Evolution of the candidacy requirements and patient perioperative assessment protocols for cochlear implantation.

Cochlear implantation as an approved clinical therapy ushered in an exciting era of innovation for the treatment of hearing loss. The U.S. Food and Drug Administration approved the use of cochlear implants as a treatment option for adults with profound sensorineural hearing loss in 1985. The landscape for treating adults and children with significant hearing loss has changed dramatically over the last three decades. The purpose of this paper is to examine the evolving regulatory process and changes to clinical care. A significant emerging trend in cochlear implantation is the consideration of steroids to preserve hearing during and following surgery. This parallels the quest for hearing preservation in noise-induced hearing disorders, especially considering the current interest in biological drug therapies in this population. The future will likely usher in an era of combination therapeutics utilizing drugs and cochlear implantation. For over 30+ years and following regulatory compliance, the Rocky Mountain Ear Center has developed an extensive candidacy and outcome assessment protocol. This systematic approach evaluates both unaided and aided auditory performance during candidacy stages and post-implantation. Adjunctive measures of cognition and quality-of-life augment the auditory assessment in specific populations. Practical insights into lessons learned have directed further clinical research and have resulted in beneficial changes to clinical care.

The management of synchronous bilateral Wilms tumor: a report from the National Wilms Tumor Study Group.

OBJECTIVE: To provide guidelines for future trials, we reviewed the outcomes of children with synchronous bilateral Wilms tumors (BWT) treated on National Wilms Tumor Study-4 (NWTS-4). METHODS: NWTS-4 enrolled 3335 patients including 188 patients with BWT (5.6%). Treatment and outcome data were collected. RESULTS: Among 188 BWT patients registered with NWTS-4, 195 kidneys in 123 patients had initial open biopsy, 44 kidneys in 31 patients had needle biopsies. Although pre-resection chemotherapy was recommended, 87 kidneys in 83 patients were managed with primary resection: Complete nephrectomy 48 in 48 patients, 31 partial/wedge nephrectomies in 27 patients, enucleations 8 in 8 patients. No initial surgery was performed in 45 kidneys in 43 patients, 5 kidneys in 3 patients not coded. Anaplasia was diagnosed after completion of the initial course of chemotherapy in 14 patients (initial surgical procedure: 9 open biopsies, 4 needle biopsies, 1 partial nephrectomy). The average number of days from the start of chemotherapy to diagnosis of anaplasia was 390 (range 44-1925 days). Relapse or progression of disease occurred in 54 children. End stage renal failure occurred in 23 children, 6 of whom had bilateral nephrectomies. The 8 year event free survival for BWT with favorable histology was 74%, and overall survival was 89%; whereas the event free survival for BWT with unfavorable histology was 40%, overall survival was 45%. CONCLUSION: The current analysis of patients with BWT treated on NWTS-4 shows that preservation of renal parenchyma is possible in many patients after initial preoperative chemotherapy. The incidence of end-stage renal disease remains significantly higher in children with BWT. Future studies are warranted to address the need for earlier biopsy in nonresponsive tumors and earlier definitive surgery to recognize unfavorable histology in these high-risk patients.

Antioxidant micronutrient impact on hearing disorders: concept, rationale, and evidence.

PURPOSE: Although auditory disorders are complex conditions, device-related modalities dominate current treatment. However, dysfunction from the central cortex to the inner ear apparatus is increasingly thought to be related to biochemical pathway abnormalities and to free radical-induced oxidative damage and chronic inflammation. Therefore, considering appropriate biologic therapy as an adjunct to standard care against these damaging factors may provide rational expansion of treatment options for otolaryngologists and audiologists. METHODS: This review outlines the biologic concepts related to some auditory and vestibular conditions and details the current rationale for utilizing antioxidants for a spectrum of hearing disorders. The strategy is based on the authors' collective experience in antioxidant science and supported with published research, pilot animal data and preliminary clinical observations. RESULTS: A comprehensive micronutrient approach was developed to exploit these pathways, and demonstrated safety and efficacy against oxidative damage and inflammation and clinically relevant neuroprotection. Cooperative research with Department of Defense institutions used prospective, randomized designs to show (1) reduction in oxidative damage measured in plasma and urine over six months, (2) protection against oxidative damage during 12 weeks of intense military training, (3) protection against inflammation after total body blast exposure (rodents), (4) strong neuroprotection against chemically-induced Parkinson's disease (rodents), (5) nerve VIII function improvement after concussive head injury in military personnel, and (6) tinnitus improvement in majority of patients after 90-day evaluation. CONCLUSION: This systematic review of biologic strategies against hearing disorders combined with new animal and human observations may provide a rational basis for expanding current practice paradigms.

