Imaging Bone Metastases in Breast, Prostate, and Lung Cancers

• Indication Overview
• Methods
• Search Results
• Summary Table
• References
• Appendix 1
• Appendix 2
• Appendix 3
• Appendix 4

Indication Overview

Radionuclide imaging is used in patients who have new symptoms suggestive of metastasis.¹ Bone scanning is performed in patients with known cancer to detect possible metastasis and is also conducted in patients for staging and subsequent treatment planning.

Population: Patients with cancer (limited to lung, prostate, and breast) undergoing staging and including patients with known cancer presenting with or without bone pain.

Intervention: Bone scanning, also known as bone scintigraphy, using technetium-99m–labelled methylene diphosphonate (^99mTc-MDP).²

During a bone scan, the ^99mTc-MDP is injected intravenously and accumulates in bone after several hours.^3,4 A gamma camera is then used to detect "hot spots," which represent the areas of bone that have high metabolism or vasculature where the ^99mTc has accumulated, such as in areas of bone metastasis.

Comparators: For this report, the following diagnostic tests are considered as alternatives to bone scanning:

• Positron emission tomography (PET) using 18F-fluoride (¹⁸F) or 18F-fluorodeoxyglucose (¹⁸FDG)

Outcomes: Eleven outcomes (referred to as criteria) are considered in this report:

• Criterion 1: Size of the affected population
• Criterion 2: Timeliness and urgency of test results in planning patient management
• Criterion 3: Impact of not performing a diagnostic imaging test on mortality related to the underlying condition
• Criterion 4: Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition
• Criterion 5: Relative impact on health disparities
• Criterion 6: Relative acceptability of the test to patients
• Criterion 7: Relative diagnostic accuracy of the test
• Criterion 8: Relative risks associated with the test
• Criterion 9: Relative availability of personnel with expertise and experience required for the test
• Criterion 10: Accessibility of alternative tests (equipment and wait times)
• Criterion 11: Relative cost of the test.

Definitions of the criteria are in Appendix 1.

Methods

The literature search was performed by an information specialist using a peer-reviewed search strategy.

Published literature was identified by searching the following bibliographic databases: MEDLINE with In-Process records and daily updates via Ovid; The Cochrane Library (2011, Issue 2) via Ovid; and PubMed. The search strategy consisted of both controlled vocabulary, such as the National Library of Medicine's MeSH (Medical Subject Headings), and keywords. The main search concepts were radionuclide imaging and bone tumours.

Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, and non-randomized studies, including diagnostic accuracy studies. Where possible, retrieval was limited to the human population and English-language documents. No date limits were applied for systematic reviews. For primary studies, the retrieval was limited to documents published between January 1, 2006, and March 14, 2011. Regular alerts were established to update the search until October 2011. See Appendix 2 for the detailed search strategies.

Grey literature (literature that is not commercially published) was identified by searching relevant sections of the Grey Matters checklist. Google and other Internet search engines were used to search for additional web-based materials. The searches were supplemented by reviewing the bibliographies of key papers. See Appendix 2 for more information on the grey literature search strategy.

Targeted searches were done as required for the criteria, using the aforementioned databases and Internet search engines. When no literature was identified that addressed specific criteria, experts were consulted.

Search Results

Thirty-one potential articles were identified through the health technology assessment/systematic review/meta-analysis (HTA/SR/MA) filtered search and 12 were subjected to full-text review. A total of 380 potential primary studies were identified with the primary studies search. Additional studies were identified in searches for grey literature, targeted searches, and alerts.

For criterion 7 on diagnostic accuracy, systematic reviews were included. In addition, primary studies published between 2006 and 2011 that were not included in any of the systematic reviews were summarized individually. In total, six systematic reviews^5-10 and five primary studies^11-15 were included for criterion 7.

For all the remaining criteria, included studies were not limited by study design or date, and were obtained from the HTA/SR/MA search, grey literature searching, a primary studies search, targeted searching, and handsearching.

Summary table

Table 1: Summary of Criterion Evidence

Domain 1: Criteria Related to the Underlying Health Condition
Criterion		Synthesized Information
1	Size of the affected population	The estimated number of new cases of breast, prostate, and lung cancer in 2011 is tabulated. Based on data from a population-based analysis of approximately 100,000 women with breast cancer and 125,000 men with prostate cancer, the incidence of bone metastasis at diagnosis or during follow-up (median 3.3 years) was 7.3%16 and 7.7%,17 respectively. Similar data were not available for lung cancer. Studies have reported an incidence of bone metastases of approximately 30% for patients with non–small cell lung cancer.18 Using these data, the possible number of cases of metastasis was estimated. Cases of Bone Metastasis Cancer Type 2011 Estimated Number of New Cases per 100,00019  Estimated Number of Cases of Bone Metastasis per 100,000* Breast 102† 7.4 (0.0074) Prostate 122 9.5 (0.0095) Lung 57 17.1 (0.0171) *Calculated from estimated new cases and the reported rates of bone metastasis for each type of cancer.20 †Females only Notably, these patients would undergo repeat imaging if there is suggestion that there was disease progression to the bone. Therefore, each patient could receive multiple scans. Given this, the size of the affected population is estimated to be more than 1 in 1,000 (0.1%) and less than or equal to 1 in 100 (1%).
2	Timeliness and urgency of test results in planning patient management	Imaging to detect bone metastases required for staging to plan treatment and follow-up. Benchmark wait times for bone scan and PET are immediate to 24 hours for an emergency case, within 7 days for an urgent case, and within 30 days for a scheduled case.21 Patient management (i.e., surgery, chemotherapy, radiation) depends on imaging findings. A delay in test results may have a negative effect on the workflow. The target time frame for performing the test is between 8 and 30 days, and obtaining the test results has significant impact on the management of the condition or the effective use of health care resources.
3	Impact of not performing a diagnostic imaging test on mortality related to the underlying condition	The estimated 5-year relative survival ratio (for the period 2004-2006) is 88%, 96%, and 19% for breast, prostate, and lung cancer, respectively. If an imaging test was not performed, staging information cannot be obtained and treatment cannot be appropriately planned. However, if the test was performed, there is ultimately no impact on mortality.
4	Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition	Imaging is required for accurate staging of disease and for selecting the appropriate treatment. Without accurate staging information, patients may receive less aggressive treatment (e.g., a patient with clinical stage I or II disease who would have been restaged to stage III with imaging findings and, subsequently, managed differently) or more aggressive treatment (e.g., surgery being unnecessarily performed on a patient who would not benefit from it, based on diagnostic imaging information — for instance, if they had metastatic disease that has spread throughout the body, which would have been detected by imaging). Diagnostic imaging test results can have a significant impact on morbidity or quality of life.

 

 

