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© 2000 American Society for Clinical Oncology Quantitative Bone Single-Photon Emission Computed Tomography for Prediction of Pain Relief in Metastatic Bone Disease Treated With Rhenium-186 EtidronateFrom the Departments of Nuclear Medicine, Oncology, and Neurology, Rambam Medical Center; Department of Oncology, Lady Davis Carmel Hospital; and B. Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. Address reprint requests to O. Israel, MD, Department of Nuclear Medicine, Rambam Medical Center, Haifa 35254, Israel; email drisrael{at}netvision.net.il
PURPOSE: To calculate radiation doses of rhenium-186 (186Re) etidronate in painful bone metastases using quantitative bone single-photon emission computed tomography (SPECT) and to determine the threshold dose for predicting pain relief. We also wanted to determine whether technetium-99m (99mTc) methylene diphosphonate (MDP) concentrations predict radiation doses of 186Re etidronate in painful lesions. MATERIALS AND METHODS: Forty-eight patients with breast and prostate cancer were evaluated. Patients received therapeutic doses of 186Re etidronate. The area under the pain over time curve (AUPC) was measured for 8 weeks after treatment. Response was calculated as the percentage of change in AUPC. Quantitative bone SPECT (QBS)–measured concentration of 186Re etidronate was used for calculating radiation doses. Receiver operating characteristics curve analysis determined the radiation dose threshold that best separated responders from nonresponders. SPECT-measured concentration of 186Re etidronate in the urinary bladder was correlated with its concentration in the voided urine. Concentration of 99mTc MDP was compared with radiation doses to painful metastases. RESULTS: The radiation dose threshold was 2.10 Gy. For a decrease of 50% in the AUPC, the positive predictive value (PPV) of this value was 75% and the negative predictive value (NPV) was 88%. For a decrease in pain of 33%, the PPV was 84% and the NPV was 81%. In prostate cancer patients only, the PPV was 81% and the NPV was 92%. The correlation between in vivo/in vitro measured urine concentration was 0.90. The correlation between 99mTc MDP concentration and radiation doses of 186Re etidronate was 0.92. CONCLUSION: QBS-measured radiation doses of 186Re etidronate in painful metastases are a good predictor of pain relief. Bone SPECT using 99mTc MDP predicts radiation doses delivered by 186Re etidronate.
BONE PAIN IS PRESENT in approximately 80% of patients with bone metastases.1 Different types of local and systemic treatment options—such as external-beam radiotherapy, chemotherapy, hormone treatment, and, recently, bisphosphonates—are used for palliation of metastatic bone pain.1,2 Systemic administration of bone-seeking beta-emitting radiopharmaceuticals has a beneficial effect on painful bone metastases, which is well documented for hormone-resistant prostate cancer and to some extent for advanced breast cancer, with success rates ranging between 60% and 80%.1,2 The presence of additional gamma radiation in some of these radiopharmaceuticals has been suggested as potentially useful for accurate radiation dosimetry.3-5 Dosimetry has been shown to be important for evaluation of toxicity to vital organs, establishing the optimal safe dose to be administered.3,6 In patients who do not respond, the treatment is without clinical benefit, prolongs the time the patient remains without specific analgetic relief, and is also unnecessarily expensive. Prediction of success of treatment with unsealed sources in the individual patient may provide a better, more efficient, and more cost-effective use for this type of therapy. Rhenium-186 (186Re) etidronate has been used for pain palliation in bone metastases for more than a decade.4,5,7-12 Uptake of hydroxy-ethylene diphosphonate (HEDP) bound to 186Re is similar to that of methylene diphosphonate (MDP) bound to technetium-99m (99mTc), which is used for routine bone scintigraphy.4,7 186Re emits beta radiation with an average range of approximately 0.5 mm in bone and a 137-keV gamma photon of 9% abundance. Whereas the beta radiation is used to irradiate the cancer, the gamma radiation can be used for imaging and quantitation of concentration of this bone seeking radiopharmaceutical. The present study investigated the use of quantitative single-photon emission computed tomography (SPECT)13-18 for measuring radiation doses to painful metastatic sites. SPECT-measured radiation doses were compared with pain relief obtained in each patient. Uptake of 186Re etidronate and 99mTc MDP was also compared to determine whether quantitative results of routine bone SPECT could be used to predict the radiation dose delivered to individual patients by subsequent therapeutic 186Re etidronate administration.
