This JCO podcast provides observations and commentaries on the JCO article entitled "Indeterminate Pulmonary Nodules at diagnosis in Rhabdomyosarcoma: Are they clinically significant?" A report from the European Pediatric Soft Tissue Sarcoma Study Group by Bas Vaarwerk, MD et al.

My name is Alberto Pappo and I am the head of the division of solid tumors at St Jude Children’s Research Hospital in Memphis, TN. My oncology specialty is pediatric oncology.

In this report, Bas Vaarwerk, and investigators from the European Pediatric Soft Tissue Sarcoma Study Group evaluated the significance of indeterminate pulmonary nodules at diagnosis in children with rhabdomyosarcoma defined as the presence of less than 5 pulmonary nodules measuring less than 5mm or 1 pulmonary nodule that measured between 5 and 9 millimeters.

This analysis included 316 patients who were enrolled on the EpSSG RMS 2005 study for non-metastatic rhabdomyosarcoma from September 2005 through December 2013 and for whom chest computed tomography scans were obtained at diagnosis and were available for review. Treatment in the EpSSG RMS 2005 study was stratified according to risk group, pathology, post-surgical stage, site, nodal involvement, size and age. All patients received multi agent chemotherapy with ifosfamide (except for low risk patients), vincristine and actinomycin D (IVA chemotherapy). High risk patients were randomized to IVA or IVA with doxorubicin and after 9 courses if in complete remission, were eligible for a second randomization between end of therapy and additional maintenance therapy with 6 courses of vinorelbine and cyclophosphamide

Local control was determined by risk group, tumor site, age and response to therapy and radiotherapy was given at week 13 in doses ranging from 36 to 51.4Gy. All chest computed tomography scans were reviewed by the local radiologist at the treating center. Data was obtained and recorded using case report forms. All computed tomography scans were performed with minimum slice thickness of 3 to 5 mm.

The median age at diagnosis for the 316 eligible patients was 5.4 years and the median follow up time for the cohort was 75 months. There were 249 (78%) patients who did not have a pulmonary nodule and 67 (21%) who had at least one indeterminate pulmonary nodule. Patient and treatment characteristics were similar between the 2 groups; 80% of the patients presented with Group III unresectable disease, 54% had high risk disease, and 71% had favorable histology tumors such as embryonal histology tumors. Twenty four percent of patients received maintenance chemotherapy and 77% were treated with local radiotherapy

A total of 100 nodules were identified in the 67 patients. Nodules ranged in size from 1 to 8 mm. 69% of the patients presented with one pulmonary nodule, 92% of the patients had nodules that measured less than 5 mm 85% of the nodules were unilateral. The 5-year event-free survival for patients with indeterminate pulmonary nodules was 77% and for those without nodules 73.2%. These differences were not statistically significant with a p value of 0.68. The 5-year overall survival rates were 82% for patients with indeterminate pulmonary nodules and 80.8% for those without nodules. The differences between these 2 groups were not statistically significant with a p value of 0.76. There were no significant differences in outcomes based on the number or size of the nodules. Similarly, there were no differences in clinical outcome based on histology, fusion status, age and type of chemotherapy received. Lung metastases developed in 3% of patients with indeterminate pulmonary nodules and in 1.6% of patients without nodules a value that was not statistically significant. The authors conclude that the presence of indeterminate pulmonary nodules in newly diagnosed children with rhabdomyosarcoma as defined in this report does not adversely affect the outcome of these patients and these children can be adequately treated with non-metastatic risk-based clinical protocols.

This report highlights the challenges of assigning risk and therapy based on the presence of a limited number of small pulmonary nodules in children with newly diagnosed rhabdomyosarcoma when they are detected using newer imaging modalities such as thin cut computed tomography of the chest. The authors have successfully demonstrated in this retrospective study that newly diagnosed patients with rhabdomyosarcoma who present with indeterminate oligometastatic disease to the lung which in this study was defined as the presence of 4 or fewer pulmonary nodules measuring less than 5 mm or one nodule that measures 5 to 9 mm, have similar outcomes to patients who present without pulmonary nodules. More importantly, these patients can be treated with less intense trials that may include the use whole lung irradiation which is known to significantly increase the risk of breast cancer in childhood cancer survivors. The authors have implemented a standardized definition for indeterminate oligometastatic lung disease which is highly reproducible and easily implemented. Their results are thought provoking and deserve further validation in a well- designed prospective clinical trial.

Because of the lack of pathologic correlation with imaging findings in this report, it is not possible to determine which patients truly had oligometastatic disease to the lung. It is conceivable that some of the 67 patients with indeterminate nodules did not have actual metastatic rhabdomyosarcoma in the lung, or alternatively these results may also indicate that current risk-based therapies for localized disease are effective at eradicating small oligometastatic disease. It is important to point out however, that in this report, about one fourth of the patient population was assessed using reconstruction widths of ≤ 1.25 mm, which might have identified a larger number of small nodules of uncertain significance. In addition, 69% of the patients with indeterminate nodules had only one nodule, 92% had nodules that measured less than 5 mm and 85% had unilateral disease. All of these factors have been associated with a significantly lower likelihood of identifying biopsy proven metastatic disease in pediatric patients with sarcomas. These findings raise questions as to whether thin cuts < 5mm in thickness are of any value in the assessment of pulmonary metastases in children with rhabdomyosarcoma.

In summary, this report opens new areas for clinical research that could lead to a uniform strategy for defining metastatic pulmonary disease in pediatric rhabdomyosarcoma and a more precise method for risk-stratifying disease in this patient population.

This concludes this JCO Podcast. Thank you for listening.

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How Should We Interpret Indeterminate Pulmonary Nodules at Diagnosis in Children With Rhabdomyosarcoma?