Domain 2: Criteria Comparing 99mTc with an Alternative or Comparing Between Clinical Uses
Criterion		Synthesized Information
5	Relative impact on health disparities	To be scored locally.
6	Relative acceptability of the test to patients	Bone scanning: Limited information was identified on the acceptability to patients of bone scanning with 99mTc-MDP. Patients may have concerns about radiation exposure and the intravenous injection of radiopharmaceutical agent. PET: Patients are required to fast prior to an 18FDG-PET scan. The level of acceptability to patients of bone scanning with 99mTc-radiolabelled isotopes: is similar to 18FDG-PET is minimally lower than 18F-PET.
7	Relative diagnostic accuracy of the test	The sensitivity and specificity of bone scanning, 18FDG-PET, and 18F-PET were reported in 6 systematic reviews and 5 observational studies. For the modality of PET, all of the included studies used the pharmaceutical 18FDG. No primary studies were identified for inclusion (which were not already included in a systematic review) that used 18F. The data are sum Diagnostic Accuracy Test Sensitivity Range (%) Specificity Range (%) Detection of Bone Metastases — Breast Cancer Bone scan 78 to 100 80 to 100 18FDG-PET or 18FDG- PET/CT 78 to 100 88 to 100 Detection of Bone Metastases or Staging — Lung Cancer Bone scan 67 to 92 69 to 94 18FDG-PET or 18FDG- PET/CT 92 to 96 97 to 99 Detection of Bone Metastases or Staging — Prostate Cancer Bone scan 46 to 71 32 to 100 marized according to cancer type. CT = computed tomography; 18FDG-PET = 18-fluorodeoxyglucose positron emission tomography.  No information was available regarding the diagnostic accuracy of bone scanning and other imaging techniques according to cancer stage. Overall, with respect to breast cancer, the diagnostic accuracy of bone scanning with 99mTc-radiolabelled isotopes is: similar to 18FDG-PET minimally lower than 18F-PET. Overall, with respect to prostate cancer, based on feedback from MIIMAC, the diagnostic accuracy of bone scanning with 99mTc-radiolabelled isotopes is: moderately lower than 18F-PET. Overall, with respect to lung cancer, the diagnostic accuracy of bone scanning with 99mTc-radiolabelled isotopes is: moderately lower than 18FDG-PET minimally lower than 18F-PET.
8	Relative risks associated with the test	Non–radiation-related Risks Patients may experience soreness and swelling at the site of injection of the 99mTc, and there is a small risk of cell or tissue damage due to the radiation. Some patients may have difficulty lying still during the test.4,22 Although rare, allergic reactions to MDP are possible.23 Radiation-related Risks The radiation dose for bone scans is lower than that of 18FDG-PET/CT.10 Radiation doses for the modalities used in bone tumour imaging are tabulated. Effective Doses of Radiation24,25 Procedure Average Dose (mSv) Bone scan 6.3 Whole body PET 14.1 Average background dose of radiation per year 1 to 3.026-28 mSv = millisievert; PET = positron emission tomography. Overall, the safety profile of bone scanning with 99mTc-radiolabelled isotopes is: similar to that of 18FDG-PET similar to that of 18F-PET.
9	Relative availability of personnel with expertise and experience required for the test	Interobserver agreement of bone scans has been reported as moderate,29,30 Another study reported good agreement for bone scanning and 18FDG-PET/CT.31 As of 2006 in Canada, there were 2,034 diagnostic radiologists; 221 nuclear medicine physicians; 12,255 radiological technologists; 1,781 nuclear medicine technologists, and 2,900 sonographers available across Canada. The Territories do not have the available personnel to perform and interpret tests to detect bone metastases. Other jurisdictions (e.g., PEI) may offer limited nuclear medicine services. Assuming the necessary equipment is available, if bone scanning with 99mTc radiolabelled isotopes is not available, it is estimated that: fewer than 25% of the procedures can be performed in a timely manner using 18FDG-PET fewer than 25% of the procedures can be performed in a timely manner using 18F-PET.
10	Accessibility of alternative tests (equipment and wait times)	Wait times Wait times for urgent bone scan ranged from 1 to 6 days, and for scheduled scans ranged from 7 to 73 days.32 Equipment Overall, the availability of equipment required for bone scanning is good — except in areas where nuclear medicine services are limited (e.g., Prince Edward Island) or unavailable (all three Territories). As of November 2010, there were approximately 31 Canadian centres performing publicly funded PET scans.33 These centres are all located in the provinces of British Columbia, Alberta, Manitoba, Ontario, Quebec, New Brunswick, and Nova Scotia.33 There are 36 PET or PET/CT scanners, 4 of which are used for research purposes only.33 Assuming personnel with the necessary expertise and experience are available, if bone scanning with 99mTc-radiolabelled isotopes is not available, it is estimated that: fewer than 25% of the procedures can be performed in a timely manner using 18FDG-PET fewer than 25% of the procedures can be performed in a timely manner using 18F-PET.
11	Relative cost of the test	According to our estimates, the cost of whole body bone scan with 99mTc-based radioisotopes is $278.70. 18F-PET and 18FDG-PET are significantly more costly alternatives. Relative Costs Test Total costs ($) Cost of Test Relative to 99mTc-based Test ($) Whole body bone scan 278.70 Reference 18F-PET 850.00 +571.30 18FDG-PET 1050.00 +771.30

CT = computed tomography; ¹⁸FDG-PET = 18-fluorodeoxyglucose positron emission tomography; mSv = millisievert; PET = positron emission tomography; ^99mTc-MDP = ^99mtechnetium-labelled methylene diphosphonate; ^99mTc = technetium-99m.

Criterion 1: Size of affected population (link to definition)

Bone is a common site of metastasis, and the most common types of tumours to metastasize to bone are breast, prostate, lung, kidney, and thyroid.³⁴ The estimated numbers of new cases of breast, prostate, and lung cancer in 2011 are tabulated. Based on data from a population-based analysis of approximately 100,000 women with breast cancer and 125,000 men with prostate cancer, the incidence of bone metastasis at diagnosis or during follow-up (median 3.3 years) was 7.3%¹⁶ and 7.7%,¹⁷ respectively. Similar data were not available for lung cancer. Studies have reported an incidence of bone metastases of approximately 30% for patients with non–small cell lung cancer (NSCLC).¹⁸ Using the estimated number of new cases reported by the Canadian Cancer Society (CCS) for 2011,¹⁹ and these reported rates of metastasis, Table 2 reports the estimated number of cases of bone metastasis per 100,000 people.

Table 2: Cases of Bone Metastasis

Cancer Type	2011 Estimated Number of New Cases/100,00019	Estimated Number of Cases of Bone Metastasis per 100,000*
Breast	102† (0.102%)	7.4 (0.0074%)
Prostate	122 (0.122%)	9.4 (0.0094%)
Lung	57 (0.057%)	17.1 (0.0171%)

*Calculated from estimated new cases and the reported rates of bone metastasis for each type of cancer.^16-18
†Females only.

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Criterion 2: Timeliness and urgency of test results in planning patient management (link to definition)

Imaging to detect bone metastases is needed to enable treatment planning and follow-up.²⁰ Pain and quality of life have been reported to improve in prostate cancer patients with bone metastasis who are treated with hormonal therapy or bisphosphonates.^20,35 In patients with breast cancer, detection of metastases may prevent complications and control disease progression.⁷

A study in patients with myxoid liposarcoma, which commonly metastasizes to the spine, reported the effects of treatment following detection of spinal metastasis.³⁶ Thirty-three patients with detected spinal metastasis were treated with either radiation alone (n = 8), surgery and radiation (n = 14), surgery alone (n = 4), or did not receive treatment (n = 7). Treatment with surgery and radiation improved pain scores in all patients with reported pain. In addition, two patients who were treated (one with surgery alone, one with surgery and radiation) were disease free at long-term follow-up. All patients who were untreated were either no longer alive, or alive with disease. This study concluded that diagnosis of bone metastasis and early treatment can improve outcomes such as controlling pain.

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Criterion 3: Impact of not performing a diagnostic imaging test on mortality related to the underlying condition (link to definition)

Data from the 2011 Canadian Cancer Society Statistics reported that the estimated five-year relative survival ratio (for the period 2004 to 2006) is 88%, 96%, and 19% for breast, prostate, and lung cancer, respectively. Survival ratios are influenced significantly by the stage of disease.¹⁹

If an imaging test was not performed, staging information cannot be obtained and treatment cannot be appropriately planned. Diagnostic imaging test results can have a moderate impact on mortality.

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Criterion 4: Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition (link to definition)

Bone metastasis has been reported to be associated with pain, hypercalcemia, nerve compression, fractures, and disability.^7,20,37 Detection and subsequent treatment of bone metastasis can improve outcomes such as pain and quality of life.

Imaging is required for accurate staging of disease and for selecting the appropriate treatment. Without accurate staging information, patients may receive less aggressive treatment (e.g., a patient with clinical stage I or II disease who would have been restaged to stage III as a result of imaging findings and, subsequently, managed differently) or more aggressive treatment (e.g., surgery being unnecessarily performed on a patient who would not benefit from it, based on diagnostic imaging information — for instance, if they had metastatic disease that has spread throughout the body, which would have been detected by imaging).

Diagnostic imaging test results can have a significant impact on morbidity or quality of life.

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Criterion 5: Relative impact on health disparities (link to definition)

A 2005 study reported that diagnostic imaging tests were conducted more frequently in patients with a higher socioeconomic status than those with a lower socioeconomic status.³⁸

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Criterion 6: Relative acceptability of the test to patients (link to definition)

Bone scanning
Patients, or parents of patients, may have concerns about radiation exposure and the intravenous injection of radiopharmaceutical agent. Limited information was identified on the acceptability of bone scanning to pediatric patients. A retrospective study on the use of bone scanning in children with osteosarcoma or Ewing sarcoma suggested that any test, including a bone scan, causes psychological strain on the children and the parents.³⁹

¹⁸F or ¹⁸FDG-PET 
Patients may have concerns about radiation exposure and the intravenous injection of radiopharmaceutical agent. Patients undergoing ¹⁸FDG-PET are required to fast prior to the scan.

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Criterion 7: Relative diagnostic accuracy of the test (link to definition)

Based on the American College of Radiology Appropriateness Criteria,^40-42 the following whole body bone scans using ^99mTc are "usually appropriate" or "may be appropriate" for the following indications:

Breast cancer

• Patients with stage II carcinoma who are presenting with back and hip pain
• Patients with known bone metastatic disease who are presenting with pathological fracture of left femur on x-ray

Prostate cancer

• Asymptomatic patients with nodule on physical exam determined to be poorly differentiated carcinoma and who have a prostate specific antigen (PSA) level greater or equal to 20 mg/mL

Lung cancer

• Patients with a 1 cm lung nodule determined to be non–small cell who are presenting for staging and resection
• Patients who are undergoing non-invasive staging of NSCLC. (Note: may be appropriate — not needed if PET scan was performed.)

