Palliative Medicine Doctors Meeting

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1 Updates on the Disease Management of Bone Metastases Dr. Carmen LEUNG Department of Clinical Oncology, Queen Elizabeth Hospital Correspondence: ABSTRACT: Bone metastases are a frequent complication of cancer. This article reviewed the new advancements in the management of bone metastasis, including both systemic and local treatments. Systemic therapies include bone modifying agents and bone target radionuclides therapy. Local treatment includes the use of stereotactic radiotherapy. This article will focus more on the indications, side effects and advantages of these new advancements compared with the traditional techniques. HKSPM Newsletter 2017 Dec Issue 2 p Background Bone metastases are a frequent complication of cancer. World Health Organization (WHO) data suggests that approximately 4 million people worldwide experience daily pain due to malignant disease; in half of these people, metastatic bone pain is the dominant source of symptoms. 1 Bone metastases are most common in breast and prostate cancer. 2 They can cause severe pain, bone fractures, life-threatening electrolyte imbalances, and neurological impairment secondary to compression of nerves in the spine. The pain and nerve dysfunction may be difficult to treat and significantly affect the quality of life (QOL). A wide array of advances in treatment has developed to relieve pain, slow its progression and prevent its complication from occurrence. Advances in management for bone metastases broadly classified as systemic and local treatments. Depending on the extent and location of the metastases, one or both of these types of treatment can be used. Systemic Therapy In general, anticancer systemic therapies can act by controlling the overall cancer disease burden but they are not specifically aimed at bone metastases. Whereas certain systemic treatments, such as radionuclides and bone target therapy, are aimed more specifically at cancer on bone. Sometimes both types of treatments are used simultaneously. Bone target therapy Mechanism of action: Bisphosphonates work by slowing down the action of osteoclasts. It has direct apoptotic effect on osteoclasts. It inhibits their differentiation and maturation and acts as a potent inhibitor of bone resorption. However, its anti-tumor and /or anti-angiogenic effects are still not proven yet. Denosumab also keeps osteoclasts from being turned on by a different mechanism. It is a fully human, monoclonal, synthetic antibody that binds to RANKL with high affinity and hence it can inhibit the osteoclast activity. Clinical results of bone target therapy: 1. Prevention of skeletal morbidity in metastatic bone disease (including pathologic fracture and need for radiotherapy and/or surgery to bone or spinal cord compression) HKSPM Newsletter 2017 Dec Issue 2 p.21

2 The systemic review of Bisphosphonates and Other Bone Agents for Breast Cancer by Cochrane Database of Systematic Reviews in 2012 had included thirty-four randomized controlled trials (RCTs) for analysis. 3 In nine studies (2806 patients), they compared bisphosphonates with placebo or no bisphosphonates. They found that the risk of skeletal related event (SRE) in metastatic bone disease was significantly reduced by 15% (risk ratio (RR) 0.85; 95% confidence interval (CI) 0.77 to 0.94; P = 0.001). In particular, women with bone metastases of breast cancer treated with bisphosphonates showed significant delays in the median time to SREs, improvement in bone pain and global QOL. 2. Prevention of treatment induced bone loss Bisphosphonates can be used as treatment for the therapy-associated osteoporosis especially under endocrine therapy such as the aromatase inhibitors or GnRH analogues. Choice of bone target agent: From the Cochrane Database of Systematic Reviews, the efficacy of various bisphosphonates in the metastatic setting has also been evaluated. 3 A direct comparison of zoledronic acid and pamidronate confirmed at least equivalent efficacy in a single large study. In three studies (3405 patients), subcutaneous denosumab was more effective in reducing the risk of SREs (RR 0.78; 95% CI 0.72 to 0.85; P < ) compared with bisphosphonates. In particular, compared to zoledronic acid, denosumab also significantly reduced the SRE rate, delayed the time to SREs, improvement in bone pain and global QOL. So far there was no difference in survival between patients treated with denosumab and zoledronic acid. In view of the ease of administration, ESMO Clinical Practice Guidelines 2014 for Bone Health in Cancer Patients has recommended starting zoledronic acid or denosumab rather than pamidronate in all patients with metastatic bone disease especially breast, prostate and myeloma cancer patients. 