Radiol Oncol 1998; 32(4): 367-71.
review
Palliation of painful osseous metastases in patients with prostate cancer using Re-186-HEDP
Susanne Klutmann, Karl H. Bohuslavizki, Ulrike Schulte, Sabine Kroger, Christian Bleckmann, Janos Mester, Malte Clausen
Department of Nuclear Medicine, University Hospital Eppendorf, Germany
The skeleton is the second most common site of metastases in patients with prostate cancer. While curative means are strongly limited in these patients their life expectancy may be still several years. Therefore, it is essential to improve quality of life of these patients. Sufficient therapy of painful osseous ■metastases is the main goal in patients with advanced prostate cancer. The primary approach to relieve bone pain is the application of peripheral or central analgesics. In case of bone pain due to a single metastatic site local external beam radiation may provide pain relief in a reasonable amount of patients. In case of painful mul-tilocular metastases systemic application of radiopharmaceuticals may irradiate bone metastases while normal tissue is sparedfrom [3-irradiation. Due to their physical characteristics Re-186 and Sm-153 have been developed for palliative treatment of metastatic bone pain. The response rate amounts to about 70-80% of all patients treated. Pain relief may last for 1-6 months. Due to its low grade toxicity which is mainly dominated by a transient thrombocytopenia therapy can be repeated. However; Re-186-HEDP therapy does not alter life expectancy.
Key words: prostatic neoplasms; bone neoplasms-secondary; pain-therapy; rhenium, radioisotopes, Re-186-HEDP
Introduction
Prostate cancer is the second most common malignancy in men in Western Europe. The incidence is 15-16 per 100000 habitants per year with increasing tendency. As much as 80% of patients with prostate cancer will develop bone metastases.1 In about one third
Correspondence to: Dr. Karl H. Bohuslavizki, Department of Nuclear Medicine, University Hospital Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. Phone: +49 40 4717 4047; Fax: +49 40 4717 6775. E-mail: bohu@medsph2.uke.uni-hamburg.de
of all patients osseous metastases are detected at primary staging. Moreover, the skeleton is the only single site of metastases in a reasonable amount of patients.2 In case of multi-locular osseous metastases a complete remission of prostate cancer is nearly impossible.
Since osseous metastases are often associated with bone pain effective pain relief is the primary goal when caring for patients with prostate cancer and multiple osseous metas-tases.3 Traditional therapeutic approach is the application of central or peripheral analgesics in combination with neuroleptics.4
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Moreover, steroid medication, diphospho-nates, and hormonal drugs may complete analgesics effects. However, therapy with opioids is limited in many patients due to side-effects, .. i.e. nausea, vomitus and gastrointestinal symptoms5 and thus, often associated with a loss of patient's quality of life.6
Skeletal pain confined to single site metastases usually responds to external beam radiotherapy in 70-80 %.4'7'8 In case of multi-locular osseous metastases external beam radiation is helpful to avoid pathologic fractures or compression of the spinal cord.9,10 However, hemibody or whole-body irradiation for pain relief is often limited by bone marrow suppression, gastrointestinal symptoms and a radiation pneumonitis.11,12 Therefore, an effective relief of pain with low side-effects and an improvement in patient's quality of life is warranted in these patients.
Osteotropic radionuclides
The application of P-emitting osteotropic radionuclides is a promising method to selectively irradiate osseous metastases by sparing normal tissue from short-range irra-diation.13 Due to the osteoblastic character of osseous metastases the radionuclide is predominantly accumulated in malignant transformed cells which leads to a selective irradiation of bone metastases. The first agent used for this purpose, P-32-orthophos-phate, was replaced by Sr-89-chloride due to its severe bone marrow toxicity. Up to now Sr-89 is still the most commonly used agent for osteotropic radionuclide therapy.14 Sr-89 has a long physical half-life of 50,5 days with a maximum P-energy of 1,49 MeV (Table 1). Pain relief may occur 2-3 weeks after systemic application of 1,5-2,0 MBq/kg body-weight. However, Sr-89 has no y-emission and thus, posttherapeutic scintigraphy imaging is not feasible. Therefore, the aim of research was to develop alternative radianu-
clides for palliative treatment of painful osseous metastases.
Rhenium-186-HEDP
Re-186-hydroxyethylidendiphosphonate as well as Sm-153 (Table 1) have recently been developed for the palliative treatment of painful osseous metastases.15 Re-186 has a therapeutic P-emission of 1,07 MeV associated with a y-emission of 137 keV. Moreover, Re-186-HEDP and Tc-99m-HDP, that is commonly used for diagnostic bone scintigraphy, have an almost exactly similar bone distribution since both sorts of diphosphonates bridge to the hydroxyapatite of bone substance. Therefore, pretherapeutic and post-therapeutic scintigraphy is possible which allows a control of Re-186 distribution as shown in Figure l. Re-186 has a short physical half-life of 3,8 days when compared to Sr-89. This allows a single application of activities of 1110 to 1850 MBq16'17 with high tumor doses as well as an easy handling of radioactive waste, i.e. urine.
