Phase I study of escalating targeted doses of carboplatin combined with ifosfamide and etoposide in treatment of newly diagnosed pediatric solid tumors.

BACKGROUND: The combination of carboplatin, ifosfamide, and etoposide has shown promising activity in a variety of relapsed childhood solid tumors but has not been studied in newly diagnosed patients. PURPOSE: The tolerance for and activity of escalating targeted doses of carboplatin combined with ifosfamide and etoposide (ICE) were assessed in children with advanced germ cell tumors or other rare solid tumors for which no standard therapy exists. METHODS: Fifteen children with newly diagnosed solid tumors received ICE chemotherapy. Individualized carboplatin doses were calculated to achieve a target area under the concentration x time curve (AUC) and adjusted for the glomerular filtration rate (estimated by 99mTc-labeled diethylene-triamine pentaacetic acid clearance). Cohorts of at least three patients received carboplatin at an initial target AUC of 6 mg.min/mL, with escalations of 2 mg.min/mL in subsequent cohorts. Carboplatin was given on day 1, followed by ifosfamide at 2 g/m2 per day and etoposide at 100 mg/m2 per day on days 2 through 4. All patients received at least two courses of therapy in the absence of progressive disease, and as many as eight courses could be given. RESULTS: The 15 patients received a total of 46 assessable courses of ICE. Myelosuppression was the dominant toxicity; 30 courses (67%) resulted in hospitalization for febrile neutropenia. Neutropenia was dose limiting at the carboplatin target AUC of 12 mg.min/mL. One complete and eight partial responses were seen in the 14 assessable patients; two additional patients had at least partial responses documented at surgery or autopsy. Six patients are without evidence of disease at a median of 548 days after diagnosis. CONCLUSION: ICE chemotherapy, with the carboplatin dose based on a target AUC of 10 mg.min/mL, is tolerable and has significant activity in a variety of rare malignancies, including extragonadal germ cell tumors. IMPLICATIONS: The combination of carboplatin, etoposide, and ifosfamide holds promise in the treatment of rare pediatric malignancies.

Acute hypersensitivity reactions to etoposide in a VEPA regimen for Hodgkin's disease.

PURPOSE: We report an unexpectedly high incidence of hypersensitivity to etoposide among 45 patients with newly diagnosed Hodgkin's disease treated with vinblastine, etoposide, prednisone, and doxorubicin (VEPA) plus radiation. PATIENTS AND METHODS: Twenty-three of 45 patients (51%) had one or more acute hypersensitivity reactions to etoposide administration. The 23 patients were 8 to 18 years of age (median, 15 years); 12 were males. Four patients had experienced prior allergic reactions to antibiotics or intravenous contrast media. RESULTS: Hypersensitivity reactions followed the first or second dose of VEPA in most cases. The reactions occurred at a median time of 5 minutes (range, 3 to 120) from the start of the etoposide infusion. Fifteen patients reacted early (within 10 minutes), four midway through the infusion, and four after completion of the infusion. Signs and symptoms included flushing, respiratory problems, changes in blood pressure, and abdominal pain with or without nausea and vomiting. Respiratory problems included dyspnea, chest pain/tightness, bronchospasm, and cyanosis. Symptoms were alleviated by discontinuing the etoposide infusions and administering diphenhydramine and/or hydrocortisone; epinephrine was required to reverse bronchospasm in three cases. All 23 patients recovered without adverse sequelae and were rechallenged with etoposide. Fifteen patients tolerated subsequent etoposide infused at a slower rate, with antihistamine and/or corticosteroid premedication; five had recurrent hypersensitivity despite these measures. Three of these five developed similar symptoms when teniposide was substituted for etoposide. Three patients who had isolated episodes of hypotension on completion of the etoposide infusion successfully received subsequent infusions without premedication or change in infusion rate or concentration. CONCLUSION: Despite this unexpectedly high incidence of hypersensitivity among Hodgkin's disease patients treated with etoposide, rechallenge with the drug was successful in 78% of cases.

