ACR Appropriateness Criteria® Spinal Bone Metastases

The spine is a common site of involvement in patients with bone metastases. Apart from pain, hypercalcemia, and pathologic fracture, progressive tumor can result in neurologic deterioration caused by spinal cord compression or cauda equina involvement. The treatment of spinal bone metastases depends on histology, site of disease, extent of epidural disease, extent of metastases elsewhere, and neurologic status. Treatment recommendations must weigh the risk-benefit profile of external beam radiation therapy (EBRT) for the particular individual's circumstance, including neurologic status, performance status, extent of spinal disease, stability of the spine, extra-spinal disease status, and life expectancy. Patients with spinal instability should be evaluated for surgical intervention. Research studies are needed that evaluate the combination or sequencing of localized therapies with systemic therapies including chemotherapy, hormonal therapy (HT), osteoclast inhibitors (OI), and radiopharmaceuticals. The roles of stereotactic body radiation therapy (SBRT) in the management of spinal oligometastasis, radioresistant spinal metastasis, and previously irradiated but progressive spinal metastasis are emerging, but more research is needed to validate the findings from retrospective studies. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140115/1/jpm.2012.0376.pd

ACR Appropriateness Criteria® Non-Spine Bone Metastases

Abstract Bone is one of the most common sites of metastatic spread of malignancy, with possible deleterious effects including pain, hypercalcemia, and pathologic fracture. External beam radiotherapy (EBRT) remains the mainstay for treatment of painful bone metastases. EBRT may be combined with other local therapies like surgery or with systemic treatments like chemotherapy, hormonal therapy, osteoclast inhibitors, or radiopharmaceuticals. EBRT is not commonly recommended for patients with asymptomatic bone metastases unless they are associated with a risk of pathologic fracture. For those who do receive EBRT, appropriate fractionation schemes include 30?Gy in 10 fractions, 24?Gy in 6 fractions, 20?Gy in 5 fractions, or a single 8?Gy fraction. Single fraction treatment maximizes convenience, while fractionated treatment courses are associated with a lower incidence of retreatment. The appropriate postoperative dose fractionation following surgical stabilization is uncertain. Reirradiation with EBRT may be safe and provide pain relief, though retreatment might create side effect risks which warrant its use as part of a clinical trial. All patients with bone metastases should be considered for concurrent management by a palliative care team, with patients whose life expectancy is less than six months appropriate for hospice evaluation. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98458/1/jpm%2E2011%2E0512.pd

Clinical Consensus Guideline on the Management of Phaeochromocytoma and Paraganglioma in Patients Harbouring Germline SDHD Pathogenic Variants

Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches. The axiom-first, do no harm-should always be considered and an initial period of observation (ie, watchful waiting) is often appropriate to characterise tumour behaviour in patients with these pathogenic variants. These patients should be referred to specialised high-volume medical centres. This consensus guideline aims to help physicians with the clinical decision-making process when caring for patients with SDHD PPGLs

Sequential Administration of Bortezomib, Liposomal Doxorubicin and Dexamethasone (BDD) Followed by Thalidomide and Dexamethasone (TD) Results in Rapid Control of Untreated High-Risk Multiple Myeloma (MM) and Improves Depth of Response

