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Endobronchial brachytherapy for metastasis from extrapulmonary malignancies as an effective treatment for palliation of symptoms
Brachytherapy
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(2017)
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Endobronchial brachytherapy for metastasis from extrapulmonary malignancies as an effective treatment for palliation of symptoms E. Donovan1,*, E. Timotin1, T. Farrell1, B. Donde2, S. Puksa3, R. Sur1 1 Department of Radiation Oncology, McMaster University, Hamilton, Ontario, Canada Division of Oncology, Department of Radiation Oncology, Sandton Oncology Centre, Johannesburg, South Africa 3 Division of Respirology, Department of Internal Medicine, McMaster University, Hamilton, Ontario, Canada
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ABSTRACT
PURPOSE: Endobronchial metastasis (EBM) originating from primary cancers outside the lung is rare. External beam radiotherapy is often attempted for control of symptoms with variable effectiveness and retreatment is challenging if symptoms recur. There is limited documentation of highdose-rate brachytherapy for EBM in the literature. METHODS AND MATERIALS: A prospective database was created from 2006 to 2015. Patients with EBM who received high-dose-rate brachytherapy were included. Cough, dyspnea, chest pain, and hemoptysis were assessed and graded (0-4) at the time of initial consult and in followup. Symptom-free survival and re-expansion were assessed. RESULTS: Thirty-five patients with EBM were identified. Most patients received three fractions of 700 cGy, and 17 patients had prior external beam radiotherapy. Median symptom-free and overall survival were 67 and 117 days. After brachytherapy, improvement in cough was documented in 75.0%, hemoptysis in 76.4%, dyspnea in 60.0% for a median of 3-6 months. Of the 22 patients who had subsequent chest imaging, re-expansion was documented in 32%. There were no significant toxicities reported. CONCLUSIONS: Brachytherapy appears effective in achieving durable symptom control of cough hemoptysis, and dyspnea in patients with EBM and should be considered routinely for palliation where available. Further studies are required to better characterize expected symptom improvement, lung re-expansion rates, and efficacy in comparison with other local treatments. Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Endobronchial metastasis; Brachytherapy; Hemoptysis; Dyspnea; Palliation
Background The lung is a common site of metastasis for extrapulmonary malignancies. Metastatic lesions are generally located in the lung parenchyma, and metastasis to the tracheobronchial tree is rare. The most common primary sites for endobronchial metastasis (EBM) include colon, breast, and renal cell carcinomas (1), and the most
Received 20 September 2016; received in revised form 20 December 2016; accepted 9 January 2017. No conflicts of interest to disclose, no copyrights to disclose, and no patient photo use. This study has been approved by the Hamilton Integrated Research Ethics Board. * Corresponding author. Department of Radiation Oncology, McMaster University, 699 Concession Street, 3rd Floor Room 3-226, Hamilton, Ontario, Canada L8V5C2. Tel.: 905-387-9495x64791; fax: 905-575-6350. E-mail address: [email protected] (E. Donovan).
commonly reported symptoms are cough, dyspnea, and hemoptysis (2). Endobronchial brachytherapy has demonstrated utility in patients with localized symptomatic disease in the bronchus (3, 4), including those who otherwise may not be candidates for systemic therapy or external beam radiotherapy (EBRT) because of previous treatment or comorbidities. A recent Cochrane review (5) suggests that palliative EBRT most effectively improves symptoms in advanced lung cancer patients in comparison to endobronchial brachytherapy. This review focuses on patients with primary lung cancers, however, which have potentially different histologies and natural histories than EBM, and may respond differently to treatments, warranting further investigation of management. Furthermore, 28% of the patients in the EBRT arm of one trial discussed in this review still required subsequent intraluminal brachytherapy for recurrent symptoms (6). In patients with a history of EBRT, limitations also
1538-4721/$ - see front matter Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2017.01.003
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E. Donovan et al. / Brachytherapy
exist to lung re-irradiation, given concerns of provoking side effects of esophagitis and pneumonitis (7). Brachytherapy has the potential to safely deliver ablative doses of radiotherapy directly to endoluminal tumors via bronchoscopically placed catheters, while avoiding high doses to the surrounding structures. It has been used successfully to treat endobronchial disease in primary lung cancer with a 70% symptom response rate (3) and documented improvement in quality of life (8e10). Treatment of metastasis from extrapulmonary malignancies, on the other hand, has been reported in only a few studies. A review of published EBM cases suggests that only 7.2% of patients received intraluminal brachytherapy (2). We report a prospectively followed cohort of patients with EBM treated with high-dose-rate (HDR) brachytherapy at our center for palliative relief of symptoms.
Methods Since 2006, patients with intraluminal disease in the tracheobronchial tree determined on bronchoscopy and/ or imaging with symptoms of obstruction have been considered candidates for treatment at the Juravinski Cancer Centre HDR brachytherapy program. Patient and treatment data in those treated with intraluminal brachytherapy to the lung were recorded in a prospective database. This database was approved by the Hamilton Integrated Research Ethics Board. To be deemed an eligible for brachytherapy, patients must have radiographic proof of disease within the bronchial lumen (on CT); symptoms of cough, hemoptysis, dyspnea, or pain; and visible disease in the lumen of the main stem, lobar, or segmental bronchi at bronchoscopy before treatment. At the Juravinski Cancer Centre, in an attempt to minimize the volume of normal lung treated, any patient with radiographic and/or bronchoscopic evidence of intraluminal disease, who is deemed eligible by a respirologist to tolerate the procedure, is generally considered for brachytherapy upfront with EBRT reserved for recurrent symptoms. Patients are considered candidates regardless of tumor size, performance status, extent of pulmonary disease or systemic metastasis, and prior systemic therapy. Patients with no radiographic disease obstructing the bronchi and/or no luminal disease on endoscopy are deemed ineligible for brachytherapy. Patients were scored using a modified version of the European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-13 scale (11) with one question asked regarding each domain of dyspnea with exertion (Question 34), hemoptysis (Question 32), cough (Question 31), and chest pain (Question 40) at the time of initial consult and at followup. An additional grade of severe was added to the
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scale so that the final scoring system ranged from 0 to 4 (absent [0], mild [1], moderate [2], significant [3], and severe [4]). A prospective database of patients with primary or metastatic lung disease was developed with the institutional review board’s approval from 2006 to 2015 including demographic, symptom, treatment, and outcome information. Patients with EBM from any primary site outside the lung who received one or more brachytherapy treatments were included in the analysis. Some patients who had received prior EBRT were also treated with brachytherapy for recurrent symptoms and were included in the analysis. All patients had EBM from a biopsy-proven extrapulmonary primary cancer site. For treatment delivery, patients were premedicated with topical xylocaine 1% and sedated with intravenous fentanyl and midazolam. A respirologist visualized the tumor using flexible fiberoptic bronchoscopy. Treatment catheters were inserted under endoscopic vision with fluoroscopic guidance by the respirologist and radiation oncologist. The methodology of implantation has been described elsewhere in previous publications from the department (3). Patient vital signs were monitored continuously during treatment. Treatments were repeated one to three additional times typically at 2e3-week intervals. Typically, a dose of 7 Gy (range, 5e8 Gy) was prescribed to 0.5 cm or 1.0 cm from the source axis depending on how proximal the lesion was to the central bronchi. This dose was selected based on the American Brachytherapy Society guidelines for lung brachytherapy (12), which suggest that patients receive 14.2e20 Gy in two fractions or 22.5 Gy in three fractions. The guideline also suggests that CT-based planning should be used; however, all our patients were treated before 2015 when the guideline was created. Patients were asked about symptoms, and scores were recorded monthly until 3 months and then followed every 3 months until discharge or death. Date of death was recorded from the chart if available, and otherwise, last seen date was considered date of death for survival calculations. Symptom-free survival (SFS) was determined using duration of at least one scale point of response in those with initial symptoms. KaplaneMeier curves were used to estimate SFS and overall survival (OS). Imaging was not routinely completed to assess re-expansion; however, charts were reviewed for incidental chest x-ray or chest CT scan reports. Re-expansion was documented as yes or no in those patients with incidental imaging, based on explicit statements of re-expansion from the reporting radiologist. Any magnitude of improvement in lung expansion was recorded as yes, and no comment of reexpansion was recorded as no. Assessment of tumor response on repeat bronchoscopy was not routinely or objectively documented and therefore has not been included in our study results.
