Thomas A. Olson

Treatment of Children and Adolescents With Stage II Testicular and Stages I and II Ovarian Malignant Germ Cell Tumors: A Pediatric Intergroup Study—Pediatric Oncology Group 9048 and Children's Cancer Group 8891

PURPOSE To determine whether children with localized gonadal malignant germ cell tumors (MGCT) stage II testicular and stages I and II ovarian treated with four cycles of standard-dose cisplatin combined with etoposide and low-dose bleomycin (PEB) have an event-free survival (EFS) of at least 85% without significant toxicity. PATIENTS AND METHODS Between May 1990 and July 1995, eligible pediatric patients with stage II or recurrent from stage I (as a stage II) testicular MGCT and stages I and II ovarian MGCT were enrolled onto this Pediatric Oncology Group and Childrens Cancer Group study. PEB chemotherapy consisted of bleomycin 15 U/m2 on day 1, cisplatin 20 mg/m2/d on days 1 to 5, and etoposide 100 mg/m2/d on days 1 to 5. Patients received four cycles of therapy at 21-day intervals. RESULTS Seventy-four patients with a median age of 10.5 years (range, 8.7 months to 16.7 years) were enrolled. Primary sites included: stage II testicular (n = 17), stage I ovarian (n = 41), and stage II ovarian MGCT (n = 16). Treatment with standard PEB resulted in 6-year EFS of 95% and overall survival (OS) of 95.7%. EFS and OS by primary site were as follows: stage II testicular, 100% and 100%; stage I ovarian, 95.1% and 95.1%; and stage II ovarian, 87.5% and 93.8%, respectively. Two patients died from recurrent disease, and one patient died of secondary acute myelocytic leukemia. Infrequent grade 3 to 4 hematologic toxicity was reported. No grade 3 to 4 renal, pulmonary, or ototoxicity was observed. CONCLUSION Combination chemotherapy with PEB results in excellent EFS and OS with minimal toxicity in children and adolescents with localized gonadal MGCT.

Genetic analysis of mediastinal nonseminomatous germ cell tumors in children and adolescents

Primary mediastinal germ cell tumors (M‐GCTs) represent a heterogeneous group of tumors that varies with regard to age at presentation, histologic differentiation, and outcome. We retrospectively analyzed archival tissue samples of mediastinal mature and immature teratomas (n = 15) and malignant nonseminomatous M‐GCTs (n = 20) with comparative genomic hybridization (CGH). The aim of this study was to define distinct genetic subgroups of M‐GCT among the pediatric cohort that may differ in their clinical behavior and prognosis. All pure teratomas showed normal CGH profiles. Malignant M‐GCTs in infants and children < 8 years old most frequently showed a gain of 1q, 3, and 20q and a loss of 1p, 4q, and 6q. Gain of 12p and sex chromosomal abnormalities were not observed in this age group. In contrast, the gain of 12p was the most common aberration in M‐GCTs that arose in children ≥ 8 years old. Additional recurrent changes included the loss of chromosome 13 and the gain of chromosome 21. All ten adolescents with malignant M‐GCT were male, and five showed a gain of the X chromosome. In two of these five patients, Klinefelter syndrome was confirmed by cytogenetic analysis or by fluorescence in situ hybridization (FISH). In conclusion, CGH analysis of M‐GCTs defines distinct genetic subgroups. Mediastinal teratomas show no genetic gains or losses. Malignant M‐GCTs in children < 8 years old show the same pattern of gains and losses identified in sacrococcygeal and testicular GCTs at this age, and they lack sex‐chromosomal abnormalities. Malignant M‐GCTs in children ≥ 8 years old show the same genetic profile previously reported in gonadal GCTs at this age. In addition, approximately 50% demonstrate a gain of the X chromosome, consistent with Klinefelter syndrome. Cooperative group studies reveal a significantly better prognosis of malignant M‐GCT arising in infants compared to that in adolescents, suggesting that these genetic differences are associated with differences in clinical behavior.

Prognostic factors in children with extragonadal malignant germ cell tumors : A pediatric intergroup study