Chemotherapy dose-intensification for pediatric patients with Ewing's family of tumors and desmoplastic small round-cell tumors: a feasibility study at St. Jude Children's Research Hospital.

PURPOSE: To evaluate the feasibility of dose-intensification for patients with Ewing's family of tumors (EFT) and desmoplastic small round-cell tumors. PATIENTS AND METHODS: From February 1992 to June 1996, we treated 53 consecutive patients on our Ewing's protocol. Induction comprised three cycles of ifosfamide/etoposide on days 1 to 3 and cyclophosphamide (CTX)/doxorubicin on day 5, followed by granulocyte colony-stimulating factor. Local control using surgery and/or radiotherapy started at week 9 along with vincristine/dactinomycin. Maintenance included four alternating cycles of ifosfamide/etoposide and doxorubicin/CTX, with randomization to one of two CTX dose levels to determine the feasibility of dose-intensification during maintenance. RESULTS: Patients had a median age of 13.4 years (range, 4.5 to 24.9 years); 34 patients were male and 43 patients were white. Nineteen patients presented with metastatic disease, 29 had tumors greater than 8 cm in diameter, and 26 had primary bone tumors. These patients received 155 induction cycles, 91% of which resulted in grade 4 neutropenia, 68% in febrile neutropenia, and 68% in grade 3 to 4 thrombocytopenia. During maintenance, grade 4 neutropenia and grade 3 to 4 thrombocytopenia occurred in 81% and 85% of cycles, respectively. Thirty-five patients (66%) completed all therapy, only 13 without significant delays; three developed secondary myeloid malignancies. The toxicity and time to therapy completion were similar in both CTX arms. Estimated 3-year survival and event-free survival were 72%+/-8% and 60%+/-9%, respectively. CONCLUSION: Although intensifying therapy seems feasible for 25% of patients on this study, toxicity was considerable. Therefore, the noninvestigational use of dose-intensification in patients with EFT should await assessment of its impact on disease-free survival.

Phase I study of escalating targeted doses of carboplatin combined with ifosfamide and etoposide in children with relapsed solid tumors.

PURPOSE: The tolerance of escalating targeted doses of carboplatin combined with ifosfamide (IFOS)/etoposide (VP-16) (ICE) was assessed in children with recurrent solid tumors. PATIENTS AND METHODS: To reduce interpatient variability in carboplatin systemic exposure, 45 children were treated with doses individualized to a target area under the serum concentration versus time curve (AUC) based on renal function, using technetium 99-diethyl-enetriamine pentaacetic acid (99mTc-DTPA) clearance to estimate glomerular filtration rate (GFR). Cohorts of at least three patients received carboplatin at an initial target AUC of 2 mg/mL x min, with escalations of 1 mg/mL x min in subsequent cohorts. Courses consisted of carboplatin on day 1 followed by IFOS 2 g/m2 plus VP-16 100 mg/m2 on days 2 and 3. Patients received at least two courses, with a maximum of eight courses possible in the absence of progressive disease. When only moderate toxicity occurred after escalation to 5 mg/mL x min, a third dose of IFOS plus VP-16 was added. After three patients were treated at this level, carboplatin escalation proceeded. RESULTS: Neutropenia and thrombocytopenia were the dominant toxicities in the 43 assessable patients. At the target AUC of 8 mg/mL x min, 13 of 20 cycles were associated with febrile neutropenia. For phase II trials, we recommend a carboplatin target AUC of 6 mg/mL x min with three doses of IFOS and VP-16 for patients with prior craniospinal irradiation or high-dose cisplatin (CDDP)/VP-16, or 7 mg/mL x min for patients without such histories. There were two complete responses (CRs), 13 partial responses (PRs), and 17 objective responses (ORs). CONCLUSION: The ICE regimen shows promising activity in pediatric solid tumors. The clear relationship between hematologic toxicity and carboplatin systemic exposure supports the use of targeted dosing in further trials of ICE chemotherapy.

