ABSTRACT
The childhood cancer survival rate is currently 75% in industrialized countries. Rates in developing countries are much lower. The Franco-African Childhood Cancer Group (French acronym, GFAOP) was founded in 2000 with aim of reducing this unfavorable situation in Africa. The GFAOP has developed two forms of action. The main form consists of organizing two- to twelve-month training sessions for physicians and nurses in France and Morocco. The other form involves assessing the feasibility of modern treatment protocols for various cancers in Africa. The first feasibility trials were carried out on nephroblastoma and Burkitt's lymphoma in 12 pilot units in North Africa, West Africa, and Madagascar. In the first study from 2001 to 2005 we treated 306 cases of Burkitt's lymphoma using French LMB protocols adapted to the African setting and achieved a survival rate of 61%. A second study started in 2005 using Endoxan alone achieved a highly satisfactory survival rate of 73% for neuroblastoma in all stages except bilateral. Altogether from 2001 to 2007 more than 1000 cases of nephroblastoma and Burkitt's lymphoma were treated in African hospitals by African doctors and nurses. No patients were transferred to Europe. The GFAOP supplied drugs when necessary and took care of most travel expenses. African and French doctors worked together on protocol design, trial management, and data analysis. These promising results show that the latest therapeutic techniques can be used to treat childhood cancer in Africa by adapting the protocol to conditions in developing countries. Sanofi-Aventis Laboratories in association with the International Union against Cancer has launched a major campaign to improve Pediatric Oncology in developing countries. Projects in four GFAOP units are being financed through this campaign. In 2006 the GFAOP began assessment of two new treatment protocols, i.e., one for acute lymphoblastic leukemia and the other for Hodgkin's disease. Two other projects are being planned, i.e., one for treatment of retinoblastoma and the other for treatment of some types of brain tumors.
Subject(s)
International Cooperation , Neoplasms/therapy , Africa , Child , Clinical Protocols , Developing Countries , France , HumansSubject(s)
Neoplasms/therapy , Societies, Medical/organization & administration , Africa , Child , France , HumansSubject(s)
Lymphoma, B-Cell/drug therapy , Wilms Tumor/drug therapy , Adolescent , Africa , Child , Child, Preschool , Female , France , Humans , Infant , MaleABSTRACT
BACKGROUND: Present treatment for Wilms' tumour is very successful. Now, efforts are aimed at reducing toxicity and burden of treatment by shortening schedules without loss of effectiveness. The objective of this randomised trial was to assess whether postoperative chemotherapy for patients with stage I intermediate-risk and anaplastic Wilms' tumour could be shortened to only 4 weeks from the standard 18 weeks, while maintaining equivalent event-free survival. METHODS: Between June, 1993, and June, 2000, 410 patients were randomly assigned after four doses of vincristine plus one course of dactinomycin postoperatively either to stop further adjuvant chemotherapy (no further chemotherapy group, n=200), or to receive a further two courses of the same chemotherapy (standard group, n=210). Previous treatment consisted of chemotherapy before nephrectomy of four doses of vincristine and two courses of dactinomycin followed by surgical resection of the tumour. Eligible patients were at least 6 months old and had stage I tumours with either intermediate-risk histology or anaplasia. The primary endpoint of this equivalence trial was 2-year event-free survival. Both per-protocol and intention-to-treat analyses were done. FINDINGS: By 2 years, 18 recurrences were reported in the standard group, and 22 in the no further chemotherapy group. Event-free survival was 91.4% (95% CI 87.5-95.2) for the no further chemotherapy group and 88.8% (84.3-93.2) for the standard group (difference=2.6%, upper 97.5% confidence limit 8.4%). The null hypothesis, that experimental treatment is less effective than standard treatment, could be rejected (p=0.008). CONCLUSIONS: Shortening duration of chemotherapy could reduce acute and late side-effects and inconvenience for patient and parents while maintaining effectiveness, and could be beneficial in terms of health costs.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Kidney Neoplasms/drug therapy , Wilms Tumor/drug therapy , Adolescent , Child , Child, Preschool , Combined Modality Therapy , Dactinomycin/administration & dosage , Disease-Free Survival , Female , Humans , Infant , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Male , Survival Rate , Vincristine/administration & dosage , Wilms Tumor/mortality , Wilms Tumor/secondary , Wilms Tumor/surgeryABSTRACT
Experience of the International Society of Paediatric Oncology (SIOP) Trials and Studies indicates that the preoperative chemotherapy in Wilms' tumour improves stage distribution, decreases complication rate and reduces postoperative treatment. However, some situations may lead to prompt primary surgery. The aim of the study is to assess reasons leading to primary emergency nephrectomy. Records of 720 patients with non-metastatic unilateral nephroblastoma who were registered in the SIOP Trial and Study 9 were reviewed. Twenty-four (3%) cases of primary emergency nephrectomy were identified. Reasons leading to emergency nephrectomy were massive bleedings from ruptured tumours in 13 patients, suspicion of an "acute abdomen" in 7, bowel occlusion in 2 and other in 2. Postoperative treatment included radiotherapy in 71% of cases and anthracyclines in 92%. Complications were frequent and happened in 25% of patients, the outcome however, was favourable and 22 of 24 patients are alive (from 9 to 79 months). The 7 patients with a suspicion of an "acute abdomen" probably constitute the group which could have been markedly reduced if adequately diagnosed and observed prior to surgery.
