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Technology & Services Section

Palliation of Metastatic Bone Pain with Quadramet

a report by

®

Marnix G.E.H Lam

Department of Nuclear Medicine,University Medical Center Utrecht, Utrecht, The Netherlands

Samarium-153-lexidronam (Quadramet®) is dedicated to the relief of bone pain treatment for multiple painful osteoblastic skeletal metastases previously detected by skeletal scintigraphy. The radiopharmaceutical consists of the radionuclide samarium-153, the radioactive compound, linked to a tetraphosphonate chelating agent, ethylene-diamine-tetramethylene phosphonic acid (EDTMP). It is administered as a simple bolus injection in a day-care setting. Quadramet® has two major advantages: a short time to response (days after one injection) and a long duration of response (several weeks or months). Furthermore, treatment may be safely repeated with a minimal interval of eight weeks. Large clinical experience showed good pain relief in a majority of treated patients who suffered from various cancers including breast and prostate cancers, with a decrease of analgaesic intake and an improvement in quality of life. Quadramet® administration is associated with bone marrow depression with a transient and predictable decrease in white blood cell counts and platelet counts. Recovery is complete after eight weeks. First results show that Quadramet may be safely combined with bisphosphonates

®

153Sm­EDTMP,

and its low blood and bone marrow activity suggest offers appropriate nuclear properties with a

that this complex is effective in treating metastatic bone disease. The radionuclide

153Sm

physical half life of 46.3 hours (relatively short) and emission of beta particles of 233keV (mean energy), which is sufficiently energetic to deposit a high radiation dose to the tumour with low damage to the bone marrow due to its short penetration in tissue (depth of 2­3mm).1 Its gamma-ray emission of 103keV allows scintigraphy, which can be used for biodistribution and dosimetric assessment of the radiopharmaceutical in the individual patient.3

153Sm-EDTMP

clears through the kidneys with excretion of approximately

half of the administered dose (53.4%±10.4%) into the urine during the first eight hours, and 56.1%±10.5% at 24 hours. The remaining dose is deposited in the skeleton with little soft-tissue uptake.4 Dosage and Toxicity In a phase I/II study, 52 patients with prostate cancer were treated with doses ranging from 37MBq/kg (1.0mCi/kg) to 111MBq/kg (3.0mCi/kg), with increments of 18.5MBq/kg (0.5mCi/kg).3 As two out of four patients at the 93MBq/kg (2.5mCi/kg) dosage level and two out of four patients at the 111MBq/kg (3mCi/kg) dosage level developed grade 3 or 4 haematologic toxicity (neutrophils <900/mm3 and/or platelets < 50,000/mm3), the maximum tolerated dosage in this trial was determined to be 93MBq/kg (2.5mCi/kg). Sixteen more patients were treated in both the 37MBq/kg (1.0mCi/kg) and 93MBq/kg (2.5mCi/kg) dosage groups. In the 37MBq/kg (1.0mCi/kg) group two out of 20 patients, and in the 93MBq/kg (2.5mCi/kg) group eight out of 20 patients experienced grade 3 or 4 haematologic toxicity.5 Using an escalating dose schedule (22 patients; dosages from 3.7­37MBq/kg [0.1­1.0mCi), Farhanghi et al. found a decrease in platelet count in patients receiving a dose 13MBq/kg (0.35mCi/kg), and decrease in white blood cell (WBC) count in patients receiving a dose 28 MBq/kg (0.75mCi/kg), without any significant difference between dosing groups.6 The platelet count fell below 140x109/l (86­140x109/l) in 35% of the treatment courses (mean nadir of four weeks; recovery after six to eight weeks), and leucopaenia of less than 3500/mm3 occurred in only two instances (recovery after six to eight weeks). Non-haematological toxicity was limited to a transient exacerbation of pre-existing pain (flare reaction; 4/22 patients), beginning two to three days after therapy, lasting three to four days.6 These and other efficacy studies led to the currently approved dosage of 37MBq/kg (1.0mCi/kg). Serafini et al. combined the toxicity results of three controlled studies, in which patients were treated with 37Mbq/kg (1.0mCi/kg)

