89Sr治疗老年患者前列腺癌骨转移骨痛的临床观察

目的 评价89^SrCl2对老年患者前列腺癌骨转移伴骨痛的临床疗效及不良反应.方法 对外科去势治疗术后的老年患者前列腺癌骨转移伴有不同程度骨痛患者48例,使用89^SrCl2静脉注射治疗,观察其镇痛效果、骨转移灶的变化、前列腺特异性抗原（PSA）及不良反应等.结果 48例患者接受89^Sr治疗后,止痛的总有效率达89.6%,无效10.4%,骨转移灶有明显减少.对PSA有不同程度的下降.所有治疗者均未发现严重的不良反应和毒副作用.结论 89^SrCl2对去势治疗术后的老年患者前列腺癌骨转移骨痛的临床止痛疗效明显,特别是对多发骨转移癌伴骨痛患者是一种有效的治疗方法.     

放射性药物联合双膦酸盐类药物治疗肿瘤骨转移研究现状

骨转移是恶性肿瘤远处转移最常见类型之一,其发生率仅次于肺转移和肝转移。前列腺癌、乳腺癌以及肺癌是骨转移发生率最高的恶性肿瘤,近70%的乳腺癌或前列腺癌发展到晚期都会发生骨转移。肿瘤骨转移往往会引起疼痛、骨折以及高钙血症等不适,从而严重影响患者的生活质量。肿瘤骨转移目前尚无标准的规范化治疗方案,往往需要结合多种治疗方法进行综合治疗。双膦酸盐类药物和放射性药物是目前临床治疗多发骨转移广泛应用的药物,对于两者的应用,目前较为普遍的还是单药治疗,关于两者是否应该联合应用的问题一直存在争议。笔者系统回顾了近年来关于放射性药物联合双膦酸盐类药物治疗的相关研究。     

Radium-223 dichloride in clinical practice: a review

The onset of skeletal metastases is typical of advanced-stage prostate cancer and requires a multidisciplinary approach to alleviate bone pain and try to delay disease progression. The current therapeutic armamentarium includes conventional analgesics, chemotherapeutic agents, immunotherapy, androgen-deprivation therapy, osteoclast inhibitors (bisphosphonates, denosumab), surgical interventions, external-beam radiotherapy and radionuclide metabolic therapy. Many studies in recent decades have demonstrated the efficacy of various radiopharmaceuticals, including strontium-89 and samarium-153, for palliation of pain from diffuse skeletal metastases, but no significant benefit in terms of disease progression and overall survival has been shown. The therapeutic landscape of metastatic skeletal cancer significantly changed after the introduction of radium-223, the first bone-homing radiopharmaceutical with disease-modifying properties. In this paper we extensively review the literature on the use of radium-223 dichloride in metastatic castration-resistant prostate cancer.     

放射性核素治疗癌转移性骨痛

癌性骨转移原发病灶常见于前列腺癌、乳腺癌、肺癌等,转移发生的病理生理机制、疼痛机制目前不十分明确。止痛治疗尤其是对广泛骨转移性疼痛的治疗是临床医师面对的主要挑战,放射性核素及其标记药物治疗是一种有效、价廉、不良反应较小的治疗方法,对广泛转移的止痛治疗及微转移患者的治疗独具优势,目前有待充分利用。     

Pathogenesis and pharmacological treatment of bone pain in skeletal metastases.

Sixty-five percent of patients with advanced cancer present bone metastases and most of them present a rather slow clinical course characterized by pain, mobility deficiencies and skeletal complications such as fractures and spinal cord compression. Metastatic involvement of the bone is one of the most frequent causes of pain in cancer patients and represents one of the first signs of widespread neoplastic disease. The pain may originate directly from the bone, from nerve root compression or from muscle spasms in the area of the lesions. The mechanism of metastatic bone pain is mainly somatic (nociceptive) even though, in some cases, neuropathic and visceral stimulations may overlap. The conventional symptomatic treatment of metastatic bone pain requires the use of multidisciplinary therapies such as radiotherapy in association with systemic treatment (hormonotherapy, chemotherapy, radioisotopes) with the support of analgesic therapy. Recently, studies have indicated the use of bisphosphonates in the treatment of pain and in the prevention of skeletal complications in patients with metastatic bone disease. In some patients pharmacological treatment, radiotherapy, radioisotopes administered alone or in association are not able to manage pain adequately. The role of neuroinvasive techniques in treating metastatic bone pain is debated. The clinical conditions of the patient, his life expectancy and quality of life must guide the physician in the choice of the best possible therapy.     