See Appendix 3 for more information regarding the ACR Appropriateness Criteria applicable to bone tumour imaging.

Breast Cancer

For patients with breast cancer, three systematic reviews^5-7 and three observational studies^11,12,43 were included that compared the diagnostic accuracy of bone scan for detecting bone metastases with either ¹⁸FDG-PET or ¹⁸FDG-PET/CT.

Systematic reviews and meta-analyses
A 2011 systematic review and meta-analysis compared bone scan, ¹⁸FDG-PET, and magnetic resonance imaging (MRI) for detection of bone metastasis.⁵ Databases were searched between 1995 and 2010, without any restriction on language. Studies were included that used ¹⁸FDG-PET, MRI, or bone scan with ^99mTc-MDP to identify bone metastases in patients with breast cancer; used histopathological analysis or imaging and clinical follow-up as the reference standard; and reported per-patient or per-lesion data that could be used to calculate measures of diagnostic accuracy. Studies of children, case reports, letters, editorials, and reviews were excluded, as were studies that used radiopharmaceuticals other than ¹⁸FDG or ^99mTc-MDP (e.g., technetium-99m-hexakismethoxy-isobutyl-isonitril [^99mTc-MIBI] bone scan). Quality of the included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) instrument and only those with a score of 9 or higher were included.

The study characteristics for included articles were not published. This information was requested, but not received. Table 3 reports the sensitivity and specificity of the imaging tests on a per-patient and per-lesion basis. The authors described the quality of the included studies as suboptimal, due to issues with the reference standard and blinding of the individuals interpreting images. Overall, the study concluded that on a per-patient basis, MRI was more effective at detecting bone metastases in breast cancer patients compared with ¹⁸FDG-PET or bone scan, whereas ¹⁸FDG-PET had lower sensitivity than bone scanning on a per-lesion basis. However, further information regarding the patient characteristics should be considered.

Table 3: Sensitivity and Specificity of Diagnostic Methods to Detect Bone Metastases in Patients with Breast Cancer⁵

Test	Sensitivity (95% CI)	Specificity (95% CI)	Sensitivity (95% CI)	Specificity (95% CI)
	Patient Basis		Lesion Basis
Bone scan	87.0 (82.1 to 90.9)	88.1 (84.6 to 91.0)	87.8 (83.9 to 91.1)	96.1 (94.7 to 97.2)
MRI	97.1 (90.1 to 99.7)	97.0 (89.5 to 99.6)	NS	NS
18FDG-PET	83.3 (78.2 to 90.8)	94.5 (88.5 to 98.0)	52.7 (47.0 to 58.4)	99.6 (98.9 to 99.0)

CI = confidence interval; ¹⁸FDG =18F fluorodeoxyglucose; MRI = magnetic resonance imaging; NS = no studies; PET = positron emission tomography.

In a 2010 systematic review, Escalona et al.⁶ evaluated the use of ¹⁸FDG-PET in breast cancer. One objective was to evaluate the accuracy of ¹⁸FDG-PET in detecting metastases. Studies that compared the diagnostic accuracy of ¹⁸FDG-PET with a reference test in patients with breast cancer were included. Health technology assessments, systematic reviews, meta-analyses, and observational and experimental studies were eligible for inclusion. Studies that included mixed cancer populations (in which data for breast cancer were not reported separately) were excluded. There was no limitation on the search time frame, which ran until February 2007. The quality of the included studies was assessed using a checklist for diagnostic studies.

In total, 73 studies were included in the systematic review, eight of which evaluated ¹⁸FDG-PET compared with bone scan in the detection of bone metastases. A total of 382 patients were included across the eight studies. The quality of the included studies was described as low, due to small sample sizes, failure to report on blinding of the individual interpreting images, use of multiple PET scanners and provision of only aggregate results, and the inclusion of patients with different tumour stages without presenting results according to stage. The authors of the systematic review did not pool diagnostic accuracy data across studies and were unable to report results according to tumour stage, given the available data. No patient characteristics were reported for the individual studies, making it unclear as to whether patients were symptomatic or asymptomatic.

The sensitivity of both ¹⁸FDG-PET and bone scan in detecting bone metastases ranged from 77.7% to 100%. The specificity of ¹⁸FDG-PET ranged from 88.2% to 100%, while the specificity of bone scan ranged from 80% to 100%. The positive predictive value (PPV) and negative predictive value of ¹⁸FDG-PET were reported in only one study, and were 85.7% and 95.8%, respectively, compared with 70.6% and 95.2%, respectively, for bone scan. Estimates of the accuracy of ¹⁸FDG-PET ranged from 83.1% to 97.7% and 78.7% to 93.2% for bone scan. It was unclear if the results presented were on a patient or lesion basis. The authors concluded that ¹⁸FDG-PET appears to be more specific than bone scan in detecting bone metastases in patients with breast cancer, but should not be used in isolation.

Shie et al. published a systematic review and meta-analysis in 2008 comparing ¹⁸FDG-PET and bone scans to detect bone metastasis.⁷ Studies including breast cancer patients who underwent both ¹⁸FDG-PET and bone scans within three months of one another, with positive finding confirmed by CT, MRI, or biopsy, were included. Patients of all stages were included (no breakdown was provided). In addition, it was not stated if the patients had symptoms of bone metastasis. Formal quality assessment of the included studies did not appear to be performed.

Six studies were included in the analysis. On a patient basis (184 patients from three studies), the pooled sensitivity was 81% for ¹⁸FDG-PET and 78% for bone scan, and specificity was 93% for ¹⁸FDG-PET and 79% for bone scan. On a lesion basis (1,207 patients from four studies), the sensitivity was 69% and 88%, and the specificity was 98% and 87% for ¹⁸FDG-PET and bone scan, respectively. The authors concluded that it is unclear which modality is superior for detection of bone metastasis in patients with breast cancer, but ¹⁸FDG-PET may be a more useful confirmatory test due to its higher specificity.

Observational studies
Two observational studies were identified that evaluated the diagnostic performance of bone scan relative to another imaging modality for the detection of bone metastases in patients with breast cancer.^11,12 These studies were not included in any of the three systematic reviews and are summarized individually in Tables 13 and 14 in Appendix 4. Bone scan with ^99mTc-MDP was compared with ¹⁸FDG-PET/CT¹¹ and ¹⁸FDG-PET¹² (Appendix 4, Table 13). One study was a prospective cohort study¹² and the second was a retrospective cohort study.¹¹ Both studies were conducted in the United States. ^11,12 It was unclear in either of the studies if the patients were symptomatic or asymptomatic, but patients in these studies were either high risk for metastases or were suspected of having metastases.^11,12

Neither of the two studies reported outcomes according to cancer stage. In one study, the concordance between bone scan and ¹⁸FDG-PET/CT was 81% (Appendix 4, Table 14).¹¹ Sensitivity and specificity were not reported in this study. In the second study, the sensitivity of conventional imaging (bone scan and CT) and ¹⁸FDG-PET was equivalent (80%), while the specificity was greater with ¹⁸FDG-PET than with conventional imaging (94% versus 79%).¹² Conclusions and limitations of the individual studies can be found in Appendix 4, Table 14.

Lung Cancer

For patients with lung cancer, one systematic review⁸ and two observational studies^13,14 were included that compared the diagnostic accuracy of bone scan in detecting bone metastases with either ¹⁸FDG-PET or ¹⁸FDG-PET/CT.

Systematic reviews and meta-analyses
Bone scan, MRI, and ¹⁸FDG-PET for detecting bone metastasis in patients with lung cancer were compared in a systematic review and meta-analysis published in 2011.⁸ Databases were searched between 1995 and 2010, without any restriction on language. Studies were included that used ¹⁸FDG-PET or bone scan with ^99mTc-MDP to detect bone metastases in patients with lung cancer; reported per-patient or per-lesion data that could be used to calculate measures of diagnostic accuracy. Clinical follow-up, imaging follow-up, histopathological analysis, or radiographic confirmation were used as reference standards. Studies of children, case reports, letters, editorials, and reviews were excluded, as were studies that used radiopharmaceuticals other than ¹⁸FDG or ^99mTc-MDP (e.g., ^99mTc-MIBI bone scan). Quality of the included studies was assessed using the QUADAS instrument and only those with a score of 9 or higher were included. The study characteristics for included articles were not published. This information was requested, but not received.

