Contemporary approaches for imaging skeletal metastasis

Abstract

The skeleton is a common site of cancer metastasis. Notably high incidences of bone lesions are found for breast, prostate, and renal carcinoma. Malignant bone tumors result in significant patient morbidity. Identification of these lesions is a critical step to accurately stratify patients, guide treatment course, monitor disease progression, and evaluate response to therapy. Diagnosis of cancer in the skeleton typically relies on indirect bone-targeted radiotracer uptake at sites of active bone remodeling. In this manuscript, we discuss established and emerging tools and techniques for detection of bone lesions, quantification of skeletal tumor burden, and current clinical challenges.

Cancer: Imaging the spread into bone

Methods are emerging to improve the imaging of skeletal metastasis, in which cancer spreads into bone. Detecting skeletal metastasis is vital for evaluating and treating primary cancers and their complications. This detection is critical for such common cancers as breast, prostate, thyroid, kidney and lung cancer. Daniel Thorek of John Hopkins University School of Medicine in Baltimore, USA and colleagues in New York and Sweden, have reviewed the use, challenges and limitations of existing and emerging imaging techniques. Scans that detect the uptake of various radioactive compounds are the most commonly used methods, but results can be complicated by changes in bone that are not related to cancer. Researchers are developing targeted imaging agents that are incorporated selectively into specific types of cancer cells. Semi-automated and whole-body image systems are also being refined.

References

[1] Rini BI, Halabi S, Rosenberg JE et al Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol, 2008, 26: 5422-5428

[2] Motzer RJ, Hutson TE, Tomczak P et al Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med, 2007, 356: 115-124

[3] Roodman GD. Mechanisms of bone metastasis. N Engl J Med, 2004, 350: 1655-1664

[4] Stenbygaard LE, Sørensen JB, Olsen JE. Metastatic pattern at autopsy in non-resectable adenocarcinoma of the lung – a study from a cohort of 259 consecutive patients treated with chemotherapy. Acta Oncol, 1997, 36: 301-306

[5] Tsuya A, Kurata T, Tamura K, Fukuoka M. Skeletal metastases in non-small cell lung cancer: a retrospective study. Lung Cancer, 2007, 57: 229-232

[6] Barth A, Wanek LA, Morton DL. Prognostic factors in 1,521 melanoma patients with distant metastases. J Am Coll Surg, 1995, 181: 193-201

[7] Hindié E, Zanotti-Fregonara P, Keller I et al Bone metastases of differentiated thyroid cancer: impact of early 131I-based detection on outcome. Endocr Relat Cancer, 2007, 14: 799-807

[8] Li S, Peng Y, Weinhandl ED et al Estimated number of prevalent cases of metastatic bone disease in the US adult population. Clin Epidemiol, 2012, 4: 87-93

[9] Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer, 2002, 2: 584-593

[10] Carlin BI, Andriole GL. The natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma. Cancer, 2000, 88: 2989-2994

[11] Sathiakumar N, Delzell E, Morrisey MA et al Mortality following bone metastasis and skeletal-related events among men with prostate cancer: a population-based analysis of US Medicare beneficiaries, 1999-2006. Prostate Cancer Prostatic Dis, 2011, 14: 177-183

[12] Manders K, van de Poll-Franse LV, Creemers GJ et al Clinical management of women with metastatic breast cancer: a descriptive study according to age group. BMC Cancer, 2006, 6: 179

[13] Durante C, Haddy N, Baudin E et al Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab, 2006, 91: 2892-2899

[14] Coleman RE, Smith P, Rubens RD. Clinical course and prognostic factors following bone recurrence from breast cancer. Br J Cancer, 1998, 77: 336-340

[15] Nørgaard M, Jensen AØ, Jacobsen JB, Cetin K, Fryzek JP, Sørensen HT. Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol, 2010, 184: 162-167

[16] Sabbatini P, Larson SM, Kremer A et al Prognostic significance of extent of disease in bone in patients with androgen-independent prostate cancer. J Clin Oncol, 1999, 17: 948-957

[17] Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer, 2009, 9: 274-284

[18] Sorensen LB, Archambault M. Visualization of the liver by scanning with Mo⁹⁹ (molybdate) as tracer. J Lab Clin Med, 1963, 62: 330-340

[19] Guérin B, Tremblay S, Rodrigue S et al Cyclotron production of ^99mTc: an approach to the medical isotope crisis. J Nucl Med, 2010, 51: 13N-16N

[20] Chopra A. ^99mTc-Methyl diphosphonate. Molecular Imaging and Contrast Agent Database (MICAD) [Internet], 2004 Bethesda (MD) National Center for Biotechnology Information

