Arndt, Carola A.S.

Abstract Background To determine outcomes of children with rhabdomyosarcoma (RMS) with isolated lung metastases. Methods Data were analyzed for 428 patients with metastatic RMS treated on COG protocols. Categorical variables were compared using Chi‐square or Fisher's exact tests. Event‐free survival (EFS) and overall survival (OS) were estimated using Kaplan–Meier method and compared using the log‐rank test. Results Compared with patients with other metastatic sites ( n = 373), patients with lung‐only metastases ( n = 55) were more likely to be <10 years of age, have embryonal histology (embryonal rhabdomyosarcoma), have N0 disease, and less likely to have primary extremity tumors. Lung‐only patients had significantly better survival outcomes than patients with all other sites of metastatic disease ( p < .0001) with 5‐year EFS of 48.1 versus 18.8% and 5‐year OS of 64.1 versus 26.9%. Patients with lung‐only metastases, and those with a single extrapulmonary site of metastasis, had better survival compared with patients with two or more sites of metastatic disease ( p < .0001). In patients with ERMS and lung‐only metastases, there was no significant difference in survival between patients ≥10 years and 1–9 years (5‐year EFS: 58.3 vs. 68.2%, 5‐year OS: 66.7 vs. 67.7%). Conclusions With aggressive treatment, patients with ERMS and lung‐only metastatic disease have superior EFS and OS compared with patients with other sites of metastatic disease, even when older than 10 years of age. Consideration should be given to including patients ≥10 years with ERMS and lung‐only metastases in the same group as those <10 years in future risk stratification algorithms.

Abstract The Children's Oncology Group (COG) uses Clinical Group (CG) and modified Tumor Node Metastasis (TNM) stage to classify rhabdomyosarcoma (RMS). CG is based on surgicopathologic findings and is determined after the completion of initial surgical procedure(s) but prior to chemotherapy and/or radiation therapy. The modified TNM stage is based on clinical and radiographic findings and is assigned prior to any treatment. These systems have evolved over several decades. We review the history, evolution, and rationale behind the current CG and modified TNM classification systems used by COG for RMS. Data from the seven most recently completed and reported frontline COG trials (D9602, D9802, D9803, ARST0331, ARST0431, ARST0531, ARST08P1) were analyzed, and confirm that CG and modified TNM stage remain relevant and useful for predicting prognosis in RMS. We propose updates based on recent data and discuss factors warranting future study to further optimize these classification systems.

Abstract Paratesticular rhabdomyosarcoma (PT‐RMS) carries a favorable prognosis, but questions persist regarding optimal management. Our goal was to determine the importance of primary tumor resection and surgical assessment of retroperitoneal lymph nodes during staging in patients with PT‐RMS. We analyzed patients with localized PT‐RMS enrolled onto one of four Children's Oncology Group studies (D9602, ARST0331, D9803 or ARST0531). Surgical resection of the primary tumor prior to chemotherapy and radiotherapy was encouraged when possible with retroperitoneal lymph node dissection (RPLND) recommended for patients ≥10 years of age. Among 279 patients (median 8.1 years old), most tumors were resected with negative margins (78.5%) and most patients did not have radiographic enlargement of regional lymph nodes (90.3%). In patients older than 10 years, imaging alone will miss over 51.5% of nodal disease. Five‐year event‐free survival (EFS) was 92.0% (95% CI 88.4%‐95.6%). Sampling ≥7 to 12 retroperitoneal lymph nodes appeared optimal for detecting positive nodes; while there was a trend toward improved EFS among those undergoing template RPLND, this was not statistically significant ( P = .068). Age ( P = .28), N‐stage ( P = .39), T‐stage ( P = .11) and pathologic node involvement ( P = .53) were not associated with overall survival. However, older age and larger tumor size had an additive impact on EFS ( P = .027) though not overall survival ( P = .13). In conclusion, outcomes for patients with PT‐RMS are excellent. Reliance on imaging to detect nodal involvement will miss pathologic node involvement and may result in undertreatment. Surgical nodal staging requires at least 7 to 12 nodes to accurately identify patients with regional nodal disease.

Hereditary thrombotic thrombocytopenic purpura is an ultra-rare disorder caused by biallelic mutations in the ADAMTS13 gene. Because it can be difficult to diagnose, plasma ADAMTS13 activity assessment should be considered in patients with thrombocytopenia, anemia, and schistocytes on peripheral blood smear. We present the diagnostic evaluation of a patient with hereditary thrombotic thrombocytopenic purpura. Genetic testing revealed one known pathogenic mutation and one novel mutation of ADAMTS13 classified as likely pathogenic on the basis of parental genetic testing and in silico analyses. We further discuss off-label use of prophylactic plasma-derived Factor VIII (Koate-DVI) and the benefit of rare disease registries.