Long-term outcomes for infants with very low risk Wilms tumor treated with surgery alone in National Wilms Tumor Study-5.

OBJECTIVE: To determine the event-free survival (EFS) and overall survival (OS) of children with very low risk Wilms tumor (VLRWT) treated with surgery only. BACKGROUND: Previous studies suggested that postoperative chemotherapy had not improved the prognosis of children with VLRWT. A total of 77 children <24 months of age with small (<550 g) Stage I favorable histology Wilms tumors were treated with surgery only. This study was closed based on stopping rules to ensure that the 2-year EFS was > or =90%. METHODS: A total of 77 children were assessed for EFS and OS. Of these patients, 21 enrolled at the time of closure were recalled, treated with dactinomycin and vincristine (regimen EE4A), and censored for analysis thereafter. About 111 children subsequently treated with EE4A were available for comparison. RESULTS: Median follow-up of surviving patients was 8.2 years for surgery only (range, 1.9-11.8 years) and 5.2 years for the EE4A group (range, 1.6-8.9 years). The estimated 5-year EFS for surgery only was 84% (95% confidence interval [CI]: 73%, 91%); for the EE4A patients it was 97% (95% CI: 92%, 99%, P = 0.002). One death was observed in each treatment group. The estimated 5-year OS was 98% (95% CI: 87%, 99%) for surgery only and 99% (95% CI: 94%, 99%) for EE4A (P = 0.70). CONCLUSION: The surgery-only EFS was lower than anticipated but, coupled with a much higher than anticipated salvage rate of the chemotherapy naive patients whose disease recurred, led to an observed long-term OS equivalent to that seen with 2-drug chemotherapy. This approach to the treatment of patients with VLRWT eliminates the toxic side-effects of chemotherapy for a large majority of patients. A follow-up study is underway to confirm these findings.

Treatment of Wilms tumor relapsing after initial treatment with vincristine, actinomycin D, and doxorubicin. A report from the National Wilms Tumor Study Group.

OBJECTIVE: We evaluated the use of alternating cycles of cyclophosphamide/etoposide and carboplatin/etoposide in children entered on National Wilms Tumor Study (NWTS)-5 who were diagnosed between August 1, 1995 and May 31, 2002 and who relapsed after chemotherapy with vincristine, actinomycin D, and doxorubicin (VAD) and radiation therapy (DD-4A). PATIENTS AND METHODS: One hundred three patients who relapsed or had progressive disease after initial VAD chemotherapy and radiation therapy were registered on stratum C of the NWTS-5 Relapse protocol. Twelve patients were not evaluable: five due to insufficient data, six due to major protocol violations, and one for refusal of therapy. Among the 91 remaining patients, 14 with stage V Wilms tumor (WT), 1 with contralateral relapse, and 16 who did not achieve a complete response (CR) to the initial three-drug chemotherapy were not included in this analysis. Relapse treatment included alternating courses of the drug pairs cyclophosphamide/etoposide and carboplatin/etoposide, surgery, and radiation therapy. RESULTS: The outcomes of 60 patients were analyzed. The lung was the only site of relapse for 33 patients; other sites of relapse included the operative bed, the abdomen, and liver. Four-year event-free survival (EFS) and overall survival (OS) were 42.3 and 48.0% respectively for all patients and were 48.9 and 52.8% for those who relapsed in the lungs only. Thrombocytopenia was the most frequent toxicity. CONCLUSION: These results demonstrate that approximately one-half of children with unilateral WT who relapse after initial treatment with VAD and radiation therapy can be successfully retreated.

Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms tumor: a report from the National Wilms Tumor Study Group.

PURPOSE: To determine if tumor-specific loss of heterozygosity (LOH) for chromosomes 1p or 16q is associated with a poorer prognosis for children with favorable-histology (FH) Wilms tumor entered on the fifth National Wilms Tumor Study (NWTS-5). PATIENTS AND METHODS: Between August 1995 and June 2002, 2,021 previously untreated children with FH or anaplastic Wilms tumor, clear-cell sarcoma of the kidney (CCSK) or malignant rhabdoid tumor of the kidney (RTK), were treated with stage- and histology-specific therapy. Their tumors were assayed for LOH for polymorphic DNA markers on chromosomes 1p and 16q. ResultsLOH for 1p or 16q was rarely observed in CCSK (n = 90) or RTK (n = 22). The relative risk (RR) of relapse for patients with FH stage I to IV tumors with LOH, stratified by stage, was 1.56 for LOH 1p (P = .01) and 1.49 for LOH 16q (P = .01), whereas the RR of death was 1.84 (P = .03) and 1.44 (P = .15), respectively. When the effects of LOH for both regions were considered jointly among patients with stage I to II FH disease, the risks of relapse and death were increased for LOH 1p only (RR = 2.2, P = .02 for relapse; RR = 4.0, P = .02 for death), for LOH 16q only (RR = 1.9, P = .01 and RR = 1.4, P = .60) and for LOH for both regions (RR = 2.9, P = .001 and RR = 4.3, P = .01) in comparison with patients with LOH at neither locus. The risks of relapse and death for patients with stage III to IV FH tumors were increased only with LOH for both regions (RR = 2.4, P = .01 and RR = 2.7, P = .04). CONCLUSION: Tumor-specific LOH for both chromosomes 1p and 16q identifies a subset of FH Wilms tumor patients who have a significantly increased risk of relapse and death. LOH for these chromosomal regions can now be used as an independent prognostic factor together with disease stage to target intensity of treatment to risk of treatment failure.

Radiation therapy for favorable histology Wilms tumor: prevention of flank recurrence did not improve survival on National Wilms Tumor Studies 3 and 4.

PURPOSE: To determine whether radiation therapy (RT) of patients with Wilms tumor of favorable histology prevented flank recurrence and thereby improved the survival outcomes. METHODS AND MATERIALS: Recurrence and mortality risks were compared among groups of patients with Stage I-IV/favorable histology Wilms tumor enrolled in the third (n = 1,640) and fourth (n = 2,066) National Wilms Tumor Study Group studies. RESULTS: Proportions of patients with flank recurrence were 0 of 513 = 0.0% for 20 Gy, 12 of 805 = 1.5% for 10 Gy, and 44 of 2,388 = 1.8% for no flank RT (p trend = 0.001 adjusted for stage and doxorubicin); for intra-abdominal (including flank) recurrence they were 5 of 513 = 1.0%, 30 of 805 = 3.7%, and 58 of 2,388 = 2.4%, respectively (p trend = 0.02 adjusted). Survival percentages at 8 years after intra-abdominal recurrence were 0 of 5 = 0% for 20 Gy, 10 of 30 = 33% for 10 Gy, and 34 of 58 = 56% for no RT (p trend = 0.0001). NWTS-4 discontinued use of 20 Gy RT, and the 8-year flank recurrence risk increased to 2.1% from 1.0% on NWTS-3 (p = 0.013). However, event-free survival was unaltered (88% vs. 86%, p = 0.39), and overall survival was better (93.8% vs. 90.8%, p = 0.036) on NWTS-4. CONCLUSIONS: Partly because of lower postrecurrence mortality among nonirradiated patients, prevention of flank recurrence by RT did not improve survival. It is important to evaluate entire treatment policies with regard to long-term outcomes.

