- Email: [email protected]
Long-Term Results of Conformal Radiotherapy for Progressive Airway Amyloidosis
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Thoracic Cancer
Long-Term Results of Conformal Radiotherapy for Progressive Airway Amyloidosis Minh Tam Truong, M.D.,* Lisa A. Kachnic, M.D.,* Gregory A. Grillone, M.D.,y Harry K. Bohrs, B.S.,* Richard Lee, M.D.,* Osamu Sakai, M.D., Ph.D.,z and John L. Berk, M.D.x Departments of *Radiation Oncology, yOtolaryngology, zRadiology, and xMedicine, Amyloid Treatment and Research Program, Boston University School of Medicine, Boston Medical Center, Boston, MA Received May 9, 2011, and in revised form Jul 26, 2011. Accepted for publication Jul 28, 2011
Summary Ten patients with symptomatic airway amyloidosis were followed for a median of nearly 7 years after 20 Gy external beam radiotherapy. RT appeared effective in controlling progressive airway amyloidosis of the larynx and tracheobronchial tree in 8 of 10 patients by stabilizing amyloid deposits and improving pulmonary function. It did so with no obvious late morbidity.
Purpose: To evaluate the efficacy of conformal external beam radiotherapy (RT) for local control of progressive airway amyloidosis. Methods and Materials: We conducted a retrospective review of patients with biopsy-proven progressive airway amyloidosis treated with conformal RT between 2000 and 2006 at Boston Medical Center. The patients were evaluated for performance status and pulmonary function, with computed tomography and endoscopy after RT compared with the pretreatment studies. Local control was defined as the lack of progression of airway wall thickening on computed tomography imaging and stable endobronchial deposits by endoscopy. Results: A total of 10 symptomatic airway amyloidosis patients (3 laryngeal and 7 tracheobronchial) received RT to a median total dose of 20 Gy in 10 fractions within 2 weeks. At a median follow-up of 6.7 years (range, 1.5e10.3), 8 of the 10 patients had local control. The remaining 2 patients underwent repeat RT 6 and 8.4 months after initial RT, 1 for persistent bronchial obstruction and 1 for progression of subglottic amyloid disease with subsequent disease control. The Eastern Cooperative Oncology Group performance status improved at a median of 18 months after RT compared with the baseline values, from a median score of 2 to a median of 1 (p Z .035). Airflow (forced expiratory volume in 1 second) measurements increased compared with the baseline values at each follow-up evaluation, reaching a 10.7% increase (p Z .087) at the last testing (median duration, 64.8 months). Acute toxicity was limited to Grade 1-2 esophagitis, occurring in 40% of patients. No late toxicity was observed. Conclusions: RT prevented progressive amyloid deposition in 8 of 10 patients, resulting in a marginally increased forced expiratory volume in 1 second, and improved functional capacity, without late morbidity. Ó 2012 Elsevier Inc. Keywords: Tracheobronchial Radiotherapy
Reprint requests to: Minh Tam Truong, M.D., Department of Radiation Oncology, Boston Medical Center, Moakley Lower Level 830 Harrison Avenue, Boston, MA 02118. Tel: (617) 638-7070; Fax: (617) 638-7037; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 83, No. 2, pp. 734e739, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2011.07.036
amyloidosis,
Airway
amyloid,
Laryngeal
amyloidosis,
Presented in part at the 49th Annual Meeting of the American Society for Radiation Oncology, October 28, 2007 to November 1, 2007, Los Angeles, CA. Conflict of interest: none.
Volume 83 Number 2 2012
Introduction Amyloidoses are characterized by the extracellular deposition of insoluble fibrillar proteins in tissues and organs. Amyloid deposition in the laryngeal and tracheobronchial airways is rare and constitutes approximately 1% of benign tumors in these areas. Small populations of clonal plasma cells located outside the airway are thought to be the source of local light chain immunoglobulin amyloid formation. Laryngeal and tracheobronchial amyloid lesions can progress, leading to airway obstruction. Surgical debulking can relieve the airway obstruction caused by amyloid deposits but does not prevent recurrence (1). Low-dose radiation induces plasma cell apoptosis in other plasma cell dyscrasias and lymphoproliferative disorders, such as multiple myeloma and lymphoma (2, 3). We, therefore, hypothesized that radiotherapy (RT) could eliminate the amyloidogenic plasma cells, thereby arresting amyloid production and preventing disease progression or lesion recurrence. Patients with tracheobronchial amyloidosis constitute approximately 11 of 1,000 referrals to the Amyloid Treatment and Research Program at Boston University School of Medicine, Boston Medical Center (1). We report the Boston Medical Center experience using low-dose external beam, three-dimensional conformal RT as localized treatment of progressive obstructive airway amyloidosis in our initial cohort of patients.
Methods and Materials Study cohort The institutional review board at Boston Medical Center approved the study as a retrospective review with a waiver of informed consent. The study followed the National Institutes of Health Insurance Portability and Accountability Act guidelines. Between 2000 and 2006, 10 consecutive patients with biopsy-proven progressive airway amyloidosis received RT. These patients were initially evaluated at the Amyloid Airway Clinic at Boston Medical Center. The histologic diagnosis of amyloidosis was established by the appearance of birefringence under polarized light after Congo Red staining. All available pathology slides were reviewed at our institution, and the diagnosis was confirmed before treatment. Each patient underwent a multidisciplinary evaluation at the Amyloid Airway Clinic with a pulmonologist, radiation oncologist, and otolaryngologist. The indications for RT as a part of airway amyloidosis management included amyloid recurrence after surgical excision and progressive airway obstruction due to amyloid deposits. The pretreatment workup included airway endoscopy, pulmonary function tests, and computed tomography (CT) imaging of the involved airways.