Abstract Background: Doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective, well-tolerated regimen for pts with MM. We previously reported an overall response rate (ORR) of 90.5%, with 35% achieving nCR/CR in 45 newly diagnosed pts, the majority of whom were ISS I (62%). Despite similar ORR, a survival analysis demonstrated inferior outcomes for pts with ISS II, ISS III or softtissue involvement by disease. Based on our experience, we designed a phase II study incorporating bortezomib and liposomal doxorubicin into the upfront treatment of pts with high-risk MM (ISS II, III or ISS I with soft-tissue disease). The aims of the study were to determine the safety and efficacy of bortezomib, pegylated doxorubicin and dexamethasone followed by thalidomide and dexamethasone (with or without bortezomib) in pts with untreated poor-risk or primary refractory MM. We correlated disease response with PET response to determine if there was concordance (or discordance) in these pts. Methods: 34 pts with high-risk MM have been enrolled. Treatment includes BDD (bortezomib 1.3mg/m2 IV days 1, 4, 8, and 11, liposomal doxorubicin 30mg/m2 IV on day 4, and dexamethasone 20mg PO on the day of and the day after bortezomib) for three 21-day cycles followed by 2 cycles of TD (thalidomide 200mg PO daily and dexamethasone 40mg PO on days 1–4, 9–12, 17–20) every 28 days for patients achieving at least PR, or BTD (less than a PR after BDD). Prophylactic use of acyclovir, fluconazole, and pyridoxine was implemented throughout the study. Aspirin 81mg or low molecular weight heparin (in patients with increased risk for VTE) was mandated during the TD portion of the study. Response was assessed using International Myeloma Working Group (IMWG) uniform response criteria. PET scans were performed at baseline, following BDD and at end of study (EOS) to determine the role of functional imaging in pts with high-risk MM. Results: At the time of this analysis, 28 pts have completed study and are evaluable. Baseline characteristics include median age of 58 years (range 41–80), 61% male, 43% (12/28) ISS II, 46% (13/28) ISS III, and 11% (3/28) ISS I with soft-tissue disease. Sixty-four percent of pts have abnormal cytogenetics: 39% (11/28) del 13q, 11% (3/28) t(4;14) and 7% (2/28) loss of p53 gene. Following BDD (1–3 cycles) the ORR was 79% with 25% CR/nCR and 36% ≥VGPR. At the EOS, the ORR remained 79%, however there is a significant improvement in the quality of response with 43% of pts achieving CR/nCR (p = 0.03) and 61% ≥VGPR (p = 0.008). Only 1 pt progressed on study based on skeletal survey findings despite achieving a serologic VGPR and improving clinically. Poor-risk cytogenetics (del 13q, t (4;14) or loss of p53) or soft-tissue disease did not affect response (p = 0.20 and p = 1.0, respectively). Of 11 pts with del 13q, 82% had ≥VGPR. Of the 5 pts with t (4;14) or loss of p53, 100% achieved ≥VGPR. There was poor agreement between EOS and PET response in the 19 pts who had PET data available, Kappa 0.11. The majority of pts (15/19) had PR by PET and 3 pts had SD. In the only pt that had progression by PET, IMWG response was VGPR and biopsy confirmed granulomatous disease rather than MM. Grades 3/4 neutropenia and thrombocytopenia occurred in 18% and 36% of pts, respectively. The incidence of neuropathy was 28%, but was grade 3 in only 1 pt (4%). Five pts developed DVT. Two pts developed asymptomatic decline in LVEF that improved with medical therapy. Fifty-seven percent of pts (16/28) have had successful stem cell harvest and have undergone ASCT. Three more pts have ASCT planned. Conclusions: BDD followed by TD (or BTD) results in rapid disease control with manageable toxicity in a poor-risk group of pts with MM. The depth of response is significantly improved with the sequential administration of novel agents, as has been demonstrated by other investigators (Jagannath ASH 2007). The 79% ORR is modest, however the ≥61% VGPR and 43% nCR/CR rates seen in these very high risk pts are comparable to initial therapy with VTD and Rev/Vel/Dex (Rajkumar ASH 2007 and Richardson ASH 2007, respectively) and are encouraging. High-quality responses were seen independent of cytogenetic abnormalities or the presence of soft-tissue disease. BDD followed by TD represents a promising therapeutic option for these pts. PET response does not correlate with IMWG response, perhaps due to the high sensitivity and lack of specificity of functional imaging

Sequential Administration of Bortezomib, Liposomal Doxorubicin and Dexamethasone (BDD) Followed by Thalidomide and Dexamethasone (TD) Results in Rapid Control of Untreated High-Risk Multiple Myeloma (MM) and Improves Depth of Response

