Jan Godzinski

Treatment of Children With Nonmetastatic Paratesticular Rhabdomyosarcoma: Results of the Malignant Mesenchymal Tumors Studies (MMT 84 and MMT 89) of the International Society of Pediatric Oncology

PURPOSE To report the results of the Malignant Mesenchymal Tumors studies (MMT 84 and 89) of the International Society of Pediatric Oncology (SIOP) in males with nonmetastatic paratesticular rhabdomyosarcoma. PATIENTS AND METHODS From 1984 to 1994, 96 males were treated in SIOP protocols. Radical inguinal orchidectomy was recommended, but initial retroperitoneal lymph node dissection was not performed. Disease was staged according to the SIOP tumor-node-metastasis staging system. Treatment was stratified by stage. In the MMT 89 study, males with completely resected tumors at diagnosis received less chemotherapy (vincristine and dactinomycin) than patients in the MMT 84 study (ifosfamide, vincristine, and dactinomycin). RESULTS Median age at diagnosis was 65 months. Thirty-one tumors were larger than 5 cm, and 13 males were older than 10 years with a tumor larger than 5 cm. At a median follow-up of 7 years, 87 patients were alive; 79 were in first complete remission and eight were in second complete remission. Relapse occurred in 16 patients (17%). At 5 years, the overall survival (OS) rate was 92%, with an event-free survival (EFS) rate of 82%. OS and EFS were significantly worse for males with tumors greater than 5 cm and for males older than 10 years at diagnosis. CONCLUSION Males with paratesticular RMS have an excellent prognosis except for a selected group of patients older than 10 years or with tumor greater than 5 cm. Intensified chemotherapy incorporating alkylating agents for this subgroup may be preferred to the use of systematic lymphadenectomy to improve survival while minimizing the burden of therapy.

Pancreatoblastoma: A report from the European cooperative study group for paediatric rare tumours (EXPeRT)

BACKGROUND Pancreatoblastoma is a very rare malignant tumour typically occurring in the early years of life. Due to its rarity, standardised diagnostic and therapeutic guidelines are not available for pancreatoblastoma. METHODS The newborn cooperative group denominated EXPeRT - European cooperative study group for paediatric rare tumours - combined in a joint analysis of all cases registered between 2000 and 2009 by the national groups of Italy, France, United Kingdom, Poland and Germany. RESULTS Twenty patients <18years old (median age 4years) were analysed: nine had distant metastases at diagnosis. Seventeen patients had tumour resection, at initial or delayed surgery. Eighteen received chemotherapy (response rate 73%), seven received radiotherapy. For the whole series, 5-year event-free survival and overall survival were 58.8% and 79.4%, respectively. Outcome did not correlate with tumour site and size, but was strongly influenced by the feasibility of tumour complete resection. CONCLUSIONS This international study confirms the rarity of the disease, the critical role of surgical resection both as therapy and as a prognostic variable, and the potential efficacy of chemotherapy. The adoption of an intensive multidisciplinary approach is required, as well as the referral to highly experienced centres. Further international cooperation is needed to collect larger series and stimulate biological studies to improve our understanding of the biology and the natural history of PBL.

Characteristics and outcome of stage II and III non-anaplastic Wilms’ tumour treated according to the SIOP trial and study 93-01

PURPOSE To determine the prognosis of children with stage II and III of low or intermediate risk histology (SIOP classification) in unilateral localised Wilms tumour (WT) after neoadjuvant chemotherapy according to the trial and study of the International Society of Paediatric Oncology, SIOP 93-01. PATIENTS AND METHODS Patients with unilateral localised WT and stage II or III with low (LR) or intermediate risk (IR) histology between 6 months and 18 years of age, were selected from the total sample of patients registered in the SIOP 93-01 study between June 1993 and December 2001. All patients received 4 weeks of actinomycin-D/vincristine before surgery. Postoperative chemotherapy consisted of actinomycin-D, vincristine and epirubicin/doxorubicin for 27 weeks. Flank or whole abdomen irradiation was given for stage III. Event-free survival (EFS) and overall survival (OS) were analysed for various subgroups. RESULTS Of 1476 registered patients 594 (40%) met the inclusion criteria for this analysis. Four hundred and two (67%) had stage II disease and 563 (95%) had intermediate risk histology. Median tumour volume was 439 ml at diagnosis and 163 ml after preoperative chemotherapy. With a median follow-up of 8 years, 5-year EFS was 90% (95% confidence interval [95% CI]: 87-92%) and OS 95% (95% CI: 93-97%). Patients with stage III, blastemal type histology and a large volume at surgery had a worse outcome. CONCLUSION Treatment for stage II and III LR or IR WT is successful in a neoadjuvant setting as advised by the SIOP. Stage, tumour volume and blastemal type histology are the most important prognostic factors.