Oxidative Damage and Inflammation Biomarkers: Strategy in Hearing Disorders.

IMPORTANCE: Excess free radical-induced oxidative stress and inflammatory processes are increasingly recognized as causative factors in hearing and balance disorders. Antioxidant micronutrients neutralize free radicals and, at adequate doses, reduce inflammation and demonstrate benefits in animal models and human trials. Therefore, it is reasonable to expect that biomarkers of oxidative damage and inflammation are appropriate correlative biological outcome parameters in clinical hearing intervention studies. OBJECTIVE: To provide the otology investigator a selected panel of biomarkers from the large universe of available tests that can be used as reasonable secondary endpoints in hearing and balance research. BACKGROUND SETTING: The tenets of antioxidant science dictate that there are a great variety of free radicals and that they impact different cellular targets. They also demonstrate varying functions in different cellular environments. In addition, oxidative stress and inflammation may cause direct injury to tissues, cell membrane lipids, proteins and mitochondrial, and nuclear DNA. To accommodate these many pathways, the useful categories of potential biomarkers become extensive. The degree of injury is also reflected by separate markers of inflammation and measures of antioxidant levels. Therefore, to provide a reliable indication of oxidative damage, inflammation and antioxidant level, it is necessary to determine a broad spectrum of lipid peroxidation markers, adducts of DNA, oxidation levels of proteins and pro-inflammatory cytokines. CONCLUSION: This report highlights some of the most clinically relevant and well-studied biomarkers in each category of tissue damage. It also includes those markers with which the authors have had direct positive clinical experience. The outcome from these studies is intended to provide a list of adjunctive measures that can be recommended as a relevant biomarker panel in hearing disorder clinical trials.

Prophylactic urokinase in the management of long-term venous access devices in children: a Children's Oncology Group study.

PURPOSE: Infection and thrombosis are serious complications of long-term vascular access devices in children undergoing chemotherapy. Since routine fibrinolytic therapy may decrease these complications, the purpose of this study was to compare the efficacy of an every-2-week administration of urokinase with standard heparin flushes in reducing the incidence of device-related infections and occlusions. MATERIALS AND METHODS: This study was a prospective, randomized phase III multicenter trial conducted by the Children's Cancer Group, in which patients with implantable ports or tunneled catheters received either urokinase or heparin every 2 weeks for 12 months. Study end points were time to first occlusion or time to first device-related infection. RESULTS: Five hundred seventy-seven patients from 29 institutions were enrolled, of whom 51% had external catheters and 49% had ports. Urokinase administration resulted in fewer occlusive events than heparin (23% v 31%; P =.02), a longer time to first occlusive event (log-rank analysis, P =.006), and a 1.6-fold difference in the rate of occlusive events (Poisson regression, P =.003). Similar results were noted when comparing ports and tunneled catheters. The urokinase group also had a 1.4-fold difference in the rate of infection (Poisson regression, P =.05) and longer time to first infection (log-rank, P =.07), but the difference was significant only in tunneled catheters. CONCLUSION: Urokinase administration every 2 weeks significantly affects the rate of occlusive events in ports and tunneled catheters and of infectious events in external catheters compared with heparin administration.

Effect of duration of treatment on treatment outcome for patients with clear-cell sarcoma of the kidney: a report from the National Wilms' Tumor Study Group.