10538 Background: Rhabdomyosarcoma (RMS) of the female genital tract is rare, accounting for 3.5% of cases of rhabdomyosarcomas. Germline DICER1 mutations are associated with predisposition to pleuropulmonary blastoma and other tumors including sarcomas. Recently DICER1-associated RMS of the uterus/ovary has ben reported.. The aim of this study is to evaluate demographic characteristics, molecular pathogenesis, treatment and long term outcome of female genital tract rhabdomyosarcoma. Methods: Files of children with RMS of the female genital tract diagnosed at the Istanbul University, Oncology Institute during 1990-2019 were reviewed. Molecular genetic sequencing was performed by polymerase chain reaction amplification of genomic DNA extracted from the formalin-fixed, paraffin embedded tumors, followed by Sanger sequencing. Genetic testing for DICER1 variants of the proband and family members was performed if DICER1 mutation was detected in the tumor of the proband. Results: Of 210 RMS cases, 11 arose from the female genital tract. The median age at diagnosis was 52 months (10 months-15 years). Primary sites were vaginal (n = 5), uterus (n = 4), and ovary(n = 2). Presenting symptoms included vaginal mass (n = 6), vaginal bleeding (n = 5), and abdominal pain (n = 3). Four had group 1, five group 3, two group 2 disease and all received chemotherapy (vincristine, actinomycinD + cyclophosphamide).Three received radiotherapy; three underwent hysterectomy. DICER1 mutation was detected in tumor tissue in three patients:[ c.5113G > A (p.E1705K); c.5428G > T (p.D1810Y); c.1870C > T (p.Arg624Ter)] Genetic testing revealed germline DICER1 pathogenic variation in two patients and their family members, one of whom had cystic nephroma in infancy and history of Wilms tumor in an uncle. They were referred for surveillance for the DICER1 related diseases. A patient with metachronous bilateral ovarian RMS died. Two are married, one has children. The 5 year survival for RMS of the female genital tract was 85.7 % at a median follow-up of 34 (4-298) months. Conclusions: Rhabdomyosarcoma of the female genital tract is associated with a favorable prognosis, however some individuals undergo aggressive local therapies. Individuals with RMS of the female genital tract should be tested for DICER1 pathogenic variation. The detection of a DICER1 mutation in an individual or family members is important to facilitate surveillance for related tumors, so that they may be detected at the earliest possible stage, potentially increasing survival and decreasing risks of late effects.

10012 Background: The prognostic significance of response to induction therapy for rhabdomyosarcoma (RMS) by anatomic imaging (computerized tomographic [CT] or magnetic resonance imaging [MRI] scan) is controversial. We previously reported no relationship between early response and failure-free survival (FFS) for patients on IRS-IV. We repeated the same analysis using an independent cohort of patients with non-metastatic, initially unresected RMS treated on a more recent clinical trial. Methods: A total of 338 patients enrolled in Children’s Oncology Group study D9803 met the following inclusion criteria for this analysis: 1) non-metastatic, initially unresected (Group III); 2) embryonal (ERMS) or alveolar (ARMS) histology; 3) documented response to induction chemotherapy (excluding progressive disease) based on anatomic imaging; and 4) documented therapy beyond week 12. Response at week 12 was determined by the treating institution as complete response (CR, complete resolution), partial response (PR, decrease of >= 50% of the sum of the products of maximum perpendicular diameters), or no response (NR, between 50% reduction and 25% increase in the sum of the products of maximum perpendicular diameters). FFS was estimated using the Kaplan-Meier method, and comparisons between groups were made using the log-rank test. Results: Overall objective response rate (CR+PR) at week 12 of therapy was 85%, with similar responses for ERMS and ARMS. FFS was similar among all patients with CR, PR, or NR (p=0.49). Restricting the analysis to either ERMS or ARMS, there was no difference in FFS by histology (p=0.20 and p=0.45, respectively). Conclusions: These findings provide additional evidence that anatomic imaging assessment of early response to therapy among RMS patients does not predict outcome and should not be used to tailor subsequent therapy. Clinical trial information: NCT00003958. [Table: see text]

