- Email: [email protected]
Definitive Radiotherapy for Unresected Adenoid Cystic Carcinoma of the Trachea
7. Ishii H, Trapnell BC, Tazawa R, et al; Japanese Center of the Rare Lung Disease Consortium. Comparative study of high-resolution CT findings between autoimmune and secondary pulmonary alveolar proteinosis. Chest. 2009;136(5): 1348-1355. 8. Verma H, Nicholson AG, Kerr KM, et al. Alveolar proteinosis with hypersensitivity pneumonitis: a new clinical phenotype. Respirology. 2010;15(8):1197-1202.
Definitive Radiotherapy for Unresected Adenoid Cystic Carcinoma of the Trachea Lara P. Bonner Millar, MD; Diana Stripp, MD; Joel D. Cooper, MD, FCCP; Stefan Both, PhD; Paul James, CMD; and Ramesh Rengan, MD, PhD
Adenoid cystic carcinoma is a rare malignancy that usually originates in the salivary glands of the head and neck but has rarely been known to originate in the trachea. This histology has a predilection for perineural invasion and a tendency for both local and distant recurrences. While surgical resection is the mainstay of treatment of tracheal adenoid cystic carcinoma, tumor size, location, and patient comorbidities may preclude surgery, and the optimal nonsurgical management remains undefined. In the absence of locoregional lymph node metastases, we recommend highly conformal radiotherapy alone to a dose of 80 Gy. We report on two patients with unresectable disease who were treated with definitive radiotherapy: one using conventional photons and one treated with a combination of photon and proton beams. Both patients were treated to a dose of 80 Gy with acceptable toxicities and objective clinical and radiographic response. The patient treated with conventional photons has no evidence of recurrent disease at 5 years; the patient treated with protons has continued evidence of response without evidence of disease recurrence 11 months after treatment. CHEST 2012; 141(5):1323–1326 Abbreviations: ACC 5 adenoid cystic carcinoma; IMRT 5 intensity modulated radiotherapy; NSCLC 5 non-small cell lung cancer
T
racheal tumors are rare, comprising only 0.2% of all respiratory malignancies in the United States.1 Among these tumors, squamous cell carcinoma predominates
Manuscript received April 12, 2011; revision accepted September 20, 2011. Affiliations: From the Department of Radiation Oncology (Drs Bonner Millar, Stripp, Both and Rengan and Mr James), Hospital of the University of Pennsylvania, Philadelphia, PA; and Department of Surgery (Dr Cooper), Division of Thoracic Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA. Correspondence to: Ramesh Rengan, MD, PhD, Department of Radiation Oncology, Hospital of the University of Pennsylvania, 2-W, 3400 Civic Center Blvd, Philadelphia, PA 19104; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.11-0925 www.chestpubs.org
(60%-90%); adenoid cystic carcinoma (ACC) accounts for about 10% to 20%.2,3 Patients with tracheal tumors typically present with signs or symptoms of upper airway obstruction such as cough, dyspnea, hoarseness, wheezing, stridor, dysphonia, or hemoptysis.4 Symptoms may be present for some time prior to diagnosis, and patients may be treated for more common benign processes such as asthma and chronic bronchitis. Moreover, chest radiograph, which may be the first imaging performed in the symptomatic patient, is likely to be nondiagnostic since tracheal tumors do not involve the lung parenchyma itself, further delaying diagnosis.5,6 In contrast with squamous cell carcinoma, ACCs are less commonly associated with smoking; are slower in clinical onset, with symptoms often present for months to years on detailed questioning; and are less likely to be ulcerative or exophytic.7 Histologically, ACCs of the tracheal tree are identical to ACCs of the salivary glands. They typically form polypoid lesions but may have longitudinal or circumferential extension. ACC is characterized by perineural invasion, an adverse risk factor for local recurrences. After definitive resection, tracheal ACC has a propensity for late recurrence, both local and distant.8 Surgical resection is the treatment of choice for tracheal malignancies, but resectability depends on the size, location, extent of tumor, as well as patient comorbidities. While there have been some reports and case series on surgical treatment of this diagnosis, very little has been reported on nonsurgical therapeutic alternatives. In the largest surgical series of tracheal tumors, about 70% were resectable and in patients with ACC, 70% were radiated postoperatively.9 The 5- and 10-year survival rates for resected ACCs were 52% and 29%, respectively. In ACC, because of mucosal or submucosal spread of disease along the airways, complete resection is not always possible or advisable and R0 resections are achieved in approximately 50% of patients.10 Although there are no trials exploring the role of adjuvant radiation therapy in ACC, radiotherapy is usually recommended for incomplete resections or positive margins.11 For unresectable cases, external beam radiation, and in some cases, chemotherapy is employed.12-14 Local control for definitive radiotherapy has varied between 20% and 70%, with improvement in outcome when tumor dose above 60 Gy is used.15-17 One series reported a 5-year survival of 33%.18 Other radiation modalities less commonly used include neutron beam radiotherapy and high doserate endobronchial brachytherapy.19,20 In this report, we present two patients with tracheal ACC who received treatment with definitive radiotherapy alone.
