今日の臨床サポート

転移性骨腫瘍

著者: 末松篤樹 名古屋第二赤十字病院 総合内科

監修: 野口善令 豊田地域医療センター 総合診療科

著者校正済:2019/03/22
現在監修レビュー中
参考ガイドライン:
  1. 日本臨床腫瘍学会:骨転移診療ガイドライン. 南江堂、2015
  1. 日本放射線腫瘍学会編:放射線治療計画ガイドライン2016年版.金原出版、2016;359-362
患者向け説明資料

概要・推奨   

  1. 骨転移が悪性腫瘍の最初の症候であった症例において、原発巣は肺、前立腺、乳房、肝臓の頻度が高い。
  1. 骨転移の部位は椎骨、骨盤、大腿骨、肋骨の順に多い。
  1. 原発が不明、または画像所見で良性/悪性の区別が困難であれば、積極的に骨生検を考慮する(推奨度1)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
末松篤樹 : 特に申告事項無し[2021年]
監修:野口善令 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 骨転移診療ガイドライン(2015)に基づき、デノスマブの記載を追加した。
  1. 緊急対応が必要な場合についての記載を追加した。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 骨転移は、無症状で偶発的に骨の画像検査で発見されるか、骨痛、骨折の原因検索として行った画像検査で発見されることが多い。
  1. 骨転移は、前立腺、乳房、肺、腎、甲状腺、消化管、肉腫によるものの頻度が高い。
 
骨転移しやすい悪性腫瘍

骨転移しやすい悪性腫瘍を、覚えやすく化学式のベンゼン環に似た形で示す。このベンゼン環はヒトの身体を模してあり、ほぼ解剖学的位置に一致する。肉腫は例外で身体のどこにでも起こり得る。

出典

 
  1. 前立腺、乳房、肺を原発部位とするものが、転移性骨腫瘍全体の80%を占めている。
  1. 骨破壊が起こっている症例では、高カルシウム(Ca)血症による症状がみられることがある。
 
  1. 骨転移が悪性腫瘍の最初の症候であった症例において、原発巣は肺、前立腺、乳房、肝臓の頻度が高い。
  1. 骨転移が悪性腫瘍の最初の症候であった64例において、原発巣は肺23例(36%)、前立腺11例(17%)、乳房5例(8%)、肝臓5例(8%)の順であったとの報告がある。5例(8%)では原発巣が不明であった(o)[1]
 
  1. 骨転移の部位は椎骨、骨盤、大腿骨、肋骨の順に多い。
  1. 病理組織所見で確定診断された転移性骨腫瘍390例において、骨転移の部位は椎骨(47.7%)、骨盤(18.2%)、大腿骨(15.4%)、肋骨(12.6%)であったと報告されている(o)[2]
問診・診察のポイント  
問診:
  1. 局所の痛み(骨痛:背部痛、腰痛、大腿部痛、殿部痛、胸痛)の有無。徐々に進行しているかどうか。夜間痛の有無

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文献 

著者: H Katagiri, M Takahashi, J Inagaki, H Sugiura, S Ito, H Iwata
雑誌名: Cancer. 1999 Aug 1;86(3):533-7.
Abstract/Text BACKGROUND: When skeletal metastasis is the presenting problem and the primary site is occult, there is a need to identify the primary site as soon as possible. However, the search for the primary tumor is often time-consuming and difficult. The purpose of this study was to analyze the efficacy of particular diagnostic approaches and to devise an efficient and optimal diagnostic strategy.
METHODS: Among 213 patients with skeletal metastasis treated between 1990 and 1996 were 64 in whom skeletal lesions were the first manifestation of malignancy. The authors retrospectively analyzed both the final diagnosis and the process by which it was made in these 64 cases.
RESULTS: The primary cancer was identified antemortem in 56 (88%) of the 64 patients by examination and in 3 patients at autopsy. Lung carcinoma, the most frequently observed primary lesion, was identified in 23 patients. Other primary lesions were prostate carcinoma in 11 patients, breast carcinoma in 5, and hepatocellular carcinoma in 5. The primary malignancy was not determined in 5 patients. Thoracic and abdominal computed tomography (CT) scans were useful, especially in the diagnosis of patients with lung, hepatocellular, renal cell, and pancreatic carcinomas. Tumor markers were abnormally elevated in 73% of patients with carcinomas.
CONCLUSIONS: Although thoracic and abdominal CT scans were useful, examination of the gastrointestinal tract and pelvic CT scan seldom revealed the primary lesion and therefore should not be performed as an initial routine study in the absence of abdominal symptoms. Tumor markers are useful in differentiating carcinoma from hematologic malignancy and primary bone tumor.

