Appendix 2. Final list candidate research questions and associated tiers for progression to Phase III
Tier 1–Met INCLUSION Threshold
1 Question
Question No. / Research Question / Study Design / Category1 / Does denosumab and/or systemic bisphosphonates reduce recurrence rates in resectable GCT? / RCT / Benign Bone Tumor
Tier 2–Met NONCONSENSUS Threshold (Average Consensus ≥70%)
15 Questions
Question No. / Research Question / Study Design / Category2 / Does pre- versus postoperative denosumab decrease recurrence rates in resectable GCT? / RCT / Benign Bone Tumor
3 / What are the long-term effects of denosumab in unresectable GCT? / Prospective Cohort / Benign Bone Tumor
6 / Does cementation reduce aseptic loosening compared with press fit in endoprosthetic reconstruction? / RCT / Sarcoma–General
8 / What treatment options are effective for patients with OS or EWS who do not respond to standard therapy? / Phase II Trial (of novel compounds) / Malignant Bone Tumor
9 / What is the role of immunotherapy in sarcoma? / Phase I Trial / Sarcoma–General
15 / Does less intensive surveillance of patients with sarcoma affect survival? / RCT (stratified by sarcoma risk) / Sarcoma–General
16 / What is an effective negative margin? / Prospective Cohort (with attention to sarcoma subtype [such as myxofibrosarcoma]) / Sarcoma–General
21 / Does silver coating on endoprostheses reduce surgical site infections? / RCT / Sarcoma–General
25 / Development of a validated PROM specific for patients with extremity sarcoma. / Prospective Cohort / Sarcoma–General
26 / Development of targeted therapy for patients with sarcoma. / Bench Work / Preclinical
34 / Is surveillance of low-grade cartilage lesions necessary? / Prospective Cohort (with a focus on imaging modalities) / Malignant Bone Tumor
43 / Does local TXA reduce postoperative blood loss in sarcoma surgery? / RCT / Sarcoma–General
44 / Does systemic TXA reduce blood loss in sarcoma surgery? / RCT / Sarcoma–General
49 / Do circulating tumor cells in patients with OS predict outcome? / Prospective Cohort / Malignant Bone Tumor
69 / What is the most effective second-line chemotherapy protocol for refractory OS? / RCT / Malignant Bone Tumor
Tier 3 – Met NONCONSENSUS Threshold (Average Consensus = 65%-69%)
10 Questions
Question No. / Research Question / Study Design / Category4 / Do local bisphosphonates and/or cementation reduce local recurrence rates in resectable GCT? / RCT / Benign Bone Tumor
10 / Development of decision-making algorithm for MBD and validation of existing prediction models. / Prospective Cohort / Metastatic Bone Disease
14 / Prospective orthopaedic oncology unified registry that includes any implant data (US versus international). / Registry / Sarcoma–General
17 / Can margins be determined intraoperatively? / Prospective Cohort (of novel approaches) / Sarcoma–General
19 / What is the relative efficacy of radiation versus surgery in pelvic EWS with respect to toxicities and functional and oncologic outcomes? / RCT / Malignant Bone Tumor
28 / Is proton beam radiotherapy effective in unresectable chordoma and chondrosarcoma? / Prospective Cohort / Malignant Bone Tumor
29 / Is local doxorubicin activation in STS effective for local and systemic control? / Phase I Trial / SoftTissue Sarcoma
38 / What are the PROs in rotationplasty versus growing prostheses in children? / Prospective Cohort / Sarcoma–General
48 / What are the risk factors for local relapse in patients with sarcomas resected with a negative margin? / Prospective Cohort / Sarcoma–General
58 / What is the natural history of untreated fibromatosis? / Prospective Cohort (International) / Fibromatosis
Tier 4–Met NONCONSENSUS Threshold (Average Consensus = 60%-64%)
13 Questions
Question No. / Research Question / Study Design / Category5 / What are the risk factors for aseptic loosening in distal femur endoprostheses? / Prospective Cohort / Sarcoma–General
11 / What are the best treatment options for patients with MBD that do not require surgery? / RCT / Metastatic Bone Disease
18 / What is the relative power of PET versus CT in sarcoma surveillance and treatment response? / RCT / Sarcoma–General
22 / What is the efficacy of standard cytotoxic chemotherapy in STS? / RCT / SoftTissue Sarcoma
23 / What is the relative efficacy and associated toxicities of 50 Gy versus 65 Gy in postoperative radiotherapy for STS with the use of IMRT? / RCT / SoftTissue Sarcoma
24 / What is the relative efficacy and associated toxicities of preoperative versus postoperative 50 Gy radiotherapy for STS with the use of IMRT? / RCT / SoftTissue Sarcoma
40 / What is the optimal filling agent for cavitary bone defects? / RCT (allograft versus cement versus synthetic) / Benign Bone Tumor
47 / Is miRNA targeting effective in sarcoma management? / Bench/Animal Work followed by Phase I Trial / Preclinical
51 / What is the efficacy of stereotactic radiation for lung metastases with respect to survival and local control of the metastases? / Phase II Trial / Sarcoma-General
54 / What reconstruction approach provides the best functional outcomes for proximal humerus reconstruction? / RCT (APC versus endoprosthesis versus reverse shoulder arthroplasty) / Malignant Bone Tumor
59 / What are the outcomes of treated fibromatosis? / Registry (International) / Fibromatosis
60 / What are the relative efficacies of systemic options versus surgery versus radiotherapy in fibromatosis? / RCT / Fibromatosis
66 / What are the success rates of one- versus two-stage reimplantation for infected endoprostheses? / RCT / Sarcoma–General
Tier 5–Met NONCONSENSUS Threshold (Average Consensus = 50%-59%)
17 Questions
Question No. / Research Question / Study Design / Category7 / What percent necrosis indicates a good prognosis in bone sarcoma? / Prospective Cohort / Malignant Bone Tumor
12 / Does computer-assisted/navigated oncologic surgery improve functional and oncologic outcomes? / Cluster RCT / Sarcoma–General