Radiopharmaceuticals for bone lesions. Imaging and therapy in clinical practice.

Bone scintigraphy continues to be one of the most commonly performed procedures in nuclear medicine. The radionuclide bone scan remains an excellent modality to detect metastatic disease in patients suffering from primary malignancies. This article reviews a number of aspects of bone scintigraphy such as bone physiology, radiopharmaceuticals and uptake mechanisms. As 99mTc labelled bis(di)phosphonates are the most frequently used this article is centred around these imaging agents. In addition to diagnostic bone scintigraphy the use of various bone seeking agents has been extended to the palliative treatment of bone metastases. In this context the radiobiological characteristics of various radionuclides as 89Sr, 32p, 153Sm, 186Re and 117Sn is elucidated. In addition, the clinical efficacy for pain killing of these radionuclides is elucidated on the basis of the radiation properties of these agents. It is concluded that 89Sr and 186Re are presently the radionuclides of choice. The latter agent has a slight advantage as its imaging photons enable individual dosimetry, resulting in an optimosed application scheme.     

Bone pain palliation with 85Sr therapy.

The aim of this retrospective study was to evaluate the efficacy of 85Sr in the palliation of metastatic bone pain. 85Sr decays by electron capture with a gamma emission of 514 keV and associated x-ray emissions of 10-15 keV; physical half-life is 64 d. METHODS: Between 1977 and 1992, 119 doses of 85Sr chloride (mean activity 335 MBq [9 mCi]) were intravenously administered to 108 patients with hyperalgic generalized bone metastases from prostatic carcinoma (52 patients), breast carcinoma (41) or other cancers (15). Pain, performance status, blood and urinary excretion values were investigated during follow-up, and survival time was recorded. Strontium bone scans were obtained up to 8 wk after injection to document isotope biodistribution and to estimate absorbed doses. RESULTS: At 12 wk, 72.2% of patients showed significant benefit from treatment, i.e., enhanced quality of life and pain relief; 49.1% became free of pain. These beneficial effects lasted from 1 to 36 mo (mean 4.3 mo). The best symptomatic improvement was seen in patients treated at an early stage of metastatic skeletal disease and in prostate cancer patients. No evidence of a significant dose-response relationship was found in the data analysis. The mean absorbed dose ratio of metastases to marrow was estimated at 8.2. We found no evidence that hematological toxicity was a major problem; however, all patients experienced a reduction in blood counts, especially in platelets. CONCLUSION: Systemic radionuclide therapy using 85Sr is a feasible, effective and well-tolerated palliative treatment in patients with refractory bone pain. We attained at least the same response rate as that reported with bone-seeking beta-emitting radionuclides such as 89Sr. The patients who benefited the most from 85Sr treatment were in an early stage of metastatic disease or had prostate cancer. Our clinical findings could not be linked to either the total injected activity of 85Sr or the estimated absorbed dose delivered to metastases.     

A review of the efficacy of bone scanning in prostate and breast cancer.

Bone scintigraphy has provided valuable data in the assessment and management of neoplastic disease since being first described in the early 1960s. There have been many developments in imaging techniques and radiopharmaceuticals over the years allowing more reliable detection of metastatic spread to bone. Other imaging modalities are also evolving roles in the detection of metastatic spread including computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). Despite this, isotope bone scans continue to have a central role in detection and surveillance of bone metastases in breast and prostate cancer. Paralleling developments in imaging there have been enormous changes in the treatment options available for cancers of the breast and prostate that have metastasised to bone. Bone specific treatments including radionuclides and bisphosphonates as well as high dose chemotherapy provide potential improvement in disease control. There is also evidence that earlier treatment of bone metastases may prolong survival. This increases the need for efficient methods of detection and monitoring of disease. In this article we discuss the efficacy of bone scintigraphy in breast and prostate cancer from the point of view of staging, systematic follow-up of asymptomatic patients, evaluation of symptomatic patients and the assessment of response to therapy.     