PMID 10430264  Cancer. 1999 Aug 1;86(3):533-7.
著者: Dong-Liang Xu, Xin-Tao Zhang, Guo-Hai Wang, Fo-Bao Li, Jun-Yong Hu
雑誌名: Ai Zheng. 2005 Nov;24(11):1404-7.
Abstract/Text BACKGROUND & OBJECTIVE: With the development of diagnostic techniques of imaging and pathology, early diagnosis of metastatic bone tumors has been greatly improved, but the clinical characteristics which are essential for diagnosis are rarely reported. In this article, the clinical features of pathologically confirmed metastatic bone tumors were analyzed for further improvement of early diagnosis and treatment.
METHODS: Clinical data of 390 patients with pathologically confirmed metastatic bone tumors, treated from 1980 to 2003 at The First Affiliated Hospital of Sun Yat-sen University, were reviewed respectively to summarize the clinical features, including disease history, predilection sites, clinical manifestation, and imaging presentations.
RESULTS: Of the 390 patients, the ratio of men to women was 2.12:1; the median age was 55.7 years, and 81.5% of the patients were over 41 years old. The primary tumors were lung cancer (21.8%), prostate cancer (13.1%), breast cancer (7.4%), liver cancer (6.4%), gastrointestinal cancer (5.7%), and unknown cancers (24.6%). The common metastatic sites were spine (47.7%), pelvis (18.2%), femur (15.4%), and rib (12.6%). Multiple metastases occurred in 20.5% of the patients. The main symptoms were skeletal pain (53.3%), pathologic fractures (10.3%), dysfunction (4.9%), and paraplegia (2.1%). Primary tumor detected before metastasis accounted for 29.7% of the patients with a median metastatic time of 319 days, and the metastatic intervals were uncertain in 70.3% of the patients. Osteolytic types accounted for 80.7% of the cases in radiographic patterns, followed by osteosclerotic (10.5%) and mixed types.
CONCLUSIONS: Metastatic bone tumors most frequently occur in patients older than 41 years, and commonly originate from lung, prostate, breast, and liver. Vertebrae, pelvis, femur, and rib are the most common sites of metastases. The clinical manifestation is extensive and nonspecific. Most lesions present osteolytic patterns. Metastases with unknown origin account for 24%. In spite of complexity, the clinical features should be mastered for early diagnosis and treatment.

PMID 16552972  Ai Zheng. 2005 Nov;24(11):1404-7.
著者: Hui-Lin Yang, Tao Liu, Xi-Ming Wang, Yong Xu, Sheng-Ming Deng
雑誌名: Eur Radiol. 2011 Dec;21(12):2604-17. doi: 10.1007/s00330-011-2221-4. Epub 2011 Sep 2.
Abstract/Text OBJECTIVE: To perform a meta-analysis to compare (18)FDG PET, CT, MRI and bone scintigraphy (BS) for the diagnosis of bone metastases.
METHODS: Databases including MEDLINE and EMBASE were searched for relevant original articles published from January 1995 to January 2010. Software was used to obtain pooled estimates of sensitivity, specificity and summary receiver operating characteristic curves (SROC).
RESULTS: 67 articles consisting of 145 studies fulfilled all inclusion criteria. On per-patient basis, the pooled sensitivity estimates for PET, CT, MRI and BS were 89.7%, 72.9%, 90.6% and 86.0% respectively. PET=MRI>BS>CT. ("="indicated no significant difference, P > 0.05; ">" indicated significantly higher, P < 0.05). The pooled specificity estimates for PET, CT, MRI and BS were 96.8%, 94.8%, 95.4% and 81.4% respectively. PET = CT = MRI>BS. On per-lesion basis, the pooled sensitivity estimates for PET, CT, MRI and BS were 86.9%, 77.1%, 90.4% and 75.1% respectively. PET = MRI>BS>CT. The pooled specificity estimates for PET, CT, MRI and BS were 97.0%, 83.2%, 96.0% and 93.6% respectively. PET>MRI>BS>CT.
CONCLUSION: PET and MRI were found to be comparable and both significantly more accurate than CT and BS for the diagnosis of bone metastases.

