A comparative study of 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr in the treatment of painful skeletal metastases

AIM: The surface bone-seeking radiopharmaceuticals 188Re-HEDP, 186Re-HEDP and 153Sm-EDTMP, and the volume seeker 89Sr were investigated to determine the efficacy and toxicity in pain palliation of bone metastases. METHOD: The effect of treatment with 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr on pain symptoms, quality of life, and bone marrow function were studied. In total, 79 patients (18 with breast cancer and 61 with prostate cancer) were treated (31 patients with 188Re-HEDP, 15 patients each with 186Re-HEDP and 153Sm-EDTMP, and 18 patients with 89Sr). All patients were interviewed using standardized sets of questions before and after therapy weekly for 12 weeks. Blood counts were taken weekly for 6 weeks and after 12 weeks. RESULTS: In total, 73% of patients reported pain relief (77% after 188Re-HEDP, 67% after 186Re-HEDP 73% after 153Sm-EDTMP, and 72% after 89Sr). Fifteen percent of patients could discontinue their analgesics and were pain-free. Pain showed a decrease from 3.6+/-1.7 to a maximum of 2.2+/-1.8 at visual analogue scale in 10 steps (P<0.01). Patients described an improvement on the Karnofsky performance scale from 70+/-10% to 78+/-14% 12 weeks after treatment (P=0.15). There were eight patients with a thrombocytopenia grade I, two patients with grade II and one with grade III. The maximum nadir of platelet and leukocyte counts were observed between the 2nd to 5th week after treatment and was reversible within 12 weeks. There were no significant differences in pain palliation, Karnofsky performance status (KPS) and bone marrow toxicity between the different radionuclides (P=0.087-0.449). CONCLUSION: All radiopharmaceuticals were effective in pain palliation, without induction of severe side effects or significant differences in therapeutic efficacy or toxicity.     

186Re-etidronate. Efficacy of palliative radionuclide therapy for painful bone metastases.

Pain palliation with bone-seeking radiopharmaceuticals is an effective treatment modality in patients with advanced metastatic bone cancer. Several studies have shown encouraging clinical results of palliative therapy using 186Re-HEDP, with an overall reported response rate of +/-71% for painful osseous metastasized prostate and breast cancer patients. 186Re-HEDP is a very potential isotope with numerous advantageous characteristics for this purpose. Myelosuppressive toxicity is limited and reversible, which makes repetitive treatment safe. However, individual studies are difficult to compare, and are hampered by the numerous and different methods used to assess clinical response. Standardized clinical response assessment using the objective multi-dimensional pain evaluation model should therefore be implemented.     

Dose escalation study of rhenium-186 hydroxyethylidene diphosphonate in patients with metastatic prostate cancer

Rhenium-186 hydroxyethylidene diphosphonate (¹⁸⁶Re-HEDP) has been used for the palliative treatment of metastatic bone pain. A phase 1 dose escalation study was performed using ¹⁸⁶Re-HEDP Twenty-four patients with hormone-resistant prostate cancer entered the study. Each patient had at least four bone metastases and adequate haematological function. Groups of at least three consecutive patients were treated with doses starting at 1295 MBq and increasing to 3515 MBq (escalated in increments of 555 MBq). Thrombocytopenia proved to be the dose-limiting toxicity, while leucopenia played a minor role. Early death occurred in one patient (10 days after administration) without clear relationship to the ¹⁸⁶Re-HEDP therapy. Transient neurological dysfunction was seen in two cases. Two patients who received 3515 MBq ¹⁸⁶Re-HEDP showed grade 3 toxicity (thrombocytes 25–50 × 10⁹/1), defined as unacceptable toxicity. After treatment alkaline phosphatase levels showed a transient decrease in all patients (mean: 26% ± 10% IUA; range: 11%–44%). Prostate-specific antigen values showed a decline in eight patients, preceded by a temporary increase in three patients. From this study we conclude that the maximally tolerated dose of ¹⁸⁶Re-HEDP is 2960 MBq. A placebo-controlled comparative study on the efficacy of ¹⁸⁶Re-HEDP has been initiated.     

