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Pitfalls in Oncologic Imaging: Complications of Chemotherapy and Radiotherapy in the Chest
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Pitfalls in Oncologic Imaging: Complications of Chemotherapy and Radiotherapy in the Chest Chitra Viswanathan MD, Brett W. Carter MD, Girish S. Shroff MD, Myrna C.B. Godoy MD, Edith M. Marom MD, Mylene T. Truong MD
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S0037-198X(15)00008-5 http://dx.doi.org/10.1053/j.ro.2015.01.007 YSROE50507
To appear in:
Seminar in Roentgenology
Cite this article as: Chitra Viswanathan MD, Brett W. Carter MD, Girish S. Shroff MD, Myrna C.B. Godoy MD, Edith M. Marom MD, Mylene T. Truong MD, Pitfalls in Oncologic Imaging: Complications of Chemotherapy and Radiotherapy in the Chest, Seminar in Roentgenology, http://dx.doi.org/10.1053/j.ro.2015.01.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pitfalls in Oncologic Imaging: Complications of Chemotherapy and Radiotherapy in the Chest Chitra Viswanathan MD1 Brett W. Carter, MD2 Girish S. Shroff, MD2 Myrna C. B. Godoy, MD2 Edith M. Marom, MD3 Mylene T. Truong, MD2 Corresponding Author: Chitra Viswanathan Department of Diagnostic Imaging UT MD Anderson Cancer Center 1 1515 Holcombe Boulevard, Unit 1473 Houston, Texas 77030 [email protected] Fax 713.745.1302 Telephone 713.470.8440 *The authors have no disclosures.
All other authors: 2
Department of Diagnostic Imaging UT MD Anderson Cancer Center 3 Department of Diagnostic Imaging The Chaim Sheba Medical Center Tel Hashomer, Israel
Pitfalls in Oncologic Imaging: Complications of Chemotherapy and Radiotherapy in the Chest Introduction Advances in cancer chemotherapy and radiation therapy continue to improve patients’ lives and impact patient care. Chemotherapy has progressed from cytotoxic agents to newer targeted agents that are geared to attack specific mutations in the cancer cell. The toxicities of these newer cytotoxic drugs and targeted agents have specific imaging
appearances depending on the mechanism of action. Similarly, advances in radiation therapy allow for better delivery to the tumor, with less effect on normal adjacent structures. Knowledge of the imaging appearance of toxicities of therapy is crucial for the radiologist to accurately diagnose complications of therapy and to avoid imaging pitfalls. The radiologist must utilize the clinical history and mechanism of action of the drugs in order to impact patient care and prevent misdiagnosis. In this article we will review some of the common pitfalls of imaging that arise due to complications of therapy. Chemotherapy Cytotoxic chemotherapy is based on interfering with rapidly dividing cells and interrupting deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis. These include intercalating agents such as cisplatin and the newer agent oxaliplatin. Topoisomerase inhibitors include irinotecan and topotecan. Antimetabolites include methotrexate and gemcitabine. The expected toxicities are seen in the gastrointestinal system and bone marrow, but toxicity may also be seen in other rapidly growing cells, such as in the thorax (methotrexate, gemcitabine). The newer targeted therapies are designed to target receptors on the cell, and therefore the toxic effects may be more widespread. The mechanism of action may be helpful in determining the toxicity. Drugs that target the vascular endothelial growth factor (VEGF) receptor include bevacizumab, sorafenib, sunitib, and pazopanib.
Erlotinib and Gefitinib target the epidermal growth factor receptor (EGFR). Everolimus and temsirolimus target the mammalian target of rapamycin (mTor). Drugs targeting the transmembrane protein with tyrosine kinase (kit) receptor include imatinib and sunitinib. Rituximab targets the B‐lymphocyte antigen CD20 receptor. Ipilimumab is an example of an immunomodulating agent that exerts effects upon T cell receptors.
These agents may have more toxicities seen on imaging than the conventional agents. Radiation Technology in radiation therapy has evolved in order to give the greatest dose to the tumor and decrease the effect on the normal tissues. The new technologies include intensity‐modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT) and proton therapy (PT). Acute effects usually manifest in the first 3 months of therapy and may be a precursor for chronic effects, which typically occur after 1 year. Chemotherapy Lung Complications Pulmonary Toxicity
Lung toxicity due to chemotherapy may occur during the start of, during, or after many years of treatment. Risk factors include advanced age, smoking history, history of pre‐ existing lung disease, prior radiation, or concurrent chemotherapy and radiation. Multiple agents including the cytotoxic therapies and the newer cytotoxic and the targeted therapies can cause pulmonary toxicity. There are many different patterns of pulmonary toxicity, including hypersensitivity pneumonitis,
nonspecific
interstitial
pneumonitis,
cryptogenic
organizing
pneumonia/bronchiolitis obliterans, and diffuse alveolar damage. A sample list of agents that cause pulmonary toxicity is listed in Table 1[1‐4]. Computed tomography (CT) findings include ground glass nodules and opacities, reticular nodules, interstitial opacities, consolidative opacities. Findings vary amongst the causative agents (Figures 1‐3). Correlation with the type of chemotherapy and timing of chemotherapy is crucial. Drug toxicity is a potential imaging pitfall, as the varied imaging presentations can mimic pneumonia and metastatic disease. Treatment is with cessation of the agent and corticosteroids[5]. Pulmonary hemorrhage While diffuse alveolar hemorrhage has been reported with hematological malignancies treated with chemotherapy and stem cell transplantation, severe pulmonary hemorrhage (PH) has now been reported as a toxicity of some of the targeted therapy agents. Bevacizumab has been associated with fatal PH; the risk factors include
squamous histology, baseline tumor cavitation, and vessel infiltration[6, 7]. Drugs such as sorafenib and sunitinib have also been reported to cause pulmonary hemorrhage[3, 8]. Drugs such as rituximab used in treatment of lymphoma and gefitinib are also associated with pulmonary hemorrhage. On CT, there are bilateral ground glass opacities that represent alveolar filling with blood. “Crazy paving” may be present[9, 10]. Pleural Complications Pleural Effusion Chemotherapy agents can cause fluid retention as a result of their mechanism of action. If patient has interval development of significant pleural effusion, it may due to therapy rather than metastatic disease. For example, imatinib and dasatinib may cause fluid retention due to their effect on the platelet derived growth factor (PDGF) pathway[5]. Gemcitabine acts on the capillaries, causing capillary leak and leading to pleural effusion. Methotrexate and paclitaxel can also have similar effect. If patients are symptomatic, then cessation of the agent is necessary. Thoracentesis may be required in recurrent and refractory cases. Talc pleurodesis Talc pleurodesis is performed for the treatment of recurrent pleural effusion or pneumothorax. The pleural space then takes on a nodular and thickened appearance.
