Neoadjuvant pazopanib in nonrhabdomyosarcoma soft tissue sarcomas (ARST1321): A report of major wound complications from the Children's Oncology Group and NRG Oncology.

BACKGROUND AND OBJECTIVES: The impact upon wound healing of targeted molecular therapies, when incorporated into neoadjuvant therapy of soft tissue sarcoma, is largely unknown. Here, we describe wound complications following addition of pazopanib, a tyrosine kinase inhibitor (TKI), to neoadjuvant radiotherapy (RT) +/- chemotherapy for soft tissue sarcoma. METHODS: Wound complications were evaluated on dose-finding and randomized arms of ARST1321, a phase II/III study incorporating neoadjuvant RT, +/- pazopanib, +/- ifosfamide/doxorubicin (ID) for sarcoma therapy. RESULTS: Of 85 evaluable patients, 35 (41%) experienced postoperative wound complications. Most (57%) were grade III. Randomization to pazopanib + RT + ID carried a 50% wound complication rate (17/34, with 47% grade III), compared to 22% (5/23) with ID + RT alone. In nonchemotherapy study arms, pazopanib + RT resulted in a 59% wound complication rate versus 25% for those receiving RT alone. Grade III wound complications occurred among 26% (15/58) of all patients receiving pazopanib. Wound complications occurred a median of 35 days postoperatively. Some occurred following diagnostic biopsies and at remote surgical sites. CONCLUSION: The addition of pazopanib to neoadjuvant chemotherapy and RT resulted in a higher wound complication rate following therapy of soft tissue sarcoma. The rate of grade III complications remained comparable to that reported in contemporary literature.

Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial.

BACKGROUND: Outcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone. METHODS: In this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and <18 years) from 57 hospitals in the USA and Canada with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma, which were larger than 5 cm in diameter and of intermediate or high grade. Eligible patients had Lansky (if aged ≤16 years) or Karnofsky (if aged >16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m2 per dose intravenously on days 1-3 with mesna) and doxorubicin (37·5 mg/m2 per dose intravenously on days 1-2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients <18 years 350 mg/m2 once daily; if patients ≥18 years 600 mg once daily) or not (control group), with pazopanib not given immediately before or after surgery at week 13. The study projected 100 randomly assigned patients were needed to show an improvement in the number of participants with a 90% or higher pathological response at week 13 from 40% to 60%. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867. FINDINGS: Between July 7, 2014, and Oct 1, 2018, 81 eligible patients were enrolled and randomly assigned to the pazopanib group (n=42) or the control group (n=39). At the planned second interim analysis with 42 evaluable patients and a median follow-up of 0·8 years (IQR 0·3-1·6) in the pazopanib group and 1 year (0·3-1·6) in the control group, the number of patients with a 90% pathological response or higher was 14 (58%) of 24 patients in the pazopanib group and four (22%) of 18 patients in the control group, with a between-group difference in the number of 90% or higher pathological response of 36·1% (83·8% CI 16·5-55·8). On the basis of an interim analysis significance level of 0·081 (overall one-sided significance level of 0·20, power of 0·80, and O'Brien-Fleming-type cumulative error spending function), the 83·8% CI for response difference was between 16·5% and 55·8% and thus excluded 0. The improvement in pathological response rate with the addition of pazopanib crossed the predetermined boundary and enrolment was stopped. The most common grade 3-4 adverse events were leukopenia (16 [43%] of 37 patients), neutropenia (15 [41%]), and febrile neutropenia (15 [41%]) in the pazopanib group, and neutropenia (three [9%] of 35 patients) and febrile neutropenia (three [9%]) in the control group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. Paediatric and adult patients had a similar number of grade 3 and 4 toxicity. There were seven deaths (three in the pazopanib group and four in the control group), none of which were treatment related. INTERPRETATION: In this presumed first prospective trial of soft tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathological near complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft tissue sarcoma. The comparison of survival outcomes requires longer follow-up. FUNDING: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation.

Bone Tumors and Reconstructive Options in Pediatric and Young Adult Patients.

Sarcomas represent less than 1% of adult cancers but account for approximately 21% of pediatric malignancies and pose great risks for mortality and morbidity in children and young adults. Both benign bone and soft-tissue tumors may not be life-threatening but can be limb-threatening. Missed diagnosis, misdiagnosis, and mismanagement of either benign or malignant tumors may lead to increased mortality and morbidity. A good understanding of the clinical presentation, radiographic findings, and treatment options is needed to make the proper diagnosis and successfully treat these patients. Children and young adults present unique challenges in the management these tumors. Often, there is no right or wrong answer. Surgeons must work with patients and their families to make the right reconstructive decision.

Pazopanib therapy for desmoid tumors in adolescent and young adult patients.