PURPOSE: To evaluate the effect of conventional and standard (ST) versus pulse-intensive (PI) chemotherapy and short-duration versus long-duration chemotherapy on relapse-free survival (RFS) and overall survival rates of patients with clear-cell sarcoma of the kidney (CCSK) entered onto the National Wilms' Tumor Study (NWTS)-4. PATIENTS AND METHODS: The 5-year and 8-year RFS rates were determined for patients with CCSK treated on the NWTS-4. After August 6, 1986, 40 previously untreated children younger than 16 years with CCSK were randomly assigned, after the completion of 6 months of chemotherapy, to discontinue (short) or continue 9 additional months (long) of treatment with chemotherapy regimens that included vincristine and either divided-dose (ST) courses (5 days) or single-dose (PI) treatment with dactinomycin and divided-dose (ST) courses (3 days) or single-dose (PI) treatment with doxorubicin. RESULTS: For patients with CCSK, the 5- and 8-year RFS rates were 65.2% and 60.6%, respectively, for patients randomly assigned to the short chemotherapy and 87.8% (both 5- and 8-year RFS) for patients randomly assigned to the long chemotherapy (P =.08). The overall survival rates for patients at 5 and 8 years were 95.5% and 85.9%, respectively, for the short chemotherapy and 87.5% (both 5- and 8-year overall survival) for the long chemotherapy (P =.99). In NWTS-4, the overall survival rates for patients with CCSK improved from NWTS-3 (83% v 66.9% at 8 years, respectively; P <.01). CONCLUSION: CCSK patients exhibit an improved RFS from a longer course of therapy when using vincristine, doxorubicin, and dactinomycin, but their long-term survival is unchanged compared with patients receiving 6 months of therapy. The overall survival rates for patients with CCSK have improved from NWTS-3.

Impact of radiotherapy for high-risk neuroblastoma: a Children's Cancer Group study.

PURPOSE: To assess the effect of local radiation administered to primary disease sites in children with high-risk neuroblastoma. MATERIALS AND METHODS: A total of 539 eligible patients were entered on protocol CCG-3891, consisting of chemotherapy, primary surgery, and 10 Gy of external beam radiation therapy (EBRT) to gross residual disease, followed by randomized assignment to continuation chemotherapy (CC) or autologous bone marrow transplantation (ABMT). ABMT patients received total body irradiation (TBI). RESULTS: Estimated event-free survival and overall survival at 5 years were 25% +/- 2% and 35% +/- 2%, respectively. Estimated 5-year locoregional recurrence rates were 51% +/- 5% and 33% +/- 7% for CC and ABMT patients (p = 0.004). For patients who received 10 Gy of EBRT to the primary, the addition of 10 Gy of TBI and ABMT decreased local recurrence compared with CC (22% +/- 12% and 52% +/- 8%, p = 0.022). EBRT did not increase acute toxicity, except for increased total parenteral nutrition administration. CONCLUSIONS: In combination with EBRT to the primary tumor site, the addition of 10 Gy of TBI as a component of high-dose chemotherapy with ABMT improved local control compared with CC without TBI. Results suggest a dose-response relationship for local EBRT. Short-term toxicity of local EBRT is limited.

Intraoperative spillage of favorable histology wilms tumor cells: influence of irradiation and chemotherapy regimens on abdominal recurrence. A report from the National Wilms Tumor Study Group.

PURPOSE: We undertook this study to determine (1) the frequency with which spilled tumor cells of favorable histology produced intra-abdominal disease in patients treated with differing chemotherapy regimens and abdominal radiation therapy (RT) and (2) the patterns of relapse and outcomes in such patients. METHODS AND MATERIALS: The influence of RT dose (0, 10, and 20 Gy), RT fields (flank, whole abdomen), and chemotherapy with dactinomycin and vincristine (2 drugs) vs. added doxorubicin (three drugs) on intra-abdominal tumor recurrence rates was analyzed by logistic regression in 450 patients. Each patient was considered at risk for two types of failure: flank and subdiaphragmatic beyond-flank recurrence, with the correlation between the two outcomes accounted for in the analyses. RESULTS: The crude odds ratio for the risk of recurrence relative to no RT was 0.35 (0.15-0.78) for 10Gy and 0.08 (0.01-0.58) for 20Gy. The odds ratio for the risk of recurrence for doxorubicin to two drugs after adjusting for RT was not significant. For Stage II patients (NWTS-4), the 8-year event rates with and without spillage, respectively, were 79% and 87% for relapse-free survival (p = 0.07) and 90% and 95% for overall survival (p = 0.04). CONCLUSIONS: Irradiation (10 Gy or 20 Gy) reduced abdominal tumor recurrence rates after tumor spillage. Tumor spillage in Stage II patients reduced relapse-free survival and overall survival, but only the latter was of statistical significance. These data provide a basis for assessing the risks vs. benefits when considering treatment for children with favorable histology Wilms tumor and surgical spillage.

