Patrick R.M. Thomas

Results of a Prospective Randomized Trial Comparing Standard Dose Neuraxis Irradiation (3,600 cGy/20) with Reduced Neuraxis Irradiation (2,340 cGy/13) in Patients with Low-Stage Medulloblastoma

PURPOSEnTo determine in a prospective randomized trial the effect on survival, progression-free survival, and patterns of relapse of a decrease in the neuraxis radiation dose from 3,600 cGy in 20 fractions to 2,340 cGy in 13 fractions in patients with newly diagnosed medulloblastoma between 3 and 21 years of age with low T stage (T1, T2 and T3A), minimal postoperative residual tumor, and no evidence of dissemination (M0).nnnMETHODS AND MATERIALSnBetween June 1986 and November 1990, the Childrens Cancer Group and the Pediatric Oncology Group randomized 126 patients in a two-arm study comparing the two different doses of neuraxis irradiation. In both arms, the posterior fossa received 5,400 cGy in 30 fractions. All patients were staged with myelography, postoperative lumbar cerebrospinal fluid cytology, and postoperative contrast-enhanced cranial computerized tomography to ensure no evidence of dissemination and no more than 1.5 cm3 residual tumor volume. Overall survival, progression-free survival, and patterns of recurrence were carefully monitored. Prospective endocrine and psychometric studies were performed to determine the benefit of decreasing the neuraxis radiation dose.nnnRESULTSnFollowing an interim analysis at a median time on study of 16 months, the study was closed, since a statistically significant increase was observed in the number of all relapses as well as isolated neuraxis relapses in patients randomized to the lower dose of neuraxis radiation.nnnCONCLUSIONSnIn patients with newly diagnosed medulloblastoma considered to have a good prognosis on the basis of low T stage, minimal residual tumor after at least subtotal resection, and no evidence of dissemination after thorough evaluation, there is an increased risk of early relapse associated with lowering the dose of neuraxis radiation from 3,600 cGy in 20 fractions to 2,340 cGy in 13 fractions.

Renal failure in Wilms' tumor patients: A report from the National Wilms' Tumor Study Group

This report defines the incidence and determines the etiology of renal failure (RF) in patients undergoing treatment for Wilms tumor (WT). The database of the National Wilms Tumor Study (NWTS) was searched to identify all children reported to have developed chronic renal failure. There were 55 patients found to have RF. Of these, 39 patients had bilateral tumors, 15 with unilateral disease and one with a WT in a solitary kidney. The median interval from diagnosis to the onset of renal failure was 21 months. The incidence of RF in bilateral WT was 16.4% for NWTS-1 & -2, 9.9% for NWTS-3, and 3.8% for NWTS-4. The incidence of RF in unilateral WT remained stable. The most common etiologies of RF were: bilateral nephrectomy for persistent or recurrent tumor (24 pts), Drash syndrome (12 pts), progressive tumor in the remaining kidney (5 pts), radiation nephritis (6 pts), and other causes (5 pts). The etiology of renal failure was not reported in three children. Children with unilateral WT and a normal contralateral kidney have a very low incidence of RF, and this review does not support a recommendation for parenchymal sparing procedures in these patients. Children with bilateral WT are at risk for the development of RF, and parenchymal sparing procedures are warranted.

Response of growing bone to irradiation: A proposed late effects scoring system

The effect of radiation on epiphyseal bone growth is one of the most important dose-limiting factors in the radiotherapeutic management of children with malignant neoplasms. Clinical and laboratory evidence suggest that many factors may influence the severity of radiation-induced growth arrest. However, the absence of a consistent scoring system for late effects has hampered efforts to analyze the influence of various therapeutic maneuvers or to compare and collate results from different reported series. In this review, laboratory and clinical studies of radiation effects on growing bone are summarized, and a late effects scoring system is proposed.

