Remaining problems and controversies in the management of childhood head and neck soft tissue sarcomas: Retrospective (national) Multicenter Study of the Polish Pediatric Solid Tumors Group.

Soft tissue sarcomas in children are a heterogeneous group of malignant diseases. Among these, tumors localized in the head and neck region are especially difficult to treat. While multidisciplinary care has dramatically improved the prognosis of sarcoma patients, their treatment remains uncertain because of demand on radical surgical resection of the tumor. Achieving cure without deforming or mutilating the child remains the primary goal of treatment. This study is the multicenter (nationwide, 11 Polish centers) retrospective analysis of the treatment results in children having soft tissue sarcoma in the head and neck region during the previous decade (from 1991 to 2001). Late effects of the treatment are documented in long-term survivals. Eighty-five children from 1 to 212 months of age were included. Different multimodal treatment protocols were utilized (CWS-91, SIOP-MMT-91, and CWS-96). The median observation time was 25 months. Data on long-term effects were collected in 34 long-term survivals. Complete remission was achieved in 68 (80%) patients. Primary treatment failure occurred in 13 (15.3%) patients, all of whom succumbed in disease progression. Relapse occurred in 21 (30.9%) patients primarily achieving complete remission. Second primary neoplasm occurred in 3 children. The estimated 5-year event-free survival and the 5-year total survival rates for the whole group are 0.38 and 0.55, respectively. The main late effect documented in long-term survivals were cosmetic defects in 12 (35.3%) and visual field deficit or blindness in 8 (26.5%). Despite substantial improvement of the prognosis of pediatric soft tissue sarcomas, the multimodal treatment of head and neck region tumors remains controversial. Improved long-term outcome and focusing on psychosocial difficulties raise the important and difficult problem of functional results and cosmesis. Tumors localized in the orbit carry an excellent prognosis. However, the main late sequela is vision impairment and cosmetic defect due to the therapy given many years earlier. Two other tumor localizations--the parameningeal and nonparameningeal ones--still have bad prognosis. The observations made in this study confirm that main prognostic factors are the size of the primary tumor and the tumor stage. The worst prognosis remains invasive tumor (T2-stage) with a size over 5 cm. Individually adjusted multimodal therapy, which imperatively needs to be radical, though not mutilating, might minimize the late effects. Psychosocial problems in long-term survivors need to be focused on at the national level and better support must be provided in the future, involving a team of different medical and paramedical profiles.

Multicenter retrospective analysis of various primary pediatric malignant hepatic tumors--management in a series of 47 Polish patients (1985-1995).

Forty-seven children treated in various Polish centers between 1985 and 1995 for primary malignant liver tumors were retrospectively analyzed. Hepatoblastoma (HB) prevailed--it was found in 39 cases. There were 6 hepatocarcinoma (HCC) cases and 2 cases of undifferentiated sarcoma (UDS). In 44% of HB patients the tumor involved both liver lobes. 18% of children with HB presented with pulmonary metastases at diagnosis. Chemotherapy was applied in 92% of cases (preoperatively in 67%). Tumor resection was performed in 56% of HB patients. Overall survival of patients with hepatoblastoma was 43.6%, while it was 50% for hepatocarcinoma and 100% for undifferentiated sarcoma (2 cases only). Mean observation time was 58 months. The hepatoblastoma subgroup, being the largest (83% of all cases), was analyzed separately for prognostic factors. Completeness of tumor excision strongly influenced survival. Involvement of both lobes of the liver and multifocality of the tumor were other adverse prognostic factors.

[Treatment regimen for children and adolescents with Hodgkin's disease designed to decrease late complications of radiotherapy]. / Program leczenia choroby hodgkina u dzieci i mlodziezy zmierzajacy do ograniczenia powiklan po radioterapii.