Case 1 A 43-year-old woman presented with increasing dyspnea on exertion for 3 weeks. In retrospect, she noted intermittent wheezing and dyspnea on exertion for about 2 years prior to presentation. A chest radiograph showed an opacity within the right apex of the lung as well as lobulation of the anterior paratracheal stripe. This was further evaluated with a CT scan of the chest without contrast. This revealed a soft tissue mass measuring 2.2 3 1.9 cm located posterior to the carina with resulting compression and narrowing of the right mainstem bronchus and posterior CHEST / 141 / 5 / MAY, 2012
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carina, consistent with a primary tumor of the trachea (Fig 1A). There was also a 4-mm pleural-based nodule within the apex of the right upper lobe of indeterminate etiology. A PET/CT scan showed increased tracer uptake within the tracheal mass, while the pleural-based nodule had a low standard uptake value of 1.3 to 1.5 favoring an inflammatory, nonmalignant process. Bronchoscopic biopsy was performed, revealing an adenoid cystic carcinoma. After thoracic surgery and radiation oncology evaluation, she was treated with definitive radiotherapy given the low likelihood of complete resection of disease. A threedimensional conformal radiation treatment plan was developed using 6-MV photons. She received 32 Gy in 2 Gy per fraction via anterior and posterior opposed fields followed by serial oblique “off cord” cone-down fields for additional 48 Gy, for a total tumor dose of 80 Gy. Acute reactions to treatment included subjective chest tightness and esophagitis, managed medically; the patient continued to work full-time through treatment. One month after treatment, her chest CT scan demonstrated significant reduction in the tumor (Fig 1B). Now 6 years after treatment, the patient reports some chest tightness and chest wall pain with extreme exertion, although she is able to maintain her exercise regimen. She also has gastroesophageal reflux disease due to esophageal incompetence and valve stiffness, as well as diminished force of cough, and atrophy of chest wall musculature. Her 5-year follow-up CT scan showed no evidence of disease (Fig 1C) and the previously reported pleural nodule remained stable, favoring old inflammation. At present, she continues to do well and is followed with annual CT scans.
Case 2 A 57-year-old woman presented with 1 month of dyspnea on exertion. In retrospect, she noted dyspnea for approximately 1 year prior to presentation. She saw her primary care physician and was prescribed an antibiotic without improvement in symptoms. Physical examination was notable for stridor at rest, but clear lungs. A chest radiograph revealed tracheal narrowing potentially secondary to a tracheal mass. A subsequent CT scan of the chest was performed which showed a posterior mediastinal mass compressing the trachea. Biopsy confirmed an adenoid cystic carcinoma. PET-CT scan showed uptake in
the primary tumor with no evidence of nodal or distant disease. A repeat chest CT scan showed a lobulated mass in the distal trachea, narrowing the lumen of the trachea and right mainstem bronchus (Fig 2A). Bronchoscopy and esophagogastroduodenoscopy revealed a mass about 5 cm in length with no evidence of mucosal extension into the esophagus. Tumor was identified within the distal trachea involving primarily the membranous wall. The left main bronchus appeared unremarkable, but the orifice to the right main bronchus was almost completely occluded with tumor though there was no visible extension into segmental bronchi. At multidisciplinary tumor board, the consensus was for definitive radiation therapy, given the high likelihood of operative mortality, estimated at 30%, due to the need for carinal resection. A four-dimensional scan for radiation treatment planning was performed. This allowed for assessment of tumor motion throughout the respiratory cycle, and revealed a 5-mm range of excursion during the respiratory cycle. A treatment plan was then developed to deliver 80 Gy to the tumor with an additional margin to account for microscopic extension of disease, respiratory motion, and daily variance in patient positioning. For the first phase of treatment, she received 46 Gy in 2 Gy per fraction, using 6-MV photon beams delivered via an intensity modulated radiotherapy (IMRT) technique. IMRT was chosen because the ability to modulate the fluence within the beam allowed for preferential dose delivery to the target while minimizing the dose to surrounding structures. Midtreatment, a second four-dimensional CT scan was obtained to plan the proton therapy phase of her treatment. On this second scan, there was evident regression of the tumor with increased luminal opening of the trachea as well as the right mainstem bronchus. The second phase of radiotherapy with protons continued at 2 Gy per day to deliver an additional 34 Gy for a total tumor dose of 80 Gy (Fig 2B). The proton plan beam arrangement consisted of left posterior oblique, lateral, and left anterior oblique fields, equally weighted. A direct anterior field was not used given the proportionally greater anterior tumor motion and, therefore, potentially increased range uncertainty. Target delineation was done on the CT scan at maximum inspiration and maximum expiration phases and then summed for both phases to create a composite internal target volume. A 5-mm margin was added to account for daily variance in patient positioning.
