Sheri L. Spunt

Purpose: Evaluate efficacy and safety of carboplatin plus mirvetuximab soravtansine (MIRV) in folate receptor alpha (FRa)-expressing recurrent PSOC. Patients and Methods: This phase 2, single arm trial enrolled patients with recurrent FRa-expressing (≥25% of tumor cells with ≥2+ membrane intensity) PSOC and 1 prior platinum-based therapy. Patients received up to 6-8 cycles of carboplatin (AUC 5) plus MIRV (6mg/kg AIBW) Q3W, followed by single-agent MIRV. Primary and key secondary endpoints were investigator-assessed objective response rate (ORR) per RECIST v1.1 in the FRa ≥50% group and FRa ≥25% group (ie, overall population), respectively. Results: Among 125 enrolled patients (102 FRα ≥50%; 61 prior PARPi), ORR by end of 6 combination cycles was 62.7% (95% CI, 52.6–72.1) in the FRα ≥50% group and 62.4% (95% CI, 53.3–70.9) in the overall population. Most patients (n=101; 81%) transitioned to single-agent MIRV continuation with durable responses. Patients with FRa ≥25% had median duration of response of 11.2 months (95% CI, 8.5–13.6) and median progression-free survival of 11.0 months (95% CI, 9.8–13.1). Most common adverse events (AEs) were blurred vision (81%) and corneal events (74%); 96.7% of corneal cases resolved or had final grade 1. Treatment-emergent AEs led to MIRV and carboplatin discontinuation in 15% and 9%, respectively. Adjudicated treatment-related pneumonitis occurred in 19 (15.2%) patients: 14 grade 1–2; 3 grade 3–4, and 2 fatal cases. Conclusions: Carboplatin plus MIRV was manageable with dose modifications for AEs and showed meaningful activity, including in PARPi-exposed patients, supporting further evaluation in PSOC.

Background: The cornerstone of the treatment of malignant peripheral nerve sheath tumors is surgical resection. Radiation and chemotherapy are variably employed. The optimal treatment remains uncertain, particularly for unresectable or metastatic disease and patients with neurofibromatosis type 1 (NF-1). Methods: We present data for 58 patients with newly diagnosed malignant peripheral nerve sheath tumors enrolled on the Children’s Oncology Group study ARST0332. Patients were treated with risk-adapted therapy including surgery with or without radiotherapy and ifosfamide and doxorubicin chemotherapy. Results: Most patients had primary tumors that were greater than 5 cm (86%), deep (95%), and invasive (74%), and 10% had distant metastases. Of the patients, 32 (55%) had germline NF-1, and 26 (45%) did not. Among patients, 31 received neoadjuvant therapy, and 22 were evaluable for response with 5 (23%) attaining an objective response, 10 (45%) stable disease, and 7 (32%) progressive disease. Estimated 5-year event-free survival was 87%, 52%, and 0% for the low- (n = 8), intermediate-, (n = 44), and high-risk (n = 6) patients, respectively. In univariate analysis, event-free survival and overall survival differed by sex, presence or absence of metastatic disease, risk group, and achievement of upfront or delayed R0 and/or R1. There was no difference in event-free survival or overall survival based on germline NF-1 status. Conclusion: The treatment strategy in ARST0332 achieved excellent outcomes for low-risk malignant peripheral nerve sheath tumors. Patients with high-risk (metastatic) malignant peripheral nerve sheath tumors have poor outcomes, and novel treatments are needed (NCT00346164).

Background: Although research has improved the prognosis of childhood cancer, many challenges remain, especially for high‐risk, recurrent, and rare cancers. The recognition that diverse cancer types may share molecular alterations that can be therapeutically targeted has stimulated “precision medicine” approaches in research. Understanding parent and patient interest in genomic‐derived therapeutic options in the clinical setting is limited and offers a potential for improved care.Methods: A qualitative study was conducted to explore how young adult (YA) patients and parents of children and adolescent patients regard targeted therapy options. These patients had high‐risk, recurrent, or rare cancer for which there was no known curative therapy and were enrolled in a study evaluating investigational genomic tumor profiling. Clinical data were retrieved from medical records, and interviews were conducted.Results: Seventeen participants were interviewed (11 parents and six YA patients). Six themes emerged: (i) Genomic Understanding, (ii) Partnerships in Decision‐Making, (iii) Connection with and Trust in Providers, (iv) Quality‐of‐Life (QOL) Considerations, (v) Understanding of Prognosis, and (vi) Nurturing Hope. Treatment decision‐making is complex and depends on the connection (with providers and others), understanding (of prognosis, genomic literacy), care goals (QOL considerations), and planning for the future (hope).Conclusions: Participants favored partnership in decision‐making, expressed trust in their providers, and recognized the value of research. Engaging parents and YA patients in the planning of precision medicine translational research may be a path to designing an integrated research and care model that maximizes translational research implemented in real time, leading to improved outcomes.