Patient Population and Baseline Evaluation Sixty-three patients with painful bone metastases from histologically diagnosed prostate or breast cancer were enrolled onto the study. Bone metastases were diagnosed by 99mTc MDP bone scintigraphy. Eleven patients who did not complete the 8-week follow-up period (emergency change in treatment for spinal cord compression, severe deterioration of general status, or death) and four patients for whom SPECT data were technically inadequate were excluded from the analysis. The study presents the results for 48 patients. There were 10 women with advanced-stage metastatic breast cancer and 38 men with advanced-stage metastatic prostate cancer. A total of 116 painful metastatic sites were evaluated. There was a range of one to five painful metastatic sites in each patient. The mean age of the patients was 70.8 years (range, 40 to 89 years). The mean duration of the primary disease from diagnosis until treatment with 186Re etidronate was 3.9 years (range, 1 to 10 years). Only patients with a Karnofsky index of more than 70 were included. All patients had been previously treated with conventional therapy for their malignancy as indicated by routine treatment protocols. Thirteen patients had previously received chemotherapy, 36 patients had previously underwent radiotherapy, and 45 patients had received hormonal therapy. None of the patients received chemotherapy or external-beam radiation for at least 8 weeks before entering the study or bisphosphonates for at least 12 weeks before entering the study. All patients required chronic analgetic treatment for relief of bone pain. No major changes were performed in the daily use of medication in any of the patients for the 8 weeks before entering the study. All patients gave informed consent and the Helsinki Committee of our institution approved the study. Patient evaluation upon entering the study included medical history, physical examination, and laboratory tests to evaluate the hematologic and renal status. These tests were performed 14 days before and on the day of receiving treatment, before the administration of the radiopharmaceutical. All patients enrolled in the study had a baseline requirement of a total WBC count of 4,000/µL or more, baseline total platelet count of at least 100,000/µL, and serum creatinine levels of 1.5 mg/dL or less. At 14 days before treatment, after the initial clinical evaluation, all patients underwent bone scintigraphy using 740 MBq of 99mTc MDP. Two hours after the injection, patients underwent planar scintigraphy of the whole skeleton to identify the painful sites as areas of pathologically increased uptake and SPECT of the areas in which the painful metastases were located. The SPECT studies were then used for quantitative measurement of concentration of 99mTc MDP in the painful metastases.14,17,18 For treatment, patients received an intravenous (IV) injection of 186Re etidronate produced by Mallinckrodt Medical Inc (Petten, the Netherlands). The mean dose, based on availability, was 1,532 MBq, with a range of 1,380 to 1,850 MBq. The amount of etidronate injected per patient was 5 mg.7 The time and dose of the injected radiopharmaceutical were recorded in each patient. A normal hydration status was maintained to reduce radiation exposure to nontarget organs.
Evaluation of Patient Response
Quantitative Scintigraphy Concentration of 186Re etidronate in the sites of painful metastases was measured using the previously described method of quantitative bone SPECT (QBS).14 In a preliminary study in a series of 30 phantoms with volumes of 20 to 50 mL and concentrations of 2.59 x 10-2 to 29.6 x 10-2 MBq/mL of 186Re, a threshold of 46% was found to give the best correlation between measured and actual concentrations. Using this threshold, the measured concentration (counts/voxel) was converted into concentration units (MBq/mL).13,15 The time-dependent curve of the concentration in each painful lesion was drawn from the amount of MBq/mL measured in each lesion at 2, 4, 24, and 120 hours after the injection of the radiopharmaceutical. Two-exponential fitting was performed. The area under the curve was calculated for each painful site, assuming homogenous distribution of the radiopharmaceutical in the lesion and a density of 1 g of tissue per a bone volume of 1 mL. This represented the cumulative concentration of 186Re etidronate in the lesion over time, expressed as MBq/g x days. 186Re etidronate excretion is predominantly renal. In vivo SPECT–measured concentration of 186Re etidronate in the urinary bladder at 2 or 24 hours after the injection was compared in 18 patients to the in vitro concentration of the radiopharmaceutical in the urine measured in a well counter. The urine was obtained by the patient micturating immediately after completion of the SPECT study.