4 Bisphosphonates tend to work better in osteolytic bony disease rather than purely osteoblastic metastases. Optimal duration of treatment Bone target therapy should be started as soon as metastases are definitely diagnosed in order to delay the first SRE and reduce subsequent complications. Once initiated, these should be continued in the initial dosage until there is a substantial decline in the patient s general condition. 4 However, the results of the OPTIMIZE-2 trial presented at the ASCO Congress in 2014 revealed that women who had stable disease on monthly zoledronate infusions for several years could continue the therapy in a once every three months regimen. 5 This lengthening of the drug interval not only had no influence on the incidence of skeletal morbidity, but also reduced the risk of some undesired side effects. Comparing zoledronic acid every 4 weeks versus every 12 weeks, the latter was observed to have no osteonecrosis of the jaw (versus 1 % in the control group) and fewer nephrological complications (7.9 vs. 9.6 %). Table 1: Summary of anti-resorptive agent for bone metastases 4 Drug Zoledronic acid Pamidronate Clodronate Ibandronate Denosumab Common side effects: Bisphosphonates usually are well tolerated but occasionally they can cause transient myalgia, arthralgia, nausea and flu-like symptom with fever. It can induce kidney damage (6-8%) and hence close renal monitoring needs to be taken in case of renal impairment. Bisphosphonates should be withheld if creatinine clearance is less than 30ml/min. Dosage 4mg i.v. every 3-4 weeks 90mg i.v. every 3-4 weeks 1600mg p.o. daily 50mg p.o. daily, 6mg i.v. monthly 120mg s.c. every 4 weeks HKSPM Newsletter 2017 Dec Issue 2 p.22

3 Side effects of denosumab include nausea, diarrhea and malaise. Furthermore, there is significant risk of associated symptomatic hypocalcemia and hence prophylactic Calcium and Vitamin D replacement need to be taken with denosumab. Unlike the bisphosphonates, this drug is safe for patients with kidney problems. Both bisphosphonates and denosumab can cause osteonecrosis of the jaw (ONJ) which is a rare but serious side effect. Similar incidence in both bone target agents (1.6%). This can lead to tooth loss and infections or open sores of the jaw bone which is difficult to heal and hard to treat. Therefore, preventive pre-treatment dental check-up and appropriate preventive dentistry are needed before starting the drug. Maintaining good oral hygiene by flossing and brushing, making sure that dentures fit properly, and having regular dental check-ups might also help to prevent ONJ. Lastly, it is important to avoid dental procedures during therapy if possible. Bone Target Radionuclides Therapy (Unsealed radioactive sources) (1) Radio-active Strontium-89 (Metastron) and Samarium-153 (Quadramet) These are beta (β)-emitting radio-isotopes which concentrate at the sites of osteoblastic activity and deliver a localized high dose of irradiation at the metastatic bone lesions. This is indicated to manage multifocal metastatic bone pain following failure of conventional analgesics and to palliate recurrent pain within a previously irradiated site. It is also indicated if the side effects of high-dose analgesics become intolerable and significantly compromise the quality of life, even if pain control is adequate. 6 Strontium [89Sr] is approved for pain palliation in patients with bone metastases from prostate cancer; samarium [153Sm] can also be used in patients with osteoblastic metastases of other tumor types. This is simple to administer and requires only a single intravenous injection. The activity of samarium [153Sm] is adjusted for the patient's body weight (37 MBq/kg), whereas 89Sr-chloride is prescribed as standardized activity (150 MBq). 6 Depending on the half-life and radiation energy of the specific radionuclide, they exert a different effect and toxicity profile. Several studies have shown encouraging clinical results of an overall reported pain response in a rate of 70-80%. Evidence of pain relief is generally seen within 7 to 21 days and sustained for 3 to 6 months. A repeat dose can be administered at 3-month intervals if necessary. 7 The advantage of 89Sr is a longer mean response duration of approximately 4 to 6 months, but this benefit must be weighed against the delayed onset of symptom palliation of days after administration and the increased risk of myelosuppression. 