Carboplatin/ifosfamide window therapy for osteosarcoma: results of the St Jude Children's Research Hospital OS-91 trial.

PURPOSE: To determine the activity of carboplatin/ifosfamide in patients with previously untreated osteosarcoma and to estimate patient outcomes after a multiagent chemotherapy protocol that eliminated cisplatin. PATIENTS AND METHODS: Sixty-nine patients with newly diagnosed, previously untreated osteosarcoma received three cycles of carboplatin (560 mg/m(2) x 1) and ifosfamide (2.65 g/m(2)/d x 3). Assessment of response was evaluated after two (week 6) and three (week 9) chemotherapy cycles. At week 9, histologic response was assessed. Adjuvant therapy comprised two additional carboplatin/ifosfamide cycles, doxorubicin, and high-dose methotrexate. Patients were stratified at enrollment: stratum A, resectable primary tumor without metastases; stratum B, unresectable primary tumor; and stratum C, metastatic disease at diagnosis. Week 6 response was compared with that of a historic group that received only ifosfamide during the initial window evaluation. RESULTS: The clinical and radiographic response rate to three cycles of carboplatin/ifosfamide was 67.7% (95% confidence interval, 55.0% to 78.8%). Compared with the historic population who received only ifosfamide, the combination of carboplatin and ifosfamide reduced the progressive disease rate at week 6 (31.9% v 9%, P: = .003). For patients in stratum A, the 3-year event-free survival and survival were 72.3% +/- 6.7% and 76.4% +/- 6.4%, respectively. Patients who received carboplatin-based therapy had less long-term renal toxicity and ototoxicity. CONCLUSION: This pilot trial suggests that carboplatin/ifosfamide combination chemotherapy has substantial antitumor activity. In the context of a multiagent chemotherapy protocol comprising high-dose methotrexate and doxorubicin, we found that the addition of carboplatin/ifosfamide resulted in patient outcomes comparable to trials using cisplatin-based therapy with less long-term toxicity.

Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: A Pediatric Oncology Group/Children's Cancer Group Intergroup Study.

PURPOSE: To determine whether the 3-year event-free survival (EFS) of children with completely resected immature teratomas is greater than 85%. PATIENTS AND METHODS: Patients with immature teratomas treated at Pediatric Oncology Group or Children's Cancer Group institutions were eligible. Pathology was centrally reviewed to confirm diagnosis and tumor grading. Follow-up included physical examination, measurement of tumor markers (alpha fetoprotein and human chorionic gonadotropin), and imaging. All patients were monitored for events, defined as tumor recurrence, second malignancy, or death. RESULTS: Seventy-three children (median age, 7.8 years) with extracranial immature teratomas were enrolled on study. Primary tumor sites included ovarian (n = 44), testicular (n = 7), and extragonadal (n = 22). However, on review, 23 patients had foci of yolk sac tumor (n = 21) or primitive neuroectodermal tumor (n = 2), whereas 50 had pure immature teratomas. Twenty-five patients had increased alpha fetoprotein (n = 18), human chorionic gonadotropin (n = 5), or both (n = 2); nine had foci of yolk sac tumor on review. Pathology review identified 23 patients with grade 1, 29 with grade 2, and 21 with grade 3 immature teratomas. With a median follow-up of 35 months, the overall 3-year EFS was 93% (95% confidence interval, 86% to 98%), with 3-year EFS of 97.8%, 100%, and 80% for patients with ovarian, testicular, and extragonadal tumors, respectively. Only four of 23 patients with immature teratoma and malignant foci developed recurrence, suggesting that surgical resection followed by close observation are effective treatment. Overall, five patients had disease recurrence 4 to 7 months from diagnosis, and four (80%) are disease free after platinum-based therapy. The fifth patient has residual tumor after cisplatin, etoposide, and bleomycin treatment requiring further therapy. CONCLUSION: Surgical excision is safe and effective treatment for 80% to 100% of children with immature teratoma.