Figure 1. A, Axial preradiotherapy treatment CT scan. B, Axial 1-month postradiotherapy CT scan showing near complete regression. C, Five-year postradiotherapy axial CT scan showing tracheal patency. 1324
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Figure 2. A, Coronal pretreatment CT scan. B, Coronal view of the proton treatment plan: Note the absence of dose to the contralateral lung. C, Coronal 4-month postradiotherapy CT scan showing near complete regression.
Proton therapy was used for the second phase of treatment to take advantage of their distinct physical properties. Protons differ from photons in that they deposit their dose primarily at the end of their path in tissue, in contrast to photons where much of the dose is deposited near the skin surface. Additionally, unlike photons which deposit dose from the point of entry in the patient to the point of exit, protons can be calibrated to end their path within tumor, thereby eliminating any dose deposition to structures beyond the tumor. This favorable dosedeposition profile allows for additional sparing of normal tissue for tumors that are located in close proximity to critical structures relative to that which can be achieved with a photon-based treatment plan. The patient tolerated radiotherapy without significant side effects. A few days into treatment, she had subjective worsening of her dyspnea from acute radiation inflammation which resolved with a course of steroids and nebulized epinephrine. During the later phase of treatment, the patient had a skin reaction of erythema without moist desquamation consistent with radiation dermatitis. Upon the conclusion of treatment, her breathing was at baseline and her stridor had completely resolved. At present, 11 months after treatment, she is asymptomatic with continued radiographic tumor response (Fig 2C).
Discussion While surgical resection is the first-line treatment of tracheal ACC, definitive radiation can result in excellent control of disease. Higher doses may improve tumor control, but there is also potential for increased complications. In the absence of randomized trials to dictate the optimal dose and fractionation of radiotherapy for tracheal ACC, advanced modalities (proton therapy) and techniques (intensity modulation) should be used to facilitate dose escalation and minimize morbidity. At the time the first patient was treated, our institution did not have proton or IMRT capabilities, therefore, three-dimensional conformal radiotherapy was used. This treatment was well tolerated, and the patient is disease-free at 6 years (with CT imaging 5 years after treatment). The patient does have long-term functional sequelae, including gastroesophageal reflux and atrophy of the chest wall musculature. The second patient, www.chestpubs.org
who received treatment with protons and IMRT, is also currently without evidence of active disease 11 months after treatment. There is a paucity of information on the late effects seen after definitive radiotherapy for tracheal ACC; however, it should be acknowledged that high-dose thoracic radiotherapy has been associated with a finite risk of damage to the bronchi such as fistula or airway narrowing.21,22 Miller et al22 found that eight of 103 patients with unresectable non-small cell lung cancer (NSCLC) experienced symptomatic bronchial stenosis with doses ranging from 73.6 to 86.4 Gy; a dose-response relationship was suggested, supported by a 9% rate of stenosis at 74 Gy, 6% at 80 Gy, and 25% at 86 Gy. The majority of patients with bronchial stenosis received induction chemotherapy, and it is unclear whether that played a role in the development of airway toxicity. Interestingly, Kelsey et al21 reported that at doses . 73.6 Gy, stenosis occurred within the bronchi but not in the trachea, suggestive of differential tolerances among structures that comprise the airway. In contrast, Jeremic et al23 documented delayed tracheal toxicity after doses of 70 Gy. Notably, most of the high-dose thoracic radiotherapy toxicity data have been gathered from patients with locally advanced NSCLC, of whom a majority receives concurrent or sequential chemotherapy.24 Lee et al25 also reported on late toxicities among patients with NSCLC treated with radiotherapy from 66 to 90 Gy, most with concurrent chemotherapy, and found no longterm toxicity in the 80-Gy group. At higher doses—82, 86, and 90 Gy—more patients experienced pulmonary late toxicity than those who did not, with a latency of 2 to 7 months. There are also phase 1 data for dose escalation with radiotherapy alone in NSCLC; Sura et al26 reported on radiotherapy for inoperable NSCLC where the majority of patients had stage III disease and doses were safely escalated to 84 Gy. This is of particular relevance to our report since both patients were also treated with radiotherapy alone. Finally, the QUANTEC (quantitative analysis of normal tissue effects in the clinic) report suggests that limiting the dose to 80 Gy or lower using standard fractionation may reduce the risk of central airway stenosis.27 Regarding the use of high-dose proton therapy, a dosimetric comparative study of IMRT, passive scattering protons, and intensity modulated protons for locally advanced lung cancer found that with intensity modulated proton CHEST / 141 / 5 / MAY, 2012
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dose could be escalated to 83.5 Gy while maintaining sparing of heart, lung, spinal cord, and esophagus.28 We hypothesize that as a result of using advanced techniques, long-term toxicity will be diminished.