Fourteen articles that in total reported data on 5,676 patients were included in the analysis. Issues with study quality were identified, mainly with regard to the reference standard and blinding of the individual interpreting images. Table 4 reports the sensitivity and specificity of the three modalities on a per-patient and per-lesion basis. ¹⁸FDG-PET was reported to have better diagnostic accuracy than MRI or bone scanning. The authors concluded that ¹⁸FDG-PET is superior for detecting bone metastasis in patients with lung cancer. However, further information regarding the patient characteristics should be considered.

Table 4: Sensitivity and Specificity of Diagnostic Methods to Detect Bone Metastasis in Lung Cancer⁸

Test	Sensitivity (95% CI)	Specificity (95% CI)	Sensitivity (95% CI)	Specificity (95% CI)
	Patient Basis		Lesion Basis
Bone scan	91.8 (89.1 to 94.1)	68.8 (65.8 to 71.6)	71.5 (66.9 to 75.8)	91.0 (89.2 to 92.7)
MRI	80.0 (67.0 to 89.6)	90.6 (85.8 to 94.3)	83.8 (77.0 to 89.2)	96.3 (95.3 to 97.1)
18FDG-PET	91.9 (88.8 to 94.3)	96.8 (96.0 to 97.6)	95.0 (93.5 to 96.2)	94.6 (93.5 to 95.5)

CI = confidence interval; ¹⁸FDG =18F fluorodeoxyglucose; MRI = magnetic resonance imaging; PET = positron emission tomography.

Observational studies
Two observational studies, one in patients with NSCLC and one in patients with small cell lung cancer (SCLC), were identified that evaluated the diagnostic performance of bone scan relative to ¹⁸FDG-PET¹³ or ¹⁸FDG-PET/CT¹⁴ for preoperative staging. These studies are summarized in Tables 13 and 14 in Appendix 4. Bone scan was performed with ^99mTc-labelled oxydronate in one study,¹⁴ while the radiopharmaceutical used in the other study was not specified.¹³ Both studies used prospective cohort designs. One was conducted in Italy¹³ and one was conducted in Denmark.¹⁴ It was unclear if patients in the two studies were symptomatic or asymptomatic.

Outcomes were not reported according to cancer stage. In patients with NSCLC, the sensitivity of bone scan was 67% compared with 96% with ¹⁸FDG-PET, while the specificity of bone scan was 94% compared with 99% with ¹⁸FDG-PET. For patients with SCLC, the sensitivity of bone scan was 75% but was not reported for ¹⁸FDG-PET/CT.¹⁴ In 17% of patients, ¹⁸FDG-PET/CT suggested a different stage than conventional staging.¹⁴ Conclusions and limitations of the individual studies can be found in Appendix 4, Table 14.

Prostate Cancer

Observational studies
One US-based prospective cohort observational study was identified that evaluated the diagnostic performance of bone scan relative to ¹⁸FDG-PET for the detection of bone metastases in patients with prostate cancer.¹⁵ Further information on this study is available in Tables 13 and 14 in Appendix 4.

Outcomes were not reported according to cancer stage. The authors reported that ¹⁸FDG-PET/CT detected bone metastases in 72.1% of patients compared with 86.1% with bone scan (P = 0.01) (Appendix 4, Table 14).¹⁵ Conclusions and limitations can be found in Appendix 4, Table 14.

Studies Involving Multiple Cancer Types

A systematic review and meta-analysis published in 2011 compared ¹⁸FDG-PET/CT with bone scintigraphy in the detection of bone metastases in patients with malignancies.⁹ English-language studies published between 2000 and 2010 were eligible for inclusion if they compared ⁸FDG-PET/CT with bone scan in patients of any age or disease stage; presented sufficient data to calculate measures of diagnostic accuracy; used histopathological follow-up, clinical follow-up, and/or combined imaging as the reference test; and reported on at least six patients. Study quality was assessed using the QUADAS instrument.

Six studies involving a total of 1,560 patients were included in the meta-analysis. Three studies were prospective and three were retrospective. Patient-based data were reported in five studies, while lesion-based data were reported in one. Three studies included only patients with NSCLC, one study included patients with either NSCLC or SCLC, one study included patients with nasopharyngeal cancer, and one study included patients with Ewing sarcoma, ganglioneuroblastoma, rhabdomyosarcoma, neuroblastoma, or granulocytic sarcoma. Of the 1,560 patients, 1,341 had NSCLC. Details on cancer stage or whether patients were symptomatic were not reported.

The authors described all studies as being of moderate quality and reported that the main weakness in the included studies involved the reference standard, which was not independent of the index test or not the same for all patients. Table 5 reports the sensitivity and specificity of the imaging methods on a per-patient basis. The authors concluded that the pooled sensitivity and specificity of ¹⁸FDG-PET/CT were higher than bone scan, but that further research was required to evaluate ¹⁸FDG-PET/CT in other malignancies such as breast and prostate cancer.

Table 5: Sensitivity and Specificity of Diagnostic Methods to Detect Bone Metastasis⁹

Test	Sensitivity (95% CI)	Specificity (95% CI)
Bone scan	0.71 (0.64 to 0.76)	0.91 (0.90 to 0.93)
18FDG-PET/CT	0.93 (0.89 to 0.96)	0.98 (0.97 to 0.98)

CI = confidence interval; ⁸FDG = 18F fluorodeoxyglucose; PET/CT = positron emission tomography/computed tomography.

A systematic review and meta-analysis published in 2010¹⁰ reported the diagnostic accuracy of ¹⁸FDG-PET, ¹⁸FDG-PET/CT, bone scan, and bone scan plus single-photon emission computed tomography (SPECT) for detecting bone metastasis. Eleven studies involving 425 patients were included in the analysis and studies were characterized based on whether patients were analyzed on a patient basis (350 patients) or a lesion basis (255 patients). The population included patients with lung cancer, prostate cancer, breast cancer, and hepatocellular carcinoma, and it was not reported in six of the included studies. The reference standard varied across the 11 studies, and included CT, MRI, radiography, ¹⁸FDG-PET, clinical follow-up, or biopsy. Table 6 reports the sensitivity and specificity of the imaging methods. Some studies combined the findings from PET and PET/CT or bone scan and bone scan plus SPECT. Only the results of the individual tests are included in Table 6.

Table 6: Sensitivity and Specificity of Diagnostic Methods to Detect Bone Metastasis¹⁰

Test	Sensitivity (95% CI)	Specificity (95% CI)	Sensitivity (95% CI)	Specificity (95% CI)
	Patient Basis		Lesion Basis
BS	0.468 (0.398 to 0.537)	0.883 (0.829 to 0.936)	0.579 (0.526 to 0.632)	0.954 (0.924 to 0.984)
BS + SPECT	0.815 (0.706 to 0.923)	0.990 (0.973 to 1.000)	0.357 (0.198 to 0.516)	0.961 (0.921 to 1.000)
18FDG-PET	0.949 (0.912 to 0.986)	0.987 (0.972 to 1.000)	0.958 (0.942 to 0.974)	0.983 (0.969 to 0.996)
18FDG-PET/CT	0.977 (0.938 to 1.000)	0.959 (0.905 to 1.000)	0.978 (0.964 to 0.991)	0.978 (0.966 to 0.990)

BS = bone scan; CI = confidence interval; CT = computed tomography; ¹⁸FDG =18F fluorodeoxyglucose; PET = positron emission tomography; SPECT = single-photon emission computed tomography.

Overall, the sensitivity and specificity of ¹⁸FDG-PET and ¹⁸FDG-PET/CT were higher for detection of bone metastasis compared with bone scan with or without SPECT. The authors concluded that ¹⁸FDG-PET or PET/CT can be substituted for bone scanning with ^99mTc during a supply shortage. The radiation dose was reported to be higher for ¹⁸FDG-PET and PET/CT (range: 2.7 to 28 mSv) than bone scans (range: 4.2 to 5.7 mSv), and therefore should be a consideration. A major limitation of this report is that it was not stated whether the patients with known cancer were symptomatic/asymptomatic or if imaging was being conducted for staging purposes. The list of included studies evaluated patient populations that are likely very different. For example, one study evaluated bone imaging in high-risk prostate cancer patients and another in newly diagnosed lung cancer patients.

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Criterion 8: Relative risks associated with the test (link to definition)

Non-radiation Risks

Bone scanning
Several studies^44-47 reported mild adverse events with ^99mTc-labelled tracers (e.g., skin reactions) and one case report published in 1985 reported a patient who experienced a rash following two bone scans with ^99mTc-MDP, one in 1983 and one the following year.²³ The authors concluded this patient had an allergic reaction to MDP on both occasions. This case report references an older study that reported 22 adverse reactions to ^99mTc-MDP, in which 20 of the reactions were either "probably" or "possibly" caused by MDP.  