Candida tropicalis infections in children with leukemia.

The Candida species account for approximately three-fourths of fungal infections in patients with cancer. Although Candida albicans is the most frequent cause, C. tropicalis is increasingly implicated as an important pathogen. Over a 12 year period 19 children treated for leukemia at our institution developed C. tropicalis infections. We describe their clinical presentation, extent of fungal infection, treatment, and outcome. Fungemia without meningitis in 11 children was treated successfully, whereas C. tropicalis meningitis in 7 children was uniformly fatal. An additional patient had unsuspected, widespread infection detected at autopsy. Multiple sites, including the cerebrospinal fluid yielded C. tropicalis. Previously reported risk factors including neutropenia, broad-spectrum antibiotic usage, corticosteroid therapy, and total parenteral nutrition were observed in our cases. A high index of suspicion and the early use of aggressive antifungal therapy are critical to the successful management of C. tropicalis infections in children with leukemia.

Nucleoside transport in normal and neoplastic cells.

The permeation of nucleosides across the plasma membrane of mammalian cells is complex and mediated by at least five distinct transporters that differ in their sensitivity to inhibitors and in their specificity for nucleosides. The basic properties and permeant specificity of these transporters are summarized in Table 3. It appears that there may be differences in the distribution of these transporters in tumors and normal tissues that might be exploited for chemotherapeutic purposes. The human tumor cell lines examined express predominantly the NBMPR-sensitive equilibrative transporter es which can be blocked by low concentrations of NBMPR and dipyridamole. It is reasonable to expect that tumors with transport properties similar to the CCRF-CEM and Rh28 cell lines (Table 1) that have no detectable NBMPR-insensitive transport activity will be highly susceptible to the therapeutic approach of combining a transport inhibitor such as dipyridamole or NBMPR with an inhibitor of de novo pyrimidine biosynthesis. On the other hand, this approach to therapy is unlikely to succeed against tumors with transport phenotypes similar to the WI-L2 cell line that may permit the salvage nucleosides in the presence of these inhibitors. The majority of tumor cells examined, however, fall between these extremes, and it is not yet known what level of NBMPR-insensitive transport activity can be tolerated without seriously compromising this therapeutic approach. With respect to normal tissues, the mature absorptive cells of the intestine have predominantly Na(+)-dependent nucleoside transporters that are insensitive to NBMPR and dipyridamole. The proliferating crypt cells also appear to have Na(+)-dependent nucleoside transport, although they may also have an NBMPR-sensitive component of transport (Belt, unpublished data). Bone marrow granulocyte-macrophage progenitor cells also appear to have one or more concentrative nucleoside transporters. Thus these tissues, which are most vulnerable to the toxicity of antimetabolites, may be able to salvage nucleosides in the presence of inhibitors of equilibrative transport and be protected from the toxicity of de novo synthesis inhibitors. It is likely, however, that a successful application of this therapeutic approach will require the analysis of the nucleoside transport phenotype of individual tumors in order to identify those patients that may benefit from such therapy. Since the development of antibodies and cDNA probes for the various nucleoside transporters is currently underway in several laboratories, it is likely that analysis of the nucleoside transport phenotype of tumors from biopsy material will be feasible in the future.

Infrared, thermistor, and glass-mercury thermometry for measurement of body temperature in children with cancer.