Between 1997 to 1999 in 9 centres of the Polish Paediatlic Leukemia/Lymphoma Study Group, 167 children and adolescents (aged 2-19 years) with stage 1 to IV Hodgkin's disease (HD) were treated according to a regimen with a limited use of radiotherapy (RT). All patients received B-DOPA and MVPP chemotherapy. The number of cycles of chemotherapy was adjusted in respective risk groups. In 13 children with stage IA and IIA disease with favourable prognostic factors chemotherapy alone was used. In other patients the dose of RT applied to lymphatic regions was 15-46,4 Gy. In case of a small tumour at presentation and good response to initial chemotherapy the RT dose was 15-16 Gy. In other cases doses of 25-30 Gy were planned. The use of higher doses, particularly exceeding 35 Gy, in eleven patients, was not justified. Among all the 167 patients, three oftliem (1.2%) with advanced disease (Stage III-1V) did not achieve first remission. The 4-year overall survival (OS), relapse free survival (RFS) and event free survival (EPS) were 99%. 93% and 90%, respectively. Relapses occurred in 8 children (first remission lasted for 4-29 (median = 9 months). All 13 children in whom chemotherapy alone was used remain in first remission. In the group of children who received RT in the dose of 15-16 Gy relapse occurred in one child. Our preliminary analysis indicates that limited use of RT in selected cases of HD in children and adolescents did not show worse results of treatment. However, the assessment of possible influence of this regimen on the decreased rate of late complications requires longer follow-up.

Echocardiographic assessment of right atrial thrombus related to the implanted port device in patient receiving chemotherapy for non-Hodgkin's lymphoma.

The case of a potentially life-threatening complication related to the use of implanted port device in a 8 year old Non-Hodgkin's Lymphoma patient receiving chemotherapy is described. The device was inserted in early 1997 and used repeatedly for chemotherapy without any complications. In late 1997 during routine screening for cardiac left ventricular function before re-introduction of chemotherapy, an abnormal 1.43 x 1.53 cm mass, consistent with a non-mobile thrombus was found in the right atrium. The initial thrombolytic therapy with recombinant tissue plasmin activator (rt-PA) infused by a central venous catheter was combined with daily echocardiographic examination in order to assess both the timing and mode of thrombus resolution. After 8 days systemic fibrinolytic therapy was discontinued as major hemorrhage from venipuncture sites occurred and the clot dissolution was not obtained. Patient underwent right atriotomy utilizing cardiopulmonary bypass and subsequent surgical thrombus removal was successful. The study evaluated the contribution of two-dimensional echocardiography (2D) in the follow-up of vascuport and other central venous catheter (CVC) location and early diagnosis of related complications such as thrombi. The authors consider that pulmonary flow analyzed with Doppler echocardiography as a reliable, suitable and non-invasive method to evaluate increased pulmonary artery pressure in children with right atrial thrombi and probability of pulmonary microembolism or embolism. As the incidence of right atrial thrombi is highly associated with the catheter tip position in the right atrium, in contrast to their positioning in the superior vena cava or in its junction with the right atrium, the authors recommend that special attention and effort should be given to placing of the catheter tip in the superior vena cava or in its junction with the right atrium avoiding the right atrium during the implantation procedure. The surgical right atrium thrombus removal in patients with no clot dissolution despite systemic thrombolytic treatment underscores the importance of surgical therapy in treating this life-threatening complication of indwelling catheters.

[Adverse reactions associated with the use of L-asparaginase during therapy of patients with nB non-Hodgkin's lymphoma. Report of the Polish Paediatric LeuKaemia/Lymphoma Study Group]. / Objawy niepozadane leczenia preparatami L-asparaginazy u chorych z nieziarniczym chloniakiem zlosliwym typu NB w oparciu o material Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków Zlosliwych u dzieci.