PET 
The Pharmacopeia Committee of the Society of Nuclear Medicine conducted a four-year prospective evaluation of adverse reactions to PET and reported no adverse reactions among the 33,925 scans conducted in 22 participating PET centres in the United States.⁴⁸

Radiation Exposure

Among the modalities available for bone tumour imaging, bone scanning and PET expose the patient to ionizing radiation. The average effective dose of radiation delivered with each of these procedures is shown in Table 7. For comparison, the average effective dose of natural background radiation to which individuals are exposed over a year duration is 3.0 mSv.²⁸

The radiation dose reported in the systematic review by Tateishi et al. was lower for bone scans (4.2 to 5.7 mSv) than ¹⁸FDG-PET and PET/CT (2.7 to 28 mSv).¹⁰ Another study reported that the calculated dose of radiation for a bone scan is 5 to 6 mSv.³⁹

Table 7: Effective Doses of Radiation^24,25

Procedure	Average Effective Dose (mSv)
Bone scan	6.3
Whole body PET	14.1
Average background dose of radiation per year	1 to 3.026-28

CT = computed tomography; mSv = millisievert; PET = positron emission tomography.

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Criterion 9: Relative availability of personnel with expertise and experience required for the test (link to definition)

Expertise

Reliability of the interpretation of bone scans (or other diagnostic imaging tests) by different readers (interobserver agreement) is routinely assessed using the kappa (?) score — a measure of agreement beyond that expected by chance alone.⁴⁹ A kappa score of less than 0.20 means poor agreement, 0.21 to 0.40 fair agreement, 0.41 to 0.60 moderate agreement, 0.61 to 0.80 good agreement, and 0.81 to 1.00 very good agreement.⁵⁰

Interobserver agreement of bone scans was compared in a retrospective study published in 2008 of 59 breast and prostate cancer patients.²⁹ Thirty-seven physicians with daily experience in reading bone scans were involved in the study. Clinical examination (including bone scan results, laboratory results, other diagnostic tests, and follow-up examination) of all patients by the same experienced physician was used as the gold standard. Pairwise comparisons between two different examiners were calculated for 666 pairs. The mean kappa coefficient between the observers was 0.48, which is classified as a "moderate" level of agreement. The mean kappa coefficient for inexperienced observers compared with the gold standard was 0.40, and the moderately experienced and experienced observers had a mean kappa coefficient of 0.51.

Interobserver agreement was also reported in the study by Balliu et al.³⁰ The agreement between two observers for bone scanning was low for a four-point scale (kappa index = 0.260) but moderate on a two-point scale (kappa index = 0.524). Takenaka et al.³¹ also reported interobserver agreement between tests. The kappa index was 0.67 for bone scanning and 0.65 for ¹⁸FDG-PET/CT, indicating substantial agreement with either test.

Personnel

Bone scintigraphy
In Canada, physicians involved in the performance, supervision, and interpretation of bone scans should be nuclear medicine physicians or diagnostic radiologists with training/expertise in nuclear imaging.⁵¹ Physicians should have a Fellowship of Certification in Nuclear Medicine or Diagnostic Radiology with the Royal College of Physicians and Surgeons of Canada and/or the Collège des médecins du Québec. Nuclear medicine technologists are required to conduct bone scans. Technologists must be certified by the Canadian Association of Medical Radiation Technologists (CAMRT) or an equivalent licensing body.

All alternative imaging modalities
Service engineers are needed for system installation, calibration, and preventive maintenance of the imaging equipment at regularly scheduled intervals. The service engineer's qualification will be ensured by the corporation responsible for service and the manufacturer of the equipment used at the site.

Qualified medical physicists (on site or contracted part-time) should be available for the installation, testing, and ongoing quality control of nuclear medicine equipment.⁵¹

PET 
In Canada, physicians involved in the performance, supervision, and interpretation of PET scans should be nuclear medicine physicians or diagnostic radiologists with training/expertise in nuclear imaging. Physicians should have a Fellowship of Certification in Nuclear Medicine or Diagnostic Radiology with the Royal College of Physicians and Surgeons of Canada and/or the Collège des médecins du Québec. Technologists must be certified by CAMRT or an equivalent licensing body.

A summary of the availability of personnel required for the conduct of bone tumour imaging, by bone scanning or any of the alternative imaging modalities, is provided in Table 8.

Table 8: Medical Imaging Professionals in Canada⁵²

Jurisdiction	Diagnostic Radiology Physicians	Nuclear Medicine Physicians	Nuclear Medicine Technologists	Medical Physicists
NL	46	3	15	NR
NS	71	5	71	NR
NB	47	3	55	NR
PEI	7	0	3	0
QC	522	90	460	NR
ON	754	69	693	NR
MB	58	8	42	NR
SK	61	4	36	NR
AB	227	18	193	NR
BC	241	21	212	NR
YT	0	0	0	0
NWT	0	0	1	0
NU	0	0	0	0
Total	2,034	221	1,781	322*

AB = Alberta; BC = British Columbia; MB = Manitoba; NB = New Brunswick; NL = Newfoundland and Labrador; NR = not reported by jurisdictions; NS = Nova Scotia; NU = Nunavut; NWT= Northwest Territories; ON = Ontario; PEI = Prince Edward Island; QC = Quebec; YT = Yukon.
*This represents a total for all of the jurisdictions.

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Criterion 10: Accessibility of alternative tests (equipment and wait times) (link to definition)

Wait Times

Wait-time benchmarks were reported by the Canadian Medical Association for the Wait Time Alliance (WTA) in 2005.²¹ For bone scanning and ¹⁸FDG-PET, the wait-time benchmark was immediate to 24 hours for an emergency case, within seven days for an urgent case, and within 30 days for a scheduled case. The WTA reported wait times for urgent bone scan as ranging from one to six days throughout the provinces, and for scheduled cases, the range was seven to 73 days.³²

Equipment

There are notable variations in the availability of medical imaging technologies within hospitals across Canada. Nuclear medicine cameras are not available in the Yukon, the Northwest Territories, and Nunavut. Table 9 provides an overview of the availability of equipment required to imaging bone metastases. Data for nuclear medicine cameras (including SPECT) are current to January 1, 2007. The number of SPECT/CT scanners is current to January 1, 2010. Information on the availability of PET and PET/CT scanners is current to November 30, 2010.

Bone scanning
For bone scintigraphy, nuclear medicine facilities with gamma cameras (including SPECT) are required. Three jurisdictions — the Yukon, the Northwest Territories, and Nunavut — do not have any nuclear medicine equipment.⁵²

PET 
A 2010 Environmental Scan published by us reported that approximately 31 Canadian centres are equipped to perform PET scans.³³ These centres are located in the provinces of British Columbia, Alberta, Manitoba, Ontario, Quebec, New Brunswick, and Nova Scotia.³³ There are 36 PET or PET/CT scanners, four of which are used for research purposes only.³³

Table 9: Diagnostic Imaging Equipment in Canada^33,52,53

	Nuclear Medicine Cameras	SPECT/CT Scanners	PET or PET/CT Scanners
Number of devices	60352	9653	3633
Average number of hours of operation per week (2006-2007)52	40	NA	NA
Provinces and Territories with no devices available	YT, NT, NU	PEI, YT, NT, NU	NL, PEI, SK, YT, NT, NU

NA = not available; NS = Nova Scotia; NT = Northwest Territories; NU = Nunavut; PEI = Prince Edward Island; YT = Yukon.

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Criterion 11: Relative cost of the test (link to definition)

Fee codes from the Ontario Schedule of Benefits were used to estimate the relative costs of bone scanning and its alternatives. Technical fees are intended to cover costs incurred by the hospital (i.e., radiopharmaceutical costs, medical/surgical supplies, and non-physician salaries). Maintenance fees are not billed to OHIP — estimates here were provided by St. Michael's Hospital in Toronto. Certain procedures (i.e., PET scan) are paid for, in part, out of the hospital's global budget; these estimates were provided by The Ottawa Hospital. It is understood that the relative costs of imaging will vary from one institution to the next.

According to our estimates (Table 10), the cost of whole body bone scan with ^99mTc-based radioisotopes is $278.70. ¹⁸F-PET and ¹⁸FDG-PET are significantly more costly alternatives.

