Johannes Czernin • Ken Herrmann
This chapter discusses the role of radionuclide imaging and therapy in the management of primary and metastatic bone tumors. We are reviewing the epidemiology of primary and metastatic bone disease, its classification, and staging definitions. We then address the role of radionuclide imaging in initial and subsequent treatment strategy considerations. Throughout the chapter we will emphasize the sometimes unique and at other times complimentary role of radionuclide approaches as an important component of the management of patients with primary or metastatic bone cancer and are providing guidelines for the appropriate use and applications of diagnostic radionuclide approaches for the assessment of bone diseases. We also present overviews of imaging protocols whereby we follow the guidelines of the Society of Nuclear Medicine and Molecular Imaging (whenever available). Finally, we will discuss radionuclide-based treatment approaches for malignant bone diseases.
The chapter will first focus on primary bone tumors by highlighting the three major types—osteosarcoma, chondrosarcoma, and Ewing sarcoma. The role of imaging in multiple myeloma will be discussed separately. In the subsequent sections we will review the role of radionuclide imaging in metastatic prostate, breast, and lung cancer in the context of other available diagnostic imaging approaches. The ability of hybrid imaging technologies to achieve improved diagnostic accuracy will be emphasized. When appropriate we will discuss the potential role of emerging PET imaging probes for assessing bone malignancies. Finally, we are reviewing the availability and effectiveness of radionuclide-based therapeutic approaches for malignant bone diseases.
PRIMARY BONE TUMORS
Classification and Epidemiology
Primary malignant bone tumors occur at an incidence of about 8/106 persons and account for less than 0.5% of all cancers. They have been classified by the World Health Organization (WHO) based on histology and differentiation (Table 24.1).1 A total of 2,890 new cases of primary bone cancers (excluding myeloma) were predicted in the United States and 1,410 patients were expected to die from primary bone cancer in 2012.2 Approximately 55% of primary bone malignancies occur in males. Osteosarcomas, chondrosarcomas, and Ewing sarcomas account for approximately 35%, 30%, and 16% of primary bone malignancies, respectively.3,4 Osteosarcoma and Ewing sarcoma occur mainly in children and young adults whereas chondrosarcoma has a predilection for older patients.
Osteosarcoma arises most frequently from the metaphyses of long bones, in particular the distal femur, proximal tibia, and proximal humerus5 and its incidence ranges from 3.5 to 5.6 per year per million persons.6 At 2.4%, osteosarcoma ranks eighth among childhood cancers following leukemia (30%), brain and other nervous system cancers (22.3%), neuroblastoma (7.3%), Wilms tumor (5.6%), non-Hodgkin lymphoma (4.5%), rhabdomyosarcoma (3.1%), and retinoblastoma (2.8%).6 Approximately 400 individuals younger than 20 years are diagnosed with osteosarcoma annually in the United States.7
Extraosseous osteosarcoma is a malignant mesenchymal neoplasm without direct attachment to the skeletal system. Although it occurs at any age, its incidence peaks in the second and third decades5 and ranges from 3.5 to 5.6 per year per million persons.6
The incidence of chondrosarcomas is around 3/106 people. They are most frequently located in the femur, pelvis, and humerus. Eighty-five percent arise as primary lesions whereas the remaining 15% develop in initially benign lesions such as enchondromas or osteochondromas (secondary chondrosarcomas). They are characterized by production of cartilaginous matrix.
The incidence of Ewing sarcoma family of tumors (ESFTs) has remained unchanged for 30 years at approximately 2/1,000,000 per year.8 It peaks at 9 to 10/1,000,000 in patients 10 to 19 years of age and occurs nine times more frequently in Caucasians than in African Americans.9 The most frequent primary sites are the lower extremity (41%), pelvis (26%), chest wall (16%), and upper extremity (9%). Extraosseous Ewing sarcoma occurs most frequently in the trunk (32%), extremity (26%), head and neck (18%), and retroperitoneum (16%).10
Diagnosis of Primary Malignant Bone Tumors
Workup for the diagnosis of primary bone tumors is prompted by symptoms such as painful swelling, limited limb motion, or bone fracture.11 However, patients may also present following trauma which may obscure the diagnosis. A plain film x-ray is performed first that can frequently provide the diagnosis.12,13 Suspicious x-ray findings lead invariably to a biopsy, frequently after an MRI scan is performed. Biopsy usually provides the definitive diagnosis and identifies the histologic subtype.
WORLD HEALTH ORGANIZATION CLASSIFICATION OF MALIGNANT BONE TUMORS
Osteosarcomas must, by definition, produce osteoid.14 The osteosarcoma subtypes are depicted in Table 24.1.1 The most prevalent variant, conventional central osteosarcoma, features areas of necrosis, atypical mitoses, and contains malignant osteoid. The other osteosarcoma subtypes are much less common, each occurring at a frequency of less than 5%.
Chondrosarcomas are characterized by the production of cartilage tissue (Table 24.1).
Ewing sarcomas and Askin tumors (primitive neuroectodermal tumors [PNETs] of the chest wall) belong to the group of PNETs. All are derived from the same bone marrow–derived mesenchymal stem cell.15 They belong to the group of “small, round, blue-cell” tumors.16
Prognosis of Primary Bone Tumors
The prognosis of osteosarcomas is determined by histologic response to chemotherapy17 and is better in patients in whom clean surgical margins are achieved.18 The 5-year survival rates range from 60% to 70% but an average of only 10% to 30% for patients with metastatic disease at the time of diagnosis. Patient age is inversely correlated with higher survival6 rates in patients younger than 30 years of age.19 Fifty percent of osteosarcomas in patients older than 60 years are associated with pre-existing Paget disease. The prognosis of such patients is significantly worse than that of patients with primary osteosarcoma.20 However, these data were not confirmed in more recent studies.21,22
In adolescents and young adults with osteosarcoma, age 18 to 30 years is associated with a statistically significant poorer outcome because of an increased rate of relapse. This worse outcome is not explained by tumor location, histologic response, or metastatic disease at presentation.23 Other prognostic factors include radiologic evidence of lung, bone, or distant metastases.
Metastases are found in approximately 20% of patients at diagnosis, with 85% to 90% presenting in the lungs. The second most common site of metastasis is a single additional or multiple bones.24 The syndrome of multifocal osteosarcoma refers to a presentation with multiple foci of osteosarcoma without a clear primary tumor, often with symmetrical metaphyseal involvement. These tumors carry an extremely poor prognosis.25
Chondrosarcomas are relatively indolent. In a series of 201 patients, survival was 92% and 84% at 5 and 10 years, respectively. Outcome was associated with histologic grade.26 Overall 5-year survival was better than 75% in a study of more than 200 patients whereby patients with low-grade tumors had a significantly better outcome than those with high-grade disease.27 Survival of patients with high-grade variants ranges from 40% to 70%.28,29 However, dedifferentiated cancers carry 5-year survival rates of only 20%.30 In another report outcome was only associated with tumor proliferative activity.31 Pelvic location of the primary tumor denotes a less favorable prognosis. Local recurrence increases the risk for distant metastasis and is associated with poor survival.28,32
In the ESFTs, the 5-year survival of localized disease is currently around 70% but it is lower for patients aged 15 to 19 than for those younger than 15 years of age (76% versus 49%, respectively).33 The prognosis of early stage Ewing sarcoma patients depends on tumor location whereby pelvic location denotes a less favorable outcome.34 Twenty-six percent to 28% of the patients present with metastatic disease. Their 5-year survival is only around 40%.8,35–37 Among these, patients with lung involvement have better survival rates than those with bone metastases.38
Patient characteristics and outcomes differ among patients with extraosseous and those with skeletal Ewing sarcoma. The latter have a slightly better prognosis and are likely older, female, nonwhite, and more frequently have pelvic primary sites.39 Older age is a marker of poor prognosis.40 Moreover, patients with large tumors (maximal diameter >8 cm) have a poorer outcome than those with smaller tumors.41 Patients with primary tumors of the distal extremities have the best prognosis followed by those with proximal extremity and pelvic primaries38,40,42,43 whereas tumors of the sacrum carry the worst prognosis.44 Other prognostic parameters include age and gender, histopathologic treatment response,45 and pretreatment serum Lactate dehydrogenase (LDH) levels.42 As expected, presence of metastatic disease at the time of diagnosis carries a poor prognosis.46
AMERICAN JOINT COMMITTEE ON CANCER (AJCC) STAGING SYSTEM FOR OSTEOSARCOMA
Staging of Primary Bone Malignancies
In general all primary bone tumors are staged using the AJCC TNM system4 (Table 24.2); however, tumor grade is also included in the staging system. T1, T2, and T3 denote tumors that are <8 cm, >8 cm, or discontinuous, respectively, in the primarily affected bone. M1a signifies lung metastases whereas M1b indicates other distant disease sites. However, in osteosarcoma an older staging system is frequently still used. This system, proposed by Enneking in 198047 classifies low-grade bone tumors as stage I, high-grade tumors as stage II, and metastatic tumors as stage III. T1 denotes intracompartmental tumors whereas extracompartmental tumors are classified as T2.
The original AJCC staging system48 included presence or absence of lymph node involvement and added grade 3 (poorly differentiated) and grade 4 (undifferentiated) to further subclassify tumor differentiation.
Management of Patients with Primary Bone Tumors
Complete tumor resection in conjunction with systemic combination chemotherapy (with doxorubicin, ifosfamide, cisplatin, or high-dose methotrexate) is the first-line treatment of osteosarcoma. Surgery alone results in 5-year survival rates of only 15% to 20%. In early randomized trials the addition of adjuvant chemotherapy more than doubled49 or tripled 2-year disease-free survival rates.50 With the addition of adjuvant chemotherapy 5-year survival now averages 61%.51 The role of neoadjuvant therapy is not well established but tumor response to preoperative chemotherapy appears to be an independent prognosticator.43 Nonresectable patients appear to benefit from radiation treatment.52
Patients with chondrosarcoma have a relatively favorable prognosis.26 They are treated with surgery because these tumors are chemotherapy and radiation therapy resistant which is explained by their relatively low proliferative activity and poor vascularity.53 Wide en-bloc excision is necessary in intermediate- and high-grade lesions whereas low-grade lesions are treated with curettage.54 Radiation treatment may be effective in treating positive resection margins. Axial tumor sites (pelvis and spine) are difficult to treat surgically and thus, these disease sites are associated with a less favorable outcome.