186Re-HEDP for metastatic bone pain in breast cancer patients

Two-thirds of patients with metastatic cancer suffer from pain. Pain originating from skeletal metastases is the most common form of cancer-related pain. Bone pain, often exacerbated by pressure or movement, limits the patient's autonomy and social life. Pain palliation with bone-seeking radiopharmaceuticals has proven to be an effective treatment modality in patients with metastatic bone pain. These bone-seeking radiopharmaceuticals are extremely powerful in treating scattered painful bone metastases, for which external beam radiotherapy is impossible because of the large field of irradiation. (186)Re-hydroxyethylidene diphosphonate (HEDP) is a potentially useful radiopharmaceutical for this purpose, having numerous advantageous characteristics. Bone marrow toxicity is limited and reversible, which makes repetitive treatment safe. Studies have shown encouraging clinical results of palliative therapy using (186)Re-HEDP, with an overall response rate of ca. 70% in painful bone metastases. It is effective for fast palliation of painful bone metastases from various tumours and the effect tends to last longer if patients are treated early in the course of their disease. (186)Re-HEDP is at least as effective in breast cancer patients with painful bone metastases as in patients with metastatic prostate cancer. It is to be preferred to radiopharmaceuticals with a long physical half-life in this group of patients, who tend to have more extensive haematological toxicity since they have frequently been pretreated with bone marrow suppressive chemotherapy. This systemic form of radionuclide therapy is simple to administer and complements other treatment options. It has been associated with marked pain reduction, improved mobility in many patients, reduced dependence on analgesics, and improved performance status and quality of life.     

Pharmacokinetics of rhenium-186 after administration of rhenium-186-HEDP to patients with bone metastases.

The pharmacokinetics of 186Re-HEDP, a radiopharmaceutical for palliative treatment of metastatic bone pain, was investigated in 11 patients (17 studies) who suffered from metastatic breast or prostate cancer. Half-life times of 186Re in three blood fractions (whole blood, plasma and plasma water) were 40.1 +/- 5.0, 41.0 +/- 6.0 and 29.5 +/- 6.4 hr, respectively. Time-dependent increase in plasma-protein binding was observed, probably caused by in vivo decomposition of 186Re-HEDP. Total urinary 186Re excretion was 69% +/- 15%, of which 71% +/- 6% was excreted in the first 24 hr after injection. The BSI (i.e., fraction of the skeleton showing scintigraphic evidence of metastatic disease) closely correlated with the fraction of dose non-renally cleared (r = 0.98). This implies that the amount of radioactivity taken up by the skeleton and hence the bone marrow absorbed dose can be predicted from a diagnostic pre-therapy 99mTc-HDP scintigram. The pharmacokinetic behavior indicates that 186Re-HEDP has suitable properties to justify its application.     

Short- and long-term effects of 186Re-1,1-hydroxyethylidene diphosphonate in the treatment of painful bone metastases.

This study evaluates the short- and long-term therapeutic efficacy of 186Re-1,1-hydroxyethylidene diphosphonate (HEDP) in the palliation of painful bone metastases and the influence of variables before therapy in determining the characteristics of pain palliation. METHODS: Sixty patients with painful bone metastases from different tumor types were treated with 1406 MBq 186Re-HEDP. After treatment, the patients were followed up clinically at weekly intervals for the first month and monthly thereafter up to 1 y, until death or pain relapse. Pain response was graded as complete, partial, minimal, or absent using the Wisconsin test scoring system. Duration of pain relief, performance status, tumor markers, serum alkaline phosphatase levels, hematologic toxicity, and metastatic bone progression were also evaluated. RESULTS: Overall, 80% of individuals experienced prompt relief of pain, with 31% complete, 34% partial, and 15% minimal responses. Transient World Health Organization grade 1-2 hematologic toxicity was apparent, with a decrease in the mean platelet (32%) and mean leukocyte (18%) counts at 3 and 4 wk, respectively. The degree of pain response did not correlate with any pretreatment variable. The duration of pain relief ranged from 3 wk to 12 mo and correlated positively with the degree of response (P = 0.02) and negatively with pretreatment scintigraphic scores and alkaline phosphatase levels (P = 0.02). CONCLUSION: 186Re-HEDP is effective for fast palliation of painful bone metastases from various tumors. The effect tends to last longer if patients are treated early in the course of their disease.     