E. Donovan et al. / Brachytherapy
Thirty-five patients with EBM from extrapulmonary malignancies were identified, the most common sites being colorectal and breast cancers. Other common sites included melanoma, sarcoma, lymphoma, renal cell cancer, and esophageal cancer. Most patients were of Eastern Cooperative Oncology Group 1 performance status with at least one major comorbidity, including Type II diabetes mellitus, cardiovascular disease, or pulmonary disease. Patient demographic and disease characteristics are shown in Table 1. Most patients received three HDR brachytherapy fractions of 700 cGy. Treatment characteristics and tumor location (including main stem bronchus, secondary bronchi, and tertiary bronchi) are documented in Table 2. Median time to brachytherapy after diagnosis of metastasis was 2 months (range, 0e174). Median followup was 4.5 months. Baseline symptoms were reported in all patients: cough in 80%, hemoptysis in 48.87%, dyspnea in 85.70%, and pain in 70%. Improvement by at least one point was documented in cough (75%), hemoptysis (76.40%), and pain (25.71%) for a median duration of 3 months and dyspnea (60%) for a median of 6 months. Baseline symptom scores and change in scores over time are reported in Table 3. Absent to mild (0 or 1) scores were maintained in a proportion of patients initially reporting cough (22.85%), hemoptysis (48.57%), dyspnea (17.14%), and pain (62.85%) for a median of 2e4 months. Two patients experienced worsening shortness of breath Table 1 Patient demographics and disease characteristics
Patient demographics Major comorbidities (diabetes, cardiovascular disease, or pulmonary disease) No major comorbidities Smoking history No smoking history Gender M F ECOG 0 1 2 3 4 Primary disease site Colorectal Breast Esophagus Sarcoma Lymphoma/myeloma Melanoma Renal Head and neck Cervix/testicle Hepatobiliary
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Table 2 Treatment characteristics
Results
Patient characteristics
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n (%) 21 (60) 14 (40) 10 (28.57) 25 (71.42) 19 (54.28) 16 (45.71) 2 19 6 6 2
(5.71) (54.28) (17.14) (17.14) (5.71)
9 5 3 3 3 3 3 2 2 2
(25.71) (14.28) (8.57) (8.57) (8.57) (8.57) (8.57) (5.71) (5.71) (5.71)
M 5 male; F 5 female; ECOG 5 Eastern Cooperative Oncology Group.
Treatment
n (%)
Median dose per fraction (Gy) Total no. of HDR treatments 1 2 3 Additional HDR O 3 mo after first fraction No EBRT EBRT Median dose EBRT given before brachytherapy EBRT given after brachytherapy Concurrent Number of catheters used 1 2 3 Location treated Main stem bronchus (right or left) Lobar bronchi Segmental bronchi
7 (range, 5e8) 7 (20) 10 (28.57) 18 (51.43) 3 (8.57) 13 (37.14) 22 (62.86) 3000 (range, 600e6000) 17 (48.57) 3 (8.57) 2 (5.71) 23 (67.6) 10 (29.5) 1 (2.9) 7 (4.8) 23 (54.6) 12 (28.6)
HDR 5 high dose rate; EBRT 5 external beam radiotherapy.
after brachytherapy, whereas no patients reported worsening pain, hemoptysis, or cough after treatment. Median SFS was 67 days for all symptoms. Median OS was 112 days (range, 5e1001) (Fig. 1). Seventeen patients received EBRT to the lung before brachytherapy and presented with recurrent symptoms. Of these patients, 73.33% experienced relief of cough, 70% in hemoptysis, 57.14% in dyspnea, and 50% in pain after brachytherapy. Most of these patients experienced a onepoint improvement in symptoms, 3 patients had a two-point improvement in cough, and 2 patients had a two-point improvement in pain. In those with a response, the median improvement in cough score was 2 months (range, 1e9); in hemoptysis, the score was 7.5 months (range, 3e12); and in dyspnea, the score was 9 months (range, 2e12). There were no significant differences in SFS achieved with brachytherapy in domains of cough ( p 5 0.46), pain ( p 5 0.92), hemoptysis ( p 5 0.47), or dyspnea ( p 5 0.47), between patients who had received prior EBRT vs. those who did not (Fig. 2). Repeat imaging of the chest was not routinely completed; however, patients’ charts were reviewed for incidental subsequent images of the chest including CT scans or chest x-rays. Of the 22 patients who had subsequent chest imaging, re-expansion was documented in 7 patients (32%). No Grade 3 or 4 toxicities were reported. No adverse events occurred during the procedures (e.g., massive hemoptysis or desaturation requiring posttreatment ventilation).
Discussion The lung parenchyma is a common site of metastasis for many extrapulmonary malignancies, yet involvement of the
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Table 3 Baseline symptom scores and change in symptom scores
Symptom Cough
Hemoptysis
Dyspnea
Pain
Baseline score
No. of patients per severity score
0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4
7 13 6 5 4 18 7 5 3 2 5 7 12 9 2 21 7 6 1 0
Any improvement, n (%)
Improved two points, n (%)
Improved three points, n (%)
Maintained score of 0e1, X (%)
Median numerical score improvement (range)
Median duration, mo (range)
21/28 (75)
8/28 (28.57)
2/28 (7.14)
8 (median, 2 mo)
1 (1e3)
3 (1e15)
13/17 (76.47)
6/17 (35.29)
2/17 (11.76)
17 (median, 3 mo)
1 (1e2)
3 (1e8)
18/30 (60)
9/30 (30)
0/30 (0)
6 (median, 4 mo)
1 (1e3)
6 (1e18)
1/9 (11)
0/35 (0)
22 (median, 4 mo)
1 (1)
3 (1e18)
9/35 (25.71)
tracheobronchial tree is relatively rare. Although the range of primary sites observed in our study was wide, the most commonly reported sites were breast and colorectal, a finding consistent with reported cases in the literature (1). Median time to development of EBM after primary diagnosis ranges widely from 18 to 50 months in the literature (13e15). Patients most commonly presented with dyspnea (up to 80%), cough (up to 66%), hemoptysis (up to 33%) (13), as well as pain and sputum production (8). Radiographic findings include atelectasis distal to obstructed bronchi with hilar or mediastinal lymphadenopathy (16). Radiotherapy for palliation of primary lung cancers has been described in depth (6); however, EBM represents a heterogenous group of tumors with different histologies and radiotherapy sensitivities, which may respond differently to treatments. Treatment approach for EBM generally depends on primary etiology, systemic disease extent, acuity of symptoms, and extent and duration of distal lung collapse (14). Systemic therapy plays a primary role in many cases (1, 17); however, patient comorbidities or poor performance status may be a limiting factor. In other cases, patients may have only isolated EBM without high burden of systemic disease, and systemic therapy may not be warranted. In either case, local symptom relief is of prime importance. Many of the most common sites for EBM, including renal cell, breast, and colon cancers have prolonged disease courses even with a diagnosis of metastatic disease. These patients may therefore benefit from long-term control of symptoms using a method, which confers minimal toxicity (16).