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.     

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.     

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.     

Therapy of metastatic bone pain.

Bone metastasis is a common sequella of solid malignant tumors such as prostate, breast, lung, and renal cancers, which can lead to various complications, including fractures, hypercalcemia, and bone pain, as well as reduced performance status and quality of life. A multidisciplinary approach is usually required not only to address the etiology of the pain and its complicating factors but also to treat the patient appropriately. Currently, the treatment of bone pain remains palliative at best with systemic therapy (analgesics, hormones, chemotherapy, steroids, and bisphosphonates) as well as local treatments (such as surgery, nerve blocks, and external beam radiation). However, many of these treatments are limited in their efficacy or duration and have significant side effects that seriously limit the cancer patient's quality of life. Various radiopharmaceuticals have shown good efficacy in relieving bone pain secondary to bone metastasis. This systemic form of metabolic radiotherapy is simple to administer and complements other treatment options. This has been associated with improved mobility in many patients, reduced dependence on narcotic and non-narcotic analgesics, improved performance status and quality of life, and, in some studies, improved survival. Additional radiopharmaceuticals are under investigation and appear promising. All of these agents, although comprising different physical and chemical characteristics, offer certain advantages in that they are simple to administer, are well tolerated by the patient if used appropriately, and can be used alone or in combination with the other forms of treatment.     

The prostate: diagnostic evaluation of metastatic disease

One of the single most important considerations in clinical management of the patient with prostate cancer is whether or not metastatic disease is present. The identification of metastatic disease in a patient with newly diagnosed prostate cancer represents an absolute contraindication to definitive local therapies such as radial prostatectomy or radiation therapy. Similarly, the identification of metastatic disease in a patient with disease recurrence after definitive local therapy represents an absolute contraindication to salvage radiotherapy or cryosurgery. Patients with metastatic disease do not benefit from definitive therapy, and the cost and morbidity associated with such treatment should therefore be avoided in these patients. Because of the significance of metastatic disease to clinical management, it is important for the diagnostic radiologist to be aware of important considerations in the metastatic work-up of patients with newly diagnosed prostate cancer and patients with suspected cancer recurrence after definitive local therapy.     

Osteoblastic response to successful treatment of metastatic cancer of the prostate.

Increasing sclerosis of bone in patients with prostatic cancer most commonly is associated with disease progression. In a study of serial radiographs in a group of 18 patients who experienced objective clinical remission after treatment of metastatic cancer of the prostate, eight (44%) showed an osteoblastic response as part of their healing reaction to successful therapy. The importance of a blastic response as a possible sign of clinical improvement is emphasized. Clinical, biochemical, and bone scan correlations are discussed as they apply to patients who respond favorably to treatment of metastatic cancer of the prostate.     

Results of strontium-89 therapy in patients with prostate cancer resistant to chemotherapy

PURPOSE: Strontium-89 (Sr-89) chloride is an effective palliative treatment of the bone metastases of prostate cancer. Chemotherapy has also been shown to have a palliative benefit in this disease. We aimed to determine the benefits and complications of Sr-89 therapy in patients with prostate cancer who had become refractory to chemotherapy. We conducted a retrospective review of 14 treatments administered to 13 patients with chemotherapy-resistant and hormone-resistant prostate cancer. RESULTS: Of the 14 administered treatments, 8 (57%) resulted in improved pain control, with 2 patients able to stop analgesia. The median duration of response was 56 days. No prostate-specific antigen response was seen in the 8 patients tested. There was significant and prolonged bone marrow toxicity, with 6 patients requiring red blood cell transfusion. Prolonged thrombocytopenia was seen, with platelet counts remaining below baseline levels after treatment in all but one patient. Leukopenia was generally mild and not associated with infection. CONCLUSIONS: Sr-89 is an effective treatment of patients with chemotherapy-refractory prostate cancer, but careful and prolonged monitoring of hematologic parameters after therapy is required.     