Subject(s)
Kidney Neoplasms/surgery , Nephrectomy , Wilms Tumor/surgery , Child , Child, Preschool , Clinical Trials as Topic , Emergency Medical Services , Humans , Infant , Kidney Neoplasms/complications , Kidney Neoplasms/pathology , Neoplasm Staging , Postoperative Complications , Retrospective Studies , Rupture, Spontaneous , Wilms Tumor/complications , Wilms Tumor/pathologyABSTRACT
PURPOSE: To determine the optimal duration of preoperative chemotherapy to further increase the proportion of stage I tumors by comparison of two regimens in the treatment of patients older than 6 months who have unilateral Wilms' tumor. PATIENTS AND METHODS: Eligible patients (n = 382) initially received four weekly doses of vincristine (VCR) and two courses of actinomycin D (AMD) and were randomized either to be operated on (4-week group [n = 193]) or to receive 4 more weeks of the same chemotherapy regimen (8-week group [n = 189]). The assessment criterion was the observed percentage of stage I tumors. After surgery, patients were assigned according to tumor stage and histology to four different treatment groups: stage I and favorable histology (n = 5) were to have no further treatment (NFT); stage I and standard histology or anaplasia (n = 244), VCR and AMD for 17 weeks (AV); stages II and III and favorable or standard histology, VCR, AMD, and an anthracycline for 27 weeks (AVE) with no abdominal radiotherapy for stage II N0 disease (n = 75) or with a 15-Gy dose of abdominal irradiation (RTH) in case of stages IIN1 and III (n = 56). Anaplastic tumors staged higher than I or clear-cell sarcoma of the kidney (14), AMD, VCR, an anthracycline, and ifosfamide for 36 weeks (DEVI). RESULTS: No advantage was found in favor of prolonged preoperative treatment. The percentages obtained for the 4-week and the 8-week groups, respectively, were as follows: stage I, 64% versus 62%; intraoperative tumor rupture rate, 1% versus 3%; 2-year EFS, 84% versus 83%; and 5-year OS, 92% versus 87%. Two-year EFS and 5-year OS rates, respectively, of the different treatment groups were as follows: NFT, 100% for both EFS and OS; AV, 88% and 93%; AVE, 84% and 88%; AVE RTH, 71% and 85%; and DEVI, 71% and 71%. The rate of abdominal recurrences in stage II N0 nonirradiated patients was 6.6%. CONCLUSION: The 4-week schedule pre-nephrectomy chemotherapy regimen should be considered the standard treatment. Clinical trials should continue to improve the cure rate of high-risk patients and the quality of life of children with a more favorable prognosis.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Kidney Neoplasms/drug therapy , Wilms Tumor/drug therapy , Adolescent , Antibiotics, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Chemotherapy, Adjuvant , Child , Child, Preschool , Dactinomycin/administration & dosage , Drug Administration Schedule , Humans , Infant , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Neoplasm Staging , Nephrectomy , Survival Analysis , Vincristine/administration & dosage , Wilms Tumor/pathology , Wilms Tumor/surgeryABSTRACT
Hereditary and sporadic forms of tumors are generally related to germ-line and somatic mutations of the same tumor suppressor gene. Unexpectedly, in Wilms' tumor, somatic mutations of the WT1 gene were found only occasionally in sporadic cases, although constitutional mutations of this gene are clearly associated with predisposition. It has been suggested that abnormal splicing may be another mode of somatic WT1 alteration. However, this idea was based on the analysis of a small series of tumors, precluding accurate evaluation of the frequency of such changes. To investigate WT1 changes at the somatic level in more detail, we analyzed the levels of the four isoform transcripts produced by alternative splicing events in a large series of 50 tumors, normal mature kidneys, and fetal kidneys. We characterized splicing alterations in 63% of sporadic Wilms' tumors. Moreover, taking into account the decreased and increased overall levels of WT1 mRNA, the percentage of sporadic tumors with changes in WT1 expression reached 90%. Whether and how these alterations of expression play a role in the tumorigenic process remain to be evaluated.