Calculation of Radiation Doses The mean concentration (MBq/mL) in painful metastatic sites at 2 hours after the IV injection of 99mTc MDP was compared with the SPECT-measured radiation doses of 186Re HEDP in 44 patients. In four patients, quantitative SPECT data after injection of 99mTc MDP were technically suboptimal.
Statistical Analysis Analysis of QBS was performed at the end of the follow-up period. Calculation of QBS-measured radiation dose and analysis of the pain report were performed by different investigators who were blinded to the results of the analyses performed by the other team members.
After treatment with 186Re etidronate, 26 patients (54%) had a decrease of 50% or more in the AUPC for 8 weeks after treatment and were considered good responders to treatment. Moderate response, with a decrease of at least 33% in the AUPC, was found in 30 patients (63%). In the subgroup of 38 patients with prostate carcinoma, good response was found in 22 patients (58%). Eight patients (17%) had a transient increase in pain during the first week after treatment, the flare response, which has been previously described in the literature.2,8-12,20 None of the patients experienced any clinically evident acute side effects. There was only a minimal decrease in hematologic values after the administration of 186Re etidronate, with only five patients showing transient decrease in total platelet count to less than 100,000/µL. There was no statistically significant difference when the mean ACS before treatment (14.4 ± 19.1) was compared with the mean value after administration of 186Re etidronate (16.5 ± 35.8). Mean measured cumulative concentration of 186Re etidronate in the 116 painful metastatic sites was 0.69 MBq/g x days (range, 0.07 to 2.7 MBq/g x days). Mean calculated radiation dose to the painful metastatic sites in the 48 patients was 3.26 Gy (range, 0.36 to 8.03 Gy). Concentration of 186Re etidronate in the urine was measured in 18 patients. SPECT-measured concentration in the urinary bladder in vivo ranged from 0.02 to 0.67 MBq/mL. Concentration measured in the well counter in the urine obtained after voiding ranged from 0.09 to 0.90 MBq/mL. The correlation of in vivo SPECT–measured and in vitro–measured concentration of 186Re etidronate in the urine was r = 0.90 and is shown in Fig 1.
Using receiver operating characteristics curve analysis, the best cutoff value to distinguish between responders and nonresponders to treatment with 186Re etidronate was found at 2.10 Gy. A patient was defined as TP when he received a mean radiation dose of 2.10 Gy or more and responded to treatment. A TN patient had a mean radiation dose of less than 2.10 Gy and did not respond to treatment. FP patients received a radiation dose of 2.10 Gy or more and did not respond to treatment, and FN patients had a radiation dose of less than 2.10 Gy with significant decrease in pain. For a decrease in AUPC of 50% or higher, there were 24 TP, 14 TN, eight FP, and two FN patients. The PPV value of in vivo QBS–measured radiation doses of 186Re etidronate was 75%, and the NPV was 88% in predicting a good response to treatment. For a decrease in AUPC of at least 33%, there were 27 TP, 13 TN, five FP, and three FN patients. The PPV of in vivo QBS–measured radiation doses of 186Re etidronate was 84% and the NPV was 81% in predicting moderate pain palliation. We also evaluated the value of QBS in predicting good response to treatment in the subgroup of 38 patients with prostate carcinoma. There were 21 TP, 11 TN, five FP, and one FN patient, with a PPV of 81% and a NPV of 92% in predicting good palliative effect of 186Re etidronate in metastatic prostate cancer. The value of QBS-measured radiation dose in predicting good or moderate response in the whole patient population and good response in the subgroup of patients with prostate carcinoma is shown in Fig 2.