Surgery is the treatment of choice in patients with Ewing sarcoma with local disease whereas primary radiation therapy is most frequently used in those with unresectable, nonmetastatic disease. Systemic chemotherapy with or without radiation treatment and surgery is used in patients with primary and metastatic disease. Chemotherapy usually includes vincristine, doxorubicin, ifosfamide, and etoposide and is usually given for 6 to 12 months. In patients younger than 30 years of age who underwent surgery or radiation treatment for local disease control the addition of ifosfamide and etoposide to a standard combination chemotherapy regimen improved 5-year survival to 69 ± 3 months.40 Chemotherapy is the treatment modality of choice in patients with metastatic disease; however, 5-year event-free survival only ranges from 20% to 30%.46,55
Traditionally, the treatment of extraosseous Ewing sarcoma has not included anthracyclines, a standard component of the treatment for primary Ewing sarcoma of bone. A recent study suggests, however, that a modified protocol including anthracyclines significantly improved 5-year survival from 59% to 83%. The outcome of patients with extraosseous Ewing sarcoma thus appears to be comparable to those with primary Ewing of the bone.56
ROLE OF IMAGING IN INITIAL TREATMENT STRATEGY ASSESSMENTS OF PRIMARY BONE TUMORS
A plain film x-ray, prompted by patient symptoms can frequently provide the diagnosis.12,13 The initial assessment of tumor site and tumor extent is used to define the best initial approach for local control, that is, surgery versus radiation. Radiographic patterns of osteoblastic, osteolytic (occurring in <10% of all cases), and mixed tumors (the most prevalent radiographic finding) have no prognostic significance.13 As another limitation, plain film radiographs provide no insights into the whole-body distribution of the disease.
In general, initial staging should include bone scintigraphy, chest x-rays, and chest CT if abnormalities are noted on plain films.57 18F-FDG PET and MRI are increasingly used for staging because local as well as distant sites of disease involvement can be characterized better. For instance, local disease may involve intra- and extramedullary structures. The extent of intramedullary involvement including skip metastases determines the extent of surgery. Involvement of extramedullary structures such as joints determines the feasibility of limb-saving surgery.58 Presence of distant disease involvement might alter the chemotherapeutic strategy. It should be noted that MRI is limited in its ability to detect lung involvement.
The Children’s Oncology Group (COG) Bone Tumor Committee has provided guidelines that specifically address imaging modalities at presentation prior to local control, at baseline after local control, surveillance on and post chemotherapy.36 They were established by an expert panel consisting of pediatric oncologists, biologists, surgeons, radiologists, and radiation oncologists and apply to children, adolescents, and young adults. They include recommendations for anatomical and functional imaging and can reasonably be also applied to older adults.
Imaging examinations at baseline are identical for osteosarcoma, chondrosarcoma, and Ewing sarcoma and first rely on plain film x-rays of the primary tumor.59 Advanced imaging methods are applied to determine the extent of tumors, possible involvement of adjacent bones, joints and muscles, vascular structures, and nerves. Figures 24.1–24.3 depict patients with osteosarcoma, chondrosarcoma, and Ewing sarcoma, respectively, imaged with plain film x-rays, conventional bone scans, and MRI.
FIGURE 24.1. A 7-year-old patient with right forearm pain after injury. Radiograph revealed an osteolytic lesion with cortical breakage in the distal radius (A). The lesion was hypervascular on dynamic flow phase (upper row, B)and showed increased blood pool activity (lower row, B). Whole-body bone scan confirmed a solitary lesion in the distal right radius (C). MRI showed an aggressive enhancing tumor (gadolinium) on T1-weighted image (D). There was disruption of the anterior cortex of the radius with extension into the flexor compartment of the forearm. CT-guided biopsy confirmed the lesion as osteosarcoma. (Reprinted with permission from Wang K, Allen L, Fung E, et al. Bone scintigraphy in common tumors with osteolytic components. Clin Nucl Med. 2005;30:655–671.)
Local staging is frequently considered to be best accomplished by MRI using T1-weighted sequences (Fig. 24.4).58 In an early study of 56 patients with primary bone sarcomas (predominantly osteosarcomas), MRI predicted bone disease extent with a significantly higher accuracy than CT or bone scintigraphy. Moreover, MRI was as accurate as CT in determining cortical bone and joint involvement and was more accurate in determining muscle involvement.60 However, a subsequent larger multicenter trial in 367 patients did not confirm these findings and reported a near equal accuracy of both modalities.61
Nevertheless, it could be argued that MRI should be the local staging modality of choice especially in the pediatric population to avoid the radiation exposure associated with CT. Advantages of CT imaging include the rapid image acquisition, more accurate assessment of lung involvement, and the identification of subtle cortical lesions and new bone formation.62
Assessment of metastatic disease is also necessary at initial presentation because 20% of patients with osteosarcoma and 25% of those with Ewing sarcoma present with metastases to lungs or bones. Metastases are rare in the initial presentation of chondrosarcoma. Noncontrast-enhanced CT is recommended for lung evaluations63; however, the limitations of CT in differentiating benign from malignant lung lesions are well established.64,65 Thus, biopsies are frequently needed for verification of the CT findings. MRI is ill-suited for lung assessments.
FIGURE 24.2. Chondrosarcoma: A 65-year-old female presented with painful left thigh swelling. Radiograph showed an expansile, lobulated osteolytic lesion with endosteal scalloping and spiculated periosteal reaction in the proximal femur (arrow, A). Irregular matrix calcification (arrowheads) was present. Bone scan revealed a solitary lesion with increased activity at its periphery compared to the center (B). The pathologic diagnosis was chondrosarcoma. (Reproduced with permission from Wang K, Allen L, Fung E, et al. Bone scintigraphy in common tumors with osteolytic components. Clin Nucl Med.2005;30:655–671.)
FIGURE 24.3. A 10-year-old boy presented with right forearm pain. Radiograph showed a permeative osteolytic lesion in the distal right ulna, with a spiculated and onion skin type of periosteal reaction (A). Bone scan revealed intense tracer accumulation at the corresponding site and also showed a pulmonary metastasis by demonstrating tracer accumulation in the right lung (arrows, B) which correlated to a lung mass on chest radiograph (not shown). Sagittal T1-weighted MRI showed the hypointense tumor mass (C). Biopsy of the forearm lesion showed Ewing sarcoma. (Reprinted with permission from Wang K, Allen L, Fung E, et al. Bone scintigraphy in common tumors with osteolytic components. Clin Nucl Med. 2005;30:655–671.)
FIGURE 24.4. A 13-year-old boy with distal femoral osteosarcoma. A: Lateral radiograph showing typical features of osteoblastic osteosarcoma. The relationship of intraosseous tumor to the growth plate cannot be determined. The proximal tumor margin is not included on the radiograph. B:99mTc-MDP bone scan indicates that tumor extends to the level of the growth plate. C: Sagittal T1-weighted spin echo MR image clearly demonstrates that tumor stops at least 1 cm short of the physis, permitting joint-sparing surgery. The proximal tumor margin is not included on the image. (Reprinted with permission from Saifuddin A. The accuracy of imaging in the local staging of appendicular osteosarcoma. Skeletal Radiol. 2002;31:191–201.)
Bone imaging using 99mTc-labeled diphosphonates is recommended for the initial evaluation of primary bone tumors. Small studies have suggested that 99mTc-MDP scans are more sensitive than 18F-FDG for bone metastases in osteosarcoma but not in Ewing sarcoma.64,66 However, this was not confirmed in a recent study in patients with bone and soft tissue sarcomas67 in which 18F-FDG PET/CT and 99mTc-MDP performed equally well in Ewing and osteosarcoma.
18F-FDG PET imaging can play a significant role in characterizing lung lesions64 and its use prior to local control, although not required, is recommended.68 Moreover, with the emergence of PET/CT imaging anatomical and functional information about primary tumors and distant metastases can now be obtained in a single session.69
The pooled accuracy of 18F-FDG PET for diagnosing and staging of bone sarcomas is around 90%.70 Moreover, 18F-FDG not 99mTc-MDP tumor-to-background ratios provided valuable prognostic information in patients with osteosarcoma.71
In contrast to the recent guidelines proposed by the COG,36 the guidelines of the European Society for Medical Oncology do not include 18F-FDG PET or PET/CT.14 This is inconsistent with the practice of many institutions where 18F-FDG PET/CT imaging has become an important component of the standard of care for osteosarcoma staging. The considerable adoption of 18F-FDG PET/CT is, at least in part, based on promising data from a prospective trial in 46 pediatric patients, 11 of which had osteosarcoma. In these patients bone metastases were equally well detected with 18F-FDG PET and conventional imaging including bone scans. Although lung metastases were significantly better detected with CT than PET the emergence of PET/CT renders this an insignificant advantage.64
18F-FDG PET/CT has also been used to predict progression-free and overall survival in osteosarcoma patients.71,72 High baseline SUV was associated with poor outcomes.
Skeletal scintigraphy is of limited value in chondrosarcoma. In a retrospective analysis of 188 patients planar bone imaging failed to add meaningful information to that obtained by MRI of the primary site.73 In fact, many additional sites of increased tracer activity were explained by degenerative joint disease, Paget disease, and in one case a previously undiagnosed melanoma metastasis. Thus, areas of focally increased uptake might result in a number of “false-positive” results.
Patients with Ewing sarcoma need to undergo bone marrow biopsies to rule out bone marrow involvement.11 The literature does not provide sufficient information about the utility of 18F-FDG PET/(CT) for staging of chondrosarcoma.
Because the diagnosis of bone cancer is made by biopsy the major role of imaging in developing the initial treatment strategy is the appropriate staging of the disease. A recent meta-analysis examined the accuracy of 18F-FDG PET/(CT) for staging (and restaging) of Ewing sarcoma.74 Based on a priori established quality criteria five studies that included a total of 279 patients were included. Pooled sensitivity and specificity were 96% and 92%, respectively. Although 18F-FDG PET/(CT) was in general more accurate than other imaging modalities, small lung metastases, as expected, tended to be better detected with chest CT.
