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Radiation recall myositis: Two sites, one patient
PRRO-00334; No of Pages 4 Practical Radiation Oncology (2014) xx, xxx–xxx
www.practicalradonc.org
Teaching Case
Radiation recall myositis: Two sites, one patient Surbhi Grover MD, MPH a,⁎, Joshua A. Jones MD a , Ursina Teitelbaum MD b , Smith Apisarnthanarax MD c a
Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Department of Medicine, Division of Medical Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania c Department of Radiation Oncology, University of Washington, Seattle, Washington b
Received 18 January 2014; revised 18 March 2014; accepted 20 March 2014
Case presentation A 63 year-old-man presented to his physician with worsening left shoulder and left hip pain. Magnetic resonance imaging (MRI) of the shoulder was concerning for metastatic disease to the left acromion. Biopsy of this lesion revealed metastatic adenocarcinoma. Positron emission tomography and computed tomography revealed areas of increased fluorodeoxyglucose uptake in a large pancreatic tail lesion as well as in the thoracic spine, left lung, and left acetabulum. Fine needle aspiration of the pancreatic lesion showed 2 distinct tumor types: adenocarcinoma (TTF-1 negative) and neuroendocrine neoplasm. Further immunostains or tumor markers could not definitively identify the primary origin of the tumor. The patient was evaluated by oncology and was diagnosed with stage IV adenocarcinoma with neuroendocrine features of unknown primary (lung vs pancreas) with metastases to the thoracic spine, left acromion, and left acetabulum. Examination of the shoulder revealed fullness of the left acromion and tenderness on palpation. The left hip was uncomfortable although he could ambulate. His pain was managed adequately with multiple opioids. The left hip and left acromion were treated with palliative intent radiation therapy (RT) to 30 Gy in 10 daily Conflicts of interest: None. ⁎ Corresponding author. Hospital of the University of Pennsylvania, Department of Radiation Oncology, 3400 Civic Center Blvd, TRC 2W, Philadelphia, PA 19104. E-mail address: [email protected] (S. Grover).
fractions. Both sites were treated concurrently using anteroposterior or posteroanterior field arrangements. The patient had excellent pain relief and was completely off of his opioid regimen by the end of radiation. Gemcitabine (1250 mg/m 2) and carboplatin (area under the curve [AUC] 5) chemotherapy was initiated 2 weeks after RT. Four weeks post-RT, the patient developed worsening pain in his left shoulder and left hip. The pain was described as a “severe muscle ache” in the left hip. The MRI showed soft tissue edema of the muscles adjacent to the left acromion and the left hip. These areas of inflammation and edema in the hip and shoulder corresponded to the patient’s RT fields treated 1 month ago (Figs 1 and 2). Figure 1 shows the coronal view of the MRI of the left hip juxtaposed over patient’s hip RT fields, anatomically correlating well-defined area of myositis (arrows) with dose shown in color wash. Figure 2 shows the axial correlation with the dose color wash. The patient’s symptoms were thought be secondary to gemcitabine-associated radiation recall in the muscles within the RT field. He continued to require narcotics until his pain gradually resolved on its own 5 months after RT. He was continued on gemcitabine-based therapy.
Discussion The efficacy of palliative RT is well described in the literature and represents the standard of care for patients with uncomplicated bone metastases. 1 Approximately 25% of patients who receive palliative RT for uncomplicated bone metastases will have complete pain relief while
http://dx.doi.org/10.1016/j.prro.2014.03.009 1879-8500/© 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
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Practical Radiation Oncology: Month 2014
Figure 1 Coronal view of the magnetic resonance image of the left hip juxtaposed over patient’s hip radiation fields with anatomically correlating well-defined area of myositis (arrows) with dose shown in color wash.
a total 60% of patients will have complete or partial pain relief after RT. 2 For patients with recurrent pain after a response to palliative RT, understanding the etiology of the pain is necessary to provide optimal treatment. The differential diagnosis for recurrent pain at previously irradiated sites can be divided into the following 3 broad categories: pain related to progressive cancer; treatmentrelated morbidity; and nononcologic causes of pain (such as trauma, infection, etc). Treatment-related pain syndromes can include postsurgical pain syndromes (not relevant to this patient), systemic therapy reactions (such as gemcitabine-induced myositis or “pseudocellulitis”), and pain flare from RT or radiation recall reactions. As with any pain syndrome, a detailed pain history focused physical exam and indicated imaging is important. The history should include the intensity, quality, and character of pain, the time course of the pain, and precipitating, aggravating, and alleviating factors. 3 A brief improvement in pain followed by increase in worst pain score or immediate decrement of worst pain score after initiation of RT can indicate pain flare from radiation
therapy. 4 Pain from radiation-induced flare, by definition, would return to baseline within 10 days. Radiologic factors evaluated prior to RT (including lytic lesions, extent of cortical destruction, location of lesion) can predict a higher likelihood of subsequent pathologic fracture. 5,6 If there is no evidence of systemic or proximal disease progression, a suspected pain flare has not resolved, and there is no pathologic fracture, MRI of the site of progressive pain can evaluate for the presence of progressive disease and the presence of soft tissue reactions that could contribute to pain.