[21] Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone, 1996, 18: 75-85

[22] Riggs SA Jr, Wood MB, Cooney WP 3rd, Kelly PJ. Blood flow and bone uptake of ^99mTc-labeled methylene diphosphonate. J Orthop Res, 1984, 1: 236-243

[23] Lavender JP, Khan RA, Hughes SP. Blood flow and tracer uptake in normal and abnormal canine bone: comparisons with Sr-85 microspheres, Kr-81m, and Tc-99m MDP. J Nucl Med, 1979, 20: 413-418

[24] Sagar VV, Piccone JM, Charkes ND. Studies of skeletal tracer kinetics. III. Tc-99m(Sn)methylenediphosphonate uptake in the canine tibia as a function of blood flow. J Nucl Med, 1979, 20: 1257-1261

[25] Einhorn TA, Vigorita VJ, Aaron A. Localization of technetium-99m methylene diphosphonate in bone using microautoradiography. J Orthop Res, 1986, 4: 180-187

[26] Ogawa K, Saji H. Advances in drug design of radiometal-based imaging agents for bone disorders. Int J Mol Imaging, 2011, 2011: 537687

[27] McAfee JG, Singh A, Roskopf M et al Experimental drug-induced changes in renal function and biodistribution of ^99mTc-MDP. Invest Radiol, 1983, 18: 470-478

[28] Elmaleh DR, Hnatowitch DJ, Cochavi S, McKusick KA, Brownell GL, Strauss WH. Emission tomographic images of the skull with fluorine-18. Int J Nucl Med Biol, 1980, 7: 289-293

[29] Phelps ME, Huang SC, Hoffman EJ, Selin C, Sokoloff L, Kuhl DE. Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method. Ann Neurol, 1979, 6: 371-388

[30] Schirrmeister H, Guhlmann A, Elsner K et al Sensitivity in detecting osseous lesions depends on anatomic localization: planar bone scintigraphy versus 18F PET. J Nucl Med, 1999, 40: 1623-1629

[31] Even-Sapir E, Metser U, Mishani E, Lievshitz G, Lerman H, Leibovitch I. The detection of bone metastases in patients with high-risk prostate cancer: ^99mTc-MDP Planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med, 2006, 47: 287-297

[32] Satyamurthy N, Amarasekera B, Alvord CW, Barrio JR, Phelps ME. Tantalum [18O]water target for the production of [18F]fluoride with high reactivity for the preparation of 2-deoxy-2-[18F]fluoro-D-glucose. Mol Imaging Biol, 2002, 4: 65-70

[33] Garcia-Torano E, Medina VP, Ibarra MR. The half-life of 18F. Appl Radiat Isot, 2010 1561-1565

[34] Win AZ, Aparici CM. Factors affecting uptake of NaF-18 by the normal skeleton. J Clin Med Res, 2014, 6: 435-442

[35] Piert M, Zittel TT, Becker GA et al Assessment of porcine bone metabolism by dynamic. J Nucl Med, 2001, 42: 1091-1100

[36] Wootton R, Dore C. The single-passage extraction of 18F in rabbit bone. Clin Phys Physiol Meas, 1986, 7: 333-343

[37] Frost ML, Blake GM, Cook GJ, Marsden PK, Fogelman I. Differences in regional bone perfusion and turnover between lumbar spine and distal humerus: (18)F-fluoride PET study of treatment-naive and treated postmenopausal women. Bone, 2009, 45: 942-948

[38] Grynpas MD. Fluoride effects on bone crystals. J Bone Miner Res, 1990, 5: S169-S175

[39] Hawkins RA, Choi Y, Huang SC et al Evaluation of the skeletal kinetics of fluorine-18-fluoride ion with PET. J Nucl Med, 1992, 33: 633-642

[40] Tomlinson RE, Shoghi KI, Silva MJ. Nitric oxide-mediated vasodilation increases blood flow during the early stages of stress fracture healing. J Appl Physiol 1985, 2014, 116: 416-424

[41] Love C, Din AS, Tomas MB, Kalapparambath TP, Palestro CJ. Radionuclide bone imaging: an illustrative review. Radiographics, 2003, 23: 341-358

[42] Vande Berg BC, Malghem J, Lecouvet FE, Maldague B. Magnetic resonance imaging of the normal bone marrow. Skeletal Radiol, 1998, 27: 471-483

[43] Lecouvet FE, Geukens D, Stainier A et al Magnetic resonance imaging of the axial skeleton for detecting bone metastases in patients with high-risk prostate cancer: diagnostic and cost-effectiveness and comparison with current detection strategies. J Clin Oncol, 2007, 25: 3281-3287