18F-FDG PET was especially helpful in detecting bone metastases as confirmed in a prospective comparative trial of 18F-FDG and planar 99mTc-diphosphonate imaging.66 However, none of the major professional organizations currently endorses the routine use of 18F-FDG PET/(CT) for initial treatment strategy assessments in Ewing sarcoma.
Subsequent treatment strategy assessments for primary bone malignancies include restaging and monitoring of therapeutic interventions. Restaging or posttreatment surveillance includes AP and lateral x-rays of the primary site and the chest at 3-month intervals for the first 2 years, then in 6-month intervals for 5 to 10 years and subsequently at 6- to 12-month intervals.57 Chest CTs should be performed if plain film x-rays identify abnormalities and an abdominal MRI should be done if further interventions are contemplated. Bone scanning is optional and 18F-FDG PET/(CT) or MRI can be considered.57
The recommendations for treatment response assessments include plain films of the primary tumor, chest CT, bone scans, and optional 18F-FDG PET/(CT).36 Contrast-enhanced MRI should be considered if further interventions are contemplated. Plain films and CT should be done after 10 cycles of chemotherapy (approximately half way through chemotherapy).
Whole-body bone (unless negative at baseline) and 18F-FDG PET/(CT) scans (unless negative on baseline scan) are suggested at the end of cytotoxic treatment. In a mixed population of patients with Ewing sarcoma and osteosarcoma decreases in tumor SUV by ≥60% predicted histopathologic response to neoadjuvant chemotherapy with a good accuracy (Fig. 24.5).75 Similar findings were reported recently by others.76–78
However, the degree of changes in SUV that predicts histopathologic response might differ between Ewing sarcoma and Osteosarcoma.79 In fact, Ewing sarcoma responded to treatment with larger reductions in metabolic tumor volume (MTV) than osteosarcoma. A 50% reduction in MTV was associated with histopathologic response in osteosarcoma but not in Ewing sarcoma for which a 90% decrease in MTV was required.79 Thus, different 18F-FDG PET response criteria might apply to these two types of primary bone tumors.
In another study, 18F-FDG PET and MRI were performed prior to and after completion of neoadjuvant chemotherapy (Fig. 24.6).80 Reductions in tumor 18F-FDG uptake and absolute SUVmax at the end of treatment discriminated best among responders and nonresponders in osteosarcoma. MRI parameters including tumor volume changes, contrast enhancement, and changes in soft tissue component did not significantly discriminate responders from nonresponders. 18F-FDG PET was superior to MRI parameters for response predictions in osteosarcoma but not in Ewing sarcoma patients in whom both PET and MRI failed to provide reliable response assessments.
Another study reported that a posttreatment tumor SUV of <2.5 was associated with improved progression-free survival.81
FIGURE 24.5. FDG PET/CT at baseline, early follow-up, and late follow-up—after completion of neoadjuvant treatment in two patients with osteosarcoma. A histopathologic responder (top) and a nonresponder (bottom) are shown. Note the significant decrease in tumor 18F-FDG uptake in the responder whereas uptake increased in the nonresponder. (Reprinted with permission from Benz M, Czernin J, Tap W, et al. FDG PET/CT imaging predicts histopathologic treatment responses after neoadjuvant therapy in adult primary bone sarcomas. Sarcoma. 2010;2010:1–7.)
FIGURE 24.6. A 15-year-old girl with osteosarcoma of the left femur visualized by MRI prior to neoadjuvant treatment (top row): (left column, unenhanced T1-weighted; second column, T2-weighted; third column, contrast-enhanced fat-saturated T1-weighted) as well as FDG PET (right column). After neoadjuvant chemotherapy (bottom row), local MRI shows a stable tumor size (volume reduction 9%) and unchanged soft tissue component; patterns of T2 signal and contrast enhancement remained similar to baseline. FDG PET reveals a partial response with a reduction of 77%. Histopathologic evaluation confirmed good response to neoadjuvant chemotherapy. (Reprinted with permission from Denecke T, Hundsdörfer P, Misch D, et al. Assessment of histologic response of paediatric bone sarcomas using FDG PET in comparison to morphological volume measurement and standardized MRI parameters. Eur J Nuc Med Mol Imaging. 2010;37: 1842–1853.)
Taken together these 18F-FDG PET/CT data raise more questions than providing answers. First, all but one study were retrospective. Second, the proportion of patients with Ewing sarcoma versus Osteosarcoma varied. Third, no prospective trials have attempted to apply a response threshold as suggested by PERCIST82 or EORTC.83 Finally, end of treatment evaluations of patients undergoing neoadjuvant therapy have a limited impact on patient management. Although no further PET-based management changes can be implemented at the end of neoadjuvant treatment PET responses may allow predictions about the effectiveness of postsurgical chemotherapy.
Therefore, prospective studies in larger patient populations are required to determine whether early monitoring of neoadjuvant therapy, after one or two cycles (when changes in therapeutic approaches are still possible) might provide sufficiently accurate histopathologic response predictions to base management decisions on 18F-FDG PET/(CT).
In summary, radionuclide imaging approaches play an important role in the management of patients with primary bone tumors. 18F-FDG PET/CT is emerging as an important tool for staging and restaging as well as for therapy response assessments in these patients. Although its role is not yet firmly defined in guidelines provided by various professional organizations, it is anticipated that its use will significantly increase over the next few years.
In the United States, more than 21,000 new cases of myeloma will occur and more than 12,000 patients are expected to die from this cancer in 2012.2 It is a disease of the elderly population with the highest incidence among patients older than 75 years of age. Bone pain associated with fractures is the most common symptom at presentation.
Multiple myeloma is a clonal B-cell disease that initially arises from the bone marrow but later results in predominantly lytic bone destruction. As a consequence of bone marrow infiltration and bone destruction patients develop anemia, thrombocytopenia, and leucopenia and are prone to infections. Bone pain and fractures occur as do hypercalcemia and renal insufficiency. Monoclonal gammopathy (most frequently IgG or IgA) measurable in serum or urine, fractures, and pain together with the typical lytic lesion lead to the diagnosis.
Staging of Multiple Myeloma
Staging of multiple myeloma traditionally has followed the Durie–Salmon system.84 This classification considers serum hemoglobin and calcium levels, bone x-ray findings, and other parameters (Table 24.3). A recently revised system, the Durie–Salmon PLUS staging system takes into account the number of bone lesions identified with PET or MRI imaging. In addition, serum creatinine levels are included.85 Thus, the important role of 18F-FDG PET imaging for refining prognostication is now acknowledged.
An international staging system that considers serum albumin and β2-microglobulin has been introduced more recently and provides important prognostic information (Table 24.4).86 Although mean survival for stage I disease is around 5 years, it averages only 2.5 years for patients with stage III disease.
Management of Multiple Myeloma
Although overall survival durations have improved over the last decade multiple myeloma remains essentially noncurable.87 Treatment with a variety of chemotherapeutic agents (vincristine, doxorubicin, dexamethasone) has been used for many years; other therapeutic approaches include ifosfamide or cyclophosphamide combined with etoposide and epirubicin, or dexamethasone alone. More recent strategies include bortezomib (a proteasome inhibitor) combined with cyclophosphamide or adriamycin and dexamethasone. Thalidomide and lenalidomide have also been combined with dexamethasone.88 Novel treatment approaches include targeted small molecule inhibitors and others.88 Significant survival benefits have been reported with autologous stem cell transplant but cure has not been achieved.
DURIE–SALMON STAGING SYSTEM OF MYELOMA
Role of Imaging in Multiple Myeloma
Conventional bone scanning does not play a role in initial or subsequent treatment strategy assessments in multiple myeloma. In a comparison with plain film x-rays bone scintigraphy missed or underestimated disease in 27% of known disease sites among 51 patients with known myeloma. Moreover, scintigraphic findings were not predictive of hematologic parameters of myeloma activity.89 Thirty-six percent of the positive scintigraphic findings were associated with fractures whereas the remaining 64% of abnormal findings were associated with bone destruction without fracture evidence. False-negative results are most likely explained by the relatively minimal or even absent osteoblastic response to bone destruction in myeloma.90,91 The lytic nature of bone lesions also explains why some myeloma lesions appear as “cold spots” on bone scintigraphy.92 However, skeletal scintigraphy might perform better than plain film x-rays in some locations such as the lumbar spine and ribs.93
A recent consensus recommendation for the diagnostic workup of multiple myeloma includes standard serum and urine tests as well as imaging studies.94 Radiologic skeletal bone surveys (plain film radiographs) including spine, pelvis, skull, humerus, and femurs are mandatory. Disadvantages of plain film x-rays include a limited sensitivity and specificity, observer dependence, and their inability to reliably assess therapeutic responses.94 As an advantage, plain film x-rays are inexpensive.
CT imaging detects more lesions and determines more accurately fracture risk than plain film x-rays.95 Advantages include high sensitivity for small osteolytic lesions, good specificity, and fast whole-body assessments of soft tissues and bones.94 One theoretical disadvantage of CT is the involvement of ionizing radiation. However, there are no data to support the notion that even very frequent CT scans increase the risk for a secondary cancer in this population of mostly elderly patients with an underlying disease that carries a poor prognosis and is treated aggressively.
INTERNATIONAL STAGING SYSTEM FOR MULTIPLE MYELOMA
MRI is frequently used and recommended to assess myeloma patients. Its advantages include a high sensitivity for bone lesions in the axial skeleton, its ability to distinguish between bone marrow and bone and to determine nerve involvement. An additional advantage is its capability to distinguish among monoclonal gammopathy of unknown significance (MGUS), asymptomatic myeloma, and solitary plasmocytoma.94
The diagnostic performance of 18F-FDG PET/(CT) was systematically compared to that of plain film x-ray surveys in a recent analysis.96 This revealed superior diagnostic performance of PET for all body regions except for the skull. As expected, 18F-FDG PET/CT was superior for treatment response assessments. Integrated PET/CT using 18F-FDG detects myeloma lesions with a high accuracy.97 In a study of 66 patients who underwent 98 PET/CT studies disease presence, remission, relapse, and activity were assessed with a high accuracy. MGUS was accurately distinguished from active disease.98 In patients with suspected solitary plasmocytoma, 18F-FDG PET detected additional disease involvement in 8/23 patients.99
In another study, PET-CT was superior to planar radiographs in 46% of the patients including 19% with negative whole-body x-rays. However, MRI revealed an abnormal pattern of bone marrow involvement in the spine in 30% of the patients in whom 18F-FDG PET-CT was negative. When the information from MRI of the spine and pelvis was combined with that from 18F-FDG PET-CT an accuracy of 92% for bone lesion detection was achieved.100
Taken together, these data suggest that the emergent hybrid PET/MRI technology might become an important tool in the management of myeloma patients.