Phase II Trial of Neoadjuvant Vincristine, Ifosfamide, and Doxorubicin With Granulocyte Colony-Stimulating Factor Support in Children and Adolescents With Advanced-Stage Nonrhabdomyosarcomatous Soft Tissue Sarcomas: A Pediatric Oncology Group Study

PURPOSEnTo describe the response rate and survival of children and adolescents with unresected or metastatic nonrhabdomyosarcomatous soft tissue sarcomas (NRSTS) treated with vincristine, ifosfamide, and doxorubicin.nnnPATIENTS AND METHODSnBetween September 1996 and June 2000, 39 eligible patients received vincristine (1.5 mg/m(2) weekly for 13 doses), ifosfamide (3 g/m(2) daily for 3 days every 3 weeks for seven cycles), doxorubicin (30 mg/m(2) daily for 2 days for six cycles), and mesna (750 mg/m(2) for four doses after ifosfamide). Granulocyte colony-stimulating factor was administered daily (5 mug/kg) after each cycle of chemotherapy. Radiotherapy was administered from weeks 7 through 12.nnnRESULTSnThe median patient age at diagnosis was 11.7 years; the most common primary tumor site was lower extremity (36%); and synovial sarcoma was the predominant histology. More than three fourths of all tumors were 5 cm or greater at their largest diameters. The overall objective combined partial and complete response rate was 41% (95% CI, 25.7% to 56.7%). The estimated 3-year overall survival and progression-free survival rates (+/- standard deviation) for eligible patients were 59% +/- 8.2% and 43.6% +/- 7%, respectively. Patients with clinical group III disease had significantly better 3-year and progression-free survival rates compared with patients who presented with metastatic disease.nnnCONCLUSIONnThe vincristine, ifosfamide, and doxorubicin regimen was moderately active against pediatric NRSTS. Patients with synovial sarcoma had higher response rates than other patients, and patients with unresected disease had improved outcomes. Patients with metastatic disease continue to fare poorly, and newer approaches are indicated for these patients.

Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: A Pediatric Oncology Group Study

BACKGROUNDnThe objectives of this study were to compare vincristine/actinomycin D/cyclophosphamide/adriamycin (VACA) with VACA/plus imidazole carboxamide (DTIC) (VACAD) therapy in regards to complete/partial response and event free survival rates in children and adolescents with metastatic non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) or previously chemotherapy-naive recurrent NRSTS or locally persistent gross residual tumor after surgery and radiation therapy.nnnPROCEDURESnBetween 1986 and March 1994, 75 patients entered this randomized study comparing VACA and VACAD, given at 3 week intervals. Sixty-one patients were considered eligible and received chemotherapy and radiation therapy to the primary tumor and areas of metastases. Thirty-six patients had regional unresected (Group III) disease, and 25 had metastatic disease (Group IV) at time of accession. Thirty-six patients received VACA (11 were not randomized), and 25 received VACAD.nnnRESULTSnWith a median follow-up of greater than 4 years, overall and event-free survival for all eligible patients are 30.6% and 18.4% respectively (S.E: 9.5% and 6.8%). There was insufficient evidence that DTIC offered any advantage to event free survival, but there was evidence for better outcome for patients in Group III disease in comparison to patients with Group IV disease, and for patients with a Grade 1 and 2 histology in comparison to Grade 3 lesions.nnnCONCLUSIONSnCombination chemotherapy with VACA and VACAD were insufficient to prevent recurrent or progressive disease in children and adolescents with high stage NRSTS. The use of vincristine/ifosfamide/doxorubicin with cytokine support is under study.

Management and outcome of inoperable Wilms tumor. A report of National Wilms Tumor Study-3.

MethodsThe authors reviewed 131 children enrolled in National Wilms Tumor Study-3 (NWTS-3) who received preoperative treatment for tumors unable to be resected at surgery or judged inoperable by imaging evaluation. Preoperative biopsies were performed on 103 patients. Patients were assigned a pretreatment stage: stage II (11 patients), stage III (39 patients), stage IV (66 patients), and unknown (15 patients). The chemotherapy regimen included dactinomycin and vincristine (81 patients), dactinomycin, vincristine, and doxorubicin (30 patients), dactinomycin, vincristine, doxorubicin, and cyclophosphamide (10 patients), and other (8 patients). Preoperative radiation therapy was started concurrently with chemotherapy (27 patients) or because of lack of response (14 patients). Two patients were given preoperative irradiation without chemotherapy. ResultsResponse to therapy was assessed after the first trial of chemotherapy. Partial responses were noted in 110 patients (85%), 3 had complete responses, 13 had no response or progression of disease, and 5 patients were not able to be evaluated. There were no significant differences in preoperative response to the different chemotherapy regimens. Median time interval from diagnosis to nephrectomy was 58.5 days. When compared with NWTS-3 patients not receiving preoperative treatment, survival was reduced for patients treated preoperatively (88% vs. 74%, respectively, 4-year survival), which was only partially explained by differences in stage distribution. Median duration of follow-up was 5.9 years. Lack of response to the preoperative treatment was associated with a poor prognosis. Eight children died before removal of the primary tumor. All eight had either progressive disease or no response to the preoperative treatment. ConclusionsThe use of preoperative treatment can facilitate subsequent surgical resection in selected patients with inoperable Wilms tumors. Although these very large tumors—judged unable to be resected—have a somewhat worse prognosis, nephrectomy was completed in 93% of patients after preoperative treatment. However, preoperative treatment wil lead to less accurate surgical and pathologic staging, and undertreatment should be avoided in these high-risk patients.