153

and/or chemotherapy to synergistically improve the palliative effect. Quadramet® is commercially available in the US (Cytogen) and Europe (CIS bio international). Bone-seeking Radiopharmaceuticals Bone metastases from most tumours will induce some osteoblastic response in bone, leading to an increased uptake of bone-seeking radiopharmaceuticals. Radiopharmaceuticals concentrate in osteoblastic lesions that take up phosphonates with a high bone turnover around the lesion. Bone-seeking radiopharmaceuticals are indicated for the alleviation of pain from osseous metastases at multiple localisations, or bone pain at sites where former external beam radiotherapy was performed. Bone-seeking radiopharmaceuticals generally consist of a combination of a radionuclide and a carrier ligand (bisphosphonate analogues). The radionuclide exerts its therapeutic effect by means of beta-radiation (`electron-radiation' which deposits its energy over a path length of several millimetres of its origin). The carrier ligand ensures that the radionuclides are delivered at a specific location. Quadramet ® Samarium |153Sm] Lexidronam At the University of Missouri, Columbia, it was demonstrated by Goeckeler et al. that stable readily produced.

1,2

153Sm

phosphonate complexes could be proved to have the most optimal

153Sm­EDTMP

characteristics. It had good selective skeletal localisation, low blood levels and low soft tissue retention, including the liver (confirmed by scintigraphic imaging). No significant non-osseous tissue accumulation was observed. The high lesion concentration of

Sm-EDTMP.7. Haematologic

© TOUCH BRIEFINGS 2007

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Technology & Services Section

toxicity grades were based on the National Cancer Institute Common Toxicity Criteria. Approximately 10% of the patients experience transient grade 3 or 4 haematologic toxicity with a nadir between three to five weeks after treatment, and recovery after eight weeks.7 Re-treatment is possible with an interval of two to three months. Toxicity after re-treatment is comparable with that after single dosage treatment.8,10 Efficacy Several studies have been performed on the efficacy of 153Sm-EDTMP.5; 6;

8­19

scores for both active groups decreased during each of the four weeks after administration, with larger decreases observed at each week for the 37MBq/kg dosing group. Decreases for the higher dosing group were significant at each of the first four weeks, but only at the first week for the lower dosing group. These findings correlated well with the physician's global assessment. In the 37MBq/kg group, two-thirds of those judged to be responders at week four were still responding at week 16. The significant improvements in pain scores in this group were correlated with an ability to decrease their use of opioid analgaesics. As in previous studies, a mild transient, dose-related myelosuppression was the only side effect experienced.16 Another double-blind placebo controlled study compared the efficacy of the radioactive (

152 153

Some papers also studied the efficacy of repeated treatment with The mean response rate for all these studies is 73% Sm with a placebo constituted of non-radioactive

153Sm-EDTMP.9,10

(range 61­95%). Three of them will be discussed in further detail. They include a well-designed randomised dose-controlled study and two published double-blind placebo-controlled studies.13,15,16 One of the first reported studies on the efficacy of

153Sm-EDTMP

Sm) lexidronam complex.15 This ensured that the chelating agent

(EDTMP) could not explain the treatment effects. This placebo was administered to 51 patients, while 101 patients received 37MBq/kg

153

Sm-EDTMP. All patients had hormone-refractory prostate carcinoma

153

compared two different dosages in a randomised controlled study.13 Fifty-five patients received single doses of 18.5MBq/kg and 59 patients received single doses of 37MBq/kg. The study population mostly consisted of patients with prostate or breast carcinoma, and some other tumours (lung, miscellaneous). Multi-modality assessment of pain was used in this study. Level of pain, sleep characteristics and analgaesic use were recorded in a diary that each patient completed once a day from the week before dose administration (baseline) until the end of week four, and then once a week from week five to week 16. The physician evaluated the clinical condition of the patient by global assessment. During the first four weeks after treatment both study groups experienced alleviation of their bone pain, measured by Visual Analogue Scale (VAS). For the 18.5MBq/kg dosing group this never reached significant differences from baseline. The 37MBq/kg dosing group, however, had a significant reduction of pain in week three and four, with a significant difference between dosing groups in week four. For the other characteristics all the results were in favour of 37MBq/kg with significant improvement compared with baseline. The physicians judged that 70% of the patients in the 37MBq/kg dosing group had a clinical response to therapy, compared with 55% of the patients in the lower dosing group. After 16 weeks, 39% of the patients of the higher dosing group were still experiencing some degree of pain relief. Concerning toxicity, a decrease in haematological parameters was the only toxicity noted. The mean nadirs were lower, and the changes from baseline greater for the 37MBq/kg dosing group than for the 18.5MBq/kg dosing group for both platelets and white blood cells, but were acceptable for both groups. Toxicity grade 3 or 4 was reached in only about 10% of the cases. In most of these cases patients received either external beam radiation therapy or chemotherapy after receiving the study agent.13 The first double-blind placebo-controlled study to be published reported results on 118 patients with painful metastases, treated with either 18.5MBq/kg (40 patients), 37MBq/kg (39 patients) or placebo (39 patients).