The prognostic implications of 18F-FDG PET-CT and MRI in patients with newly diagnosed myeloma were determined in a recent large prospective trial that included 239 patients by Bartel et al.101 (Fig. 24.7). By multivariate analysis, the number of focal 18F-FDG PET-CT lesions was correlated with gene expression profiles, focal lesions on MRI, and osteolytic tumor burden on plain films. Predictors of event-free and overall survival (by multivariate analysis) included >3 focal lesions on 18F-FDG PET, serum LDH levels >190 U/L, serum albumin <3.5 g/dL, and gene expression profiling. Moreover, absence of 18F-FDG uptake prior to transplantation in initially positive lesions was associated with significantly longer survival both in low- and high-risk groups as defined by serum and biopsy markers. Among all imaging tests 18F-FDG PET was most highly correlated with patient prognosis. In fact, it identified 30% of patients who were at high risk that were otherwise classified as low risk by gene profiling.
FIGURE 24.7. Baseline imaging studies (top row) showed no osteolysis on plain film x-rays (top left), several foci on STIR-weighted MRI images with the largest in the left ischium (top middle), and 2 foci on FDG PET/CT imaging (top right) with the largest again in the left ischium with a maximum SUV of 4.1. The patient was in near-complete remission 168 days later, with a significant decrease in focal activity in the left ischial lesion on PET (bottom right ). (Reprinted with permission from Bartel T, Haessler J, Brown T, et al. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Blood. 2009;114: 2068–2076.)
The National Oncology PET Registry (NOPR) group reported that 18F-FDG PET/(CT) affected the management in more than 40% of 1,784 myeloma patients at initial staging102 or restaging.103,104 Such comprehensive data are not available for any other imaging modality.
Guidelines: Despite these promising data, 18F-FDG PET/CT is mentioned but not recommended in the working group guidelines.94 It is listed as “optional” in the National Comprehensive Cancer Network (NCCN) guidelines.105It should be mentioned, however, that the study by Bartel et al.101 had not yet been included in the development of these guidelines.
In summary, although not yet firmly established in the diagnostic guidelines it is anticipated that 18F-FDG PET/CT will emerge as a critically important tool for optimizing initial and subsequent treatment strategies in myeloma patients.106 A specific role for PET/MRI imaging will have to be established by comparative prospective studies.
METASTATIC BONE DISEASE
Epidemiology and Classification
Metastatic bone disease is a highly relevant health care problem. The postmortem incidence of bone metastasis ranges from 20–25% for renal cell carcinoma to 65% to 75% for breast and prostate cancer (Table 24.5).107Complications of bone metastasis include severe bone pain and spinal cord compression that can occur in more than 5% of prostate cancer patients and less frequently in breast cancer and myeloma. Pathologic fractures occur in up to 40% of breast cancer patients. Palliative or preventative radiation is required in 20% to 30% of patients with breast and prostate cancer.108 Bone metastatic involvement is a major health problem as it is associated with severe patient suffering and enormous health care expenditures that amounted to $12.7 billion in 2007.109
Phenotypes of Bone Metastases
Bone metastases arise most frequently in the axial skeleton. Bone metastases and their phenotypes are driven by an interplay between invading tumor cells and osteoblast activity resulting in sclerotic lesions (signifying abnormal bone formation) and osteoclast activity that leads to osteolytic lesions.110 Osteolytic and osteoblastic activities frequently coexist resulting in mixed lesions. Bone metastases from breast,111 lung, thyroid, and renal cell carcinoma are predominantly osteolytic whereas those from prostate cancer are predominantly osteoblastic.112 The accurate assessment of skeletal involvement in cancer is important because its treatment reduces the number of skeletal events113 as discussed later.
Prognosis of Metastatic Bone Disease
Prostate and breast cancer patients with bone metastases can achieve multi-year survival. Nevertheless, presence of bone metastases signifies adverse long-term outcome when compared to patients without metastases. Moreover, bone only disease carries a better prognosis than visceral metastases with or without bone involvement in breast cancer patients.107,114
In metastatic lung cancer overall survival is measured in months and bone involvement has little prognostic impact.
POSTMORTEM INCIDENCE OF BONE METASTASES (%)
FIGURE 24.8. Kaplan–Meier survival curves: (A) FDG PET SUV—survival curves for 22 patients with low (≤6.1) and 21 patients with high (>6.1) SUVmax, p = 0.002. B: Bone scan index (BSI)—survival curves for 22 patients with low (≤1.27) and 21 patients with high (>1.27) BSI, p = 0.004. C: Joint analysis of SUVmax and BSI showing two patient groups with distinct prognosis. In the low SUV and low BSI group, median survival is 32.6 months; in the “high” SUV and BSI group, survival was 14.4 months and there is a distinct difference between the curves ( p = 0.001). (Reprinted with permission from Meirelles G, Schöder H, Ravizzini G, et al. Prognostic value of baseline [18f ] fluorodeoxyglucose positron emission tomography and 99mtc-MDP bone scan in progressing metastatic prostate cancer. Clin Cancer Res. 2010;16:6093–6099.)
In prostate cancer, presence and extent of metastatic bone disease as detected by bone scintigraphy predict long-term survival.115,116 However, in one report only lesion 18F-FDG SUV but not extent of disease was an independent survival predictor by multivariate analysis117 (Fig. 24.8) suggesting that more aggressive therapeutic interventions might be warranted in patients with high glycolytic activity of prostate cancer metastases.
Diagnosis and Detection of Bone Metastases
A variety of imaging methods can be used to detect bone metastases the choice of which depends among others on test accuracy, cost, and radiation considerations. These include radionuclide imaging techniques, including planar whole-body and SPECT imaging, SPECT/CT, PET/CT, plain film x-rays, CT, and MRI. The utilization of conventional bone imaging using 99mTc-diphosphonates introduced by Subramanian et al.118 in 1972 has decreased in recent years. This is in part explained by modifications of management guidelines from various professional organizations but is also caused by increased utilization of 18FDG PET/CT and MRI for bone metastasis detection.
99mTc-labeled diphosphonates accumulate in regions of increased osteoblastic activity such as for instance in regions of bone growth, trauma, and in response to benign neoplastic, inflammatory, infectious, or malignant processes. Thus, radionuclides targeting osteoblastic activity provide nonspecific information (Table 24.6). More specific information can be obtained by using a variety of PET tracers targeting various phenotypes of bone metastases as discussed later (Table 24.7).
SELECTED REASONS FOR FALSE-NEGATIVE AND FALSE-POSITIVE BONE SCAN FINDINGS
SPECT imaging using 99mTc-diphosphonates can improve the characterization of bone lesions as malignant or benign. In a study of more than 100 patients with a variety of primary cancers, sensitivity, specificity, and accuracy of SPECT were 90.5%, 92.8%, and 92.4%, respectively. The accuracy for detecting spinal involvement in the subgroup of patients with breast cancer was 95.7%.119 In another study of 174 patients, SPECT had a sensitivity of 87%, a specificity of 91%, and an accuracy of 90% whereas planar imaging had a lower sensitivity (74%), specificity (81%), and accuracy (79%) in diagnosing vertebral metastasis.120 Overall, SPECT appears to be more accurate than planar imaging for the assessment of spinal involvement because disease localized to the facet joints (most frequently benign) can be differentiated from involvement of the pedicles (most frequently malignant).
However, the accuracy of planar and SPECT imaging for detecting osteolytic bone lesions is limited. This is because osteoblastic responses to such lesions can be minimal. 18F-FDG PET therefore plays an increasing role in the staging of lung and breast cancer that most frequently exhibit osteolytic or mixed bone lesions.
In a retrospective comparative study of 257 patients with lung cancer, the accuracy of planar scintigraphy and 18F-FDG PET121 was 85% and 94% ( p < 0.05), respectively. The sensitivity of PET was also higher (91% versus 75%) whereas the specificity was near identical (95% and 96%), respectively. Thus, in lung cancer patients who undergo staging with 18F-FDG PET/(CT) the addition of bone scans appears to be redundant.
Similarly, 18F-FDG PET detects bone involvement in breast cancer patients with a high accuracy during staging,122–124 restaging,125–127 and in inflammatory breast cancer.128
In general, the accuracy of 18F-FDG PET for detecting bone involvement appears to be superior to that of conventional imaging.
The predominant phenotype of bone metastases affects their detectability with radionuclide methods. In general, osteoblastic lesions are well detected with planar or SPECT bone scintigraphy and 18F-sodium fluoride (18F-NaF) PET/(CT) whereas osteolytic lesions are well delineated with 18F-FDG PET/(CT). This is because conventional bone scans probe osteoblastic activity whereas 18F-FDG PET identifies viable tumor cells.
Thyroid and renal cell cancer patients also develop predominantly osteolytic metastases. In these malignancies planar imaging and SPECT have a limited sensitivity for detecting bone involvement and 18F-FDG PET might play an important role for initial and subsequent management decisions.
A study in 23 patients with RCC revealed that 18F-FDG PET correctly identified 7/7 documented bone metastases.129 In another retrospective study of 66 patients who underwent 90 PET scans 26/33 bone metastases were detected with 18F-FDG PET.130 In one prospective study 18F-FDG PET was superior to CT imaging for detecting distant metastases.131
PET PROBES FOR IMAGING BONE METASTASES
The performance of 99mTc-diphosphonate imaging was compared to 18F-FDG PET in 19 patients with 40 bone metastases. As expected (because of the lytic nature of bone metastases from renal cancer) 18F-FDG PET detected all 40 metastatic lesions whereas 99Tc-diphosphonate imaging identified only 31/40 lesions.132
In thyroid cancer, 18F-FDG PET has also been used for detecting bone metastases. In one study of 19 patients with differentiated thyroid cancer 18F-FDG PET detected 5/6 documented bone metastases after TSH stimulation.133This is in agreement with other studies that showed increased uptake in metastatic lesions after TSH stimulation.134,135
131I is sensitive for detecting well-differentiated thyroid cancer metastases and lesion location is greatly improved by performing SPECT/CT scans.136 However, especially in patients with negative whole-body 131I scans 18F-FDG detects bone metastases with a high accuracy.137 The degree and number of 18F-FDG-avid bone metastatic lesions from thyroid cancer have prognostic implications as demonstrated in a retrospective analysis of 400 patients. Age, initial stage, histology, serum thyroglobulin levels, radioiodine uptake, and PET findings correlated with survival by univariate analysis whereas only age and PET results predicted outcome by multivariate analysis.138
These findings in renal cell and thyroid cancer are important because such baseline information is a prerequisite for monitoring therapeutic interventions in patients with 18F-FDG-positive bone metastases.