Pain palliation with rhenium-186 HEDP in breast cancer patients with disseminated bone metastases.

PURPOSE: For patients with metastatic prostate cancer, first results have shown that rhenium-186 (Re-186) hydroxyethylidene diphosphonate (HEDP) is efficient in pain palliation of disseminated bone metastases. The aim of this study was to determine whether significant pain reduction can also be achieved in breast cancer patients with Re-186 HEDP. METHODS: Thirty patients with breast cancer who had multifocal painful bone metastases received a total of 38 intravenous Re-186 HEDP injections. Pain relief was assessed through daily documentation of the visual analog scale and analgesic consumption. A significant response to treatment was determined if the visual analog scale or analgesic consumption decreased significantly for at least 2 weeks. Blood counts were controlled at baseline and at weeks 4 and 8. RESULTS: A response to pain therapy was observed in 60% (18 of 30) of the patients. A reversible thrombocytopenia and leukopenia of grade 2 (according to World Health Organization criteria) was found in 4 and 2 patients, respectively. CONCLUSION: Patients with disseminated osseous metastases resulting from breast cancer can benefit from therapy with Re-186 HEDP.     

Dose escalation study with rhenium-188 hydroxyethylidene diphosphonate in prostate cancer patients with osseous metastases

The aim of this study was to determine the maximum tolerated dose of rhenium-188 hydroxyethylidene diphosphonate (HEDP) in prostate cancer patients with osseous metastases who are suffering from bone pain. Twenty-two patients received a single injection of escalating doses of carrier-added 188Re-HEDP [1.3 GBq (35 mCi), 2.6 GBq (70 mCi), 3.3 GBq (90 mCi) and 4.4 GBq (120 mCi)]. Blood counts and biochemical parameters were measured weekly over a period of 8 weeks. Haematological toxicity (WHO grading) of grade 3 or 4 was considered unacceptable. Clinical follow-up studies including methods of pain documentation (medication, pain diary) were performed for 6 months after treatment. In the 1.3-GBq group, no haematological toxicity was observed. First haematotoxic results were noted in those patients with a dose of 2.6 GBq 188Re-HEDP. In the 3.3-GBq group, one patient showed a reversible thrombopenia of grade 1, one a reversible thrombopenia of grade 2 and three a reversible leukopenia of grade 1. In the 4.4-GBq group, thrombopenia of grades 3 and 4 was observed in one and two patients (baseline thrombocyte count <200x10(9)/l), respectively, and leukopenia of grade 3 was documented in one patient. The overall nadir of thrombopenia was at week 4. The individual, maximum percentage decrease in thrombocytes in the 1.3-, 2.6-, 3.3- and 4.4-GBq groups was 17%, 40%, 60% and 86%, respectively. In two patients, a transient increase in serum creatinine was observed (max. 1.6 mg/dl). Pain palliation was reported by 64% of patients, with a mean duration of 7.5 weeks. The response rate seemed to increase with higher doses, reaching 75% in the 4.4-GBq group. It is concluded that in prostate cancer patients, the maximum tolerated dose of 188Re-HEDP is 3.3 GBq if the baseline thrombocyte count is below 200x10(9)/l. In patients with thrombocyte counts significantly above 200x10(9)/l, a dose of 4.4 GBq might be tolerable. Thrombo- and leukopenia are the most important side-effects. Pain palliation can be achieved in 60%-75% of patients receiving a dose of 2.6 GBq or more of 188Re-HEDP. Studies in a larger patient population are warranted to evaluate further the palliative effect of 188Re-HEDP.     