There was no significant difference between the clinical characteristics of patients with in vivo–measured radiation doses of more or less than 2.10 Gy (Table 1). The mean change from baseline in the weekly VAS score of patients who had a radiation dose of 2.10 Gy or more was compared with the mean weekly value of those with a QBS-measured radiation dose of less than 2.10 Gy. There was no statistically significant difference between the mean values in these two groups of patients for the first 3 weeks after administration of the radiopharmaceutical. The decrease in mean VAS score in the group of patients with high radiation doses was significantly higher than in those with low radiation doses for the subsequent weeks 4 to 8 of follow-up, as shown in Fig 3.
Uptake of both 186Re etidronate and 99mTc MDP was present in all painful metastases (Fig 4). Quantitative SPECT data of 99mTc MDP were available in 44 patients. A correlation of r = 0.92 was found in these patients between the mean concentration of 99mTc MDP at 2 hours after the injection and the mean SPECT-measured radiation doses of 186Re etidronate (Fig 5). A threshold of 0.04 MBq/mL of 99mTc MDP was found to give the best cutoff value in separating responders and nonresponders to treatment with 186Re etidronate. Only three patients were defined differently than based on calculations for 186Re etidronate: one patient defined as FP with 186Re etidronate was considered TN for 99mTc MDP measurements, and two patients who were defined as TN for 186Re etidronate were considered FP for 99mTc MDP. In 41 patients there was no difference in the predicted response based on uptake measurements with both radiopharmaceuticals.
Prediction of response to treatment is difficult in cancer patients. Response is usually evaluated by follow-up of large matched cohorts of patients. Results of the clinical follow-up are then used to predict response to treatment in subsequent groups of patients. Two variable factors determine response to treatment in the individual patient: the dose of the drug that reaches the tumor and its effect on the cancer cells. Treatment with unsealed sources for pain palliation in patients with painful bone metastases has been reported with success rates between 60% and 80%.1,2 Radiation dosimetry has been performed after treatment with radiopharmaceuticals for bone pain palliation. A number of techniques have been described for measurement of concentration. Uptake of the radiopharmaceutical in the skeleton has been derived from subtracting the activity excreted in the urine from the total injected amount.4,8,21,22 This is, however, inaccurate, with large variations (between 45% and 90%) in retained activity.20 The bone scan index has been advocated as another measure of the extent of metastatic involvement on bone scintigraphy and has been shown to be useful for general toxicity calculations.7,9-12,23 These methods give only a gross estimation of the concentration of the radiopharmaceutical in the whole skeleton. Different bones, healthy and metastatic, take up variable amounts of the radiopharmaceutical.4,14,17,18 Therefore, no relationship has been found between bone scintigraphy patterns, bone pain in skeletal metastases, and patient response.10-12,22,24,25 Calculation of radiation doses, to be expected from treatment with strontium-89, has been attempted in a few patients after injection of tracer doses of strontium-85.20-23 The physical characteristics of this isotope are not optimal for imaging, and, therefore, predicted radiation doses have been either over- or underestimated according to the extent of metastatic involvement.22,26 The Monte Carlo simulation is a theoretical, experimental model to calculate radiation doses for 186Re HEDP.27 Because it considers heterogeneous uptake of the radiopharmaceutical in the bony lesions, precision of the calculations is improved, but it is invasive in that it requires bone specimens obtained during bone biopsy for histomorphometry.27 It is also impaired by long computation times, and its clinical use has not been proven.6 The goal of previously described studies was mainly to calculate toxicity to the bone marrow for establishing the safest doses to be administered. They also give good estimates of radiation doses received by painful sites but have not been correlated with the degree of pain relief and patient outcome. Data derived from theoretical models or from groups of patients are of limited value in predicting successful pain palliation in an individual patient. In the present study, the ability of SPECT to quantitate uptake of radiolabeled organic phosphates in specific painful skeletal metastases was evaluated to calculate the percentage of injected dose in these sites treated with 186Re etidronate. This is not an indirect estimate of the amount of radioactivity, but a direct measurement of concentration of the drug in the individual painful lesion. In previous studies, when the amount of 99mTc MDP measured in vivo in specific bones by quantitative SPECT was compared with its concentration in samples of the same bone obtained during surgery, a correlation of 0.96 was obtained.14 QBS is thus an accurate technique with good repeatability and reproducibility that has been used for in vivo quantitation of uptake of radiophosphates in bone.14,17,18 The good correlation (r = 0.90) between concentration of 186Re etidronate in the urine measured in vivo with SPECT and the actual concentration