Neutrophil to lymphocyte ratio (NTLR) predicts local control and overall survival after stereotactic body radiotherapy (SBRT) in metastatic sarcoma.

The neutrophil to lymphocyte ratio (NTLR) and absolute lymphocyte count (ALC) recovery are prognostic across many cancers. We investigated whether NLTR predicts SBRT success or survival in a metastatic sarcoma cohort treated with SBRT from 2014 and 2020 (N = 42). Wilcox Signed Rank Test and Friedman Test compare NTLR changes with local failure vs. local control (N = 138 lesions). Cox analyses identified factors associated with overall survival. If local control was successful, NLTR change was not significant (p = 0.30). However, NLTR significantly changed in patients with local failure (p = 0.027). The multivariable Cox model demonstrated higher NLTR before SBRT was associated with worse overall survival (p = 0.002). The optimal NTLR cut point was 5 (Youden index: 0.418). One-year overall survival in SBRT metastatic sarcoma cohort was 47.6% (CI 34.3%-66.1%). Patients with an NTLR above 5 had a one-year overall survival of 37.7% (21.4%-66.3%); patients with an NTLR below 5 had a significantly improved overall survival of 63% (43.3%-91.6%, p = 0.014). Since NTLR at the time of SBRT was significantly associated with local control success and overall survival in metastatic sarcoma treated with SBRT, future efforts to reduce tumor inhibitory microenvironment factors and improve lymphocyte recovery should be investigated.

Consensus recommendations in the management of Ewing sarcoma from the National Ewing Sarcoma Tumor Board.

Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue that most often occurs in adolescents and young adults. Despite an international coordinated approach, several nuances, discrepancies, and debates remain in defining the standard of care for treating ES. In this review, the authors leverage the expertise assembled by formation of the National Ewing Sarcoma Tumor Board, a multi-institution, multidisciplinary virtual tumor board that meets monthly to discuss complicated and challenging cases of ES. This report is focused on select topics that apply to the management of patients with newly diagnosed ES. The specific topics covered include indications for bone marrow aspirate and biopsy for initial evaluation compared with fluorodeoxyglucose-positron emission tomography, the role of interval compressed chemotherapy in patients aged 18 years and older, the role of adding ifosfamide/etoposide to vincristine/doxorubicin/cyclophosphamide for patients with metastatic disease, the data on and role of high-dose chemotherapy with autologous stem cell transplantation, maintenance therapy, and whole-lung irradiation. The data referenced are often limited to subgroup analyses and/or compiled from multiple sources. Although not intended to replace the clinical judgement of treating physicians, the guidelines are intended to provide clarity and recommendations for the upfront management of patients with ES. PLAIN LANGUAGE SUMMARY: Ewing sarcoma is a malignant tumor of bone and soft tissue that most often occurs in adolescents and young adults. For this review, the authors used the experience of the National Ewing Sarcoma Tumor Board, a multi-institution, multidisciplinary virtual tumor board that meets monthly to discuss complicated and challenging cases of Ewing sarcoma. Although not intended to replace the clinical judgement of treating physicians, the guidelines will focus on the development of consensus statements for the upfront management of patients with Ewing sarcoma.

Neutrophil to Lymphocyte Ratio (NTLR) Predicts Local Control Failure and Overall Survival after Stereotactic Body Radiotherapy (SBRT) In Metastatic Sarcoma.

The neutrophil to lymphocyte ratio (NTLR) and absolute lymphocyte count (ALC) recovery are prognostic across many cancers. We investigated whether NLTR predicts SBRT success or survival in a metastatic sarcoma cohort treated with SBRT from 2014 and 2020 (N = 42). Wilcox Signed Rank Test and Friedman Test compare NTLR changes with local failure vs. local control (N = 138 lesions). Cox analyses identified factors associated with overall survival. If local control was successful, NLTR change was not significant (p = 0.30). However, NLTR significantly changed in patients local failure (p = 0.027). The multivariable Cox model demonstrated higher NLTR before SBRT was associated with worse overall survival (p = 0.002). The optimal NTLR cut point was 5 (Youden index: 0.418). One-year overall survival in SBRT metastatic sarcoma cohort was 47.6% (CI 34.3%-66.1%). Patients with an NTLR above 5 had a one-year overall survival of 37.7% (21.4%-66.3%); patients with an NTLR below 5 had a significantly improved overall survival of 63% (43.3%-91.6%, p = 0.014). Since NTLR at the time of SBRT was significantly associated with local control success and overall survival in metastatic sarcoma treated with SBRT, future efforts to reduce tumor inhibitory microenvironment factors and improved lymphocyte recovery should be investigated.