The talc nodules which develop in the parietal pleura cause an inflammatory reaction, which may be F‐18‐fluorodeoxyglucose (FDG)‐avid on positron emission tomography‐ computed tomography (PET‐CT) and mimic metastatic disease[11] (Figure 4) . Pneumothorax Spontaneous pneumothorax has also been reported as a complication of chemotherapy. It is thought that the tumor response causes necrosis in the tumor, causing it to rupture in the pleural space, leading to pneumothorax[12, 13]. Vascular Complications Vasculitis Vasculitis of the head and neck and thoracic vasculature has been reported with patients treated with gemcitabine. Other agents reported to cause vasculitis are Tamoxifen, filgastrim and anastrazole. Patient symptoms include fever, pain and swelling after the administration of chemotherapy[14]. On imaging, the affected vessel walls are thickened and show uniform contrast enhancement[15]. The thickened wall of the vessel may be metabolically active on PET‐CT due to inflammatory change and may mimic a node, a potential pitfall. Knowledge of this complication is essential to recognize this entity and alert the clinician to start treatment with steroids and stop the causative agent.
Thrombus and Hemorrhage Arterial and venous thrombosis and hemorrhage occur as a result of anti‐angiogenic therapy. Drugs such as thalidomide can cause venous thromboembolism. The older agents such as cisplatin and newer agents such as bevacizumab, sunitinib and sorafenib are associated with arterial thromboembolism due to their action on the VEGF receptor[4, 16]. There is also an increased risk of hemorrhage with the VEGF/VEGFR agents[17]. Patients present with hypotension and a change in their hemoglobin and hematocrit (Figure 5). Aortic Dissection Aortic dissection may occur as a result of hypertension in patients treated with the anti‐ angiogenesis agents bevacizumab, sunitinib and sorafenib. Hypertension is the most common side effect of bevacizumab. These drugs induce development of hypertension or worsening of pre‐existing hypertension through their actions on the VEGF receptor. These drugs should be used with caution in patients with pre‐existing hypertension. Careful attention should be paid to the patients blood pressure while on therapy to prevent this complication[18]. Cardiac Complications
Chemotherapy can have toxic effects upon the heart. There are two types of cardiac effects, one that is dose related and cumulative causing myocyte death, and the other not dose related or cumulative and causing cell dysfunction or hibernation. Risk factors include advanced age, peripheral and coronary artery disease, and medical comorbities. Toxicities due to chemotherapy include arrhythmias, coronary artery disease, cardiomyopathy, hypertension and left ventricular dysfunction, pericardial effusion, and acute coronary syndrome[19, 20]. Patients may present with cardiac tamponade that may mimic a malignant pericardial effusion. Radiation Lung Disease Risk factors for radiation induced lung disease are divided into patient risk factors such as underlying lung conditions, chemotherapy and tumor location near mediastinum and nerves, and therapy‐related factors, such as dose and the characteristics of the radiation. Radiation changes may be present for up to 15 months after completion of radiotherapy. Radiation effects can be divided into early phase which is 1‐6 months after completion of radiation, and late phase 6‐12 months or longer after completion of radiation.
Patients may present with dyspnea and cough, fever and chest pain. Chronic fibrosis may cause cor pulmonale. On imaging, the acute phase may have ground glass and consolidative opacities. These findings may be FDG‐avid on PET‐CT, mimicking recurrent disease and pneumonia. Radiation changes are typically confined to the radiation treatment plan and evolve over time (Figure 6). Chronic fibrosis may cause volume loss, scarring, pleural thickening and ipsilateral displacement of the mediastinum. Other long‐term effects such as bronchopleural fistula and sinus tracts may occur [21, 22] (Figure 7). Esophageal Disease The incidence of radiation related complications are increased with the administration of concurrent chemotherapy. Acute complications include esophagitis and esophageal dysmotility. Chronic complications of radiation include strictures, tracheoesophageal fistula, and radiation induced esophageal cancer. Patients may develop symptoms starting 2 weeks after the initiation of therapy. Inflammation, ulceration or strictures can be metabolically active on PET‐CT and can be misinterpreted as recurrent or residual disease[23, 24] (Figure 8). Cardiac Disease
The effects of radiation on the heart are most frequently seen in patients that are younger treated for Hodgkin’s disease, those that receive mediastinal radiation > 30 Gy and higher dose techniques. It can occur at lesser doses in patients treated for breast cancer. Complications of radiation to the heart include vasculopathy, coronary artery disease, ascending aorta calcification, and pericardial disease, including pericardial effusion and pericardial thickening. Pericardial effusion may be seen soon after therapy, and pericardial thickening can occur greater than 48 months after therapy. The other cardiac effects usually present years after exposure to radiation[25, 26]. Bone Disease Benign Bone Conditions Radiation injury to the bone can result in fractures, osteoradionecrosis, and osteomyelitis[25, 27]. Findings may mimic metastatic disease (Figure 9). Secondary Malignancy Radiation induced secondary malignancy is a complication of radiation that may occur any time from a few years to fifty years after the treatment. The characteristics of a postradiation sarcoma include the history of radiation, time lapse from radiation to onset of tumor, location within the radiation treatment plan, and pathologic finding of
