R. Lor Randall

Feasibility and dose discovery analysis of zoledronic acid with concurrent chemotherapy in the treatment of newly diagnosed metastatic osteosarcoma: A report from the Children’s Oncology Group

AIMnPatients with metastatic osteosarcoma (OS) have a poor outcome with conventional therapies. Zoledronic acid (ZA) is a third-generation bisphosphonate that reduces skeletal-related events in many adult cancers, and pre-clinical data suggest a possible benefit in OS. This study assessed the maximum tolerated dose (MTD) and the feasibility of ZA when combined with chemotherapy in patients with metastatic OS.nnnPATIENTS AND METHODSnPatients with a histological diagnosis of OS were eligible if they were <40 years of age, had initially metastatic disease and met organ function requirements. Treatment combined surgery and a conventional chemotherapy regimen. ZA was given concurrent with chemotherapy for a total of eight doses over 36 weeks. Three dose levels of ZA were tested: 1.2 mg/m(2) [max 2 mg], 2.3 mg/m(2) [max 4 mg] and 3.5 mg/m(2) [max 6 mg]. The MTD was determined during induction. Six patients were to be treated at each dose level, with an additional six patients treated with the MTD to help assess post-induction feasibility.nnnRESULTSnTwenty-four patients (median age 13.5 years [range, 7-22]; 16 females) were treated. Five patients experienced dose-limiting toxicities (DLTs) during induction, including three patients treated with 3.5 mg/m(2). DLTs included hypophosphatemia, hypokalemia, hyponatremia, mucositis, limb pain and limb oedema. There were no reports of excessive renal toxicity or osteonecrosis of the jaw. The MTD was defined as 2.3 mg/m(2) (max 4 mg).nnnCONCLUSIONSnZA can be safely combined with conventional chemotherapy with an MTD of 2.3 mg/m(2) (max 4 mg) for patients with metastatic osteosarcoma.

Effect of Time to Resumption of Chemotherapy After Definitive Surgery on Prognosis for Non-Metastatic Osteosarcoma

BACKGROUNDnThe dose intensity of chemotherapy has been described as affecting the outcome of the treatment of a number of different types of tumors. A delay in the resumption of chemotherapy after definitive surgery for the treatment of osteosarcoma can decrease the overall dose intensity. The goal of this study was to assess the prognostic significance of the time to resumption of chemotherapy after definitive surgery in patients with localized osteosarcoma in an extremity.nnnMETHODSnThe relationships of the time between definitive surgery and resumption of chemotherapy with death and adverse events in 703 patients with a localized resectable osteosarcoma in an extremity (556 treated in the Childrens Oncology Group [COG] Study [INT 0133] and 147 treated at five tertiary care cancer centers) were assessed with use of Cox proportional hazards models.nnnRESULTSnThe twenty-fifth, fiftieth, and seventy-fifth percentiles of time from definitive surgery to resumption of chemotherapy were twelve, sixteen, and twenty-one days, respectively. Overall survival was poorer for patients who had had a delay of greater than twenty-one days before the resumption of chemotherapy compared with those who had had a shorter delay (hazard ratio = 1.57 [95% confidence interval = 1.04 to 2.36]; p = 0.03). Of seventy-one COG-study patients with postoperative complications, 32% (twenty-three) had a delay of more than twenty-one days before resumption of chemotherapy, but 20% (eighty-nine) of 444 patients with no complications had a similar delay.nnnCONCLUSIONSnIn this retrospective analysis, increased time from the definitive surgery to the resumption of chemotherapy was found to be associated with an increased risk of death of patients with localized osteosarcoma in an extremity. Within the limitations of a retrospective study, the data indicate that it is best to resume chemotherapy within twenty-one days after definitive surgery. Surgeons, oncologists, patients, and those responsible for scheduling need to work together to ensure timely resumption of chemotherapy after surgery.

Reconstruction of Noncontained Distal Femoral Defects with Polymethylmethacrylate and Crossed-Screw Augmentation: A Biomechanical Study