Phase II Study of ONC201 in Neuroendocrine Tumors including Pheochromocytoma-Paraganglioma and Desmoplastic Small Round Cell Tumor.

PURPOSE: Tumor dopamine-like DRD2 receptor expression is higher in pheochromocytoma-paraganglioma (PC-PG) compared with other cancers. ONC201 is a bitopic DRD2 antagonist with preclinical ONC201 activity in desmoplastic small round cell tumor (DSRCT). PATIENTS AND METHODS: Patients (N = 30) with neuroendocrine tumors were treated on this investigator-initiated trial (NCT03034200). ONC201 dose and schedule were 625 mg orally weekly in cohorts A (PC-PG) + B (other neuroendocrine tumors) and 625 mg orally on 2 consecutive days each week in cohort C, which included 5 responding patients. The primary endpoint was radiographic response measured using RECIST. Secondary endpoints included progression-free survival, overall survival, and safety. RESULTS: In arm A (n = 10; all PC-PG), 50% (5/10) exhibited a partial response (PR) and 2 additional patients had stable disease (SD) >3 months. Median duration of therapy for arm A patients was 9 months (range: 1.5-33 months) with 5 patients treated >1 year. In arm B (n = 12), there were 1 PR (DSRCT) and 2 SD (DSRCT; neuroblastoma) >3 months. Median duration of therapy in arm A was 18 months (range: 1-33 months) and arm B was 3 months (range: 1.5-33 months). Arm C PC-PG (N = 8) showed 1 PR and 7 SD at 3 months, with median duration of therapy >10 months. There was no decline in Karnofsky performance status at week 12 for 28 of 30 patients and no dose modification due to treatment-related adverse events. CONCLUSIONS: Oral ONC201 was well tolerated in patients with metastatic neuroendocrine tumors and associated with clinical benefit, including tumor responses, particularly in some patients with DSRCT and the majority of patients with PC-PG. See related commentary by Owen and Trikalinos, p. 1748.

Multiple Site SBRT in Pediatric, Adolescent, and Young Adult Patients With Recurrent and/or Metastatic Sarcoma.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is increasingly used for patients with recurrent and or metastatic tumors. Sarcomas are generally considered not sensitive to radiotherapy and SBRT may allow for increased biological effectiveness. We report intermediate outcomes and toxicity for pediatric, adolescent, and young adult patients treated with SBRT to sites of recurrent and or metastatic sarcoma. PROCEDURE: We queried an Institutional Review Board-approved registry of patients treated with SBRT for metastases from pediatric sarcomas. Patients age 29 and below were assessed for local control, survival, and toxicity. RESULTS: Thirty-one patients with a total of 88 lesions met eligibility criteria. Median patient age was 17.9 years at treatment. Sixteen patients were treated with SBRT to >1 site of disease. The median dose was 30 Gy in 5 fractions. The median follow-up time was 7.4 months (range: 0.2 to 31.4 mo). Patients were heavily pretreated with systemic therapy. In 57 lesions with >3 months of radiographic follow-up, the 6-month and 12-month local control rates were 88.3%±4.5% and 83.4%±5.5%, respectively. Radiographic local failures were rare (6/57 in-field, 4/57 marginal). Only 1/88 treated lesions was associated with a radiation-related high-grade toxicity; late grade 3 intestinal obstruction in a re-irradiated field while on concurrent therapy (gemcitabine and docetaxel). No acute grade ≥3 toxicity was observed. CONCLUSIONS: SBRT was well tolerated in the majority of patients with favorable local control outcomes. Additional studies will be required to determine the optimal SBRT dose and fractionation, treatment volume, and appropriate concurrent therapies.

223-Radium for metastatic osteosarcoma: combination therapy with other agents and external beam radiotherapy.