The aim of the study was to determine the side effects of asparaginase administration during treatment protocol for childhood non-Hodgkin's lymphoma (NHL). Drug adverse reactions occurred in 20/66 of patients (30,3%) treated in 9 centres in Poland between 1993 and 1998. The most common side effects were coagulation disturbances in 12/66 of the children (18,2%), which occurred due to reduced production of important coagulation factors. Six patients (9,1%) developed impairment of liver function (9,1%). Drug toxicity caused the modifications of treatment protocol in 12/66 (18,2%) of patients, mainly in the induction phase; 3 children died due to relapse of disease.

[Abdominal presentation of B-cell non-Hodgkin's lymphoma (B-NHL) - surgical treatment and its results. Report of the Polish Paediatric Leukaemia/Lymphoma Study Group]. / Manifestacja brzuszna chloniaka B-komórkowego u dzieci - interwencja chirurgiczna i wyniki leczenia. Raport PPGLBC.

The aim of this study was to analyse the effect of LMB-89 protocol and surgical procedure at initial laparotomy on the outcome in children with abdominal B-cell NHL. The initial surgery intervention was: complete resection (20% pts), subtotal resection (20%), partial resection (4%), biopsy (36%). Postoperative complications occurred in 5 children. Complete recovery (CR) was achieved in 92% pts. There were 4% non responder patients. Two patients died before CR evaluation (tumour lysis syndrome; bleeding and multi organ failure after initial surgery). One patient died in CCR from sepsis probably influenced by the previous local operation. 10.8% patients relapsed. The estimate EFS for all patients with AB-NHL is 81%, 85% for stage III and 73% for stage IV. Major surgery in advanced stages is not recommended since it delays chemotherapy and fails to improve overall survival.

[The incidence and treatment of the first relapse in children with Hodgkin's disease]. / Wystepowanie i leczenie pierwszej wznowy choroby Hodgkina u dzieci.

From January 1988, to December 1997, among 447 children with Hodgkin's disease (HD) who underwent initial treatment in seven centres of the Polish Paediatric Leukaemia/Lymphoma Study Group, 442 patients obtained a complete remission (CR). The initial treatment consisted of multidrug chemotherapy (B-DOPA and MVPP) combined with local radiotherapy. Relapses occurred in 35 cases (7,9%). Two patients from other centres were also included in this analysis. Four patients were lost to follow-up; 33 patients with relapses were analysed. Early relapses (first complete remission (CR) shorter than 12 months) occurred in 17 cases. Treatment of the first relapse consisted of different types of multidrug chemotherapy. Six patients underwent high-dose chemotherapy and peripheral blood stem cells transplantation. Radiotherapy was used in 19 children. Second CR was achieved in 28 patients (85%). In 10 children (36%) second relapse occurred after 4 to 21 months (median = 10). In 17 cases the second CR lasted 12-14 (median=54) months. The probability of the 7-year freedom from second relapse was 64%. Eleven patients died; one of them in second CR due to toxic liver damage. Results of treatment in children with early relapses were significantly worse. In 17 patients with early relapse, and 16 children with late relapse, the second CR was achieved in 70% and 100% of cases, respectively. The probability of the 7-year overall survival, freedom from second relapse and event-free survival in children with early and late relapse was: 42, 58, 40%, and 94, 69, and 66%, respectively. The therapeutic results in the subgroups of children with relapses treated with different methods were not comparable because of the small number of children in each group. The use of multidrug chemotherapy with or without radiotherapy allows to achieve a long lasting second CR in more than 50% of children with HD who relapsed after initial combined modality treatment. The optimal treatment of relapsed HD in patients initially treated with multidrug chemotherapy with or without of radiotherapy, is currently unknown.

[G-CSF and GM-CSF in treatment of neutropaenia after chemotherapy in children with neoplasms]. / G-CSF i GM-CSF w leczeniu neutropenii po chemioterapii nowotworów u dzieci.