[44] Venkitaraman R, Cook GJ, Dearnaley DP et al Whole-body magnetic resonance imaging in the detection of skeletal metastases in patients with prostate cancer. J Med Imaging Radiat Oncol, 2009, 53: 241-247

[45] Iagaru A, Young P, Mittra E, Dick DW, Herfkens R, Gambhir SS. Pilot prospective evaluation of ^99mTc-MDP scintigraphy, 18F NaF PET/CT, 18F FDG PET/CT and whole-body MRI for detection of skeletal metastases. Clin Nucl Med, 2013, 38: e290-e296

[46] Warburg O. On the origin of cancer cells. Science, 1956, 123: 309-314

[47] Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 2009, 324: 1029-1033

[48] Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol, 1927, 8: 519-530

[49] Wahl RL, Cody RL, Hutchins GD, Mudgett EE. Primary and metastatic breast carcinoma: initial clinical evaluation with PET with the radiolabeled glucose analogue 2-[F-18]-fluoro-2-deoxy-D-glucose. Radiology, 1991, 179: 765-770

[50] Song JW, Oh YM, Shim TS, Kim WS, Ryu JS, Choi CM. Efficacy comparison between (18)F-FDG PET/CT and bone scintigraphy in detecting bony metastases of non-small-cell lung cancer. Lung Cancer, 2009, 65: 333-338

[51] Ota N, Kato K, Iwano S et al Comparison of (1)(8)F-fluoride PET/CT, (1)(8)F-FDG PET/CT and bone scintigraphy (planar and SPECT) in detection of bone metastases of differentiated thyroid cancer: a pilot study. Br J Radiol, 2014, 87: 20130444

[52] Cook GJ, Houston S, Rubens R, Maisey MN, Fogelman I. Detection of bone metastases in breast cancer by 18FDG PET: differing metabolic activity in osteoblastic and osteolytic lesions. J Clin Oncol, 1998, 16: 3375-3379

[53] Shreve PD, Grossman HB, Gross MD, Wahl RL. Metastatic prostate cancer: initial findings of PET with 2-deoxy-2-[F-18]fluoro-D-glucose. Radiology, 1996, 199: 751-756

[54] Kao CH, Hsieh JF, Tsai SC, Ho YJ, Yen RF. Comparison and discrepancy of 18F-2-deoxyglucose positron emission tomography and Tc-99m MDP bone scan to detect bone metastases. Anticancer Res, 2000, 20: 2189-2192

[55] Katayama T, Kubota K, Machida Y, Toriihara A, Shibuya H. Evaluation of sequential FDG-PET/CT for monitoring bone metastasis of breast cancer during therapy: correlation between morphological and metabolic changes with tumor markers. Ann Nucl Med, 2012, 26: 426-435

[56] Simoncic U, Perlman S, Liu G, Staab MJ, Straus JE, Jeraj R. Comparison of NaF and FDG PET/CT for assessment of treatment response in castration-resistant prostate cancers with osseous metastases. Clin Genitourin Cancer, 2015, 13: e7-e17

[57] Morris MJ, Akhurst T, Larson SM et al Fluorodeoxyglucose positron emission tomography as an outcome measure for castrate metastatic prostate cancer treated with antimicrotubule chemotherapy. Clin Cancer Res, 2005, 11: 3210-3216

[58] Jadvar H. Prostate cancer: PET with 18F-FDG, 18F- or 11C-acetate, and 18F- or 11C-choline. J Nucl Med, 2011, 52: 81-89

[59] Lebtahi R, Cadiot G, Delahaye N et al Detection of bone metastases in patients with endocrine gastroenteropancreatic tumors: bone scintigraphy compared with somatostatin receptor scintigraphy. J Nucl Med, 1999, 40: 1602-1608

[60] Mojtahedi A, Thamake S, Tworowska I, Ranganathan D, Delpassand ES. The value of (68)Ga-DOTATATE PET/CT in diagnosis and management of neuroendocrine tumors compared to current FDA approved imaging modalities: a review of literature. Am J Nucl Med Mol Imaging, 2014, 4: 426-434

[61] Osborne JR, Green DA, Spratt DE et al A prospective pilot study of (89)Zr-J591/prostate specific membrane antigen positron emission tomography in men with localized prostate cancer undergoing radical prostatectomy. J Urol, 2014, 191: 1439-1445