PMID 21887484  Eur Radiol. 2011 Dec;21(12):2604-17. doi: 10.1007/s0033・・・
著者: Guohua Shen, Houfu Deng, Shuang Hu, Zhiyun Jia
雑誌名: Skeletal Radiol. 2014 Nov;43(11):1503-13. doi: 10.1007/s00256-014-1903-9. Epub 2014 May 20.
Abstract/Text Published data on the diagnosis of bone metastases of prostate cancer are conflicting and heterogeneous. We performed a comprehensive meta-analysis to compare the diagnostic performance of choline-PET/CT, MRI, bone SPECT, and bone scintigraphy (BS) in detecting bone metastases in parents with prostate cancer. Pooled sensitivity, specificity, and diagnostic odds ratios (DOR) were calculated both on a per-patient basis and on a per-lesion basis. Summary receiver operating characteristic (SROC) curves were also drawn to obtain the area under curve (AUC) and Q* value. Sixteen articles consisting of 27 studies were included in the analysis. On a per-patient basis, the pooled sensitivities by using choline PET/CT, MRI, and BS were 0.91 [95% confidence interval (CI): 0.83-0.96], 0.97 (95% CI: 0.91-0.99), 0.79 (95% CI: 0.73-0.83), respectively. The pooled specificities for detection of bone metastases using choline PET/CT, MRI, and BS, were 0.99 (95% CI: 0.93-1.00), 0.95 (95% CI: 0.90-0.97), and 0.82 (95% CI: 0.78-0.85), respectively. On a per-lesion basis, the pooled sensitivities of choline PET/CT, bone SPECT, and BS were 0.84 (95% CI: 0.81-0.87), 0.90 (95% CI: 0.86-0.93), 0.59 (95% CI: 0.55-0.63), respectively. The pooled specificities were 0.93 (95% CI: 0.89-0.96) for choline PET/CT, 0.85 (95% CI: 0.80-0.90) for bone SPECT, and 0.75 (95% CI: 0.71-0.79) for BS. This meta-analysis indicated that MRI was better than choline PET/CT and BS on a per-patient basis. On a per-lesion analysis, choline PET/CT with the highest DOR and Q* was better than bone SPECT and BS for detecting bone metastases from prostate cancer.

PMID 24841276  Skeletal Radiol. 2014 Nov;43(11):1503-13. doi: 10.1007/・・・
著者: Claire Destombe, Estelle Botton, Grégoire Le Gal, Anne Roudaut, Sandrine Jousse-Joulin, Valérie Devauchelle-Pensec, Alain Saraux
雑誌名: Joint Bone Spine. 2007 Jan;74(1):85-9. doi: 10.1016/j.jbspin.2006.05.009. Epub 2006 Nov 30.
Abstract/Text OBJECTIVES: To evaluate the respective contributions of various investigations used to identify the primary tumor in a cohort of patients referred for diagnostic evaluation of one or more bone metastases.
METHODS: A single-center retrospective study was conducted in a cohort of patients admitted between October 1990 and January 2000 for evaluation of one or more bone metastases with no known primary. All patients underwent radionuclide bone scanning, a chest radiograph, and an abdominal ultrasound scan. Computed tomography (CT) of the chest and abdomen, CT of the brain, and tumor marker assays were performed as clinically indicated. Using the final diagnosis as the reference standard, we evaluated the diagnostic usefulness of each investigation.
RESULTS: The 152 patients (104 men and 48 women) had a mean age of 63.5+/-12.5 years. The primary was located in the lung in 37 patients, prostate in 26, breast or female genital tract in 24, urinary system in 11, gastrointestinal tract in 11, head and neck in 6, and other organs in 4. In 33 patients, no primary was identified. The extraskeletal metastases were located chiefly in the liver (20.4%), lung (17.1%), pleura (13.2%), and brain (7.2%). Bone biopsies were performed in 107 patients: 84 had a single bone biopsy, 16 had two bone biopsies, and 7 had three bone biopsies. The first bone biopsy was taken in the rheumatology department with or without fluoroscopic guidance in 62 patients, in the radiology department under CT guidance in 6 patients, and in the surgery department in 32 patients; this information was unavailable for the 7 remaining patients. The first bone biopsy was taken from the iliac bone in 48 patients, spine in 32, sacrum in 10, rib in 3, and other sites in 7. The histological biopsy findings indicated adenocarcinoma in 58 cases, epidermoid carcinoma in 28 cases, undifferentiated carcinoma in 2 cases, and other histological patterns in 9 cases. In 80 patients, another metastatic site was easier to access than the bone metastasis. Tumor marker assays were of limited value for determining the site of the primary, with the exception of prostate-specific antigen.
CONCLUSION: Bone biopsies performed by rheumatologists, generally under fluoroscopic guidance, usually indicate the site of the primary or at least the histological type. Tumor markers are often positive but are of limited usefulness for identifying the primary.