Body temperature is often the sole determinant of whether or not the neutropenic cancer patient is admitted to the hospital for empiric antibiotic therapy. Recently developed infrared tympanic thermometers offer rapid readings, but their accuracy has not been established. We studied two infrared thermometers (FirstTemp and Thermoscan) and a thermistor (IVAC) in children with cancer. Mean infrared measurements did not differ significantly between right and left ear canals, and the mean IVAC temperature did not differ significantly from the left to the right axilla (P greater than 0.05, paired t test). IVAC predictive mode mean temperature was 0.2 degrees C lower than monitor mode mean temperature in the axilla (P less than 0.0001), but 0.1 degree C higher than monitor mode orally (P less than 0.0001). Aiming the infrared instrument at the tympanic membrane using an ear tug resulted in a 0.2 degree C higher mean temperature than casual placement in the ear canal (P less than 0.0001). After compensation for the mean difference in reference oral glass-mercury versus test instrument temperatures, the FirstTemp, Thermoscan, and oral and axillary predictive mode IVAC measurements yielded sensitivities for the detection of fever of 84%, 84%, 82%, and 86%; specificities of 100%, 99%, 100%, and 100%; positive predictive values of 100%, 93%, 100%, and 100%; and negative predictive values of 95%, 98%, 98%, and 98%, respectively. We conclude that each of these instruments detects fever with comparable reliability. Infrared instruments are especially attractive alternatives due to their time efficiency.

Leukemias and lymphomas in children.

Leukemias and lymphomas, the most common type of neoplasms in children, represent a heterogenous group of diseases that display a wide spectrum of clinical, morphologic, immunologic, cytogenetic, and molecular features. Modern treatment is curative for most children with lymphoid neoplasms; however, new approaches to therapy of acute nonlymphoblastic leukemias are necessary if current results are to be improved. This article focuses on the clinical and biologic characteristics, and the modalities of treatment of this group of diverse diseases.

Diagnosis and treatment of the most common solid tumors in childhood.

Childhood cancer is the leading cause of death from disease in children between 1 and 15 years of age. Since the introduction of modern multimodality therapy, the prognosis for solid tumors has improved dramatically, with 50% to 60% cure rates. Advances in cytogenetic and molecular genetic techniques are now being used for risk-based treatment in various tumors, including neuroblastoma and rhabdomyosarcoma. Further use of these research tools may lead to a better understanding of oncogenic molecular events, permitting treatment targeted to specific genetic lesions. This article focuses on the clinical features, treatment, and potential future research directions for this diverse group of diseases.

Effect of nucleoside transport inhibitors on thymidine salvage and the toxicity of nucleoside analogs in mouse bone marrow granulocyte-macrophage progenitor cells.

In an attempt to elucidate the types of nucleoside transporters present in bone marrow stem cells, this study examined the effect of nucleoside transport inhibitors on the toxicity of nucleoside analogs and on the salvage of thymidine by mouse bone marrow granulocyte and macrophage progenitor cells using the CFU-GM assay. Concentrations of NBMPR (nitrobenzylmercaptopurine riboside) as low as 10 nM protected these cells from the toxicity of the adenosine analog tubercidin and provided a partial block of thymidine-rescue of the granulocyte-macrophage progenitor cells from methotrexate toxicity. Dipyridamole had similar effects but generally required higher concentrations. These results suggested that the major nucleoside transporter in these cells is the NBMPR-sensitive equilibrative carrier, es. In contrast to the results with tubercidin, the toxicity of 2-chlorodeoxyadenosine was increased 8- to 10-fold by 1 microM NBMPR. These results suggested that the bone marrow granulocyte-macrophage progenitor cells also have a concentrative nucleoside transporter that is capable of pumping 2-chlorodeoxyadenosine into the cells while efflux of the nucleoside via es is blocked by NBMPR.

Sacrococcygeal yolk sac carcinoma: imaging findings during treatment.

Sacrococcygeal teratomas and their malignant counterparts (germ cell tumors) are the most common solid tumors in neonates. Prompt diagnosis is essential because the frequency of malignant transformation increases from 10-20 % in neonates to 67 % in patients over 2 months of age. Cross-sectional imaging has largely replaced surgical exploration for staging these tumors and assessing their response to chemotherapy. Radiologists must be familiar with changes in the imaging findings of these tumors during and after treatment so that they can advise clinicians regarding the efficacy of therapy and the presence or absence of recurrent disease. From our study, magnetic resonance imaging appears to be a better modality for assessing sacral invasion and metastases and distinguishing fibrotic masses from recurrent tumor.