13. 14.
Conclusion Treatment of tracheal ACC is challenging, particularly when faced with borderline resectable or unresectable cases. In the available literature, although radiotherapy has been put forth as the appropriate therapy for unresectable disease, doses reported, which range from 40 to 72 Gy have had varying success.15,29,30 To our knowledge, this is the first report documenting treatment strategy and outcomes for tracheal ACC with radiotherapy to 80 Gy as well as the first report of proton therapy for unresected tracheal ACC. Based on our experience with a maximum follow-up of 6 years, this dose appears feasible and safe when highly conformal treatment techniques are implemented.
15. 16. 17. 18.
19. 20.
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
21. 22.
References 1. Gaissert HA, Mark EJ. Tracheobronchial gland tumors. Cancer Contr. 2006;13(4):286-294. 2. Bhattacharyya N. Contemporary staging and prognosis for primary tracheal malignancies: a population-based analysis. Otolaryngol Head Neck Surg. 2004;131(5):639-642. 3. Honings J, van Dijck JA, Verhagen AF, van der Heijden HF, Marres HA. Incidence and treatment of tracheal cancer: a nationwide study in the Netherlands. Ann Surg Oncol. 2007; 14(2):968-976. 4. Yang KY, Chen YM, Huang MH, Perng RP. Revisit of primary malignant neoplasms of the trachea: clinical characteristics and survival analysis. Jpn J Clin Oncol. 1997;27(5):305-309. 5. Velez Jo ET, Morehead RS. Hemoptysis and dyspnea in a 67-year-old man with a normal chest radiograph. Chest. 1999; 116(3):803-807. 6. McCarthy MJ, Rosado-de-Christenson ML. Tumors of the trachea. J Thorac Imaging. 1995;10(3):180-198. 7. Macchiarini P. Primary tracheal tumours. Lancet Oncol. 2006; 7(1):83-91. 8. Prommegger R, Salzer GM. Long-term results of surgery for adenoid cystic carcinoma of the trachea and bronchi. Eur J Surg Oncol. 1998;24(5):440-444. 9. Grillo HC, Mathisen DJ. Primary tracheal tumors: treatment and results. Ann Thorac Surg. 1990;49(1):69-77. 10. Maziak DE, Todd TR, Keshavjee SH, Winton TL, Van Nostrand P, Pearson FG. Adenoid cystic carcinoma of the airway: thirty-two-year experience. J Thorac Cardiovasc Surg. 1996;112(6):1522-1531. 11. Gaissert HA. Primary tracheal tumors. Chest Surg Clin N Am. 2003;13(2):247-256. 12. Sasiaja M, Funa N, Kamata M, Furutani K, Matsumoto A, Kodaira T. Unresectable adenoid cystic carcinoma of the
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trachea treated with chemoradiotherapy. Clin Oncol (R Coll Radiol). 2000;12(4):272. Videtic GM, Campbell C, Vincent MD. Primary chemoradiation as definitive treatment for unresectable cancer of the trachea. Can Respir J. 2003;10(3):143-144. Allen AM, Rabin MS, Reilly JJ, Mentzer SJ. Unresectable adenoid cystic carcinoma of the trachea treated with chemoradiation. J Clin Oncol. 2007;25(34):5521-5523. Cheung AY. Radiotherapy for primary carcinoma of the trachea. Radiother Oncol. 1989;14(4):279-285. Chow DC, Komaki R, Libshitz HI, Mountain CF, Ellerbroek N. Treatment of primary neoplasms of the trachea. The role of radiation therapy. Cancer. 1993;71(10):2946-2952. Ogino T, Ono R, Shimizu W, Ikeda H. Adenoid cystic carcinoma of the tracheobronchial system: the role of postoperative radiotherapy. Radiat Med. 1995;13(1):27-29. Gaissert HA, Grillo HC, Shadmehr MB, et al. Long-term survival after resection of primary adenoid cystic and squamous cell carcinoma of the trachea and carina. Ann Thorac Surg. 2004;78(6):1889-1896. Carvalho Hde A, Figueiredo V, Pedreira WL Jr, Aisen S. High dose-rate brachytherapy as a treatment option in primary tracheal tumors. Clinics (Sao Paulo). 2005;60(4):299-304. Bittner N, Koh WJ, Laramore GE, Patel S, Mulligan MS, Douglas JG. Treatment of locally advanced adenoid cystic carcinoma of the trachea with neutron radiotherapy. Int J Radiat Oncol Biol Phys. 2008;72(2):410-414. Kelsey CR, Kahn D, Hollis DR, et al. Radiation-induced narrowing of the tracheobronchial tree: an in-depth analysis. Lung Cancer. 2006;52(1):111-116. Miller KL, Shafman TD, Anscher MS, et al. Bronchial stenosis: an underreported complication of high-dose external beam radiotherapy for lung cancer? Int J Radiat Oncol Biol Phys. 2005;61(1):64-69. Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Radiotherapy for primary squamous cell carcinoma of the trachea. Radiother Oncol. 1996;41(2):135-138. Socinski MA, Blackstock AW, Bogart JA, et al. Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105. J Clin Oncol. 2008;26(15):2457-2463. Lee CB, Stinchcombe TE, Moore DT, et al. Late complications of high-dose (./5 66 Gy) thoracic conformal radiation therapy in combined modality trials in unresectable stage III non-small cell lung cancer. J Thorac Oncol. 2009; 4(1):74-79. Sura S, Yorke E, Jackson A, Rosenzweig KE. High-dose radiotherapy for the treatment of inoperable non-small cell lung cancer. Cancer J. 2007;13(4):238-242. Marks LB, Bentzen SM, Deasy JO, et al. Radiation dosevolume effects in the lung. Int J Radiat Oncol Biol Phys. 2010;76(suppl 3):S70-S76. Zhang X, Li Y, Pan X, et al. Intensity-modulated proton therapy reduces the dose to normal tissue compared with intensitymodulated radiation therapy or passive scattering proton therapy and enables individualized radical radiotherapy for extensive stage IIIB non-small-cell lung cancer: a virtual clinical study. Int J Radiat Oncol Biol Phys. 2010;77(2):357-366. Fields JN, Rigaud G, Emami BN. Primary tumours of the trachea. Results of radiation therapy. Cancer. 1989;63(12): 2429-2433. Chang CY, Cheng SL, Chang SC. Adenoid cystic carcinoma of trachea treated with tumor curettage and adjuvant intensity modulated radiation therapy. South Med J. 2011;104(1):68-70.