10554 Background: Age at diagnosis is a prognostic factor in patients with RMS. We sought to determine whether AYA with metastatic alveolar (ARMS) or embryonal (ERMS) RMS had a different failure-free survival (FFS) compared to younger patients, and to identify treatment related factors that may be associated with outcome. Methods: COG ARST0431 patients were reviewed. The incidence of toxicities (AE, grade3/4 using CTCAEv3) by age was determined in 4 reporting periods (RP: wks 1-6; RP2:7-19; RP3: 20-34; RP4: 35-54). The AEs in younger patients (<=13 years) were compared with those in AYA. Fisher’s exact test was used to compare differences between the groups. Results: Of 109 patients, 60 (55%) were AYA. In RP1, they were more likely to have nausea/vomiting (4.1 vs. 16.9%, p=0.06), pain (6.1 vs. 20.3%, p=0.05), and metabolic disturbances (4.1 vs. 20.3%, p=0.02) compared to younger patients. In RP4, older patients trended to have less infection (15.8 vs. 30.1, p=0.07). All other toxicities were similar between the two age cohorts in the other RPs. AYA were less likely to complete therapy (52 vs. 73%, p=0.03) and more likely (in RP 4) to have unplanned dose modifications (outside of protocol guidelines) (23 vs. 2.7%). Of patients that completed therapy, there was no age-related difference in the time to completion. As shown in the table, younger patients had better 3-yr FFS, driven by a lower FFS for AYA with ARMS. Conclusions: This evaluation suggests that AYA with RMS were less likely to complete therapy and experienced a higher prevalence of pain and nausea compared to younger patients; the role of reporting bias and reasons for treatment discontinuation need further study. Children were more likely than AYA to have infection. Inferior FFS was only seen in AYA with ARMS suggesting a clear need for novel therapies for these patients. This study may be underpowered to demonstrate significant differences in other toxicities or in FFS among ERMS patients. [Table: see text]

11570 Background: Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols included treatment modifications, which may have ameliorated late health outcomes for rhabdomyosarcoma (RMS) survivors treated in more recent era. Methods: We evaluated chronic health conditions (CHCs) and late mortality ( > 5 years from diagnosis) among survivors treated 1970-1990 (IRSG I-III) and 1991-1999 (IRSG IV), and associations with specific treatments to identify treatment-related factors for adverse outcomes. Associations between treatments and CHCs and mortality were evaluated using Fine and Gray’s proportional hazards method accounting for competing risks. Results: 856 survivors treated 1970-90 (median diagnosis age 5.4 years [0- 20]) and 306 treated 1991-99 (median diagnosis age 5.5 years [0-20]) were included. Significant exposure differences between eras included higher percentage (53% vs. 17%, p < 0.01) receiving ≥ 20gm/m2 cumulative alkylators in 1991-99, but more receiving platinums (13% vs 5%, p < 0.01) and abdomen/ pelvis radiation (29% vs. 23%, p = 0.04) in 1970-90. 20-year cumulative incidence for any (40% vs. 28%, p < 0.01), ≥2 (16% vs. 7%, p < 0.01), and endocrine (8% vs. 2.5%, p < 0.01) grade 3-5 CHCs was higher in 1970-90 compared to 1991-99. The hazard ratio (HR) for any (HR 0.7, 95% Confidence Interval [CI] 0.55-0.9), ≥2 (HR 0.38, 95% CI 0.22-0.66) and endocrine (HR 0.25, 95% CI 0.09-0.67) grade 3-5 CHC was lower for 1991-99 survivors than 1970-90. The effect of era (1991-99 vs 1970-90, HR 0.73; 95% CI 0.59-0.91) on CHC was not attenuated when treatment variables were added to multivariable model. Exposures with increased risk of grade 3-5 CHC included platinums (hearing, HR 2, 95% CI 1.07-3.8), anthracycline ≥250mg/m2 (cardiovascular, HR 2.7, 95% CI 1.2-6) and abdomen/ pelvis radiation (second malignant neoplasms, HR 2.1, 95% CI 1.1-4, gastrointestinal, HR 7.4, 95% CI 3.5-16 and endocrine, HR 2.5, 95% CI 1.4-4.4). Gonadal dysfunction was the most common endocrine CHC. There was no difference in all cause or cause-specific mortality between the two cohorts. Conclusions: RMS survivors from the IRSG IV era are at reduced risk for late onset chronic health conditions compared to previous era.

Overview: The role of doxorubicin in treatment of rhabdomyosarcoma (RMS) has been controversial for 30 years. Despite its known activity in RMS, because of its risk of cardiotoxicity, its use is not justified in low-risk patients who have an excellent chance of cure with vincristine, actinomycin with or without cyclophosphamide, and primary tumor treatment. For patients with intermediate and high risks, the risk/benefit ratio must be carefully considered. In addition, the peak incidence of RMS is in toddlers, with whom the risk of cardiotoxicity of anthracyclines is higher. A number of trials both in North America and Europe, which are reviewed in this article, have investigated the role of doxorubicin in RMS, with no conclusive outcomes. In addition, differences in risk-group assignment on two sides of the Atlantic further complicate comparisons and analyses. The current European EpSSG 2005 study for high-risk RMS (by the European definition) may come closest to giving an answer to the role of doxorubicin in RMS.