BACKGROUND: Bone-seeking radiopharmaceuticals can deposit radiation selectively to some osteosarcoma tumours because of the bone-forming nature of this cancer. OBJECTIVES: This is the first report of using 223-radium, an alpha-emitting calcium analogue with a high therapeutic index, in combination therapy with other agents in 15 patients with metastatic osteoblastic osteosarcoma. METHODS: Candidates for alpha-radiotherapy if 99mTc-MDP bone scan had avid bone-forming lesions and no therapy of higher priority (eg, definitive surgery). Monthly 223-radium infusions (1.49 µCi/kg or 55.13 kBq/kg) were given. RESULTS: The median infusion number was three and the average time to progression was 4.3 months for this cohort receiving 223-radium+other agents. Agents provided during 223-radium included (1) drugs to reduce skeletal complications: monthly denosumab (n=13) or zolendronate (n=1); (2) agents with antivascular endothelial growth factor activity, pazopanib (n=8) or sorafenib (n=1), (3) alkylating agents: oral cyclophosphamide (n=1) or ifosfamide, given as a 14-day continuous infusion (n=1, two cycles), (4) high-dose methotrexate (n=1), pegylated liposomal doxorubicin (n=1); and (5) two other combinations: nivolumab and everolimus (n=1) and rapamycin and auranofin (n=1). Radiation therapy, including stereotactic body radiotherapy (SBRT), was also given to 11 patients concurrently with 223-radium (n=2), after 223-radium completion (n=3), or both concurrently and then sequentially for other sites (n=6). After 223-radium infusions, patients without RT had a median overall survival of 4.3 months compared with those with SBRT and/or RT, who had a median overall survival of 13.5 months.Conclusion Although only 1/15 of patients with osteoblastic osteosarcoma still remain alive after 223-radium, overall survival.

Alveolar Rhabdomyosarcoma Following Mandibular Distraction Osteogenesis.

The authors present a rare case of anaplastic alveolar rhabdomyosarcoma (ARMS) occurring after Mandibular Distraction Osteogenesis. A 16-month-old male presented with a rapidly enlarging left lower jaw mass after removal of mandibular distractors placed shortly after birth for Pierre Robin Sequence and severe obstructive sleep apnea. Incisional biopsy of the mass revealed ARMS with anaplastic features. Although ARMS is an extremely rare entity, craniofacial surgeons should have a low threshold for seeking further diagnostic modalities of a growing mass postmandibular distraction.

Spine radiosurgery in adolescents and young adults: early outcomes and toxicity in patients with metastatic Ewing sarcoma and osteosarcoma.

OBJECTIVE: There are limited data on spine stereotactic radiosurgery (SRS) in treating adolescent and young adult (AYA) patients. SRS has the advantages of highly conformal radiation dose delivery in the upfront and retreatment settings, means for dose intensification, and administration over a limited number of sessions leading to a decreased treatment burden. In this study, the authors report the oncological and toxicity outcomes for AYA patients with metastatic sarcoma treated with spine radiosurgery and provide clinicians a guide for considerations in dose, volume, and fractionation. METHODS: An institutional review board-approved database of patients treated with SRS in the period from October 2014 through December 2018 was queried. AYA patients, defined by ages 15-29 years, who had been treated with SRS for spine metastases from Ewing sarcoma or osteosarcoma were included in this analysis. Patients with follow-ups shorter than 6 months after SRS were excluded. Local control, overall survival, and toxicity were reported. RESULTS: Seven patients with a total of 11 treated lesions were included in this study. Median patient age was 20.3 years (range 15.1-26.1 years). Three patients had Ewing sarcoma (6 lesions) and 4 patients had osteosarcoma (5 lesions). The median dose delivered was 35 Gy in 5 fractions (range 16-40 Gy, 1-5 fractions). The median follow-up was 11.1 months (range 6.8-26.0 months). Three local failures were observed within the follow-up period. No acute grade 3 or greater toxicity was observed. One patient developed late grade 3 toxicity consisting of radiation enteritis. This patient had previously received radiation to an overlapping volume with conventional fractionation. SRS re-irradiation for this patient was also performed concurrently with chemotherapy administration. No late grade 4 or higher toxicities were observed. No pain flare or vertebral compression fracture was observed. Three patients died within the follow-up period. CONCLUSIONS: SRS for spine metastases from Ewing sarcoma and osteosarcoma can be considered as a treatment option in AYA patients and is associated with acceptable toxicity rates. Further studies must be conducted to determine long-term local control and toxicity for this treatment modality.

The safety and efficacy of clofarabine in combination with high-dose cytarabine and total body irradiation myeloablative conditioning and allogeneic stem cell transplantation in children, adolescents, and young adults (CAYA) with poor-risk acute leukemia.