Background: Adult survivors of unilateral, nonmetastatic, non‐syndromic Wilms tumor (WT) treated with whole abdomen radiation therapy (WART) are at risk for impaired kidney function. The impact of bias and accuracy on estimated glomerular filtration rate (eGFR) among adult survivors of WT has not been well documented.Procedure: We clinically evaluated male and female WT survivors with creatinine and cystatin C, calculated eGFR using the Chronic Kidney Disease—Epidemiology equations with and without cystatin C, and measured ^99mTc diethylenetriamine pentaacetic acid (DTPA) plasma clearance. WT survivors treated with unilateral nephrectomy (UN), non‐nephrotoxic chemotherapy (NNC) and WART or treated with UN, no radiation therapy, and NNC were enrolled. Correlations between ^99mTc DTPA clearance and eGFR were calculated. Bias and the percentage of eGFR calculations that differed from the ^99mTc DTPA clearance by 10% or less (P₁₀) or 30% or less (P₃₀) (accuracy) were calculated.Results: Among female WT survivors, none of the eGFR calculations was statistically significantly correlated with ^99mTc DTPA clearance. Among both unirradiated and WART‐treated male WT survivors, ^99mTc DTPA clearance correlated well with eGFR calculations that included creatinine. eGFR calculations that included creatinine were positively biased among female participants compared to ^99mTc DTPA clearance, and no P₃₀ was greater than 90% among either irradiated males or females.Conclusions: Among female survivors of unilateral, nonmetastatic, non‐syndromic WT who have undergone UN, eGFR is poorly correlated with, is positively biased, and lacks sufficient accuracy, compared to ^99mTc DTPA clearance.

Background: In retrospective analyses, the Pediatric Oncology Group [POG) and the Federation National des Centres de Lutte Contre le Cancer (FNCLCC) histologic grade predict outcome in pediatric non‐rhabdomyosarcoma soft tissue sarcoma (NRSTS), but prospective data on grading, clinical features, and outcomes of low‐grade NRSTS are limited. Methods: We analyzed patients less than 30 years of age enrolled on Children's Oncology Group (COG) study ARST0332 (NCT00346164) with POG grade 1 or 2 NRSTS. Low‐risk patients were treated with surgery alone. Intermediate‐/high‐risk patients received ifosfamide/doxorubicin and radiotherapy, with definitive resection either before or after 12 weeks of chemoradiotherapy. Results: Estimated 5‐year event‐free and overall survival were 90% and 100% low risk ( n = 80), 55% and 78% intermediate risk ( n = 15), and 25% and 25% high risk ( n = 4). In low‐risk patients, only local recurrence was seen in 10%; none with margins greater than 1 mm recurred locally. Sixteen of 17 intermediate‐/high‐risk patients who completed neoadjuvant chemoradiotherapy underwent gross total tumor resection, 80% with negative margins. Intermediate‐/high‐risk group events included one local and seven metastatic recurrences. Had the FNCLCC grading system been used to direct treatment, 29% of low‐risk (surgery alone) patients would have received radiotherapy ± chemotherapy. Conclusions: Most low‐risk patients with completely resected POG low‐grade NRSTS are successfully treated with surgery alone, and surgical margins greater than 1 mm may be sufficient to prevent local recurrence. Patients with intermediate‐ and high‐risk low‐grade NRSTS have outcomes similar to patients with high‐grade histology, and require more effective therapies. Use of the current FNCLCC grading system may result in overtreatment of low‐risk NRSTS curable with surgery alone.

High-grade endometrial stromal sarcoma is a rare and aggressive soft tissue tumor characterized by YWHAE::NUTM2A/B translocations, diagnosis at a median of 50-60 years, and a poor prognosis (overall survival 30%-40%). We describe a 16-year-old patient with high-grade endometrial stromal sarcoma and regional nodal and pulmonary metastases who is a long-term survivor after grossly complete tumor resection, intensive chemotherapy, and pelvic radiotherapy. We discovered a previously undescribed YWHAE::NUTM2E translocation in the tumor. Our patient’s favorable outcome suggests that intensive multimodality therapy with curative intent is appropriate for young patients with high-grade endometrial stromal sarcoma and highlights the importance of fertility preservation.