A total number of 608 cycles of G-CSF and/or GM-CSF was applied in 280 patients aged from 6 months to 20 years during neutropaenia associated with chemotherapy of children's neoplasms (NHL-124, NBL-42, RMS-36, Nephroblastoma-18, Osteosarcoma-17, Ewing's Sarcoma-14, Hepatoblastoma-6, Neurofibrosarcoma-6, PNET-5, Medulloblastoma-3, Fibrohistiocytoma-3, Angiosarcoma-2, other - 4). G-CSF - Neupogen (Filgastrim, Hoffman La Roche - 492 cycles) and GM-CSF - Leucomax (Molgramostim, Shering Plough - 116 cycles) were administered 5 mg/kg/day s.c. Forty one children with malignancies (NHL -21 cases, solid tumours -17) treated before cytokines were in use served as a control group. Our study demonstrated that G-CSF and GM-CSF therapy, gives a shorter period of neutropaenia, reduction of the number of febrile days, decreased frequency of infection and shortened its duration.

Childhood stage IV Hodgkin disease: therapeutic results of the Polish pediatric leukemia/lymphoma study group.

BACKGROUND: The therapeutic management in patients with stage IV Hodgkin disease is still controversial. PROCEDURE: Among 783 children with Hodgkin disease treated from 1971 to 1996, 56 patients (7.3%) were diagnosed with stage IV. The treatment consisted of MVPP or MVPP/B-DOPA chemotherapy combined with involved-field radiotherapy in 50 children. RESULTS: The results of treatment of stage IV patients were compared in the three sequential time periods, during which the therapy was modified. In these periods, the first complete remission was obtained in 67%, 86%, and 90% of children, respectively, and the 10-year event-free survival was 42%, 64%, and 85%, respectively. CONCLUSIONS: Alternate multidrug chemotherapy combined with low-dose involved-field radiotherapy is at present a satisfactory therapeutic method in children with stage IV Hodgkin disease.

[Does residual mediastinal mass in children with completed treatment of Hodgkin's disease affect the incidence of relapses?]. / Czy resztkowy guz sródpiersia przetrwaly po zakonczeniu leczenia choroby Hodgkina u dzieci ma wplyw na czestosc wystepowania wznów?

Four hundred and four children with Hodgkin's disease (stage I-IV) were treated in seven cooperating centers of Polish Paediatric Leukaemia/Lymphoma Study Group between 1988 and 1996. Mediastinal masses and/or hilar involvement were found in 261 (65%) patients. Remission was obtained in 256 (98%) of this group. In 31 (12%) children residual mediastinal/hilar masses were found after completing the treatment. For this reason in 13 cases the number of chemotherapy courses and/or the dose of radiation therapy were increased. In two cases thoracotomy or thoracoscopy were performed, and in one case gallium scan was performed. In none of these patients active disease was found. Relapses occurred in 4 (12.9%) from the group of 31 children with residual mediastinal/hilar involvement 8-15 months after cessation of the therapy. Twenty seven children have been in first remission for 5-113 months (median, 34). In 225 patients with a complete resolution of their mediastinal/hilar masses, relapses occurred in 13 (5.7%) cases. Patients with residual mediastinal mass should be carefully evaluated before making a decision to complete their treatment, including CT scan, MRI, and gallium scan. In doubtful cases histopathological verification should be done.

[The analysis of failures in the treatment of children with non-B non-Hodgkin's lymphoma. Polish pediatric leukemia/lymphoma study group report]. / Analiza niepowodzen w leczeniu dzieci z nieziarniczym chloniakiem zlosliwym typu NB. Raport Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków zlosliwych u dzieci.

The aim of the study was to evaluate the results of treatment of 46 children with non B non-Hodgkin's Lymphoma registered in 7 centers of Polish Paediatric Leukaemia/Lymphoma Study Group from 1993 to 1998. The patients were treated according to BFM-90 protocol based on German regimen. The overall probability of event-free survival for the all children after 4 years of follow-up was 71%, for patients in stage III--65%, stage IV--70%. The achieved results were not as positive as in the BFM Study Group, what was related to: the great number of children with advanced stage of disease (54.3%), the late final diagnosis, the great number of recurrences (22.5%) and deaths caused by the toxicity of medication (6.5%) (infections, drug toxicity).