Subject(s)
Alternative Splicing , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Wilms Tumor/genetics , Blotting, Southern , DNA, Complementary/metabolism , DNA-Binding Proteins/chemistry , Exons , Germ-Line Mutation , Humans , Kidney/metabolism , Mutation , Protein Isoforms , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/chemistry , Transcription, Genetic , WT1 ProteinsABSTRACT
More than 25 years after introducing preoperative chemotherapy for Wilms' tumor, the benefits of this approach are well known. The preoperative protocol results in easier operations with significantly fewer tumor ruptures during surgery and a favorable stage distribution. Acute toxicity and late effects are minimized without jeopardizing disease-free and overall survival. Future clinical trials of Wilms' tumor should seek additional risk factors to stratify and individualize treatment. These prognostic factors will improve the cure rates for high-risk patients by intensifying therapy and the quality of life for children with more favorable prognosis by lowering therapy to a minimum. As is true for radical surgery, partial nephrectomy in unilateral disease must be evaluated in carefully selected patients according to clear and well-defined indications. Molecular genetic studies should increase understanding of Wilms' tumor, influencing treatment and outcome.
Subject(s)
Antineoplastic Agents/therapeutic use , Kidney Neoplasms/drug therapy , Wilms Tumor/drug therapy , Antibiotics, Antineoplastic/therapeutic use , Child , Clinical Trials as Topic , Dactinomycin/therapeutic use , Humans , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Neoplasm Staging , Preoperative Care , Prognosis , Survival Analysis , Wilms Tumor/mortality , Wilms Tumor/pathologyABSTRACT
BACKGROUND: The SIOP Nephroblastoma therapeutic protocols include a period of preoperative chemotherapy followed by nephrectomy and a period of postoperative chemotherapy. From the outset, identification of low-risk groups has been an aim of the SIOP Nephroblastoma Trials and Studies. Now that 90% of children with Wilms tumor can be cured, attention is even more focused on the identification of patients who could benefit from less aggressive postoperative therapy, thus minimizing the morbidity and late effects associated with treatment. The prognostic implications of total necrosis in nephroblastoma after chemotherapy have not been investigated hitherto. PROCEDURE: Between November 1, 1987 and June 30, 1993, 599 patients referred to the SIOP-9 Nephroblastoma Trial and Study were preoperatively treated and classified as stages I-IV nonanaplastic Wilms tumor. RESULTS: Of these 599 patients, pathologic examination of the nephrectomy specimen revealed a completely necrotic Wilms tumor (CNWT) with no viable tumor remaining in 59 (10%): these comprised 37 stages I-III and 22 stage IV. Of these patients, 58 (98%) had no evidence of disease at 5 years vs. 90% for the rest of the cohort (P < 0.05). Stages I-III patients represented 63% of CNWT and had a 97% overall survival rate. The only death was related to veno-occlusive disease and occurred in a stage I patient in the month following nephrectomy. Stage IV patients represented 37% of CNWT (vs. only 10% of all other cases of unilateral nonanaplastic Wilms tumor) and had a 100% rate of survival. Children with CNWT were older (mean 59 months vs. 43 months); their tumor at diagnosis was larger and had regressed more significantly at subsequent ultrasound examination. The data also uphold the hypothesis that Wilms tumors of blastemic pattern are most aggressive, but also are extremely responsive to chemotherapy. CONCLUSIONS: Patients with unilateral nonanaplastic WT that showed total necrosis following preoperative chemotherapy had excellent outcome and should benefit from less aggressive postoperative treatment in further trials. Other very responsive tumors, such as Wilms with <10% viable tumor, should also be assessed.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Kidney Neoplasms/drug therapy , Wilms Tumor/drug therapy , Adolescent , Child , Europe , Female , Humans , Kidney Neoplasms/pathology , Male , Necrosis , Neoplasm Staging , Prognosis , Remission Induction , Risk Factors , Survival Analysis , Treatment Outcome , Wilms Tumor/pathologyABSTRACT