PURPOSE To investigate prognostic factors for pediatric extragonadal malignant germ cell tumors (PEMGCT). MATERIALS AND METHODS Between 1990 and 1996, patients with stage I through IV PEMGCT were eligible for a trial of cisplatin dose intensity. We retrospectively investigated prognostic factors for PEMGCT, including age, stage, primary site, treatment, and elevated alfa fetoprotein by univariate and multivariate analysis. RESULTS The 165 patients had a median age of 1.9 years (range, 3 days to 18.5 years); 109 were female; and 99 had alfa fetoprotein > or = 10,000. There were 30 stage I/II, 61 stage III, and 74 stage IV tumors; primary sites included 88 sacrococcygeal, 39 thoracic, and 38 others. The 5-year overall survival (OS) and event-free survival (EFS) rates with standard deviations were 83.4% +/- 3.7% and 79.0% +/- 4.1%, respectively. Univariate analysis identified age > or = 12 years as a highly significant prognostic factor for EFS (5-year EFS, 48.9% +/- 15.6% v 84.1% +/- 3.9%; P < .0001) and for OS (5-year OS, 53.7% +/- 14.9% v 88.5% +/- 3.4%; P < .0001), whereas treatment was of borderline significance (P = .0777). Multivariate Cox proportional hazards regression identified only age > or = 12 years as a significant prognostic factor for EFS (P = .0002). In multivariate Cox regression for OS, the combination of age and primary site was highly significant (P < .0001). Patients > or = 12 years of age with thoracic tumors had six times the risk of death compared with patients younger than 12 years with other primaries. CONCLUSION Age is the most predictive factor of EFS in PEMGCT. There is a significant interaction between age and primary site, suggesting that patients > or = 12 years of age with thoracic tumors are a biologically distinct group.

Surveillance After Initial Surgery for Pediatric and Adolescent Girls With Stage I Ovarian Germ Cell Tumors: Report From the Children's Oncology Group

PURPOSE To determine whether overall survival (OS) can be preserved for patients with stage I pediatric malignant ovarian germ cell tumor (MOGCT) with an initial strategy of surveillance after surgical resection. PATIENTS AND METHODS Between November 2003 and July 2011, girls age 0 to 16 years with stage I MOGCT were enrolled onto Childrens Oncology Group study AGCT0132. Required histology included yolk sac, embryonal carcinoma, or choriocarcinoma. Surveillance included measurement of serum tumor markers and radiologic imaging at defined intervals. In those with residual or recurrent disease, chemotherapy with compressed PEB (cisplatin, etoposide, and bleomycin) was initiated every 3 weeks for three cycles (cisplatin 33 mg/m(2) on days 1 to 3, etoposide 167 mg/m(2) on days 1 to 3, bleomycin 15 U/m(2) on day 1). Survivor functions for event-free survival (EFS) and OS were estimated using the Kaplan-Meier method. RESULTS Twenty-five girls (median age, 12 years) with stage I MOGCT were enrolled onto AGCT0132. Twenty-three patients had elevated alpha-fetoprotein (AFP) at diagnosis. Predominant histology was yolk sac. After a median follow-up of 42 months, 12 patients had evidence of persistent or recurrent disease (4-year EFS, 52%; 95% CI, 31% to 69%). Median time to recurrence was 2 months. All patients had elevated AFP at recurrence; six had localized disease, two had metastatic disease, and four had tumor marker elevation only. Eleven of 12 patients experiencing relapse received successful salvage chemotherapy (4-year OS, 96%; 95% CI, 74% to 99%). CONCLUSION Fifty percent of patients with stage I pediatric MOGCT can be spared chemotherapy; treatment for those who experience recurrence preserves OS. Further study is needed to identify the factors that predict recurrence and whether this strategy can be extended successfully to older adolescents and young adults.

One year follow-up of children and adolescents with chronic immune thrombocytopenic purpura (ITP) treated with rituximab

We previously showed in a prospective study that rituximab appears to be effective in some children and adolescents with severe chronic immune thrombocytopenia. Eleven of 36 patients achieved and maintained platelet counts over 50,000/mm3 within the first 12 weeks. These patients were followed for the next year.

NUT Midline Carcinoma in a Newborn with Multiorgan Disseminated Tumor and a 2-Year-Old with a Pancreatic/Hepatic Primary

NUT midline carcinoma (NMC) is a rare and aggressive malignant epithelial tumor defined by rearrangement of the NUT gene on chromosome 15. In two thirds of cases, NUT is involved in a balanced translocation with BDR4 on chromosome 19, while in the remaining cases, NUT is rearranged with variant fusion partners such as BRD3. These undifferentiated tumors primarily affect midline structures, usually in the upper aerodigestive tract and mediastinum. Most reported cases have followed a rapidly lethal clinical course. We report the clinical and pathological findings of NMC in the youngest patients identified so far. The 1st case involves a newborn who presented with a supraorbital mass and extensive multiorgan involvement, including the spine, lungs, liver, pancreas, adrenal glands, and subcutaneous tissue. The 2nd patient was a 2-year-old male with an abdominal mass involving the liver and pancreas with pulmonary metastasis. Histopathological analysis of both tumors showed undifferentiated malignant neoplasms, and immunohistochemistry showed positivity for epithelial markers. Both tumors demonstrated t(15;19), and immunohistochemistry with NUT monoclonal antibodies and fluorescent in situ hybridization confirmed NUT rearrangement. The patients died from disease at 1 and 2 months postpresentation. Thus far, 25 cases have been reported, including our 2 current cases. Presentation ages range from 0 to 78 years (mean, 23 years). Herein, we report the 2 youngest reported cases of NMC, including the 1st congenital case and the 1st case arising within the liver/pancreas. Increased awareness and further molecular studies are required for a better understanding of NMC pathobiology and improved therapeutic outcomes.