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Definitive Radiotherapy for Unresected Adenoid Cystic Carcinoma of the Trachea Lara P. Bonner Millar, MD; Diana Stripp, MD; Joel D. Cooper, MD, FCCP; Stefan Both, PhD; Paul James, CMD; and Ramesh Rengan, MD, PhD
Adenoid cystic carcinoma is a rare malignancy that usually originates in the salivary glands of the head and neck but has rarely been known to originate in the trachea. This histology has a predilection for perineural invasion and a tendency for both local and distant recurrences. While surgical resection is the mainstay of treatment of tracheal adenoid cystic carcinoma, tumor size, location, and patient comorbidities may preclude surgery, and the optimal nonsurgical management remains undefined. In the absence of locoregional lymph node metastases, we recommend highly conformal radiotherapy alone to a dose of 80 Gy. We report on two patients with unresectable disease who were treated with definitive radiotherapy: one using conventional photons and one treated with a combination of photon and proton beams. Both patients were treated to a dose of 80 Gy with acceptable toxicities and objective clinical and radiographic response. The patient treated with conventional photons has no evidence of recurrent disease at 5 years; the patient treated with protons has continued evidence of response without evidence of disease recurrence 11 months after treatment. CHEST 2012; 141(5):1323–1326 Abbreviations: ACC 5 adenoid cystic carcinoma; IMRT 5 intensity modulated radiotherapy; NSCLC 5 non-small cell lung cancer
T
racheal tumors are rare, comprising only 0.2% of all respiratory malignancies in the United States.1 Among these tumors, squamous cell carcinoma predominates
Manuscript received April 12, 2011; revision accepted September 20, 2011. Affiliations: From the Department of Radiation Oncology (Drs Bonner Millar, Stripp, Both and Rengan and Mr James), Hospital of the University of Pennsylvania, Philadelphia, PA; and Department of Surgery (Dr Cooper), Division of Thoracic Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA. Correspondence to: Ramesh Rengan, MD, PhD, Department of Radiation Oncology, Hospital of the University of Pennsylvania, 2-W, 3400 Civic Center Blvd, Philadelphia, PA 19104; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.11-0925 www.chestpubs.org
(60%-90%); adenoid cystic carcinoma (ACC) accounts for about 10% to 20%.2,3 Patients with tracheal tumors typically present with signs or symptoms of upper airway obstruction such as cough, dyspnea, hoarseness, wheezing, stridor, dysphonia, or hemoptysis.4 Symptoms may be present for some time prior to diagnosis, and patients may be treated for more common benign processes such as asthma and chronic bronchitis. Moreover, chest radiograph, which may be the first imaging performed in the symptomatic patient, is likely to be nondiagnostic since tracheal tumors do not involve the lung parenchyma itself, further delaying diagnosis.5,6 In contrast with squamous cell carcinoma, ACCs are less commonly associated with smoking; are slower in clinical onset, with symptoms often present for months to years on detailed questioning; and are less likely to be ulcerative or exophytic.7 Histologically, ACCs of the tracheal tree are identical to ACCs of the salivary glands. They typically form polypoid lesions but may have longitudinal or circumferential extension. ACC is characterized by perineural invasion, an adverse risk factor for local recurrences. After definitive resection, tracheal ACC has a propensity for late recurrence, both local and distant.8 Surgical resection is the treatment of choice for tracheal malignancies, but resectability depends on the