Monitoring Therapeutic Interventions in Patients with Bone Metastases
Osteolytic bone metastases usually exhibit a high glycolytic activity and hence are intensely 18F-FDG avid. In contrast, osteoblastic, sclerotic bone lesions show lower or no 18F-FDG uptake. In fact, in a study of 25 patients with breast cancer only 60% of osteoblastic but 94% of osteolytic and more than 80% of mixed lesions showed increased 18F-FDG uptake.139 The degree of lesion uptake was size dependent (Fig. 24.9).
Following treatment 80% of the 18F-FDG-positive osteolytic lesions converted into sclerotic, 18F-FDG-negative metastases. On the other hand, only around 50% of the 18F-FDG-positive sclerotic and the mixed lytic/sclerotic lesions converted into 18F-FDG-negative sclerotic lesions following treatment (Fig. 24.10).139 These findings suggest that both metabolic and anatomic changes can provide important insights into treatment responses of bone metastases. The well-known flair phenomenon is also consistent with conversion of lytic into blastic lesions signifying healing of osteolytic lesions.140,141
Various tumor response criterion have been proposed for instance in breast cancer patients but neither of those developed by the International Union against cancer (UICC)142 or Response Criteria in solid Tumors (RECIST) meet the clinical needs for assessing therapeutic responses of bone metastases.111 However, the revised, RECIST 1.1, now consider osteolytic or mixed (those with a soft tissue component), but not osteoblastic, sclerotic bone metastases as measurable disease.143,144 A measurable bone lesion is defined as one that can be accurately measured in at least one dimension and has a diameter of at least 10 mm by CT. Bone scans or plain film x-rays are not considered adequate to measure disease. Following treatment complete response (CR) and partial response (PR) are defined as a complete disappearance and at least 30% reduction in the sum of diameters of target lesions, respectively. Progressive disease (PD) denotes an at least 20% increase in the sum of diameters of all lesions or new lesions. Stable disease (SD) is characterized by neither sufficient shrinkage to qualify for PR or by insufficient increase to be classified as PD.
FIGURE 24.9. 18F-FDG uptake intensity of bone metastases. The FDG-avid lesions are grouped by radiographic appearances on computed tomography (CT). The FDG uptake intensity (maximum standardized uptake value [SUVmax] on positron-emission tomography) and the size (the maximum long axis on CT) of 123 FDG-avid bone lesions are presented. p values indicate the SUVmax statistical differences between different groups of lesions. (Reprinted with permission from Du Y, Cullum I, Illidge T, et al. Fusion of metabolic function and morphology: Sequential [18F]fluorodeoxyglucose positron-emission tomography/computed tomography studies yield new insights into the natural history of bone metastases in breast cancer. J Clin Oncol. 2007; 25:3440–3447.)
FIGURE 24.10. Left, osteolytic bone metastases responding to hormonal therapy: (A) Baseline 18F-FDG PET/CT study shows two FDG-avid osteolytic metastatic lesions in the third lumbar vertebra (arrows); (B) 3-month, (C) 7-month, and (D) 24-month follow-up studies show the gradual and long-lasting osteoblastic change. Apart from multiple FDG-negative osteoblastic lesions, this patient is clinically well at 26-month follow-up. Right, progressive osteoblastic bone metastasis: (A) Baseline 18F-FDG PET/CT study shows an FDG-avid osteoblastic lesion in the fifth lumbar vertebra (arrows) (B) 4-month, (C) 9-month, and (D) 18-month follow-up studies show the CT radiographic and FDG metabolic changes of this progressive lesion. Iliac crest biopsy after the 18-month FDG PET/CT study confirmed bone marrow metastasis. (Reprinted with permission from Du Y, Cullum I, Illidge T, et al. Fusion of metabolic function and morphology: Sequential [18F]fluorodeoxyglucose positron-emission tomography/computed tomography studies yield new insights into the natural history of bone metastases in breast cancer. J Clin Oncol. 2007;25:3440–3447.)
The role of 18F-FDG PET is also addressed in the revised RECIST 1.1 guidelines143,144 as follows: 18F-FDG-negative bone lesions that convert to positive lesions after treatment are consistent with PD. A positive posttreatment PET scan in patients without a baseline scan is consistent with PD if this lesion corresponds to a new lesion on CT. If the lesion pre-existed on CT then this is consistent with stable disease.
PET response criteria in solid tumors (PERCIST)82 does not specifically address bone metastatic responses to therapy. However, it appears to be reasonable to apply PERCIST also to these lesions. A complete metabolic response would be defined as a complete resolution of 18F-FDG uptake within a measurable lesion whereas a partial metabolic response would require a ≥30% reduction in lesion 18F-FDG uptake. Increases of lesion 18F-FDG uptake by more than 30% would be consistent with progressive metabolic disease whereas stable metabolic disease would be defined as absence of complete or partial metabolic response or progression of disease.82
Monitoring the effects of therapy on bone metastases can be accomplished with 18F-FDG PET/CT. In a retrospective study of 115 patients with metastatic breast cancer the number of circulating tumor cells and the 18F-FDG PET response (>25% reduction in lesion 18F-FDG uptake) were predictive of survival by univariate analysis. By multivariate analysis only the number of circulating tumor cells (< versus > than 5 cells/7.5 mL of blood) remained predictive. However, in a subset of patients the information derived from PET and that from circulating tumor cells was discordant. In PET nonresponders who had less than five circulating tumor cells 18F-FDG PET provided important treatment response information.145
In another retrospective study of 102 patients with breast cancer146 reductions in lesion 18F-FDG uptake by ≥8.5% predicted a favorable response with a good accuracy.
Thus, a variety of imaging modalities as well as imaging probes (as discussed later) are available for the assessment of bone metastases. However, current guidelines do not yet include advanced imaging approaches.
Guidelines for Imaging
The American College of Radiology has recently published their recommendations for the appropriate use of imaging of bone metastasis.147 In breast cancer, bone imaging with any modality is unnecessary for stage I disease. In contrast, 99mTc-diphosphonate imaging is considered highly appropriate in patients with ≥stage II disease who report hip and/or back pain. An equally strong recommendation was made for plain film x-rays of the spine and hips. 18F-FDG PET imaging was considered to be of intermediate appropriateness.
In patients who are followed up (subsequent treatment strategy) a solitary “hot spot” in the spine should prompt an MRI if plain film x-rays are negative. In patients with three hot spots but no back pain, x-rays, and if negative, MRI of the spine would be suggested whereas 18F-FDG PET is of intermediate appropriateness. An additional SPECT study of the spine could be added. Again, in this setting 18F-FDG PET was considered to be of intermediate appropriateness.147
Solitary rib lesions on bone scans are highly unlikely to represent metastases and should be further evaluated with plain film x-rays.148 Single hot spots in the sternum on follow-up should be further evaluated with a noncontrast CT or MRI. Based on a large retrospective study such lesions are much more likely benign and represent metastases in less than 10% of cases.149 Plain film x-rays, 18F-FDG PET, and SPECT imaging are again of intermediate appropriateness.
When breast cancer patients present with a pathologic fracture on plain film x-rays, whole-body bone scans should be done first and, if results are negative, this might be followed by a whole-body 18F-FDG PET scan.
Initial imaging assessments of the skeleton are straightforward in patients with prostate cancer.147 Revised guidelines suggest that imaging including bone scans is not necessary unless PSA is ≥20 ng/mL or the tumor is poorly differentiated. This is based in part on an analysis of 23 studies that reported that metastases were detected in only around 2% and 5% of patients with serum PSA levels of less than 10 and 10.1 to 19.9 ng/mL, respectively.150Furthermore regular imaging follow-up is not recommended unless symptoms suggest bone involvement or serum PSA rises rapidly.151
The recommendations by the National Comprehensive Cancer Network are slightly different and suggest bone scans for patients with a PSA level >10 ng/mL, a Gleason score ≥8, presence of symptoms consistent with bony metastases, or any clinical T3 or T4 prostate cancer.151
18F-FDG PET/(CT) imaging is firmly entrenched in the initial staging and bone evaluation of patients with non–small cell lung cancer.147 A bone scan is not needed if a whole-body 18F-FDG PET/CT is done.
In summary, conventional bone imaging using 99mTc-diphosphonates is firmly entrenched in the assessment of bone metastases in prostate cancer. In lung cancer and breast cancer, because of their predominantly osteolytic or mixed osteolytic/osteoblastic phenotypes, 18F-FDG PET(CT) is emerging as an important assessment tool. However, professional organizations have not yet fully recognized its relevance and importance. Novel and previously established PET probes that can provide important information on bone involvement in cancer will be discussed later.
KINETICS, DOSIMETRY, AND PROTOCOLS FOR RADIONUCLIDE BONE IMAGING
The four radiopharmaceuticals that have been used for bone imaging are 99mTc-MDP (methylene disphosphonate), 99mTc-HMDP (hydroxyethylidene diphosphonate), 99mTc-HEDP (hydroxyethylidene diphosphonate), and 99mTc-PP (pyrophosphate).152 99mTc-MDP is most frequently used in the United States. All are prepared by adding 99mTc-pertechnetate to stannous ions and either a diphosphonate or a pyrophosphate ligand.
After intravenous injection the tracer equilibrates with the extravascular fluid compartment in about 2 hours153 and 99mTc-MDP is cleared to bone and excreted through the kidneys. Retention in bone tissue depends on osteoblastic activity, blood flow, and renal function.154 Twenty-five percent of 99mTc-MDP binds initially to plasma protein, a fraction that increases to about 70% after 24 hours. Binding to hydroxyapatite is reversible.154,155 The low first-pass extraction fraction together with the slow renal clearance results in a low bone-to-background activity ratio at early time points. Thus, imaging has to be performed 2 to 5 hours after tracer injection when the target to background ratio is high.