Radiation recall myositis The radiation recall reaction was first described in 1959 by D’Angio et al. 7 The recall of a radiation response long after the completion of RT has been described in almost all tissues. 8 While detailed data about incidence of radiation recall reactions are not available, these reactions appear to be rare based on small observational series. 9 Agents that may induce a radiation recall reaction include many antineoplastic drugs, antibiotics, and other nononcologic
Practical Radiation Oncology: Month 2014
Radiation recall myositis
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Figure 2 Axial view of the magnetic resonance image of the left hip juxtaposed over patient’s hip radiation fields with anatomically correlating well-defined area of myositis (arrows) with dose shown in color wash.
medications. Based on multiple reports, gemcitabine recall reactions appear to have a predilection for occurring in soft tissues and viscera, causing pain and even leading to compartment syndrome in 1 case. 10-13 It appears that larger separations in time between RT and systemic therapy may decrease the frequency of recall reactions, but radiation recall has been reported even up to 15 years after the completion of RT. 14 Dose per fraction and total RT dose also do not appear to impact incidence of recall reactions, although there is a suggestion from a single case report that higher RT doses can lead to more severe recall reactions. 15 The pathophysiology of radiation recall reactions also remains unclear, making diagnosis and management more challenging. Timing of occurrence of radiation recall is highly variable, ranging from a few weeks after treatment to months. 8 Unfortunately, given the paucity of data in the literature, there are no models for the prediction of which patients will develop radiation recall reactions nor which patients will have recall reactions to specific drugs. The management of radiation recall reactions is similarly unclear. Identifying the offending agent followed by cessation of that agent may result in resolution of
symptoms. However, decisions about whether or not to stop an efficacious systemic antineoplastic agent need to be weighed against the severity of symptoms. Options for symptom management without stopping the offending agent include treatment with corticosteroids, nonsteroidal anti-inflammatory drugs, and intensive pain management with opioids. In summary, radiation recall reaction should be considered in the differential diagnosis in cases of pain recurrence or flares in previously irradiated areas after systemic therapy and should be managed conservatively after other possible etiologies such as disease progression or pathologic fractures have been excluded.
References 1. Lutz S, Berk L, Chang E, et al. Palliative radiotherapy for bone metastases: An ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys. 2011;79:965-976. 2. Chow E, Zeng L, Salvo N, Dennis K, Tsao M, Lutz S. Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol (R Coll Radiol). 2012;24:112-124.
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3. Swarm R, Abernethy AP, Anghelescu DL, et al. Adult cancer pain. J Natl Compr Canc Netw. 2010;8:1046-1086. 4. Hird A, Chow E, Zhang L, et al. Determining the incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: Results from three Canadian cancer centers. Int J Radiat Oncol Biol Phys. 2009;75:193-197. 5. Harrington KD. Impending pathologic fractures from metastatic malignancy: Evaluation and management. Instr Course Lect. 1986;35:357-381. 6. Mirels H. Metastatic disease in long bones: A proposed scoring system for diagnosing impending pathologic fractures. 1989. Clin Orthop Relat Res. 2003;(415 Suppl):S4-13. 7. D'Angio GJ, Farber S, Maddock CL. Potentiation of x-ray effects by actinomycin D. Radiology. 1959;73:175-177. 8. Burris III HA, Hurtig J. Radiation recall with anticancer agents. Oncologist. 2010;15:1227-1237. 9. Kodym E, Kalinska R, Ehringfeld C, Sterbik-Lamina A, Kodym R, Hohenberg G. Frequency of radiation recall dermatitis in adult cancer patients. Onkologie. 2005;28:18-21.
Practical Radiation Oncology: Month 2014 10. Jeter MD, Jänne PA, Brooks S, et al. Gemcitabine-induced radiation recall. Int J Radiat Oncol Biol Phys. 2002;53:394-400. 11. Schwarte S, Wagner K, Karstens JH, Bremer M. Radiation recall pneumonitis induced by gemcitabine. Strahlenther Onkol. 2007;183: 215-217. 12. 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: 156-161. 13. 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: 1793-1799. 14. Burdon J, Bell R, Sullivan J, Henderson M. Adriamycin-induced recall phenomenon 15 years after radiotherapy. JAMA. 1978;239: 931. 15. Mallik S, Gupta S, Munshi A. Memoirs of differential radiation doses: Gemcitabine induced radiation recall. Acta Oncol. 2010;49: 261-262.