sarcoma[28]. The most common radiation induced tumors of bone are osteosarcomas, and the most common soft tissue sarcoma due to radiation is malignant fibrous histiocytoma[29]. Imaging findings include soft tissue mass, abnormal enhancement, and bony destruction (Figure 10). This may mimic metastatic disease or infection. Conclusion In conclusion, it is critical that the radiologist be aware of the imaging appearance of complications of therapy in order to avoid these potential pitfalls and provide accurate and timely information to the clinician to impact patient management. References 1. Myung HJ, Jeong SH, Kim JW, et al. Sorafenib‐induced interstitial pneumonitis in a patient with hepatocellular carcinoma: a case report. Gut and liver 2010; 4:543‐546 2. Ryu JH. Chemotherapy‐Induced Pulmonary Toxicity in Lung Cancer Patients. Journal of Thoracic Oncology 2010; 5:1313‐1314 1310. 3. Sharma N, Pennell N, Nickolich M, et al. Phase II trial of Sorafenib in conjunction with chemotherapy and as maintenance therapy in extensive‐ stage small cell lung cancer. Invest New Drugs 2014; 32:362‐368 4. Vahid B, Marik PE. Pulmonary complications of novel antineoplastic agents for solid tumors. Chest 2008; 133:528‐538 5. Chikarmane SA, Khurana B, Krajewski KM, et al. What the emergency radiologist needs to know about treatment‐related complications from conventional chemotherapy and newer molecular targeted agents. Emergency radiology 2012; 19:535‐546
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Reck M, Barlesi F, Crinò L, et al. Predicting and managing the risk of pulmonary haemorrhage in patients with NSCLC treated with bevacizumab: a consensus report from a panel of experts. Annals of Oncology 2012; 23(5):1111‐20 Sandler AB, Schiller JH, Gray R, et al. Retrospective evaluation of the clinical and radiographic risk factors associated with severe pulmonary hemorrhage in first‐line advanced, unresectable non‐small‐cell lung cancer treated with Carboplatin and Paclitaxel plus bevacizumab. J Clin Oncol 2009; 27:1405‐ 1412 Yamada T, Ohtsubo K, Izumi K, et al. Metastatic renal cell carcinoma complicated with diffuse alveolar hemorrhage: a rare adverse effect of sunitinib. Int J Clin Oncol 2010; 15:638‐641 Spira D, Wirths S, Skowronski F, et al. Diffuse alveolar hemorrhage in patients with hematological malignancies: HRCT patterns of pulmonary involvement and disease course. Clinical Imaging; 37:680‐686 Torrisi JM, Schwartz LH, Gollub MJ, Ginsberg MS, Bosl GJ, Hricak H. CT Findings of Chemotherapy‐induced Toxicity: What Radiologists Need to Know about the Clinical and Radiologic Manifestations of Chemotherapy Toxicity. Radiology 2011; 258:41‐56 Asad S, Aquino SL, Piyavisetpat N, Fischman AJ. False‐positive FDG positron emission tomography uptake in nonmalignant chest abnormalities. AJR American journal of roentgenology 2004; 182:983‐989 Leslie MD, Napier M, Glaser MG. Pneumothorax as a complication of tumour response to chemotherapy. Clinical oncology 1993; 5:181‐182 Anupama Upadya MD, Yaw Amoateng‐Adjepong MD, Raymond G. Haddad MD. Recurrent Bilateral Spontaneous Pneumothorax Complicating Chemotherapy for Metastatic Sarcoma. Southern Medical Journal 2003; 96:821‐823 Ramsay LB, Stany MP, Edison JD, Bernstein SA, Schlegal KE, Hamilton CA. Gemcitabine‐Associated Large Vessel Vasculitis Presenting as Fever of Unknown Origin. JCR: Journal of Clinical Rheumatology 2010; 16:181‐182 Bendix N, Glodny B, Bernathova M, Bodner G. Sonography and CT of Vasculitis During Gemcitabine Therapy. American Journal of Roentgenology 2005; 184:S14‐S15 Fernandes DD, Louzada ML, Souza CA, Matzinger F. Acute aortic thrombosis in patients receiving cisplatin‐based chemotherapy. Current oncology 2011; 18:e97‐e100 Zangari M, Fink LM, Elice F, Zhan F, Adcock DM, Tricot GJ. Thrombotic events in patients with cancer receiving antiangiogenesis agents. J Clin Oncol 2009; 27:4865‐4873 Aragon‐Ching JB, Ning YM, Dahut WL. Acute aortic dissection in a hypertensive patient with prostate cancer undergoing chemotherapy containing bevacizumab. Acta oncologica 2008; 47:1600‐1601 Tan T, Scherrer‐Crosbie M. Cardiac Complications of Chemotherapy: Role of Imaging. Curr Treat Options Cardio Med 2014; 16:1‐19
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Walker CM, Saldana DA, Gladish GW, et al. Cardiac complications of oncologic therapy. Radiographics : a review publication of the Radiological Society of North America, Inc 2013; 33:1801‐1815 Choi YW, Munden RF, Erasmus JJ, et al. Effects of Radiation Therapy on the Lung: Radiologic Appearances and Differential Diagnosis. Radiographics : a review publication of the Radiological Society of North America, Inc 2004; 24:985‐997 Benveniste MF, Welsh J, Godoy MC, Betancourt SL, Mawlawi OR, Munden RF. New era of radiotherapy: an update in radiation‐induced lung disease. Clinical radiology 2013; 68:e275‐290 Bruzzi JF, Munden RF, Truong MT, et al. PET/CT of esophageal cancer: its role in clinical management. Radiographics : a review publication of the Radiological Society of North America, Inc 2007; 27:1635‐1652 Erasmus JJ, Munden RF, Truong MT, et al. Preoperative chemo‐radiation‐ induced ulceration in patients with esophageal cancer: a confounding factor in tumor response assessment in integrated computed tomographic‐positron emission tomographic imaging. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2006; 1:478‐486 Libshitz HI, DuBrow RA, Loyer EM, Charnsangavej C. Radiation change in normal organs: an overview of body imaging. European radiology 1996; 6:786‐795 Mesurolle B, Qanadli SD, Merad M, et al. Unusual radiologic findings in the thorax after radiation therapy. Radiographics : a review publication of the Radiological Society of North America, Inc 2000; 20:67‐81 Takahashi I, Kaneyasu Y, Yamamoto Y, et al. Radiation‐induced pyogenic vertebral osteomyelitis after re‐irradiation for para‐aortic lymph node metastases in a patient with cervical cancer. Int Canc Conf J 2014:1‐4 Hall EJ, Wuu CS. Radiation‐induced second cancers: the impact of 3D‐CRT and IMRT. International journal of radiation oncology, biology, physics 2003; 56:83‐88 Gladdy RA, Qin L‐X, Moraco N, et al. Do Radiation‐Associated Soft Tissue Sarcomas Have the Same Prognosis As Sporadic Soft Tissue Sarcomas? Journal of Clinical Oncology 2010; 28:2064‐2069
Figurre Legends s Figurre 1. Pulmonary toxiccity due to chemothera c apy - Bleom mycin. 33-yyear-old fema ale with Hod dgkin’s lymphoma trea ated with Ad driamycin, Bleomycin,, Vinblastine, dac carbazine, and a rituximab for 7 mo onths. Patient develop ped progressive pulmonary opa acities throughout both lungs, co ompatible with w drug B mycin, the patient p wen nt toxiccity due to Bleomycin. Despite disscontinuation of Bleom on to o develop pneumothor p races, pneu umomediastinum and subcutaneo s ous emph hysema as a result of the lung disease. A, B. Axial CT Ts in lung windows w and d show w diffuse gro ound glass opacities throughout t both lungs and air in the t pleural spacce, mediastinum and subcutaneo s us tissues. As her Ble eomycin rellated drug toxiccity was sterroid refractive, patient required care in the In ntensive Ca are Unit and ventiilatory supp port.