[62] Szabo Z, Mena E, Rowe SP et al. Initial evaluation of [F]DCFPyL for prostate-specific membrane antigen (PSMA)-targeted PET imaging of prostate cancer. Mol Imaging Biol 2015 Apr 21. [Epub ahead of print]

[63] Afshar-Oromieh A, Malcher A, Eder M et al PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions. Eur J Nucl Med Mol Imaging, 2013, 40: 486-495

[64] Perik PJ, Lub-De Hooge MN, Gietema JA et al Indium-111-labeled trastuzumab scintigraphy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol, 2006, 24: 2276-2282

[65] Brouwers AH, Dorr U, Lang O et al 131 I-cG250 monoclonal antibody immunoscintigraphy versus [18 F]FDG-PET imaging in patients with metastatic renal cell carcinoma: a comparative study. Nucl Med Commun, 2002, 23: 229-236

[66] Brouwers AH, Buijs WC, Oosterwijk E et al Targeting of metastatic renal cell carcinoma with the chimeric monoclonal antibody G250 labeled with (131)I or (111)In: an intrapatient comparison. Clin Cancer Res, 2003, 9: 3953S-3960S

[67] Mankoff DA, Pryma DA, Clark AS. Molecular imaging biomarkers for oncology clinical trials. J Nucl Med, 2014, 55: 525-528

[68] O’Connor JP, Jackson A, Asselin MC, Buckley DL, Parker GJ, Jayson GC. Quantitative imaging biomarkers in the clinical development of targeted therapeutics: current and future perspectives. Lancet Oncol, 2008, 9: 766-776

[69] Strimbu K, Tavel JA. What are biomarkers? Curr Opin HIV AIDS, 2010, 5: 463-466

[70] Therasse P, Arbuck SG, Eisenhauer EA et al New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst, 2000, 92: 205-216

[71] Imbriaco M, Larson SM, Yeung HW et al A new parameter for measuring metastatic bone involvement by prostate cancer: the Bone Scan Index. Clin Cancer Res, 1998, 4: 1765-1772

[72] Wakabayashi H, Nakajima K, Mizokami A et al Bone scintigraphy as a new imaging biomarker: the relationship between bone scan index and bone metabolic markers in prostate cancer patients with bone metastases. Ann Nucl Med, 2013, 27: 802-807

[73] Ulmert D, Kaboteh R, Fox JJ et al A novel automated platform for quantifying the extent of skeletal tumour involvement in prostate cancer patients using the Bone Scan Index. Eur Urol, 2012, 62: 78-84

[74] Pierce TP, Jauregui JJ, Cherian JJ, Elmallah RK, Mont MA . Imaging evaluation of patients with osteonecrosis of the femoral head. Curr Rev Musculoskelet Med 2015 Jun 5. [Epub ahead of print]

[75] Maas O., Joseph G.B., Sommer G., Wild D., Kretzschmar M.. Association between cartilage degeneration and subchondral bone remodeling in patients with knee osteoarthritis comparing MRI and 99m Tc-DPD-SPECT/CT. Osteoarthritis and Cartilage, 2015, 23 10 1713-1720

[76] Ha S, Hong SH, Paeng JC et al Comparison of SPECT/CT and MRI in diagnosing symptomatic lesions in ankle and foot pain patients: diagnostic performance and relation to lesion type. PLoS One, 2015, 10: e0117583

[77] Segall G, Delbeke D, Stabin MG et al SNM practice guideline for sodium 18F-fluoride PET/CT bone scans 1.0. J Nucl Med, 2010, 51: 1813-1820

[78] Schirrmeister H. Detection of bone metastases in breast cancer by positron emission tomography. Radiol Clin North Am, 2007, 45: 669-676

[79] Muzahir S, Jeraj R, Liu G et al Differentiation of metastatic vs degenerative joint disease using semi-quantitative analysis with (18)F-NaF PET/CT in castrate resistant prostate cancer patients. Am J Nucl Med Mol Imaging, 2015, 5: 162-168

[80] Vogel CL, Schoenfelder J, Shemano I, Hayes DF, Gams RA. Worsening bone scan in the evaluation of antitumor response during hormonal therapy of breast cancer. J Clin Oncol, 1995, 13: 1123-1128

[81] Rossleigh MA, Lovegrove FT, Reynolds PM, Byrne MJ, Whitney BP. The assessment of response to therapy of bone metastases in breast cancer. Aust N Z J Med, 1984, 14: 19-22

[82] van Schelven WD, Pauwels EK. The flare phenomenon: far from fair and square. Eur J Nucl Med, 1994, 21: 377-380

