Successful treatment of severe extremity pain in myelofibrosis with low‐dose single‐fraction radiation therapy
Authors: Michelle A. Neben‐Wittich, Paul D. Brown, Ayalew Tefferi
Journal: American Journal of Hematology (2010)

Myelofibrosis (MF) is characterized by cytopenias/cytoses, leukoerythroblastic blood picture, bone marrow fibrosis, and extramedullary hematopoiesis. Extremity bone pain can be a feature of MF. There has been one case report of a patient with MF and bone pain treated with radiation. We treated five patients with MF and extremity pain with radiation at our institution between 2004 and 2010. All patients had severe pain unresponsive to narcotic medication. Radiation was one fraction of 100 to 600 cGy. Most patients saw improvement in the pain within days and achieved a complete response within days to weeks. The response lasted between 1 month and 2 years. Retreatment was performed in four patients and achieved a durable response in three patients. No patients reported any acute or late side effects from radiation. Bone involvement in MF can cause disabling pain, but single-fraction low-dose radiation is a safe and effective treatment, often leading to a durable response. Retreatment is also safe and effective in patients who experience recurrent pain. MF can occur as a de novo primary myelofibrosis (PMF) or can develop from a primary myeloproliferative disorder such as polycythemia vera (PV) or essential thrombocythemia (ET). Post-PV MF and post-ET MF refer to MF arising from PV and ET, respectively [1]. MF can be associated with extramedullary hematopoiesis, which can involve the liver, spleen, lungs, and other areas including bones [2-6]. Radiation treatment has been used for extramedullary hematopoiesis in the lungs, spleen, and spine with good symptomatic response [2, 7-13]. There are also reports of bone and joint involvement in MF [14-17]. Bone pain can be a presenting or late feature of MF. Pain is often in the metaphyses of long bones [18, 19] and has been attributed to hematopoiesis, periostitis, and osteosclerosis [14, 17, 19]. We present a series of five patients with MF and extremity pain treated with radiation at our institution between 2004 and 2010. Table I summarizes the clinical presentation, treatment, and outcome for these patients. Case 1 is a 45-year-old man diagnosed with post-PV MF in 2008. One year later, he developed excruciating 8–10/10 bone pain from mid-thigh to ankles. Oral and intravenous narcotics were ineffective, and he became wheelchair bound. A nuclear medicine bone marrow scan showed mild expansion of bone marrow within the distal femur, proximal tibia, and proximal humeri. Radiation was given to bilateral lower extremities from above the knees to the ankles. Two hundred centigray in one fraction was given with an anterioposterior/posterioanterior (AP/PA) field technique. Within 3 days of treatment he decreased his narcotics, within 10 days he noticed dramatic improvement in his pain, and by 2 weeks he was out of his wheelchair. He had persistent 4/10 pain after tapering off his narcotics, and a second 200 cGy dose of radiation was given 1 month later. Four days after the second course of radiation, he noticed significant improvement, and ∼1 week after the second course, he was pain free. This complete response has lasted 8 months at last followup. He subsequently developed bilateral upper extremity pain below the elbows. He rated the pain at a 5/10 even on pain medications and noted that the pain kept him up at night. He received a single radiation fraction of 200 cGy to bilateral upper extremities. Six days later, his pain had decreased to a 1/10 without the need for pain medications. He has been pain free for 4 months at last followup. Case 2 is a 60-year-old man diagnosed with post-PV MF. At that time, he presented with progressive severe lower and upper extremity pain that was not ameliorated by high-dose narcotics. A bone scan showed mildly increased uptake in the long bones, pelvis, and calvarium. He was given one 400 cGy dose of radiation to bilateral lower extremities using an AP/PA field arrangement. He subsequently received one dose of radiation to bilateral upper extremities. He had significant pain relief noted in less than 10 days. The pain continued to improve over the next 3 months, and he became pain free without pain medications. Six months later, he had a recurrence of the pain and a second single-fraction treatment of radiation was given. This also resulted in a complete resolution of the pain, and he remained pain free until his death 2 years later. Case 3 is a 44-year-old woman with a diagnosis of PMF made in 2003. Two and a half years after her diagnosis, she developed bilateral lower extremity pain from above her knees to her ankles, followed by bilateral upper extremity pain. The pain was not controlled on high-dose narcotics. X-rays showed patchy sclerosis of metaphyses of the distal femurs and tibia/fibula with periosteal new bone formation in distal femurs. Bone scan showed increased uptake in the lower extremity long bones. Nuclear medicine bone marrow scan was negative in the extremities. She underwent radiation to 600 cGy in one fraction to the bilateral lower extremities using AP/PA fields. She reported her pain had improved 25% in 2 weeks, 50% in 3 weeks, 75% in 4 weeks, and 90% in 5 weeks. She had recurrence of her pain 6 months later and received 100 cGy to the bilateral upper and lower extremities. This treatment led to pain control in 3 weeks, and her pain control was durable for almost 2 years. At that time, she had recurrent pain in the right shoulder and right hip. She received 100 cGy to the right humerus, shoulder, and right hip. This initially achieved excellent pain control but she had both new and recurrent pain in only 3 weeks. Retreatment