BACKGROUND: A major problem for children receiving Wilms tumor (WT) chemotherapy is hepatotoxicity, which may even be life-threatening. Dactinomycin (AMD) has been shown to be an important factor, as has abdominal irradiation. PROCEDURE: In the nephroblastoma trial and study SIOP-9 (SIOP-9) two different regimens for the application of AMD were used (standard dose over 3-5 days vs. double dose on a single day). In children at increased risk for local relapse, postoperative abdominal irradiation was given. We analyzed the influence of AMD and radiotherapy on the development of hepatotoxicity in 481 children treated in centers of the German Paediatric Oncology and Haematology Society (GPOH). A special questionaire was sent out for all patients with reduced treatment or delay of more than 1 week because of hepatotoxicity. Because SIOP and the National Wilms Tumor Study (NWTS) used different criteria to asses hepatotoxicity,we applied both definitions. RESULTS: All 72 cases of mild or severe hepatotoxicity occurred during treatment with AMD over 3-5 days with the standard dose (9.4-22.5 microgram/kg/week) compared to none in the group receiving a double dose on 1 day (3.75-8 microgram/kg/week; P < 0.001). Irradiation of the right abdomen, including parts of the liver, enhanced liver toxicity significantly, with a relative risk (RR) of 2.6 (P < 0.003). Preoperative liver toxicity was more frequent in smaller children (P = 0.02) and especially if no dose reduction was done in children with body weight of less than 12 kg (RR 5.3, P = 0.01). If severe liver toxicity was defined according to NWTS criteria, 10% of all treated patients were affected compared to 4.8% if McDonald's criteria for hepatic veno-occlusive disease (VOD) were applied. CONCLUSIONS: To diminish the hepatotoxicity of WT treatment, AMD dose intensity should be reduced (below 10 microgram/kg per week), especially in smaller children or when the liver is irradiated.
Subject(s)
Antibiotics, Antineoplastic/adverse effects , Dactinomycin/adverse effects , Kidney Neoplasms/drug therapy , Liver/drug effects , Wilms Tumor/drug therapy , Adolescent , Antibiotics, Antineoplastic/administration & dosage , Child , Child, Preschool , Dactinomycin/administration & dosage , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Infant , Kidney Neoplasms/radiotherapy , Male , Wilms Tumor/radiotherapyABSTRACT
In the Wilms tumour trials and studies of the International Society of Paediatric Oncology (SIOP), the postoperative treatment is based on the extension (stage) and the histological type. Incorrect staging results in under- or overtreatment. The authors studied the causes and consequences of misstaging in SIOP 6. In this study, the final stage was defined by a central panel of pathologists after review of the surgical and histopathological forms and study of representative microscopical sections. In 46 out of 509 trial patients there was a discrepancy between the final stage and the stage determined at the participating centres: 33 patients were understaged of whom 27 survived more than 5 years (18% died) and 13 patients were overstaged of whom 11 survived more than 5 years (15.3% died). All children with tumour extension into the renal pelvis and treated as stage I instead of stage II survived without evidence of disease. Therefore, it was decided to treat these children in the next study as a stage I. In 17 cases the treatment was based on the surgical stage before the pathological stage was known or the treatment was given according to the stage determined by the local pathologist without waiting for the panel review. The numbers are too small to conclude on the consequences of overtreatment on late effects. For all clinicians the main and most important conclusion of this study is: wait for the final pathology report before initiating postoperative therapy.