Table 10: Cost Estimates Based on the Ontario Schedule of Benefits for Physician Services Under the Health Insurance Act (September 2011)⁵⁴

Fee Code	Description	Tech. Fees ($)	Prof. Fees ($)	Total Costs ($)
Whole Body Bone Scan
J850	Bone scintigraphy — general survey	106.35	62.80	169.15
J866	Application of tomography (SPECT), maximum one per nuclear medicine examination	44.60	31.10	75.70
Maintenance fees — global budget		33.85		33.85
TOTAL		184.80	93.90	278.70
18F-PET
J706	NSCLC		250.00	250.00
Technical cost — from global budget		600.00		600.00
TOTAL		600.00	250.00	850.00
18FDG-PET
J706	NSCLC		250.00	250.00
Technical cost — from global budget		800.00		800.00
TOTAL		800.00	250.00	1,050.00

CT = computed tomography; ¹⁸F = 18F-fluoride; ¹⁸FDG = 18F-fluorodeoxyglucose; NSCLC = non–small cell lung cancer; PET = position emission tomography; prof = professional; SPECT = single-photon emission computed tomography; tech. = technical.

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Appendix 1: Multi-Criteria Decision Analysis Definitions

Domain 1: Criteria Related to the Underlying Health Condition
Criterion	Definition
1. Size of the affected population	The estimated size of the patient population that is affected by the underlying health condition and that may potentially undergo the test. The ideal measure is point prevalence, or information on how rare or common the health condition is.
2. Timeliness and urgency of test results in planning patient management	The timeliness and urgency of obtaining the test results in terms of their impact on the management of the condition and the effective use of health care resources.
3. Impact of not performing a diagnostic imaging test on mortality related to the underlying condition	Impact of not performing the test, in whatever way, on the expected mortality of the underlying condition. Measures could include survival curves showing survival over time and/or survival at specific time intervals with and without the test.
4. Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition	Impact of not performing the test, in whatever way, on the expected morbidity or on the quality of life reduction of the underlying condition. Measures of impact may include natural morbidity outcome measures such as events or disease severity, or might be expressed using generic or disease-specific quality of life rating scales, with and without the test.
Domain 2: Criteria Comparing 99mTc with an Alternative, or Comparing between Clinical Uses
Criterion	Definition
5. Relative impact on health disparities	Health disparities are defined as situations where there is a disproportionate burden (e.g., incidence, prevalence, morbidity, or mortality) amongst particular population groups (e.g., gender, age, ethnicity, geography, disability, sexual orientation, socioeconomic status, and special health care needs). Impact on health disparities is assessed by estimating the proportion of current clients of the technetium-99m (99mTc)-based test that are in population groups with disproportionate burdens. (Explanatory note: The implication of this definition is that, everything else being the same, it is preferable to prioritize those clinical uses that have the greatest proportion of clients in groups with disproportionate burdens.)
6. Relative acceptability of the test to patients	Acceptability of the 99mTc-based test from the patient's perspective compared with alternatives. Patient acceptability considerations include discomfort associated with the administration of the test, out-of-pocket expenses or travel costs, factors that may cause great inconvenience to patients, as well as other burdens. This criterion does not include risks of adverse events but is about everything related to the experience of undergoing the test.
7. Relative diagnostic accuracy of the test	Ability of the test to correctly diagnose the patients who have the condition (sensitivity) and patients who do not have the condition (specificity) compared with alternatives.
8. Relative risks associated with the test	Risks associated with the test (e.g., radiation exposure, side effects, adverse events) compared with alternatives. Risks could include immediate safety concerns from a specific test or long-term cumulative safety concerns from repeat testing or exposure.
9. Relative availability of personnel with expertise and experience required for the test	Availability of personnel with the appropriate expertise and experience required to proficiently conduct the test and/or interpret the test findings compared to alternatives.
10. Accessibility of alternatives (equipment and wait times)	Availability (supply) of equipment and wait times for alternative tests within the geographic area. Includes consideration of the capacity of the system to accommodate increased demand for the alternatives. Excludes any limitation on accessibility related to human resources considerations.
11. Relative cost of the test	Operating cost of test (e.g., consumables, health care professional reimbursement) compared with alternatives.

 

Appendix 2: Literature Search Strategy

OVERVIEW
Interface:		Ovid
Databases:		Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present EBM Reviews - Cochrane Database of Systematic Reviews 2005 to February 2011 EBM Reviews - Database of Abstracts of Reviews of Effects 1st Quarter 2011 EBM Reviews - Cochrane Central Register of Controlled Trials 1st Quarter 2011 EBM Reviews - Health Technology Assessment 1st Quarter 2011 EBM Reviews - NHS Economic Evaluation Database 1st Quarter 2011  Note: Duplicates between databases were removed in Ovid.
Date of Search:		March 14, 2011
Alerts:		Monthly search updates began March 14, 2011 and ran until October 2011.
Study Types:		Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies, and diagnostic accuracy studies.
Limits:		English language Humans No date limits for systematic reviews; publication years Jan 2006 to March 2011 for primary studies.
SYNTAX GUIDE
/	At the end of a phrase, searches the phrase as a subject heading
MeSH	Medical subject heading
.fs	Floating subheading
exp	Explode a subject heading
*	Before a word, indicates that the marked subject heading is a primary topic; or, after a word, a truncation symbol (wildcard) to retrieve plurals or varying endings
?	Truncation symbol for one or no characters only
ADJ	Requires words are adjacent to each other (in any order)
ADJ#	Adjacency within # number of words (in any order)
.ti	Title
.ab	Abstract
.hw	Heading word: usually includes subject headings and controlled vocabulary
.tw	Text word: searches title, abstract, captions, and full text
.mp	Keyword search: includes title, abstract, name of substance word, subject heading word and other text fields
.pt	Publication type
.nm	Name of substance word: used to search portions of chemical names and includes words from the CAS Registry/EC Number/Name (RN) fields
.jw	Journal words: searches words from journal names
/du	Diagnostic use
/ri	Radionuclide imaging

 