[The efficacy of G-CSF and GM-CSF in the adjunctive treatment of infections complicating chemotherapy of solid tumors in children. Report of Polish Pediatric Leukemia/Lymphoma Treatment Group]. / Skutecznosc G-CSF i GM-CSF w leczeniu wspomagajacym zakazen wiklajacych chemioterapie guzów litych u dzieci. Raport PPG/LBC.

Total number of 306 cycles of GM-CSF-Leucomax Sandoz (5 mg/kg/day s.c.) and/or G-CSF Filgrastim Hoffmann-La Roche (5-10 mg/kg/day s.c.) was applied in 146 children aged from 0.5-18 years during neutropenia associated with chemotherapy of solid tumours. Seventeen children with malignancies served as a historical control group. Our study have demonstrated after both G- and GM-CSF therapy shorter period of neutropenia, reduction of the number of febrile days and a decreased frequency of infectious complications and infection's duration.

[The effectiveness of G-CSF and GM-CSF in the adjunctive treatment of infections complicating chemotherapy of non-Hodgkin's lymphoma in children. Report of Polish Pediatric Leukemia/Lymphoma Treatment Group]. / Skutecznosc G-CSF i GM-CSF w leczeniu wspomagajacym zakazen wiklajacych chemioterapie nieziarniczych chloniaków zlosliwych u dzieci. Raport PPG/LBC.

Total number of 252 cycles of GM-CSF-Leucomax Sandoz (5 mg/kg/day s.c.) and/or G-CSF Filgrastim Hoffmann-La Roche (5-10 mg/kg/day s.c.) was applied in 124 children aged from 0.5-20 years during neutropenia associated with chemotherapy of non-Hodgkin's lymphoma (NHL). Twenty four children with NHL treated according to the same chemotherapy protocol but without G-CSF and GM-CSF served as a control group. Our study have demonstrated the good efficacy of both G-CSF and GM-CSF therapy. They shortened the period of neutropenia, reduced the number of febrile days, infection's duration and decreased the frequency of infectious complications.

[The role of local surgical and radiological control in the treatment of soft tissue sarcoma sensitive to chemotherapy in children. Report of Polish Pediatric Solid Tumors Treatment Group]. / Udzial lokalnej kontroli chirurgicznej i radiologicznej w wynikach leczenia nowotworów tkanek miekkich wrazliwych na chemioterapie u dzieci. Raport PPG/GL.

In this paper the role local surgical and radiological control in the treatment of soft tissue sarcomas in children was analyzed. All children were treated according to CWS-91 and SIOP-IV protocols. Eighty three children with RMS A + E, EES/PNET, SS, UDS were included in the analysis. The primary surgery consisted of R0 (5%), R1 (18%) or R2 (16%) resection. In majority of cases (61%) primary surgical intervention was limited to diagnostic biopsy. Conventional or hyperfractionated radiotherapy was performed in 42.8%, 73.8% and 75% of children with disease stage II, III and IV, respectively. Delayed surgery was performed in 20 out of 53 (37.7%) children with stage III of the disease. In 5 patients without primary focus (urinary bladder in 3 and prostate in 2 cases) removed, progression of the disease occurred. In 5 children (stage IV) with progression of the disease no secondary surgery was performed. In 4 of them the primary tumor exceeded 10 cm in diameter. No delayed surgery was performed in 69% of relapsed children with stage III of the disease. Planned radiation therapy was not performed in 15.9% of cases. Primary local surgical control of primary tumor is of great importance for remission duration. In children who underwent delayed surgery the estimated EFS was of 0.7, in comparison with 0.5 EFS of those without secondary surgical treatment.

[Use of filgrastim (RHU G-CSF) in supplemental treatment of non Hodgkin's lymphoma (NHL) in children]. / Zastosowanie filgrastimu (rHu G-CSF) w leczeniu uzupelnijaçym nieziarniczych chloniaków zlosliwych (NHL) u dzieci.