[83] Pollen JJ, Witztum KF, Ashburn WL. The flare phenomenon on radionuclide bone scan in metastatic prostate cancer. AJR Am J Roentgenol, 1984, 142: 773-776

[84] McNamara MA, George DJ. Pain, PSA flare, and bone scan response in a patient with metastatic castration-resistant prostate cancer treated with radium-223, a case report. BMC Cancer, 2015, 15: 371

[85] Cook GJ, Venkitaraman R, Sohaib AS et al The diagnostic utility of the flare phenomenon on bone scintigraphy in staging prostate cancer. Eur J Nucl Med Mol Imaging, 2011, 38: 7-13

[86] Schneider JA, Divgi CR, Scott AM et al Flare on bone scintigraphy following Taxol chemotherapy for metastatic breast cancer. J Nucl Med, 1994, 35: 1748-1752

[87] Chao HS, Chang CP, Chiu CH, Chu LS, Chen YM, Tsai CM. Bone scan flare phenomenon in non-small-cell lung cancer patients treated with gefitinib. Clin Nucl Med, 2009, 34: 346-349

[88] Gillespie PJ, Alexander JL, Edelstyn GA. Changes in 87mSr concentractions in skeletal metastases in patients responding to cyclical combination chemotherapy for advanced breast cancer. J Nucl Med, 1975, 16: 191-193

[89] Sugawara Y, Kajihara M, Semba T, Ochi T, Fujii T, Mochizuki T. Healing focal “flare” phenomenon after radiotherapy in a bone metastasis from bladder cancer. Clin Nucl Med, 2005, 30: 672-673

[90] Cheng TH, Holman BL. Increased skeletal:renal uptake ratio: etiology and characteristics. Radiology, 1980, 136: 455-459

[91] Swislocki AL, Barnett CA, Darnell P, Noth RH. Hyperthyroidism: an underappreciated cause of diffuse bone disease. Clin Nucl Med, 1998, 23: 241-243

[92] Ell PJ. The contribution of PET/CT to improved patient management. Br J Radiol, 2006, 79: 32-36

[93] Scher HI, Halabi S, Tannock I et al Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol, 2008, 26: 1148-1159

[94] Lee RJ, Saylor PJ, Michaelson MD et al A dose-ranging study of cabozantinib in men with castration-resistant prostate cancer and bone metastases. Clin Cancer Res, 2013, 19: 3088-3094

[95] Fay AP, Albiges L, Bellmunt J. Current role of cabozantinib in metastatic castration-resistant prostate cancer. Expert Rev Anticancer Ther, 2015, 15: 151-156

[96] Doran Michael G., Spratt Daniel E., Wongvipat John, Ulmert David, Carver Brett S., Sawyers Charles L., Evans Michael J.. Cabozantinib Resolves Bone Scans in Tumor-Naïve Mice Harboring Skeletal Injuries. Molecular Imaging, 2014, 13 8 7290.2014.00026

[97] Gentili A, Miron SD, Bellon EM. Nonosseous accumulation of bone-seeking radiopharmaceuticals. Radiographics, 1990, 10: 871-881

[98] Cerci SS, Suslu H, Cerci C et al Different findings in Tc-99m MDP bone scintigraphy of patients with sickle cell disease: report of three cases. Ann Nucl Med, 2007, 21: 311-314

[99] Loutfi I, Collier BD, Mohammed AM. Nonosseous abnormalities on bone scans. J Nucl Med Technol, 2003, 31: 149-153

[100] Zhang H, Huang R, Cheung NK et al Imaging the norepinephrine transporter in neuroblastoma: a comparison of [18F]-MFBG and 123I-MIBG. Clin Cancer Res, 2014, 20: 2182-2191

[101] Beekman FJ, van der Have F, Vastenhouw B et al U-SPECT-I: a novel system for submillimeter-resolution tomography with radiolabeled molecules in mice. J Nucl Med, 2005, 46: 1194-1200

[102] Beekman F, van der Have F. The pinhole: gateway to ultra-high-resolution three-dimensional radionuclide imaging. Eur J Nucl Med Mol Imaging, 2007, 34: 151-161

[103] Torigian DA, Zaidi H, Kwee TC et al PET/MR imaging: technical aspects and potential clinical applications. Radiology, 2013, 267: 26-44

[104] Hofmann M, Pichler B, Scholkopf B, Beyer T. Towards quantitative PET/MRI: a review of MR-based attenuation correction techniques. Eur J Nucl Med Mol Imaging, 2009, 36: S93-S104

[105] Jadvar H, Colletti PM. Competitive advantage of PET/MRI. Eur J Radiol, 2014, 83: 84-94