Subject(s)
Kidney Neoplasms/pathology , Wilms Tumor/pathology , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Kidney/pathology , Kidney Neoplasms/mortality , Kidney Neoplasms/surgery , Male , Neoplasm Staging , Nephrectomy , Reproducibility of Results , Survival Rate , Wilms Tumor/mortality , Wilms Tumor/surgeryABSTRACT
Treatment of Wilms' tumor is an example of success of modern oncology. A combination of surgery, radiotherapy, and chemotherapy is widely accepted as the efficacious treatment of nephroblastoma. However, timing of each part of the treatment differs, in various protocols: the Societe Internationale d'Oncologie Pediatrique (SIOP) recommends the diagnosis based on imaging and metabolic exclusion of neuroblastoma to reduce the biopsy-related risk of spillage. In patients more than 6 months old, the treatment starts with the preoperative chemotherapy to improve the stage distribution at surgery and decrease the complications rate. Patients with advanced nephroblastoma, as those with vena cava thrombus and lung metastases, can benefit the most from the pretreatment. Results from the SIOP studies 6 and 9 confirm these statements: the stage distribution after the pretreatment reveals more than 50% of cases staged I, the 4-year disease-free survival in pulmonary stages IV was 83%, and of 42 patients with vena cava thrombus still present at surgery, 38 are alive from 27 to 109 months.
Subject(s)
Kidney Neoplasms/therapy , Wilms Tumor/therapy , Child , Combined Modality Therapy , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/surgery , Wilms Tumor/drug therapy , Wilms Tumor/surgeryABSTRACT
Cancer incidence is low in children. Childhood tumors are different from cancers seen in adults: their growth is rapid, but they respond well to radiotherapy and chemotherapy. In the case of Wilms Tumor, Actinomycin D, Vincristine and Doxorubicin were first used with success. Ifosfamide, Etoposide and Carboplatin are now also used in selected cases. But efficient treatments have important drawbacks: growth defects in the case of radiotherapy, late cardiac toxicity due to Doxorubicin, leukemias as second tumors following Etoposide. Treatment strategy is based on prognostic factors in Wilms' tumor, and the risk/benefit ratio assessment for each group of patients, considering survival probability and the risk of late effects. Large randomised studies in the USA and in Europe resulted in cure rates over 90%, with very few expected sequelae. Preoperative chemotherapy is now successfully applied to other tumors in children.
Subject(s)
Antineoplastic Agents/therapeutic use , Kidney Neoplasms/drug therapy , Models, Biological , Wilms Tumor/drug therapy , Child, Preschool , France/epidemiology , Humans , Incidence , Infant , Kidney Neoplasms/epidemiology , Wilms Tumor/epidemiologyABSTRACT
PURPOSE: The three-drug combination of melphalan (M), etoposide (E), and carboplatin (C) followed by autologous stem-cell (ASC) rescue has been evaluated prospectively by the French Society of Pediatric Oncology (SFOP) in pediatric high-risk recurrent (HRR) Wilms' tumor (WT) patients with chemotherapy-responsive disease. PATIENTS AND METHODS: From October 1988 to October 1994, 29 patients with HRR WT were treated in nine SFOP centers. Two additional patients with stage IV anaplastic WT were consolidated in first complete response (CR) with the same regimen and have been studied separately. The regimen consisted of M 180 mg/m2 for 1 day, E 200 mg/m2/d for 5 days, and C at a daily targeted area under the concentration-time curve (AUC) of 4 mg x min/mL for 5 days. ASCs were reinfused 48 hours after M. RESULTS: Twelve of 28 assessable patients with HRR WT are still in continuous CR at a median of 48.5 months (range, 36 to 96) after consolidation. Disease-free survival (DFS) and overall survival (OS) estimated by the Kaplan-Meier method at 3 years were 50%+/-17% and 60%+/-18%, respectively. Sixteen patients relapsed at a median of 8.5 months (range, 3 to 53) after consolidation. Toxicity data are available in 31 grafted patients. Grade III and IV toxicities included hematologic side effects (n=31), hemorrhage (n=8), mucositis (n=24), diarrhea (n=12), renal disorders (n=8), and pneumonitis (n=3). CONCLUSION: The adverse prognostic factors (APF) used to select patients for this dose-intensive chemotherapy define children with very-poor-risk recurrent WT. Despite high treatment-related toxicity, about half of these patients remain disease-free at 3 years. Patient outcome is statistically better when high-dose chemotherapy (HDCT) is performed as early as the second CR or partial response (PR). Novel therapeutic approaches with innovative preparative regimens are warranted for the remaining high-risk patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation , Kidney Neoplasms/therapy , Wilms Tumor/therapy , Adolescent , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carboplatin/adverse effects , Child , Child, Preschool , Combined Modality Therapy , Disease-Free Survival , Etoposide/administration & dosage , Etoposide/adverse effects , Female , Follow-Up Studies , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Infant , Kidney Neoplasms/drug therapy , Male , Melphalan/administration & dosage , Melphalan/adverse effects , Neoplasm Recurrence, Local , Wilms Tumor/drug therapyABSTRACT
The aim of the study was to assess rates and types of nephrectomy-related complications in children nephrectomized for nephroblastoma after preoperative chemotherapy. Records of 598 Wilms' tumour patients registered in the International Society of Paediatric Oncology Trial & Study No. 9 (SIOP-9), and pretreated correctly according to the protocol with vincristine + actinomycin D +/- epirubicine or adriamycin prior to nephrectomy, were retrospectively reviewed. Forty-nine patients (8%), who suffered from 54 complications, were identified. Most frequent events were small-bowel occlusions (3.7%) and tumour ruptures (2.8%). Other complications were registered in 2.0% of cases. The low rate of nephrectomy complications and no deaths related to registered ones, are another argument for preoperative chemotherapy in Wilms' tumour patients.
Subject(s)
Kidney Neoplasms/surgery , Nephrectomy/adverse effects , Wilms Tumor/surgery , Adolescent , Antibiotics, Antineoplastic/therapeutic use , Antineoplastic Agents, Phytogenic/therapeutic use , Chemotherapy, Adjuvant , Child , Child, Preschool , Dactinomycin/therapeutic use , Europe , Humans , Infant , Kidney Neoplasms/drug therapy , Randomized Controlled Trials as Topic , Retrospective Studies , Vincristine/therapeutic use , Wilms Tumor/drug therapyABSTRACT
INTRODUCTION: Hepatotoxicity consistent with the clinical diagnosis of veno-occlusive disease (VOD) of the liver has been suspected after conventional anti-cancer chemotherapy in children. METHODS: To establish the incidence of hepatotoxicity and its relationship with VOD, we analyzed toxicity data obtained on 511 children affected by Wilms tumor and treated according to the SIOP-9 protocol. They all received pre- and postnephrectomy chemotherapy using dactinomycin (AD) and vincristine (VCR) +/- other drugs +/- radiotherapy according to surgical stage and histology. RESULTS: Sixty-four patients suffered at least one episode of hepatotoxicity and 41 satisfied the criteria for a clinical diagnosis of VOD. In this latter group, toxicity occurred during preoperative treatment in 15 patients and was confirmed histopathologically in 9 of the 16 liver biopsies obtained. There was a higher percentage of children aged less than 1 year at diagnosis in the VOD group than in the other patients (24% vs. 11.4%). The degree of liver damage in the younger patients seems important, as suggested by a higher increase in transaminases. VOD developed in 12% of the 68 irradiated children vs. 7% in the non-irradiated group. Statistical analysis showed an increased risk of VOD in younger patients (p < 0.001) and in those receiving radiotherapy (p < 0.001). All patients recovered after 6-180 days using supportive therapy only. CONCLUSIONS: (1) 8% of children treated according to the SIOP-9 protocol, developed hepatotoxicity consistent with VOD. Excluding patients who received radiotherapy, the incidence was 6%. These figures are much higher than in earlier reports, though different diagnostic criteria were used. (2) Chemotherapy with AD and VCR seems to be a major cause of VOD. (3) Risk factors are young age and concomitant radiotherapy. (4) VOD does not prejudice positive outcome for these patients.