size, location, extent of tumor, as well as patient comorbidities. While there have been some reports and case series on surgical treatment of this diagnosis, very little has been reported on nonsurgical therapeutic alternatives. In the largest surgical series of tracheal tumors, about 70% were resectable and in patients with ACC, 70% were radiated postoperatively.9 The 5- and 10-year survival rates for resected ACCs were 52% and 29%, respectively. In ACC, because of mucosal or submucosal spread of disease along the airways, complete resection is not always possible or advisable and R0 resections are achieved in approximately 50% of patients.10 Although there are no trials exploring the role of adjuvant radiation therapy in ACC, radiotherapy is usually recommended for incomplete resections or positive margins.11 For unresectable cases, external beam radiation, and in some cases, chemotherapy is employed.12-14 Local control for definitive radiotherapy has varied between 20% and 70%, with improvement in outcome when tumor dose above 60 Gy is used.15-17 One series reported a 5-year survival of 33%.18 Other radiation modalities less commonly used include neutron beam radiotherapy and high doserate endobronchial brachytherapy.19,20 In this report, we present two patients with tracheal ACC who received treatment with definitive radiotherapy alone.
Case 1 A 43-year-old woman presented with increasing dyspnea on exertion for 3 weeks. In retrospect, she noted intermittent wheezing and dyspnea on exertion for about 2 years prior to presentation. A chest radiograph showed an opacity within the right apex of the lung as well as lobulation of the anterior paratracheal stripe. This was further evaluated with a CT scan of the chest without contrast. This revealed a soft tissue mass measuring 2.2 3 1.9 cm located posterior to the carina with resulting compression and narrowing of the right mainstem bronchus and posterior CHEST / 141 / 5 / MAY, 2012
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carina, consistent with a primary tumor of the trachea (Fig 1A). There was also a 4-mm pleural-based nodule within the apex of the right upper lobe of indeterminate etiology. A PET/CT scan showed increased tracer uptake within the tracheal mass, while the pleural-based nodule had a low standard uptake value of 1.3 to 1.5 favoring an inflammatory, nonmalignant process. Bronchoscopic biopsy was performed, revealing an adenoid cystic carcinoma. After thoracic surgery and radiation oncology evaluation, she was treated with definitive radiotherapy given the low likelihood of complete resection of disease. A threedimensional conformal radiation treatment plan was developed using 6-MV photons. She received 32 Gy in 2 Gy per fraction via anterior and posterior opposed fields followed by serial oblique “off cord” cone-down fields for additional 48 Gy, for a total tumor dose of 80 Gy. Acute reactions to treatment included subjective chest tightness and esophagitis, managed medically; the patient continued to work full-time through treatment. One month after treatment, her chest CT scan demonstrated significant reduction in the tumor (Fig 1B). Now 6 years after treatment, the patient reports some chest tightness and chest wall pain with extreme exertion, although she is able to maintain her exercise regimen. She also has gastroesophageal reflux disease due to esophageal incompetence and valve stiffness, as well as diminished force of cough, and atrophy of chest wall musculature. Her 5-year follow-up CT scan showed no evidence of disease (Fig 1C) and the previously reported pleural nodule remained stable, favoring old inflammation. At present, she continues to do well and is followed with annual CT scans.