In our study, patients were deemed candidates for brachytherapy if they presented with intraluminal disease, which could be visualized on bronchoscopy. At our center, brachytherapy is used routinely to deliver high doses of radiotherapy to tumors inside the bronchial lumen without delivering high radiotherapy doses to the surrounding lung and mediastinum. It has been used successfully in the treatment of primary lung cancers as reported in another series by Goldberg et al. (3). As indicated by our results, brachytherapy may also relieve symptoms successfully in EBM patients. Several patients were referred either internally or from different centers after developing recurrent symptoms of hemoptysis, cough, or shortness of breath after treatment with EBRT. There is some experience reported using endoscopic techniques for local relief of symptoms. A French study reports on 42 patients treated with mechanical resection (69% complete), and additional cryotherapy in 16.7%, silicon stent insertion in 9.5%, and neodymium-doped yttrium aluminum garnet laser in 11.9% in whom bleeding developed. Symptom relief within 24 h was demonstrated in 7 of 16 patients reporting dyspnea, in 9 of 16 reporting cough, and only 1 of 5 reporting hemoptysis; however, overall clinical improvement was documented in 72% of patients. Forced expiratory volume in 1 s was also measured and improved by a mean of 34%. Ten patients required additional intervention at 6 months (18). The use of endoscopic argon plasma coagulation has also been reported in cases of metastatic melanoma (19, 20). Many EBM case series have included a variety of treatment modalities and few patients. Turkish series (N 5 15)
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1,0
0,8
0,8
0,6
0,4
0,2
0,0
5 Hematemesis Free Survival Complete Censored
1,0
Cumulative Proportion Surviving
Cumulative Proportion Surviving
Complete Censored Cough Free Survival
-
0,6
0,4
0,2
0
100
200
0,0
300
0
100
Days
0,8
0,8 Cumulative Proportion Surviving
Cumulative Proportion Surviving
1,0
0,6
0,4
0,6
0,4
0,2
0,2
0
50
100
150
200
250
0,0
300
0
50
100
200
250
300
200
250
300
Overall Survival Complete Censored
Symptom Free Survival Complete Censored 1,0
1,0
0,8
0,8 Cumulative Proportion Surviving
Cumulative Proportion Surviving
150 Days
Days
0,6
0,4
0,2
0,0
300
Pain Free Survival Complete Censored
Dyspnea Free Survival Complete Censored 1,0
0,0
200 Days
0,6
0,4
0,2
0
50
100
150
200
250
Days
300
0,0
0
50
100
150 Days
Fig. 1. Symptom-free survival in days for individual symptom scores and overall. (Top left) Cough-free survival. (Top right) Hemoptysis-free survival. (Middle left) Dyspnea-free survival. (Middle right) Pain-free survival. (Bottom left) Overall symptom-free survival. (Bottom right) Overall survival.
reported on EBM patients treated with chemotherapy (n 5 8), EBRT (n 5 1), combination chemoradiotherapy (n 5 3), or supportive care (n 5 3); however, symptom relief was not reported per modality (13). Another series reports on six of eight cases treated with systemic therapy, which had little effect on EBM, even with radiologic
response in parenchymal pulmonary nodules in two cases (21). Photodynamic therapy was reported to improve symptoms in 9 patients in one series, with severe complications occurring in only 1 patient (22). Although palliative EBRT has been used effectively as a local therapy, durability and effectiveness is variable.
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Overall Surival by External Beam before Brachytherapy (group1) or after Brachytherapy (group2) Complete Censored 1,0
Cumulative Proportion Surviving
0,8
0,6
0,4
0,2
0,0
20
40
60
80 100 120 140 160 180 200 220 240 260 280 300 Days
Group 0, Group 1,
Fig. 2. Overall survival for patients who received external beam radiotherapy either before or after brachytherapy.
Symptom relief has been reported in patients treated with EBRT for EBM (21) for a few months; however, additional treatment may be required to the irradiated lung parenchyma and airways if symptoms recur or disease progresses. Radiotherapy doses and dose per fraction are limited by the tolerance of surrounding normal tissues, including the lung, great vessels, heart, tracheobronchial tree, and esophagus to EBRT. Most reports of thoracic reirradiation focus on patients with primary lung cancer, who may have initially received radical doses of radiotherapy to the lung. One study reports pneumonitis rates of 12% and esophagitis rates of 17% in patients receiving thoracic reirradiation (7). Nevertheless, given the intent of treatment is for palliative symptom relief, physicians may be hesitant to prescribe additional radiotherapy to patients at the risk of precipitation of adverse side effects. Brachytherapy has the potential to deliver highly localized treatment with minimal side effects and doses to adjacent organs (23). Intraluminal brachytherapy has been used successfully in primary and recurrent lung cancers to relieve symptoms. According to a review by Nguyen et al. (9), palliative relief of symptoms in primary lung cancer cases is achieved in 43e92% of cases, with studies reporting 70e100% relief of hemoptysis and 33e85% relief of dyspnea. Intraluminal brachytherapy has also been used to improve outcomes in primary lung cancers when used in combination with EBRT in randomized studies (9). Goldberg et al. (3) reported on a prospective cohort of
inoperable lung cancer patients treated with brachytherapy with or without EBRT and found no significant difference in duration of symptom relief for cough, hemoptysis, or dyspnea between groups. Based on previous experience using endoluminal brachytherapy for primary lung cancer reported at our center (3) and in the literature (9), it appears to be a safe and effective alternative to EBRT. There are very minimal reported adverse events or side effects, and in patients with no previous treatment, it reserves the opportunity for EBRT if required in the future. For these reasons, it is the practice at our center to first offer brachytherapy for palliative symptom relief of obstructing tumors in the bronchus and reserve EBRT for symptom recurrence. Patients are generally not excluded based on tumor size or systemic or pulmonary disease burden. There is minimal experience reported in the literature with endobronchial brachytherapy to treat metastatic disease. A review in 2004 found of 204 reported patients with EBM, only 7% of patients received brachytherapy (2). Table 3 summarizes treatment and outcome details of several publications of EBM patients treated with brachytherapy. Investigators in Austria reported on 11 patients treated with brachytherapy and found symptom relief in 73% of patients and a complete anatomic response in 20% at last followup (24). Another report of 22 EBM patients (81 total including primary lung cancers) treated with brachytherapy
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found no difference in local control (77% overall at 1 year) in those with EBM vs. primary disease; specifically, relief was reported in 85% with dyspnea, 77% with cough, and 100% with hemoptysis at presentation (25). The results with HDR brachytherapy were also durable, with 77% and 64% progression-free survival at 12 and 24 months, respectively (22). One of the largest experiences of brachytherapy for EBM (N 5 37) found symptom resolution in both shortterm and long-term survivors, in 67% of patients with hemoptysis, 42% of patients with dyspnea, and 50% of patients with cough. Patients received a single dose of 15 Gy in 29 of 37 cases and in comparison to our regimen of 700 cGy for two to three fractions. These large fraction sizes appeared to be safe with no adverse events; however, duration of symptom relief, description of symptom assessment tools, and baseline symptom scores as well as magnitude of symptom relief were not reported (4). There were also no reports of re-expansion in this study (Table 4). Investigators in Brazil reported 13 EBM patients of 78 overall treated with intraluminal brachytherapy with a dose of 750 cGy in three fractions, a similar regimen to that used in our study. Response rates included 100%, 33.9%, and 57.4% of those with hemoptysis, cough, and dyspnea, respectively, for all patients. There was also a 74.3% response rate in those examined radiographically or bronchoscopically (8). Another study used one or two large fractions of 10 Gy in 7 patients with EBM (39 total including primary lung cancer cases) and reported response rates of dyspnea in 80% and hemoptysis in 93%. Of 18 patients with repeat endoscopy, 78% demonstrated response (26). A case series reported on eight colon cancer cases with EBM treated with endoscopic laser resection, two with stent insertion, and three with brachytherapy. All patients attained improved symptoms; however, the extent and duration of relief was not compared between regimens (27). Brachytherapy has also been used effectively in cases with rare extrapulmonary primary sites, such as malignant chondroid syringoma with both endoscopic response and relief of dyspnea and cough (28). Brachytherapy ideally delivers radiation dose to a highly localized area around the tumor and only minimal amounts to normal tissues (4, 26). Toxicity is rare and may include early bronchitis, bronchospasm, or pneumonitis (29). Stranzl et al. (24) reported that 3 of 11 patients developed asymptomatic radiation bronchitis, which is thought to be related to dose and volume treatment (30). Stricture, hemoptysis, and fistula are late complications that have been reported in rare cases of brachytherapy for EBM (4, 8, 23, 26). One study reported a 7.4% incidence of massive hemoptysis; however, all but one case was in fact because of progressive disease rather than treatment toxicity (30). The complication risk is thought
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to be higher using larger fraction sizes and large target volumes beyond the bronchial wall (9). Using multiple fractionated treatments (e.g., 14 Gy in two to three fractions) and confining the prescription point to 1 cm or 0.5 cm from the center of source axis depending on location in the bronchi, as is the protocol at our center, minimizes the risk of these late toxicities. It has also been suggested that the total dose, or maximum point dose, to the tracheal or bronchial wall (85 Gy to more than 2 cc volume suggested by one study), influences late respiratory complications (31). There were no reports of significant early or late toxicity in our cohort. Studies have generally reported lung re-expansion in the range of 20e46% (6, 26) after endobronchial brachytherapy treatments, consistent with our result of 23%. Reexpansion rates were difficult to determine in our study however, as patients primarily had repeat imaging or bronchoscopy only if symptomatic. We therefore may have underestimated the percentage of responders. Determining re-expansion rates and extent in collapsed lung tissue in future studies may be useful in predicting which patients may benefit the most from brachytherapy treatments. Unfortunately, although repeat bronchoscopy and documentation of response was not routinely completed in our study, this may also be a valuable method of response assessment in future studies. Reimaging of the lungs with chest x-ray or CT scan may be a safer alternative to characterize re-expansion, however, is less sensitive (25). Duration of symptom relief is also not well documented in the literature. Our study reports an SFS of 67 days considering relief of cough, hemoptysis, dyspnea, and pain. Median OS was 112 days, suggesting that symptom control was achieved for a clinically significant period in these patients. Improvement by two scores in cough, dyspnea, and hemoptysis was seen in approximately 30% of the patients. Many of the patients in our study had been previously treated with EBRT (48.57%) and developed recurrent symptoms. Symptom relief was reported in all categories, particularly cough and hemoptysis. There was also no significant difference in the duration of response in patients who had received previous EBRT. This suggests that brachytherapy is an effective alternative for patients with recurrent or refractory symptoms after EBRT or patients who are radiotherapy naive in the lung. Further research will be fundamental in identifying those patients who will obtain symptomatic relief from brachytherapy and provide guidelines in the safe incorporation of brachytherapy into single- or multimodality regimens. Furthermore, assessment of early vs. late intervention with brachytherapy may delineate appropriate timing to pursue this treatment. Despite limited experience, ours and other studies have shown that this treatment is safe and effective in palliative symptom relief and should be considered more readily in patients with EBM.