Strontium-89 (Metastron) and the bisphosphonate olpadronate reduce the incidence of spinal cord compression in patients with hormone-refractory prostate cancer metastatic to the skeleton

Spinal cord compression (SCC) is a devastating complication of metastatic cancer. We investigated the potential beneficial effect of two palliative therapies--strontium-89 (Metastron) and the nitrogen-containing bisphosphonate olpadronate--on the incidence of SCC in hormone-refractory prostate cancer (HRPC) metastatic to the skeleton. We retrospectively studied 415 patients with histologically proven prostate cancer who underwent bone scintigraphy at the time of diagnosis and were followed up at the Leiden University Medical Center between 1990 and 1999. Medical or surgical castration was undertaken in 172 patients with evidence for skeletal metastases. Within 2 years, 147 of these patients (85%) developed HRPC associated with severe progressive bone pain. Palliative treatment was given to 131 patients in the form of local radiotherapy ( n=10), 89Sr ( n=46) or intravenous olpadronate ( n=66), with ( n=57) or without ( n=9) maintenance oral olpadronate. Nine patients received both 89Sr and olpadronate at various intervals. Sixteen patients who did not receive any of these treatments were used as historical controls. There was no significant difference in baseline characteristics between treatment modalities. The incidence of SCC was 17% in the whole group, and highest in controls receiving no palliation (50%). None of the patients treated with local radiotherapy, only 4% of patients receiving 89Sr and 21% of patients given olpadronate developed this complication. Our findings suggest a significant reduction in SCC in patients with symptomatic HRPC metastatic to the skeleton who receive palliative therapies. Local radiotherapy completely prevents the incidence of SCC, 89Sr leads to an important decrease in this complication and olpadronate induces a significant, albeit smaller decrease in the incidence of SCC. The use of these agents opens new avenues in the difficult management of patients with advanced prostate cancer who are most at risk of developing SCC.     

Positron emission tomography for prostate, bladder, and renal cancer

Prostate cancer, renal cancer, bladder, and other urothelial malignancies make up the common tumors of the male genitourinary tract. For prostate cancer, common clinical scenarios include managing the patient presenting with 1) low-risk primary cancer; 2) high-risk primary cancer; 3) prostate-specific antigen (PSA) recurrence after apparently successful primary therapy; 4) progressive metastatic disease in the noncastrate state; and 5) progressive metastatic disease in the castrate state. These clinical states dictate the appropriate choice of diagnostic imaging modalities. The role of positron emission tomography (PET) is still evolving but is likely to be most important in determining early spread of disease in patients with aggressive tumors and for monitoring response to therapy in more advanced patients. Available PET tracers for assessment of prostate cancer include FDG, 11C or 18F choline and acetate, 11C methionine, 18F fluoride, and fluorodihydrotestosterone. Proper staging of prostate cancer is particularly important in high-risk primary disease before embarking on radical prostatectomy or radiation therapy. PET with 11C choline or acetate, but not with FDG, appears promising for the assessment of nodal metastases. PSA relapse frequently is the first sign of recurrent or metastatic disease after radical prostatectomy or radiation therapy. PET with FDG can identify local recurrence and distant metastases, and the probability for a positive test increases with PSA. However, essentially all studies have shown that the sensitivity for recurrent disease detection is higher with either acetate or choline as compared with FDG. Although more data need to be gathered, it is likely that these two agents will become the PET tracers of choice for staging prostate cancer once metastatic disease is strongly suspected or documented. 18F fluoride may provide a more sensitive bone scan and will probably be most valuable when PSA is greater than 20 ng/mL in patients with high suspicion or documented osseous metastases. Several studies suggest that FDG uptake in metastatic prostate cancer lesions reflects the biologic activity of the disease. Accordingly, FDG can be used to monitor the response to chemotherapy and hormonal therapy. Androgen receptor imaging agents like fluorodihydrotestosterone are being explored to predict the biology of treatment response for progressive tumor in late stage disease in castrated patients. The assessment of renal masses and primary staging of renal cell carcinoma are the domain of helical CT. PET with FDG may be helpful in the evaluation of "equivocal findings" on conventional studies, including bone scan, and also in the differentiation between recurrence and posttreatment changes. The value of other PET tracers in renal cell carcinoma is under investigation. Few studies have addressed the role of PET in bladder cancer. Because of its renal excretion, FDG is not a useful tracer for the detection of primary bladder tumors. The few studies that investigated its role in the detection of lymph node metastases at the time of primary staging were largely disappointing. Bladder cancer imaging with 11C choline, 11C methionine, or 11C- acetate deserves further study.     