Abstract Background: Doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective, well-tolerated regimen for pts with MM. We previously reported an overall response rate (ORR) of 90.5%, with 35% achieving nCR/CR in 45 newly diagnosed pts, the majority of whom were ISS I (62%). Despite similar ORR, a survival analysis demonstrated inferior outcomes for pts with ISS II, ISS III or softtissue involvement by disease. Based on our experience, we designed a phase II study incorporating bortezomib and liposomal doxorubicin into the upfront treatment of pts with high-risk MM (ISS II, III or ISS I with soft-tissue disease). The aims of the study were to determine the safety and efficacy of bortezomib, pegylated doxorubicin and dexamethasone followed by thalidomide and dexamethasone (with or without bortezomib) in pts with untreated poor-risk or primary refractory MM. We correlated disease response with PET response to determine if there was concordance (or discordance) in these pts. Methods: 34 pts with high-risk MM have been enrolled. Treatment includes BDD (bortezomib 1.3mg/m2 IV days 1, 4, 8, and 11, liposomal doxorubicin 30mg/m2 IV on day 4, and dexamethasone 20mg PO on the day of and the day after bortezomib) for three 21-day cycles followed by 2 cycles of TD (thalidomide 200mg PO daily and dexamethasone 40mg PO on days 1–4, 9–12, 17–20) every 28 days for patients achieving at least PR, or BTD (less than a PR after BDD). Prophylactic use of acyclovir, fluconazole, and pyridoxine was implemented throughout the study. Aspirin 81mg or low molecular weight heparin (in patients with increased risk for VTE) was mandated during the TD portion of the study. Response was assessed using International Myeloma Working Group (IMWG) uniform response criteria. PET scans were performed at baseline, following BDD and at end of study (EOS) to determine the role of functional imaging in pts with high-risk MM. Results: At the time of this analysis, 28 pts have completed study and are evaluable. Baseline characteristics include median age of 58 years (range 41–80), 61% male, 43% (12/28) ISS II, 46% (13/28) ISS III, and 11% (3/28) ISS I with soft-tissue disease. Sixty-four percent of pts have abnormal cytogenetics: 39% (11/28) del 13q, 11% (3/28) t(4;14) and 7% (2/28) loss of p53 gene. Following BDD (1–3 cycles) the ORR was 79% with 25% CR/nCR and 36% ≥VGPR. At the EOS, the ORR remained 79%, however there is a significant improvement in the quality of response with 43% of pts achieving CR/nCR (p = 0.03) and 61% ≥VGPR (p = 0.008). Only 1 pt progressed on study based on skeletal survey findings despite achieving a serologic VGPR and improving clinically. Poor-risk cytogenetics (del 13q, t (4;14) or loss of p53) or soft-tissue disease did not affect response (p = 0.20 and p = 1.0, respectively). Of 11 pts with del 13q, 82% had ≥VGPR. Of the 5 pts with t (4;14) or loss of p53, 100% achieved ≥VGPR. There was poor agreement between EOS and PET response in the 19 pts who had PET data available, Kappa 0.11. The majority of pts (15/19) had PR by PET and 3 pts had SD. In the only pt that had progression by PET, IMWG response was VGPR and biopsy confirmed granulomatous disease rather than MM. Grades 3/4 neutropenia and thrombocytopenia occurred in 18% and 36% of pts, respectively. The incidence of neuropathy was 28%, but was grade 3 in only 1 pt (4%). Five pts developed DVT. Two pts developed asymptomatic decline in LVEF that improved with medical therapy. Fifty-seven percent of pts (16/28) have had successful stem cell harvest and have undergone ASCT. Three more pts have ASCT planned. Conclusions: BDD followed by TD (or BTD) results in rapid disease control with manageable toxicity in a poor-risk group of pts with MM. The depth of response is significantly improved with the sequential administration of novel agents, as has been demonstrated by other investigators (Jagannath ASH 2007). The 79% ORR is modest, however the ≥61% VGPR and 43% nCR/CR rates seen in these very high risk pts are comparable to initial therapy with VTD and Rev/Vel/Dex (Rajkumar ASH 2007 and Richardson ASH 2007, respectively) and are encouraging. High-quality responses were seen independent of cytogenetic abnormalities or the presence of soft-tissue disease. BDD followed by TD represents a promising therapeutic option for these pts. PET response does not correlate with IMWG response, perhaps due to the high sensitivity and lack of specificity of functional imaging.</jats:p