of the shoulder to 400 cGy and treatment of the bilateral hips to 200 cGy did achieve better pain control in 3 days, but the patient died of her disease 1 month after the last treatment. Case 4 is a 54-year-old woman who was diagnosed with PMF in 1998. Six years later, she developed severe refractory bone pain in bilateral legs, low back, and left upper arm. This pain was uncontrolled on large doses of narcotic medications and was so severe she could not eat or drink. X-rays of the extremities showed sclerosis in the metaphyses of the proximal tibia and the pelvis. Radiation was given to bilateral lower extremities, bilateral forearms, and lumbar spine. One hundred centigray was delivered using AP/PA fields to the extremities and a single posterior field to the lumbar spine. Due to the large treatment area, the sites were treated one at a time and blood counts were monitored. She did not have any hematologic toxicity. She was pain free 11 days after treatment. However, the pain recurred in 3 weeks, and she had retreatment to all three areas to 200 cGy in separate sessions. She had relief in 7 days and again was pain free on minimal pain medications by 1 month. Unfortunately, 2 months later, her disease transformed to acute myelocytic leukemia. Case 5 is a 50-year-old man with PMF diagnosed in 2004. He developed bilateral shoulder pain in 2006. The pain was a 6/10 and Ultram gave him modest relief. CT scan showed skeletal sclerosis, MRI showed marrow changes consistent with MF, and a nuclear medicine bone marrow scan was negative for abnormal hematopoiesis in the shoulders. Radiation to 200 cGy was given to both shoulders with a multiple field setup. The patient did not note a significant pain response by 1 month and subsequently had a musculoskeletal procedure performed on his shoulders. Shortly, after the procedure, his pain resolved and this response has lasted 3 years. The main potential toxicity of low-dose radiation to the extremities would be decreased blood counts, but we did not see this or any other acute or chronic toxicity in our patients. This is the only series in the literature describing the entity of extremity pain in MF, which can be treated successfully with radiation. The bone pain that arises in these patients is a severe, disabling pain not well controlled with pain medications. In four cases, the radiation treatments allowed the patient to decrease or stop their pain medication and resume their activities of daily living. In the fifth case, an orthopedic procedure, or a combination of the procedure and radiation, provided complete relief of the pain. Bone pain in this disease may be related to increased bone blood flow and periostitis [14, 20]. In two of our patients, periosteal new bone formation or periostitis was noted on X-rays. In two others, X-rays were either negative or showed sclerosis. In two patients, bone scans showed mild increased uptake in the long bones. One of three bone marrow scans showed abnormal tracer localization in the long bones. We feel that in our patients the most common cause of the pain was periostitis but lack of consistent imaging makes this difficult to determine. Irradiation has been used for patients with extremity involvement of MF. The earliest case was from Beattie and Withey in 1953 [21]. They reported a patient with PV who underwent radiation to the spleen, humeri, and femora with reduction in the blood count. More recently, Mason et al. [14] presented a case of a man with MF with fevers and leg pain requiring parenteral narcotics. X-rays showed striking tibial periostitis, and a bone scan showed increased uptake over the entire skeleton, while a bone marrow scan showed decreased reticuloendothelial activity. Radiation of 200 rads in one fraction was given to each lower leg. He had decreased pain, swelling, and warmth over the next 6 months. In our series, most patients had a response to treatment that lasted 6 months or more. However, we did have two patients who initially responded to treatment but had a recurrence of pain in a few weeks. In both patients, the recurrent pain was associated with development of more aggressive disease. The optimal dose of radiation for this condition is not known. Single-fraction doses in this series ranged from 100 to 600 cGy. All but one of our patients required retreatment for recurrent pain. It is unclear if dose escalation would provide a more durable response. Severe extremity bone pain in MF is a rare entity but represents a typical clinical syndrome. It causes disabling symptoms and does not respond to pain medications. However, single-fraction low-dose radiation is a safe and effective treatment. Symptomatic response can be seen in days, and the duration of pain relief can range from 6 months to long term. Retreatment is safe and effective for patients with recurrent pain and can also achieve a durable response. This study was approved by the Mayo Foundation Institutional Review Board. In accordance with Minnesota state law, only patients who authorized review of their medical records were included. A computer search of the Department of Radiation Oncology tumor registry was performed for patients seen at the Mayo Clinic between 2004 and 2010. Five patients with MF were identified who underwent radiation to the extremities with External beam radiation therapy (EBRT). We performed a retrospective chart review to ascertain the dose, technique, clinical results, side effects, and complications of EBRT. We also examined diagnostic data and reviewed imaging related to the extremity symptoms. The toxicity associated with radiation therapy was scored according to the Common Terminology Criteria for Adverse Events Version 3.0. Michelle A. Neben-Wittich*, Paul D. Brown*, Ayalew Tefferi , * Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota.