Skeletal Radiol (2015) 44:451–455 DOI 10.1007/s00256-014-1996-1

CASE REPORT

Gemcitabine-induced radiation recall myositis Joshua Adam Delavan & Junzo P. Chino & Emily N. Vinson

Received: 12 June 2014 / Revised: 31 July 2014 / Accepted: 20 August 2014 / Published online: 6 September 2014 # ISS 2014

Abstract Radiation recall is an uncommon phenomenon in which administration of a chemotherapeutic agent induces an acute inflammatory reaction in previously irradiated tissues, often weeks to years after completion of radiotherapy. This entity is well known to medical and radiation oncologists, however only three cases have been reported in radiology journals. We present a case of gemcitabine-induced radiation recall that manifested as myositis with associated dermatitis in the posterior thigh of a patient with remote history of localized radiotherapy for biopsy-proven breast cancer metastasis. We also present a brief literature review to update the topic of radiation recall in imaging, and emphasize the importance of knowledge of this phenomenon when considering the differential diagnosis of myositis/dermatitis in a patient who has received cancer treatment. Keywords Radiation recall . Myositis . Gemcitabine

initially described by D’Angio et al. in 1959 as inflammation of a prior radiation site after administration of actinomycin D [1]. Many other chemotherapeutic agents have since been implicated in radiation recall. Gemcitabine has been well documented as a causative agent [2], however to our knowledge, radiation recall myositis and dermatitis have not been reported in radiology journals since the landmark case in 1959, and gemcitabine-induced radiation recall has never been reported in radiology journals. We present a case of gemcitabine-induced radiation recall that manifested as myositis greater than dermatitis in the posterior thigh of a patient with a remote history of localized radiotherapy for biopsy-proven breast cancer metastasis. We also present a brief literature review to update the topic of radiation recall in imaging, and emphasize the importance of knowledge of this phenomenon when considering the differential diagnosis of myositis/dermatitis in a patient who has received cancer treatment.

Introduction Case report Radiation recall is an uncommon phenomenon in which administration of a chemotherapeutic agent induces an acute inflammatory reaction in previously irradiated tissues, often weeks to years after completion of radiotherapy. It was J. A. Delavan (*) : E. N. Vinson Department of Radiology, Duke University Medical Center, Box 3808, Durham, NC 27710, USA e-mail: [email protected] E. N. Vinson e-mail: [email protected] J. P. Chino Department of Radiation Oncology, Duke University Medical Center, Box 3085, Durham, NC 27710, USA e-mail: [email protected]

A 54-year-old female patient with a history of metastatic infiltrating ductal breast carcinoma presented to the emergency department with 1 week of increasing pain and swelling in the posterior left thigh. A biopsy-proven left semimembranosis intramuscular metastasis was initially treated with single fraction radiation therapy (8 Gy × 1 fraction) 4 years prior, with subsequent progression of disease. Chemotherapeutic regimens from 4 years to 4 months prior to presentation included vinorelbine (Navelbine), bevacizumab (Avastin), eribulin, paclitaxel (Abraxane), and cisplatin. Four months prior to presentation, a second course of radiation therapy to the posterior left thigh was completed (3 Gy × 13 fractions). Gemcitabine was then administered from 3 to 1 months prior to presentation. She presented to the emergency

452

department 107 days after completing the final course of radiotherapy to the thigh, 90 days after the first dose of gemcitabine, and 27 days after the final dose of gemcitabine. She was afebrile and mildly tachycardic. Vital signs were otherwise normal. There was obvious asymmetric enlargement of the left thigh with firmness and warmth to palpation, however no erythema, ulceration, or crepitus were present (Fig. 1). Skin thickening was present in the posterior thigh coinciding with the prior radiation field. Laboratory studies at presentation were remarkable for leukocytosis. Ultrasound of the left lower extremity was negative for deep venous thrombosis. Radiographs of the left thigh showed nonspecific soft tissue swelling. Empiric antibiotics were initiated for cellulitis, however a lack of erythema in light of marked thigh asymmetry led the treatment team to favor inflammatory changes related to underlying cancer progression or medication/radiation reaction, over infection. Magnetic resonance (MR) imaging, obtained the following day after a lack of symptom subsidence on antibiotics, showed a decreased size of the soft tissue metastasis in the left semimembranosis muscle since the previous study obtained 8 months prior, however marked increase in signal intensity throughout the posterior worse than anterior thigh musculature, deep and superficial fascial planes, and subcutaneous fat on fat-suppressed T2-weighted images (Fig. 2).