RT planning and delivery Patients with laryngeal amyloidosis were immobilized using a custom-made thermoplastic head mask; a custom vac loc bag was used for those with tracheobronchial amyloid. Thin-slice, high-resolution CT images were obtained with the patient in the treatment position. The gross tumor volume consisted of the extent of the amyloid deposits in the airway lining, defined by CT and direct airway endoscopic visualization. The clinical target volume included the amyloid deposits (gross tumor volume) with
Conformal RT for airway amyloidosis
735
a 10e15-mm margin to encompass the adjacent grossly uninvolved airway. A subsequent planning target volume incorporated a 5e10-mm margin beyond the clinical target volume to account for treatment setup accuracy. The adjacent critical structures, including the lung, esophagus, and spinal cord, were defined as the organs at risk.
Efficacy assessment After RT completion, the patients underwent physical examination, CT imaging, endoscopic surveys, and pulmonary function testing at 6e12-month intervals. Local control was defined as the lack of progression of existing amyloid depositions, stable airway wall thickening and lumen caliber, and the absence of new amyloid deposits identified on CT, bronchoscopy, and/or laryngoscopy within the radiation field. Local control was measured from the end of RT to the date of local relapse or the last follow-up visit. In-field progression was defined as the growth of amyloid deposits within the radiated field. Out-of-field progression was defined as newly occurring amyloid deposits or growth of previously identified disease in the untreated airways. Salvage therapy included subsequent surgery or RT performed after the initial RT to the treated lesion. The survival time was measured from the end of RT until death or the last follow-up examination.
Post-treatment surveillance The performance status, using the Eastern Cooperative Oncology Group criteria, was assessed before the start of RT and at each follow-up visit. We compared the pretreatment status and followup status at 12 months. Pulmonary function testing, including forced expiratory volume in 1 second (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO), was performed before and every 6e12 months after treatment completion.
Toxicity Toxicity was documented at each follow-up examination and was retrospectively scored using the Common Toxicity Criteria, version 3.0, of the U.S. National Institutes of Health (available from: http://ctep.cancer.gov/reporting/ctc.html).
Statistical analysis The paired Student t test (for the mean values) and Wilcoxon signed rank sum test (for the median values) were used to compare the pre- and post-treatment pulmonary function and performance status. A two-sided a-level of 0.05 was regarded as statistically significant. All analyses were conducted using the SAS software, version 9.1 (SAS Institute, Cary, NC).
Results Patient and treatment characteristics The median age at diagnosis was 39.5 years (range, 31.8e71.5). The median age at the start of RT was 40.6 years (range,
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Table 1 Pt. No. 1 2 3a 3b 4 5 6 7 8 9a 9b 10
Treatment characteristics Treatment site Right bronchus Larynx Right bronchus Right bronchus Bilateral tracheobronchial tree Bilateral tracheobronchial tree Left bronchus Bilateral tracheobronchial tree Larynx Larynx Larynx Right bronchus
Beam energy (photons) (MV) 18 4 18 18 18 18/6 18 18 4 6 6 18/6
Technique APePA Opposed lateral fields RAO/LPO LAO/RPO APePA APePA APePA APePA Opposed lateral fields Oblique lateral fields IMRT APePA
Field size (cm2) Total dose (Gy) 10 7 11 11 13.5 17 10 19 5 7.6 15.5 7
8 12 13.6 13.4 16 14 12 22 12 15 11 9
18 20 20 10 19.8 20 20 19.8 20 20 20 20
Abbreviations: Pt. No. Z patient number; MV Z megavoltage; APePA Z opposed anteroposterioreposteroanterior fields; RAO Z right anterior oblique fields; LPO Z left posterior oblique fields; RPO Z right posterior oblique fields; IMRT Z intensity-modulated radiotherapy. Patients 3 and 9 underwent repeat RT, with “a” and “b” representing first and second RT course.
32.4e72.6). The duration of symptoms before diagnosis was 1.34 years (range, 0.34e9.29). The disease sites included 3 patients with laryngeal amyloid and 7 with tracheobronchial amyloid. Of the 10 patients, 2 were men and 8 were women. The pretreatment symptoms included bronchitis in 40%, dyspnea in 90%, cough in 40%, hemoptysis in 30%, and hoarseness in 30%. Three patients underwent surgical debulking using carbon dioxide laser dissection before RT. One patient underwent three surgical procedures. Another patient underwent bronchodilation and stent placement, and one required emergency tracheostomy. The 10 patients underwent 3-dimensional conformal RT. Portal imaging or on-board imaging was used to verify the daily setup. The median prescribed dose to the clinical target volume was 20 Gy (range, 18e20) in 10 daily fractions, within a median of 13 days (range, 10e15). Megavoltage photons (4e18 MV) were used. The treatment characteristics and field design of each patient are listed in Table 1.
Efficacy
performance status at baseline and a median of 18 months after RT was 2 and 1, respectively (p Z .035).
Pulmonary function after RT Serial spirometry and gas diffusion measurements after RT were compared with the baseline values. At each point after RT, the FEV1 had increased. Specifically, the FEV1 at 6e12 months (median duration, 11.5), 12e24 months (median, 13.9), 24e36 months (median, 24.9), and the last follow-up examination (median, 58.1) had increased to 6.67% (p Z .239), 9.40% (p Z .054), 19.00% (p Z .092), and 10.67% (p Z .087), respectively (Figs. 1 and 2). The DLCO had decreased by a median 3.5% (p Z .540) at 6e12 months.
Failure patterns and salvage therapy Of the 10 patients, 2 underwent repeat RT; 1 for persistent bronchial obstruction at 6 months and 1 for in-field progression of
Radiotherapy to a median dose of 20 Gy produced local control of airway amyloid disease in 8 of the 10 treated patients at a median of 6.7 years of follow-up (range, 1.5e10.3). Of the 10 patients, 9 were alive at the last follow-up examination. One patient had died 7.4 years after RT of causes unrelated to amyloid disease.