A
B
Figurre 2. Pulmo onary toxicity due to ch hemotherap py: temsiro olimus. 69--year-old fema ale with mettastatic metaplastic brreast cance er treated with w temsirolimus prese ented with cough and malaise. A, A B. Axial CT scans show s bilate eral lower lobe consolidatiive opacitie es and meta astatic nodu ule in right middle m lobe e. nchoscopy yielded y neg gative culturres and cyttology was negative fo or malignant Bron cells. Temsiroliimus was discontinued d d, and patie ent was sta arted on steroids for presu umed drug toxicity. C, C D. Axial CT C scans tw wo months after disco ontinuation of tem msirolimus and startin ng steroids show s impro ovement in the bilatera al lower lobe opacities. Metastatic M nodule is slightly large er. Patient also reportted marked ovement in her well-be eing and co ough after starting s sterroids. impro A
C
B
D
Figurre 3. Pulmo onary toxicity due to ch hemotherap py- gemcita abine and docetaxel. d 45-ye ear-old male with radia ation-inducced angiosa arcoma of th he left claviicle treated with 3 months of o gemcitab bine and docetaxel afte er progresssion on pacllitaxel and acizumab. Patient hass had increa asing shortn ness of bre eath, mild dry cough, beva and upper u respiratory symptoms. Axxial CT lung window sh hows bilaterral perihilarr linea ar and consolidative op pacities and d peribronchovascularr thickening g with effussions, and differential d c consideratio ons include e pneumoniia, lymphan ngitic spread of tum mor and drrug toxicity. Bronchosccopy was performed p a showed and d no signs of ma alignancy and a culturess were nega ative. Drug g toxicity du ue to gemciitabine mayy prese ent in this fashion f and d mimic infe ection and metastatic m d disease.
Figurre 4. Talc pleurodesis p s. 64-year-old female with historyy of a T2 N1 stage IIB non-small cell lu ung cancerr treated witth right middle lobecto omy and talcc T-CT perforrmed 2 years later sho ows continu ued FDG pleurrodesis. A.. Axial PET avidity in the ple eural space e. B. Axial correspond ding CT shows these areas of uptakke correspo onding to th he high atte enuation talc deposits (arrows). The FDG avid pleural rea action due to o talc should not be co onfused witth recurrencce or meta astasis. The inflamma atory reactio on produced by talc may persist years y after the procedure. p If the pleura al thickenin ng increases, then susspicion musst be raised for tu umor. A
B
Figurre 5. Hemo orrhage due e to rituximab. 74-year-old female e with marg ginal zone lymp phoma treatted with 10 days of ritu uximab and d bendamusstine presenting with hypo otension, sh hortness of breath and d chest pain n. A. Axial CT C prior to therapy show ws right paratracheal adenopathy a y. B. Axial CT after the initiation of chem motherapy shows s deve elopment off high atten nuation fluid d within the mediiastinum an nd bilateral pleurae, co onsistent with hemorrh hage. Rituxximab is a mono oclonal antibody used for treatme ent of lymphoma and rheumatoid d arthritis and is i also asso ociated with h pulmonarry toxicity. Symptoms S of hypotension should d raise e suspicion for hemorrhage in pattients taking g Rituximab b.
A
B
Figurre 6. Radia ation Induce ed Lung Injjury. 67-year-old male e with right upper lobe squa amous cell carcinoma c treated with h chemorad diation. A. Axial CT sh hows the prima ary tumor in n the right upper u lobe (arrow). B. Restaging CT 3 montths after the e start of radiation n shows a new n cavitarry lesion in the right up pper lobe (w white arrow w). Because e of its foca ality within the t radiation treatment plan and irregular appe earance, the e lesion wa as suspiciou us for metastatic disea ase. C. PE ET-CT show wed mild inc crease in FDG-avidity in the rightt upper lobe e cavitary le esion. The lesion was biopsied, and pathology p showed lung g parenchym ma with exttensive c inflammation and neccrotizing pn neumonitis without ma alignancy. D. D fibrossis, chronic Follo ow up CT 5 months aftter the startt of radiation shows filling in of the cavitary lesion and deve elopment off other adja acent opacitties, consisstent with ra adiation chan nge. B
C
A
D
Figurre 7. Radia ation Induce ed Fistula/S Sinus tract to t superior vena cava (SVC). 75 year old female e with stage e IV lung cancer with bilateral b lung g tumors with left hilarr ph nodes tre eated with chemoradia c ation with proton thera apy to the le eft lung and d lymp convventional fra actionation radiation th herapy to th he right hila ar nodes two o years prior. Patient has had long g history off recurrent infections and a radiation fibrosis. ent presents s with coug gh, fever an nd shortness of breath. Axial CT scan Patie show wed a new linear l air co ollection exttending from m the trach hea to the SVC S (arrow). The combinatio on of radiatio on fibrosis and chronicc infection predispose ed the ent to development of this t tract. patie
Figurre 8. Radia ation Induce ed Esophag geal Strictu ure. 80-yea ar-old male with historyy of recurrent Can ndida esophagitis diag gnosed with h esophage eal adenoca arcinoma att diation. Pattient had sig gnificant 25-29 cm and trreated with concurrentt chemorad p e dysphagia a 8 months after treatm ment. A. Axial A CT for restaging and progressive show ws thickenin ng of the wa all of the mid esophag gus (white arrow) a with an adjacen nt enlarrged node. B. Coron nal PET-CT T shows a lo ong segmen nt of FDG-a avidity within the treate ed mid esop phagus (arrrow). C. En ndoscopic image show ws esop phagitis and d stricture at a 26-cm. D. Patient underwent dilation d of th he stricture with relief of dys sphagia. Post-radiatio P on complica ations are a potential pitfall p as they may have FDG-avidity and mimic malignan ncy.