in the same urine measured in a well counter validates the feasibility and accuracy of measurement of concentrations of 186Re etidronate in vivo. 186Re etidronate is taken up by bone by a mechanism similar to other organic phosphates.7 Etidronate has been recommended for palliation of bone pain in Paget’s disease in therapeutic doses varying between 400 and 1,200 mg for a period of 14 to 60 days.28,29 The administration of a single radiolabeled tracer dose of 5 mg is therefore not expected to have any palliative effect. It emits beta radiation, which affects cancer cells locally, and gamma radiation, which can be recorded and, as shown in the present study, used for quantitation. Prediction of which patients will and will not respond to treatment with 186Re etidronate is clinically important. For those in whom pain relief is not expected, the clinical approach can be changed, either by increasing the injected dose or by using another, more suitable treatment. One must remember, of course, that pain and its response to treatment are affected by sex and social and psychologic factors. Evaluation of pain is subjective and difficult to reproduce.30 The AUPC used in this study to determine response considers all important parameters of pain evaluation, including the level of initial pain and the frequency of pain, as well as the promptness and duration of pain relief.31 Pain relief for each metastatic site is difficult to assess. As shown, uptake of both 186Re etidronate and 99mTc MDP varied between different painful sites in the same patients and in different patients. The decision to treat an individual patient should be made on the basis of the predicted response of the patient as a whole. For the purpose of simplifying dosimetry calculations, a uniform distribution of the radiopharmaceutical in the lesions was assumed, as done previously by other authors.4,6,8,23,26 This is more the case in metastatic prostate cancer, in which lesions are predominantly osteoblastic and uptake of organic phosphates reflects tumor burden more correctly than in breast cancer.9,30 This may explain the better results obtained in the subgroup of 38 patients with prostate cancer. Although quantitative SPECT can accurately measure the radiation dose delivered by 186Re etidronate to painful sites, the radiosensitivity of the target lesions is as yet unpredictable.32 This is probably the cause for the few FN and FP cases. The high NPV in patients with prostate cancer indicates, however, the low chance of error of this technique. A good correlation (r = 0.92) was found between uptake of 99mTc MDP and the number of grays delivered by treatment with 186Re etidronate. Radiation doses are calculated using the cumulated activity in the lesions. Cumulative activity depends on the maximal uptake and half-life of skeletal retention of the radiopharmaceutical. Maximal uptake occurs early (2 to 4 hours after injection) and seems to be the principal factor in determining radiation dose. Bone scintigraphy with 99mTc MDP, when performed as part of routine management of oncologic patients with the addition of quantitative SPECT, can thus provide predictive information on response in an individual patient regarding the radiation dose that painful metastases will receive from treatment with 186Re etidronate. This simple and inexpensive procedure can be used to predict the effect of treatment. Predicted doses delivered in the individual patient with painful bone metastases should be a criterion for choosing radiopharmaceuticals and doses for palliative treatment. There is no definite proof today that escalating the administered dose in all patients up to 2,405 to 3,515 MBq, as recommended in recent publications,9-11 will lead to better general response rates. A similar study of predicting delivered radiation must be repeated for each dose of 186Re etidronate before tailoring the administered amount in each patient. A threshold could be determined for each dose level, allowing for clinical decisions on the administration of the amount of radiopharmaceutical that will yield the highest therapeutic efficacy with the least toxicity. Patients with a lower predicted radiation dose may be treated with the higher dose and have a better chance for success. Quantitative SPECT can be potentially used for any radionuclide that emits both gamma and beta radiation and is taken up by bone metastases by the same mechanism as 99mTc MDP, such as samarium-153 ethylenediaminetetramethylene phosphate.20,26,33 In vivo/in vitro correlation and validation of radiation doses need to be performed for each radiopharmaceutical. In conclusion, this study describes a technique for measuring radiation dose from 186Re etidronate to bone metastases, with a good predictive value for response to treatment. This is in contrast with previous statements that it is virtually impossible to indicate nonresponders before treatment.3 This method identifies the patients who will benefit from treatment and, with a high NPV, will identify patients in whom such treatment has little chance of being effective. This could increase the rate of successful pain palliation in metastatic bone disease and improve cost-effective cancer management. Pain from bone metastases can be palliated using IV administration of radiopharmaceuticals. Routine bone scintigraphy with quantitative SPECT can predict the rate of success and therefore exclude patients for whom this therapy is inappropriate.