Acute leukemias in children with CR3, refractory relapse, or induction failure (IF) have a poor prognosis. Clofarabine has single agent activity in relapsed leukemia and synergy with cytarabine. We sought to determine the safety and overall survival in a Phase I/II trial of conditioning with clofarabine (doses 40 - 52 mg/m2), cytarabine 1000 mg/m2, and 1200 cGy TBI followed by alloSCT in children, adolescents, and young adults with poor-risk leukemia. Thirty-seven patients; Age 12 years (1-22 years); ALL/AML: 34:3 (18 IF, 10 CR3, 13 refractory relapse); 15 related, 22 unrelated donors. Probabilities of neutrophil, platelet engraftment, acute GvHD, and chronic GvHD were 94%, 84%, 49%, and 30%, respectively. Probability of day 100 TRM was 8.1%. 2-year EFS (event free survival) and OS (overall survival) were 38.6% (CI95: 23-54%), and 41.3% (CI95: 25-57%). Multivariate analysis demonstrated overt disease at time of transplant (relative risk (RR) 3.65, CI95: 1.35-9.89, P = 0.011) and umbilical cord blood source (RR 2.17, CI95: 1.33-4.15, P = 0.019) to be predictors of worse EFS/OS. This novel myeloablative conditioning regimen followed by alloSCT is safe and well tolerated in CAYA with very poor-risk ALL or AML. Further investigation in CAYA with better risk ALL and AML undergoing alloSCT is warranted.

Adult Primary Bone Sarcoma and Time to Treatment Initiation: An Analysis of the National Cancer Database.

OBJECTIVE: The time to treatment interval (TTI), defined as the period from diagnosis to first definitive treatment, has very limited descriptions toward understanding delays in primary bone sarcoma (PBS) care. Our primary goal was to determine the national standard for time to treatment initiation (TTI) in PBS in adults and to identify characteristics associated with TTI variability. METHODS: An analysis of the National Cancer Database identified 15,083 adult patients with PBS diagnosed from 2004 to 2013. Kruskal-Wallis analysis identified differences between covariates regarding TTI and regression modeling identified covariates that independently influenced TTI. RESULTS: The median TTI was 22 days. Approximately 60% of patients were definitively treated in the same center where the index diagnosis was made. Increased TTI was correlated with a transition in care institution (incidence rate ratio (IRR) = 1.89; P < 0.001), being uninsured (IRR = 1.36; P < 0.001), primary tumor site in the pelvis (IRR = 1.26; P < 0.001), Medicaid insurance status (IRR = 1.22; P < 0.001), care at an academic center (IRR = 1.14; P < 0.001), non-white race (IRR = 1.12; P=0.002), and Medicare insurance status (IRR = 1.08; P=0.017). Decreased TTI was correlated with a diagnosis of chondrosarcoma (IRR = 0.85; P < 0.001), having surgery as the index treatment (IRR = 0.88; P < 0.001), a primary tumor site of the lower (IRR = 0.91; P=0.001) or upper extremity (IRR = 0.92; P=0.023), and stage II or stage III disease (IRR = 0.91; P=0.010). CONCLUSIONS: TTI is associated with tumor, treatment, and socioeconomic and healthcare system characteristics. Transitions in care between institutions are responsible for the greatest increase in TTI. As TTI is more commonly used as a quality metric, physicians need to be aware of the causes for prolonged TTI, as we work to improve national delays in diagnosis and treatment initiation.

Influences on patient satisfaction in healthcare centers: a semi-quantitative study over 5 years.