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(HRPC). Statistically significant improvement occurred in analgaesic consumption and pain for patients treated with Sm-EDTMP. In week three and four after treatment, analgaesic consumption was significantly reduced in the `treated' group compared to the `placebo' group. The same result was found for reduction in the VAS, a linear model to scale pain complaints, and the `nonlinear' Pain Descriptor Scale (PDS), in which patients described their pain in words. The differences between the proportion of complete responders favoured the experimental arm compared with the placebo group (38% versus 18%). Overall response rate for the `treated' group was 65%, compared with 45% in the `placebo' group. During a follow-up period of 16 weeks, seven patients in the `treated' group showed a decrease in prostatespecific antigen of more than 50% compared with two patients in the `placebo' group. No differences in survival were noted between treatment arms. In the study, the only significant toxicity was mild transient myelosuppression.15 All studies indicate the efficacy of single dosage treatment with

153Sm-

EDTMP in an optimal dosage of 37MBq/kg. It is both effective and safe. In case of good response, treatment may be repeated. In a recent multicenter, open-label study (22 centers in the US, Canada and Europe) of the 131 patients who received Quadramet treatment for bone metastases, a total of 55 patients received more than 1 dose of 153Sm, 11 received 3 infusions, 4 received 4 infusions, 2 received 6 infusions and 1 received 11 infusions. The results demonstrates that treatment with Quadramet may be repeated without significantly increasing toxicity. Pain responses after multiple administrations were similar to that after initial administration both in terms of decrease in pain intensity scores and percentage of patients responding.10 Repeated dose of

153

-Sm- EDTMP may be considered as reasonable

treatment option in patients whose bone pain recurs after initial dose provided that baseline hemtologic criteria are adequate for administration.

10

Most of the primary tumours were either prostate

(68%) or breast carcinomas (18%). Response to therapy was assessed by pain diary scores (VAS), physician's global assessment and opioid analgaesic use. These parameters were recorded every week until week four and every month thereafter until week 16. Where the mean pain scores for the placebo group remained relatively unchanged, the In a period of 28 months, another patient with advanced hormonerefractory prostate cancer was given 11 treatments of 37MBq/kg 153SmEDTMP. He experienced improvement in pain, quality of life and his ability to perform activities of daily living.9 Toxicity is mostly confined to

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EUROPEAN ONCOLOGICAL DISEASE 2007

Palliation of Metastatic Bone Pain with Quadramet ®

transient myelosuppression with a nadir at week three to five after treatment and recovery after approximately eight weeks. Like single dosage treatment, repeated dosage treatment is not only safe but effective as well. New Perspectives Treatment with bone-seeking radiopharmaceuticals is a well-established modality for the treatment of pain. In order to improve patient care even more (patient survival), it has been proposed to combine several other treatment modalities (chemotherapy, external beam radiotherapy and bisphosphonates) with bone-seeking radiopharmaceuticals.20,21 Ricci et al. reported the synergistic effect on survival of Quadramet® in combination with chemotherapy given to HRPC patients.

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performing (within eight weeks prior treatment) skeletal scintigraphy before treatment. Patients are treated in the outpatient clinic or in daycare. The dose is 37MBq/kg adjusted to body weight. The pharmaceutical is injected through an intravenous running line. Contraindications for the use of bone-seeking radiopharmaceuticals are thrombocytopenia (<100x109/l) or leukopenia (<3x109/l), spinal cord compression (in that case acute external beam radiotherapy is indicated), acute renal insufficiency and pregnancy. The aim of the treatment is palliation of pain, improvement of the quality of life of patients and less intake of analgaesics. Conclusion Treatment with Quadramet® is effective and safe. Approximately 70% of the treated patients show at least a clinical response with a consequent decrease of pain and an improvement in quality of life. Toxicity is usually mild and transient. Furthermore, it is cost-effective, and may be repeated when indicated. In clinical practice it should be actively considered, especially in patients with pain and widespread metastasis. Clinical studies focused on combining current treatment modalities, to bring response beyond palliation, towards improved survival are ongoing.