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Table 4 Reported HDR brachytherapy experience for EBM
Study
Patients with EBR (n) 37 EBM
Solomonov et al., 2001 (28) Case report Stranzl et al., 2002 (24)
1 EBM
11 EBM
16/8, 50% 15 Gy 1 HDR brachytherapy (10, 20, or multiple 10e15 Gy); EBRT (in 10.8%); and chemotherapy (in 24.3%) 7 Gy 3 HDR brachytherapy; 1/1, 100% EBRT; and chemotherapy 5e6 Gy 3e4 HDR brachytherapy
Sorensen, 2004 (2) 204 EBM
24/10, 42%
Not described
NR
Median, 280 d
NR
1/1, 100%
NR
1/1 bronchoscopy þ radiographic
NR
NR, 11/8, and 73% overall symptom 61/NR
Subjective assessment
11/8, 73%, and endoscopic response NR
15 mo followup
24/23, 95.8%
24/18, 75%
NR, 100%, NR, 100%, symptom relief symptom relief
NR
Median, 15.2 mo
Reported as partial or complete resolution NR
81/79, 97.5% bronchoscopy NR
50% OS at 2 y
81/42 51.8% significant response on bronchoscopy 14/33 and 13.86% radiographic 18/14 78%, endoscopic response
Median, 14.7 mo
23/23, 100%
53/45, 85%
From 2005 EORTC lung questionnaire, prior not described
80%
13/14, 93%
NR
Subjectivedexcellent, good, or no response
28/21, 75%
17/13, 76.47%
30/18, 60%
Five-point scale, 4 22/7, 32% re-expansion Median, 112 d domains from modified of lung on CT or CXR EORTC-QLQ-13
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35 EBM
OS
18/12, 67%
(2017)
Present study, Donovan, 2016
10 Gy 1 or 2; HDR brachytherapy; EBRT (in 71.4%); and chemotherapy (in 28.6%) 7 Gy 2e3 majority (patients received 1e4) and prior EBRT in 17
Bronchial obstruction examined/improved
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7 EBM/39 total
Measurement reported
NR, 11/8, and NR, 11/8, and 73% overall 73% overall symptom symptom 80/NR 61/NR
Brachytherapy 13 (in 7%); EBRT (in 19.6%); chemotherapy (in 23%); and surgery (in 19.6%) Escobar-Sacristan 5 EBM/81 5 Gy 4 HDR brachytherapy; 34/30, 88.2% et al., 2004 (29) total EBRT; chemotherapy; and surgery (81.5%) Bar-Gil Shitrit 8 EBM 3/8 laser þ HDR brachytherapy; NR, 100%, symptom et al., 2007 (27) 5/8 laser alone or laser þ stent; and chemotherapy (in 100%) relief Dagnault et al., N 5 22/81 EBM 5 Gy 4 HDR brachytherapy; 43/33, 77% 2010 (25) EBRT (in 44%); and chemotherapy (in 41%)
Pisch, 2011
Dyspnea, N 5 reporting/ improved
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Quantrill et al., 2000 (4)
Treatment
Cough, Hemoptysis, N 5 reporting/ N 5 reporting/ improved improved
Median, 6.3 mo
HDR 5 high dose rate; EBM 5 endobronchial metastasis; OS 5 overall survival; EBRT 5 external beam radiotherapy; NR 5 not reported; EORTC QLQ-13 5 European Organization of Research and Treatment of Cancer Quality of Life Questionnaire 13; CXR 5 chest x-ray.
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Conclusion Brachytherapy appears effective in achieving durable symptom control of cough, hemoptysis, and dyspnea in patients with metastatic disease located in the bronchus. It can be used in combination with or as an alternative to EBRT and should be considered routinely where available in this patient population. Further studies are required to better characterize expected symptom improvement and lung reexpansion rates.
References [1] Kim JH, Min D, Song SH. Endobronchial metastasis from extrathoracic malignancies: Recent 10 years experience in a single university hospital. Tuberc Respir Dis (Seoul) 2013;74:169e176. [2] Sorensen J. Endobronchial metastasis from extrapulmonary solid tumors. Acta Oncol 2004;43:73e79. [3] Goldberg M, Timotin E, Farrell T, et al. A prospective analysis of high-dose-rate endobronchial brachytherapy in the palliation of obstructive symptoms in lung cancer patients: A single-institution experience. Brachytherapy 2015;14:655e661. [4] Quantrill S, Burt P, Barber P, et al. Treatment of endobronchial metastasis with intraluminal radiotherapy. Respir Med 2000;94: 369e372. [5] Reveiz L, Rueda JR, Cardona AF. Palliative endobronchial brachytherapy for non-small cell lung cancer. Cochrane Database Syst Rev 2012;12:CD004284. [6] Stout R, Barber P, Burt P, et al. Clinical and quality of life outcomes in the first United Kingdom randomized trial of endobronchial brachytherapy (intraluminal radiotherapy) vs. external beam radiotherapy in the palliative treatment of inoperable non-small cell lung cancer. Radiother Oncol 2000;56:323e327. [7] Drodge CS, Ghosh S, Fairchild A, et al. Thoracic reirradiation for lung cancer: A literature review and practical guide. Ann Palliat Med 2014;3:75e91. [8] de Aquino Gorayeb MM, Gregorio MG, de Oliveira EQ, et al. Highdose-rate brachytherapy in symptom palliation due to malignant endobronchial obstruction: A quantitative assessment. Brachytherapy 2013;12:471e478. [9] Nguyen NT, Timotin E, Hunter R, et al. Endotracheal brachytherapy alone: An effective palliative treatment for tracheal tumors. Brachytherapy 2015;14:543e548. [10] Rodrigues G, Videtic GM, Sur R, et al. Palliative thoracic radiotherapy in lung cancer: An American Society for Radiation Oncology evidence-based clinical practice guideline. Pract Radiat Oncol 2011; 1:60e71. [11] Bergman B, Aaronson NK, Ahmedzai S, et al. The EORTC QLQLC13: A modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. EORTC Study Group on Quality of Life. Eur J Cancer 1994;30A: 635e642. [12] Stewart A, Parashar B, Patel M, et al. American Brachytherapy Society consensus guidelines for thoracic brachytherapy for lung cancer. Brachytherapy 2016;15:1e11.
