, whereas those in high dose rate brachytherapy ranged between 10 and 25 Gy administered in two to four fractions. The combined treatment can be radical or palliative [5]. The above treatment also leads to a small proportion of late radiation complications. However, there have been only few reports to confirm that the number of local remissions and long-term survival rates have been increased in patients treated with teletherapy combined with brachytherapy. In this article, we report the findings of our observational study done on patients with oesophagus carcinoma who received concurrent chemotherapy and external beam radiotherapy followed by intraluminal brachytheray boost and evaluated the clinical response and toxicity associated with it, especially the high dose rate intraluminal brachytherapy component. 2. Materials and methods In this prospective observational study 20 patients with histopathologically proven oesophagus carcinoma were included with following criteria: Age between 30 and 65 years with Karnosky performance score of more than 70 with no metastasis or comorbidities and no previous treatment. 2.1. Treatment design All patients received external radiotherapy to the whole length of oesophagus along with lymph nodes with a dose of 50 Gy in 25 fractions with 6 MV photons on high energy linear

accelerator Clinac DMX (Varian medical systems). Contouring of gross tumor volume, clinical target volume and organs at risk was done as per Radiotherapy Oncology Group (RTOG) guidelines. Patients also received concurrent chemotherapy with cisplatin 40 mg/m2 once a week for five times. After completion of external radiotherapy, patients were assessed by endoscopy; intraluminal brachytherapy and two fractions was given by high dose rate brachytherapy machine “Co0.A86” (Eckert and Zigler BEBIG, Germany) using a cobalt source with a dose of 5 Gy in two fractions (10 Gy/2 fractions) to the involved site one week apart. A gap of 10 to 15 days was given between external beam radiotherapy and intraluminal brachytherapy. For the procedure of intraluminal brachytherapy, the patients were taken to the endoscopy room where a local anaesthesia endoscope was passed through the oral cavity with the help of a gastroenterologist to evaluate the extent of the tumor and mark the upper and lower margins of the tumor by applying radioopaque markers on the skin 3 cm above and 3 cm below the lesion under C arm guidance. Then, a 6-mm diameter oesophageal applicator (Nucletron Oesophageal applicator) was inserted on the guide wire into the oesophagus and fixed to the mouth piece for immobilization. The lower end of the applicator was placed 3 cm below lower end of the lesion. The patient was kept under observation for 15 min postprocedure and then moved for computed tomography (CT) scan of the thoracic area using Siemens SOMATOM definition AS scanner (Siemens Medical systems, Germany). CT images of 3 mm slice thickness were taken and were imported on treatment planning system (TPS) (Fig. 1a). A 100% of dose was calculated 0.5 cm from the surface of the source. Patient was lying down in lateral position in the brachytherapy room and the source tube was passed through the applicator lumen till its lower end and the patient was treated (Fig. 1b). 2.2. Response evaluation After the completion of treatment, response was evaluated after 1 month and at 1 year of completion of treatment. Evaluation was done clinically (relief from dysphagia) as well as by endoscopy and CT scan. Response was evaluated as per RECIST criteria for solid tumors version1.1. Local recurrence is defined as reappearance of primary lesion on endoscopy and CT scan. Local control with distant metastasis is defined as no primary lesion in oesophagus on endoscopy but patient present with lung and liver metastasis on CT scan. Toxicity was evaluated within 1 month as acute toxicity and within 6 months of treatment as chronic toxicity by history, physical examination and laboratory tests, endoscopy, CT scan. The grading of toxicity was done as per RTOG/European Organisation for Research and Treatment of Cancer (EORTC) radiation morbidity criteria. 2.3. Statistical analysis All statistical analyses were done using Graph Pad (Demo Version). P-value was calculated. P value < 0.05 was considered as significant difference and P value > 0.05 as non significant difference. Chi-square test was applied to find the association of toxicity with 1 month and 1 year response.

Please cite this article in press as: Nag P, et al. Intraluminal brachytherapy boost following external beam radiotherapy with concurrent chemotherapy of oesophagus carcinoma: Results of a prospective observational study. Cancer Radiother (2017), https://doi.org/10.1016/j.canrad.2017.09.008

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Table 2 Prospective observational study on the response to treatment in patients receiving external beam radiotherapy with concurrent chemotherapy followed by intraluminal brachytherapy boost for a carcinoma of the oesophagus: response evaluation at one year (n = 20). Status

n

%

Local control Local recurrence Local control with distant metastasis Death

13 2 3 2

65 10 15 10

Table 3 Prospective observational study on the response and toxicity profile in patients receiving external beam radiotherapy with concurrent chemotherapy followed by intraluminal brachytherapy boost for a carcinoma of the oesophagus (n = 20): oesophagitis within one month. Grade

n

%

0 1 2 3 4

0 2 14 4 0

0 10 70 20 0

Table 4 Prospective observational study on the response and toxicity profile in patients receiving external beam radiotherapy with concurrent chemotherapy followed by intraluminal brachytherapy boost for a carcinoma of the oesophagus: stricture and fistula in six months (n = 20).