Fig. 1 A 54-year-old female with metastatic breast carcinoma to the posterior left thigh and gemcitabine-induced radiation recall reaction 4 months after completion of radiotherapy. Note asymmetric enlargement of the left thigh without other signs of infection such as erythema, induration, ulceration, or crepitus

Skeletal Radiol (2015) 44:451–455

Given that edema was most pronounced in the region of remote posterior thigh radiation port, that symptoms were not improving on empiric antibiotics, and that the patient had recently received gemcitabine chemotherapy, the care team changed therapy from antibiotics to dexamethasone to treat presumed gemcitabine-induced radiation recall myositis. Her pain and swelling dramatically improved over 3 days of steroid administration. She was discharged without antibiotics on a slow steroid taper, and was symptom free upon follow-up 1 week later.

Discussion Radiation recall occurs when a chemotherapeutic agent, commonly gemcitabine, is given days to years after radiation therapy, causing an inflammatory reaction in the previously irradiated tissues, “recalling” increased radiation effects to those tissues. The specific mechanism is unknown, and many theories have been proposed, mainly related to chronic changes of localized tissue injury such as changes to DNA repair, vascular damage, epithelial stem cell inadequacy, or tissue hypersensitivity from radiation. The prevailing hypothesis is that radiation recall reactions are caused by idiosyncratic drug hypersensitivity reactions, possibly mediated by continued low-level secretion of inflammatory-mediated cytokines by the local tissues, induced by the initial radiation. Subsequent chemotherapy agents upregulate these cytokines, resulting in radiation recall reactions weeks to years after completion of radiotherapy [2–5]. Only three case reports of radiation recall have been reported in the radiology literature—the landmark case of dermatitis caused by actinomycin D in 1959 [1], esophagitis caused by adriamycin in 1979 [6], and pneumonitis caused by actinomycin D and adriamycin in 1993 [7]. Multiple medications have been implicated in radiation recall reactions, including anticancer agents [3], antibiotics [8], antituberculosis drugs [9], tamoxifen [10–12], simvastatin [13], and even exposure to ultraviolet light [14]. No common features of the drugs, drug classes, dosage, or regimen have been established. Reactions have occurred with a wide range of dosages of different drug classes [4]. Gemcitabine-induced radiation recall was first reported in 1999 by Welsh et al. [15], and gemcitabine has since been well documented as a causative agent [2], however to our knowledge, gemcitabine-induced radiation recall has never been reported in radiology journals. Differentiation should be made between radiation recall and radiosensitization. Radiosensitization is much more common than radiation recall and typically occurs within the first 7 days after radiotherapy, a window during which tissues may develop increased sensitivity to systemically administered drugs. Reactions brought about by drugs fewer than 7 days after radiotherapy should be considered radiosensitization

Skeletal Radiol (2015) 44:451–455

453

Fig. 2 A 54-year-old female with metastatic breast carcinoma and gemcitabine-induced radiation recall reaction. Axial (c) and coronal (d) fat-suppressed T2weighted images show a marked increase in T2 hyperintense signal throughout the posterior musculature, deep and superficial fascial planes, and subcutaneous fat since 8 months prior (a and b), despite decreased size of the intramuscular metastasis (arrows). Edema has also increased anteriorly, but less pronounced than in the posterior radiation field

(a)

(b)

(c)

(d)

rather than radiation recall [5]. Radiation recall is differentiated by a delayed recurrence of symptoms—more than 7 days— after completion of radiotherapy, suggesting the mechanism may be different from that of radiosensitization. Radiation recall symptoms have been reported to occur from weeks to years after radiotherapy [3, 4, 16, 17], triggered by subsequent chemotherapeutic agents. One case of recall dermatitis occurred with pemetrexed administered 25 years after completion of radiotherapy, and occurred again in the same radiation field after rechallenge with pemetrexed [17]. Although widely variable, the average time interval between the end of radiotherapy and initiation of precipitating chemotherapy averages approximately 40 days, based on a collection of case reports [5]. Once chemotherapy has been administered, radiation recall usually develops hours to days later. Our

patient presented 107 days after completing radiotherapy to the thigh, 90 days after the first dose of gemcitabine, and 27 days after the final dose of gemcitabine, supporting the timeline variability of the relationship of initial radiotherapy with subsequent chemotherapy and symptom development. Radiation recall reactions can involve multiple organs including the lungs, oral mucosa, gastrointestinal system, genitourinary tract, central nervous system, muscles, and skin, and always occur in previously irradiated tissues [4]. Skin reactions comprise approximately two-thirds of all radiation recall cases [4] and are managed clinically, therefore most cases are unlikely to be imaged. Gemcitabine is an antimetabolite nucleoside analogue that incorporates into replicating tumoral DNA and leads to cellular apoptosis. It is commonly used in the treatment of breast,