Radiologic imaging and endoscopic changes after RT Endoscopic and CT evaluation of local control at 12 months of follow-up did not reveal changes in airway wall thickening or lumen caliber after treatment. The airway endoscopic assessment documented decreased mucosal edema and stable endobronchial pathologic findings without significant regression of the amyloid deposits at 6 and 12 months after RT. Progressive amyloid endobronchial growth was seen on endoscopy within the treatment field after RT in 1 (10%) of 10 patients at 8.4 months after RT.
Performance status The performance status after RT improved for the whole patient cohort. The median Eastern Cooperative Oncology Group
Fig. 1. Spirometry before and after radiotherapy (RT). Forced expiratory volume in 1 second (FEV1) was measured at four intervals after RT: 6e12, 12e24, and 24e36 months and a final examination (median, 5.4 years). Baseline and follow-up FEV1 mean data standard error of mean are presented.
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toxicities were noted, specifically; no patients developed secondary malignancies.
Discussion
Fig. 2. Spirometric changes after radiotherapy (RT). FEV1% change at 6e12, 12e24, and 24e36 months and final examination (median, 5.4 years) presented as mean data standard error of mean. amyloid deposits at 8.4 months after RT. The first patient had stable amyloid deposits after RT; however, recurrent right upper lobe infections due to bronchial stent obstruction of the right upper lobe bronchus prompted repeat RT to 10 Gy in five fractions 6 months after the initial 20-Gy RT course in an unsuccessful effort to induce amyloid regression. After stent removal, the patient’s exercise performance improved, permitting a return to full-time work. The same patient developed out-of-field progression of amyloidosis in the aerodigestive tract (nasopharynx and paranasal sinuses) at 80 months after RT. A second patient with circumferential laryngeal amyloid deposits developed hemoptysis from progressive amyloid disease within the RT field 8.4 months after RT. The patient underwent surgical carbon dioxide laser excision and repeat RT of the airway deposits with 20 Gy in 10 fractions with disease control at 22 months after RT. A third patient developed out-of-field progression of amyloid deposits in the contralateral bronchus at 22 months. The patterns of failure and subsequent salvage therapy are listed in Table 2.
Toxicity All patients tolerated treatment to completion without any break in radiation delivery. No acute or late Common Tissue Toxicity criteria, version 3, Grade 3e5 toxicities were observed. Four patients experienced Grade 1-2 esophagitis, and one developed community-acquired pneumonia at 2 months after RT. No late
Table 2
The present study has demonstrated that RT arrests the progression of laryngeal and tracheobronchial amyloidosis, permitting improvement in spirometry and performance status. Low-dose RT (20 Gy) achieved local disease control in 8 of 10 cases. Repeat RT alone or in combination with surgical management prevented amyloid progression in the remaining cases. The toxicities were limited to mild esophagitis in cases receiving full airway RT and small declines in DLCO, suggesting subclinical parenchymal lung injury. Multiple publications report the treatment of airway amyloid with low-dose RT; all except one were limited to 1 case experience (4e7). In the present study, serial FEV1 measurements documented little change at 6 or 12 months after RT, although continued improvement from 12e36 months after RT was observed. Airway remodeling, as reflected by the FEV1 and endoscopic disease burden, coincided with improved performance status. In contrast, Neben-Wittich et al. (8) reported a 7-case series from the Mayo Clinic, with a median 40-month follow-up, with evaluations limited to 12 months in >40% of the cases. The airway disease and FEV1 measurements were performed at 1e7 months after RT. Our 10-case series with 10 years of posttreatment observations and a median 6.7-year follow-up extends the Mayo Clinic experience. The amyloid deposits in patients with localized disease involving the airways, urinary tract, breast, eye, and skin are almost uniformly composed of misfolded immunoglobulin light chain proteins (9e17). Clonally expanded plasma cells residing in the affected organ are credited with the amyloid production (18). Low-dose RT induces plasma cell apoptosis in other plasma cell dyscrasias and lymphoproliferative disorders such as multiple myeloma and lymphoma (2, 3). We speculate that RT eliminates the amyloidogenic plasma cells residing within and immediately outside the affected airways, thereby arresting amyloid production and preventing disease progression or lesion recurrence. Radiation-related disruption of amyloid deposits, an alternative explanation, does not appear to occur (19). The radiation dose used to treat airway amyloid ranges from 20 to 45 Gy, although most patients received 20e24 Gy (5, 7, 8). Our experience, combined with the series from Neben-Wittich et al. (8), supports the use of 20e24 Gy to control airway amyloid deposits in most cases. Neuner et al. (4) used 45 Gy in 1.8 Gy daily fractions in 1 case of laryngeal amyloid, derived the dosing from data for solitary plasmacytoma treatment. The plasma
Patterns of failure and salvage treatment
Pt. No.
Failure site
In-field or out-of-field failure
3 9 10 3
Right bronchus Larynx Contralateral (left) bronchus Nasopharynx and paranasal sinuses
In-field In-field Out-of-field Out-of-field
Abbreviations as in Table 1. Patient numbers refer to corresponding patient in Table 1.