BACKGROUNDnCurettage and cementation with polymethylmethacrylate are frequently used in the treatment of aggressive benign bone lesions such as giant-cell tumors, but strength and stiffness of the reconstructed bone have been concerns. This biomechanical study was undertaken to determine whether augmenting the cement with crossed screws would result in a stronger reconstruction.nnnMETHODSnLarge noncontained defects were created in the medial femoral condyles of twenty matched pairs of human cadavera. Four groups were organized to compare three types of reconstruction: (1) polymethylmethacrylate alone, (2) polymethylmethacrylate and intramedullary Steinmann pins, and (3) polymethylmethacrylate with crossed screws engaging the opposite cortex. The specimens were subjected to 2000 compressive cycles and were subsequently monotonically loaded to failure under a controlled displacement rate. Failure load and stiffness were determined for each femur that survived the cycling process.nnnRESULTSnFemora reconstructed with crossed screws and cement failed at higher loads and had greater stiffness than those reconstructed with cement alone (p = 0.025 and p = 0.0007) or cement augmented with intramedullary Steinmann pins (p = 0.019). Failure of femora reconstructed with cement and crossed screws occurred through an extra-articular transverse fracture, while failure in those with cement alone and cement with Steinmann pins occurred through an intra-articular (intercondylar) fracture.nnnCONCLUSIONSnIn this in vitro cadaver study, augmentation of polymethylmethacrylate cement with crossed screws resulted in a stronger reconstruction of distal femoral tumor defects than that obtained with cement alone or with cement and intramedullary Steinmann pins.

Surgery alone is sufficient therapy for children and adolescents with low-risk synovial sarcoma: A joint analysis from the European paediatric soft tissue sarcoma Study Group and the Children's Oncology Group

BACKGROUNDnMultimodal risk-adapted treatment is used in paediatric protocols for synovial sarcoma (SS). Retrospective analyses suggest that low-risk SS patients can be safely treated with surgery alone, but no prospective studies have confirmed the safety of this approach. This analysis pooled data from the two prospective clinical trials to assess outcomes in SS patients treated with a surgery-only approach and to identify predictors of treatment failure.nnnMETHODSnPatients with localised SS enrolled on the European paediatric Soft tissue sarcoma Study Group (EpSSG) NRSTS2005 and on the Children Oncology Group (COG) ARST0332 trials, treated with surgery alone were eligible for this analysis. Patients must have undergone initial complete resection with histologically free margins, with a grade 2 tumour of any size or a grade 3 tumour ≤5xa0cm.nnnRESULTSnSixty patients under 21 years of age were eligible for the analysis; 36 enrolled in the COG (from 2007 to 2012) and 24 in the EpSSG study (from 2005 to 2012). The 3-year event-free survivalxa0was 90% (median follow-up 5.2 years, range 1.9-9.1). All eight events were local tumour recurrence, whereas no metastatic recurrences were seen. All patients with recurrence were effectively salvaged, resulting in 100% overall survival.nnnCONCLUSIONnThis joint prospective analysis showed that patients with adequately resected ≤5xa0cm SS, regardless of grade, can be safely treated with a surgery-only approach. Avoiding the use of adjuvant chemotherapy and radiotherapy in this low-risk patient population may decrease both short- and long-term morbidity and mortality.

Bone Metastases: Epidemiology and Societal Effect

The incidence of skeletal metastases is increasing as survival from cancer increases. This introductory chapter looks at the epidemiology of metastatic bone disease and the impact of increasing survival of patients with cancer. The incidence of skeletal related events (SREs) and pathological fracture are reviewed from epidemiological data and the placebo wings of randomized trials of bisphosphonate therapy in metastatic bone disease. The economic and social burden of SREs in metastatic bone disease to health organizations, both patients and caregivers, and the wider economy are reviewed and updated to 2014 costs.

Twenty Years of CTOS: The Transdisciplinary Society Dedicated to Studying the Rare and Helping the Underserved

Since its inception in 1995, the international Connective Tissue Oncology Society (CTOS) has been dedicated to improving the clinical outcomes for patients with a rare but often aggressive form of mesenchymal neoplasia, collectively known as sarcomas. Physicians and scientists from around the world have come together once a year to share their latest data, imparting wisdom but also taking critical feedback from the membership. Every medical discipline is represented in the Society as well as on the board of directors and presidential line. Over the span of 20 years, we have grown from an initial meeting of ten experts gathering in the basement of Massachusetts General Hospital to over 1100 members from 29 countries. The last meeting, held in Salt Lake City, Utah, hosted 354 abstracts covering all aspects of sarcomatology and honored our founding father, Herman Suit, MD. Our featured speakers included two world-renowned clinical and molecular pathologists, Christopher Fletcher, MD, and Julia Bridge, MD, respectively. Symposia included models and approaches to the study of sarcoma, genetic risk, and adolescent and young adult oncology. We also had a special session dedicated to circulating tumor DNA. Each year has seen a growth in the quantity and quality of intellectual effort. Much thanks must be given to our immediate past president, Paolo Dei Tos, MD, our program co-chair, Matt van de Rign, MD, PhD, and the program committee. Because the majority of the sarcoma professional community travels to CTOS, the American Association for Cancer Research (AACR) holds their sarcoma basic biology meeting adjacent to CTOS when in the United States. Furthermore, SARC, the clinical trials organization, also holds one of their semiannual meetings at CTOS (the other being ASCO). This coming fall, we travel to Lisbon under the auspices of the Annals’ own Alessandro Gronchi, who currently serves as our president. It is sure to be a magnificent program, with the latest and most relevant research in sarcomatology presented by our committed international membership. In this month’s issue of the Annals, two articles have been chosen to celebrate and reflect our commitment and passion to studying the rare and helping the underserved. The first, by colleagues in the Netherlands, investigates cell cycle activity in synovial sarcoma (SS), the most common soft tissue sarcoma in adolescents and young adults. Although it is a connective tissue cancer whose cell of origin remains obfuscating (although it may be the myoblast), its relatively well-defined molecular chimeric pathogenic signature (SS18, -SSX1,2,4) makes it an attractive sarcoma to investigate for molecular targeting. SS can be quite aggressive, often consuming its host from metastatic propagation, and accordingly more refined biotargeting is needed. Specifically, Vlenterie et al. looked at in vitro cyclin-dependent kinase activity but also assay expression of several key cell cycle regulators to determine its prognostic significance in over 40 human specimens. They also suggested that pablociclib may have a therapeutic role in a subset of SSs. While these data requires further preclinical support, perhaps in patient-derived xenographs or genetically engineered mouse models, it lays a foundation for further inquiry where therapeutic options remain quite limited. The second article, by an Italian group, looked at response rates of the exceptionally rare epithelioid hemangioendothelioma (EHE) to sirolimus, a mammalian target of rapamycin (mTOR) inhibitor. By combining the Society of Surgical Oncology 2016

