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Pain (Professional) (cont.)

Radiation Therapy

Radiation therapy (RT) has been established as an effective treatment for pain caused by bony metastases. Local, half-body, or whole-body RT enhances the effectiveness of analgesic drugs and other noninvasive therapies by directly affecting the cause of pain (i.e., reducing primary and metastatic tumor bulk).[1][Level of evidence: I] RT reduces both pain and its interference with function among ambulatory cancer patients with symptomatic bone metastases.[2]

External-beam Radiation for Bone Metastases

External-beam radiation therapy (EBRT) produces significant reduction in bone pain in 50% to 80% of patients, with complete pain relief in 30% to 50% of patients.[3] Dose fractionation schedules utilized for painful bone metastases vary considerably. Common fractionation schemes include 30 Gy in ten fractions, 24 Gy in six fractions, 20 Gy in five fractions, and 8 Gy in one fraction. Single- or multiple-fraction regimens of EBRT are equally effective when RT is administered for pain relief; however, re-treatment is needed more frequently after single-fraction RT.[4][Level of evidence: I];[2] Fractionated RT courses have been associated with a need for re-treatment in 8% of patients versus a need for re-treatment in 20% of patients after a single fraction.[3,4,5,6,7,8][Level of evidence: I]

Choice of dose and fractionation must achieve a balance between the amount of RT required to kill tumor cells and the amount that would adversely affect normal cells or allow repair of damaged tissue. Data from several prospective randomized trials have failed to show any increased rates of long-term toxicity with single-fraction palliative RT compared with multiple-fraction therapy. In addition to pain control considerations, impact on the patient and caregiver related to the number of treatments delivered must be considered, with many patients finding increased convenience with single-fraction treatment. Another consideration is treatment cost, with single-dose fractionation regimens being less costly because of the smaller number of RT treatments delivered.

Stereotactic body RT (SBRT) is used to treat bone metastases by delivering large doses of RT in a highly conformal manner. Most commonly used to treat spinal metastatic disease, SBRT delivers large doses with a steep dose gradient, thereby potentially sparing adjacent neural structures. Most published data on SBRT have come from single-institution, retrospective studies. The complexities of target delineation, total dose, and fractionation have yet to be fully defined. SBRT may also be used when re-treatment is required in areas previously irradiated. Data regarding RT dose or patient selection for the treatment of recurrent, painful spinal bony metastases with SBRT are not yet definitive.[9]

Pain flare, defined as an increase in pain after palliative RT, can occur, although the incidence has not been well documented. A relatively small, prospective, randomized, controlled trial comparing 8 Gy in one fraction with 20 Gy in five fractions reported pain flare in 15 of 44 patients (34%) for a median duration of 3 days. The flare occurred in 10 of 23 patients (44%) in the 8-Gy group and in 5 of 21 patients (24%) in the 20-Gy group.[10][Level of evidence: I] A multicenter study included three outpatient clinics and 111 patients to determine the incidence of pain flare after palliative RT. Pain flare was defined as an increase in pain severity before achieving pain relief as distinguished from progression of pain by requiring the worst pain score and a return to baseline levels of analgesic intake after the increase/flare. Most patients received 8 Gy in one fraction (64%) or 20 Gy in five fractions (25%). The overall pain flare incidence was 40% (39% with 8 Gy and 41% with multiple fractions).[11][Level of evidence: II]

The use of RT with bisphosphonates has been evaluated in several prospective trials. The combination of zolendronic acid with either higher-dose palliative RT (30 Gy in ten fractions) or lower-dose RT (15 Gy in five fractions) for the treatment of single or multiple osteolytic or osteoblastic painful bony metastases in breast cancer patients was evaluated in a phase IV, randomized, controlled trial.[12] Zolendronic acid, 4 mg, was given every 28 days starting with RT. There was no difference in analgesic or pain scores between the two regimens. However, it has not been shown that the combination of these agents with RT is superior to RT alone for pain relief. Additional prospective trials are needed.

Radiopharmaceuticals

Radiopharmaceuticals are also utilized in the palliation of painful bony metastases. Single intravenous injections of beta-emitting agents such as iodine 131, phosphorus-32-orthophosphate, and strontium 89 as well as newer agents such as rhenium 186 and samarium 153 can relieve pain in widespread bony metastases.[13,14][Level of evidence: II];[15,16] Response rates range from 20% to 85%, depending on the agent used.

These agents have most commonly been used to treat osteoblastic metastases when there are several symptomatic sites and/or when the number of sites exceeds reasonable treatment with EBRT. Small-volume osteolytic metastases may respond to radiopharmaceuticals, but large-volume osteolytic disease usually does not respond. In patients with inadequate pain relief, studies have demonstrated that approximately half of patients treated with radiopharmaceuticals respond to a second treatment. A prospective, multicenter, open-label trial of samarium suggested that multiple doses (i.e., more than two doses) may be administered to patients with advanced cancer and painful bone metastases with repeated benefit and adequate safety if there was an initial response to the initial samarium dose.[17][Level of evidence: II]

Available data do not suggest that these radiopharmaceuticals eliminate the need for palliative EBRT.[9] Limited studies compare the effectiveness of one radiopharmaceutical with another. In a small randomized trial comparing strontium to samarium in patients with painful bony metastases, there was no statistically significant difference in the degree of analgesia seen. Toxicity, primarily hematologic, was likewise similar.[18]

Radiofrequency Ablation

Radiofrequency ablation (RFA) is a relatively new method for the treatment of symptomatic bony metastasis. Through the use of electromagnetic energy, RFA induces thermal energy that damages tissue around the inserted electrode. The destruction of tissue depends on both the temperature achieved and the duration of heating. With the use of image guidance, the goal of RFA is to maintain temperatures between 55°C and 100°C for 4 to 6 minutes to achieve cell kill. Because of slow thermal conduction through tissue, treatment time may increase up to 30 minutes. Preliminary results suggest that RFA may achieve palliation in patients with painful bony metastases.[19,20,21,22],[23][Level of evidence: III]