454

lung, ovarian, pancreatic, soft tissue, and hematologic cancers. Contrary to most radiation recall-precipitating chemotherapeutic agents, which typically cause dermatitis, gemcitabineinduced radiation recall reactions predominately manifest as myositis [2, 18]. While gemcitabine typically causes myositis in remote radiation ports, gemcitabine-induced multifocal myositis has also been reported in patients who had either never been irradiated or who developed symptoms outside of a radiation port [19], and this was likely due to a systemic drug reaction rather than a radiation recall reaction. While myositis is the most common presentation with gemcitabine, cases of radiation recall duodenitis [20], brainstem necrosis, typhlitis, colitis, and optic neuritis [21] have also been reported. Since the diagnosis of radiation recall is often based on clinical history, treatment timeline, and physical exam findings, and since the majority of cases manifest as dermatitis and myositis, the diagnostic radiologist may rarely encounter this entity. However, patients experiencing radiation recall may be initially evaluated by clinicians unfamiliar with this entity, and depending on their symptoms at presentation may be referred for imaging evaluation due to concern for a potentially infectious etiology, as happened in our case. In addition, given the familiarity of radiation recall to medical and radiation oncologists, it is important for the diagnostic radiologist to become familiar with radiation recall imaging findings. Radiographs and computed tomography (CT) may show nonspecific soft tissue swelling and edema. As in our case, MR imaging shows increased signal intensity throughout the involved muscles, fascial planes, and subcutaneous fat on fatsuppressed T2-weighted images, most pronounced within the prior radiation port. Skin thickening may be present from prior radiation. Marrow changes are variable—normal, fatty replaced, or edematous—depending on the time interval since the most recent radiotherapy. Increasing dermatitis, myositis, and fasciitis in a remote radiotherapy port despite improving tumor burden, triggered by recent chemotherapy, are hallmarks of a radiation recall reaction. The differential diagnosis for nonspecific dermatitis, myositis, and fasciitis is broad and includes infection, acute drug reaction, acute radiation reaction, neurogenic etiologies, vasculitis, and diabetic myonecrosis (in the appropriate clinical setting). Radiation recall myositis and dermatitis can be differentiated from other causes of nonspecific edema by relatively sharp margins that extend in a non-anatomic orientation, correlating with a remote radiation port. Around a known metastasis, one differential consideration for increasing soft tissue edema includes worsening metastatic disease, differing from radiation recall in that tumor size and extent will have increased. Another consideration is focal inflammation from intratumoral necrosis or hemorrhage, in which new intratumoral cystic change or signal characteristics consistent with blood products will be present. Knowledge of radiation recall and increasingly accessible patient history in

Skeletal Radiol (2015) 44:451–455

electronic medical records should allow the radiologist to consider this phenomenon as part of the differential for myositis, dermatitis, and fasciitis in a patient who has received cancer treatment. No specific treatment option exists for radiation recall, as the pathophysiology is not well understood. Symptomatic and supportive therapy depends on the organ system involved and the severity of the reaction. Typically the precipitating agent is withdrawn. Corticosteroids and non-steroidal anti-inflammatory medications are administered, however some debate remains whether these medications actually speed recovery compared with the natural disease course once the offending agent has been removed [5]. Our patient dramatically improved upon steroid administration. Most case reports indicate that after steroid treatment and termination of gemcitabine, symptom resolution coincides with improved imaging findings. One recent case of gemcitabine-induced forearm myositis, the first published about a pediatric patient and the first associated with compartment syndrome, reported persistent abnormal imaging findings as far as 1 year after complete symptom resolution [2]. Although the etiology for this is not known for certain, perhaps chronic low-level cytokine upregulation in irradiated tissues is more robust in the pediatric population, allowing for longer-lasting subclinical imaging findings. Another factor may have been the development of compartment syndrome, perhaps causing more permanent microstructural damage compared to other less severe cases of myositis. Our case report does have some limitations. First, a tissue sample was not obtained, as the patient improved rapidly with steroids and the intramuscular mass had significantly decreased in size since comparison imaging, suggesting improved metastatic disease. Second, as detailed in the case report, the patient’s chemotherapy and radiation treatment regimen was complex during the 4 years leading up to the hospital admission and included multiple medications and two courses of radiation. The most recent regimen prior to presentation involved radiotherapy to the thigh followed by gemcitabine monotherapy, implicating gemcitabine-induced radiation recall. We can only infer the cause-and-effect relationship of gemcitabine and the radiation recall reaction, given the patient’s relatively benign response to her initial radiotherapy without concurrent gemcitabine, and given her rapid response to steroid therapy during the most recent presumed gemcitabine-induced radiation recall reaction. Third, she was initially treated with two doses of empiric antibiotics for presumed cellulitis and was switched to steroids thereafter. It is highly unlikely that the short regimen of antibiotics would have completely treated a mimicking case of infectious cellulitis, particularly since she responded dramatically to steroids, which would likely have worsened any underlying infection.

Skeletal Radiol (2015) 44:451–455

Conclusions Given the familiarity of radiation recall to medical and radiation oncologists, it is important for the diagnostic radiologist to know about the radiation recall phenomenon and imaging findings, which include increasing soft tissue edema in a remote radiotherapy port, triggered by recent chemotherapy (often gemcitabine), despite stable or improving tumor burden.

Conflict of interest The authors declare they have no conflicts of interest.

References 1. D’Angio GJ, Farber S, Maddock CL. Potentiation of X-ray effects by actinomycin D. Radiology. 1959;73:175–7. 2. Eckardt MA, Bean A, Selch MT, Federman N. A child with gemcitabine-induced severe radiation recall myositis resulting in a compartment syndrome. J Pediatr Hematol Oncol. 2013;35(2):156– 61. 3. Azria D, Magne N, Zouhair A, Castadot P, Culine S, Ychou M, et al. Radiation recall: a well-recognized but neglected phenomenon. Cancer Treat Rev. 2005;31(7):555–70. 4. Burris 3rd HA, Hurtig J. Radiation recall with anticancer agents. Oncologist. 2010;15(11):1227–37. 5. Camidge R, Price A. Characterizing the phenomenon of radiation recall dermatitis. Radiother Oncol. 2001;59(3):237–45. 6. Boal DK, Newburger PE, Teele RL. Esophagitis induced by combined radiation and adriamycin. AJR Am J Roentgenol. 1979;132(4): 567–70.

455 7. Ma LD, Taylor GA, Wharam MD, Wiley JM. "Recall" pneumonitis: adriamycin potentiation of radiation pneumonitis in two children. Radiology. 1993;187(2):465–7. 8. Garza LA, Yoo EK, Junkins-Hopkins JM, VanVoorhees AS. Photo recall effect in association with cefazolin. Cutis. 2004;73(1):79–80. 5. 9. Extermann M, Vogt N, Forni M, Dayer P. Radiation recall in a patient with breast cancer treated for tuberculosis. Eur J Clin Pharmacol. 1995;48(1):77–8. 10. Parry BR. Radiation recall induced by tamoxifen. Lancet. 1992;340(8810):49. 11. Bostrom A, Sjolin-Forsberg G, Wilking N, Bergh J. Radiation recall– another call with tamoxifen. Acta Oncol. 1999;38(7):955–9. 12. Singer EA, Warren RD, Pennanen MF, Collins BT, Hayes DF. Tamoxifen-induced radiation recall dermatitis. Breast J. 2004;10(2): 170–1. 13. Abadir R, Liebmann J. Radiation reaction recall following simvastatin therapy: a new observation. Clin Oncol (R Coll Radiol). 1995;7(5): 325–6. 14. Del Guidice SM, Gerstley JK. Sunlight-induced radiation recall. Int J Dermatol. 1988;27(6):415–6. 15. Welsh JS, Torre TG, DeWeese TL, O’Reilly S. Radiation myositis. Ann Oncol. 1999;10(9):1105–8. 16. Burdon J, Bell R, Sullivan J, Henderson M. Adriamycin-induced recall phenomenon 15 years after radiotherapy. JAMA. 1978;239(10):931. 17. Barlesi F, Tummino C, Tasei AM, Astoul P. Unsuccessful rechallenge with pemetrexed after a previous radiation recall dermatitis. Lung Cancer. 2006;54(3):423–5. 18. Friedlander PA, Bansal R, Schwartz L, Wagman R, Posner J, Kemeny N. Gemcitabine-related radiation recall preferentially involves internal tissue and organs. Cancer. 2004;100(9):1793–9. 19. Pentsova E, Liu A, Rosenblum M, O’Reilly E, Chen X, Hormigo A. Gemcitabine-induced myositis in patients with pancreatic cancer: case reports and topic review. J Neurooncol. 2012;106(1):15–21. 20. Saif MW, Sellers S, Russo S. Gemcitabine-related radiation recall in a patient with pancreatic cancer. Anticancer Drugs. 2006;17(1):107–11. 21. Jeter MD, Janne PA, Brooks S, Burstein HJ, Wen P, Fuchs CS, et al. Gemcitabine-induced radiation recall. Int J Radiat Oncol Biol Phys. 2002;53(2):394–400.

Gemcitabine-induced radiation recall myositis.

Radiation recall is an uncommon phenomenon in which administration of a chemotherapeutic agent induces an acute inflammatory reaction in previously ir...
528KB Sizes 0 Downloads 7 Views