In our centre we recently (Zometa®)

studied the combination of zoledronic acid, a bisphosphonate

with Quadramet®. The combination proved to be safe and effective. It is therefore unnecessary to stop bisphosphonates when treatment with Quadramet® is scheduled. Practical Use of Quadramet ® The existence of osteoblastic metastases must be confirmed by

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Goeckeler WF, Troutner DE, Volkert WA, et al. 153Sm radiotherapeutic bone agents. Int J Rad Appl Instrum B. 1986;13:479-482. Goeckeler WF, Edwards B, Volkert WA, et al Skeletal localization of samarium-153 chelates: potential therapeutic bone agents. J Nucl Med. 1987;28:495-504. Cameron PJ, Klemp PF, Martindale AA, et al Prospective 153Sm-EDTMP therapy dosimetry by whole-body scintigraphy. Nucl Med Commun. 1999;20:609-615. Singh A, Holmes RA, Farhangi M, et al. Human pharmacokinetics of samarium-153 EDTMP in metastatic cancer. J Nucl Med. 1989;30:1814-1818. Collins C, Eary JF, Donaldson G, et al Samarium-153-EDTMP in bone metastases of hormone refractory prostate carcinoma: a phase I/II trial. J Nucl Med. 1993;34:1839-1844. Farhanghi M, Holmes RA, Volkert WA, et al. Samarium-153EDTMP: pharmacokinetic, toxicity and pain response using an escalating dose schedule in treatment of metastatic bone cancer. J Nucl Med. 1992;33:1451-1458. Serafini AN. Samarium Sm-153 lexidronam for the palliation of bone pain associated with metastases. Cancer. 2000;88:2934-2939. Alberts AS, Smit BJ, Louw WK, et al. Dose response relationship and multiple dose efficacy and toxicity of samarium-153-EDTMP in metastatic cancer to bone. Radiother Oncol. 1997;43:175-179.

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Menda Y, Bushnell DL, Williams RD, et al Efficacy and safety of repeated samarium-153 lexidronam treatment in a patient with prostate cancer and metastatic bone pain. Clin Nucl Med. 2000;25:698-700. Sartor O, Reid R, Bushnell, D et al, Safety and Efficacy of Repeat Administration of Samarium Sm-153 Lexidronam to Patient with Metastatic Bone Pain. Cancer; 2007;109:3-3. Dolezal J. Systemic radionuclide therapy with Samarium-153EDTMP for painful bone metastases. Nucl Med Rev Cent East Eur. 2000;3:161-163. Etchebehere EC, Pereira Neto CA, Lima MC, et al Treatment of bone pain secondary to metastases using samarium-153EDTMP. Sao Paulo Med J. 2004;122:208-212. Resche I, Chatal JF, Pecking A, et al. A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer. 1997;33:1583-1591. Sapienza MT, Ono CR, Guimaraes MI, et al. Retrospective evaluation of bone pain palliation after samarium-153-EDTMP therapy. Rev Hosp Clin Fac Med Sao Paulo. 2004;59:321-328. Sartor O, Reid RH, Hoskin PJ, et al. Samarium-153Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology. 2004;63:940-945. Serafini AN, Houston SJ, Resche I, et al. Palliation of pain associated with metastatic bone cancer using samarium-153

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lexidronam: a double-blind placebo-controlled clinical trial. J Clin Oncol. 1998;16:1574-1581. Tian JH, Zhang JM, Hou QT, et al. Multicentre trial on the efficacy and toxicity of single-dose samarium-153-ethylene diamine tetramethylene phosphonate as a palliative treatment for painful skeletal metastases in China. Eur J Nucl Med. 1999;26:2-7. Turner JH, Martindale AA, Sorby P, et al. Samarium-153 EDTMP therapy of disseminated skeletal metastasis. Eur J Nucl Med. 1989;15:784-795. Wang RF, Zhang CL, Zhu SL, et al. A comparative study of samarium-153-ethylenediaminetetramethylene phosphonic acid with pamidronate disodium in the treatment of patients with painful metastatic bone cancer. Med Princ Pract. 2003;12:97-101. Sciuto R, Festa A, Rea S, et al. Effects of low-dose cisplatin on 89Sr therapy for painful bone metastases from prostate cancer: a randomized clinical trial. J Nucl Med. 2002;43:79-86. Tu SM, Millikan RE, Mengistu B, et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial. Lancet. 2001;357:336-341. Ricci S, Boni G, Pastina I, et al. Clinical benefit of bonetargeted radiometabolic therapy with (153)Sm-EDTMP combined with chemotherapy in patients with metastatic hormone-refractory prostate cancer. Eur J Nucl Med Mol Imaging. 2007.

Contact Information

Marnix G.E.H Lam, MD University Medical Center. Utrecht Department of Nuclear Medicine PO Box 85500 3508 GA Utrecht The Netherlands Telephone +31-30-2508818

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