Candida tropicalis and Candida albicans fungemia in children with leukemia.

The records were reviewed for all patients hospitalized at a pediatric oncology center for complications of leukemia (n = 822) or lymphoma (n = 290) during an 8-year period. The results of surveillance cultures (throat, rectal, and urine) and blood cultures were analyzed to identify cases of Candida tropicalis and C. albicans colonization and/or fungemia. None of the patients with lymphoma who had positive surveillance cultures for C. albicans (n = 89) or C. tropicalis (n = 23) had fungemia. Among patients with leukemia, significant fungal infection was documented in 12 of 107 colonized with C. tropicalis (11.2%) versus 14 of 700 (2%) colonized with C. albicans (P less than 0.001). The two groups of children with fungemia were similar in primary diagnoses (predominantly acute lymphoblastic leukemia) and in the frequency of several known risk factors for infection, including the duration of neutropenia (absolute neutrophil counts, less than 500/microliters). Patients with C. tropicalis fungemia all had disseminated disease compared with nine of 14 patients with C. albicans fungemia. Also, subcutaneous abscesses were unique to patients with C. tropicalis in this series. Two patients in each group died of their infection; central nervous system involvement was present in both fatal cases of C. tropicalis fungemia. A high index of suspicion and the early institution of appropriate antifungal therapy are critical to the successful management of these infections in patients with leukemia.

Peripheral primitive neuroectodermal tumor (peripheral neuroepithelioma) in children. A review of the St. Jude experience and controversies in diagnosis and management.

All patients diagnosed with primitive neuroectodermal tumor (PNET) and extraosseous Ewing's sarcoma in one institution between 1962 and 1987 were reviewed. Of the 26 cases studied, 16 had been diagnosed originally as PNETs, seven tumors were rediagnosed as PNET or EOE by histologic review, and three tumors had an original diagnosis of extraosseous Ewing's sarcoma. To determine whether these diagnoses determine a group of tumors with unique biologic behavior and identifiable pathologic characteristics, clinical and treatment response data were compiled, and electron microscopic and immunohistochemical studies were done for those patients with adequate samples. With combined modality therapy, this group achieved a substantially shorter disease control interval than patients with disseminated osseous Ewing's sarcoma or disseminated neuroblastoma--10.8 months versus 17 months and 16 months, respectively. The pattern of relapse and distant spread also differed among these tumor types. Immunohistochemical studies (for example, neuron-specific enolase and beta 2 microglobulin) were helpful in confirming the diagnosis but were not definitive in themselves. Tentative diagnostic criteria are proposed for use in studies designed to provide further information on the nature and treatment of PNET. Some of the controversies regarding diagnosis are discussed. The authors propose a uniform approach to treatment of extraosseous Ewing's sarcoma and PNET in order to try to clarify their relation.

Successful treatment of acute lymphoblastic leukemia in a child with cystic fibrosis.

A 3 1/2 year old girl with cystic fibrosis who underwent successful treatment for acute lymphoblastic leukemia remains in complete remission 36 months after diagnosis. We also report high clearance rates of three antineoplastic agents in this patient. Drug doses were adjusted to achieve optimal systemic exposure.

The role of second-look surgery in the management of advanced germ cell malignancies.