A
B
C
D
Figurre 9. Radia ation Induce ed Osteomyelitis. 50-year-old female with small s cell carciinoma treatted with che emoradiatio on to the rig ght lower lo obe 3 years prior and radia ation to the right upperr lobe 2 yea ars prior. A.. Axial conttrast enhan nced CT in bone e algorithm showed rig ght mediasttinal and hilar soft tissu ue and cavitary chan nges in the right lung with w destrucction of the adjacent ve ertebral bod dies. B. Axiall PET-CT showed s incrreased FDG G-avidity in the right lu ung soft tisssues conssistent with tumor recurrence. FDG-avid scle erotic chang ges of T5 and a T6 are susp picious for metastatic m d disease. C. Sagittal MRI M T1 Fat Saturated S im mage post contrrast showed d enhancem ment of T5 and T6, su uspicious fo or metastaticc disease. Biopsy showed osteomyelitis and diskitis.
A.
B
C
Figurre 10. Rad diation Inducced Sarcom ma. 45-yea ar-old male treated with mediiastinal radiation at ag ge 6 for acu ute lymphob blastic leuke emia develo oped arm pain and weakn ness. Axial CT of the thorax t show w a soft tisssue mass (a arrow) with he left clavicle. Biopsyy showed angiosarcom a ma. This iss a radiation ndestrruction of th inducced sarcom ma given the e long laten ncy period from f the rad diation trea atment to deve elopment off the tumor (39 years), history of radiation r to o the mediastinum, and d patho ologic findin ngs.
Table 1. Possible causative agents of pulmonary toxicity Bleomycin
Cytotoxic
Paclitaxel
Cytotoxic
Oxaliplatin
Cytotoxic
Everolimus, temsirolimus Gefitinib
mTor
Erlotinib
TKI HER1/EGFR
Imatinib Sorafenib
TKI MKI
TKI EGFR
Pulmonary opacities Ground glass opacities Interstitial opacities Interstitial opacities interstitial pneumonitis, diffuse alveolar damage, fibrosis and alveolar hemorrhage. Severe pneumonitis and respiratory failure Pneumonitis Interstitial Pneumonitis
Abbreviations: mTor mammalian target of rapamycin TKI Tyrosine Kinase Inhibitor EGFR endothelial growth factor receptor STKI serine/threonine kinase inhibitor HER human epidermal growth factor receptor MKI multitargeted kinase inhibitors GIST gastrointestinal stromal tumor CML chronic myelogenous leukemia HCC hepatocellular carcinoma
Leukemia Breast Cancer Colon cancer Lung cancer, renal cell Lung cancer
Lung cancer
GIST, CML HCC, renal cell
Pitfalls in Oncologic Imaging: Complications of Chemotherapy and Radiotherapy in the Chest Chitra Viswanathan MD, Brett W. Carter MD, Girish S. Shroff MD, Myrna C.B. Godoy MD, Edith M. Marom MD, Mylene T. Truong MD
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S0037-198X(15)00008-5 http://dx.doi.org/10.1053/j.ro.2015.01.007 YSROE50507
To appear in:
Seminar in Roentgenology
Cite this article as: Chitra Viswanathan MD, Brett W. Carter MD, Girish S. Shroff MD, Myrna C.B. Godoy MD, Edith M. Marom MD, Mylene T. Truong MD, Pitfalls in Oncologic Imaging: Complications of Chemotherapy and Radiotherapy in the Chest, Seminar in Roentgenology, http://dx.doi.org/10.1053/j.ro.2015.01.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pitfalls in Oncologic Imaging: Complications of Chemotherapy and Radiotherapy in the Chest Chitra Viswanathan MD1 Brett W. Carter, MD2 Girish S. Shroff, MD2 Myrna C. B. Godoy, MD2 Edith M. Marom, MD3 Mylene T. Truong, MD2 Corresponding Author: Chitra Viswanathan Department of Diagnostic Imaging UT MD Anderson Cancer Center 1 1515 Holcombe Boulevard, Unit 1473 Houston, Texas 77030 [email protected] Fax 713.745.1302 Telephone 713.470.8440 *The authors have no disclosures.
All other authors: 2
Department of Diagnostic Imaging UT MD Anderson Cancer Center 3 Department of Diagnostic Imaging The Chaim Sheba Medical Center Tel Hashomer, Israel
Pitfalls in Oncologic Imaging: Complications of Chemotherapy and Radiotherapy in the Chest Introduction Advances in cancer chemotherapy and radiation therapy continue to improve patients’ lives and impact patient care. Chemotherapy has progressed from cytotoxic agents to newer targeted agents that are geared to attack specific mutations in the cancer cell. The toxicities of these newer cytotoxic drugs and targeted agents have specific imaging
appearances depending on the mechanism of action. Similarly, advances in radiation therapy allow for better delivery to the tumor, with less effect on normal adjacent structures. Knowledge of the imaging appearance of toxicities of therapy is crucial for the radiologist to accurately diagnose complications of therapy and to avoid imaging pitfalls. The radiologist must utilize the clinical history and mechanism of action of the drugs in order to impact patient care and prevent misdiagnosis. In this article we will review some of the common pitfalls of imaging that arise due to complications of therapy. Chemotherapy Cytotoxic chemotherapy is based on interfering with rapidly dividing cells and interrupting deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis. These include intercalating agents such as cisplatin and the newer agent oxaliplatin. Topoisomerase inhibitors include irinotecan and topotecan. Antimetabolites include methotrexate and gemcitabine. The expected toxicities are seen in the gastrointestinal system and bone marrow, but toxicity may also be seen in other rapidly growing cells, such as in the thorax (methotrexate, gemcitabine). The newer targeted therapies are designed to target receptors on the cell, and therefore the toxic effects may be more widespread. The mechanism of action may be helpful in determining the toxicity. Drugs that target the vascular endothelial growth factor (VEGF) receptor include bevacizumab, sorafenib, sunitib, and pazopanib.
Erlotinib and Gefitinib target the epidermal growth factor receptor (EGFR). Everolimus and temsirolimus target the mammalian target of rapamycin (mTor). Drugs targeting the transmembrane protein with tyrosine kinase (kit) receptor include imatinib and sunitinib. Rituximab targets the B‐lymphocyte antigen CD20 receptor. Ipilimumab is an example of an immunomodulating agent that exerts effects upon T cell receptors.