The usual administered activity for adult patients is 740 to 1,110 MBq (20 to 30 mCi) injected intravenously. For markedly obese adult patients, the administered activity may be increased to 11 to 13 MBq/kg (300 to 350 μCi/kg). For pediatric patients, the administered activity is 9 to 11 MBq/kg (250 to 300 μCi/kg), with a minimum of 20 to 40 MBq (0.5 to 1 mCi). The maximum administered activity for pediatric patients should not exceed the administered activity for an adult.152
Procedure guidelines for 99mTc-diphosphonate planar, SPECT, and SPECT/CT bone imaging were provided by the Society of Nuclear Medicine.156,157 Patient preparation includes hydration between injection and the time of image acquisition. Frequent urination (before and after imaging) as well as continued fluid intake for at least 24 hours after injection is recommended to reduce radiation doses to the urinary bladder.
For tumor studies, delayed images are usually acquired from 2 to 5 hours after injection. Spot images or whole-body images may be acquired in anterior and posterior views using high-resolution collimators until 500,000 to 1 million counts are obtained. When whole-body scanning is used >1.5 million counts are desirable.
SPECT imaging is helpful to better characterize the presence, location, and extent of disease, especially when spinal involvement is of concern. Additional views may be added as clinically indicated. Repeat imaging after voiding may be helpful to improve visualization of pelvic bones that can be obscured by bladder activity.
The Society of Nuclear Medicine SPECT/CT guidelines do not provide specific indications for the use of SPECT/CT in skeletal evaluations.157 However, various considerations address the use of the CT component. Usually, SPECT/CT is performed when planar and SPECT imaging does not provide clear answers to the pertinent clinical questions.
Patient preparation and precautions are identical for planar, SPECT, and SPECT/CT imaging. However, the addition of CT increases the radiation dose to patients, and thus, the as low as reasonably achievable (ALARA) principle applies. Most frequently, specific sections of the body are imaged. The CT can be done for attenuation correction or lesion localization only. For these studies a low-dose CT is sufficient. For a diagnostic CT scan, standard CT settings are recommended.
Abnormally increased tracer uptake can be focal or diffuse and denotes increased osteoblastic activity and/or increased blood flow. Focally reduced tracer might be explained by osteolytic lesions, prior surgical interventions resulting in absent bone, and artifacts. The pattern of a superscan is characterized by poor or lack of visualization of the kidneys and intense uptake throughout the axial skeleton. This denotes widespread bone metastatic disease.
PET Imaging Probes for the Assessment of Bone Metastases
18F-FDG is a probe of tumor glucose metabolism that is a major source of energy for rapidly growing tissue.158 Glucose metabolism also provides the carbon backbone for DNA and RNA syntheses.159 The targets of 18F-FDG are Glut1 and Glut3 as well as hexokinase, all of which are upregulated to various degrees in cancer (Table 24.7). As discussed above, 18F-FDG PET/CT imaging accurately detects osteolytic bone metastases whereas osteoblastic lesions might exhibit low or no FDG uptake. It is thus not surprising that 18F-FDG PET/CT has frequently replaced conventional bone scans for staging or restaging of cancers that most frequently generate osteolytic or mixed lesions including (among others) lung cancer and breast cancer.160
18F-FDG PET and PET/CT imaging protocols as well as its dosimetry are described elsewhere in this book.
18F-NaF is delivered to bone via blood flow (the rate-limiting step).161,162 Single pass extraction of 18F-NaF approaches 100%.163 Its first pass extraction by bone is higher than that of 99mTc-MDP.
Around one-third of the injected 18F-NaF is present in red blood cells. Because 18F-NaF is freely diffusible across membranes, this does not interfere with tracer delivery.164
The initial 18F-NaF distribution represents blood flow that varies among different bones.165 Because of rapid renal clearance only 10% of 18F-NaF remains in plasma 1 hour after injection. Before being deposited in bone 18F-ions “need to pass from plasma through the extracellular fluid space into the shell of bound water surrounding each crystal, onto the crystal surface and in the interior of the crystal.”161 18F binds to hydroxyapatite by chemisorption and subsequently exchanges rapidly for OH on the surface of the hydroxyapatite matrix (Ca10(PO4)6OH2) to slowly form fluoroapatite (Ca10(PO4)6F2).161,166 The area of the “exposed” bone surface is larger in various benign or malignant bone disorders resulting in abnormal uptake patterns. The interplay between osteoblastic and osteoclastic activities determines the incorporation of 18F-NaF into the bone matrix.167 Rapid blood and renal clearance168 as well as high bone uptake result in high target-to-background ratios which enables whole-body imaging as early as 30 minutes after tracer injection.
18F-NaF imaging, largely abandoned in the 1970s when 99mTc-labeled compounds became available,118 has gained renewed interest. This is because of the availability of PET/CT, electronic generator networks, and the shortage of 99mTc generators. Few studies have systematically evaluated its performance for detecting bone metastases. However, the superior spatial resolution and the tomographic capabilities of PET should result in an exquisitely high sensitivity of this approach. This advantage comes at the potential cost of a reduced specificity. With the advent of hybrid PET/CT imaging, however, the specificity can be significantly improved as shown in a study that compared 18F-NaF PET to 18F-NaF PET/CT.169 In a population of 44 patients with a variety of malignancies the specificity of PET/CT was significantly higher than that of PET (97% versus 72%, p < 0.001). Advantages were most pronounced for the thoracic cage and the spine. The overall sensitivity also significantly improved by PET/CT (85% versus 72%; p < 0.001).
The high sensitivity of the PET approach is also underscored by a study that compared planar bone scans to 18F-NaF PET in patients with breast cancer.170 Despite the high prevalence of lytic lesions in these patients the sensitivity and specificity of 18F-NaF PET by ROC analysis was high with an area under the curve of 1 for PET versus 0.82 for the planar bone scans (p < 0.05). A high detection rate of osteolytic lesions was also reported in another study of breast cancer patients.171
In a study of more than 120 patients with lung cancer 18F-FDG PET/CT and 18F-NaF PET detected bone metastases with a comparable accuracy and both PET approaches were superior to planar bone scans.172 These results reflect our clinical experience and might explain the increasing number of 18F-FDG scans performed at the expense of bone scans in lung cancer patients.121
Bone SPECT is used with increasing frequency. A comparison between 18F-NaF PET, planar, and SPECT imaging was therefore performed in 44 patients with high-risk prostate cancer.173 The addition of SPECT to planar imaging resulted in a specificity of around 65% which was similar to that achieved with PET. However, PET/CT imaging provided a sensitivity and specificity of 100% on a patient-based analysis.
The dosimetry of 18F-NaF is favorable when compared with that of 99mTc-MDP. Its effective dose is 0.024 mSv/MBq in adults and 0.086 mSv/MBq in children, or approximately 1/10th of the effective dose of 99mTc-MDP. The critical organ is the urinary bladder for 18F-NaF and bone surfaces for 99mTc-MDP.174
Guidelines for 18F-NaF PET/CT imaging were provided by the Society of Nuclear Medicine.175 Tracer administration should be avoided in pregnancy “unless the potential benefits outweigh the radiation risk to the mother and fetus.” Hydration (two or more 8-oz glasses of water within 1 hour before and after 18F injection) is advised to reduce radiation to the urinary bladder. The urinary bladder should be emptied immediately before imaging. Neither fasting nor discontinuation of any medication is required.
18F-NaF is injected intravenously at a dose of 185 to 370 MBq (5 to 10 mCi) in adults. Pediatric activity should be weight-based (2.22 MBq/kg [0.06 mCi/kg]), with a range of 18.5 to 185 MBq (0.5 to 5 mCi).
Patients may be imaged in the “arms-up” (to avoid CT beam hardening artifacts) or “arms-down” position.
Noncontrast-enhanced CT is sufficient for evaluation of the skeleton. CT data are used for attenuation correction but can also provide critically important information for lesion detection and characterization. ALARA should be applied. The Society of Nuclear Medicine guidelines suggest that high-quality images can be obtained with or without attenuation correction. However, the addition of CT improves the specificity for lesion characterization.169,176 No specific guidelines for CT protocols were provided.175
PET image acquisition starts as early as 30 to 45 minutes after tracer administration. The Society of Nuclear Medicine suggests a longer tracer uptake (90 to 120 minutes) time to obtain high-quality images of the extremities. Recent generation PET/CT systems only permit acquisition in the 3D mode, which in turn allows for short image acquisition times which range from 3 to 5 minutes per bed position. The same iterative reconstruction protocols as used for 18F-FDG PET imaging may be used for 18F-NaF.175
18F-NaF is faintly visible in the kidneys, ureters, and visible in the urinary bladder (Fig. 24.11). Soft tissue activity reflects the amount of circulating 18F in the blood pool at the time of imaging. It may be increased in patients with renal insufficiency resulting in higher background activity. Hyperemia results in locally increased tracer uptake. Skeletal tracer uptake is high and relatively uniform. Increased uptake is seen in children and adolescents in the growth plates (Fig. 24.12).
Osteoblastic activity in new or reactive bone formation causes increased uptake of 18F-NaF. This occurs in benign tumors, inflammatory, degenerative, traumatic, or infectious diseases as well as in malignant lesions. Focally increased tracer activity is therefore not specific for malignancy (Table 24.6).
To avoid false-positive image interpretation for cancer, correlations with plain film, CT or MRI frequently need to be performed. However, the addition of CT in PET/CT frequently obviates the need for such further correlations. The number of false-positive finding can likely be reduced by careful inspection of the CT images (Fig. 24.13).
FIGURE 24.11. Normal biodistribution of 18F-NaF; note the absence of bladder activity; kidneys and ureters are faintly visualized. (Reprinted with permission from Drubach L, Connolly S, Palmer E. Skeletal scintigraphy with 18F-NaF PET for the evaluation of bone pain in children. AJR Am J Roentgenol. 2011;197:713–719.)