Multi-database Strategy
#	Searches
Bone tumours concept
1	exp Bone Neoplasms/
2	exp Neoplasms, Bone Tissue/
3	Chondrosarcoma/
4	Bone Marrow Neoplasms/
5	((bone or bony or skeletal* or skeleton* or spine or spines or spinal or orbital* or skull* or nose or nasal or jaw or jaws or maxillary or mandible or femoral* or femur or saccrococcygeal or sacroccyx or osseus or osteolytic or osteoblastic or osteoid) adj3 (metastatic or metastases or metastasis or neoplasm* or cancer* or tumor* or tumour* or malignanc* or carcinoma* or sarcoma*)).ti,ab.
6	(osteosarcoma* or osteogenic sarcoma*).ti,ab.
7	MBD.ti,ab.
8	(chondrosarcoma* or Ewing* sarcoma* or ESFT? or chordoma* or adamantinoma*).ti,ab.
9	(osteoma* or osteochondroma* or osteoblastoma*).ti,ab.
10	or/1-9
Radionuclide imaging concept
11	Technetium/ or exp Technetium Compounds/ or exp Organotechnetium Compounds/ or exp Radiopharmaceuticals/
12	Radionuclide Imaging/
13	(Technetium* or Tc-99 or Tc99 or Tc-99m or Tc99m or 99mTc or 99m-Tc).ti,ab,nm.
14	radioisotope*.ti,ab.
15	((radionucl* or nuclear or radiotracer*) adj2 (imag* or scan* or test* or diagnos*)).ti,ab.
16	Tomography, Emission-Computed, Single-Photon/
17	(single-photon adj2 emission*).ti,ab.
18	(SPECT or scintigraph* or scintigram* or scintiphotograph*).ti,ab.
19	exp Bone Neoplasms/ri
20	exp "Bone and Bones"/ri
21	Technetium Tc 99m Medronate/
22	(medronate or methyl diphosphonate).ti,ab.
23	((bone or MDP) adj2 (imaging or scan*)).ti.
24	or/11-23
25	10 and 24
Filter: human studies
26	exp animals/
27	exp animal experimentation/
28	exp models animal/
29	exp animal experiment/
30	nonhuman/
31	exp vertebrate/
32	animal.po.
33	or/26-32
34	exp humans/
35	exp human experiment/
36	human.po.
37	or/34-36
38	33 not 37
39	(comment or newspaper article or editorial or letter or note).pt.
40	25 not (38 or 39)
Filter: randomized controlled trials, non-randomized studies, diagnostic accuracy
41	Randomized Controlled Trial.pt.
42	Controlled Clinical Trial.pt.
43	(Clinical Trial or Clinical Trial, Phase II or Clinical Trial, Phase III or Clinical Trial, Phase IV).pt.
44	Multicenter Study.pt.
45	(random* or sham or placebo*).ti.
46	((singl* or doubl*) adj (blind* or dumm* or mask*)).ti.
47	((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti.
48	(control* adj3 (study or studies or trial*)).ti.
49	(non-random* or nonrandom* or quasi-random* or quasirandom*).ti.
50	(allocated adj "to").ti.
51	Cohort Studies/
52	Longitudinal Studies/
53	Prospective Studies/
54	Follow-Up Studies/
55	Retrospective Studies/
56	Case-Control Studies/
57	Cross-Sectional Study/
58	(observational adj3 (study or studies or design or analysis or analyses)).ti.
59	cohort.ti.
60	(prospective adj7 (study or studies or design or analysis or analyses or cohort)).ti.
61	((follow up or followup) adj7 (study or studies or design or analysis or analyses)).ti.
62	((longitudinal or longterm or (long adj term)) adj7 (study or studies or design or analysis or analyses or data or cohort)).ti.
63	(retrospective adj7 (study or studies or design or analysis or analyses or cohort or data or review)).ti.
64	((case adj control) or (case adj comparison) or (case adj controlled)).ti.
65	(case-referent adj3 (study or studies or design or analysis or analyses)).ti.
66	(population adj3 (study or studies or analysis or analyses)).ti.
67	(cross adj sectional adj7 (study or studies or design or research or analysis or analyses or survey or findings)).ti.
68	Comparative Study.pt.
69	(Validation Studies or Evaluation Studies).pt.
70	exp "Sensitivity and Specificity"/
71	False Positive Reactions/
72	False Negative Reactions/
73	(sensitivit* or distinguish* or differentiat* or enhancement or identif* or detect* or diagnos* or accura* or comparison*).ti.
74	(predictive adj4 value*).ti,ab.
75	or/41-74
76	75 not case reports.pt.
77	40 and 76
Results: primary studies
78	limit 77 to english language [Limit not valid in CDSR,ACP Journal Club,DARE,CCTR,CLCMR; records were retained]
79	limit 78 to yr="2006 -Current" [Limit not valid in DARE; records were retained]
80	remove duplicates from 79
Filter: health technology assessments, systematic reviews, meta-analyses
81	meta-analysis.pt.
82	meta-analysis/ or systematic review/ or meta-analysis as topic/ or exp technology assessment, biomedical/
83	((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).ti,ab.
84	((quantitative adj3 (review* or overview* or synthes*)) or (research adj3 (integrati* or overview*))).ti,ab.
85	((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).ti,ab.
86	(data synthes* or data extraction* or data abstraction*).ti,ab.
87	(handsearch* or hand search*).ti,ab.
88	(mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*).ti,ab.
89	(met analy* or metanaly* or health technology assessment* or HTA or HTAs).ti,ab.
90	(meta regression* or metaregression* or mega regression*).ti,ab.
91	(meta-analy* or metaanaly* or systematic review* or biomedical technology assessment* or bio-medical technology assessment*).mp,hw.
92	(medline or Cochrane or pubmed or medlars).ti,ab,hw.
93	(cochrane or health technology assessment or evidence report).jw.
94	(meta-analysis or systematic review).md.
95	or/81-94
96	40 and 95
Results: health technology assessments, systematic reviews, meta-analyses
97	limit 96 to english language [Limit not valid in CDSR,ACP Journal Club,DARE,CCTR,CLCMR; records were retained]
98	remove duplicates from 97

 

OTHER DATABASES
PubMed	Same MeSH, keywords, limits, and study types used as per MEDLINE search, with appropriate syntax used.

 

GREY LITERATURE SEARCHING
Dates for Search:	March 10 to 18, 2011
Keywords:	Included terms for bone cancer, bone tumours, and diagnostic imaging
Limits:	Focus on publication years 2005 to present.

The following sections of the grey literature checklist, "Grey matters: a practical search tool for evidence-based medicine" (http://www.cda-amc.ca/grey-matters), were searched:

• Health Technology Assessment Agencies (selected)
• Clinical Practice Guidelines
• Databases (free)
• Internet Search

 

Appendix 3: ACR Appropriateness Criteria^40-42

The American College of Radiology (ACR) uses a modified Delphi process to reach its appropriateness criteria. ACR authors first review relevant information and create a summary. This summary is reviewed by clinicians and other medical professionals. The process allows for the incorporation of expert consensus when published evidence is lacking. A panel of experts rates the information to determine appropriateness of the imaging intervention.

Appropriateness is rated between 1 and 9 and is grouped into three categories: "usually not appropriate" (scores of 1, 2, and 3) or as not indicated in a certain clinical setting and unlikely to have a favourable risk-benefit ratio for patients; "maybe appropriate" (scores of 4, 5, and 6) or as potentially indicated in certain clinical settings and having potential to have an equivocal risk-benefit for patients; and "usually appropriate" (scores of 7, 8, and 9) or as indicated in certain clinical settings and having a favourable risk-benefit ratio for patients. All ratings are based on peer-reviewed literature and the opinions of the expert panel. The expert panel must reach consensus (defined as 80% agreement) after three rounds of scoring before the ACR appropriateness scores are finalized.

Table 12: American College of Radiology Appropriateness Criteria

Breast Cancer
Type: Stage I carcinoma — initial presentation is asymptomatic
Modality	Rating and comments
99mTc bone scan — whole body	Rating = 1 ("usually not appropriate")
Myelography and post-myelography CT spine	Rating = 1 ("usually not appropriate")
MRI with or without contrast — area of interest	Rating = 1 ("usually not appropriate")
18FDG-PET scan — whole body	Rating = 1 ("usually not appropriate")
Type: Stage I carcinoma — purpose is to rule out bone metastases
Modality	Rating and comments
99mTc bone scan — whole body	Rating = 2 ("usually not appropriate")
18FDG-PET scan — whole body	Rating = 2 ("usually not appropriate")
Type: Stage II carcinoma — presenting with back and hip pain
Modality	Rating and comments
99mTc bone scan — whole body	Rating = 9 ("usually appropriate")
99mTc bone scan (with SPECT) — hip and spine	Rating = 1 ("usually not appropriate")
Myelography and post-myelography CT spine	Rating = 1 ("usually not appropriate")
CT (with or without contrast) — hip and spine	Rating = 1 ("usually not appropriate")
MRI (with or without contrast) — hip and spine	Rating = 1 ("usually not appropriate")
18FDG-PET scan — whole body	Rating = 5 ("may be appropriate")
Type: Known bone metastatic disease — presenting with pathological fracture of left femur on x-ray
Modality	Rating and comments
99mTc bone scan — whole body	Rating = 9 ("usually appropriate")
18FDG-PET scan — whole body	Rating = 5 ("may be appropriate"); if bone scan is negative, findings on PET will influence the use of systemic treatment.
CT without contrast — femur	Rating = 1 ("usually not appropriate")
MRI without contrast — femur	Rating = 1 ("usually not appropriate")
Prostate Cancer
Type: Nodule on physical exam; moderately or well-differentiated carcinoma; PSA < 20mg/mL; asymptomatic patients
Modality	Rating and comments
99mTc bone scan — whole body	Rating = 1 ("usually not appropriate")
CT with or without contrast — area of interest	Rating = 1 ("usually not appropriate")
MRI with or without contrast — area of interest	Rating = 1 ("usually not appropriate")
18FDG-PET scan — whole body	Rating = 1 ("usually not appropriate")
Type: Nodule on physical exam; poorly differentiated carcinoma; PSA ³ 20mg/mL; asymptomatic patients
Modality	Rating and comments
99mTc bone scan — whole body	Rating = 9 ("usually appropriate")
CT with or without contrast — area of interest	Rating = 1 ("usually not appropriate")
MRI with or without contrast — area of interest	Rating = 1 ("usually not appropriate")
18FDG-PET scan — whole body	Rating = 1 ("usually not appropriate")
Lung Cancer
Type: 1 cm lung nodule; NSCLC at needle biopsy — presenting for staging and resection
Modality	Rating and comments
99mTc bone scan — whole body	Rating = 9 ("usually appropriate"); not needed if a PET scan is performed for initial nodule workup.
18FDG-PET scan — whole body	Rating = 9 ("usually appropriate")
CT without contrast — chest	Rating = 1 ("usually not appropriate")
MRI without contrast — chest	Rating = 1 ("usually not appropriate")
Type: Non-invasive staging of NSCLC
Modality	Rating and comments
99mTc bone scan — whole body	Rating = 5 ("may be appropriate"); not needed if a PET scan has been performed
18FDG-PET scan — skull base to mid-thigh	Rating = 9 ("usually appropriate"); attenuation correction by radionuclide or CT
CT with or without contrast — chest	Rating = 9 ("usually appropriate"); contrast is preferred if not contraindicated
CT with contrast —abdomen	Rating = 5 ("may be appropriate"); contrast is preferred if not contraindicated
CT with contrast — head	Rating = 5 ("may be appropriate"); used if MRI is contraindicated and the patient has neurological symptoms
MRI with or without contrast — head	Rating = 7 ("usually appropriate"); if the patient has neurological symptoms; or if the patient is asymptomatic, but the tumour is > 3 cm and has adenocarcinoma histology or mediastinal adenopathy
MRI with or without contrast — chest	Rating = 3 ("usually appropriate"); evaluating chest wall or cardiac invasion and for local staging of superior sulcus tumours.