27 / Does pelvic reconstruction improve functional outcomes in sarcoma surgery? / RCT / Malignant Bone Tumor
30 / What are the functional outcomes of patients with MBD? / Registry or Prospective Cohort (with functional evaluations) / Metastatic Bone Disease
35 / What are the functional and surgical outcomes of resection versus internal fixation for MBD of the proximal femur? / RCT (various surgical techniques) / Metastatic Bone Disease
37 / What is the complication rate of growing implants in children requiring reoperation and what are the PROs? / Prospective Cohort / Sarcoma–General
39 / What is the efficacy of novel synthetic agents designed to reduce the impact of local tissue damage in large and irradiated surgical fields? / Phase I Trial (of synthetic agents) / Sarcoma–General
46 / Does resection versus stabilization improve oncologic outcomes in oligometastatic bone disease without compromising functional and surgical outcomes? / RCT / Metastatic Bone Disease
52 / Are adjuvant treatments effective in chondrosarcoma? / RCT (radiotherapy versus systemic agents) / Malignant Bone Tumor
53 / What is the most sensitive screening modality for lymph node metastases? / Prospective Cohort (with pathologic confirmation) / Sarcoma–General
55 / What is the relative efficacy and toxicity of immediate (24 hours) versus delayed (14 days) postoperative radiotherapy for MBD? / RCT / Metastatic Bone Disease
56 / Development of a survival prediction model in sarcoma for personalized prognosis. / Bayesian Model (using big data and molecular profiling) / Sarcoma–General
62 / Does short-stem fixation increase the risk for fracture in MBD in comparison to long-stem fixation? / RCT (monitor for DVT/PE) / Metastatic Bone Disease
63 / Does radiotherapy improve local control for low-grade STS? / RCT / SoftTissue Sarcoma
64 / Development of a Sarcoma Pathology Index. / Modified Delphi/Validation Phase Followed by International Collaboration / Sarcoma–General
67 / What are the risk factors for poor histologic response to chemotherapy in bone sarcomas? / Prospective Cohort? / Malignant Bone Tumor
68 / Development of new minimally invasive techniques for the management of MBD. / Collaboration with Industry Followed by Phase I Trial / Metastatic Bone Disease
Tier 6–Met NONCONSENSUS Threshold (Average Consensus < 50%)
13 Questions
Question No. / Research Question / Study Design / Category13 / Do custom implants in oncologic surgery improve functional and oncologic outcomes? / Cluster RCT / Sarcoma–General
20 / What is the relative efficacy of radiation versus surgery in extremity EWS with respect to toxicities and functional and oncologic outcomes? / RCT / Malignant Bone Tumor
31 / Are tumor bed resections required for local and systemic control of sarcoma? / RCT (observation versus surgery versus radiotherapy) / Sarcoma – General
32 / Does the prechemotherapy MRI predict tumor extent as per pathological assessment? / Prospective Cohort / Sarcoma – General
33 / Do planned positive margins in bone sarcoma surgery with good preoperative chemotherapy response increase the risk for local and systemic relapses? / RCT (wide versus focally positive margins) / Malignant Bone Tumor
36 / What is the relative efficacy and bleeding risk of various thromboprophylaxis options in MBD of the femur? / RCT (coumadin versus heparin versus fractionated heparin versus direct factor Xa inhibitors) / Metastatic Bone Disease
41 / What techniques and approaches are helpful in guiding growth in patients with MHE? / Prospective Cohort / Benign Bone Tumor
42 / What is the relative efficacy of preoperative versus postoperative chemotherapy in bone sarcoma with respect to surgical and functional outcomes? / RCT / Malignant Bone Tumor
45 / Do surgical drains reduce the rate of postoperative hematomas for endoprosthetic reconstruction? / RCT / Sarcoma–General
50 / What are the implications of the high volume of practicing orthopaedic oncologists with respect to practice patterns and individual surgeon volume and expertise? / Prospective Nonclinical Cohort / Miscellaneous
57 / Development of advances in osteointegration. / Bench/Animal Work / Preclinical
61 / What are the relative oncologic and functional outcomes for low-grade chondrosarcoma? / RCT (wide versus intralesional resection) / Malignant Bone Tumor
65 / What are the oncologic outcomes and surgical outcomes after reconstruction with structural allograft versus irradiated autograft in segmental bone defects? / RCT / Sarcoma–General
Tier 7–NEW Suggestions
4 Questions
Question No. / Research Question / Study Design / Category70 / Once a local recurrence is noted (earlier or later), do the interventions currently available have an impact on a patient’s outcome? / Sarcoma–General
71 / Development of patient specific followup protocol in different histotypes. / Sarcoma–General
72 / Are current doses of radiation therapy for metastatic disease adequate? / Biopsy postradiation and testing for viability in cell culture OR an RCT of conventional dose versus a higher dose / Metastatic Bone Disease
73 / Efforts should be directed toward being able to establish whether neoadjuvant chemotherapy is effective after 2 cycles. / RCT--If able to be determined in some fashion (quantifiable PET/CT,functional MRI, cell factor released upon apoptosis, etc), then stratification could be done into favorable or unfavorable arms. In the favorable arm, chemotherapy would continue for 2-4 cycles before resection and surveillance. In the unfavorable arm, additional agents and time of therapy could be added to address poor response. Surgery interrupts chemotherapy, allows emergence of resistant cells, and induces a hit to the patient's immune system, which should be avoided until upfront therapy is completed. / Malignant Bone Tumor
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