These agents may have more toxicities seen on imaging than the conventional agents. Radiation Technology in radiation therapy has evolved in order to give the greatest dose to the tumor and decrease the effect on the normal tissues. The new technologies include intensity‐modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT) and proton therapy (PT). Acute effects usually manifest in the first 3 months of therapy and may be a precursor for chronic effects, which typically occur after 1 year. Chemotherapy Lung Complications Pulmonary Toxicity
Lung toxicity due to chemotherapy may occur during the start of, during, or after many years of treatment. Risk factors include advanced age, smoking history, history of pre‐ existing lung disease, prior radiation, or concurrent chemotherapy and radiation. Multiple agents including the cytotoxic therapies and the newer cytotoxic and the targeted therapies can cause pulmonary toxicity. There are many different patterns of pulmonary toxicity, including hypersensitivity pneumonitis,
nonspecific
interstitial
pneumonitis,
cryptogenic
organizing
pneumonia/bronchiolitis obliterans, and diffuse alveolar damage. A sample list of agents that cause pulmonary toxicity is listed in Table 1[1‐4]. Computed tomography (CT) findings include ground glass nodules and opacities, reticular nodules, interstitial opacities, consolidative opacities. Findings vary amongst the causative agents (Figures 1‐3). Correlation with the type of chemotherapy and timing of chemotherapy is crucial. Drug toxicity is a potential imaging pitfall, as the varied imaging presentations can mimic pneumonia and metastatic disease. Treatment is with cessation of the agent and corticosteroids[5]. Pulmonary hemorrhage While diffuse alveolar hemorrhage has been reported with hematological malignancies treated with chemotherapy and stem cell transplantation, severe pulmonary hemorrhage (PH) has now been reported as a toxicity of some of the targeted therapy agents. Bevacizumab has been associated with fatal PH; the risk factors include
squamous histology, baseline tumor cavitation, and vessel infiltration[6, 7]. Drugs such as sorafenib and sunitinib have also been reported to cause pulmonary hemorrhage[3, 8]. Drugs such as rituximab used in treatment of lymphoma and gefitinib are also associated with pulmonary hemorrhage. On CT, there are bilateral ground glass opacities that represent alveolar filling with blood. “Crazy paving” may be present[9, 10]. Pleural Complications Pleural Effusion Chemotherapy agents can cause fluid retention as a result of their mechanism of action. If patient has interval development of significant pleural effusion, it may due to therapy rather than metastatic disease. For example, imatinib and dasatinib may cause fluid retention due to their effect on the platelet derived growth factor (PDGF) pathway[5]. Gemcitabine acts on the capillaries, causing capillary leak and leading to pleural effusion. Methotrexate and paclitaxel can also have similar effect. If patients are symptomatic, then cessation of the agent is necessary. Thoracentesis may be required in recurrent and refractory cases. Talc pleurodesis Talc pleurodesis is performed for the treatment of recurrent pleural effusion or pneumothorax. The pleural space then takes on a nodular and thickened appearance.
The talc nodules which develop in the parietal pleura cause an inflammatory reaction, which may be F‐18‐fluorodeoxyglucose (FDG)‐avid on positron emission tomography‐ computed tomography (PET‐CT) and mimic metastatic disease[11] (Figure 4) . Pneumothorax Spontaneous pneumothorax has also been reported as a complication of chemotherapy. It is thought that the tumor response causes necrosis in the tumor, causing it to rupture in the pleural space, leading to pneumothorax[12, 13]. Vascular Complications Vasculitis Vasculitis of the head and neck and thoracic vasculature has been reported with patients treated with gemcitabine. Other agents reported to cause vasculitis are Tamoxifen, filgastrim and anastrazole. Patient symptoms include fever, pain and swelling after the administration of chemotherapy[14]. On imaging, the affected vessel walls are thickened and show uniform contrast enhancement[15]. The thickened wall of the vessel may be metabolically active on PET‐CT due to inflammatory change and may mimic a node, a potential pitfall. Knowledge of this complication is essential to recognize this entity and alert the clinician to start treatment with steroids and stop the causative agent.
Thrombus and Hemorrhage Arterial and venous thrombosis and hemorrhage occur as a result of anti‐angiogenic therapy. Drugs such as thalidomide can cause venous thromboembolism. The older agents such as cisplatin and newer agents such as bevacizumab, sunitinib and sorafenib are associated with arterial thromboembolism due to their action on the VEGF receptor[4, 16]. There is also an increased risk of hemorrhage with the VEGF/VEGFR agents[17]. Patients present with hypotension and a change in their hemoglobin and hematocrit (Figure 5). Aortic Dissection Aortic dissection may occur as a result of hypertension in patients treated with the anti‐ angiogenesis agents bevacizumab, sunitinib and sorafenib. Hypertension is the most common side effect of bevacizumab. These drugs induce development of hypertension or worsening of pre‐existing hypertension through their actions on the VEGF receptor. These drugs should be used with caution in patients with pre‐existing hypertension. Careful attention should be paid to the patients blood pressure while on therapy to prevent this complication[18]. Cardiac Complications
Chemotherapy can have toxic effects upon the heart. There are two types of cardiac effects, one that is dose related and cumulative causing myocyte death, and the other not dose related or cumulative and causing cell dysfunction or hibernation. Risk factors include advanced age, peripheral and coronary artery disease, and medical comorbities. Toxicities due to chemotherapy include arrhythmias, coronary artery disease, cardiomyopathy, hypertension and left ventricular dysfunction, pericardial effusion, and acute coronary syndrome[19, 20]. Patients may present with cardiac tamponade that may mimic a malignant pericardial effusion. Radiation Lung Disease Risk factors for radiation induced lung disease are divided into patient risk factors such as underlying lung conditions, chemotherapy and tumor location near mediastinum and nerves, and therapy‐related factors, such as dose and the characteristics of the radiation. Radiation changes may be present for up to 15 months after completion of radiotherapy. Radiation effects can be divided into early phase which is 1‐6 months after completion of radiation, and late phase 6‐12 months or longer after completion of radiation.