Fig. 1. a: treatment planning of intraluminal brachytherapy of a carcinoma of the oesophagus; b: patient with an intraluminal brachytherapy applicator. a : planification d’une radiothérapie d’un cancer de l’œsophage ; b : mise en place d’un applicateur pour une curiethérapie endoluminale.

Table 1 Prospective observational study on the response to treatment in patients receiving external beam radiotherapy with concurrent chemotherapy followed by intraluminal brachytherapy boost for a carcinoma of the oesophagus: response at one month (n = 20). Étude prospective d’observation de la réponse au traitement chez des patients recevant une radiothérapie externe avec une chimiothérapie concomitante suivie d’une curiethérapie endoluminale pour un cancer de l’œsophage : réponse à un mois. Status

n

%

Complete response Partial response Progressive disease Stable disease

16 4 0 0

80 20 – –

3. Results The present study was done on 20 biopsy-proven case of oesophagus carcinoma treated by external beam radiotherapy with concurrent chemotherapy followed by intraluminal brachytherapy boost. The majority of patients was in the age group of 45 to 60 years. Male to female ratio was 14:6. Dysphagia was seen in all 20 patients with grade 2 dysphagia in ten patients, grade 3 dysphagia in eight patients and grade 4 dysphagia in two patients. All patients have growth in mid oesophagus with squamous cell carcinoma histopathology. Response results at 1 month are given in Table 1 and at 1 year of completion of treatment in Table 2. Patients with distant metastasis were treated with palliative chemotherapy. Results of the evaluation of acute toxicity within 1 month of treatment are presented in Table 3. For the relief of pain associated

Toxicity

n

%

Stricture Fistula

8 2

40 10

with oesophagitis, topical analgesics and appropriate symptomatic management were given. Grade 1 haematological toxicity was found in six patients (30%). Nephrotoxicity was not seen in any patients. The results for chronic toxicity evaluated within 6 months are presented in Table 4. Endoscopy-guided oesophageal dilatation was done in the eight patients who had stricture. Both patients with fistula died due to aspiration. Seven patients (35%) developed grade 1 lung toxicity, whereas 13 patients did not have any lung toxicity. There was no cardiac and spinal cord toxicity seen in any patients. 4. Discussion The advantage of brachytherapy boost over external beam radiotherapy boost is that intraluminal brachytherapy offers rapid tumor reduction of luminal aspect thus rapidly restoring the swallowing function and at the same time delivers relatively low dose to surrounding normal tissues particularly lung, spinal cord and adjacent normal oesophageal mucosa from radiation while at the same time providing focal dose escalation. Many studies have highlighted the effect of intraluminal brachytherapy boost following external beam radiotherapy. In a study done by Okawa et al., local control rate was higher in patients (55.8%) receiving a brachytherapy boost of 10 Gy following external beam radiotherapy dose of 60 Gy as compared to those receiving an external beam radiotherapy boost of 10 Gy following external beam radiotherapy dose of 60 Gy (49%). Rate of stricture formation was almost similar in both the arms [6]. In a study done by Sur et al., local control with brachytherapy boost dose of 12 Gy in two fractions was 70% at end of 1 year [7]. Calais et al. treated 53 patients with oesophageal cancer by chemoradiation (60 Gy in 30 fractions) followed by brachytherapy boost (10 Gy in two fractions) showed local control rate of 74% at the end of 1 year [8]. Our study shows complete response in 80%

Please cite this article in press as: Nag P, et al. Intraluminal brachytherapy boost following external beam radiotherapy with concurrent chemotherapy of oesophagus carcinoma: Results of a prospective observational study. Cancer Radiother (2017), https://doi.org/10.1016/j.canrad.2017.09.008