Treatment of Wilms tumor relapsing after initial treatment with vincristine and actinomycin D: a report from the National Wilms Tumor Study Group.

PURPOSE: NWTS-5 was a multi-institutional clinical trial for patients less than 16 years of age at diagnosis with specific renal neoplasms who were diagnosed between August 1, 1995 and May 31, 2002. A uniform approach to the treatment of patients with relapse was employed. PATIENTS AND METHODS: Seventy-two patients who relapsed after immediate nephrectomy (stages I and II), initial chemotherapy with vincristine (VCR) and actinomycin D and no radiation therapy were registered on stratum B of the NWTS-5 relapse protocol. Four patients were not evaluable: one due to insufficient data and three due to major protocol violations. Among the 68 remaining patients, one who was 19 years of age at initial diagnosis of Wilms tumor, five with bilateral Wilms tumor at diagnosis, three who developed a contralateral relapse, and one with persistent disease were not included in this analysis. Relapse treatment included surgical excision, when feasible, radiation therapy and alternating courses of VCR, doxorubicin and cyclophosphamide and etoposide and cyclophosphamide. RESULTS: The outcomes of 58 patients were analyzed. The lung was the only site of relapse for 31 patients. Event-free survival 4 years after relapse was 71.1% and 4-year overall survival was 81.8% for all patients and were 67.8 and 81.0% for those who relapsed only to their lungs. The most frequent toxicities were hematological. CONCLUSIONS: These results demonstrate that a significant proportion of children with Wilms tumor who relapse after initial treatment with VCR and actinomycin D can be successfully re-treated.

Bilateral Wilms' tumors with progressive or nonresponsive disease.

BACKGROUND: To provide guidelines for future cooperative group trials, we reviewed the outcomes of children with bilateral Wilms' tumors (BWTs) treated on National Wilms Tumor Study-4 (NWTS-4) who had progressive or nonresponsive disease (PNRD). METHODS: NWTS-4 enrolled 3335 patients from August 1986 to September 1994 including 188 patients with BWT (5.6%). Treatment and outcome data were collected on patients with BWT. Treatment guidelines were outlined in the protocol, but patients were not on study. RESULTS: Thirty-eight children with BWT had PNRD. Preoperative chemotherapy was given for a median of 7 months (range, 2-29 months) before definitive resection. After the initial chemotherapy regimen, 36 children went on to a second regimen, and of these, 21 children received a third regimen before resection. Eleven patients received irradiation to one or both kidneys. Pathology at resection revealed previously undiagnosed anaplasia in 3 patients (2 diffuse and 1 focal) treated for 14, 15, and 15 months before resection. A fourth patient developed a diffusely anaplastic tumor 13 months after therapy. Other pathological findings included rhabdomyomatous (4 patients) or differentiated stromal elements (10 patients) and complete necrosis (1 patient). Ten kidneys from 7 patients lacked biopsy at presentation or pathology review of those specimens. CONCLUSIONS: BWT patients with PNRD received prolonged courses of chemotherapy. Early and sequential biopsies to establish the reason for failure to respond should be obtained. This will identify anaplastic tumors managed best by early nephrectomy and intensive chemotherapy and will also distinguish differentiated tumors that are best managed with early resection, but less intensive therapy after nephrectomy.

Treatment of anaplastic histology Wilms' tumor: results from the fifth National Wilms' Tumor Study.