Patients may present with dyspnea and cough, fever and chest pain. Chronic fibrosis may cause cor pulmonale. On imaging, the acute phase may have ground glass and consolidative opacities. These findings may be FDG‐avid on PET‐CT, mimicking recurrent disease and pneumonia. Radiation changes are typically confined to the radiation treatment plan and evolve over time (Figure 6). Chronic fibrosis may cause volume loss, scarring, pleural thickening and ipsilateral displacement of the mediastinum. Other long‐term effects such as bronchopleural fistula and sinus tracts may occur [21, 22] (Figure 7). Esophageal Disease The incidence of radiation related complications are increased with the administration of concurrent chemotherapy. Acute complications include esophagitis and esophageal dysmotility. Chronic complications of radiation include strictures, tracheoesophageal fistula, and radiation induced esophageal cancer. Patients may develop symptoms starting 2 weeks after the initiation of therapy. Inflammation, ulceration or strictures can be metabolically active on PET‐CT and can be misinterpreted as recurrent or residual disease[23, 24] (Figure 8). Cardiac Disease
The effects of radiation on the heart are most frequently seen in patients that are younger treated for Hodgkin’s disease, those that receive mediastinal radiation > 30 Gy and higher dose techniques. It can occur at lesser doses in patients treated for breast cancer. Complications of radiation to the heart include vasculopathy, coronary artery disease, ascending aorta calcification, and pericardial disease, including pericardial effusion and pericardial thickening. Pericardial effusion may be seen soon after therapy, and pericardial thickening can occur greater than 48 months after therapy. The other cardiac effects usually present years after exposure to radiation[25, 26]. Bone Disease Benign Bone Conditions Radiation injury to the bone can result in fractures, osteoradionecrosis, and osteomyelitis[25, 27]. Findings may mimic metastatic disease (Figure 9). Secondary Malignancy Radiation induced secondary malignancy is a complication of radiation that may occur any time from a few years to fifty years after the treatment. The characteristics of a postradiation sarcoma include the history of radiation, time lapse from radiation to onset of tumor, location within the radiation treatment plan, and pathologic finding of
sarcoma[28]. The most common radiation induced tumors of bone are osteosarcomas, and the most common soft tissue sarcoma due to radiation is malignant fibrous histiocytoma[29]. Imaging findings include soft tissue mass, abnormal enhancement, and bony destruction (Figure 10). This may mimic metastatic disease or infection. Conclusion In conclusion, it is critical that the radiologist be aware of the imaging appearance of complications of therapy in order to avoid these potential pitfalls and provide accurate and timely information to the clinician to impact patient management. References 1. Myung HJ, Jeong SH, Kim JW, et al. Sorafenib‐induced interstitial pneumonitis in a patient with hepatocellular carcinoma: a case report. Gut and liver 2010; 4:543‐546 2. Ryu JH. Chemotherapy‐Induced Pulmonary Toxicity in Lung Cancer Patients. Journal of Thoracic Oncology 2010; 5:1313‐1314 1310. 3. Sharma N, Pennell N, Nickolich M, et al. Phase II trial of Sorafenib in conjunction with chemotherapy and as maintenance therapy in extensive‐ stage small cell lung cancer. Invest New Drugs 2014; 32:362‐368 4. Vahid B, Marik PE. Pulmonary complications of novel antineoplastic agents for solid tumors. Chest 2008; 133:528‐538 5. Chikarmane SA, Khurana B, Krajewski KM, et al. What the emergency radiologist needs to know about treatment‐related complications from conventional chemotherapy and newer molecular targeted agents. Emergency radiology 2012; 19:535‐546
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Figurre Legends s Figurre 1. Pulmonary toxiccity due to chemothera c apy - Bleom mycin. 33-yyear-old fema ale with Hod dgkin’s lymphoma trea ated with Ad driamycin, Bleomycin,, Vinblastine, dac carbazine, and a rituximab for 7 mo onths. Patient develop ped progressive pulmonary opa acities throughout both lungs, co ompatible with w drug B mycin, the patient p wen nt toxiccity due to Bleomycin. Despite disscontinuation of Bleom on to o develop pneumothor p races, pneu umomediastinum and subcutaneo s ous emph hysema as a result of the lung disease. A, B. Axial CT Ts in lung windows w and d show w diffuse gro ound glass opacities throughout t both lungs and air in the t pleural spacce, mediastinum and subcutaneo s us tissues. As her Ble eomycin rellated drug toxiccity was sterroid refractive, patient required care in the In ntensive Ca are Unit and ventiilatory supp port.
A
B
Figurre 2. Pulmo onary toxicity due to ch hemotherap py: temsiro olimus. 69--year-old fema ale with mettastatic metaplastic brreast cance er treated with w temsirolimus prese ented with cough and malaise. A, A B. Axial CT scans show s bilate eral lower lobe consolidatiive opacitie es and meta astatic nodu ule in right middle m lobe e. nchoscopy yielded y neg gative culturres and cyttology was negative fo or malignant Bron cells. Temsiroliimus was discontinued d d, and patie ent was sta arted on steroids for presu umed drug toxicity. C, C D. Axial CT C scans tw wo months after disco ontinuation of tem msirolimus and startin ng steroids show s impro ovement in the bilatera al lower lobe opacities. Metastatic M nodule is slightly large er. Patient also reportted marked ovement in her well-be eing and co ough after starting s sterroids. impro A
C
B
D
Figurre 3. Pulmo onary toxicity due to ch hemotherap py- gemcita abine and docetaxel. d 45-ye ear-old male with radia ation-inducced angiosa arcoma of th he left claviicle treated with 3 months of o gemcitab bine and docetaxel afte er progresssion on pacllitaxel and acizumab. Patient hass had increa asing shortn ness of bre eath, mild dry cough, beva and upper u respiratory symptoms. Axxial CT lung window sh hows bilaterral perihilarr linea ar and consolidative op pacities and d peribronchovascularr thickening g with effussions, and differential d c consideratio ons include e pneumoniia, lymphan ngitic spread of tum mor and drrug toxicity. Bronchosccopy was performed p a showed and d no signs of ma alignancy and a culturess were nega ative. Drug g toxicity du ue to gemciitabine mayy prese ent in this fashion f and d mimic infe ection and metastatic m d disease.