Supported by a research grant from Mallinckrodt Medical Inc, Petten, the Netherlands, and by grants from the Research Foundation of the Technion and the Israel Cancer Association.
1. Davis LP, Porter AT: Systemic radionuclide therapy: Nuclear medicine’s role in the palliation of painful bone metastases, in Freeman L (ed): Nuclear Medicine Annual. New York, NY,Raven Press, 1995, pp 169-184 2. McEwan AJB: Unsealed source therapy of painful bone metastases: An update. Semin Nucl Med 27:165-182, 1997[Medline] 3. Lewington VJ: Targeted radionuclide therapy for bone metastases. Eur J Nucl Med 20:66-74, 1993[Medline]
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De Klerk JMH, Van Dijk A, Van het Schip AD, et al: Pharmacokinetics of rhenium-186 after administration of rhenium-186 HEDP to patients with bone metastases. J Nucl Med 33:646-651, 1992 8. Maxon HR III, Thomas SR, Hertzberg VS, et al: Rhenium-186 hydroxyethylidene diphosphonate for the treatment of painful osseous metastases. Semin Nucl Med 22:33-40, 1992[Medline]
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De Klerk JMH, Van het Schipp AD, Zonnenberg BA, et al: Evaluation of thrombocytopenia in patients treated with rhenium-186 HEDP: Guidelines for individual dosage recommendations. J Nucl Med 35:1423-1428, 1994
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Han SH, Zonnenberg BA, De Klerk JMH, et al: Re-186 etidronate in breast cancer patients with metastatic bone pain. J Nucl Med 40:639-642, 1999 13. Iosilevsky G, Israel O, Frenkel A, et al: A practical SPECT method for quantitation of drug delivery to human tumors and organ absorbed radiation dose. Semin Nucl Med 19:33-46, 1989[Medline]
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Israel O, Gorenberg M, Frenkel A, et al: Local and systemic effects of radiation on bone metabolism measured by quantitative SPECT. J Nucl Med 33:1774-1782, 1992
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Israel O, Gips S, Hardoff R, et al: Bone loss in patients with chronic renal disease: Prediction with quantitative bone scintigraphy with SPECT. Radiology 196:643-646, 1995 19. Loevinger R, Berman A: A schema for absorbed dose calculations for biologically distributed radionuclides: MIRD pamphlet no. 1. J Nucl Med 9:7-14, 1968 (suppl 1) 20. Turner JH, Claringbold PG, Hetherington EL, et al: A phase I study of samarium-153 ethylenediaminetetramethylene phosphonate therapy for disseminated skeletal metastases. J Clin Oncol 7:1926-1931, 1989[Abstract]
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Silberstein EB: Dosage and response in radiopharmaceutical therapy of painful osseous metastases. J Nucl Med 37:249-251, 1996 31. Tong D, Gillick L, Hendrickson FR: The palliation of symptomatic osseous metastases: Final results of the study by the radiation therapy oncology group. Cancer 50:893-899, 1982[Medline] 32. Shapiro B: Optimization of radioiodine therapy of thyrotoxicosis: What have we learned after 50 years? J Nucl Med 34:1636-1637, 1993 33. Serafini AN, Houston SJ, Resche I, et al: Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: A double-blind placebo-controlled clinical trial. J Clin Oncol 4:1574-1581, 1998 Submitted October 13, 1999; accepted March 16, 2000. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
I, where Cv represents the cumulative concentration (MBq/g x days) in the lesion, and 