PMID 17218141  Joint Bone Spine. 2007 Jan;74(1):85-9. doi: 10.1016/j.j・・・
著者: Yoichi Iizuka, Haku Iizuka, Satoshi Tsutsumi, Yumi Nakagawa, Takashi Nakajima, Yasunori Sorimachi, Tsuyoshi Ara, Masahiro Nishinome, Takayuki Seki, Kenji Takagishi
雑誌名: Eur Spine J. 2009 Oct;18(10):1431-5. doi: 10.1007/s00586-009-1061-2. Epub 2009 Jun 16.
Abstract/Text When the primary site is unknown in patients with spinal metastases, there can be problems in locating the site of tumor origin. Most previous reports on metastases of unknown origin have not been limited to the spine. The purpose of this study is to assess the usefulness of laboratory analysis, chest, abdominal and pelvic CT and CT-guided biopsy in patients with spinal metastases of unknown origin (SMUO). A retrospective review of the clinical histories of 27 patients with SMUO was done. A total of 43 patients with SMUO were seen at our institution between 2002 and 2007. Of the 43 patients, 27 who underwent all 3 tests (laboratory analysis including M protein and tumor markers, chest, abdominal and pelvic CT and CT-guided biopsy) were included in this study. We retrospectively assessed the diagnostic usefulness of those 3 tests in the 27 patients. In 27 patients, the final diagnosis was obtained in 26 patients. Myeloma was the most common malignancy followed by lung carcinoma. M protein was positive in all 7 patients with myeloma and negative in patients with other malignancies. The level of tumor markers was elevated in 16 of 17 patients with a solid tumor and in all 3 with lymphoma. CA15-3 was elevated in 4 of 27 patients, CA19-9 in 5 of 27 patients, CA125 in 2 of 27 patients, CEA in 6 of 27 patients, SCC in 2 of 27 patients, NSE in 7 of 27 patients, AFP in 1 of 27 patients, PIVKA-II in 1 of 27 patients, TPA in 6 of 27 patients, IAP in 3 of 12 patients, thyroglobulin in 2 of 27 patients, sIL-2R in 3 of 24 patients, and PSA in 5 of 17 male patients. Myeloma, lymphoma and prostate carcinoma had a marker with high sensitivity and specificity (M protein, sIL-2R and PSA). Eleven primary tumor sites (40.7%) were detected (6 lung, 1 prostate, 1 kidney, 1 thyroid, 1 liver, and 1 pancreas) by chest, abdominal and CT scanning. Biopsy led to determination of the final diagnosis in 12 (44.4%) of 27 patients (5 myelomas, 3 lymphomas, 2 prostate carcinomas, 1 renal-cell carcinoma, 1 thyroid carcinoma). In the remaining 15 patients, biopsy did not lead to determination of the final diagnosis, because the histological diagnosis was either an adenocarcinoma or an undifferentiated carcinoma, the tissue sample was not diagnostic. A laboratory analysis limited to specific tumor markers such as PSA and protein electrophoresis is considered to be useful in making a final diagnosis. Chest, abdominal and pelvic CT is considered to be useful for making a final diagnosis in solid tumors, but not for hematologic tumors. A CT-guided biopsy had a low determination rate in the final diagnosis in comparison to a laboratory analysis and CT scanning for solid tumors and it is not considered to be essential for the diagnosis of hematologic tumors.

PMID 19533181  Eur Spine J. 2009 Oct;18(10):1431-5. doi: 10.1007/s0058・・・
著者: B T Rougraff, J S Kneisl, M A Simon
雑誌名: J Bone Joint Surg Am. 1993 Sep;75(9):1276-81.
Abstract/Text We carried out a prospective study of the effectiveness of a diagnostic strategy in forty consecutively seen patients who had skeletal metastases of unknown origin. The diagnostic strategy consisted of the recording of a medical history; physical examination; routine laboratory analysis; plain radiography of the involved bone and the chest; whole-body technetium-99m-phosphonate bone scintigraphy; and computed tomography of the chest, abdomen, and pelvis. After this evaluation, a biopsy of the most accessible osseous lesion was done. The laboratory values were non-specific in all patients. The history and physical examination revealed the occult primary site of the malignant tumor in three patients (8 per cent): one patient who had carcinoma of the breast; one, of the kidney; and one, of the bladder. Plain radiographs of the chest established the diagnosis of carcinoma of the lung in seventeen patients (43 per cent). Computed tomography of the chest identified an additional six primary carcinomas of the lung (15 per cent). Computed tomography of the abdomen and pelvis established the diagnosis in five patients (13 per cent): three patients who had carcinoma of the kidney; one, carcinoma of the liver; and one, carcinoma of the colon. Examination of the biopsy tissue established the diagnosis in only three additional patients (8 per cent) and confirmed it in eleven others. On the basis of the biopsy alone, we were unable to identify the primary site of the malignant tumor in twenty-six (65 per cent) of the patients. In thirty-four (85 per cent) of the forty patients, the primary site was identified with the use of the diagnostic strategy described here, and only two additional occult malignant tumors were found on follow-up studies. Our diagnostic strategy was simple and highly successful for the identification of the site of an occult malignant tumor before biopsy in patients who had skeletal metastases of unknown origin.