CT = computed tomography; ¹⁸FDG = 18F-fluorodeoxyglucose; MRI = magnetic resonance imaging; NSCLC = non–small cell lung cancer; PET = positron emission tomography; PSA = prostate-specific antigen; SPECT = single-photon emission computed tomography; ^99mTc = technetium-99m.

 

Appendix 4: Study Details

Table 13: Objective and Details of Study Design of the Included Primary Studies

Study	Objective	Population	Intervention and Comparator	Study Design	Location
Breast Cancer
Morris et al. 201011	To compare the diagnostic performance of BS and PET/CT in women with suspected metastatic breast cancer	All women undergoing evaluation of suspected metastatic breast cancer between 2003 and 2008 Excluded patients with a previous history of metastatic breast cancer or active secondary malignancy	Intervention: whole body bone scan with 99mTc-MDP Comparator: PET/CT from mid-skull to upper thighs	Retrospective cohort	Single centre in the United States
Port et al. 200612	To determine the utility of FDG-PET compared with conventional imaging in evaluating the extent of disease in patients with high-risk, operable breast cancer	Patients who presented for operative treatment of breast cancer between 2001 and 2004 who had high-risk disease, defined as: Tumour size > 5 cm (T3) and/or clinically positive lymph nodes (N1/2)	Intervention: whole body bone scan with 99mTc-MDP and CT of the chest, abdomen, and pelvis (conventional imaging) Comparator: FDG-PET	Prospective cohort	Single centre in the United States
Lung Cancer
Nosotti et al. 200813	To compare preoperative staging using PET and conventional imaging technologies	Patients with proven or strongly suspected lung cancer referred to a thoracic surgery unit between 1999 and 2004 Proven NSCLC, pulmonary mass positive to PET, no history of previous cancer, no history of severe diabetes mellitus	Intervention: bone scan (radiopharmaceutical not identified) Comparator: whole body FDG-PET	Prospective cohort	Single centre in Italy
Fischer et al. 200714	To examine PET/CT compared with conventional staging in patients with SCLC	Patients older than 18 years with histological or cytological proven SCLC were enrolled between 2003 and 2004 Patients with type 1 diabetes mellitus, known former or current malignancy other than SCLC, claustrophobia, pregnancy	Intervention: whole body bone scan with 99mTc oxydronate, bone marrow analysis, and CT scan Comparator: PET/CT (FDG-PET) from head to upper thigh	Prospective cohort	Denmark Number of centres not reported
Prostate
Meirelles et al. 201015	To evaluate BS and FDG-PET in patients with progressing metastatic prostate cancer	Patients with progressive prostate cancer who were enrolled in a prospective study between 1997 and 2000 Included those with at least 5 years of follow-up with histologically proven adenocarcinoma of the prostate and progression of disease as indicated from increasing PSA and an abnormality on imaging with BS, CT, or MRI that was consistent with bone metastases	Intervention: bone scan with 99mTc-MDP Comparator: whole-body FDG-PET	Prospective	United States Number of centres not reported

BS = bone scan; CT = computed tomography; ¹⁸FDG =18F fluorodeoxyglucose; MRI = magnetic resonance imaging; NSCLC = non–small cell lung cancer; NS = no studies; PSA = prostate specific antigen; PET = positron emission tomography; SCLC = small cell lung cancer; T = tesla; ^99mTc = technetium-99m; ^99mTc-MDP = technetium-99m–labelled methylene diphosphonate.

Table 14: Patient Characteristics, Diagnostic Accuracy, Conclusions, and Limitations of the Included Primary Studies

Study	Patient Characteristics	Diagnostic Accuracy	Conclusions	Limitations
Breast Cancer
Morris et al. 201011	N = 163 Suspicious symptoms: 84% Stages I to III breast cancer diagnosed > 12 weeks prior to imaging: 58% Estrogen receptor positive: 55% Progesterone receptor positive: 41% HER2 positive: 24%	Concordance between BS and 18FDG-PET/CT: 81% (132 of 163 studies) For the 31 patients with discordant findings: 18 had positive 18FDG-PET/CT and negative BS 2 had negative 18FDG-PET/CT and positive BS The remaining 11 patients had equivocal findings on one of the imaging techniques	There is a high degree of concordance between imaging techniques, suggesting that they could be redundant. 18FDG-PET/CT may be superior to BS for detecting metastases in patients with breast cancer.	Only patients who underwent both imaging modalities were included, which could limit the generalizability of the findings. 18FDG-PET/CT was reserved for patients with diagnostic uncertainty, which could also affect the generalizability of the findings. No analysis according to stage Sensitivity and specificity were not computed. Single-centre study Authors stated that their sample reflected a subgroup of patients with breast cancer.
Port et al. 200612	N = 80 Histological characteristics: Ductal: 78.8% Lobular: 7.5% Unknown/other: 13.8% Clinical stage at presentation: IIB: 50% Occult primary: 8.8% IIIA: 26.2% Locoregional recurrence: 15.0% Node status: Positive: 83.6% Negative: 16.4%	Sensitivity: Conventional imaging — 80% 18FDG-PET — 80% Specificity: Conventional imaging — 79% 18FDG-PET — 94%	The use of PET for determining the extent of disease in patients with breast cancer may be appropriate in selected patients at high risk for having relevant findings.	BS was in combination with CT No analysis according to stage Did not report whether patients were symptomatic Some scans were performed at outside facilities, not the study centre Single staff radiologist interpreted the images, which could affect generalizability. Single-centre study Did not report results according to stage of cancer.
Lung Cancer
Nosotti et al. 200813	N = 413 Adenocarcinoma — 64.8% Squamous cell carcinoma: 30.2% Large cell carcinoma: 5%	Sensitivity: BS — 67% 18 FDG-PET — 96% Specificity: BS — 94% 18 FDG-PET — 99% PPV: BS — 64% 18 FDG-PET — 98% NPV: BS — 95% 18 FDG-PET — 99%	PET imaging strategy is more accurate than conventional imaging for the detection of metastases.	Few patient characteristics reported. Unclear if patients were symptomatic or asymptomatic Single-centre study No information on the radiopharmaceutical used for the bone scan. No information about image interpretation or blinding of the individual(s) interpreting images was reported. Did not report results according to stage of cancer.
Fischer et al. 200714	N = 29 Final stage: Limited disease — 24% Extensive disease — 59% Undetermined — 18%	Sensitivity for bone metastases: BS — 75% 18FDG-PET/CT — 80% Specificity for bone metastases: BS — 58% 18FDG-PET/CT — not reported 18FDG-PET/CT suggested a different stage than conventional staging in 17% of patients (n = 5)	There is most likely a role for 18FDG-PET/CT in the staging of SCLC, but larger trials are needed before conclusions can be made.	Few patient characteristics reported. Unclear if patients were symptomatic or asymptomatic Specificity of 18FDG-PET/CT for bone metastases not reported Sample size of 29 patients Unclear how patients were selected for inclusion (i.e., if all patients who reported for staging during the study period were included or whether the study involved a selected population). Did not report results according to stage of cancer.
Prostate
Meirelles et al. 201015	N = 51 Castrate-resistant disease: 76% No other characteristics reported	BS detected bone metastases in significantly (P = 0.01) more patients than 18FDG-PET. Detection of metastases: BS: 86.1% 18FDG-PET: 72.1% Discordance between techniques: 18FDG-PET positive, BS negative: 0% 18FDG-PET negative, BS positive: 14%	In patients with progressing prostate cancer, bone metastases are readily identifiable on 18FDG-PET.	Unclear if the same radiologist and nuclear medicine physician interpreted all images. Did not report sensitivity and specificity. Limited patient characteristics reported. Did not report results according to stage of cancer. High risk patients — could potentially limit generalizability to other patients with prostate cancer.

BS = bone scan; CT = computed tomography; ¹⁸FDG =18F fluorodeoxyglucose; HER2 = Human Epidermal Growth Factor Receptor 2; MRI = magnetic resonance imaging; NPV = negative predictive value; NSCLC = non–small cell lung cancer; NS = no studies; PET = positron emission tomography; PPV = positive predictive value; PSA = prostate specific antigen; SCLC = small cell lung cancer.