BACKGROUND: Desmoid tumors/aggressive fibromatosis (DT/AF) lack a reliably effective medical therapy. Surgical resection may be morbid and does not preclude recurrence. Radiation may carry severe late effects, particularly detrimental in young patients. At our institution, we recently observed promising results with pazopanib therapy for DT/AF in adolescent and young adult (AYA) patients. PROCEDURE: Retrospective single-institution chart review. RESULTS: Six DT/AF patients of 3-21 years with previously treated DT/AF received pazopanib; 31 DT/AF patients received established therapies only. In both groups, median age at diagnosis was 16 years, female patients comprised 50%, and most common DT/AF site was extremity. Established therapies showed few objective responses and most patients therefore received multiple therapies. Surgical resection had a 68% recurrence rate. Of eight patients who received vinblastine/methotrexate, only one had a partial response (PR) by RECIST 1.1 and five had stable disease (SD); 62.5% required additional therapy. Of seven patients who received sulindac/tamoxifen, none showed objective improvement. In contrast, pazopanib demonstrated best responses by RECIST of PR in two of seven and SD in six of seven tumors. A PR of 66% was observed in a patient who had failed multiple prior therapies. The mesenteric DT/AF also showed PR. Maximum volumetric decrease by T2-weighted magnetic resonance imaging (MRI) was 97%. Dramatically increased fibrosis was seen on T2-weighted MRI. Patients reported pain relief and improvement in function within 1 month. Except for one case of edema, all other toxicities responded to dose reduction without sacrificing objective treatment response. CONCLUSION: Pazopanib provides a promising, well-tolerated therapy for DT/AF in the AYA population and warrants further study.

Posttreatment imaging of pediatric musculoskeletal tumors.

Pediatric patients who are diagnosed with musculoskeletal tumors often require serial imaging both during and after treatment. Although many of the treatments used in adults overlap with those used in children and adolescents, the growing skeleton presents specific challenges that require a unique approach. Surgical treatment of benign osseous lesions typically requires only curettage and bone grafting, whereas that of osseous malignancies generally consists of wide excision and limb salvage, with either endoprosthetic or biologic reconstruction. Current conventional endoprostheses consist of modular components that allow intraoperative customization; however, if there is great potential for future growth, an expandable endoprosthesis may be required. Biologic reconstruction may consist of an allograft and/or autograft and, in some circumstances, can spare the growth plates in a child, thereby allowing normal growth. Expected posttreatment imaging findings in soft-tissue tumors may include muscle flaps and postoperative fluid collections. Medical treatment, including radiation therapy and chemotherapy, can have predictable imaging manifestations, including signal alterations in bone marrow, muscle, and subcutaneous fat. Finally, treatment complications may manifest with clinical symptoms and include infection or mechanical failure, although other complications such as local tumor recurrence may go clinically undetected until surveillance imaging. Familiarity with the expected posttreatment imaging findings in pediatric patients with musculoskeletal tumors can aid in the detection of complications.

Orthopedic issues in vascular anomalies.

Vascular anomalies impact the musculoskeletal system dependent on the tissue involved (skin, subcutis, muscle, cartilage, or bone), the extent of involvement, and the type of anomalous vessels (arteries, capillaries, veins, or lymphatics). These malformations can cause a multitude of musculoskeletal problems for the patient. Leg-length discrepancy, intra-articular involvement, muscular lesions, and primary or secondary scoliosis are amongst the issues that patients face. All of these problems can cause pain, deformity, and a range of functional limitations. Surgical and nonsurgical treatment plans have a role in patient care. Patients with vascular anomalies may also suffer from life-threatening cardiovascular and hematologic abnormalities. For those patients who undergo surgery, the thromboembolic risk is elevated, wound breakdown and infection are much more common, and bleeding risk continues well into the postoperative course. Because of the complex nature of these disorders, the clinician must have a full understanding of the types of lesions, their natural history, appropriate diagnostic studies, associated medical problems, indications for treatment, and treatment options. For severe malformations, especially syndromes such as CLOVES and Klippel- Trenaunay syndrome, interdisciplinary team management is essential for the best outcomes.

Challenges in the Treatment of Sarcomas of Adolescents and Young Adults.

Adolescent and young adult (AYA) sarcoma patients do not fare as well as their younger counterparts. A variety of factors theorized to underlie such disparate outcomes have been identified including distinct tumor and host biology. Compared to younger patients, AYA patients often develop genetically distinct tumors and are more likely to suffer characteristic therapy-related toxicities. Compounding factors faced by AYA patients include education, finances, employment, and obstacles to treatment adherence. Lack of clinical trial participation among AYA patients has slowed the establishment of optimized age-specific treatment protocols and hindered the collection of biospecimens for scientific investigation. The relative rarity of sarcomas among adult cancers may limit the familiarity of oncologists with state of the art diagnostic and therapeutic aspects of sarcomas in young adults. Among other interventions, improved enrollment on clinical trials is a critical step in addressing the challenges faced by AYA patients. Further insight into unique tumor and host biology among AYA patients is also an important need.