PMID 8408149  J Bone Joint Surg Am. 1993 Sep;75(9):1276-81.
著者: Karim Fizazi, Michael Carducci, Matthew Smith, Ronaldo Damião, Janet Brown, Lawrence Karsh, Piotr Milecki, Neal Shore, Michael Rader, Huei Wang, Qi Jiang, Sylvia Tadros, Roger Dansey, Carsten Goessl
雑誌名: Lancet. 2011 Mar 5;377(9768):813-22. doi: 10.1016/S0140-6736(10)62344-6. Epub 2011 Feb 25.
Abstract/Text BACKGROUND: Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer.
METHODS: In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed.
FINDINGS: 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9-18·5) for patients on denosumab and 11·2 months (IQR 5·6-17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8-24·9) with denosumab compared with 17·1 months (15·0-19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71-0·95; p = 0·0002 for non-inferiority; p = 0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p = 0·09).
INTERPRETATION: Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer.
FUNDING: Amgen.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 21353695  Lancet. 2011 Mar 5;377(9768):813-22. doi: 10.1016/S0140・・・
著者: Matthew H F Wong, Martin R Stockler, Nick Pavlakis
雑誌名: Cochrane Database Syst Rev. 2012 Feb 15;2:CD003474. doi: 10.1002/14651858.CD003474.pub3. Epub 2012 Feb 15.
Abstract/Text BACKGROUND: Bone is the most common site of metastatic disease associated with breast cancer (BC). Bisphosphonates inhibit osteoclast-mediated bone resorption, and novel targeted therapies such as denosumab, inhibit key pathways in the vicious cycle of bone metastases.
OBJECTIVES: To assess the effect of bisphosphonates on skeletal-related events (SREs), bone pain, quality of life (QoL), recurrence and survival in women with breast cancer with bone metastases (BCBM), advanced breast cancer (ABC) without clinical evidence of bone metastases and early breast cancer (EBC).To assess the effect of denosumab on SREs, bone pain and (QoL) in women with (BCBM).
SEARCH METHODS: We searched the Specialised Register maintained by the Cochrane Breast Cancer Group (CBCGSR), MEDLINE, EMBASE and the WHO International Cancer Trials Registry Platform (WHO ICTRP) on 30 April 2011. We conducted additional handsearching of journals and proceedings of key meetings.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing: (a) bisphosphonates and control, or different bisphosphonates in women with BCBM; (b) denosumab and bisphosphonates in women with BCBM; (c) bisphosphonates and control in women with ABC; (d) bisphosphonates and control in women with EBC; and (e) early versus delayed bisphosphonate treatment in women with EBC.
DATA COLLECTION AND ANALYSIS: Two review authors (MW and NP) independently assessed the trials and extracted the data. We collected toxicity information from the trials.
MAIN RESULTS: We included thirty-four RCTs. In nine studies (2806 patients with BCBM), comparing bisphosphonates with placebo or no bisphosphonates, bisphosphonates reduced the SRE risk by 15% (risk ratio (RR) 0.85; 95% confidence interval (CI) 0.77 to 0.94; P = 0.001). This benefit was most certain with intravenous (i.v.) zoledronic acid (4 mg) (RR 0.59; 95% CI 0.42 to 0.82); i.v. pamidronate (90 mg) (RR 0.77; 95% CI 0.69 to 0.87); and i.v. ibandronate (RR 0.80; 95% CI 0.67 to 0.96). A direct comparison of i.v. zoledronic acid and i.v. pamidronate confirmed at least equivalent efficacy in a single large study. In three studies (3405 patients with BCBM), compared with bisphosphonates, subcutaneous (s.c.) denosumab was more effective in reducing the risk of SREs (RR 0.78; 95% CI 0.72 to 0.85; P < 0.00001).Bisphosphonates reduced the SRE rate in 12 studies (median reduction 28%, range 14% to 48%), with statistically significant reductions reported in 10 studies. Women with BCBM treated with bisphosphonates showed significant delays in the median time to SREs. Compared with placebo or no bisphosphonates, treatment with bisphosphonates significantly improved bone pain in six out of eleven studies. Improvements in global QoL with bisphosphonates compared to placebo were reported in two out of five studies (both ibandronate studies). Treatment with bisphosphonates did not appear to affect survival in women with BCBM. Compared to i.v. zoledronic acid, denosumab also significantly reduced the SRE rate, delayed the time to SREs and prolonged the time in developing pain for patients with no or mild pain at baseline; but there was no difference in survival between patients treated with denosumab and zoledronic acid.Bisphosphonates in women with ABC without clinically evident bone metastases did not reduce the incidence of bone metastases, or improve survival in three studies (320 patients).In seven studies (7847 patients with EBC), currently there is no evidence supporting bisphosphonates in reducing the incidence of bone metastases compared to no bisphosphonates (RR 0.94; 95% CI 0.82 to 1.07; P = 0.36). In three studies (2190 patients with EBC), early bisphosphonate treatment also did not significantly reduce the incidence of bone metastases compared to delayed bisphosphonate treatment (RR 0.73; 95% CI 0.40 to 1.33; P = 0.31). Currently, there is insufficient evidence to make a conclusion about the role of adjuvant bisphosphonates in reducing visceral metastases, locoregional recurrence and total recurrence, or improving survival. There was strong heterogeneity in EBC studies examining the outcomes of total recurrence and survival.Reported toxicity was generally mild. Renal toxicity and osteonecrosis of the jaw (ONJ) have been identified as potential problems with bisphosphonate use. ONJ was reported at similar rates for patients on denosumab compared to zoledronic acid. This highlighted a need for maintaining good oral care, prior to and during treatment, for patients who received long-term bone agents.
AUTHORS' CONCLUSIONS: In women with clinically evident BCBM, bisphosphonates (oral and i.v.) and denosumab (s.c.) reduced the risk of developing SREs, as well as delaying the time to SREs. Some bisphosphonates may also reduce bone pain and may improve QoL. The optimal timing and duration of treatment for patients with BCBM remains uncertain. There is currently insufficient evidence to support the routine use of bisphosphonates as adjuvant treatment for patients with EBC. However, a number of large clinical trials investigating bisphosphonates in EBC have completed accrual and are awaiting results.