Figurre 4. Talc pleurodesis p s. 64-year-old female with historyy of a T2 N1 stage IIB non-small cell lu ung cancerr treated witth right middle lobecto omy and talcc T-CT perforrmed 2 years later sho ows continu ued FDG pleurrodesis. A.. Axial PET avidity in the ple eural space e. B. Axial correspond ding CT shows these areas of uptakke correspo onding to th he high atte enuation talc deposits (arrows). The FDG avid pleural rea action due to o talc should not be co onfused witth recurrencce or meta astasis. The inflamma atory reactio on produced by talc may persist years y after the procedure. p If the pleura al thickenin ng increases, then susspicion musst be raised for tu umor. A
B
Figurre 5. Hemo orrhage due e to rituximab. 74-year-old female e with marg ginal zone lymp phoma treatted with 10 days of ritu uximab and d bendamusstine presenting with hypo otension, sh hortness of breath and d chest pain n. A. Axial CT C prior to therapy show ws right paratracheal adenopathy a y. B. Axial CT after the initiation of chem motherapy shows s deve elopment off high atten nuation fluid d within the mediiastinum an nd bilateral pleurae, co onsistent with hemorrh hage. Rituxximab is a mono oclonal antibody used for treatme ent of lymphoma and rheumatoid d arthritis and is i also asso ociated with h pulmonarry toxicity. Symptoms S of hypotension should d raise e suspicion for hemorrhage in pattients taking g Rituximab b.
A
B
Figurre 6. Radia ation Induce ed Lung Injjury. 67-year-old male e with right upper lobe squa amous cell carcinoma c treated with h chemorad diation. A. Axial CT sh hows the prima ary tumor in n the right upper u lobe (arrow). B. Restaging CT 3 montths after the e start of radiation n shows a new n cavitarry lesion in the right up pper lobe (w white arrow w). Because e of its foca ality within the t radiation treatment plan and irregular appe earance, the e lesion wa as suspiciou us for metastatic disea ase. C. PE ET-CT show wed mild inc crease in FDG-avidity in the rightt upper lobe e cavitary le esion. The lesion was biopsied, and pathology p showed lung g parenchym ma with exttensive c inflammation and neccrotizing pn neumonitis without ma alignancy. D. D fibrossis, chronic Follo ow up CT 5 months aftter the startt of radiation shows filling in of the cavitary lesion and deve elopment off other adja acent opacitties, consisstent with ra adiation chan nge. B
C
A
D
Figurre 7. Radia ation Induce ed Fistula/S Sinus tract to t superior vena cava (SVC). 75 year old female e with stage e IV lung cancer with bilateral b lung g tumors with left hilarr ph nodes tre eated with chemoradia c ation with proton thera apy to the le eft lung and d lymp convventional fra actionation radiation th herapy to th he right hila ar nodes two o years prior. Patient has had long g history off recurrent infections and a radiation fibrosis. ent presents s with coug gh, fever an nd shortness of breath. Axial CT scan Patie show wed a new linear l air co ollection exttending from m the trach hea to the SVC S (arrow). The combinatio on of radiatio on fibrosis and chronicc infection predispose ed the ent to development of this t tract. patie
Figurre 8. Radia ation Induce ed Esophag geal Strictu ure. 80-yea ar-old male with historyy of recurrent Can ndida esophagitis diag gnosed with h esophage eal adenoca arcinoma att diation. Pattient had sig gnificant 25-29 cm and trreated with concurrentt chemorad p e dysphagia a 8 months after treatm ment. A. Axial A CT for restaging and progressive show ws thickenin ng of the wa all of the mid esophag gus (white arrow) a with an adjacen nt enlarrged node. B. Coron nal PET-CT T shows a lo ong segmen nt of FDG-a avidity within the treate ed mid esop phagus (arrrow). C. En ndoscopic image show ws esop phagitis and d stricture at a 26-cm. D. Patient underwent dilation d of th he stricture with relief of dys sphagia. Post-radiatio P on complica ations are a potential pitfall p as they may have FDG-avidity and mimic malignan ncy.
A
B
C
D
Figurre 9. Radia ation Induce ed Osteomyelitis. 50-year-old female with small s cell carciinoma treatted with che emoradiatio on to the rig ght lower lo obe 3 years prior and radia ation to the right upperr lobe 2 yea ars prior. A.. Axial conttrast enhan nced CT in bone e algorithm showed rig ght mediasttinal and hilar soft tissu ue and cavitary chan nges in the right lung with w destrucction of the adjacent ve ertebral bod dies. B. Axiall PET-CT showed s incrreased FDG G-avidity in the right lu ung soft tisssues conssistent with tumor recurrence. FDG-avid scle erotic chang ges of T5 and a T6 are susp picious for metastatic m d disease. C. Sagittal MRI M T1 Fat Saturated S im mage post contrrast showed d enhancem ment of T5 and T6, su uspicious fo or metastaticc disease. Biopsy showed osteomyelitis and diskitis.
A.
B
C
Figurre 10. Rad diation Inducced Sarcom ma. 45-yea ar-old male treated with mediiastinal radiation at ag ge 6 for acu ute lymphob blastic leuke emia develo oped arm pain and weakn ness. Axial CT of the thorax t show w a soft tisssue mass (a arrow) with he left clavicle. Biopsyy showed angiosarcom a ma. This iss a radiation ndestrruction of th inducced sarcom ma given the e long laten ncy period from f the rad diation trea atment to deve elopment off the tumor (39 years), history of radiation r to o the mediastinum, and d patho ologic findin ngs.
Table 1. Possible causative agents of pulmonary toxicity Bleomycin
Cytotoxic
Paclitaxel
Cytotoxic
Oxaliplatin
Cytotoxic
Everolimus, temsirolimus Gefitinib
mTor
Erlotinib
TKI HER1/EGFR
Imatinib Sorafenib
TKI MKI
TKI EGFR
Pulmonary opacities Ground glass opacities Interstitial opacities Interstitial opacities interstitial pneumonitis, diffuse alveolar damage, fibrosis and alveolar hemorrhage. Severe pneumonitis and respiratory failure Pneumonitis Interstitial Pneumonitis
Abbreviations: mTor mammalian target of rapamycin TKI Tyrosine Kinase Inhibitor EGFR endothelial growth factor receptor STKI serine/threonine kinase inhibitor HER human epidermal growth factor receptor MKI multitargeted kinase inhibitors GIST gastrointestinal stromal tumor CML chronic myelogenous leukemia HCC hepatocellular carcinoma
Leukemia Breast Cancer Colon cancer Lung cancer, renal cell Lung cancer
Lung cancer
GIST, CML HCC, renal cell