The need for second-look surgery after chemotherapy in children with advanced germ cell tumors is controversial, particularly when levels of the tumor markers alpha-fetoprotein (AFP) or beta-human chorionic gonadotropin (beta HCG) are elevated at diagnosis. The authors evaluated the outcome of second-look surgery in relationship to tumor marker status in 27 patients with Stage III to IV disease who had completed four courses of chemotherapy. Markers were elevated at diagnosis in 19 patients. After chemotherapy, markers normalized in 12 of these patients. Second-look surgery confirmed complete response (CR) in these 12 patients, two of whom had residual masses on computed tomography (CT) scan (mature teratoma and necrotic tumor). The AFP decreased but did not normalize in seven patients; five had residual disease at second look and the other two later developed measurable disease. Of the eight patients with normal AFP at diagnosis, second look confirmed clinical CR in four. The other four patients had CT evidence of residual masses: surgery showed necrotic tissue in two cases, mature glial elements in one, and mature teratoma with glial elements in one. Thus second-look surgery added no information for treatment planning in children with elevated tumor markers at diagnosis and might best be reserved for patients without tumor markers at diagnosis and residual masses on CT scan, and those with persistent elevation of tumor markers and potentially resectable residual disease. Because of the possibility of small amount of residual tumor, second-look surgery may also be useful in patients whose markers normalize but who have residual masses on CT scans.

Refining therapeutic strategies for patients with resistant Wilm's tumor.

PURPOSE: Despite the excellent prognosis for 90% of patients with Wilms' tumor, survival remains poor among those with recurrent or advanced disease or tumors of unfavorable histology. We sought to identify a chemotherapy regimen for this subset of patients that offers potential efficacy with minimal nephrotoxicity. PATIENTS AND METHODS: Through a review of patients' medical records, we compared the efficacy and nephrotoxicity of ifosfamide, cisplatin, cisplatin/etoposide, and ifosfamide/carboplatin/etoposide (ICE) regimens in 32 patients with recurrent (n = 23), refractory (n = 1), or metastatic (n = 8) Wilms' tumor, including six with tumors having unfavorable histologic features. RESULTS: Single-agent ifosfamide was minimally nephrotoxic and induced responses in three of 11 patients, but none have survived. Cisplatin with or without etoposide induced responses in six of 18 patients with recurrent Wilms' tumor (there is one long-term survivor). Seven of eight patients with newly diagnosed extensive metastatic disease responded to cisplatin/etoposide plus vincristine, dactinomycin, adriamycin, and radiotherapy. This regimen produced three long-term survivors, but was associated with significant nephrotoxicity. The ifosfamide, carboplatin, and etoposide regimen induced responses in four of five patients treated, and had minimal nephrotoxicity. Two remain free of disease progression 22 months after recurrence. CONCLUSIONS: Although long-term survival remains to be determined, the ICE combination appears to be effective against recurrent Wilms' tumor without endangering the patients' single remaining kidney. Myelotoxicity can be ameliorated by administering growth factors. We suggest that ICE chemotherapy be considered for the primary treatment of high-risk patients with Wilms' tumor.

Improved prognosis of children with osteosarcoma metastatic to the lung(s) at the time of diagnosis.

BACKGROUND: A poor outcome is traditionally ascribed to osteosarcoma metastatic to the lungs, but data have been unavailable regarding the outcome of such patients after systematic treatment on clinical trials. METHODS: The clinical course and outcome of 31 patients who had osteosarcoma metastatic to the lungs diagnosed between 1962 and 1990 at St. Jude Children's Research Hospital were reviewed to determine whether the use of increasingly aggressive multimodality therapy has improved their outcome. The patients were grouped by treatment eras, based on major changes in therapy (i.e., single-agent or two-agent era, 1962-1972; standard multiagent era, 1972-1982; and intensive multiagent era, 1982-1990). RESULTS: With increasingly intensive chemotherapy, more aggressive efforts to resect metastatic disease, and earlier detection of pulmonary metastases by computed tomography, the survival of these patients has improved significantly over the 28-year study period. Those treated since 1982 have a 50% estimated probability of survival at 3 years, whereas there were no survivors at 3 years in the two earlier eras. Survival for the former group reached a plateau of 30% at 4 years. CONCLUSIONS: The use of aggressive multimodality therapy, coupled with modern pediatric imaging techniques to detect pulmonary disease, has improved the traditionally dismal outlook in pediatric patients with osteosarcoma and synchronous pulmonary metastases.