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[13] Akoglu S, Ucan E, Celik G, et al. Endobronchial metastasis from extrathoracic malignancies. Clin Exp Metastasis 2005;22: 587e591. [14] Nair S, Kumar P, Ladas G. Intratracheal metastasis secondary to soft tissue liposarcoma. Singapore Med J 2007;48:81e83. [15] Teo YK, Kor AC. ‘‘Black bronchoscopy’’dA case of endobronchial metastasis from melanoma. J Bronchol Intervent Pulmonol 2010;17: 146e148. [16] Kiryu T, Hoshi H, Matsui E, et al. Endotracheal/endobronchial metastasis: Clinicopathologic study with special reference to developmental modes. Chest 2001;3:768e775. [17] Lee Y, Wong C, Jeffrey G. Endobronchial metastasis from rectal adenocarcinoma. Respir Med 1997;91:245e248. [18] Fournel C, Bertoletti L, Nguyen B, et al. Endobronchial metastasis from colorectal cancers: Natural history and role of interventional bronchoscopy. Respiration 2009;77:63e69. [19] Capaccio P, Peri A, Fociani P, et al. Flexible argon plasma coagulation treatment of obstructive tracheal metastatic melanoma. Am J Otolaryngol 2002;23:253e255. [20] Heyman BM, Chung MM, Shofer S, et al. Endobronchial metastasis from primary anorectal melanoma. Am J Case Rep 2013;14:253e 257. [21] Katsimbri P, Bamias A, Froudarakis M, et al. Endobronchial metastasis secondary to solid tumors: Report of 8 cases and review of the literature. Lung Cancer 2000;28:163e170. [22] Magro CM, Abbas AE, Ross P Jr. The application of photodynamic therapy in the treatment of metastatic endobronchial disease. Lasers Surg Med 2006;38:376e383. [23] Langendijk J, Tjwa M, de Jong J, et al. Massive hemoptysis after radiotherapy in inoperable non-small cell lung carcinoma: Is endobronchial brachytherapy really a risk factor? Radiother Oncol 1998;49:175e183. [24] Stranzl H, Gabor S, Mayer R, et al. Fractionated intraluminal HDR Ir192 brachytherapy as palliative treatment in patients with endobronchial metastases from non-bronchogenic primaries. Strahlenther Onkol 2002;178:442e445. [25] Dagnault A, Ebacher A, Vigneault E, et al. Retrospective study of 81 patients treated with brachytherapy for endobronchial primary tumor or metastasis. Brachytherapy 2010;9:243e247. [26] Pisch J, Villamena PC, Harvey JC, et al. High dose-rate endobronchial irradiation in malignant airway obstruction. Chest 1993;104: 721e725. [27] Bar-Gil Shitrit A, Shitrit D, Bakal I, et al. Endobronchial metastasis from colon cancer without liver metastasis: Report of 8 cases. Dis Colon Rectum 2007;50:1087e1089. [28] Solomonov A, Rosenblatt E, Ben-Izhak O, et al. High-dose-rate endobronchial brachytherapy in endobronchial metastatic malignant chondroid syringoma. Respiration 2001;68:406e410. [29] Escobar-Sacristan JA, Granda-Orive JI, Gutierrez Jimenez T, et al. Endobronchial brachytherapy in the treatment of malignant lung tumors. Eur Respir J 2004;24:348e352. [30] Hennequin C, Tredaniel J, Chevret S, et al. Predictive factors for late toxicity after endobronchial brachytherapy: a multivariate analysis. Int J Radiat Oncol Biol Phys 1998;42:21e27. [31] Murakami N, Kabayashi K, Nakamura S. A total EQD2 greater than 85Gy for trachea and main bronchus D2cc being associated with severe late complications after definitive endobronchial brachytherapy. J Contemp Brachytherapy 2015;7:363e368.
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Endobronchial brachytherapy for metastasis from extrapulmonary malignancies as an effective treatment for palliation of symptoms E. Donovan1,*, E. Timotin1, T. Farrell1, B. Donde2, S. Puksa3, R. Sur1 1 Department of Radiation Oncology, McMaster University, Hamilton, Ontario, Canada Division of Oncology, Department of Radiation Oncology, Sandton Oncology Centre, Johannesburg, South Africa 3 Division of Respirology, Department of Internal Medicine, McMaster University, Hamilton, Ontario, Canada
2
ABSTRACT
PURPOSE: Endobronchial metastasis (EBM) originating from primary cancers outside the lung is rare. External beam radiotherapy is often attempted for control of symptoms with variable effectiveness and retreatment is challenging if symptoms recur. There is limited documentation of highdose-rate brachytherapy for EBM in the literature. METHODS AND MATERIALS: A prospective database was created from 2006 to 2015. Patients with EBM who received high-dose-rate brachytherapy were included. Cough, dyspnea, chest pain, and hemoptysis were assessed and graded (0-4) at the time of initial consult and in followup. Symptom-free survival and re-expansion were assessed. RESULTS: Thirty-five patients with EBM were identified. Most patients received three fractions of 700 cGy, and 17 patients had prior external beam radiotherapy. Median symptom-free and overall survival were 67 and 117 days. After brachytherapy, improvement in cough was documented in 75.0%, hemoptysis in 76.4%, dyspnea in 60.0% for a median of 3-6 months. Of the 22 patients who had subsequent chest imaging, re-expansion was documented in 32%. There were no significant toxicities reported. CONCLUSIONS: Brachytherapy appears effective in achieving durable symptom control of cough hemoptysis, and dyspnea in patients with EBM and should be considered routinely for palliation where available. Further studies are required to better characterize expected symptom improvement, lung re-expansion rates, and efficacy in comparison with other local treatments. Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Endobronchial metastasis; Brachytherapy; Hemoptysis; Dyspnea; Palliation
Background The lung is a common site of metastasis for extrapulmonary malignancies. Metastatic lesions are generally located in the lung parenchyma, and metastasis to the tracheobronchial tree is rare. The most common primary sites for endobronchial metastasis (EBM) include colon, breast, and renal cell carcinomas (1), and the most
Received 20 September 2016; received in revised form 20 December 2016; accepted 9 January 2017. No conflicts of interest to disclose, no copyrights to disclose, and no patient photo use. This study has been approved by the Hamilton Integrated Research Ethics Board. * Corresponding author. Department of Radiation Oncology, McMaster University, 699 Concession Street, 3rd Floor Room 3-226, Hamilton, Ontario, Canada L8V5C2. Tel.: 905-387-9495x64791; fax: 905-575-6350. E-mail address: [email protected] (E. Donovan).
commonly reported symptoms are cough, dyspnea, and hemoptysis (2). Endobronchial brachytherapy has demonstrated utility in patients with localized symptomatic disease in the bronchus (3, 4), including those who otherwise may not be candidates for systemic therapy or external beam radiotherapy (EBRT) because of previous treatment or comorbidities. A recent Cochrane review (5) suggests that palliative EBRT most effectively improves symptoms in advanced lung cancer patients in comparison to endobronchial brachytherapy. This review focuses on patients with primary lung cancers, however, which have potentially different histologies and natural histories than EBM, and may respond differently to treatments, warranting further investigation of management. Furthermore, 28% of the patients in the EBRT arm of one trial discussed in this review still required subsequent intraluminal brachytherapy for recurrent symptoms (6). In patients with a history of EBRT, limitations also
1538-4721/$ - see front matter Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2017.01.003
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exist to lung re-irradiation, given concerns of provoking side effects of esophagitis and pneumonitis (7). Brachytherapy has the potential to safely deliver ablative doses of radiotherapy directly to endoluminal tumors via bronchoscopically placed catheters, while avoiding high doses to the surrounding structures. It has been used successfully to treat endobronchial disease in primary lung cancer with a 70% symptom response rate (3) and documented improvement in quality of life (8e10). Treatment of metastasis from extrapulmonary malignancies, on the other hand, has been reported in only a few studies. A review of published EBM cases suggests that only 7.2% of patients received intraluminal brachytherapy (2). We report a prospectively followed cohort of patients with EBM treated with high-dose-rate (HDR) brachytherapy at our center for palliative relief of symptoms.