PURPOSE: An objective of the fifth National Wilms' Tumor Study (NWTS-5) was to evaluate the efficacy of treatment regimens for anaplastic histology Wilms' tumor (AH). PATIENTS AND METHODS: Prospective single-arm studies were conducted. Patients with stage I AH were treated with vincristine and dactinomycin for 18 weeks. Patients with stages II to IV diffuse AH were treated with vincristine, doxorubicin, cyclophosphamide, and etoposide for 24 weeks plus flank/abdominal radiation. RESULTS: A total of 2,596 patients with Wilms' tumor were enrolled onto NWTS-5, of whom 281 (10.8%) had AH. Four-year event-free survival (EFS) and overall survival (OS) estimates for assessable patients with stage I AH (n = 29) were 69.5% (95% CI, 46.9 to 84.0) and 82.6% (95% CI, 63.1 to 92.4). In comparison, 4-year EFS and OS estimates for patients with stage I favorable histology (FH; n = 473) were 92.4% (95% CI, 89.5 to 94.5) and 98.3% (95% CI, 96.4 to 99.2). Four-year EFS estimates for patients who underwent immediate nephrectomy with stages II (n = 23), III (n = 43), and IV (n = 15) diffuse AH were 82.6% (95% CI, 60.1 to 93.1), 64.7% (95% CI, 48.3 to 77.7), and 33.3% (95% CI, 12.2 to 56.4), respectively. OS was similar to EFS for these groups. There were no local recurrences among patients with stage II AH. Four-year EFS and OS estimates for patients with bilateral AH (n = 29) were 43.8% (95% CI, 24.2 to 61.8) and 55.2% (95% CI, 34.8 to 71.7), respectively. CONCLUSION: The prognosis for patients with stage I AH is worse than that for patients with stage I FH. Novel treatment strategies are needed to improve outcomes for patients with AH, especially those with stage III to V disease.

Quality assessment for Wilms' tumor: a report from the National Wilms' Tumor Study-5.

BACKGROUND/PURPOSE: Surgical technique impacts both local tumor stage and risk of local recurrence in Wilms' tumor. A surgical quality assurance program was part of National Wilms' Tumor Study-5 to assess protocol compliance. METHODS: Surgical checklists, operative, and pathology reports were reviewed concurrently to arrive at the final local tumor stage. If a protocol violation occurred, a letter was sent to the responsible surgeon. Tumor laterality, extent, type of resection, contralateral exploration, node involvement, spills, and local recurrence were reviewed. Relative risk and logistic regression analyses were performed. RESULTS: There were 1305 nephrectomies. Lymph node sampling was not performed in 117 (9%) patients: stage I, 41 (11.5%), stage II, 57 (12%), and stage III, 19 (4%). Of importance, 41% (187/457) of stage III cases were designated stage III solely on the basis of positive lymph nodes. Tumor spill occurred in 19.3% (253/1305) of children. Fifty-four local spills were in stage II tumors and 97 in stage III. Diffuse spill occurred in 102 patients with stage III tumors. Seventeen preoperative and 13 intraoperative biopsies were performed. Intraoperative tumor rupture was the most common cause of tumor spill accounting for 139 (55%) spills. Nineteen (7.5%) children were upstaged, receiving more intensive therapy because of spill. Included in the group were 3 of 17 preoperative biopsies and 5 of 13 intraoperative biopsies. Spills (13/253) were determined to be avoidable. Eight were biopsies, 5 because tumor was transected in the renal vein (4) or ureter (1). In stage II patients where lymph nodes were not sampled, there is an increase in local relapse rate that did not achieve statistical significance because of the small number of events. CONCLUSIONS: Although most surgeons complied with the surgical guidelines, numerous deviations were identified including failure to sample lymph nodes (117 cases) and unnecessary biopsies leading to tumor spill (30 cases). Protocol violations have an adverse impact on tumor staging, potentially increasing the risk for local tumor recurrence or intensity and toxicity of therapy.

Efficacy of complete resection for high-risk neuroblastoma: a Children's Cancer Group study.