Revised Risk Classification for Pediatric Extracranial Germ Cell Tumors Based on 25 Years of Clinical Trial Data From the United Kingdom and United States

PURPOSE To risk stratify malignant extracranial pediatric germ cell tumors (GCTs). PATIENTS AND METHODS Data from seven GCT trials conducted by the Childrens Oncology Group (United States) or the Childrens Cancer and Leukemia Group (United Kingdom) between 1985 and 2009 were merged to create a data set of patients with stage II to IV disease treated with platinum-based therapy. A parametric cure model was used to evaluate the prognostic importance of age, tumor site, stage, histology, tumor markers, and treatment regimen and estimate the percentage of patients who achieved long-term disease-free (LTDF) survival in each subgroup of the final model. Validation of the model was conducted using the bootstrap method. RESULTS In multivariable analysis of 519 patients with GCTs, stage IV disease (P = .001), age ≥ 11 years (P < .001), and tumor site (P < .001) were significant predictors of worse LTDF survival. Elevated alpha-fetoprotein (AFP) ≥ 10,000 ng/mL was associated with worse outcome, whereas pure yolk sac tumor (YST) was associated with better outcome, although neither met criteria for statistical significance. The analysis identified a group of patients age > 11 years with either stage III to IV extragonadal tumors or stage IV ovarian tumors with predicted LTDF survival < 70%. A bootstrap procedure showed retention of age, tumor site, and stage in > 94%, AFP in 12%, and YST in 27% of the replications. CONCLUSION Clinical trial data from two large national pediatric clinical trial organizations have produced a new evidence-based risk stratification of malignant pediatric GCTs that identifies a poor-risk group warranting intensified therapy.

Gemcitabine and docetaxel (GEMDOX) for the treatment of relapsed and refractory pediatric sarcomas

Patients with relapsed pediatric sarcomas have a poor outcome and are in need of novel effective therapies.

Sentinel lymph node biopsy in the pediatric population

BACKGROUND Sentinel lymph node biopsy (SLNB) has only been recently used for childhood neoplasms. METHODS We reviewed all patients younger than 19 years who underwent SLNB for 5 years. RESULTS Twenty patients were identified (11 male, 9 female). Sentinel lymph node biopsy was performed for 10 sarcomas (5 synovial, 3 rhabdomyosarcoma, 1 epitheliod, 1 other); 9 skin neoplasms (4 melanomas, 3 Spitz nevi, 2 melanocytomas); and 1 acinic cell carcinoma. All patients underwent Technetium 99m sulfur microcolloid injection and 4-quadrant subdermal injection with Lymphazurin 1% (Autosuture, Norwalk, Conn). Six patients required either sedation for lymphoscintigraphy. Intraoperative gamma probe was used. Primary lesions were found in lower extremity (n = 8), upper extremity (n = 6), trunk (n = 3), and head and neck (n = 3). The lymphatic basins were inguinal (n = 8), axilla (n = 8), neck (n = 3), and both inguinal and axilla (n = 1). At least one lymph node was identified in each procedure. Of 20 patients, 5 (25%) had metastatic disease (4 skin neoplasms and 1 sarcoma). There were no complications in our series, and all patients are alive with no recurrence at an average follow-up of 2.2 years. CONCLUSIONS Sentinel lymph node biopsy allows for an accurate biopsy in children. However, some younger patients may require sedation, and it may be more challenging to isolate the sentinel node.

Pediatric and Adolescent Extracranial Germ Cell Tumors: The Road to Collaboration

During the past 35 years, survival rates for children with extracranial malignant germ cell tumors (GCTs) have increased significantly. Success has been achieved primarily through the application of platinum-based chemotherapy regimens; however, clinical challenges in GCTs remain. Excellent outcomes are not distributed uniformly across the heterogeneous distribution of age, histologic features, and primary tumor site. Despite good outcomes overall, the likelihood of a cure for certain sites and histologic conditions is less than 50%. In addition, there are considerable long-term treatment-related effects for survivors. Even modest cisplatin dosing can cause significant long-term morbidities. A particular challenge in designing new therapies for GCT is that a variety of specialists use different risk stratifications, staging systems, and treatment approaches for three distinct age groups (childhood, adolescence, and young adulthood). Traditionally, pediatric cancer patients younger than 15 years have been treated by pediatric oncologists in collaboration with their surgical specialty colleagues. Adolescents and young adults with GCTs often are treated by medical oncologists, urologists, or gynecologic oncologists. The therapeutic dilemma for all is how to best define disease risk so that therapy and toxicity can be appropriately reduced for some patients and intensified for others. Further clinical and biologic insights can only be achieved through collaborations that do not set limitations by age, sex, and primary tumor site. Therefore, international collaborations, spanning different cooperative groups and disciplines, have been developed to address these challenges.