Subject(s)
Hepatic Veno-Occlusive Disease/etiology , Kidney Neoplasms/therapy , Wilms Tumor/therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Child , Child, Preschool , Clinical Trials as Topic , Dactinomycin/administration & dosage , Dactinomycin/adverse effects , Female , Follow-Up Studies , Hepatic Veno-Occlusive Disease/chemically induced , Humans , Infant , Liver/drug effects , Liver/radiation effects , Male , Radiotherapy/adverse effects , Vincristine/administration & dosage , Vincristine/adverse effectsABSTRACT
The incidence of second malignant neoplasms (SMNs) was investigated among 1,988 patients with complete data, enrolled in the SIOP Wilms tumor trials and studies 1, 2, 5, and 6, treated between September 1971 and October 1987. By the end of 1992, eight SMNs were documented, whereas only 1.3 were expected (standardized incidence ratio [SIR] = 4.15; 95% CI = 1.79, 8.17). The risk increases in the first 10 years from diagnosis, while no apparent excess of risk is observed in the subsequent periods. This finding however is difficult to interpretdue to the low statistical power. The cumulative incidence of a second cancer observed at 15 years after Wilms tumor diagnosis was 0.65%. Six SMNs were registered in the cohort of patients treated in the SIOP studies 1, 2 and 5 (999 cases) compared to the two cases observed in the SIOP6 cohort (989 cases). If the suggested reduced incidence of second cancers between SIOP1-5 and SIOP6 patient cohorts is confirmed by longer follow-up, it might reflect changes in the treatment protocols.
Subject(s)
Kidney Neoplasms/therapy , Neoplasms, Second Primary , Wilms Tumor/therapy , Adolescent , Child , Child, Preschool , Clinical Trials as Topic , Female , Follow-Up Studies , Humans , Infant , Male , Risk FactorsABSTRACT
Relapsed Wilms tumor is often very responsive to re-treatment, and cures are possible in many cases. Recurrent Wilms tumor forms a heterogeneous group because initial therapies vary widely. Given the complexity of the problem, there is a great need for an organized clinical investigative approach. Ideally, the treatment of initial relapse should be specified by the primary treatment protocol in order to better evaluate overall survival as an end-point for new primary therapy strategies. This is especially appropriate for Wilms tumor, because the investigations of this tumor over the last 20 years have attempted to determine the minimal therapy necessary for cure. Thus, survival rather than relapse-free survival is the most appropriate criterion for the success of a primary retreatment regimen. This investigative approach would also allow evaluation of treatment strategies tailored to a specific patient population. Important questions remain for those who treat recurrent Wilms tumor. Defining the role of high-dose therapy, defining the role of total body irradiation in high-dose therapy regimens, and defining the benefit and toxicity of cyclophosphamide compared with ifosfamide are three current questions under investigation. Developing new agents and regimens effective against Wilms tumor, especially against anaplastic tumors, RTK, and CCSK, is extremely important if progress is to be made in treating these tumors after relapse. Finally, there is a strong need to develop biologic information about tumors that recur, so not only will we better understand why patients relapse but also we can develop therapy tailored specifically to the biology of the recurrent tumor.
Subject(s)
Kidney Neoplasms/therapy , Neoplasm Recurrence, Local/therapy , Neoplasms, Multiple Primary/therapy , Wilms Tumor/therapy , Antineoplastic Agents/therapeutic use , Combined Modality Therapy , Humans , PrognosisABSTRACT
There are at least three loci involved in Wilms' tumor (WT) tumorigenesis: WT1 in 11p13, WT2 in 11p15.5, and WT3, as yet unmapped. A compilation of cytogenetic data published for 107 WT revealed that deletion of chromosome 16 and duplication of chromosome 12 occur as frequently as the well-documented 11p deletions. Allelic imbalance for chromosomes 16 and 12 was investigated in a series of 28 WT. By use of a large panel of restriction fragment length polymorphisms and (CA)n probes, we demonstrated loss of heterozygosity (LOH) for 16q in seven (25%) of the tumors. The whole length of 16q was involved in six of the tumors. Moreover, consistent with a previous report of 16q13 LOH in a sporadic WT and a constitutional breakpoint with a Beckwith-Wiedemann patient, we map a region of particular interest to between D16S308 and D16S320. The assumption that 16q LOH may be an early event was based on: 1) the detection of 16q LOH in one case of nephroblastomatosis; 2) the presence of a complete (clonal) 16q LOH in a tumor with partial (mosaic) 11p LOH; and 3) 16q LOH as the sole abnormality in one WT. By quantification of chromosome 12 allelic imbalance, we detected duplication in 18% of the total series and in 25% of the sporadic unilateral cases. The common region extended from the centromere to D12S7 in 12q21.1-q23. We also suggest that the various pathogenetically important loci are not equally involved in the different forms of WT and that their sequential involvement may differ.