Salvage treatment
Interval to failure after initial RT (mo)
Repeat RT with 10 Gy and stent removal Surgical excision and repeat RT with 20 Gy Observation Staged surgical excisions
6 8.4 22 80
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cell burden of airway amyloidosis and solitary plasmacytomas varies dramatically. Solitary plasmacytomas constitute a radiologically visible target. In contrast, the clonal plasma cells are difficult to locate on exhaustive histologic examination of airway amyloid. Moreover, recent studies examining the dose response for plasmacytoma have not defined a benefit beyond 30 Gy (2). Additional studies are needed to determine whether a dose response relationship exists for 20e30 Gy RT for airway amyloidosis or whether dose reductions to <20 Gy can result in similar disease control. Studies using low-dose RT for lymphoproliferative diseases such as indolent lymphoma have shown local control using 4 Gy in two fractions, with complete response rates of 30e50% and overall response rates of 80e90% (20, 21). The total body irradiation experience (22, 23) has established that fractionated doses of 4e12 Gy are sufficient to induce pancytopenia before bone marrow transplantation. These data suggest that radiation dosing <20 Gy might be sufficient to control amyloidogenic plasma cells (24). The use of 20 Gy in 10 fractions in our series was determined from the reports by Kurrus et al. (7) and the Mayo Clinic (8) treating patients with tracheobronchial amyloidosis. We reirradiated 1 patient to 10 Gy in five fractions. It is unclear whether the patient derived long-term benefit from the reduceddose repeat RT, because the patient’s condition only improved after removal of the obstructing bronchial stent. From the case report by Kurrus et al. (7), we initially anticipated airway amyloid regression after RT. Our larger cohort and extended follow-up have established that RT prevents progression of existing amyloid deposits but does not predictably induce amyloid regression, and, as such, an improvement in pulmonary function can be delayed up to 12 months after RT. Although the radiation doses used for airway amyloidosis are low compared with the doses used for malignant lung and head-and-neck tumors, the potential for lung toxicity using doses of 20 Gy should not be ignored. In our study, the slight decreases in DLCO suggested subclinical parenchymal lung injury caused by RT from the two-field technique used in the present study. Esophagitis represented the most common acute toxicity of RT in our series, occurring in patients who underwent full tracheobronchial tree RT. This can be attributed to the anteroposterioreposteroanterior technique, with a large volume of the esophagus within the radiation field for a substantial length of the mediastinum. Long-term toxicity such as esophageal stenosis did not occur. The methods to minimize tissue toxicity could include reduced treatment margins and/or intensity-modulated RT to limit exposure of esophagus, heart, and normal lung parenchyma. Radiotherapy arrests airway amyloid progression and allows airway remodeling. Under optimal circumstances, radiationinduced changes in airway caliber occur slowly. Surgical debulking, in contrast, relieves the airway obstruction caused by amyloid deposits but does not prevent recurrence (1, 12). Consequently, a combination of surgical excision and RT may prove necessary to properly manage obstructive amyloid lesions. The sequencing of RT and surgical intervention, in our experience, should reflect the rate of disease progression, degree of airway obstruction, and recognition that the functional benefits of RT might not occur for >12 months. The limitations of the present study and of other studies include the small sample size and retrospective study design inherent in treating an “orphan” disease cohort. The optimal dose fractionation could not be determined from our series, although the disease of most patients was controlled with 20 Gy of RT.
International Journal of Radiation Oncology Biology Physics
Conclusions Conformal RT using 20 Gy in conventional fractionation was effective in arresting progressive airway amyloidosis. The patients who responded to RT improved the functional capacity and airflow with no documented late morbidity. Additional studies are needed to determine whether a radiation doseeresponse relationship for controlling airway amyloidosis exists and whether dose reductions or improvements in RT delivery techniques may reduce the potential toxicity.
References 1. O’Regan A, Fenlon HM, Beamis JF Jr., et al. Tracheobronchial amyloidosis: The Boston University experience from 1984 to 1999. Medicine (Baltimore) 2000;79:69e79. 2. Knobel D, Zouhair A, Tsang RW, et al. Prognostic factors in solitary plasmacytoma of the bone: A multicenter Rare Cancer Network study. BMC Cancer 2006;6:118. 3. Mose S, Pfitzner D, Rahn A, et al. [Role of radiotherapy in the treatment of multiple myeloma]. Strahlenther Onkol 2000;176: 506e512. 4. Neuner GA, Badros AA, Meyer TK, et al. Complete resolution of laryngeal amyloidosis with radiation treatment. Head Neck Epub 2010 Nov 10. 5. Monroe AT, Walia R, Zlotecki RA, et al. Tracheobronchial amyloidosis: A case report of successful treatment with external beam radiation therapy. Chest 2004;125:784e789. 6. Kalra S, Utz JP, Edell ES, et al. External-beam radiation therapy in the treatment of diffuse tracheobronchial amyloidosis. Mayo Clin Proc 2001;76:853e856. 7. Kurrus JA, Hayes JK, Hoidal JR, et al. Radiation therapy for tracheobronchial amyloidosis. Chest 1998;114:1489e1492. 8. Neben-Wittich MA, Foote RL, Kalra S. External beam radiation therapy for tracheobronchial amyloidosis. Chest 2007;132:262e267. 9. Khaira M, Mutamba A, Meligonis G, et al. The use of radiotherapy for the treatment of localized orbital amyloidosis. Orbit 2008;27: 432e437. 10. Biewend ML, Menke DM, Calamia KT. The spectrum of localized amyloidosis: A case series of 20 patients and review of the literature. Amyloid 2006;13:135e142. 11. Merrimen JL, Alkhudair WK, Gupta R. Localized amyloidosis of the urinary tract: Case series of nine patients. Urology 2006;67:904e909. 12. Piazza C, Cavaliere S, Foccoli P, et al. Endoscopic management of laryngo-tracheobronchial amyloidosis: A series of 32 patients. Eur Arch Otorhinolaryngol 2003;260:349e354. 13. Tirzaman O, Wahner-Roedler DL, Malek RS, et al. Primary localized amyloidosis of the urinary bladder: A case series of 31 patients. Mayo Clin Proc 2000;75:1264e1268. 14. Kyle RA, Gertz MA, Greipp PR, et al. Long-term survival (10 years or more) in 30 patients with primary amyloidosis. Blood 1999;93: 1062e1066. 15. Utz JP, Swensen SJ, Gertz MA. Pulmonary amyloidosis: The Mayo Clinic experience from 1980 to 1993. Ann Intern Med 1996;124: 407e413. 16. Demoulin JC. [Cardiac amyloidosis: Report of 11 autopsy cases and review of the literature]. Ann Cardiol Angeiol (Paris) 1983;32: 325e330. 17. Kyle RA, Bayrd ED. Amyloidosis: Review of 236 cases. Medicine (Baltimore) 1975;54:271e299. 18. Setoguchi M, Hoshii Y, Kawano H, et al. Analysis of plasma cell clonality in localized AL amyloidosis. Amyloid 2000;7:41e45. 19. Patrias LM, Klaver AC, Coffey MP, et al. Effects of external-beam radiation on in vitro formation of Abeta1-42 fibrils and preformed fibrils. Radiat Res 2011;175:375e381.