Methods Since 2006, patients with intraluminal disease in the tracheobronchial tree determined on bronchoscopy and/ or imaging with symptoms of obstruction have been considered candidates for treatment at the Juravinski Cancer Centre HDR brachytherapy program. Patient and treatment data in those treated with intraluminal brachytherapy to the lung were recorded in a prospective database. This database was approved by the Hamilton Integrated Research Ethics Board. To be deemed an eligible for brachytherapy, patients must have radiographic proof of disease within the bronchial lumen (on CT); symptoms of cough, hemoptysis, dyspnea, or pain; and visible disease in the lumen of the main stem, lobar, or segmental bronchi at bronchoscopy before treatment. At the Juravinski Cancer Centre, in an attempt to minimize the volume of normal lung treated, any patient with radiographic and/or bronchoscopic evidence of intraluminal disease, who is deemed eligible by a respirologist to tolerate the procedure, is generally considered for brachytherapy upfront with EBRT reserved for recurrent symptoms. Patients are considered candidates regardless of tumor size, performance status, extent of pulmonary disease or systemic metastasis, and prior systemic therapy. Patients with no radiographic disease obstructing the bronchi and/or no luminal disease on endoscopy are deemed ineligible for brachytherapy. Patients were scored using a modified version of the European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-13 scale (11) with one question asked regarding each domain of dyspnea with exertion (Question 34), hemoptysis (Question 32), cough (Question 31), and chest pain (Question 40) at the time of initial consult and at followup. An additional grade of severe was added to the
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scale so that the final scoring system ranged from 0 to 4 (absent [0], mild [1], moderate [2], significant [3], and severe [4]). A prospective database of patients with primary or metastatic lung disease was developed with the institutional review board’s approval from 2006 to 2015 including demographic, symptom, treatment, and outcome information. Patients with EBM from any primary site outside the lung who received one or more brachytherapy treatments were included in the analysis. Some patients who had received prior EBRT were also treated with brachytherapy for recurrent symptoms and were included in the analysis. All patients had EBM from a biopsy-proven extrapulmonary primary cancer site. For treatment delivery, patients were premedicated with topical xylocaine 1% and sedated with intravenous fentanyl and midazolam. A respirologist visualized the tumor using flexible fiberoptic bronchoscopy. Treatment catheters were inserted under endoscopic vision with fluoroscopic guidance by the respirologist and radiation oncologist. The methodology of implantation has been described elsewhere in previous publications from the department (3). Patient vital signs were monitored continuously during treatment. Treatments were repeated one to three additional times typically at 2e3-week intervals. Typically, a dose of 7 Gy (range, 5e8 Gy) was prescribed to 0.5 cm or 1.0 cm from the source axis depending on how proximal the lesion was to the central bronchi. This dose was selected based on the American Brachytherapy Society guidelines for lung brachytherapy (12), which suggest that patients receive 14.2e20 Gy in two fractions or 22.5 Gy in three fractions. The guideline also suggests that CT-based planning should be used; however, all our patients were treated before 2015 when the guideline was created. Patients were asked about symptoms, and scores were recorded monthly until 3 months and then followed every 3 months until discharge or death. Date of death was recorded from the chart if available, and otherwise, last seen date was considered date of death for survival calculations. Symptom-free survival (SFS) was determined using duration of at least one scale point of response in those with initial symptoms. KaplaneMeier curves were used to estimate SFS and overall survival (OS). Imaging was not routinely completed to assess re-expansion; however, charts were reviewed for incidental chest x-ray or chest CT scan reports. Re-expansion was documented as yes or no in those patients with incidental imaging, based on explicit statements of re-expansion from the reporting radiologist. Any magnitude of improvement in lung expansion was recorded as yes, and no comment of reexpansion was recorded as no. Assessment of tumor response on repeat bronchoscopy was not routinely or objectively documented and therefore has not been included in our study results.
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Thirty-five patients with EBM from extrapulmonary malignancies were identified, the most common sites being colorectal and breast cancers. Other common sites included melanoma, sarcoma, lymphoma, renal cell cancer, and esophageal cancer. Most patients were of Eastern Cooperative Oncology Group 1 performance status with at least one major comorbidity, including Type II diabetes mellitus, cardiovascular disease, or pulmonary disease. Patient demographic and disease characteristics are shown in Table 1. Most patients received three HDR brachytherapy fractions of 700 cGy. Treatment characteristics and tumor location (including main stem bronchus, secondary bronchi, and tertiary bronchi) are documented in Table 2. Median time to brachytherapy after diagnosis of metastasis was 2 months (range, 0e174). Median followup was 4.5 months. Baseline symptoms were reported in all patients: cough in 80%, hemoptysis in 48.87%, dyspnea in 85.70%, and pain in 70%. Improvement by at least one point was documented in cough (75%), hemoptysis (76.40%), and pain (25.71%) for a median duration of 3 months and dyspnea (60%) for a median of 6 months. Baseline symptom scores and change in scores over time are reported in Table 3. Absent to mild (0 or 1) scores were maintained in a proportion of patients initially reporting cough (22.85%), hemoptysis (48.57%), dyspnea (17.14%), and pain (62.85%) for a median of 2e4 months. Two patients experienced worsening shortness of breath Table 1 Patient demographics and disease characteristics
Patient demographics Major comorbidities (diabetes, cardiovascular disease, or pulmonary disease) No major comorbidities Smoking history No smoking history Gender M F ECOG 0 1 2 3 4 Primary disease site Colorectal Breast Esophagus Sarcoma Lymphoma/myeloma Melanoma Renal Head and neck Cervix/testicle Hepatobiliary
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Table 2 Treatment characteristics
Results
Patient characteristics
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n (%) 21 (60) 14 (40) 10 (28.57) 25 (71.42) 19 (54.28) 16 (45.71) 2 19 6 6 2
(5.71) (54.28) (17.14) (17.14) (5.71)
9 5 3 3 3 3 3 2 2 2
(25.71) (14.28) (8.57) (8.57) (8.57) (8.57) (8.57) (5.71) (5.71) (5.71)
M 5 male; F 5 female; ECOG 5 Eastern Cooperative Oncology Group.
Treatment
n (%)
Median dose per fraction (Gy) Total no. of HDR treatments 1 2 3 Additional HDR O 3 mo after first fraction No EBRT EBRT Median dose EBRT given before brachytherapy EBRT given after brachytherapy Concurrent Number of catheters used 1 2 3 Location treated Main stem bronchus (right or left) Lobar bronchi Segmental bronchi
7 (range, 5e8) 7 (20) 10 (28.57) 18 (51.43) 3 (8.57) 13 (37.14) 22 (62.86) 3000 (range, 600e6000) 17 (48.57) 3 (8.57) 2 (5.71) 23 (67.6) 10 (29.5) 1 (2.9) 7 (4.8) 23 (54.6) 12 (28.6)
HDR 5 high dose rate; EBRT 5 external beam radiotherapy.
after brachytherapy, whereas no patients reported worsening pain, hemoptysis, or cough after treatment. Median SFS was 67 days for all symptoms. Median OS was 112 days (range, 5e1001) (Fig. 1). Seventeen patients received EBRT to the lung before brachytherapy and presented with recurrent symptoms. Of these patients, 73.33% experienced relief of cough, 70% in hemoptysis, 57.14% in dyspnea, and 50% in pain after brachytherapy. Most of these patients experienced a onepoint improvement in symptoms, 3 patients had a two-point improvement in cough, and 2 patients had a two-point improvement in pain. In those with a response, the median improvement in cough score was 2 months (range, 1e9); in hemoptysis, the score was 7.5 months (range, 3e12); and in dyspnea, the score was 9 months (range, 2e12). There were no significant differences in SFS achieved with brachytherapy in domains of cough ( p 5 0.46), pain ( p 5 0.92), hemoptysis ( p 5 0.47), or dyspnea ( p 5 0.47), between patients who had received prior EBRT vs. those who did not (Fig. 2). Repeat imaging of the chest was not routinely completed; however, patients’ charts were reviewed for incidental subsequent images of the chest including CT scans or chest x-rays. Of the 22 patients who had subsequent chest imaging, re-expansion was documented in 7 patients (32%). No Grade 3 or 4 toxicities were reported. No adverse events occurred during the procedures (e.g., massive hemoptysis or desaturation requiring posttreatment ventilation).