PMID 22336790  Cochrane Database Syst Rev. 2012 Feb 15;2:CD003474. doi・・・
著者: Lee S Rosen, David Gordon, Simon Tchekmedyian, Ronald Yanagihara, Vera Hirsh, M Krzakowski, M Pawlicki, Paul de Souza, Ming Zheng, Gladys Urbanowitz, Dirk Reitsma, John J Seaman
雑誌名: J Clin Oncol. 2003 Aug 15;21(16):3150-7. doi: 10.1200/JCO.2003.04.105.
Abstract/Text PURPOSE: To assess the efficacy and safety of zoledronic acid in patients with bone metastases secondary to solid tumors other than breast or prostate cancer.
PATIENTS AND METHODS: Patients were randomly assigned to receive zoledronic acid (4 or 8 mg) or placebo every 3 weeks for 9 months, with concomitant antineoplastic therapy. The 8-mg dose was reduced to 4 mg (8/4-mg group). The primary efficacy analysis was proportion of patients with at least one skeletal-related event (SRE), defined as pathologic fracture, spinal cord compression, radiation therapy to bone, and surgery to bone. Secondary analyses (time to first SRE, skeletal morbidity rate, and multiple event analysis) counted hypercalcemia as an SRE.
RESULTS: Among 773 patients with bone metastases from lung cancer or other solid tumors, the proportion with an SRE was reduced in both zoledronic acid groups compared with the placebo group (38% for 4 mg and 35% for 8/4 mg zoledronic acid v 44% for the placebo group; P =.127 and P =.023 for 4-mg and 8/4-mg groups, respectively). Additionally, 4 mg zoledronic acid significantly increased time to first event (median, 230 v 163 days for placebo; P =.023), an important end point in this poor-prognosis population, and significantly reduced the risk of developing skeletal events by multiple event analysis (hazard ratio = 0.732; P =.017). Zoledronic acid was well tolerated; the most common adverse events in all treatment groups included bone pain, nausea, anemia, and vomiting.
CONCLUSION: Zoledronic acid (4 mg infused over 15 minutes) is the first bisphosphonate to reduce skeletal complications in patients with bone metastases from solid tumors other than breast and prostate cancer.