www.practicalradonc.org
Teaching Case
Radiation recall myositis: Two sites, one patient Surbhi Grover MD, MPH a,⁎, Joshua A. Jones MD a , Ursina Teitelbaum MD b , Smith Apisarnthanarax MD c a
Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Department of Medicine, Division of Medical Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania c Department of Radiation Oncology, University of Washington, Seattle, Washington b
Received 18 January 2014; revised 18 March 2014; accepted 20 March 2014
Case presentation A 63 year-old-man presented to his physician with worsening left shoulder and left hip pain. Magnetic resonance imaging (MRI) of the shoulder was concerning for metastatic disease to the left acromion. Biopsy of this lesion revealed metastatic adenocarcinoma. Positron emission tomography and computed tomography revealed areas of increased fluorodeoxyglucose uptake in a large pancreatic tail lesion as well as in the thoracic spine, left lung, and left acetabulum. Fine needle aspiration of the pancreatic lesion showed 2 distinct tumor types: adenocarcinoma (TTF-1 negative) and neuroendocrine neoplasm. Further immunostains or tumor markers could not definitively identify the primary origin of the tumor. The patient was evaluated by oncology and was diagnosed with stage IV adenocarcinoma with neuroendocrine features of unknown primary (lung vs pancreas) with metastases to the thoracic spine, left acromion, and left acetabulum. Examination of the shoulder revealed fullness of the left acromion and tenderness on palpation. The left hip was uncomfortable although he could ambulate. His pain was managed adequately with multiple opioids. The left hip and left acromion were treated with palliative intent radiation therapy (RT) to 30 Gy in 10 daily Conflicts of interest: None. ⁎ Corresponding author. Hospital of the University of Pennsylvania, Department of Radiation Oncology, 3400 Civic Center Blvd, TRC 2W, Philadelphia, PA 19104. E-mail address: [email protected] (S. Grover).
fractions. Both sites were treated concurrently using anteroposterior or posteroanterior field arrangements. The patient had excellent pain relief and was completely off of his opioid regimen by the end of radiation. Gemcitabine (1250 mg/m 2) and carboplatin (area under the curve [AUC] 5) chemotherapy was initiated 2 weeks after RT. Four weeks post-RT, the patient developed worsening pain in his left shoulder and left hip. The pain was described as a “severe muscle ache” in the left hip. The MRI showed soft tissue edema of the muscles adjacent to the left acromion and the left hip. These areas of inflammation and edema in the hip and shoulder corresponded to the patient’s RT fields treated 1 month ago (Figs 1 and 2). Figure 1 shows the coronal view of the MRI of the left hip juxtaposed over patient’s hip RT fields, anatomically correlating well-defined area of myositis (arrows) with dose shown in color wash. Figure 2 shows the axial correlation with the dose color wash. The patient’s symptoms were thought be secondary to gemcitabine-associated radiation recall in the muscles within the RT field. He continued to require narcotics until his pain gradually resolved on its own 5 months after RT. He was continued on gemcitabine-based therapy.
Discussion The efficacy of palliative RT is well described in the literature and represents the standard of care for patients with uncomplicated bone metastases. 1 Approximately 25% of patients who receive palliative RT for uncomplicated bone metastases will have complete pain relief while
http://dx.doi.org/10.1016/j.prro.2014.03.009 1879-8500/© 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
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S. Grover et al
Practical Radiation Oncology: Month 2014
Figure 1 Coronal view of the magnetic resonance image of the left hip juxtaposed over patient’s hip radiation fields with anatomically correlating well-defined area of myositis (arrows) with dose shown in color wash.
a total 60% of patients will have complete or partial pain relief after RT. 2 For patients with recurrent pain after a response to palliative RT, understanding the etiology of the pain is necessary to provide optimal treatment. The differential diagnosis for recurrent pain at previously irradiated sites can be divided into the following 3 broad categories: pain related to progressive cancer; treatmentrelated morbidity; and nononcologic causes of pain (such as trauma, infection, etc). Treatment-related pain syndromes can include postsurgical pain syndromes (not relevant to this patient), systemic therapy reactions (such as gemcitabine-induced myositis or “pseudocellulitis”), and pain flare from RT or radiation recall reactions. As with any pain syndrome, a detailed pain history focused physical exam and indicated imaging is important. The history should include the intensity, quality, and character of pain, the time course of the pain, and precipitating, aggravating, and alleviating factors. 3 A brief improvement in pain followed by increase in worst pain score or immediate decrement of worst pain score after initiation of RT can indicate pain flare from radiation
therapy. 4 Pain from radiation-induced flare, by definition, would return to baseline within 10 days. Radiologic factors evaluated prior to RT (including lytic lesions, extent of cortical destruction, location of lesion) can predict a higher likelihood of subsequent pathologic fracture. 5,6 If there is no evidence of systemic or proximal disease progression, a suspected pain flare has not resolved, and there is no pathologic fracture, MRI of the site of progressive pain can evaluate for the presence of progressive disease and the presence of soft tissue reactions that could contribute to pain.