Discussion The lung parenchyma is a common site of metastasis for many extrapulmonary malignancies, yet involvement of the
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Table 3 Baseline symptom scores and change in symptom scores
Symptom Cough
Hemoptysis
Dyspnea
Pain
Baseline score
No. of patients per severity score
0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4
7 13 6 5 4 18 7 5 3 2 5 7 12 9 2 21 7 6 1 0
Any improvement, n (%)
Improved two points, n (%)
Improved three points, n (%)
Maintained score of 0e1, X (%)
Median numerical score improvement (range)
Median duration, mo (range)
21/28 (75)
8/28 (28.57)
2/28 (7.14)
8 (median, 2 mo)
1 (1e3)
3 (1e15)
13/17 (76.47)
6/17 (35.29)
2/17 (11.76)
17 (median, 3 mo)
1 (1e2)
3 (1e8)
18/30 (60)
9/30 (30)
0/30 (0)
6 (median, 4 mo)
1 (1e3)
6 (1e18)
1/9 (11)
0/35 (0)
22 (median, 4 mo)
1 (1)
3 (1e18)
9/35 (25.71)
tracheobronchial tree is relatively rare. Although the range of primary sites observed in our study was wide, the most commonly reported sites were breast and colorectal, a finding consistent with reported cases in the literature (1). Median time to development of EBM after primary diagnosis ranges widely from 18 to 50 months in the literature (13e15). Patients most commonly presented with dyspnea (up to 80%), cough (up to 66%), hemoptysis (up to 33%) (13), as well as pain and sputum production (8). Radiographic findings include atelectasis distal to obstructed bronchi with hilar or mediastinal lymphadenopathy (16). Radiotherapy for palliation of primary lung cancers has been described in depth (6); however, EBM represents a heterogenous group of tumors with different histologies and radiotherapy sensitivities, which may respond differently to treatments. Treatment approach for EBM generally depends on primary etiology, systemic disease extent, acuity of symptoms, and extent and duration of distal lung collapse (14). Systemic therapy plays a primary role in many cases (1, 17); however, patient comorbidities or poor performance status may be a limiting factor. In other cases, patients may have only isolated EBM without high burden of systemic disease, and systemic therapy may not be warranted. In either case, local symptom relief is of prime importance. Many of the most common sites for EBM, including renal cell, breast, and colon cancers have prolonged disease courses even with a diagnosis of metastatic disease. These patients may therefore benefit from long-term control of symptoms using a method, which confers minimal toxicity (16).
In our study, patients were deemed candidates for brachytherapy if they presented with intraluminal disease, which could be visualized on bronchoscopy. At our center, brachytherapy is used routinely to deliver high doses of radiotherapy to tumors inside the bronchial lumen without delivering high radiotherapy doses to the surrounding lung and mediastinum. It has been used successfully in the treatment of primary lung cancers as reported in another series by Goldberg et al. (3). As indicated by our results, brachytherapy may also relieve symptoms successfully in EBM patients. Several patients were referred either internally or from different centers after developing recurrent symptoms of hemoptysis, cough, or shortness of breath after treatment with EBRT. There is some experience reported using endoscopic techniques for local relief of symptoms. A French study reports on 42 patients treated with mechanical resection (69% complete), and additional cryotherapy in 16.7%, silicon stent insertion in 9.5%, and neodymium-doped yttrium aluminum garnet laser in 11.9% in whom bleeding developed. Symptom relief within 24 h was demonstrated in 7 of 16 patients reporting dyspnea, in 9 of 16 reporting cough, and only 1 of 5 reporting hemoptysis; however, overall clinical improvement was documented in 72% of patients. Forced expiratory volume in 1 s was also measured and improved by a mean of 34%. Ten patients required additional intervention at 6 months (18). The use of endoscopic argon plasma coagulation has also been reported in cases of metastatic melanoma (19, 20). Many EBM case series have included a variety of treatment modalities and few patients. Turkish series (N 5 15)
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1,0
0,8
0,8
0,6
0,4
0,2
0,0
5 Hematemesis Free Survival Complete Censored
1,0
Cumulative Proportion Surviving
Cumulative Proportion Surviving
Complete Censored Cough Free Survival
-
0,6
0,4
0,2
0
100
200
0,0
300
0
100
Days
0,8
0,8 Cumulative Proportion Surviving
Cumulative Proportion Surviving
1,0
0,6
0,4
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0,4
0,2
0,2
0
50
100
150
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250
0,0
300
0
50
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300
200
250
300
Overall Survival Complete Censored
Symptom Free Survival Complete Censored 1,0
1,0
0,8
0,8 Cumulative Proportion Surviving
Cumulative Proportion Surviving
150 Days
Days
0,6
0,4
0,2
0,0
300
Pain Free Survival Complete Censored
Dyspnea Free Survival Complete Censored 1,0
0,0
200 Days
0,6
0,4
0,2
0
50
100
150
200
250
Days
300
0,0
0
50
100
150 Days
Fig. 1. Symptom-free survival in days for individual symptom scores and overall. (Top left) Cough-free survival. (Top right) Hemoptysis-free survival. (Middle left) Dyspnea-free survival. (Middle right) Pain-free survival. (Bottom left) Overall symptom-free survival. (Bottom right) Overall survival.
reported on EBM patients treated with chemotherapy (n 5 8), EBRT (n 5 1), combination chemoradiotherapy (n 5 3), or supportive care (n 5 3); however, symptom relief was not reported per modality (13). Another series reports on six of eight cases treated with systemic therapy, which had little effect on EBM, even with radiologic
response in parenchymal pulmonary nodules in two cases (21). Photodynamic therapy was reported to improve symptoms in 9 patients in one series, with severe complications occurring in only 1 patient (22). Although palliative EBRT has been used effectively as a local therapy, durability and effectiveness is variable.
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Overall Surival by External Beam before Brachytherapy (group1) or after Brachytherapy (group2) Complete Censored 1,0
Cumulative Proportion Surviving
0,8
0,6
0,4
0,2
0,0
20
40
60
80 100 120 140 160 180 200 220 240 260 280 300 Days
Group 0, Group 1,
Fig. 2. Overall survival for patients who received external beam radiotherapy either before or after brachytherapy.
Symptom relief has been reported in patients treated with EBRT for EBM (21) for a few months; however, additional treatment may be required to the irradiated lung parenchyma and airways if symptoms recur or disease progresses. Radiotherapy doses and dose per fraction are limited by the tolerance of surrounding normal tissues, including the lung, great vessels, heart, tracheobronchial tree, and esophagus to EBRT. Most reports of thoracic reirradiation focus on patients with primary lung cancer, who may have initially received radical doses of radiotherapy to the lung. One study reports pneumonitis rates of 12% and esophagitis rates of 17% in patients receiving thoracic reirradiation (7). Nevertheless, given the intent of treatment is for palliative symptom relief, physicians may be hesitant to prescribe additional radiotherapy to patients at the risk of precipitation of adverse side effects. Brachytherapy has the potential to deliver highly localized treatment with minimal side effects and doses to adjacent organs (23). Intraluminal brachytherapy has been used successfully in primary and recurrent lung cancers to relieve symptoms. According to a review by Nguyen et al. (9), palliative relief of symptoms in primary lung cancer cases is achieved in 43e92% of cases, with studies reporting 70e100% relief of hemoptysis and 33e85% relief of dyspnea. Intraluminal brachytherapy has also been used to improve outcomes in primary lung cancers when used in combination with EBRT in randomized studies (9). Goldberg et al. (3) reported on a prospective cohort of
inoperable lung cancer patients treated with brachytherapy with or without EBRT and found no significant difference in duration of symptom relief for cough, hemoptysis, or dyspnea between groups. Based on previous experience using endoluminal brachytherapy for primary lung cancer reported at our center (3) and in the literature (9), it appears to be a safe and effective alternative to EBRT. There are very minimal reported adverse events or side effects, and in patients with no previous treatment, it reserves the opportunity for EBRT if required in the future. For these reasons, it is the practice at our center to first offer brachytherapy for palliative symptom relief of obstructing tumors in the bronchus and reserve EBRT for symptom recurrence. Patients are generally not excluded based on tumor size or systemic or pulmonary disease burden. There is minimal experience reported in the literature with endobronchial brachytherapy to treat metastatic disease. A review in 2004 found of 204 reported patients with EBM, only 7% of patients received brachytherapy (2). Table 3 summarizes treatment and outcome details of several publications of EBM patients treated with brachytherapy. Investigators in Austria reported on 11 patients treated with brachytherapy and found symptom relief in 73% of patients and a complete anatomic response in 20% at last followup (24). Another report of 22 EBM patients (81 total including primary lung cancers) treated with brachytherapy