Palliative analgesic effect of Re-186 HEDP in various cancer patients with bone metastases

The clinical picture of bone metastases is manifested by pain and loss of mechanical stability. Standard treatment options for bone metastases include external beam radiotherapy and the use of analgesics. Due to a large number of lesions in many patients, the use of radionuclide therapy with beta emitters may be preferable. Re-186 hydroxyethylidene diphosphonate (Re-186 HEDP) is one of the radiopharmaceuticals suitable for palliative treatment of metastatic bone pain. The aim of this study was to investigate palliative and side effects of Re-186 HEDP in patients with different types of cancers. MATERIAL & METHOD: Thirty one (17 male, 14 female) patients with various cancers (10 prostate, 10 breast, 4 rectum, 5 lung, 2 nasopharynx) and bone metastases were included in the study. Therapy was started with a fixed dose of 1295 MBq of Re-186 HEDP. If necessary, the same dose was repeated at least 3 times after an interval of 10-12 weeks; A total of 40 standard doses were given; 6 patients received repeated doses (3 doses in 3 patients, 2 doses in 3 patients). The patients with bone marrow suppression were excluded from the study. The pain relief was assessed the Eastern Cooperative Oncologic Group (ECOG) and the Karnofsky status index. All patients were evaluated with standard evaluation forms filled in daily for a maximum of 10 weeks. RESULTS: The mean response rate was 87.5% in patients with breast and prostate cancer, 75% in patients with rectum cancer and 20% in patients with lung cancer. The overall response rate was 67.5%. The palliation period varied between 6 and 10 weeks, with a mean of 8.1+/-1.3 weeks. The maximal palliation effect was observed between the 3rd and 7th weeks. No serious side effects were seen except mild hematologic toxicity. DISCUSSION & CONCLUSION: It is concluded that Re-186 HEDP is a highly effective agent in the palliation of metastatic bone pain in patients with prostate, breast and rectum cancer, but not effective in lung cancer. On the other hand, Re-186 seems to be a good alternative to Sr-89 because of its preferable physical characteristics (such as short half life and gamma energy emission), low side effect profile, early response and repeatability.     

Dose escalation study with rhenium-188 hydroxyethylidene diphosphonate in prostate cancer patients with osseous metastases

The aim of this study was to determine the maximum tolerated dose of rhenium-188 hydroxyethylidene diphosphonate (HEDP) in prostate cancer patients with osseous metastases who are suffering from bone pain. Twenty-two patients received a single injection of escalating doses of carrier-added ¹⁸⁸Re-HEDP [1.3 GBq (35 mCi), 2.6 GBq (70 mCi), 3.3 GBq (90 mCi) and 4.4 GBq (120 mCi)]. Blood counts and biochemical parameters were measured weekly over a period of 8 weeks. Haematological toxicity (WHO grading) of grade 3 or 4 was considered unacceptable. Clinical follow-up studies including methods of pain documentation (medication, pain diary) were performed for 6 months after treatment. In the 1.3-GBq group, no haematological toxicity was observed. First haematotoxic results were noted in those patients with a dose of 2.6 GBq ¹⁸⁸Re-HEDP. In the 3.3-GBq group, one patient showed a reversible thrombopenia of grade 1, one a reversible thrombopenia of grade 2 and three a reversible leukopenia of grade 1. In the 4.4-GBq group, thrombopenia of grades 3 and 4 was observed in one and two patients (baseline thrombocyte count <200×10⁹/l), respectively, and leukopenia of grade 3 was documented in one patient. The overall nadir of thrombopenia was at week 4. The individual, maximum percentage decrease in thrombocytes in the 1.3-, 2.6-, 3.3- and 4.4-GBq groups was 17%, 40%, 60% and 86%, respectively. In two patients, a transient increase in serum creatinine was observed (max. 1.6 mg/dl). Pain palliation was reported by 64% of patients, with a mean duration of 7.5 weeks. The response rate seemed to increase with higher doses, reaching 75% in the 4.4-GBq group. It is concluded that in prostate cancer patients, the maximum tolerated dose of ¹⁸⁸Re-HEDP is 3.3 GBq if the baseline thrombocyte count is below 200×10⁹/l. In patients with thrombocyte counts significantly above 200×10⁹/l, a dose of 4.4 GBq might be tolerable. Thrombo- and leukopenia are the most important side-effects. Pain palliation can be achieved in 60%–75% of patients receiving a dose of 2.6 GBq or more of ¹⁸⁸Re-HEDP. Studies in a larger patient population are warranted to evaluate further the palliative effect of ¹⁸⁸Re-HEDP. Received 7 July and in revised form 6 October 1999     