EANM procedure guideline for treatment of refractory metastatic bone pain

Introduction  Bone pain is a common symptom of metastatic disease in cancer, experienced with various intensities by about 30% of cancer patients, during the development of their disease, up to 60–90% in the latest phases. Discussion  In addition to other therapies, such as analgesics, bisphosphonates, chemotherapy, hormonal therapy and external beam radiotherapy, bone-seeking radiopharmaceuticals are also used for the palliation of pain from bone metastases. Substantial advantages of bone palliation radionuclide therapy include the ability to simultaneously treat multiple sites of disease with a more probable therapeutic effect in earlier phases of metastatic disease, the ease of administration, the repeatability and the potential integration with the other treatments. Conclusion  The Therapy, Oncology and Dosimetry Committees have worked together to revise the EANM guidelines on the use of bone-seeking radiopharmaceuticals. The purpose of this guideline is to assist the nuclear medicine physician in treating and managing patients undergoing such treatment.     

Effective and economical option for pain palliation in prostate cancer with skeletal metastases: 32P therapy revisited.

The role of phosphorus-32 (32P) was evaluated in patients experiencing pain due to skeletal metastases from prostate cancer and refractory to other modes of treatment. Twenty patients received 185 MBq (5 mCi)32P intravenously; 12 patients received a single dose each, five patients were injected twice and three patients three times at 3-month intervals. A blood count and clinical assessment for bone pain, tender sites, mobility and analgesic intake were performed before and 4, 8 and 12 weeks after the administration of 32P. A bone scan was performed before and 12 weeks after therapy. The results showed a significant decrease in pain at 4 weeks and a palliative response persisted for up to 12 weeks. Analgesic medication intake decreased significantly (F = 13.2213, P < 0.0001) and mobility improved after therapy. Quantitative analysis of the bone scans showed a statistically significant reduction in osteoblastic activity in metastatic lesions after therapy (t = -3.80, P < 0.001). Transient myelosuppression after 4 weeks, which was statistically significant for WBC and platelet counts only (F = 3.0226, P = 0.0358; F = 6.2514, P = 0.0009 respectively), returned within normal limits by 8 weeks. We conclude that 32P is an effective and safe therapy for pain palliation.     

Enhanced uptake of 99Tcm-MDP in skeletal metastases from prostate cancer following initiation of hormone treatment: potential for increasing delivery of therapeutic agents.

Following androgen ablation therapy, skeletal metastases from prostate cancer appear in some instances to show an increase in 99Tcm-methylene diphosphonate (99Tcm-MDP) uptake. Such a phenomenon could represent a mechanism to increase delivery of bone-seeking therapeutic agents to skeletal metastatic sites. The aim of this study was to characterize more precisely the potential increase in 99Tcm-MDP in skeletal metastases from prostate cancer following initiation of hormone therapy. Baseline bone scans were performed within 1 week of onset of hormone therapy in patients with stage D2 prostate cancer followed by multiple repeat bone scans for up to 4-6 weeks. The count density within metastatic lesions was divided by the average count density from several areas of normal bone to obtain a lesion to normal bone uptake ratio (L/N) for each lesion in each scan. Altogether, 61 skeletal metastases were identified on bone scans from five subjects. Eighty-four percent (51/61) of these lesions showed an increase in 99Tcm-MDP activity relative to normal bone following initiation of hormone therapy with a mean peak increase of 39%. Thirty-nine of these 51 metastatic lesions showed maximum uptake at 3 weeks post-onset of hormone treatment. From our findings, it appears that approximately 3 weeks following initiation of hormone blockade, most skeletal metastases from prostate cancer will demonstrate significantly enhanced 99Tcm uptake relative to normal bone. Consequently, it may be possible to improve the uptake and effectiveness of therapeutic bone-seeking radiopharmaceuticals by administering these agents following hormone therapy in patients with prostate cancer metastases.