FIGURE 24.12. Maximum intensity projection (MIP) 18F-NaF PET image of a 4-year-old boy being evaluated for injuries as a result of trauma shows typical body distribution of tracer with prominent growth plate activity. Focally increased uptake in thoracic spine (arrow) indicates compression fracture. (Reprinted with permission from Drubach L, Connolly S, Palmer E. Skeletal scintigraphy with 18F-NaF PET for the evaluation of bone pain in children. AJR Am J Roentgenol. 2011;197: 713–719.)
FIGURE 24.13. Maximum intensity projection PET image (A) and selected axial PET/CT (B, D, F, H) and CT (C, E, G, I) images of 18F-NaF PET/CT scan of a 63-year-old man with prostate cancer. Increased 18F-NaF uptake can be seen in benign changes of right cervical facet joint (green arrow in A, B, and C), healing rib fracture ( yellow arrow in A, D, and E), benign lumbar vertebral bone cyst (blue arrow in A, F, and G), and osteoblastic metastasis in sacrum (red arrow in A, H, and I). Additional value of CT to characterize focally increased tracer uptake is evident. (Reprinted with permission from Czernin J, Satyamurthy N, Schiepers C. Molecular mechanisms of bone 18F-NaF deposition. J Nucl Med. 2010;51: 1826–1829.)
FIGURE 24.14. Iodine-positive metastasis of the cervical spine. Identification is not possible with CT only (top), and identification but not localization is possible with PET only (center). Combined PET/CT allows both detection and localization (bottom). (Reprinted with permission from Freudenberg L, Jentzen W, Stahl A, et al. Clinical applications of 124I PET/CT in patients with differentiated thyroid cancer. Eur J Nucl Med Mol Imaging. 2011;38:48–56.)
FIGURE 24.15. Maximum intensity projection 18F-choline PET image shows uptake in the prostate (arrowhead ), a right pelvic lymph node (curved arrow ), and two bone metastases (straight arrows). (Reprinted with permission from Beheshti M, Imamovic L, Broinger G, et al. 18F choline PET/CT in the preoperative staging of prostate cancer in patients with intermediate or high risk of extracapsular disease: a prospective study of 130 patients. Radiology. 2010; 254:925–933.)
Emerging PET Probes for Imaging Bone Metastases
124I has a physical half-life of 4.2 days and decays by electron capture (74.4%) and positron emission (25.6%). 124I PET/CT detected tumor lesions with a higher sensitivity than CT alone or 131I scintigraphy in 12 patients will well-differentiated thyroid carcinoma (Fig. 24.14).177,178 124I was superior for detecting advanced thyroid cancer prior to treatment when compared to 131I179 and detected 50% more lesions than 131I in a study of 25 patients with advanced or metastatic well-differentiated thyroid cancer. Bone metastases were readily detected.180
These promising results suggest that 124I PET/CT imaging will play an increasingly important role in the management of thyroid cancer patients. However, larger prospective studies will have to determine whether 124I PET/CT affects patient management and outcome of thyroid cancer patients.
Many other malignancies can give rise to bone metastases. These include neuroendocrine tumors such as neuroblastoma, carcinoid, pheochromocytoma, and medullary thyroid carcinoma. Imaging probes of amino acid transport (18F-DOPA),181,182 somatostatin receptors (68Ga-labeled somatostatin receptor ligands),183 and norepinephrine transport and uptake (123I-MIBG)184,185 can be used to visualize bone metastases in these cancers. 18F-FDG PET appears to be most useful in dedifferentiated neuroendocrine tumors and in particular in patients with pheochromocytoma or paraganglioma with succinate dehydrogenase enzyme subunit B gene mutations.186
A variety of PET imaging probes have become available that depict various phenotypes of bone metastases. Among these are probes such as 11C- or 18F-choline (Fig. 24.15),187 11C-acetate, tracers of amino acid transport and metabolism, probes of hormone receptor expression and others (Table 24.7).18F-choline, 11C-choline, and 11C-acetate are metabolic imaging probes that provide insights into choline kinase and fatty acid synthase activity, respectively. Probe retention most likely reflects incorporation of the probes into membrane lipid pools and the increased cell membrane turnover in cancer.188
Recent studies provided preliminary information about the accuracy of 18F-choline PET for detecting bone metastases in prostate cancer. One prospective study included 130 presurgical patients who were at increased risk for extracapsular disease involvement. A total of 43 metastatic bone lesions were detected in 13/130 patients. It should be noted that these metastases were also evident on CT in all but two patients.187
In another study of 40 patients with prostate cancer the performance of 18F-choline PET was compared with that of 18F-NaF PET.189 Bone metastases were present in 22 patients. Sensitivity and accuracy were comparable for both tracers at around 90% and the specificity was similar for both probes (89% versus 83%; p = NS).
In a small study of eight patients with prostate cancer all bone metastases detected by 99mTc-MDP imaging were also detected with 11C-acetate.190 However, 18F-FDG detected bone metastases with a higher sensitivity than 11C-acetate in another study.191 Both the lesion uptake of 11C-acetate and 18F-FDG significantly correlated with serum PSA levels.
Taken together promising PET probes for imaging bone metastases from prostate cancer are emerging. It is however unclear whether the different imaging phenotypes provide distinctive prognostic information. Larger prospective studies addressing the prognostic value of these imaging probes are therefore needed. Moreover, their differential ability to monitor therapeutic responses as well as their impact on patient management and outcome need to be defined.
TREATMENT OF METASTATIC BONE DISEASE
Bone metastases from prostate and breast cancer account for more than 80% of all symptomatic bone involvement.192,193 Pain from metastatic bone disease has a detrimental impact on the quality of life of cancer patients. Other severe consequences of bone metastases include spinal cord compression, fractures, and the hypercalcemia syndrome of malignancies.107
The management of bone metastases is multidisciplinary194 including medical therapy (biphosphonates and RANK-ligand inhibitors, nonsteroidal anti-inflammatory drugs, steroids, narcotics), external radiation, chemotherapy, and surgery. Nevertheless, up to 45% of patients remain symptomatic even after these treatments have been applied.195 This is in part explained by dose limiting side effects and inadequate bone pain assessments.195
Combination treatments are frequently necessary to alleviate bone pain. In addition to pain medication that includes nonsteroidal anti-inflammatory drugs, opiates and others, external beam radiation is the initial therapy of choice that results in some relief in 90% and complete and lasting pain relief in 54% of patients with localized pain.196
However, external beam radiation is frequently not feasible in patients with widespread osseous involvement. Side effects of whole- or hemibody radiation are frequently severe and hospitalization is often required which adds to the cost of this strategy.
Evidence-based standards for the management of metastatic bone pain include screening for and rating of pain and functional impairment, single fraction radiation treatment of bone metastases, corticosteroids for spinal cord compression, and rapid initiation of definitive treatments (surgery or radiation treatment) within 24 hours of evidence for spinal cord compression.197 Need for as well as type and dosage of pain medication should be recorded.
Whereas no survival benefit was demonstrated, treatment with the biphopshonate pamidronate reduced all skeletal events (including fracture, need for radiation, spinal cord compression, and hypercalcemia) by around 40% in patients with breast cancer. More recently additional treatments such as denosumab, a monoclonal antibody against RANK-ligand198 that inhibits osteoclast-mediated bone destruction, have become available. In a study of 1,432 patients who were randomized to denosumab or placebo, the study drug significantly increased bone-metastasis–free survival by a median of 4.2 months. However, overall survival was not affected.199
In another randomized trial that compared denosumab to the biphosphonate zoledronic acid,200 denosumab delayed the time to the first skeletal event by more than 3 months. However, the number of serious adverse events was higher in the denosumab group.
These reports underscore the need for early and accurate detection of bone involvement in cancer because delays in symptomatic disease can be achieved. However, the symptomatic benefits come at considerable costs because biphosphonates and denosumab are expensive (>$30,000/year) and the drug costs exceed those of skeletal-related events substantially.201
A variety of radionuclides have become available but they are used infrequently because of inadequate information of treating physicians and poorly understood patient selection criteria. Patients with extensive bone metastatic disease might be candidates for radionuclide therapy.
Table 24.8 depicts radiopharmaceuticals that have been introduced and used clinically.202 Strontium-89 (89Sr) and samarium-153 (153Sm) are radioisotopes that are approved in the United States and Europe for the palliation of pain from metastatic bone cancer, whereas rhenium-186 (186Re) is only approved in some European countries and rhenium-188 (186Re) is investigational. The alpha-emitter 223Radium has been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA).
32Phosphorus was the first approved radiopharmaceutical. Administered as sodium orthophosphate it decays by β-emission with energy of 1.7 MeV. The ratio of 32P uptake in reactive bone surrounding metastatic lesion is three to five times higher than that in normal bone. The maximum particle range is around 8.5 mm and red marrow absorbs approximately 6.5 mGy/MBq.202 Therefore, significant myelosuppression results in the need for blood transfusion in up to 30% of patients.203
Thrombocytopenia was the major side effect and occurred at doses of <13 mCi. Complete blood counts usually returned to 80% of the pretreatment levels within 8 weeks. Other side effects included fever, gastroenteritis, or minor hemorrhagic manifestations. Myelosuppression developed in 24% and 47% of patients with metastatic breast and prostate carcinomas, respectively.203 32P was largely abandoned in favor of 89Strontium chloride (89Sr) that was approved for the management of cancer-related bone pain by the FDA in 1993.