A multicentre observational study of radionuclide therapy in patients with painful bone metastases of prostate cancer

A multicentre observational study was conducted by the Italian Association of Nuclear Medicine between 1996 and 1998. Twenty-nine Nuclear Medicine Departments participated. The aims of the study were to systematically evaluate the efficacy, toxicity and repeatability of radionuclide therapy of painful bone metastases (RTBM) in a large number of patients and to assess its incidence in patients with prostate cancer. Out of 818 treatments performed with a single i.v. dose of 148 MBq of strontium-89 chloride or 1,295 MBq of rhenium-186 hydroxyethylidene diphosphonate (HEDP), 610 could be evaluated (527 with 89Sr and 83 with 186Re-HEDP). Eighty-one patients received multiple (up to five) RTBM. The total number of retreatments was 100. Patients were followed up for a period of 3-24 months. Results, assessed according to pain relief and consumption of analgesic drugs, were expressed at four levels: 1, no response; 2, mild response; 3, good response; 4, excellent response. Responses were: level 1 in 19%, level 2 in 21.3%, level 3 in 33.3% and level 4 in 26.4% of cases. Retreatments showed significantly (P<0.01) worse responses (48% levels 3+4), in comparison to first RTBM. Duration of palliation was 5.0+/-3.5 months, and was longer in cases of excellent response, in first RTBM, in patients with limited metastases and when 89Sr was used. Better responses were found in cases of limited skeletal disease, under good clinical conditions, when life expectancy exceeded 3 months, and in radiologically osteoblastic or mixed bone lesions. The only statistically significant predictive factor was life expectancy (P<0.001). Flare phenomenon (14.1% of cases) did not correlate with the response. Haematological toxicity (mild to moderate in most cases) mainly affected platelets, and was observed in 25.5% of cases overall and in 38.9% of retreatments. RTBM did not seem to prolong life, though in some cases scintigraphic regression of bone metastases was observed. The two radiopharmaceuticals did not show any statistically significant differences in palliative efficacy and toxicity, either in first RTBM or in retreatments.     

186Re-etidronate in breast cancer patients with metastatic bone pain.

The aim of this study was to evaluate the efficacy of 186Re-1,1-hydroxyethylidene diphosphonate (etidronate) in breast cancer patients with painful bone metastases. METHODS: Thirty patients with advanced breast cancer who had metastatic bone pain were treated with 186Re-etidronate using different dosages in a noncomparative, open-label study. Twenty-four patients were evaluated for efficacy (6 patients had incomplete datasets). Dosages varied from 1295 to 2960 MBq (35 to 80 mCi). Efficacy was evaluated according to the multidimensional pain model using a paper-and-pencil diary. The diary was kept twice daily for 8-10 wk (2 wk before through 6-8 wk after 186Re-etidronate treatment). Response was determined with a strict criteria, in which pain intensity (PI), medication index (MI) and daily activities (DA) were core determinants. Response was defined as: (a) Reduced PI > or = 5% while MI and DA were at least constant; or (b) Reduced PI <25% in combination with improvement of MI or DA > or = 25%, without worsening of either factor. Duration of response should always exceed a minimum of 2 wk. RESULTS: Fifty-eight percent (n = 14) of all patients reported a response. The maximum follow-up period was 8 wk. Duration of response ranged from 2 to 8 wk (mean 4 wk). Patients (14/24) not only experienced considerable pain reduction, but in 12 patients this was also accompanied by noteworthy reduction in MI (> or = 25%). No clear dose-response relationship was found. CONCLUSION: With strict pain assessment criteria, 186Re-etidronate showed a response of 58% in the palliative treatment of metastatic bone pain originating from breast cancer.     