BACKGROUND/PURPOSE: Previous reports indicate that complete resection of high-risk neuroblastoma improves outcome but may entail high surgical complication rates. The authors evaluated the effect of complete primary site resection on event-free survival (EFS), overall survival (OS), and complication rates in patients entered on a high-risk neuroblastoma treatment protocol. METHODS: A total of 539 eligible patients with high-risk neuroblastoma were entered on protocol CCG-3891. Patients were assigned randomly to continuation chemotherapy or autologous bone marrow transplantation. Surgical resection was performed at diagnosis or after induction chemotherapy. Surgeons assessed resection as complete (CR), minimal residual (<5%, MR), or partial (PR). Incomplete resections received secondary resection or 10 Gy of external beam radiation. Patients were evaluated for EFS, OS, and complications of surgery based on completeness of overall best resection. RESULTS: The proportion of patients resectable at diagnosis was 27% for CR and 14% for MR. This improved after chemotherapy to 45% and 25%. Complication rates based on completeness of resection were 29%, 38%, and 36% for CR, MR, and PR, respectively. Estimated 5-year EFS rate was 30% +/- 3% for patients who achieved CR (n = 210) compared with 25% +/- 3% (P =.1010) for those with less than CR (n = 258). CONCLUSIONS: Resectability improved after neoadjuvant chemotherapy. Complete resection did not increase complications. There was a small survival benefit for complete resection. This study suggests that complete resection may still be important in the current era of intense chemotherapy and transplant.

Management of Wilms' tumour: current practice and future goals.

Most patients with Wilms' tumour in Europe and North America can be cured with treatment and subsequently lead a normal adulthood. However, for some, therapy as applied today results in long-term side-effects and creates a substantial burden on quality of life. Therefore, investigators involved in the management of patients with Wilms' tumour are increasingly focusing their efforts on curtailing the long-term sequelae of therapy. This aim has been achieved by lowering the total amount of chemotherapy, radiotherapy, or both administered to patients who have characteristics associated with favourable outcome. Although excellent survival has been maintained, many patients receive less therapy today than patients with similar characteristics did a decade or two ago. Better understanding of the biological processes that lead to this childhood cancer will allow further improvements in its management.

Doxorubicin for favorable histology, Stage II-III Wilms tumor: results from the National Wilms Tumor Studies.

BACKGROUND: After randomized trials in the 1980s, doxorubicin (DOX) was added to dactinomycin plus vincristine as standard chemotherapy for patients who had Stage III Wilms tumor (WT) of favorable histology (FH). Double-agent chemotherapy was retained for patients with Stage II disease. In this study, the authors reevaluated the efficacy of DOX using extended follow-up and additional patients. METHODS: The relative risks (RR) (DOX vs. no DOX) of disease recurrence and mortality were estimated for patients with Stage II-III/FH WT who were enrolled in the third and fourth National Wilms Tumor Studies (NWTS-3 and NWTS-4). The risk of congestive heart failure (CHF) was estimated for all patients who received DOX. RESULTS: No statistically significant effects of DOX were found for patients with Stage II tumors. For patients with Stage III tumors, the 8 year recurrence-free survival (RFS) and overall survival (OS) rates for randomized patients on NWTS-3 were 84% and 89%, respectively, for patients who received DOX (n = 130) and 74% and 83%, respectively, for patients who did not receive DOX (n = 118). Including all patients with Stage III disease who received DOX (n = 678) and did not receive DOX (n = 138), the RRs of recurrence were 0.47 (P = 0.007) and 0.40 (P = 0.011), and local recurrence respectively, after adjustment for radiation therapy (RT) dose, whereas the RR of mortality adjusted for RT and study was 0.68 (P = 0.17). The 20-year risk of CHF after primary DOX treatment on NWTS-3 and NWTS-4 was 1.2%. CONCLUSIONS: The inclusion of data from nonrandomized patients yielded estimates of DOX treatment effects for Stage III/FH WT that were stronger, albeit more susceptible to bias, than reported previously. Despite a lower reported risk of CHF, conclusive evidence that frontline therapy with DOX definitively improves survival remains elusive.