8 The most common side effect is myelotoxicity but it is limited and reversible. Absolute contraindications to radionuclides therapy include severe bone marrow depression, for beta-emitters indicated by platelets < 60,000/µl or leucopenia < 2400/µl. 9 Acute spinal cord compression, disseminated intravascular coagulation, and impaired renal function (urea > 12 mmol/l or creatinine > 150 µmol/l) are regarded as additional contraindications in German, European and American guidelines for pain palliation treatment using strontium-89 and samarium Close weekly monitoring of blood counts is essential to assess the expected temporary bone marrow suppression. Patients with urinary incontinence should be catheterized prior to treatment, to mitigate the risk of radioactive urine contamination. Besides, to allow time for bone marrow recovery and avoid unpredictable cumulative toxicity, unsealed source treatment should be delayed for 6 8 weeks after completion of chemotherapy. It is recommended that further chemotherapy should be deferred for at least 8 12 weeks, depending on the radionuclides used. 6 (2) Radium-233 (Xofiqo) Radium-233 is a bone-seeking alpha(α)-particle emitter, accumulating in areas of increased bone turnover that is being developed to target metastatic bone disease. The high linear energy transfer of α radiation results in a greater biologic HKSPM Newsletter 2017 Dec Issue 2 p.23

4 effectiveness than β radiation, as well as generation of double-strand DNA breaks, and gives rise to cytotoxicity that is independent of dose rate, cell cycle growth phase, and oxygen concentration.10 The range of the α particles (<100 μm) is much smaller than the 0.7-cm path length of 89Sr and the 0.33-cm path length of 153Sm; as a result, less hematologic toxicity for a given bone surface dose would be expected from α emitters than from β emitters. 11 Similar to the other radionuclide agents, 223Ra also effectively decreases the onset of the first skeletal related events and relieves pain. Various clinical studies on 223Ra were reported In a randomized controlled trial focused on patients experiencing pain from castration-resistant prostate cancer, patients received higher dose (100 kbq/kg) of 223Ra, 70% of patient achieved pain relief, with complete or very good pain response seen in 51%. 12 The mean pain relief duration was 44 days. In contrast to the other radioisotopes, 223Ra therapy has demonstrated significant improvement in survival as a single agent. In a double-blind, randomized, placebo-controlled phase III trial (ALSYMPCA) on patients with bone metastases and castration-resistant prostate cancer. 16 It has shown low toxicity and a mean survival of 14 months for the radium-223 group compared to 11.2 months for the placebo group. The median time of new skeletal events was 13.6 versus 8.4 months. 223Ra is well tolerated, with a small incidence of adverse events. Its myelotoxicity is infrequent (<3% for Gr 3/ 4 toxicity) and not cumulative. The myelosuppression is reversible, with the nadir occurring 2 4 week after treatment. 16 Other side effects include diarrhea, fatigue, nausea, vomiting, and bone pain. The approved dose for 223Ra is 50 kbq/kg and given as 6 doses. It is indicated in skeletal metastasis with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral disease. Contraindications include pregnancy, breast-feeding, and women of child-bearing age. Local Therapy Stereotactic body radiotherapy (SBRT) SBRT can deliver high radiation doses precisely to small volumes with very tight margins, which has significant advantages when treating tumors close to the spinal cord or at sites of retreatment. This is a way of giving radiotherapy to a bone tumour from different directions. It implies high-dose-per-fraction radiation delivered to an image-guided target, usually in 1 to 5 fractions using conformal radiation techniques. In view of the steep fall-off dose gradients and hence the risk of damage to normal surrounding tissues is low. By this radiation dose escalation, SBRT can improve long-term tumour control and give a more durable pain control. SBRT requires the following techniques: 19 (1) Secure immobilization by vac-loc bag to reduce patient movement. (2) High resolution CT for planning with fusion of dedicated MRI images for localization of tumor. Owing to the tight margin of accuracy, high demand on accurate positioning from simulation scan to treatment and verification of set up to eliminate set up error. (3) Utilization of multiple beams to reduce the dose to normal tissue. (4) Accurate tracking of surrounding organs motion. (5) Use of image guidance and tumor surrogates such as bony landmarks. Cone beam CT performed before every treatments with robotic couch to adjust for any translations /rotations (goal: <1mm translations, <1 degree rotation). (6) Use of an ablative dose and fractionation scheme delivered with millimeter accuracy. Primary SBRT is especially advantageous for patients with solitary or oligometastases after a prolonged cancer-free interval. Besides, because of the large dose delivery, radioresistant bone metastases such as melanoma, renal cell carcinoma, and sarcoma, can now be investigated as viable treatment targets. Furthermore, re-irradiation with SBRT can allow sufficient dose to control tumor while minimizing dose to the cord. HKSPM Newsletter 2017 Dec Issue 2 p.24