Predictive implications of bone turnover markers after palliative treatment with 186Re-HEDP in hormone-refractory prostate cancer patients with painful osseous metastases

Purpose  

To prospectively evaluate the predictive value of various bone formation and resorption markers in patients with bone metastases from prostate cancer after palliative treatment with ¹⁸⁶Re-1,1-hydroxyethylidene diphosphonate (¹⁸⁶Re-HEDP).     

A multicentre observational study of radionuclide therapy in patients with painful bone metastases of prostate cancer

A multicentre observational study was conducted by the Italian Association of Nuclear Medicine between 1996 and 1998. Twenty-nine Nuclear Medicine Departments participated. The aims of the study were to systematically evaluate the efficacy, toxicity and repeatability of radionuclide therapy of painful bone metastases (RTBM) in a large number of patients and to assess its incidence in patients with prostate cancer. Out of 818 treatments performed with a single i.v. dose of 148 MBq of strontium-89 chloride or 1,295 MBq of rhenium-186 hydroxyethylidene diphosphonate (HEDP), 610 could be evaluated (527 with ⁸⁹Sr and 83 with ¹⁸⁶Re-HEDP). Eighty-one patients received multiple (up to five) RTBM. The total number of retreatments was 100. Patients were followed up for a period of 3-24 months. Results, assessed according to pain relief and consumption of analgesic drugs, were expressed at four levels: 1, no response; 2, mild response; 3, good response; 4, excellent response. Responses were: level 1 in 19%, level 2 in 21.3%, level 3 in 33.3% and level 4 in 26.4% of cases. Retreatments showed significantly (P<0.01) worse responses (48% levels 3+4), in comparison to first RTBM. Duration of palliation was 5.0Dž.5 months, and was longer in cases of excellent response, in first RTBM, in patients with limited metastases and when ⁸⁹Sr was used. Better responses were found in cases of limited skeletal disease, under good clinical conditions, when life expectancy exceeded 3 months, and in radiologically osteoblastic or mixed bone lesions. The only statistically significant predictive factor was life expectancy (P<0.001). Flare phenomenon (14.1% of cases) did not correlate with the response. Haematological toxicity (mild to moderate in most cases) mainly affected platelets, and was observed in 25.5% of cases overall and in 38.9% of retreatments. RTBM did not seem to prolong life, though in some cases scintigraphic regression of bone metastases was observed. The two radiopharmaceuticals did not show any statistically significant differences in palliative efficacy and toxicity, either in first RTBM or in retreatments.     

Therapeutic effects of a 186Re-complex-conjugated bisphosphonate for the palliation of metastatic bone pain in an animal model.

Previously, based on the concept of bifunctional radiopharmaceuticals, we developed a highly stable (186)Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl]carbamoylmethyl]carbamoylmethyl]carbamoylmethanethiolate] oxorhenium(V) ((186)Re-MAG3-HBP), for the treatment of painful bone metastases. This agent showed a superior biodistribution as a bone-seeking agent in normal mice when compared with (186)Re-1-hydroxyethylidene-1,1-diphosphonate ((186)Re-HEDP). In this study, we evaluated the therapeutic effects of (186)Re-MAG3-HBP using an animal model of bone metastasis. METHODS: The model was prepared by injecting syngeneic MRMT-1 mammary tumor cells into the left tibia of female Sprague-Dawley rats. (186)Re-MAG3-HBP (55.5, 111, or 222 MBq/kg) or (186)Re-HEDP (55.5 MBq/kg) was then administered intravenously 21 d later. To evaluate the therapeutic effects and side effects, tumor size and peripheral blood cell counts were determined. Palliation of bone pain was evaluated by a von Frey filament test. RESULTS: In the rats treated with (186)Re-HEDP, tumor growth was comparable with that in untreated rats. In contrast, when (186)Re-MAG3-HBP was administered, tumor growth was significantly inhibited. Allodynia induced by bone metastasis was attenuated by treatment with (186)Re-MAG3-HBP or (186)Re-HEDP, but (186)Re-MAG3-HBP tended to be more effective. CONCLUSION: These results indicate that (186)Re-MAG3-HBP could be useful as a therapeutic agent for the palliation of metastatic bone pain.     