About 50 % of the activity injected are excreted via the kidneys into the urine within the first 6 hours post application. Nearly 70 % of the activity are urinary eliminated within the first 24 hours post application. Apart from the distribution in osseous structures Re-186-HEDP is not accumulated in any other structures of the body.
Pain relief is attained within two weeks after application of Re-186-HEDP and lasts for about 1-6 months. Response rates of Re-186-HEDP therapy of 70-80 % have been reported.2,17'18 Especially in patients with oral medication of non-opioids analgesics rhenium-therapy led either to a reduction or to a stop of taking oral drug medication. Thus, the requirement for central analgesics may be delayed. Moreover, it is known that the clinical response is influenced by the size of osseous metastases. Pain relief mainly occurs
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Table l. Characters of different radionuclides used for treatment of painful osseous metases
	P-32	Sr-89	Re-186	Sm-153
Physical half-life [d}	14.3	50.5	3.8	1.9
P-emission [keV]	1710	1490	1070	810
y-emission [keV]	0	0	137	103
Tracer	phosphate	chloride	HEDP	EDTMP
Scintigraphic imaging	0	0	possible	possible
Table 2. Inclusion criteria of patients for Re-186-HEDP therapy 20 Four or more osseous metastatic sites (at last one single site presents with bone pain) No diphosphonate therapy within 12 weeks No irradiation within 3 weeks No chemotherapy within 6 weeks No change of dosis of hormone therapy within 8 weeks Thrombocytes > 150000/|il Leukocytes > 4000/|l Creatinine < 1,3 mg/dl No clinical sign of cerebral involvement No heart insufficiency NYHA IV Karnofsky-Index > 70 % Life expectancy > 12 weeks
No level III oder level IV toxicity of previous rhenium-therapy (only in case of re-treatment)
in patients with small or medium-sized metastases, whereas large metastases with soft tissue infiltration often do not respond to radionuclide therapy.2 Therefore, the application of bone-seeking radiopharmaceuticals is a treatment option to early complete oral drug therapy. Due to the short physical halflife of Re-186 the treatment can be repeated after 4-6 months.
Side-effects
The main radiobiological side-effect of bone seeking radionuclides is their potential bone marrow toxicity. In contrast to Sr-89 which is associated with a prolonged bone marrow suppression, Re-186 has a relatively mild hematological toxicity. Thrombocytopenia plays the major role in its bone marrow suppressing effect. The decline of thrombocytes presents with a nadir about 3 weeks post
application. Prior to treatment the decrease of platelet count can be estimated for an individual patient presenting for rhenium-therapy.19 Thus, severe hematological side-effects can successfully be avoided. In general, a control of platelet counts in a two-week interval for the duration of two months is sufficient in posttherapeutic follow-up.
Patient management
Several days before the therapeutic administration of Re-186-HEDP the patients undergo conventional bone scintigraphy with labeled diphosphonates, e.g. 600 MBq Tc-99m-HDP. In case of multilocular, osseous metastases with at least four metastatic sites and at least one single painful lesion rhenium-therapy is indicated if the patient fulfills inclusion criteria20 as given in Table 2. Due to its potential bone marrow suppression
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Bone scintigraphy!!
Rhenium-therapy
anterior	posterior	anterior	posterior
Figure l. 64-year-old patient with rnultilocular bone metastases of a primary prostate cancer. The patient claimed about pain of the left femur and both scapulas. Left scintigram: Pretherapeutic conventional whole-body bone scintigraphy 3 hrs after application of 600 MBq Tc-99rn-HDP i.v. Note tracer accurnlations of the skull, the ribs, the sternum, the bassin, both proximal femurs, and the spinal column corresponding to sites of osseous metastases. Right scintigram: Posttherapeutic whole-body scintigraphy 48 hrs after application of 1.3GBq Re-186-HEDP i.v. Note distribution of Re-186-HEDP corresponds to osseous metastatic sites.
patients with thrombocytes below 150000/|l have to be excluded from therapy. In clinical routine, the blood count is defined directly prior to rhenium-application. If there are no contraindications, 1.3 GBq Re-186-HEDP with a total volume of about 2 ml are administered via an intravenous line. 48 hrs post application a whole-body scintigraphy with a scan-speed of 6 cm/min is obtained in order to evaluate the distribution of the bone-seeking Re-186-HEDP.
Conclusion
Palliative Re-186-HEDP therapy of multilocular, painful osseous metastases in patients with prostate cancer is a sufficient therapeu-
tic modality for pain alleviation with low tox-icity, thereby increasing patient's quality of life. However, life expectancy will not be affected.
References
1.	Jacobs SC. Spread of prostatic cancer to bone. Urology 1983; 21: 337-44.
2.	Palrnedo H, Bender H, Schomburg A, Griinwald F, Schöneich G, Zarnorra P, Reichmann K, Dierke-Dzierzon C, Mallmann P, Biersack HJ. Schmerztherapie mit Rhenium-186 HEDP bei multiplen Knochenmetastasen. Nucl Med 1996; 35: 63-7.