Volume 83 Number 2 2012 20. Rossier C, Schick U, Miralbell R, et al. Low-dose radiotherapy in indolent lymphoma. Int J Radiat Oncol Biol Phys 2011;81: e1ee6. 21. Chan EK, Fung S, Gospodarowicz M, et al. Palliation by low-dose local radiation therapy for indolent non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys Epub 2010 Dec 6. 22. Liu HW, Seftel MD, Rubinger M, et al. Total body irradiation compared with BEAM: Long-term outcomes of peripheral blood
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autologous stem cell transplantation for non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 2010;78:513e520. 23. Linsenmeier C, Thoennessen D, Negretti L, et al. Total body irradiation (TBI) in pediatric patients: A single-center experience after 30 years of low-dose rate irradiation. Strahlenther Onkol 2010;186:614e620. 24. Adkins DR, DiPersio JF. Total body irradiation before an allogeneic stem cell transplantation: Is there a magic dose? Curr Opin Hematol 2008;15:555e560.
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Thoracic Cancer
Long-Term Results of Conformal Radiotherapy for Progressive Airway Amyloidosis Minh Tam Truong, M.D.,* Lisa A. Kachnic, M.D.,* Gregory A. Grillone, M.D.,y Harry K. Bohrs, B.S.,* Richard Lee, M.D.,* Osamu Sakai, M.D., Ph.D.,z and John L. Berk, M.D.x Departments of *Radiation Oncology, yOtolaryngology, zRadiology, and xMedicine, Amyloid Treatment and Research Program, Boston University School of Medicine, Boston Medical Center, Boston, MA Received May 9, 2011, and in revised form Jul 26, 2011. Accepted for publication Jul 28, 2011
Summary Ten patients with symptomatic airway amyloidosis were followed for a median of nearly 7 years after 20 Gy external beam radiotherapy. RT appeared effective in controlling progressive airway amyloidosis of the larynx and tracheobronchial tree in 8 of 10 patients by stabilizing amyloid deposits and improving pulmonary function. It did so with no obvious late morbidity.
Purpose: To evaluate the efficacy of conformal external beam radiotherapy (RT) for local control of progressive airway amyloidosis. Methods and Materials: We conducted a retrospective review of patients with biopsy-proven progressive airway amyloidosis treated with conformal RT between 2000 and 2006 at Boston Medical Center. The patients were evaluated for performance status and pulmonary function, with computed tomography and endoscopy after RT compared with the pretreatment studies. Local control was defined as the lack of progression of airway wall thickening on computed tomography imaging and stable endobronchial deposits by endoscopy. Results: A total of 10 symptomatic airway amyloidosis patients (3 laryngeal and 7 tracheobronchial) received RT to a median total dose of 20 Gy in 10 fractions within 2 weeks. At a median follow-up of 6.7 years (range, 1.5e10.3), 8 of the 10 patients had local control. The remaining 2 patients underwent repeat RT 6 and 8.4 months after initial RT, 1 for persistent bronchial obstruction and 1 for progression of subglottic amyloid disease with subsequent disease control. The Eastern Cooperative Oncology Group performance status improved at a median of 18 months after RT compared with the baseline values, from a median score of 2 to a median of 1 (p Z .035). Airflow (forced expiratory volume in 1 second) measurements increased compared with the baseline values at each follow-up evaluation, reaching a 10.7% increase (p Z .087) at the last testing (median duration, 64.8 months). Acute toxicity was limited to Grade 1-2 esophagitis, occurring in 40% of patients. No late toxicity was observed. Conclusions: RT prevented progressive amyloid deposition in 8 of 10 patients, resulting in a marginally increased forced expiratory volume in 1 second, and improved functional capacity, without late morbidity. Ó 2012 Elsevier Inc. Keywords: Tracheobronchial Radiotherapy
Reprint requests to: Minh Tam Truong, M.D., Department of Radiation Oncology, Boston Medical Center, Moakley Lower Level 830 Harrison Avenue, Boston, MA 02118. Tel: (617) 638-7070; Fax: (617) 638-7037; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 83, No. 2, pp. 734e739, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2011.07.036
amyloidosis,
Airway
amyloid,
Laryngeal
amyloidosis,
Presented in part at the 49th Annual Meeting of the American Society for Radiation Oncology, October 28, 2007 to November 1, 2007, Los Angeles, CA. Conflict of interest: none.
Volume 83 Number 2 2012
Introduction Amyloidoses are characterized by the extracellular deposition of insoluble fibrillar proteins in tissues and organs. Amyloid deposition in the laryngeal and tracheobronchial airways is rare and constitutes approximately 1% of benign tumors in these areas. Small populations of clonal plasma cells located outside the airway are thought to be the source of local light chain immunoglobulin amyloid formation. Laryngeal and tracheobronchial amyloid lesions can progress, leading to airway obstruction. Surgical debulking can relieve the airway obstruction caused by amyloid deposits but does not prevent recurrence (1). Low-dose radiation induces plasma cell apoptosis in other plasma cell dyscrasias and lymphoproliferative disorders, such as multiple myeloma and lymphoma (2, 3). We, therefore, hypothesized that radiotherapy (RT) could eliminate the amyloidogenic plasma cells, thereby arresting amyloid production and preventing disease progression or lesion recurrence. Patients with tracheobronchial amyloidosis constitute approximately 11 of 1,000 referrals to the Amyloid Treatment and Research Program at Boston University School of Medicine, Boston Medical Center (1). We report the Boston Medical Center experience using low-dose external beam, three-dimensional conformal RT as localized treatment of progressive obstructive airway amyloidosis in our initial cohort of patients.