BACKGROUND: Knowledge of ambulatory patients' satisfaction with clinic visits help improve communication and delivery of healthcare. The goal was to examine patient satisfaction in a primary care setting, identify how selected patient and physician setting and characteristics affected satisfaction, and determine if feedback provided to medical directors over time impacted patient satisfaction. METHODS: A three-phase, semi-quantitative analysis was performed using anonymous, validated patient satisfaction surveys collected from 889 ambulatory outpatients in 6 healthcare centers over 5-years. Patients' responses to 21 questions were analyzed by principal components varimax rotated factor analysis. Three classifiable components emerged: Satisfaction with Physician, Availability/Convenience, and Orderly/Time. To study the effects of several independent variables (location of clinics, patients' and physicians' age, education level and duration at the clinic), data were subjected to multivariate analysis of variance (MANOVA).. RESULTS: Changes in the healthcare centers over time were not significantly related to patient satisfaction. However, location of the center did affect satisfaction. Urban patients were more satisfied with their physicians than rural, and inner city patients were less satisfied than urban or rural on Availability/Convenience and less satisfied than urban patients on Orderly/Time. How long a patient attended a center most affected satisfaction, with patients attending >10 years more satisfied in all three components than those attending <1-5 years. Level of education affected patients' satisfaction only in the component Orderly/Time; patients without a high school education were significantly less satisfied than those with more. Patients in their 40's were significantly less satisfied in Availability/Convenience than those >60 years old. Patients were significantly more satisfied with their 30-40 year-old physicians compared with those over 60. On Orderly/Time, patients were more satisfied with physicians who were in their 50's than physicians >60. CONCLUSIONS: Improvement in patient satisfaction includes a need for immediate, specific feedback. Although Medical Directors received feedback yearly, we found no significant changes in patient satisfaction over time. Our results suggest that, to increase satisfaction, patients with lower education, those who are sicker, and those who are new to the center likely would benefit from additional high quality interactions with their physicians.

A Phase I Study of Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation Followed by Dose Escalation of Targeted Consolidation Immunotherapy with Gemtuzumab Ozogamicin in Children and Adolescents with CD33+ Acute Myeloid Leukemia.

Myeloablative conditioning and allogeneic hematopoietic stem cell transplant (alloHSCT) in children with acute myeloid leukemia (AML) in first complete remission (CR1) may be associated with significant acute toxicity and late effects. Reduced-intensity conditioning (RIC) and alloHSCT in children is safe, feasible, and may be associated with less adverse effects. Gemtuzumab ozogamicin (GO) induces a response in 30% of patients with CD33+ relapsed/refractory AML. The dose of GO is significantly lower when combined with chemotherapy. We examined the feasibility and toxicity of RIC alloHSCT followed by GO targeted immunotherapy in children with CD33+ AML in CR1/CR2. Conditioning consisted of fludarabine 30 mg/m2 × 6 days, busulfan 3.2 to 4 mg/kg × 2 days ± rabbit antithymocyte globulin 2 mg/kg × 4 days followed by alloHSCT from matched related/unrelated donors. GO was administered ≥60 days after alloHSCT in 2 doses (8 weeks apart), following a dose-escalation design (4.5, 6, 7.5, and 9 mg/m2). Fourteen patients with average risk AML received RIC alloHSCT and post-GO consolidation: median age 13.5 years at transplant (range, 1 to 21), male-to-female 8:6, and disease status at alloHSCT 11 CR1 and 3 CR2. Eleven patients received alloHSCT from 5-6/6 HLA-matched family donors: 8 received peripheral blood stem cells, 2 received bone marrow, and 1 received related cord blood transplantation. Three patients received an unrelated allograft (two 4-5/6 and one 9/10) from unrelated cord blood unit and bone marrow, respectively. Neutrophil and platelet engraftment was observed in all assessable patients (100%), achieved at median 15.5 days (range, 7 to 31) and 21 days (range, 10 to 52), respectively. Three patients received GO at dose level 1 (4.5 mg/m2 per dose), 5 at dose level 2 (6 mg/m2 per dose), 3 at dose level 3 (7.5 mg/m2 per dose), and 3 at dose level 4 (9 mg/m2 per dose). Three of 14 patients received only 1 dose of GO after alloHSCT. One patient experienced grade III transaminitis, which resolved; no grade IV transaminitis, no grade III/IV hyperbilirubinemia, or sinusoidal obstructive syndrome were observed. The second dose of GO was given at median of 143 days (range, 120 to 209) after alloHSCT. Probability of grades II to IV acute and chronic graft-versus-host disease were 21% and 33.5%, respectively. Probability of overall survival after RIC alloHSCT and GO consolidation at 1 and 5 years was 78% and 61%, respectively. Probability of 5-year event-free survival after RIC alloHSCT and GO consolidation in patients in CR1 was 78%. No dose-limiting toxicities probably or directly related to GO were observed in this cohort. This preliminary data demonstrate that RIC followed by alloHSCT and consolidation with GO appears to be safe in children and adolescents with CD33+ AML in CR1/CR2. A phase II trial is currently underway investigating this approach with a GO dose of 9 mg/m2 per dose.