3.	Quirijnen JMSP, Han SH, Zonnenberg BA, de Klerk JMH, van het Schip AD, van Dijk A, ten Kroode HfJ, Blijham GH, van Rijk PP. Efficacy of
Palliation of painful osseous iiieatastases
371
Rhenium-186-etidronate in prostate cancer patients with metastatic bone pain. J Nucl Med 1996; 37: 1511-5.
4.	Schöneich G, Palmedo H, Heimbach D, Biersack HJ, Müller SC. Advanced prostate cancer: systemic radiopharmaceutical therapy of metastatic prostate cancer with Rhenium-186 hydroxyethyli-dene diphosphonate. Onkologie 1997; 20: 316-9.
5.	Schag CA, Cranz PA, Dim DS, Sim MS, Lee JJ. Quality of life in adult survivors of lung, colon and prostate cancer. Qual Life Res 1994; 3: 127-41.
6.	Schöneich G, Palmedo H, Dierke-Dzieron C, Müller SC, Biersack HJ. Rhenium-186 HEDP: palliative radionuclide therapy of painful metastases. Preliminary results. Scand J Ural Nephrol 1997; 31: 445-8.
7.	Gilbert HA, Kagan AR, Nussbaum H, Rao AR, Satzman J, Chan P, Forsythe A. Evaluation of radiation therapy for bone metastases: pain relief and quality of life. Am J Roentgenol 1977; 129: 1095-6.
8.	Hendrickson FR, Shehata WM, Kirchner AB. Radiation therapy for osseous metastasis. Int ] Radiat Oncol Biol Phys 1976; 1: 275-8.
9.	Hoskin PJ. Radiotherapy in the management of bone metastases. In: Rubens RD, Fogelman I editors. Bone metastases: diagnosis and treatment. London: Springer-Verlag 1991. p. 171-85.
10.	Poulsen HS, Nielsen OS, Klee M, Rort M. Palliative irradiation of bone metastases. Cancer Treat Rev 1989; 16: 41-8.
11.	Perez CA, Cosmatos D, Carcia DM, Eisbruch AE, Poulter CA. Irradiation in relapsing carcinoma of the prostate. Cancer 1993; 71: 1110-22.
12.	De Klerk JMH, Zonnenberg BA, van het Schip AD, van Dijk A, Han SH, Quirijen JMSP, Blijham GH, van Rijk PP. Dose escalation study of Rheni-um-186 hydroxyethylidene diphosphonate in patients with metastasic prostate cancer. Eur J Nucl Med 1994; 21: 1114-20.
13.	De Klerk JMH, van Dieren EB, van het Schip AD,
Hoekstra A, Zonnenberg BA, van Dijk A, Rutgers DH, Blijham GH, van Rijk PP. Bone marrow absorbed dose of Rhenium-186-HEDP and the relationship with decreased platelet counts. J Nucl Med 1996; 37: 38-41.
14.	Blake GM, Zivanovic MA, McEwan AJ, Ackery DM. Strontium-89 therapy: strontium kinetics in disseminated carcinoma of the prostate. Eur J Nucl Med 1986; 12: 447-54.
15.	Collins C, Eary JF, Donaldson G, Vernon C, Bush NE, Petersdorf J, Linvingston RB, Gordon EE, Chapman CR, Appelbaum FR. Samarium-53-EDTMP in bone metastases of hormone refractory prostate carcinoma: A phase I/II trial. J Nucl Med 1993; 34: 1839-44.
16.	Maxon HR, Schroder LE, Hertzberg VS. Rhenium-186 HEDP for treatment of painful osseous metastases. Results of a double blind cross over comparison with placebo. J Nucl Med 1991; 19: 1877-81.
17.	Maxon HR, Thomas SR, Hertzberg VS: Rhenium-186 HEDP for treatment of painful osseous metastases. Semin Nucl Med 1992; 22: 33-40.
18.	Zonnenberg BA, De Klerk HJM, van Rijk PP. Re-186 HEDP for treatment of painful bone metastases in patients with metastatic prostate or breast cancer. J Nucl Med 1991; 32: 1082-91.
19.	De Klerk JMH, van het Schip AD, Zonnenberg BA, van Dijk A, Stokkel MPM, Han SH, Blijham GH, van Rij PP. Evaluation of thrombocytopenia in patients treated with Rhenium-186 HEDP: Guidelines for individual dosage recommendations. J Nuc/ Med 1994; 35: 1423-8.
20.	Holle L-H, Humke U, Trampert L, Ziegler M, Kirsch CM, Oberhausen E. Palliative Schmerztherapie beim ossar metastasierten Prostatakarzinom mit dem osteotropen p-Stahler 186 Rhenium-Hydroxyethylidendiphosphonat (HEDP). Urologe 1997; 36: 540-7.