Background: Embryonal sarcoma of the liver (ESL) is a rare mesenchymal tumor most common in childhood; the optimal treatment approach is uncertain. The clinical features and outcomes of patients with ESL enrolled in a Children’s Oncology Group (COG) clinical trial that evaluated a risk‐based strategy for treating soft tissue sarcomas in patients aged 10 cm in diameter; four were metastatic. Tumor resection was performed upfront in 23 and delayed in 16. Positive surgical margins (n = 6) and intraoperative tumor rupture (n = 6) occurred only in upfront resections. Eight patients received radiotherapy. Estimated 5‐year event‐free and overall survival were 79% (95% confidence interval [CI], 65%–93%) and 95% (95% CI, 87%–100%), respectively. Positive margins increased the local recurrence risk. One of 13 patients with documented hemorrhagic ascites and/or tumor rupture developed extrahepatic intra‐abdominal tumor recurrence.Conclusions: The treatment strategy used in ARST0332 achieved favorable outcomes for patients with ESL despite a substantial proportion having high‐risk disease features. Deferring tumor resection until after neoadjuvant chemotherapy may decrease the risk of intraoperative tumor rupture and improve the likelihood of adequate surgical margins.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. ARST1321 was a phase II study designed to compare the near complete pathologic response rate after preoperative chemoradiation with/without pazopanib in children and adults with intermediate-/high-risk chemotherapy-sensitive body wall/extremity non-Rhabdomyosarcoma Soft Tissue Sarcoma (ClinicalTrials.gov identifier: NCT02180867 ). Enrollment was stopped early following a predetermined interim analysis that found the rate of near complete pathologic response to be significantly greater with the addition of pazopanib. As a planned secondary aim of the study, the outcome data for this cohort were analyzed. Eight-five eligible patients were randomly assigned to receive (regimen A) or not receive (regimen B) pazopanib in combination with ifosfamide and doxorubicin + preoperative radiotherapy followed by primary resection at week 13 and then further chemotherapy at week 25. As of December 31, 2021, at a median survivor follow-up of 3.3 years (range, 0.1-5.8 years), the 3-year event-free survival for all patients in the intent-to-treat analysis was 52.5% (95% CI, 34.8 to 70.2) for regimen A and 50.6% (95% CI, 32 to 69.2) for regimen B ( P = .8677, log-rank test); the 3-year overall survival was 75.7% (95% CI, 59.7 to 91.7) for regimen A and 65.4% (95% CI, 48.1 to 82.7) for regimen B ( P = .1919, log-rank test). Although the rate of near complete pathologic response was significantly greater with the addition of pazopanib, outcomes were not statistically significantly different between the two regimens.

Purposes: This study aims to ascertain the prevalence of cavitations in pulmonary metastases among pediatric and young adult patients with sarcoma undergoing tyrosine kinase inhibitor (TKI) therapy, and assess whether cavitation can predict clinical response and survival outcomes.Methods: In a single‐center retrospective analysis, we examined chest computed tomography (CT) scans of 17 patients (median age 16 years; age range: 4–25 years) with histopathologically confirmed bone (n = 10) or soft tissue (n = 7) sarcoma who underwent TKI treatment for lung metastases. The interval between TKI initiation and the onset of lung nodule cavitation and tumor regrowth were assessed. The combination of all imaging studies and clinical data served as the reference standard for clinical responses. Progression‐free survival (PFS) was compared between patients with cavitating and solid nodules using Kaplan–Meier survival analysis and log‐rank test.Results: Five out of 17 patients (29%) exhibited cavitation of pulmonary nodules during TKI therapy. The median time from TKI initiation to the first observed cavitation was 79 days (range: 46–261 days). At the time of cavitation, all patients demonstrated stable disease. When the cavities began to fill with solid tumor, 60% (3/5) of patients exhibited progression in other pulmonary nodules. The median PFS for patients with cavitated pulmonary nodules after TKI treatment (6.7 months) was significantly longer compared to patients without cavitated nodules (3.8 months; log‐rank p‐value = .03).Conclusions: Cavitation of metastatic pulmonary nodules in sarcoma patients undergoing TKI treatment is indicative of non‐progressive disease, and significantly correlates with PFS.

Childhood cancer survivors report self-monitoring for and worrying about symptoms of disease recurrence and secondary cancers, although symptom-related worry is associated with poorer health-related quality of life. This survey captured pediatric oncologists' beliefs and communication practices regarding symptom self-monitoring for childhood cancer survivors. Using a closed-loop snowball sampling technique, pediatric oncologists completed an online survey regarding the importance of symptom self-monitoring for off-therapy patients, the degree to which symptom self-monitoring was perceived to cause stress and worry, and communication practices. 196 pediatric oncologists (White [78%]; female [64%]; M_age = 47 years) from every continent except Antarctica participated. Oncologists believed it is important for off-therapy patients to self-monitor for symptoms of cancer recurrence (90%) and treatment late effects (94%), although some noted that recurrence (30%) and late effects (55%) are typically detected by routine surveillance before symptoms appear. Oncologists varied in their beliefs that off-therapy patients do (31%) or do not (31%) worry unnecessarily about symptoms of recurrence. Two thirds (62%) of oncologists reported often/always discussing with off-therapy patients which symptoms could indicate cancer recurrence, whereas fewer than half (43%) often/always discussed which symptoms were unlikely to indicate recurrence. Oncologists identified a need for education regarding how to communicate around symptom self-monitoring and the potential utility of a screening tool to identify those who worry excessively. Despite nearly universal belief that their off-therapy patients should self-monitor for symptoms of disease recurrence and late effects, a substantial proportion of pediatric oncologists do not counsel patients on symptom self-monitoring. Since nearly one-third believe that off-therapy patients worry unnecessarily about symptoms of recurrence, improving patient education regarding which symptoms are and are not medically concerning could decrease stress and improve health-related quality of life for pediatric cancer survivors.