Treatment efficiency, outcome and surgical treatment problems in patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma: a report from the Cooperative Soft Tissue Sarcoma trial CWS-96.

To analyze the clinical course, treatment modalities, complications and outcome of patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma (BPRMS) treated on the CWS‐96 trial.

Nephron Sparing Surgery (NSS) for Unilateral Wilms Tumor (UWT): The SIOP 2001 Experience

Total nephrectomy (TN) remains the standard treatment of unilateral Wilms tumors (uWT). The SIOP WT‐2001 protocol allowed Nephron Sparing Surgery (NSS) for polar or peripherally non‐infiltrating tumors. Aim: Inventory of the current SIOP NSS‐experience.

Rare cancers in children - The EXPeRT Initiative: a report from the European Cooperative Study Group on Pediatric Rare Tumors.

The low incidence and the heterogeneity of very rare tumors (VRTs) demand for international cooperation. In 2008, EXPeRT (European Cooperative Study Group for Pediatric Rare Tumors) was founded by national groups from Italy, France, United Kingdom, Poland and Germany. The first aims of EXPeRT were to agree on a uniform definition of VRTs and to develop the currently most relevant scientific questions. Current initiatives include international data exchange, retrospective and prospective studies of specific entities, and the development of harmonized and internationally recognized guidelines. Moreover, EXPeRT established a network for expert consultation to assist in clinical decision in VRTs.

Minimally invasive nephrectomy for Wilms tumors in children - data from SIOP 2001.

PURPOSE To analyse the surgical and oncological outcome of minimally invasive surgery (MIS) for tumor nephrectomy in Wilms tumor (WT) patients. METHODS WT patients from the SIOP 2001 trial, undergoing MIS for tumor nephrectomy were analyzed with regard to demographic characterization, surgical specifications, complications, and outcome. RESULTS There were 24 children matching the inclusion criteria. Median age at operation was 40.35 months (14.3-65.4). All patients received preoperative chemotherapy. Median tumor volume was 177.5 ml at diagnosis (46.5-958) and 73.0 ml at surgery (3.8-776). There was one surgical complication (splenic injury), no intraoperative tumor rupture occurred. Abdominal stage was I in 14, II in 7, and III in 3 patients. Adequate lymph node sampling was performed in only 2 patients. One local relapse occurred. Event-free survival was 23/24, overall survival was 24/24, median follow up was 47 months (2-114). CONCLUSIONS We present the largest series so far of minimally invasive nephrectomies for nephroblastoma based on a multinational trial. Treatment results were comparable to those of open surgery; however, experience of operating surgeons was generally high. Discipline of lymph node sampling was inadequate. Based on this analysis a prospective study on MIS in nephroblastoma is planned by the SIOP Renal Tumor Study Group.

Ovarian Sertoli Leydig cell tumours in children and adolescents: An analysis of the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT)

OBJECTIVE To analyse ovarian Sertoli-Leydig cell tumours (SLCTs) for potential prognostic markers and their use for treatment stratification. PATIENTS Forty-four patients were included. Patients were prospectively reported to the German MAKEI (Maligne Keimzelltumoren) studies (n=23), French TGM protocols (n=10), Italian Rare Tumour Project (TREP) registry (n=6), and the Polish Pediatric Rare Tumour Study group (n=5). Tumours were classified according to World Health Organisation (WHO) and staged according to International Federation of Gynecological Oncology (FIGO). RESULTS Median age was 13.9 (0.5-17.4) years. All patients underwent resection by tumour enucleation (n=8), ovariectomy (n=17), adenectomy isolated (n=18) or with hysterectomy (n=1). FIGO-stage: Ia 24pts., Ic 17pts., II/III 3pts. One patient had bilateral tumours. Four patients (stage Ia: 3, stage Ic: 1) developed a metachronous contralateral tumour. Otherwise, all stage Ia patients remained in complete remission. Among 20 patients with incomplete resection or tumour spread (stage Ic-III), eight relapsed, and five patients died. Eleven patients were initially treated with two to sixcycles of cisplatin-based chemotherapy. Of these, seven patients are in continuous remission. Poor histological differentiation was associated with higher relapse rate (5/13) compared to intermediate (3/18) and high differentiation (0/4). Tumours with retiform pattern or heterologous elements showed a high relapse rate, too (5/11). After a median follow-up of 62 months, event-free survival is 0.70±0.07, relapse-free survival 0.81±0.06 and overall survival 0.87±0.05. CONCLUSIONS Prognosis of SLCTs is determined by stage and histopathologic differentiation. Complete resection with careful avoidance of spillage is a prerequisite of cure. The impact of chemotherapy in incompletely resected and advanced stage tumours remains to be evaluated.