Methods and Materials Study cohort The institutional review board at Boston Medical Center approved the study as a retrospective review with a waiver of informed consent. The study followed the National Institutes of Health Insurance Portability and Accountability Act guidelines. Between 2000 and 2006, 10 consecutive patients with biopsy-proven progressive airway amyloidosis received RT. These patients were initially evaluated at the Amyloid Airway Clinic at Boston Medical Center. The histologic diagnosis of amyloidosis was established by the appearance of birefringence under polarized light after Congo Red staining. All available pathology slides were reviewed at our institution, and the diagnosis was confirmed before treatment. Each patient underwent a multidisciplinary evaluation at the Amyloid Airway Clinic with a pulmonologist, radiation oncologist, and otolaryngologist. The indications for RT as a part of airway amyloidosis management included amyloid recurrence after surgical excision and progressive airway obstruction due to amyloid deposits. The pretreatment workup included airway endoscopy, pulmonary function tests, and computed tomography (CT) imaging of the involved airways.
RT planning and delivery Patients with laryngeal amyloidosis were immobilized using a custom-made thermoplastic head mask; a custom vac loc bag was used for those with tracheobronchial amyloid. Thin-slice, high-resolution CT images were obtained with the patient in the treatment position. The gross tumor volume consisted of the extent of the amyloid deposits in the airway lining, defined by CT and direct airway endoscopic visualization. The clinical target volume included the amyloid deposits (gross tumor volume) with
Conformal RT for airway amyloidosis
735
a 10e15-mm margin to encompass the adjacent grossly uninvolved airway. A subsequent planning target volume incorporated a 5e10-mm margin beyond the clinical target volume to account for treatment setup accuracy. The adjacent critical structures, including the lung, esophagus, and spinal cord, were defined as the organs at risk.
Efficacy assessment After RT completion, the patients underwent physical examination, CT imaging, endoscopic surveys, and pulmonary function testing at 6e12-month intervals. Local control was defined as the lack of progression of existing amyloid depositions, stable airway wall thickening and lumen caliber, and the absence of new amyloid deposits identified on CT, bronchoscopy, and/or laryngoscopy within the radiation field. Local control was measured from the end of RT to the date of local relapse or the last follow-up visit. In-field progression was defined as the growth of amyloid deposits within the radiated field. Out-of-field progression was defined as newly occurring amyloid deposits or growth of previously identified disease in the untreated airways. Salvage therapy included subsequent surgery or RT performed after the initial RT to the treated lesion. The survival time was measured from the end of RT until death or the last follow-up examination.
Post-treatment surveillance The performance status, using the Eastern Cooperative Oncology Group criteria, was assessed before the start of RT and at each follow-up visit. We compared the pretreatment status and followup status at 12 months. Pulmonary function testing, including forced expiratory volume in 1 second (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO), was performed before and every 6e12 months after treatment completion.
Toxicity Toxicity was documented at each follow-up examination and was retrospectively scored using the Common Toxicity Criteria, version 3.0, of the U.S. National Institutes of Health (available from: http://ctep.cancer.gov/reporting/ctc.html).
Statistical analysis The paired Student t test (for the mean values) and Wilcoxon signed rank sum test (for the median values) were used to compare the pre- and post-treatment pulmonary function and performance status. A two-sided a-level of 0.05 was regarded as statistically significant. All analyses were conducted using the SAS software, version 9.1 (SAS Institute, Cary, NC).
Results Patient and treatment characteristics The median age at diagnosis was 39.5 years (range, 31.8e71.5). The median age at the start of RT was 40.6 years (range,
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Table 1 Pt. No. 1 2 3a 3b 4 5 6 7 8 9a 9b 10
Treatment characteristics Treatment site Right bronchus Larynx Right bronchus Right bronchus Bilateral tracheobronchial tree Bilateral tracheobronchial tree Left bronchus Bilateral tracheobronchial tree Larynx Larynx Larynx Right bronchus
Beam energy (photons) (MV) 18 4 18 18 18 18/6 18 18 4 6 6 18/6
Technique APePA Opposed lateral fields RAO/LPO LAO/RPO APePA APePA APePA APePA Opposed lateral fields Oblique lateral fields IMRT APePA
Field size (cm2) Total dose (Gy) 10 7 11 11 13.5 17 10 19 5 7.6 15.5 7
8 12 13.6 13.4 16 14 12 22 12 15 11 9
18 20 20 10 19.8 20 20 19.8 20 20 20 20
Abbreviations: Pt. No. Z patient number; MV Z megavoltage; APePA Z opposed anteroposterioreposteroanterior fields; RAO Z right anterior oblique fields; LPO Z left posterior oblique fields; RPO Z right posterior oblique fields; IMRT Z intensity-modulated radiotherapy. Patients 3 and 9 underwent repeat RT, with “a” and “b” representing first and second RT course.
