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Journal of Clinical Oncology, Vol 25, No 12 (April 20), 2007: pp. 1621-1623 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.3267
Radiation-Induced Sarcoma After High-Dose Thoracic Radiation Therapy in Non–Small-Cell Lung CancerMultidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, Chapel Hill, NC
Department of Pathology, University of North Carolina, Chapel Hill, NC
Division of Nuclear Medicine, University of North Carolina, Chapel Hill, NC
Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC A 61-year-old man initially presented in 1998 with an abnormal chest x-ray. A computed tomography (CT) scan was performed, which revealed a 2-cm right upper lobe lung mass and mediastinal lymphadenopathy. The patient underwent bronchoscopy, which revealed non–small-cell lung cancer (NSCLC), most consistent with squamous cell carcinoma, and mediastinoscopy which revealed involvement of the right paratracheal lymph nodes. Bone scan and head CT scan were negative for metastases, and the patient was considered to have T1N2MO disease. After obtaining informed consent, the patient was enrolled on a phase I/II trial investigating the role of induction chemotherapy with carboplatin and paclitaxel for two cycles followed by weekly with carboplatin and paclitaxel with dose escalating three-dimensional thoracic conformal radiation therapy (3D TCRT).1 This trial was approved by the protocol review committee of Lineberger Comprehensive Cancer Center (Chapel Hill, NC), and the institutional review board of the University of North Carolina (Chapel Hill, NC). The patient received 74 Gy to the right lung, hilum, and mediastinum. He tolerated the therapy without immediate complications and at his routine follow-up 8 years later he did not have symptoms for recurrence or evidence of recurrent disease on his chest x-ray. Approximately 2 months later the patient presented to an outside hospital with complaints of dysphagia with solids, anorexia, weight loss, right upper quadrant and right shoulder pain. A CT scan was performed which revealed a 2.4 x 2.2 cm mass anterior to the trachea and a 4.3 x 3.7 cm right adrenal mass. The patient underwent a positron emission tomography-CT scan which revealed increased [18F]fluorodeoxyglucose uptake in a right supraclavicular lymph node, mediastinal lymph nodes, the right adrenal, and the proximal third of the esophagus (Fig 1; upper arrow, esophageal mass; lower arrow, right adrenal). The initial differential diagnosis included recurrent NSCLC, a second primary NSCLC, small-cell lung cancer, and esophageal cancer. The patient underwent biopsies of the esophageal mass, adrenal mass, and mediastinal capsule wall.
The pathology results from the mediastinal capsule wall, right adrenal gland mass, and esophagus were examined microscopically and found to have a similar morphologic appearance to each other. Histologic sections revealed sheets of spindle cells with moderate to marked cytological atypia and foci of necrosis (Fig 2; hematoxylin and eosin [H&E], original magnification x 400). No evidence of epithelial differentiation was identified. A panel of immunohistochemical stains revealed the tumor cells to exhibit positive staining with vimentin (Fig 3; H&E, original magnification x 100) and negative staining with pancytokeratin (AE1/AE3;Fig 4; H&E, original magnification x 100), p63, and cytokeratin 5/6, mitigating against a diagnosis of recurrent squamous cell carcinoma. Additional diagnoses not supported by immunohistochemical findings include melanoma (S100, p75-NTR, and MART-1 negativity), angiosarcoma (CD31 and CD34 negativity), mesothelioma (cytokeratin 5/6, calretinin, and podoplanin negativity), leiomyosarcoma (smooth muscle actin negativity) and gastrointestinal stromal tumor (CD117 negativity). In light of the morphological and immunohistochemical findings, the biopsies were interpreted as malignant spindle cell neoplasm consistent with high grade sarcoma not otherwise specified. The pathology from the original diagnosis of NSCLC was reviewed, and no spindle cell proliferation was seen.