Outcome of localised blastemal-type Wilms tumour patients treated according to intensified treatment in the SIOP WT 2001 protocol, a report of the SIOP Renal Tumour Study Group (SIOP-RTSG)

Blastemal-type Wilms tumour (BT-WT) has been identified as a high risk histological subgroup in WT assessed after pre-nephrectomy chemotherapy in trials of the International Society of Paediatric Oncology (SIOP) Renal Tumour Study Group. Therefore, in SIOPWT2001, post-operative chemotherapy for BT-WT was intensified aiming to improve survival. Survival analysis of all unilateral BT-WT patients (SIOPWT2001) (n=238), was compared with historical BT-WT controls (SIOP93-01) (n=113). 351/4061 (8.6%) unilateral non-metastatic BT-WT patients (SIOP93-01/SIOPWT2001) were studied. Median age at diagnosis was 43 months (Inter Quartile Range (IQR) 24-68 months), stages: I (n=140, 40%), II (n=106, 30%), III (n=105, 30%). BT-WTs were higher staged, showed greater volume decrease after pre-operative chemotherapy and were diagnosed at an older median age compared to other WT patients. Patient characteristics did not differ substantially between SIOP93-01 and SIOPWT2001. Univariate analysis showed a 5-year event-free survival (EFS) of 80% (95% confidence interval (CI): 75-86%) (SIOPWT2001) compared to 67% in SIOP93-01 (95% CI: 59-76%; p=0.006) and overall survival (OS) of 88% (95% CI: 83-93%) (SIOPWT2001) compared to 84% (95% CI: 77-91%; p=0.4) in SIOP93-01. 95% of relapses were distant metastases (SIOP93-01/SIOPWT2001). Treatment protocol, age at diagnosis, tumour stage (III versus I/II) and volume (at surgery), were prognostic variables for EFS (uni- and multivariate Cox regression analysis). Independent prognosticators for OS were age at diagnosis, tumour stage and volume (at surgery). The most significant survival benefit of intensified treatment, was observed in Stage I (EFS 96% in SIOPWT2001 (OS 100%), 71% in SIOP93-01 (OS 90%)). BT-WT derived benefits from more intensive chemotherapy as reflected by a reduction in relapse risk. However, the benefit of the more intensive chemotherapy to improve OS was only observed in stage I BT-WTs, by adding doxorubicin.

Differential expression of invasion promoting genes in childhood rhabdomyosarcoma

Expression profiling of tumor tissue allows a systematic search for targeted therapies and offers relevant prognostic information. Molecular studies on rhabdomyosarcoma (RMS) revealed a more differentiated classification than the histological subgrouping into embryonal (RME) and alveolar (RMA) rhabdomyosarcoma, and reflected the chromosomal aberrations found in RMS. We addressed biological processes like cell migration and emerging drug resistance by expression profiling to identify mechanisms of metastasic invasion and differential response to chemotherapy in RMS. Gene expression analysis was performed in 19 RMS samples using the Affymetrix U133 Plus2 array. Validation of target genes was performed by qRT-PCR. Data were analyzed using Pathway analysis software. Involvement of these genes in invasion processes was evaluated in knock-down experiments using specific interference RNA and Matrigel(TM) invasion assay. In RMA tissues 211 of 534 genes were overexpressed, in RME tissues 323 genes were overexpressed. Pathway analysis software identified a group of genes involved in cell growth, morphology and motility. In patients with distant metastases especially transcription factors such as FOXF1 and LMO4 showed a high expression, which were described as determinants of tumor cell migration. Down-regulation of these factors inhibited the invasion of RMS cells >10-fold. Microarray technology is a powerful method not only to classify RMS samples, but also to identify major regulatory processes. Functional evaluation of LMO4 and FOXF1 identified targets of a molecular network for preventing metastatic invasion in RMS.