5 Despite the advantages of SBRT as mentioned, some disadvantages include: increased treatment time per fraction, difficult to be used urgently, large fractional doses that do not provide sparing for normal tissues, cannot treat subclinical disease and expensive cost. 19 In view of the increased planning and treatment time as well as the sophisticated treatment delivery requirements, SBRT generally precludes its used in the treatment of emergent cord compressions. In additional, patient with painful bone metastases also found it difficult to bear the long treatment time. SBRT also is considered to be contraindicated if there is >25% spinal canal compromise, gross tumours < 5mm from spinal cord, evidence of spine instability or bony compression of neural structure. Lastly, it is also not rational to use SBRT to treat extensive multilevel spinal disease. A range of dose-fractionation schedules have been used ranging from single doses of 15 24Gy to fractionated schedules delivering 15 35Gy in three to five fractions. Local control can be achieved in primary bone tumours of the spine in up to 95% and pain relief is seen in over 80%. Toxicity rates are low, even in series that have delivered re-irradiation with myelopathy in <1%, although the vertebral fracture may occur later. 20 Conclusion: Skeletal complications resulting from bone metastases can be associated with debilitating bone pain and can negatively affect quality of life. Both local and systemic treatment options should be carefully considered and applied timely for symptoms control, prevent skeletal complications and improve quality of life. Further research is warranted to provide more evidence-based guidance on the management of bone metastasis. References: 1. World Health Organisation Cancer pain relief and palliative care. World Health Organ Tech Rep Ser. 1990; 804: Coleman R, Rubens R. Bone metastases. In: Abeloff M, Armitage J, Niederhuber J, Kastan M, McKenna WG, editors. Clinical oncology. 3rd ed. New York, NY: Churchill Livingstone; p Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer Cochrane Database Syst Rev 20122CD Coleman R, Body JJ, Aapro M, et al. Bone Health in Cancer Patients: ESMO Clinical Practice Guidelines; Published in 2014 Ann Oncol (2014) 25 (suppl 3): iii124-iii Hortobagyi GN, Van Poznak C, Harker WG, et al. Continued Treatment Effect of Zoledronic Acid Dosing Every 12 vs 4 Weeks in Women With Breast Cancer Metastatic to Bone: The OPTIMIZE-2 Randomized Clinical Trial. JAMA Oncol Jul 1;3(7): doi: /jamaoncol Fischera M, Kampen WU. Radionuclide Therapy of Bone Metastases. Breast Care (Basel) Apr; 7(2): Radiopharmaceuticals Metastron (Strontium-89) and Samarium-153 (Quadramet) for Metastatic Bone Pain - Medical Clinical Policy Bulletins. Aetna a/v: 8. Pons F, Herranz R, Garcia A, et al. Strontium-89 for palliation of pain from bone metastases in patients with prostate and breast cancer. Eur J Nucl Med Oct;24(10): Fischer M. Guidelines for radionuclide therapy in painful bone metastasis, Nuklear-medizin. 1999; 38(6A): Sgouros G, Roeske JC, McDevitt MR, et al. MIRD pamphlet no. 22 (abridged): radiobiology and dosimetry of alpha-particle emitters for targeted radionuclide therapy. J Nucl Med. 2010;51: Hobbs RF, Song H, Watchman CJ, et al. A bone marrow toxicity model for Ra-223 alpha-emitter radiopharmaceutical therapy. Phys Med Biol. 2012;57: Parker CC, Pascoe S, Chodacki A, et al. A randomized, double-blind, dose-finding, multicenter, phase 2 study of radium chloride (Ra 223) in patients with bone metastases and castration-resistant prostate cancer. Eur Urol. 2013;63: Nilsson S, Larsen RH, Fossa SD, et al. First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res, 11 (2005), pp Nilsson S, Franzen L, Parker C, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol, 8 (2007), pp Nilsson S, Franzén L, Parker C, et al. Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases. Clin Genitourin Cancer Mar;11(1):20-6. doi: /j.clgc Epub 2012 Sep Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med, 369 (2013), pp Nilsson S, Strang P, Aksnes AK, et al. A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer. Eur J Cancer, 48 (2012), pp Carrasquillo JA, O'Donoghue JA, Pandit-Taskar N, et al. Phase I pharmacokinetic and biodistribution study with escalating doses of ²²³Ra-dichloride in men with castration-resistant metastatic prostate cancer. Eur J Nucl Med Mol Imaging Sep;40(9): doi: /s Epub 2013 May Jhaveri P, the BS, Bloch C, Amato R, Butler EB, Paulino AC. Stereotactic body radiotherapy in the management of painful bone metastases. Oncology (Williston Park) Jun;22(7): Bhattacharya IS, Hoskin PJ. Stereotactic body radiotherapy for spinal and bone metastases; Clin Oncol (R Coll Radiol) May;27(5): HKSPM Newsletter 2017 Dec Issue 2 p.25