32.4e72.6). The duration of symptoms before diagnosis was 1.34 years (range, 0.34e9.29). The disease sites included 3 patients with laryngeal amyloid and 7 with tracheobronchial amyloid. Of the 10 patients, 2 were men and 8 were women. The pretreatment symptoms included bronchitis in 40%, dyspnea in 90%, cough in 40%, hemoptysis in 30%, and hoarseness in 30%. Three patients underwent surgical debulking using carbon dioxide laser dissection before RT. One patient underwent three surgical procedures. Another patient underwent bronchodilation and stent placement, and one required emergency tracheostomy. The 10 patients underwent 3-dimensional conformal RT. Portal imaging or on-board imaging was used to verify the daily setup. The median prescribed dose to the clinical target volume was 20 Gy (range, 18e20) in 10 daily fractions, within a median of 13 days (range, 10e15). Megavoltage photons (4e18 MV) were used. The treatment characteristics and field design of each patient are listed in Table 1.
Efficacy
performance status at baseline and a median of 18 months after RT was 2 and 1, respectively (p Z .035).
Pulmonary function after RT Serial spirometry and gas diffusion measurements after RT were compared with the baseline values. At each point after RT, the FEV1 had increased. Specifically, the FEV1 at 6e12 months (median duration, 11.5), 12e24 months (median, 13.9), 24e36 months (median, 24.9), and the last follow-up examination (median, 58.1) had increased to 6.67% (p Z .239), 9.40% (p Z .054), 19.00% (p Z .092), and 10.67% (p Z .087), respectively (Figs. 1 and 2). The DLCO had decreased by a median 3.5% (p Z .540) at 6e12 months.
Failure patterns and salvage therapy Of the 10 patients, 2 underwent repeat RT; 1 for persistent bronchial obstruction at 6 months and 1 for in-field progression of
Radiotherapy to a median dose of 20 Gy produced local control of airway amyloid disease in 8 of the 10 treated patients at a median of 6.7 years of follow-up (range, 1.5e10.3). Of the 10 patients, 9 were alive at the last follow-up examination. One patient had died 7.4 years after RT of causes unrelated to amyloid disease.
Radiologic imaging and endoscopic changes after RT Endoscopic and CT evaluation of local control at 12 months of follow-up did not reveal changes in airway wall thickening or lumen caliber after treatment. The airway endoscopic assessment documented decreased mucosal edema and stable endobronchial pathologic findings without significant regression of the amyloid deposits at 6 and 12 months after RT. Progressive amyloid endobronchial growth was seen on endoscopy within the treatment field after RT in 1 (10%) of 10 patients at 8.4 months after RT.
Performance status The performance status after RT improved for the whole patient cohort. The median Eastern Cooperative Oncology Group
Fig. 1. Spirometry before and after radiotherapy (RT). Forced expiratory volume in 1 second (FEV1) was measured at four intervals after RT: 6e12, 12e24, and 24e36 months and a final examination (median, 5.4 years). Baseline and follow-up FEV1 mean data standard error of mean are presented.
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toxicities were noted, specifically; no patients developed secondary malignancies.
Discussion
Fig. 2. Spirometric changes after radiotherapy (RT). FEV1% change at 6e12, 12e24, and 24e36 months and final examination (median, 5.4 years) presented as mean data standard error of mean. amyloid deposits at 8.4 months after RT. The first patient had stable amyloid deposits after RT; however, recurrent right upper lobe infections due to bronchial stent obstruction of the right upper lobe bronchus prompted repeat RT to 10 Gy in five fractions 6 months after the initial 20-Gy RT course in an unsuccessful effort to induce amyloid regression. After stent removal, the patient’s exercise performance improved, permitting a return to full-time work. The same patient developed out-of-field progression of amyloidosis in the aerodigestive tract (nasopharynx and paranasal sinuses) at 80 months after RT. A second patient with circumferential laryngeal amyloid deposits developed hemoptysis from progressive amyloid disease within the RT field 8.4 months after RT. The patient underwent surgical carbon dioxide laser excision and repeat RT of the airway deposits with 20 Gy in 10 fractions with disease control at 22 months after RT. A third patient developed out-of-field progression of amyloid deposits in the contralateral bronchus at 22 months. The patterns of failure and subsequent salvage therapy are listed in Table 2.
Toxicity All patients tolerated treatment to completion without any break in radiation delivery. No acute or late Common Tissue Toxicity criteria, version 3, Grade 3e5 toxicities were observed. Four patients experienced Grade 1-2 esophagitis, and one developed community-acquired pneumonia at 2 months after RT. No late
Table 2
The present study has demonstrated that RT arrests the progression of laryngeal and tracheobronchial amyloidosis, permitting improvement in spirometry and performance status. Low-dose RT (20 Gy) achieved local disease control in 8 of 10 cases. Repeat RT alone or in combination with surgical management prevented amyloid progression in the remaining cases. The toxicities were limited to mild esophagitis in cases receiving full airway RT and small declines in DLCO, suggesting subclinical parenchymal lung injury. Multiple publications report the treatment of airway amyloid with low-dose RT; all except one were limited to 1 case experience (4e7). In the present study, serial FEV1 measurements documented little change at 6 or 12 months after RT, although continued improvement from 12e36 months after RT was observed. Airway remodeling, as reflected by the FEV1 and endoscopic disease burden, coincided with improved performance status. In contrast, Neben-Wittich et al. (8) reported a 7-case series from the Mayo Clinic, with a median 40-month follow-up, with evaluations limited to 12 months in >40% of the cases. The airway disease and FEV1 measurements were performed at 1e7 months after RT. Our 10-case series with 10 years of posttreatment observations and a median 6.7-year follow-up extends the Mayo Clinic experience. The amyloid deposits in patients with localized disease involving the airways, urinary tract, breast, eye, and skin are almost uniformly composed of misfolded immunoglobulin light chain proteins (9e17). Clonally expanded plasma cells residing in the affected organ are credited with the amyloid production (18). Low-dose RT induces plasma cell apoptosis in other plasma cell dyscrasias and lymphoproliferative disorders such as multiple myeloma and lymphoma (2, 3). We speculate that RT eliminates the amyloidogenic plasma cells residing within and immediately outside the affected airways, thereby arresting amyloid production and preventing disease progression or lesion recurrence. Radiation-related disruption of amyloid deposits, an alternative explanation, does not appear to occur (19). The radiation dose used to treat airway amyloid ranges from 20 to 45 Gy, although most patients received 20e24 Gy (5, 7, 8). Our experience, combined with the series from Neben-Wittich et al. (8), supports the use of 20e24 Gy to control airway amyloid deposits in most cases. Neuner et al. (4) used 45 Gy in 1.8 Gy daily fractions in 1 case of laryngeal amyloid, derived the dosing from data for solitary plasmacytoma treatment. The plasma
Patterns of failure and salvage treatment
Pt. No.