89Strontium chloride has a half-life of 50.5 days and a β-energy of less than 1.5 MeV that limits bone marrow toxicity because of a β-range of less than 3 mm.204 Following intravenous injection about 50% of the injected dose is incorporated into the inorganic bone matrix and thus, accumulates in bone. Uptake and retention is 10 times higher in metastatic lesions than in normal bone.205 Washout from normal bone (half-life of 14 days) is much faster than that from metastatic lesions. Ninety days after administration total body 89Sr retention varied from 11% to 88% dependent on the extent of scintigraphic bone involvement. Renal plasma clearance was significantly lower than in healthy adult men likely because of increased renal reabsorption associated with imbalanced calcium homoeostasis in patients with metastatic bone involvement. 89Sr retention in metastatic lesions peaked at 10 days after intravenous administration followed by a slow decline.204
PHYSICAL CHARACTERISTICS OF THERAPEUTIC RADIONUCLIDES FOR BONE PAIN PALLIATION
In 1995 Robinson et al.206 summarized the clinical experience with 89Sr therapy. They reported that pain relief was achieved in up to 80% of patients with metastases from breast or prostate cancer, an effect that lasted for several months. Pain relief was associated with improved quality of life. Twenty percent of patients became pain-free. Adverse effects included mild reversible bone marrow toxicity in many patients.206
In a study of 137 patients with complete follow-up a dose of 40 microCi/kg of 89Sr achieved response rates of as high as 80% and 89% in prostate and breast cancer, respectively.205 89Sr uptake remained high for more than 3 months in osteoblastic lesions yet bone marrow toxicity remained mild and acceptable. Eleven percent of patients became completely pain-free. The need for pain medication decreased significantly within 3 weeks after start of therapy. These results were reproduced in a multicenter trial that also showed that symptomatic improvement lasted for an average of 6 months.207
In a randomized study of patients with metastatic prostate cancer, placebo and study drug achieved similar pain alleviation but a significant survival benefit was observed in the treatment group.208
When patients were randomized to receive external beam radiation with or without 89Sr, overall survival and symptomatic relieve did not differ between groups. However, the need for pain medication and repeat radiation treatment was significantly reduced in the 89Sr group. Moreover, 89Sr treatment appeared to be associated with delayed disease progression.209 Bone marrow toxicity, albeit manageable, occurred more frequently in the 89Sr group.
In a trial of patients with metastatic prostate cancer, 89Sr treated patients required fewer radiotherapies to new disease sites.210 However, the effect on disease progression was not confirmed by others possibly caused by lower treatment doses applied.211
89Sr has also been combined with chemotherapy. For instance, 89Sr combined with low-dose cisplatinum achieved symptomatic improvement in >90% of prostate cancer patients when compared to improvement in 63% of patients who were treated with 89Sr alone.212
Taken together these results demonstrate that 89Sr therapy results in symptomatic improvements lasting for up to 6 months in patients with metastatic bone disease and one randomized trial suggested a survival benefit for patients undergoing 89Sr therapy.
186Rhenium (186Re) is a β-emitter with a maximal emission of 1.07 MeV and a half-life of 89 hours. It also emits γ-emission of 137 keV which makes it suitable for γ-camera imaging. It strongly binds to hydroxyapatite and was first proposed as a therapeutic for metastatic bone pain in 1979.213 After chelating it with hydroxyethylidene disphosphonate (HEDP) and after intravenous injection its maximal uptake in the skeleton already occurs after 3 hours214whereby lesion-to-marrow dose ratios of 30:1215 or even higher216 have been reported.
Its relatively short half-life has potential advantages including higher dose rates, limited potential for repair of radiation-induced damage, multiple dosing, and a more rapid palliation.217 Dose escalation studies revealed a maximum tolerated dose (MTD) of 2,960 and 2,405 MBq in prostate and breast cancer, respectively.218,219
Reversible myelosuppression affects thrombocytes and leucocytes with the nadir reached after 4 weeks.
The degree of myelosuppression can be predicted from the bone scan index (BSI) normalized to body surface area.214 A flare-up of symptoms occurs in about 30% of patients.220 Efficacy appears to be comparable to that of 89Sr with symptomatic response rates ranging from 50% to 92%.217
Thus, 186Re has some potential advantages over 89Sr because of its shorter half-life, rapid onset of palliative effects, lower bone marrow toxicity, and the ability to administer multiple doses. Its use has been approved in several European countries and is justified in patients with the most severe bone pain (caused by its rapid onset of action) and limited life expectancy in whom rapid pain relief is necessary.
188Rhenium (188Re), a generator produced isotope that is a high-energy β-emitter, has a short half-life of 16.9 hours. Its maximum energy is 2.1 MeV resulting in a β-range of 10 mm. Because of this long-range bone marrow toxicity is a concern. 188Re treatment results in symptomatic improvement of 64% of patients with hormone refractory prostate cancer.221 The same group subsequently conducted a randomized trial in hormone refractory prostate cancer to compare a single to repeated doses of 188Re.222 Repeated dosing resulted in improved pain palliation and improved progression-free and overall survival (by 5 months). Larger trials in a variety of cancers will be needed to firmly establish the role of 188Re for bone pain palliation.
153Samarium (153Sm) was approved by the US FDA in the late 1990s. It is a lanathanide and is chelated with ethylenediamine tetramethylene phosphate (EDTMP). It has a half-life of 46.3 hours and decays by relatively low energy β-emission (0.81 MeV maximum energy). Its target is hydroxyapatite and bone uptake is very rapid (5.5 minutes) and so is renal clearance (65 minutes).223 Overall skeletal uptake is high and correlates with tumor load.
Myelotoxicity occurs in 20% to 40% of patients but only at high doses.224 Symptomatic improvement is achieved in up to 80% of patients.225 153Sm application appears to be well tolerated and pain flare is rare.
A randomized placebo-controlled study of 118 patients who received 1 mCi/kg of 153samarium showed significant pain reductions in up to 72% of patients. Complete relief was seen in 31% by week 4. Forty-three percent of patients improved symptomatically after 16 weeks. Bone marrow suppression was mild, and no grade 4 toxicity was reported.226 153Sm but not placebo resulted in pain relief and reduced need for opiates in another randomized trial.227
Two different dose regimens (18.5 MBq/kg versus 37 MBq/kg) were assigned randomly to a mixed population of cancer patients.228 The higher dose significantly improved pain levels and sleep patterns. Survival benefits associated with the higher dose were seen in breast but not in prostate cancer patients.228
Other radiopharmaceuticals such as 117mSn and 223Ra are undergoing clinical evaluations. 223Ra (alpharadin) is of particular interest because it is the first radiopharmaceutical that appears to significantly prolong life in castrate-resistant prostate cancer patients with widespread metastatic disease. In a phase II study, patients with bone metastatic prostate cancer were treated with external beam radiation and were randomized to alpharadin or placebo. The study drug reduced bone pain, bone alkaline phosphatase, and PSA and tended to improve patient survival.229 A subsequent phase III trial in castrate-resistant prostate cancer patients with bone metastases demonstrated that “best” treatment combined with alpharadin resulted in a survival benefit of 3 months.230 Bone marrow toxicity was minimal. Because of the survival benefit the trial was stopped and alpharadin was fast tracked by the FDA. Approval of this therapeutic is expected in the near future. This new approach marks the first therapeutic radiopharmaceutical that has an impact on patient survival.
Comparison Between Radiopharmaceuticals for Bone Pain Palliation
Two randomized clinical trials compared the effectiveness of radiopharmaceuticals to alleviate bone pain in metastatic breast and prostate cancer. Comparisons between 89Sr and 153Sm231 and 89Sr versus 186Re232 have been performed.
89Sr and 153Sm achieved comparable palliation in 100 patients that was however dependent on the phenotype of bone metastases; responses were attenuated in patients mixed osteoblastic/osteolytic metastases. Complete pain responses tended to be more frequently observed with 153Sm (40% versus 29%).
In a randomized trial of 50 breast cancer patients 186Re achieved earlier pain responses than 89Sr.232 Duration of responses was comparable and averaged more than 3 months in both groups. Myelosuppression was similar in both groups but occurred earlier in patients treated with 186Re.
Similar pain responses were reported for alpharadin.230
No randomized studies that compared pain responses to external beam radiation or medical treatment with biphopshonates to those achieved by radionuclide approaches have been reported.
In summary, a variety of palliative treatment options are available for patients with bone metastases. These include medical therapy, external beam radiation, and radionuclide therapy. The recent study demonstrating a survival benefit of patients undergoing alpharadin (223Ra) therapy230 suggests that this approach that is safe and effective will be widely adopted. Future trials will have to determine whether synergistic treatment approaches that combine medical with radionuclide therapy will result in further survival benefits.
Selection of Patients for Radionuclide Therapy of Metastatic Bone Pain
Patients with limited bone involvement, those with acceptable pain control using analgesics, and those with normal complete blood count are most likely to symptomatically benefit from radionuclide therapy whereas those with widespread disease appear to benefit least. Patients with a life expectancy of less than 3 months are no longer candidates for radionuclide therapies using β-emitters because the pain flare-up might interfere with the quality of life.
Prerequisites for the use of radiopharmaceuticals include confirmation of osteoblastic lesions by bone scans shortly before treatment is administered and matching sites of pain and bone scan findings. Bone scans detect predominantly or at least partially osteoblastic lesions. This is important because radiopharmaceuticals are likely less effective in patients with osteolytic, bone scan negative lesions.
For β-emitter therapy, hematologic assessments as well as renal function tests are mandatory because impaired renal function requires dose adjustments. The glomerular filtration rate should be >30 mL/min. Impending fracture or spinal cord compressions are contraindications for radionuclide therapy because these are the domain of surgery or external beam radiation. A platelet count of >10,000/mL and a white blood cell (WBC) count of >2,500/mL are required. WBC and platelet counts should be monitored in 2-week intervals after treatment. Reductions of 50% in WBC or platelet counts can occur. Therefore, more frequent monitoring might be indicated in patients with low baseline counts. Patients can be retreated but at least 3 months should have elapsed before such retreatment is done. After this time interval retreatment is only excluded if myelosuppression persists.
Comparative studies have not shown clear therapeutic benefits of one over another β-emitting radiotherapeutic isotope. Therefore, selection of the radionuclide for pain palliation can be made based on availability, cost, and experience.233
In summary, a large body of evidence underscores the importance of radionuclide bone imaging approaches in developing initial and subsequent therapy approaches in patients with malignant bone disease. Radionuclide techniques are an essential component of the management of patients with primary and metastatic bone cancers. Hybrid imaging techniques including SPECT/CT and PET/CT have yielded improved accuracy for detecting bone involvement and for assessing therapeutic responses. A variety of novel PET imaging probes have become available that will provide insights into the metabolic phenotype of bone cancers. These include hormone receptor imaging approaches as well as probes of tumor lipid metabolism such as labeled choline which might provide additional refinements in patient stratification and treatment response assessments. These novel imaging probes will likely reshape therapeutic approaches by allowing for more individualized therapy approaches in patients with metastatic bone disease.
Radionuclide therapy for metastatic bone disease is well-established and its symptomatic benefits and impact on disease progression have been documented. It appears very likely that radionuclide therapy with 223Ra will be used extensively because of its favorable safety profile and its beneficial effect on patient survival.
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