Highlights from the first combined 2011 meeting of the Musculoskeletal Tumor Society and Connective Tissue Oncology Society: editorial comment: cooperation to move the hope curve to the right.

Cooperation. Collaboration. Working together. When we strive to embody these values, we are better. When we do not, we are less. n nOur patients are our joint responsibility. When we collaborate, caring for them together, they do better. When we do not, they do less well. n nSarcomas are a threat to life and limb, and surgery is our most effective treatment. In many ways, it is the ultimate targeted therapy. In most localized tumors, we can achieve a complete response much more effectively than by any other modality. As surgeons, we strategically remove tumors, preserving as much function as possible, and hope for the best. The best does not always come. Often, the complete responses are not sufficiently durable. Whenever possible, we look to our colleagues in other specialties to improve the results from surgery alone. n nIn certain types of sarcomas, there is a role reversal: chemotherapy is the backbone of treatment, with surgery as the adjuvant for local cleanup. For example, with systemic chemotherapy, we tripled the survival rate in osteosarcoma, Ewing’s sarcoma, and rhabdomyosarcoma, compared to the rate achieved with local control alone. Similarly, in a majority of soft tissue sarcomas, we rely on the expertise of our radiation oncology colleagues to improve our ability to control the local tumor. n nAll too often our local and systemic tools are limited, and we are left hoping for the best. New tools to enhance the impact of our care are a necessity. Enter the molecular scalpel. Biotargeting, in the form of directed monoclonal antibodies and small molecule inhibitors, to name just two, have helped save lives and move the hope curve to advantage the survival of more patients with sarcoma. Without the efforts of our research colleagues, such tools would not be available to our patients. n nThe conditions we treat are rare. Consequently, it is only through analysis of our combined experience that we can establish reliable outcome data to determine whether our treatments are effective. This requires cooperation. Leading the way toward this goal are the Radiation Therapy Oncology Group (RTOG), Eastern Cooperative Oncology Group (ECOG), SWOG (formerly the Southwest Oncology Group), Children’s Oncology Group (COG), and the Sarcoma Alliance for Research through Collaboration (SARC), to name a few. Some of us are active in these groups; more of us should be. n n nThe Musculoskeletal Tumor Society (MSTS) has convened numerous combined meetings with the International Society of Limb Salvage (ISOLS), the European Musculo-Skeletal Oncology Society (EMSOS), and now the Connective Tissue Oncology Society (CTOS). These combined meetings bring out the best from our learned societies as we search to better understand the pathophysiology of sarcomas and treat them more successfully. We hope you enjoy reading these select symposium papers from the 2011 MSTS/CTOS combined meeting. As you read them, we hope two common themes will resonate: (1) cooperation across disciplines stimulates new ways of thinking and (2) interdisciplinary approaches enhance outcomes. A commitment to transdisciplinary cooperation will promote the synergies that we need to move beyond hope and cure more patients. On behalf of both societies, we trust you will enjoy this symposium. n n n nFig.xa01 n nR. Lor Randall, MD, FACS, Past President, CTOS, and Chair, Orthopaedic Committee, COG, is shown. n n n n n n n nFig.xa02 n nJohn H. Healey, MD, FACS, President, MSTS, and Past Chair, Orthopaedic Committee, COG, is shown.