Case 2 A 57-year-old woman presented with 1 month of dyspnea on exertion. In retrospect, she noted dyspnea for approximately 1 year prior to presentation. She saw her primary care physician and was prescribed an antibiotic without improvement in symptoms. Physical examination was notable for stridor at rest, but clear lungs. A chest radiograph revealed tracheal narrowing potentially secondary to a tracheal mass. A subsequent CT scan of the chest was performed which showed a posterior mediastinal mass compressing the trachea. Biopsy confirmed an adenoid cystic carcinoma. PET-CT scan showed uptake in
the primary tumor with no evidence of nodal or distant disease. A repeat chest CT scan showed a lobulated mass in the distal trachea, narrowing the lumen of the trachea and right mainstem bronchus (Fig 2A). Bronchoscopy and esophagogastroduodenoscopy revealed a mass about 5 cm in length with no evidence of mucosal extension into the esophagus. Tumor was identified within the distal trachea involving primarily the membranous wall. The left main bronchus appeared unremarkable, but the orifice to the right main bronchus was almost completely occluded with tumor though there was no visible extension into segmental bronchi. At multidisciplinary tumor board, the consensus was for definitive radiation therapy, given the high likelihood of operative mortality, estimated at 30%, due to the need for carinal resection. A four-dimensional scan for radiation treatment planning was performed. This allowed for assessment of tumor motion throughout the respiratory cycle, and revealed a 5-mm range of excursion during the respiratory cycle. A treatment plan was then developed to deliver 80 Gy to the tumor with an additional margin to account for microscopic extension of disease, respiratory motion, and daily variance in patient positioning. For the first phase of treatment, she received 46 Gy in 2 Gy per fraction, using 6-MV photon beams delivered via an intensity modulated radiotherapy (IMRT) technique. IMRT was chosen because the ability to modulate the fluence within the beam allowed for preferential dose delivery to the target while minimizing the dose to surrounding structures. Midtreatment, a second four-dimensional CT scan was obtained to plan the proton therapy phase of her treatment. On this second scan, there was evident regression of the tumor with increased luminal opening of the trachea as well as the right mainstem bronchus. The second phase of radiotherapy with protons continued at 2 Gy per day to deliver an additional 34 Gy for a total tumor dose of 80 Gy (Fig 2B). The proton plan beam arrangement consisted of left posterior oblique, lateral, and left anterior oblique fields, equally weighted. A direct anterior field was not used given the proportionally greater anterior tumor motion and, therefore, potentially increased range uncertainty. Target delineation was done on the CT scan at maximum inspiration and maximum expiration phases and then summed for both phases to create a composite internal target volume. A 5-mm margin was added to account for daily variance in patient positioning.
Figure 1. A, Axial preradiotherapy treatment CT scan. B, Axial 1-month postradiotherapy CT scan showing near complete regression. C, Five-year postradiotherapy axial CT scan showing tracheal patency. 1324
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Figure 2. A, Coronal pretreatment CT scan. B, Coronal view of the proton treatment plan: Note the absence of dose to the contralateral lung. C, Coronal 4-month postradiotherapy CT scan showing near complete regression.