Radiation recall myositis The radiation recall reaction was first described in 1959 by D’Angio et al. 7 The recall of a radiation response long after the completion of RT has been described in almost all tissues. 8 While detailed data about incidence of radiation recall reactions are not available, these reactions appear to be rare based on small observational series. 9 Agents that may induce a radiation recall reaction include many antineoplastic drugs, antibiotics, and other nononcologic
Practical Radiation Oncology: Month 2014
Radiation recall myositis
3
Figure 2 Axial view of the magnetic resonance image of the left hip juxtaposed over patient’s hip radiation fields with anatomically correlating well-defined area of myositis (arrows) with dose shown in color wash.
medications. Based on multiple reports, gemcitabine recall reactions appear to have a predilection for occurring in soft tissues and viscera, causing pain and even leading to compartment syndrome in 1 case. 10-13 It appears that larger separations in time between RT and systemic therapy may decrease the frequency of recall reactions, but radiation recall has been reported even up to 15 years after the completion of RT. 14 Dose per fraction and total RT dose also do not appear to impact incidence of recall reactions, although there is a suggestion from a single case report that higher RT doses can lead to more severe recall reactions. 15 The pathophysiology of radiation recall reactions also remains unclear, making diagnosis and management more challenging. Timing of occurrence of radiation recall is highly variable, ranging from a few weeks after treatment to months. 8 Unfortunately, given the paucity of data in the literature, there are no models for the prediction of which patients will develop radiation recall reactions nor which patients will have recall reactions to specific drugs. The management of radiation recall reactions is similarly unclear. Identifying the offending agent followed by cessation of that agent may result in resolution of
symptoms. However, decisions about whether or not to stop an efficacious systemic antineoplastic agent need to be weighed against the severity of symptoms. Options for symptom management without stopping the offending agent include treatment with corticosteroids, nonsteroidal anti-inflammatory drugs, and intensive pain management with opioids. In summary, radiation recall reaction should be considered in the differential diagnosis in cases of pain recurrence or flares in previously irradiated areas after systemic therapy and should be managed conservatively after other possible etiologies such as disease progression or pathologic fractures have been excluded.
References 1. Lutz S, Berk L, Chang E, et al. Palliative radiotherapy for bone metastases: An ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys. 2011;79:965-976. 2. Chow E, Zeng L, Salvo N, Dennis K, Tsao M, Lutz S. Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol (R Coll Radiol). 2012;24:112-124.
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3. Swarm R, Abernethy AP, Anghelescu DL, et al. Adult cancer pain. J Natl Compr Canc Netw. 2010;8:1046-1086. 4. Hird A, Chow E, Zhang L, et al. Determining the incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: Results from three Canadian cancer centers. Int J Radiat Oncol Biol Phys. 2009;75:193-197. 5. Harrington KD. Impending pathologic fractures from metastatic malignancy: Evaluation and management. Instr Course Lect. 1986;35:357-381. 6. Mirels H. Metastatic disease in long bones: A proposed scoring system for diagnosing impending pathologic fractures. 1989. Clin Orthop Relat Res. 2003;(415 Suppl):S4-13. 7. D'Angio GJ, Farber S, Maddock CL. Potentiation of x-ray effects by actinomycin D. Radiology. 1959;73:175-177. 8. Burris III HA, Hurtig J. Radiation recall with anticancer agents. Oncologist. 2010;15:1227-1237. 9. Kodym E, Kalinska R, Ehringfeld C, Sterbik-Lamina A, Kodym R, Hohenberg G. Frequency of radiation recall dermatitis in adult cancer patients. Onkologie. 2005;28:18-21.
Practical Radiation Oncology: Month 2014 10. Jeter MD, Jänne PA, Brooks S, et al. Gemcitabine-induced radiation recall. Int J Radiat Oncol Biol Phys. 2002;53:394-400. 11. Schwarte S, Wagner K, Karstens JH, Bremer M. Radiation recall pneumonitis induced by gemcitabine. Strahlenther Onkol. 2007;183: 215-217. 12. 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: 156-161. 13. 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: 1793-1799. 14. Burdon J, Bell R, Sullivan J, Henderson M. Adriamycin-induced recall phenomenon 15 years after radiotherapy. JAMA. 1978;239: 931. 15. Mallik S, Gupta S, Munshi A. Memoirs of differential radiation doses: Gemcitabine induced radiation recall. Acta Oncol. 2010;49: 261-262.