Clinical application of glycoproteins stimulating the growth (G-CSF), differentiation and activity of the cells of granulocyte line has become a landmark in the treatment of patients with neutropenia. It has been proved that filgrastim (rHU G-CSF) applied after intensive chemotherapy shortens the duration of neutropenia and decreases the frequency of occurrence of infections. The paper discusses the efficiency and tolerance of filgrastim in children treated for NHL. Filgrastim was applied in children with NHL T cell and B cell treated according to BFM 86 protocols. It was given in a dose of 5 micrograms/kg daily i.v. The duration of therapy ranged from 5-20 days. Altogether 47 cycles were performed. 25 cycles were performed in 12 children during granulocytopenia (< 1 x 10(9)/l). The median time of neutropenia recovery, the frequency of severe infection and chemotherapy retardation were significantly lower in the examined than in the control group (p < 0.05). In 6 children 22 courses of filgrastim were given prophylactically after the cycles of intensive chemotherapy of NHL. Only during two courses due to neutropenia the chemotherapy retardation was necessary. Toleration of filgrastim was good. Application of filgrastim right after the intensive chemotherapy in children with NHL has considerably improved persistent realization of treatment programmes. Tolerance of the drug was good.

Active immunization of children with leukemias and lymphomas against infection by hepatitis B virus.

Engerix B vaccine was administered to 54 children with leukemias and lymphomas aged from 2 to 15 years. In 36 cases chemotherapy was completely stopped, and 18 cases were receiving maintenance treatment. Engerix B was given at 0, 1, 2 and 6 months in a dose of 20 micrograms to children < 10 years, and 40 micrograms to older patients. The effectiveness of active immunization was demonstrated after complete therapy cessation in 88% of cases. The levels of antibodies determined 1 year after primary vaccination remained high, and in most of the vaccinated children they were > 1000 mIU/mL. In children vaccinated in the course of maintenance treatment the levels of antibodies did not give sufficient protection against infection.

[Central venous catheters with subcutaneous ports for long-term chemotherapy in pediatric oncology]. / Cewniki z podskórnym zbiornikiem zakladane do zyl centralnych w dlugotrwalej chemioterapii w onkologii dzieciecej.

In 29 paediatric oncology patients requiring intravenous chemotherapy, intravenous antibiotics intravenous fluids and blood products transfusions the central venous catheters with subcutaneous ports were inserted. Catheters were left in place for the period lasting from two weeks up to one year in 14 children they still remain in place, 6 catheters were removed due to complications such as occlusion, local necrosis, abscess or bleeding around the place of insertion. The described method, securing long-term venous access, enables safe and painless treatment, which is specially important in paediatric oncology. Moreover, home care can replace hospital treatment and whole procedure is highly cost-effective due to extended time of catheters utilization.

[Hepatitis B in children with leukemia and lymphoma]. / Zakazenie wirusem zapalenia watroby typu B u dzieci chorych na bialaczki i chloniaki.

In the time period from February to October 1988 the indicators of hepatitis virus B infection, transaminase activity, and bilirubin level were studied in 89 children with acute leukaemias and malignant lymphomas. The age of the children was from 7 months to 16 years. Fifteen children were examined before starting the treatment with cytostatics, 48 during intensive chemotherapy, and 26 during maintenance treatment. HBV markers were found in 53 children during intensive therapy and maintenance treatment. Out of 36 children with negative HBV infection markers 31 were examined before starting the treatment with cytostatics or during the first 6 months of treatment. Nine out of 53 children in whom HBV infection markers were found had aminotransferase activity raised over 100 u/l and/or bilirubin level over 5 mg/dl and in nine cases transaminase activity and bilirubin level were raised only slightly (below 100 u/l and below 5 wg/dl). In 53 children the results were normal. The high incidence of HBV infection in children with acute leukaemias and lymphomas indicates the necessity of routine prophylactic treatment in this group of patients.