In a nonconsecutive 27-month period, 43 patients underwent RFA. Of the 43 patients, 41 (95%) experienced a decrease in worst pain (at least 2 points on an 11-point scale) that continued for up to 24 hours. After peaking at week 1, the morphine-equivalent daily dose decreased significantly at weeks 8 and 12 before rising again at week 24. Three patients experienced adverse events that included a second-degree skin burn at the grounding pad site, transient bladder and bowel incontinence after treatment of a sacral lesion, and an acetabular fracture 6 weeks after RFA of a pelvic lesion.[22] Other uncontrolled case reports confirm these findings. Further study is needed to determine potential risk and benefits.

References:

  1. Salazar OM, Sandhu T, da Motta NW, et al.: Fractionated half-body irradiation (HBI) for the rapid palliation of widespread, symptomatic, metastatic bone disease: a randomized Phase III trial of the International Atomic Energy Agency (IAEA). Int J Radiat Oncol Biol Phys 50 (3): 765-75, 2001.
  2. Wu JS, Monk G, Clark T, et al.: Palliative radiotherapy improves pain and reduces functional interference in patients with painful bone metastases: a quality assurance study. Clin Oncol (R Coll Radiol) 18 (7): 539-44, 2006.
  3. Chow E, Harris K, Fan G, et al.: Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 25 (11): 1423-36, 2007.
  4. Hartsell WF, Scott CB, Bruner DW, et al.: Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 97 (11): 798-804, 2005.
  5. Foro Arnalot P, Fontanals AV, Galcerán JC, et al.: Randomized clinical trial with two palliative radiotherapy regimens in painful bone metastases: 30 Gy in 10 fractions compared with 8 Gy in single fraction. Radiother Oncol 89 (2): 150-5, 2008.
  6. Sande TA, Ruenes R, Lund JA, et al.: Long-term follow-up of cancer patients receiving radiotherapy for bone metastases: results from a randomised multicentre trial. Radiother Oncol 91 (2): 261-6, 2009.
  7. Kaasa S, Brenne E, Lund JA, et al.: Prospective randomised multicenter trial on single fraction radiotherapy (8 Gy x 1) versus multiple fractions (3 Gy x 10) in the treatment of painful bone metastases. Radiother Oncol 79 (3): 278-84, 2006.
  8. Roos DE, Turner SL, O'Brien PC, et al.: Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05). Radiother Oncol 75 (1): 54-63, 2005.
  9. Lutz S, Berk L, Chang E, et al.: Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys 79 (4): 965-76, 2011.
  10. Loblaw DA, Wu JS, Kirkbride P, et al.: Pain flare in patients with bone metastases after palliative radiotherapy--a nested randomized control trial. Support Care Cancer 15 (4): 451-5, 2007.
  11. 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 75 (1): 193-7, 2009.
  12. Atahan L, Yildiz F, Cengiz M, et al.: Zoledronic acid concurrent with either high- or reduced-dose palliative radiotherapy in the management of the breast cancer patients with bone metastases: a phase IV randomized clinical study. Support Care Cancer 18 (6): 691-8, 2010.
  13. Cheng A, Chen S, Zhang Y, et al.: The tolerance and therapeutic efficacy of rhenium-188 hydroxyethylidene diphosphonate in advanced cancer patients with painful osseous metastases. Cancer Biother Radiopharm 26 (2): 237-44, 2011.
  14. Liepe K, Runge R, Kotzerke J: Systemic radionuclide therapy in pain palliation. Am J Hosp Palliat Care 22 (6): 457-64, 2005 Nov-Dec.
  15. Sartor O, Reid RH, Hoskin PJ, et al.: Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology 63 (5): 940-5, 2004.
  16. Coronado M, Redondo A, Coya J, et al.: Clinical role of Sm-153 EDTMP in the treatment of painful bone metastatic disease. Clin Nucl Med 31 (10): 605-10, 2006.
  17. Sartor O, Reid RH, Bushnell DL, et al.: Safety and efficacy of repeat administration of samarium Sm-153 lexidronam to patients with metastatic bone pain. Cancer 109 (3): 637-43, 2007.
  18. Baczyk M, Czepczynski R, Milecki P, et al.: 89Sr versus 153Sm-EDTMP: comparison of treatment efficacy of painful bone metastases in prostate and breast carcinoma. Nucl Med Commun 28 (4): 245-50, 2007.
  19. Dupuy DE, Liu D, Hartfeil D, et al.: Percutaneous radiofrequency ablation of painful osseous metastases: a multicenter American College of Radiology Imaging Network trial. Cancer 116 (4): 989-97, 2010.
  20. Callstrom MR, Charboneau JW: Image-guided palliation of painful metastases using percutaneous ablation. Tech Vasc Interv Radiol 10 (2): 120-31, 2007.
  21. Callstrom MR, Atwell TD, Charboneau JW, et al.: Painful metastases involving bone: percutaneous image-guided cryoablation--prospective trial interim analysis. Radiology 241 (2): 572-80, 2006.
  22. Goetz MP, Callstrom MR, Charboneau JW, et al.: Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: a multicenter study. J Clin Oncol 22 (2): 300-6, 2004.
  23. Thacker PG, Callstrom MR, Curry TB, et al.: Palliation of painful metastatic disease involving bone with imaging-guided treatment: comparison of patients' immediate response to radiofrequency ablation and cryoablation. AJR Am J Roentgenol 197 (2): 510-5, 2011.
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