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and partial response in 20% of patients at 1 month. At 1 year, 60% patients were having complete response and 10% of patients had local control with distant metastasis. Fifteen percent of patients had local recurrence and two patients died at the end of 1 year of treatment. Stricture formation, fistula and oesophageal ulceration are the common late toxicity of high dose rate brachytherapy. Vivekananda et al. reported post-radiation stricture in 59% in their study of 58 patients [9]. A study done by Chauhan et al. reported postradiotherapy stricture in 42% of patients with external beam radiotherapy followed by intraluminal brachytherapy. In our study, eight patients (40%) showed strictures on endoscopy done within 6 months of treatment [10]. One other factor, which influences late toxicity, is the size of oesophageal applicator. Akagi et al. in an optimization study treated patients with external beam radiotherapy 50 to 60 Gy followed by high dose rate intraluminal brachytherapy in two fractions of 4 or 5 Gy or four to five fractions of 2 to 2.5 Gy using a 15 mm or 20 mm diameter balloon applicator prescribed at 5 mm from the surface [11]. They recommended the use of four to five fractions of 2 to 2.5 each for high dose rate intraluminal brachytherapy after 50 to 60 Gy external beam radiotherapy based on a significantly lower probability of late morbidity. In an another study, 134 patients treated in ten Italian centres with high dose rate intraluminal brachytherapy with or without external beam radiotherapy, complication rates correlated with high dose rate intraluminal brachytherapy fraction size (for fraction size less than 5 Gy there were 9.5% complication, 20% with doses ranging 5 to 8 Gy and 38% with fraction doses above 8 Gy) and on diameter of applicator tubes when narrower tubes used the oesophagus were more severely injured (24% with tube diameter less than 2 mm, 19% with tube diameter 2 to 6 mm and 5% with tube diameter greater than 6 mm) [12]. In our study, the size of oesophageal applicator was of 6 mm, which explains the number of stricture and fistula in these patients. Caspers et al. studied 35 patients with oesophagus carcinoma treated with external beam radiation therapy and low dose rate intraluminal brachytherapy [13]. They reported dysphagia relief in almost 90% of cases at six weeks. In the present study, dysphagia relief was seen in 95% of cases. Gasper et al. in a prospective trial used 50 Gy external beam radiotherapy with concurrent chemotherapy followed by brachytherapy after a gap of 2 weeks [14]. Their results showed a median survival of 11 months in all patients, local recurrence or persistence of disease observed in 63% of patients and six patients developed fistula. In the multi-institutional analysis, a slightly higher 2-year local control rate was obtained in the group that received external beam radiotherapy with intraluminal brachytherapy (90%) than in the group that received external beam radiotherapy alone with superficial oesophageal carcinoma (77%) [14]. The review of the literature showed that swallowing ability is improved in the majority of patients receiving radiotherapy and intraluminal brachytherapy to the same extent as externally delivered radiation. Moreover, swallowing function and general well-being both appear to be better for patients receiving brachytherapy with acceptable toxicity.

5. Conclusion With the concept that high tumoricidal dose for adequate tumor control is achieved by intraluminal brachytherapy as a mean of dose escalation, while sparing surrounding normal tissue and potentially improving therapeutic ratio, external beam radiotherapy followed by intraluminal brachytherapy could be a better choice for oesophagus carcinoma. This study had a better response, found the treatment to be well tolerated and showed encouraging complete and partial response rates. Disclosure of interest The authors declare that they have no competing interest. References [1] Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006;24:2137–50. [2] Willett GC. Radiation dose escalation in combined-modality therapy for esophageal cancer. J Clin Oncol 2002;20:1151–3. [3] Sun DR. Ten year follow up of esophageal cancer treated by radical radiation: analysis of 869 patients. Int J Radiat Oncol Biol Phys 1989;16:329–34. [4] Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001;19: 305–13. [5] 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. [6] 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. [7] Sur RK, Singh DP, Sharma SC, Singh MT, Kochhar R, Negi PS, et al. Radiation therapy of esophageal cancer: role of high dose rate brachytherapy. Int J Radiat Oncol Biol Phys 1992;22:1043–6. [8] 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 oesophageal carcinoma: results of a pilot study. Int J Radiat Oncol Biol Phys 1997;38:769–75. [9] Vivekanandam S, Reddy KS, Velavan K, Balasundaram V, Ranga Rao S, Subba Rao KS, et al. External beam radiotherapy and intraluminal brachytherapy in advanced inoperable esophageal cancer: JIPMER experience. Am J Clin Oncol 2002;25:10. [10] Chauhan A, Kaur P, Annex E. Radical external beam radiotherapy with intraluminal high rate dose brachytherapy in patients with carcinoma esophagus. Internet J Gastroenterol 2008;8:1–7 [https://print.ispub.com/api/0/ispubarticle/11901]. [11] Akagi Y, Horokawa Y, Kagemoto M, Matsuura K, Ito A, Fujita K, et al. Optimum fractionation for high dose rate end esophageal brachytherapy following external irradiation of early stage esophageal cancer. Int J Radiat Oncol Biol Phys 1999;43:525–30. [12] Gava A, Fontan L, Bolner A, Botturi M, Cafaro I, Di Marco A, et al. High dose rate brachytherapy in esophageal carcinoma: The Italian experience. Radiol Med 1996;91:118–21. [13] Caspers RJ, Zwinderman AH, Griffioen G, Welvaart K, Sewsingh EN, Davelaar J, et al. Combined external beam and low dose rate intraluminal radiotherapy in oesophageal cancer. Radiother Oncol 1993;27:7–12. [14] 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 oesophagus. Radiation Therapy Oncology Study 2000 9207 final report. Cancer 2000;88:988–95.

Please cite this article in press as: Nag P, et al. Intraluminal brachytherapy boost following external beam radiotherapy with concurrent chemotherapy of oesophagus carcinoma: Results of a prospective observational study. Cancer Radiother (2017), https://doi.org/10.1016/j.canrad.2017.09.008