PMID 12915606  J Clin Oncol. 2003 Aug 15;21(16):3150-7. doi: 10.1200/J・・・
著者: David H Henry, Luis Costa, Francois Goldwasser, Vera Hirsh, Vania Hungria, Jana Prausova, Giorgio Vittorio Scagliotti, Harm Sleeboom, Andrew Spencer, Saroj Vadhan-Raj, Roger von Moos, Wolfgang Willenbacher, Penella J Woll, Jianming Wang, Qi Jiang, Susie Jun, Roger Dansey, Howard Yeh
雑誌名: J Clin Oncol. 2011 Mar 20;29(9):1125-32. doi: 10.1200/JCO.2010.31.3304. Epub 2011 Feb 22.
Abstract/Text PURPOSE: This study compared denosumab, a fully human monoclonal anti-receptor activator of nuclear factor kappa-B ligand antibody, with zoledronic acid (ZA) for delaying or preventing skeletal-related events (SRE) in patients with advanced cancer and bone metastases (excluding breast and prostate) or myeloma.
PATIENTS AND METHODS: Eligible patients were randomly assigned in a double-blind, double-dummy design to receive monthly subcutaneous denosumab 120 mg (n = 886) or intravenous ZA 4 mg (dose adjusted for renal impairment; n = 890). Daily supplemental calcium and vitamin D were strongly recommended. The primary end point was time to first on-study SRE (pathologic fracture, radiation or surgery to bone, or spinal cord compression).
RESULTS: Denosumab was noninferior to ZA in delaying time to first on-study SRE (hazard ratio, 0.84; 95% CI, 0.71 to 0.98; P = .0007). Although directionally favorable, denosumab was not statistically superior to ZA in delaying time to first on-study SRE (P = .03 unadjusted; P = .06 adjusted for multiplicity) or time to first-and-subsequent (multiple) SRE (rate ratio, 0.90; 95% CI, 0.77 to 1.04; P = .14). Overall survival and disease progression were similar between groups. Hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred at similarly low rates in both groups. Acute-phase reactions after the first dose occurred more frequently with ZA, as did renal adverse events and elevations in serum creatinine based on National Cancer Institute Common Toxicity Criteria for Adverse Events grading.
CONCLUSION: Denosumab was noninferior (trending to superiority) to ZA in preventing or delaying first on-study SRE in patients with advanced cancer metastatic to bone or myeloma. Denosumab represents a potential novel treatment option with the convenience of subcutaneous administration and no requirement for renal monitoring or dose adjustment.

PMID 21343556  J Clin Oncol. 2011 Mar 20;29(9):1125-32. doi: 10.1200/J・・・
著者: R Wong, P J Wiffen
雑誌名: Cochrane Database Syst Rev. 2002;(2):CD002068. doi: 10.1002/14651858.CD002068.
Abstract/Text BACKGROUND: Bisphosphonates form part of standard therapy for hypercalcemia and the prevention of skeletal events in some cancers. However, the role of bisphosphonates in pain relief for bony metastases remains uncertain.
OBJECTIVES: To determine the effectiveness of bisphosphonates for the relief of pain from bone metastases.
SEARCH STRATEGY: MEDLINE (1966-1999), EMBASE (1980-1999), CancerLit (1966-1999), the Cochrane library (Issue 1, 2000) and the Oxford Pain Database were searched using the strategy devised by the Cochrane Pain, Palliative and Supportive Care Group with additional terms 'diphosphonate', 'bisphosphonate', 'multiple myeloma' and 'bone neoplasms'. (Last search: January 2000).
SELECTION CRITERIA: Randomized trials of bisphosphonates compared with open, blinded, or different doses/types of bisphosphonates in cancer patients were included where pain and/or analgesic consumption were outcome measures. Studies where pain was reported only by observers were excluded.
DATA COLLECTION AND ANALYSIS: Article eligibility, quality assessment and data extraction were undertaken by both reviewers. The proportions of patients with pain relief at 4, 8 and 12 weeks were assessed. The proportion of patients with analgesic reduction, the mean pain score, mean analgesic consumption, adverse drug reactions, and quality of life data were compared as secondary outcomes.
MAIN RESULTS: Thirty randomized controlled studies (21 blinded, four open and five active control) with a total of 3682 subjects were included. For each outcome, there were few studies with available data. For the proportion of patients with pain relief (eight studies) pooled data showed benefits for the treatment group, with an NNT at 4 weeks of 11[95% CI 6-36] and at 12 weeks of 7 [95% CI 5-12]. In terms of adverse drug reactions, the NNH was 16 [95% CI 12-27] for discontinuation of therapy. Nausea and vomiting were reported in 24 studies with a non-significant trend for greater risk in the treatment group. One study showed a small improvement in quality of life for the treatment group at 4 weeks. The small number of studies in each subgroup with relevant data limited our ability to explore the most effective bisphosphonates and their relative effectiveness for different primary neoplasms.
REVIEWER'S CONCLUSIONS: There is evidence to support the effectiveness of bisphosphonates in providing some pain relief for bone metastases. There is insufficient evidence to recommend bisphosphonates for immediate effect; as first line therapy; to define the most effective bisphosphonates or their relative effectiveness for different primary neoplasms. Bisphosphonates should be considered where analgesics and/or radiotherapy are inadequate for the management of painful bone metastases.