Radionuclide therapy for painful bone metastases. An Italian multicentre observational study. Writing Committee of an Ad Hoc Study Group.

BACKGROUND: It has been affirmed that observational studies give analogous results to randomised controlled ones. METHODS: A multicentre observational trial was conducted between 1996-1998 in order to evaluate the efficacy of palliative radionuclide therapy for bone metastases in a large number of patients. An evaluation was made on 510 patients with prostate cancer and painful bone metastases, treated with a single iv. dose of 89Sr-chloride (527 treatments) or 186Re-HEDP (83 treatments), in 29 Italian Nuclear Medicine Departments. Eighty-one patients received up to five injections, totalling 100 retreatments. Patients were followed up for a period of 3 months-2 years. Results were expressed at four levels of response: excellent, good, mild, and nil. RESULTS: Responses were excellent in 26.4%, good in 33.3%, mild in 21.3% and nil in 19% of all treatments, while good and excellent responses were obtained in 48% of retreatments. No statistically significant correlations were found between response and age of patients, skeletal extension of tumour, pretherapeutic PSA levels, evidence of non-bony metastases, previous chemotherapy and/or external-beam radiotherapy; osteolytic lesions responded worse than osteoblastic or mixed ones. Hematological toxicity (mild to moderate), mainly affecting platelets, was observed in 25.5% of all treatments and in 38.9% of retreatments. No clear differences were found between the two radiopharmaceuticals employed. CONCLUSIONS: Bearing in mind that observational studies can provide just as accurate results as randomised controlled trials, this study confirms the main findings of various limited monocentre trials.     

Clinical role of Sm-153 EDTMP in the treatment of painful bone metastatic disease

PURPOSE: Sm-153 EDTMP is an effective treatment of painful bone metastases from different neoplasms. However, there are few studies describing clinical experience with this therapeutic modality. The aim of this clinical study was to evaluate the efficacy of Sm-153 EDTMP in a group of patients with skeletal metastases and poor pain control with conventional therapies. MATERIALS AND METHODS: Sixty-four patients with painful bone metastases treated with Sm-153 EDTMP were retrospectively evaluated. Nine patients were treated twice. The most common primaries were breast in 28 cases (44%) and prostate in 27 (41%). Treatment efficacy was assessed by a visual analog scale, analgesic consumption, and performance status before and after treatment. Response was graded as complete, moderate, or minor. Toxicity evaluation included analytic parameters (blood counts, renal function) and clinical follow up. RESULTS: Efficacy and toxicity were evaluated separately for each dose (total doses: 73), and complete follow up was only possible in 62 of 73 administrations. The response rate was 85% (21% complete, 40% moderate, and 24% minor). Onset of improvement took place a median of 7 days after Sm-153 EDTMP administration, and pain relief persisted for a mean of 3 months. No relevant toxicity was found in the early phase. Myelotoxicity appeared in 29% of the administrations and was mild in most cases (there was one case of grade 4 leukopenia). CONCLUSIONS: Sm-153 EDTMP is a good therapeutic option for patients with painful bone metastases. It is an effective treatment of pain relief without major secondary effects.     

Clinical applications of 188Re-labelled radiopharmaceuticals for radionuclide therapy