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found no difference in local control (77% overall at 1 year) in those with EBM vs. primary disease; specifically, relief was reported in 85% with dyspnea, 77% with cough, and 100% with hemoptysis at presentation (25). The results with HDR brachytherapy were also durable, with 77% and 64% progression-free survival at 12 and 24 months, respectively (22). One of the largest experiences of brachytherapy for EBM (N 5 37) found symptom resolution in both shortterm and long-term survivors, in 67% of patients with hemoptysis, 42% of patients with dyspnea, and 50% of patients with cough. Patients received a single dose of 15 Gy in 29 of 37 cases and in comparison to our regimen of 700 cGy for two to three fractions. These large fraction sizes appeared to be safe with no adverse events; however, duration of symptom relief, description of symptom assessment tools, and baseline symptom scores as well as magnitude of symptom relief were not reported (4). There were also no reports of re-expansion in this study (Table 4). Investigators in Brazil reported 13 EBM patients of 78 overall treated with intraluminal brachytherapy with a dose of 750 cGy in three fractions, a similar regimen to that used in our study. Response rates included 100%, 33.9%, and 57.4% of those with hemoptysis, cough, and dyspnea, respectively, for all patients. There was also a 74.3% response rate in those examined radiographically or bronchoscopically (8). Another study used one or two large fractions of 10 Gy in 7 patients with EBM (39 total including primary lung cancer cases) and reported response rates of dyspnea in 80% and hemoptysis in 93%. Of 18 patients with repeat endoscopy, 78% demonstrated response (26). A case series reported on eight colon cancer cases with EBM treated with endoscopic laser resection, two with stent insertion, and three with brachytherapy. All patients attained improved symptoms; however, the extent and duration of relief was not compared between regimens (27). Brachytherapy has also been used effectively in cases with rare extrapulmonary primary sites, such as malignant chondroid syringoma with both endoscopic response and relief of dyspnea and cough (28). Brachytherapy ideally delivers radiation dose to a highly localized area around the tumor and only minimal amounts to normal tissues (4, 26). Toxicity is rare and may include early bronchitis, bronchospasm, or pneumonitis (29). Stranzl et al. (24) reported that 3 of 11 patients developed asymptomatic radiation bronchitis, which is thought to be related to dose and volume treatment (30). Stricture, hemoptysis, and fistula are late complications that have been reported in rare cases of brachytherapy for EBM (4, 8, 23, 26). One study reported a 7.4% incidence of massive hemoptysis; however, all but one case was in fact because of progressive disease rather than treatment toxicity (30). The complication risk is thought
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to be higher using larger fraction sizes and large target volumes beyond the bronchial wall (9). Using multiple fractionated treatments (e.g., 14 Gy in two to three fractions) and confining the prescription point to 1 cm or 0.5 cm from the center of source axis depending on location in the bronchi, as is the protocol at our center, minimizes the risk of these late toxicities. It has also been suggested that the total dose, or maximum point dose, to the tracheal or bronchial wall (85 Gy to more than 2 cc volume suggested by one study), influences late respiratory complications (31). There were no reports of significant early or late toxicity in our cohort. Studies have generally reported lung re-expansion in the range of 20e46% (6, 26) after endobronchial brachytherapy treatments, consistent with our result of 23%. Reexpansion rates were difficult to determine in our study however, as patients primarily had repeat imaging or bronchoscopy only if symptomatic. We therefore may have underestimated the percentage of responders. Determining re-expansion rates and extent in collapsed lung tissue in future studies may be useful in predicting which patients may benefit the most from brachytherapy treatments. Unfortunately, although repeat bronchoscopy and documentation of response was not routinely completed in our study, this may also be a valuable method of response assessment in future studies. Reimaging of the lungs with chest x-ray or CT scan may be a safer alternative to characterize re-expansion, however, is less sensitive (25). Duration of symptom relief is also not well documented in the literature. Our study reports an SFS of 67 days considering relief of cough, hemoptysis, dyspnea, and pain. Median OS was 112 days, suggesting that symptom control was achieved for a clinically significant period in these patients. Improvement by two scores in cough, dyspnea, and hemoptysis was seen in approximately 30% of the patients. Many of the patients in our study had been previously treated with EBRT (48.57%) and developed recurrent symptoms. Symptom relief was reported in all categories, particularly cough and hemoptysis. There was also no significant difference in the duration of response in patients who had received previous EBRT. This suggests that brachytherapy is an effective alternative for patients with recurrent or refractory symptoms after EBRT or patients who are radiotherapy naive in the lung. Further research will be fundamental in identifying those patients who will obtain symptomatic relief from brachytherapy and provide guidelines in the safe incorporation of brachytherapy into single- or multimodality regimens. Furthermore, assessment of early vs. late intervention with brachytherapy may delineate appropriate timing to pursue this treatment. Despite limited experience, ours and other studies have shown that this treatment is safe and effective in palliative symptom relief and should be considered more readily in patients with EBM.
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Table 4 Reported HDR brachytherapy experience for EBM
Study
Patients with EBR (n) 37 EBM
Solomonov et al., 2001 (28) Case report Stranzl et al., 2002 (24)
1 EBM
11 EBM
16/8, 50% 15 Gy 1 HDR brachytherapy (10, 20, or multiple 10e15 Gy); EBRT (in 10.8%); and chemotherapy (in 24.3%) 7 Gy 3 HDR brachytherapy; 1/1, 100% EBRT; and chemotherapy 5e6 Gy 3e4 HDR brachytherapy
Sorensen, 2004 (2) 204 EBM
24/10, 42%
Not described
NR
Median, 280 d
NR
1/1, 100%
NR
1/1 bronchoscopy þ radiographic
NR
NR, 11/8, and 73% overall symptom 61/NR
Subjective assessment
11/8, 73%, and endoscopic response NR
15 mo followup
24/23, 95.8%
24/18, 75%
NR, 100%, NR, 100%, symptom relief symptom relief
NR
Median, 15.2 mo
Reported as partial or complete resolution NR
81/79, 97.5% bronchoscopy NR
50% OS at 2 y
81/42 51.8% significant response on bronchoscopy 14/33 and 13.86% radiographic 18/14 78%, endoscopic response
Median, 14.7 mo
23/23, 100%
53/45, 85%
From 2005 EORTC lung questionnaire, prior not described
80%
13/14, 93%
NR
Subjectivedexcellent, good, or no response
28/21, 75%
17/13, 76.47%
30/18, 60%
Five-point scale, 4 22/7, 32% re-expansion Median, 112 d domains from modified of lung on CT or CXR EORTC-QLQ-13
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35 EBM
OS
18/12, 67%
(2017)
Present study, Donovan, 2016
10 Gy 1 or 2; HDR brachytherapy; EBRT (in 71.4%); and chemotherapy (in 28.6%) 7 Gy 2e3 majority (patients received 1e4) and prior EBRT in 17
Bronchial obstruction examined/improved
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7 EBM/39 total
Measurement reported
NR, 11/8, and NR, 11/8, and 73% overall 73% overall symptom symptom 80/NR 61/NR
Brachytherapy 13 (in 7%); EBRT (in 19.6%); chemotherapy (in 23%); and surgery (in 19.6%) Escobar-Sacristan 5 EBM/81 5 Gy 4 HDR brachytherapy; 34/30, 88.2% et al., 2004 (29) total EBRT; chemotherapy; and surgery (81.5%) Bar-Gil Shitrit 8 EBM 3/8 laser þ HDR brachytherapy; NR, 100%, symptom et al., 2007 (27) 5/8 laser alone or laser þ stent; and chemotherapy (in 100%) relief Dagnault et al., N 5 22/81 EBM 5 Gy 4 HDR brachytherapy; 43/33, 77% 2010 (25) EBRT (in 44%); and chemotherapy (in 41%)
Pisch, 2011
Dyspnea, N 5 reporting/ improved
E. Donovan et al. / Brachytherapy
Quantrill et al., 2000 (4)
Treatment
Cough, Hemoptysis, N 5 reporting/ N 5 reporting/ improved improved
Median, 6.3 mo
HDR 5 high dose rate; EBM 5 endobronchial metastasis; OS 5 overall survival; EBRT 5 external beam radiotherapy; NR 5 not reported; EORTC QLQ-13 5 European Organization of Research and Treatment of Cancer Quality of Life Questionnaire 13; CXR 5 chest x-ray.
E. Donovan et al. / Brachytherapy
Conclusion Brachytherapy appears effective in achieving durable symptom control of cough, hemoptysis, and dyspnea in patients with metastatic disease located in the bronchus. It can be used in combination with or as an alternative to EBRT and should be considered routinely where available in this patient population. Further studies are required to better characterize expected symptom improvement and lung reexpansion rates.
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