PMID 12076438  Cochrane Database Syst Rev. 2002;(2):CD002068. doi: 10.・・・
著者: E Chow, L Zeng, N Salvo, K Dennis, M Tsao, S Lutz
雑誌名: Clin Oncol (R Coll Radiol). 2012 Mar;24(2):112-24. doi: 10.1016/j.clon.2011.11.004. Epub 2011 Nov 29.
Abstract/Text AIMS: To update previous meta-analyses of randomised palliative radiotherapy trials comparing single fractions versus multiple fractions.
MATERIALS AND METHODS: All published randomised controlled trials comparing single fraction versus multiple fraction schedules for the palliation of uncomplicated bone metastases were included in this analysis. Odds ratios and 95% confidence intervals were calculated for each trial. Forest plots were created using a random effects model and the Mantel-Haenszel statistic.
RESULTS: In total, 25 randomised controlled trials were identified. For intention-to-treat patients, the overall response rate was similar in patients receiving single fractions (1696 of 2818; 60%) and multiple fractions (1711 of 2799; 61%). Complete response rates were 620 of 2641 (23%) in the single fraction arm and 634 of 2622 (24%) in the multiple fraction arm. No significant difference was seen in overall or complete response rates. Pathological fracture did not favour either arm, but spinal cord compression trended towards favouring multiple fractions; however, neither was statistically significant (P = 0.72 and P = 0.13, respectively). Retreatment rates favoured patients in the multiple fraction arm, where the likelihood of requiring re-irradiation was 2.6-fold greater in the single fraction arm (95% confidence interval: 1.92-3.47; P < 0.00001). Repeated analyses excluding drop-out patients did not alter these findings. In general, no significant differences in acute toxicities were seen.
CONCLUSION: Overall and complete response rates were similar in both intention-to-treat and assessable patients. Single and multiple fraction regimens provided equal pain relief; however, significantly higher retreatment rates occurred in those receiving single fractions.

Copyright © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
PMID 22130630  Clin Oncol (R Coll Radiol). 2012 Mar;24(2):112-24. doi:・・・
著者: Thomas J Wood, Antonella Racano, Herman Yeung, Forough Farrokhyar, Michelle Ghert, Benjamin M Deheshi
雑誌名: Ann Surg Oncol. 2014 Dec;21(13):4081-9. doi: 10.1245/s10434-014-4002-1. Epub 2014 Sep 16.
Abstract/Text BACKGROUND: Surgical management of metastatic bone disease (MBD) is typically reserved for lesions with the highest risk of fracture. However, the high risk of perioperative complications associated with surgery may outweigh the benefits of improved pain and/or function. The goal of this study was to (1) assess the quality of current evidence in this domain; (2) confirm that surgical management of metastases to the long bones and pelvis/acetabulum provides pain relief and improved function; and (3) assess perioperative morbidity and mortality rates.
METHODS: We conducted a systematic review of the literature for clinical studies that reported pain relief and function outcomes, as well as perioperative complications and mortality, in patients with MBD to the long bones and/or pelvis/acetabulum treated surgically. Multiple databases were searched up to January 2012. Pooled weighted proportions are reported.
RESULTS: Forty-five studies were included in the final analysis, with 807 patients. All included studies were level IV with 'moderate' overall quality of evidence using the Methodological Index for Non-Randomized Studies scale. Pain relief following surgical management of metastases was 93, 91, and 93 % in the humerus, femur, and pelvis/acetabulum, respectively. Maintained or improved function after surgery was seen in 94, 89, and 94 % in the humerus, femur, and pelvis/acetabulum, respectively. Perioperative complications and mortality were 17 and 4 %, respectively.
CONCLUSIONS: Despite the inherent limitations of the current evidence, a benefit for the surgical management of bone metastases to the long bones and pelvis/acetabulum is evident; however, there is still substantial risk of perioperative morbidity and mortality that should be considered.

PMID 25223925  Ann Surg Oncol. 2014 Dec;21(13):4081-9. doi: 10.1245/s1・・・

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