Identification of Patients With Localized Ewing Sarcoma at Higher Risk for Local Failure: A Report From the Children's Oncology Group.

PURPOSE: To identify clinical and treatment variables associated with a higher risk of local failure in Ewing sarcoma patients treated on recent Children's Oncology Group protocols. METHODS AND MATERIALS: Data for 956 patients treated with ifosfamide and etoposide-based chemotherapy on INT-0091, INT-0154, and AEWS0031 were analyzed. Local treatment modalities were defined as surgery, definitive radiation therapy (RT), or surgery plus radiation (S+RT). Five-year cumulative incidence of local failure was determined. RESULTS: The local failure rate for the entire cohort was 7.3%, with a 3.9% rate for surgery, 15.3% for RT (P<.01), and 6.6% for S+RT (P=.12). The local failure incidence was 5.4% for extremity tumors, 13.2% for pelvis tumors (P<.01), 5.3% for axial non-spine tumors (P=.90), 9.1% for extraskeletal tumors (P=.08), and 3.6% for spine tumors (P=.49). The incidence of local failure was 14.8% for extremity tumors and 22.4% for pelvis tumors treated with RT, compared with 3.7% for extremity tumors and 3.9% for pelvis tumors treated with surgery (P≤.01). There was no difference in local failure incidence by local treatment modality for axial non-spine, spine, and extraskeletal tumors. The local failure incidence was 11.9% in patients aged ≥18 years versus 6.7% in patients aged <18 years (P=.02). Age ≥18 years (hazard ratio 1.9, P=.04) and treatment with RT (hazard ratio 2.40, P<.01) remained independent prognostic factors for higher local failure incidence on multivariate analysis. Tumor size (

Updated Outcomes of Prophylactic Femoral Fixation.

Despite an increasing number of patients with metastatic bone disease (MBD), minimal data exist regarding outcomes of patients undergoing prophylactic femoral fixation for MBD when compared with other frequently performed orthopedic operations, such as hemiarthroplasty of the femur. The authors performed a retrospective database review evaluating these procedures due to similar operative times and patient populations and also reviewed common comorbidities such as body mass index (BMI). The goal was to provide updated results of prophylactic femoral fixation and evaluate whether certain patient risk factors (eg, BMI) altered 30-day survival for patients with MBD. The authors reviewed 1849 patients with and without MBD treated by prophylactic fixation and hemiarthroplasty from 2006 to 2011 identified in the American College of Surgeons National Surgical Quality Improvement Program database. There were no significant differences in complications between patients undergoing surgical treatment for impending or actual femoral fracture. In addition, there were no differences between the 217 patients with MBD in either the hemiarthroplasty or prophylactic fixation groups because the rate of death within 30 days postoperatively was 5.56% and 3.30%, respectively (P=.526). When comparing BMI, obese patients had higher rates of wound infection, and underweight patients were more likely to develop pneumonia or die within 30 days postoperatively. Patients with impending femur fractures benefit from prophylactic fixation and perform as well in the short term as patients undergoing hemiarthroplasty. Certain BMI categories (underweight or obese) contributed to poorer outcomes. These findings provide updated information for discussing risks and benefits with surgical candidates.

Short-term results of a custom triflange acetabular component for massive acetabular bone loss in revision THA.

Managing severe periacetabular bone loss during revision total hip arthroplasty (THA) is a challenging task. Multiple treatment options have been described. A custom triflanged acetabular component is a recent treatment option. The authors retrospectively reviewed 19 hips in 19 patients with massive periacetabular bone loss (Paprosky types 3A/3B and AAOS types III/IV) treated with custom triflanged acetabular components. Mean patient age at surgery was 58 years (range, 42-79 years).At an average follow-up of 31 months (range, 16-59 months), mean Harris Hip Score had improved from 38 preoperatively to 63 postoperatively, and mean Western Ontario McMaster Osteoarthritis Index scores had improved from 43 preoperatively to 26 postoperatively. Sixty-five percent of cases were considered successful. Three (16%) patients had significant complications; 2 (11%) custom triflanged acetabular components were removed due to failure. At last follow-up, 6 (43%) of 14 patients reported that their ambulatory status was improved vs their preoperative status, 3 (21%) reported no change, and 5 (36%) reported that their ambulatory status was worse than their preoperative status.In this study, the use of a custom triflanged acetabular component for massive periacetabular bone loss in revision THA had less favorable results than in other reports. Use of a custom triflanged acetabular component for massive periacetabular bone loss in revision THA remains a viable option, but surgeon and patient expectations should be realistic.