188Re is a radionuclide in which there is widespread interest for therapeutic purposes because of its favourable physical characteristics. Moreover, it can be eluted from an on-site installable 188W/188Re generator, which has a useful shelf-life of several months. Most of the clinical experiences gained with 188Re concern the use of 188Re-1,1-hydroxyethylidenediphosphonate (188Re-HEDP) for bone pain palliation in patients suffering prostate cancer. The maximum tolerated activity was 3.3 GBq 188Re-HEDP and if the platelet count exceeded 200 x 10(9) l(-1), the administration of 4.4 GBq appeared safe. Evidence for repeated administrations of 188Re-HEDP rather than single injections was established. In general, pain palliation occurs in 60-92% of patients with only moderate transient toxicity, mainly related to changes in blood counts. Also in haematology, radioimmunotherapy by means of 188Re might play a role by selectively targeting the bone marrow in patients undergoing conditioning prior to haematopoetic stem cell transplantation. The feasibility of such an approach was proven using a Re-labelled monoclonal antibody directed toward the CD66-antigen. More recently, encouraging safety data on locoregional treatment of primary liver tumours using 188Re-labelled lipiodol were reported. The normal organs at greatest risk for toxicity are the normal liver and the lungs. About 50% of the patients reported mild and transient side effects, mainly consisting of low grade fever, right hypochondrial discomfort or aggravation of pre-existing liver impairment. Besides the applications in oncology 188Re-based therapies have also been pioneered for benign condition such as prevention of re-stenosis following angioplasty and for radiosynovectomy in cases of refractory arthritis.     

Combination 186Re-HEDP and cisplatin supra-additive treatment effects in prostate cancer cells.

Radionuclide therapy has proven to be an efficacious palliative treatment for metastatic prostate cancer. Its potential therapeutic possibilities may be substantially increased by combining it with effective radiosensitizing drugs. METHODS: This study explores the radiosensitizing properties of cisplatin when combined with 186Re-labeled hydroxyethylidene diphosphonate (HEDP) in the treatment of R3327-MATLyLu prostate cancer cells in vitro. A concomitant incubation during 4 d, combining various concentrations of cisplatin (0, 0.42, 0.83 and 1.67 micromol/L) and 186Re-HEDP (0, 1.84 and 3.69 MBq/mL [0, 50 and 100 microCi/mL, respectively]) was followed by the determination of the cell numbers surviving and the replating of these cells in semisolid agar. RESULTS: The surviving fraction of clonogenic tumor cells after combination treatment clearly showed synergism when analyzed by a panel of three different published analytical methods. In addition, analysis of variance demonstrated a significant interaction between radionuclide therapy and cisplatin-based chemotherapy (P < 0.001). Treatment with 186Re-HEDP and cisplatin by sequential incubation yielded similar, but never superior results. CONCLUSION: It is concluded that radionuclide therapy in combination with cisplatin is able, in principle, to improve therapeutic success rate in metastatic prostate cancer in a more than additive way.     

A phase 2 study of high-activity 186Re-HEDP with autologous peripheral blood stem cell transplant in progressive hormone-refractory prostate cancer metastatic to bone

Purpose We investigated the potential for improvement in disease control by use of autologous peripheral blood stem cell transplant (PBSCT) to permit administration of high activities of ¹⁸⁶Re-hydroxyethylidene diphosphonate (HEDP) in patients with progressive hormone-refractory prostate cancer (HRPC). Methods Eligible patients had progressive HRPC metastatic to bone, good performance status and minimal soft tissue disease. Patients received 5,000 MBq of ¹⁸⁶Re-HEDP i.v., followed 14 days later by PBSCT. Response was assessed using PSA, survival, pain scores and quality of life. Results Thirty-eight patients with a median age of 67 years (range 50–77) and a median PSA of 57 ng/ml (range 4–3,628) received a median activity of 4,978 MBq ¹⁸⁶Re-HEDP (range 4,770–5,100 MBq). The most serious toxicity was short-lived grade 3 thrombocytopenia in 8 (21%) patients. The median survival of the group is 21 months (95%CI 18–24 months) with Kaplan-Meier estimated 1- and 2-year survival rates of 83% and 40% respectively. Thirty-one patients (81%, 95% CI 66–90%) had stable or reduced PSA levels 3 months post therapy while 11 (29%, 95% CI 15–49%) had PSA reductions of >50% lasting >4 weeks. Quality of life measures were stable or improved in 27 (66%) at 3 months. Conclusion We have shown that it is feasible and safe to deliver high-activity radioisotope therapy with PBSCT to men with metastatic HRPC. Response rates and survival data are encouraging; however, further research is needed to define optimal role of this treatment approach.