The development of radiation-induced solid tumors has been reported in patients who have received treatment with radiation therapy for Hodgkin's disease, breast cancer, and prostate cancer.2-4 An increased rate of soft tissue sarcomas have been reported after radiotherapy for prostate cancer and breast cancer.4,5 To the best of our knowledge, this is the first report of radiation-induced sarcoma related to curative chemoradiotherapy for stage III NSCLC. Radiation-induced sarcomas are a late complication, generally occurring 5-10 years after therapy, and the current median survival for stage III NSCLC is relatively modest, thus the population currently at risk for this complication may be limited. The median survival of patients treated on this protocol was 25 months, and the 5-year survival rate was 26%.6 However, given the high incidence of NSCLC as the number of long-term survivors from stage III NSCLC increases with therapeutic advances, the number of patients at risk for this complication will increase significantly. Radiation dose may be a factor in the development of second malignancies,3,7 and this patient received a higher dose of radiation therapy (74 Gy) than the current standard (60 Gy). Several phase I and phase II trials of dose escalation of 3D TCRT have been performed,8-10 and there is currently a phase III Intergroup trial in development investigating concurrent chemoradiotherapy with weekly carboplatin and paclitaxel with either standard dose (63 Gy) versus high-dose (74 Gy) 3D TCRT followed by consolidation carboplatin and paclitaxel.11 It is possible that as patients are treated with higher doses of radiotherapy the incidence of radiation-induced sarcomas may increase. Given the rarity of this complication and the current poor prognosis of patients with locally advanced NSCLC, it is unlikely that this complication would impact current treatment decisions. However, it will be important to be vigilant for this treatment-related complication since, if it occurs at a significant rate, it may impact the length of long-term follow-up of patients and the design of future clinical trials. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest.
REFERENCES 1. Socinski MA, Rosenman J, Halle J, et al: Induction carboplatin/paclitaxel followed by concurrent carboplatin/paclitaxel and dose-escalating conformal thoracic radiation therapy in unresectable stage IIIA/B non-small cell lung cancer: A modified phase I trial. Cancer 89:534-542, 2000[CrossRef][Medline] 2. Zablotska LB, Neugut AI: Lung carcinoma after radiation therapy in women treated with lumpectomy or mastectomy for primary breast carcinoma. Cancer 97:1404-1411, 2003[CrossRef][Medline] 3. Tinger A, Wasserman TH, Klein EE, et al: The incidence of breast cancer following mantle field radiation therapy as a function of dose and technique. Int J Radiat Oncol Biol Phys 37:865-870, 1997[CrossRef][Medline] 4. Brenner DJ, Curtis RE, Hall EJ, et al: Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer 88:398-406, 2000[CrossRef][Medline] 5. Yap J, Chuba PJ, Thomas R, et al: Sarcoma as a second malignancy after treatment for breast cancer. Int J Radiat Oncol Biol Phys 52:1231-1237, 2002[CrossRef][Medline] 6. Socinski M, Halle JS, Morris DE, et al: Long-term results of aggressive combined modality therapy employing induction and concurrent carboplatin/paclitaxel with dose-escalated thoracic conformal radiation therapy. Lung Cancer 41:S239, 2003 7. Hancock SL, Tucker MA, Hoppe RT: Breast cancer after treatment of Hodgkin's disease. J Natl Cancer Inst 85:25-31, 1993 8. Blackstock AW, Socinski MA, Bogart J, et al: Induction (Ind) plus concurrent (Con) chemotherapy with high-dose (74 Gy) 3-dimensional (3-D) thoracic radiotherapy (TRT) in stage III non-small cell lung cancer (NSCLC): Preliminary report of Cancer and Leukemia Group B (CALGB) 30105. J Clin Oncol 24: 374s, 2006 (abstr 7042) 9. Bradley J, Graham MV, Winter K, et al: Toxicity and outcome results of RTOG 9311: A phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys 61:318-328, 2005[CrossRef][Medline] 10. Schild SE, McGinnis WL, Graham D, et al: Results of a phase I trial of concurrent chemotherapy and escalating doses of radiation for unresectable non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 65:1106-1111, 2006[CrossRef][Medline] 11. Lee CB, Stinchcombe TE, Rosenman JG, et al: Therapeutic advances in local-regional therapy for stage III non–small-cell lung cancer: Evolving role of dose-escalated conformal (3-dimensional) radiation therapy. Clinical Lung Cancer 8:195-202, 2006[Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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