Proton therapy was used for the second phase of treatment to take advantage of their distinct physical properties. Protons differ from photons in that they deposit their dose primarily at the end of their path in tissue, in contrast to photons where much of the dose is deposited near the skin surface. Additionally, unlike photons which deposit dose from the point of entry in the patient to the point of exit, protons can be calibrated to end their path within tumor, thereby eliminating any dose deposition to structures beyond the tumor. This favorable dosedeposition profile allows for additional sparing of normal tissue for tumors that are located in close proximity to critical structures relative to that which can be achieved with a photon-based treatment plan. The patient tolerated radiotherapy without significant side effects. A few days into treatment, she had subjective worsening of her dyspnea from acute radiation inflammation which resolved with a course of steroids and nebulized epinephrine. During the later phase of treatment, the patient had a skin reaction of erythema without moist desquamation consistent with radiation dermatitis. Upon the conclusion of treatment, her breathing was at baseline and her stridor had completely resolved. At present, 11 months after treatment, she is asymptomatic with continued radiographic tumor response (Fig 2C).
Discussion While surgical resection is the first-line treatment of tracheal ACC, definitive radiation can result in excellent control of disease. Higher doses may improve tumor control, but there is also potential for increased complications. In the absence of randomized trials to dictate the optimal dose and fractionation of radiotherapy for tracheal ACC, advanced modalities (proton therapy) and techniques (intensity modulation) should be used to facilitate dose escalation and minimize morbidity. At the time the first patient was treated, our institution did not have proton or IMRT capabilities, therefore, three-dimensional conformal radiotherapy was used. This treatment was well tolerated, and the patient is disease-free at 6 years (with CT imaging 5 years after treatment). The patient does have long-term functional sequelae, including gastroesophageal reflux and atrophy of the chest wall musculature. The second patient, www.chestpubs.org
who received treatment with protons and IMRT, is also currently without evidence of active disease 11 months after treatment. There is a paucity of information on the late effects seen after definitive radiotherapy for tracheal ACC; however, it should be acknowledged that high-dose thoracic radiotherapy has been associated with a finite risk of damage to the bronchi such as fistula or airway narrowing.21,22 Miller et al22 found that eight of 103 patients with unresectable non-small cell lung cancer (NSCLC) experienced symptomatic bronchial stenosis with doses ranging from 73.6 to 86.4 Gy; a dose-response relationship was suggested, supported by a 9% rate of stenosis at 74 Gy, 6% at 80 Gy, and 25% at 86 Gy. The majority of patients with bronchial stenosis received induction chemotherapy, and it is unclear whether that played a role in the development of airway toxicity. Interestingly, Kelsey et al21 reported that at doses . 73.6 Gy, stenosis occurred within the bronchi but not in the trachea, suggestive of differential tolerances among structures that comprise the airway. In contrast, Jeremic et al23 documented delayed tracheal toxicity after doses of 70 Gy. Notably, most of the high-dose thoracic radiotherapy toxicity data have been gathered from patients with locally advanced NSCLC, of whom a majority receives concurrent or sequential chemotherapy.24 Lee et al25 also reported on late toxicities among patients with NSCLC treated with radiotherapy from 66 to 90 Gy, most with concurrent chemotherapy, and found no longterm toxicity in the 80-Gy group. At higher doses—82, 86, and 90 Gy—more patients experienced pulmonary late toxicity than those who did not, with a latency of 2 to 7 months. There are also phase 1 data for dose escalation with radiotherapy alone in NSCLC; Sura et al26 reported on radiotherapy for inoperable NSCLC where the majority of patients had stage III disease and doses were safely escalated to 84 Gy. This is of particular relevance to our report since both patients were also treated with radiotherapy alone. Finally, the QUANTEC (quantitative analysis of normal tissue effects in the clinic) report suggests that limiting the dose to 80 Gy or lower using standard fractionation may reduce the risk of central airway stenosis.27 Regarding the use of high-dose proton therapy, a dosimetric comparative study of IMRT, passive scattering protons, and intensity modulated protons for locally advanced lung cancer found that with intensity modulated proton CHEST / 141 / 5 / MAY, 2012
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dose could be escalated to 83.5 Gy while maintaining sparing of heart, lung, spinal cord, and esophagus.28 We hypothesize that as a result of using advanced techniques, long-term toxicity will be diminished.
13. 14.
Conclusion Treatment of tracheal ACC is challenging, particularly when faced with borderline resectable or unresectable cases. In the available literature, although radiotherapy has been put forth as the appropriate therapy for unresectable disease, doses reported, which range from 40 to 72 Gy have had varying success.15,29,30 To our knowledge, this is the first report documenting treatment strategy and outcomes for tracheal ACC with radiotherapy to 80 Gy as well as the first report of proton therapy for unresected tracheal ACC. Based on our experience with a maximum follow-up of 6 years, this dose appears feasible and safe when highly conformal treatment techniques are implemented.
15. 16. 17. 18.
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Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
21. 22.
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Selected Reports
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