Failure site
In-field or out-of-field failure
3 9 10 3
Right bronchus Larynx Contralateral (left) bronchus Nasopharynx and paranasal sinuses
In-field In-field Out-of-field Out-of-field
Abbreviations as in Table 1. Patient numbers refer to corresponding patient in Table 1.
Salvage treatment
Interval to failure after initial RT (mo)
Repeat RT with 10 Gy and stent removal Surgical excision and repeat RT with 20 Gy Observation Staged surgical excisions
6 8.4 22 80
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cell burden of airway amyloidosis and solitary plasmacytomas varies dramatically. Solitary plasmacytomas constitute a radiologically visible target. In contrast, the clonal plasma cells are difficult to locate on exhaustive histologic examination of airway amyloid. Moreover, recent studies examining the dose response for plasmacytoma have not defined a benefit beyond 30 Gy (2). Additional studies are needed to determine whether a dose response relationship exists for 20e30 Gy RT for airway amyloidosis or whether dose reductions to <20 Gy can result in similar disease control. Studies using low-dose RT for lymphoproliferative diseases such as indolent lymphoma have shown local control using 4 Gy in two fractions, with complete response rates of 30e50% and overall response rates of 80e90% (20, 21). The total body irradiation experience (22, 23) has established that fractionated doses of 4e12 Gy are sufficient to induce pancytopenia before bone marrow transplantation. These data suggest that radiation dosing <20 Gy might be sufficient to control amyloidogenic plasma cells (24). The use of 20 Gy in 10 fractions in our series was determined from the reports by Kurrus et al. (7) and the Mayo Clinic (8) treating patients with tracheobronchial amyloidosis. We reirradiated 1 patient to 10 Gy in five fractions. It is unclear whether the patient derived long-term benefit from the reduceddose repeat RT, because the patient’s condition only improved after removal of the obstructing bronchial stent. From the case report by Kurrus et al. (7), we initially anticipated airway amyloid regression after RT. Our larger cohort and extended follow-up have established that RT prevents progression of existing amyloid deposits but does not predictably induce amyloid regression, and, as such, an improvement in pulmonary function can be delayed up to 12 months after RT. Although the radiation doses used for airway amyloidosis are low compared with the doses used for malignant lung and head-and-neck tumors, the potential for lung toxicity using doses of 20 Gy should not be ignored. In our study, the slight decreases in DLCO suggested subclinical parenchymal lung injury caused by RT from the two-field technique used in the present study. Esophagitis represented the most common acute toxicity of RT in our series, occurring in patients who underwent full tracheobronchial tree RT. This can be attributed to the anteroposterioreposteroanterior technique, with a large volume of the esophagus within the radiation field for a substantial length of the mediastinum. Long-term toxicity such as esophageal stenosis did not occur. The methods to minimize tissue toxicity could include reduced treatment margins and/or intensity-modulated RT to limit exposure of esophagus, heart, and normal lung parenchyma. Radiotherapy arrests airway amyloid progression and allows airway remodeling. Under optimal circumstances, radiationinduced changes in airway caliber occur slowly. Surgical debulking, in contrast, relieves the airway obstruction caused by amyloid deposits but does not prevent recurrence (1, 12). Consequently, a combination of surgical excision and RT may prove necessary to properly manage obstructive amyloid lesions. The sequencing of RT and surgical intervention, in our experience, should reflect the rate of disease progression, degree of airway obstruction, and recognition that the functional benefits of RT might not occur for >12 months. The limitations of the present study and of other studies include the small sample size and retrospective study design inherent in treating an “orphan” disease cohort. The optimal dose fractionation could not be determined from our series, although the disease of most patients was controlled with 20 Gy of RT.
International Journal of Radiation Oncology Biology Physics
Conclusions Conformal RT using 20 Gy in conventional fractionation was effective in arresting progressive airway amyloidosis. The patients who responded to RT improved the functional capacity and airflow with no documented late morbidity. Additional studies are needed to determine whether a radiation doseeresponse relationship for controlling airway amyloidosis exists and whether dose reductions or improvements in RT delivery techniques may reduce the potential toxicity.
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Volume 83 Number 2 2012 20. Rossier C, Schick U, Miralbell R, et al. Low-dose radiotherapy in indolent lymphoma. Int J Radiat Oncol Biol Phys 2011;81: e1ee6. 21. Chan EK, Fung S, Gospodarowicz M, et al. Palliation by low-dose local radiation therapy for indolent non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys Epub 2010 Dec 6. 22. Liu HW, Seftel MD, Rubinger M, et al. Total body irradiation compared with BEAM: Long-term outcomes of peripheral blood
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autologous stem cell transplantation for non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 2010;78:513e520. 23. Linsenmeier C, Thoennessen D, Negretti L, et al. Total body irradiation (TBI) in pediatric patients: A single-center experience after 30 years of low-dose rate irradiation. Strahlenther Onkol 2010;186:614e620. 24. Adkins DR, DiPersio JF. Total body irradiation before an allogeneic stem cell transplantation: Is there a magic dose? Curr Opin Hematol 2008;15:555e560.