Results of two radiation therapy randomizations in the third national Wilms' tumor study

In the third National Wilms Tumor Study (NWTS‐3), patients with Stage II favorable histologic type (FH) or Stage III FH Wilms tumor were randomized according to a factorial design for both radiation therapy (RT) and chemotherapy to be given after nephrectomy. Patients with Stage II FH disease were randomized between 2000 cGy and no postoperative RT; patients with Stage III FH disease were randomized between 2000 and 1000 cGy. No significant differences in survival were noticed. Although there were no significant differences in the rate of intraabdominal relapses, those patients with Stage III disease who received 1000 cGy and dactinomycin and vincristine (seven patients) experienced a relapse in the abdomen more frequently than those who received 2000 cGy and dactinomycin and vincristine (three patients), 1000 cGy and dactinomycin, vincristine, and doxorubicin (three patients), or 2000 cGy and dactinomycin, vincristine, and doxorubicin (two patients). This would suggest that doxorubicin might be a good substitute for the second 1000 cGy of RT. Boost doses of RT, although allowed, were rarely given and no assessment of the value of supplemental RT can be made. The dismal prognosis of abdominal relapse after RT is confirmed and delay of initiation of treatment beyond 10 days after surgery was a significant adverse factor as in NWTS‐1 and NWTS‐2.

Prognostic implications of hepatic adhesion, invasion, and metastases at diagnosis of Wilms' tumor

In the Third National Wilms Tumor Study, (NWTS‐3), 190 patients with Favorable Histology (FH) Wilms tumor (WT) were identified as having tumor adherent to, directly invading, or metastatic to the liver at diagnosis. Analyses of the 3‐year relapse‐free survival and survival of these patients show that adhesion to the liver surface, direct invasion of the liver, and liver metastases have no additional detrimental effect on prognosis stage‐for‐stage. The authors conclude that hepatic involvement, when present at the time of diagnosis, should not be regarded as different from other patterns of the disease. Treatment policies should follow those appropriate for stage. 68:2486‐2488, 1991.

Wilms' Tumor: Changing Role of Radiation Therapy

Wilms tumor is a highly curable neoplasm. Greater that 90% of all children with this disease can be expected to become long-term survivors. Although radiation therapy (RT) was once the mainstay of nonsurgical treatment, its use has been reduced both in indications and in dosage because of the chemoresponsiveness of the tumor. In the Third National Wilms Tumor Study (NWTS 3), patients with stage II tumors were shown not to require postoperative RT, and in patients with stage III tumors, 10 Gy was sufficient. In NWTS 5, patients with stage III favorable histology (FH), stage IV FH (with abdominal stage III), and stage II-IV anaplastic and all patients with clear cell sarcoma receive 10 Gy to to the abdomen (usually given as 1.8 Gy x 6-total doe 10.8Gy). Results from the International Society of Paediatric Oncology, in which downstaged patients had a higher incidence of abdominal relapse, and the United Kingdom Childrens Cancer Study Group first Wilms Tumor Study, in which omission of whole-lung RT led to lowered survival in stage IV patients, suggest caution in further modifications of RT at this time.

Long-term Neuropsychologic and Intellectual Sequelae in Brain Tumor Patients

With increasingly aggressive multimodality treatment, the ability to cure or at least obtain long-term survival for significant numbers of children with primary or secondary brain tumors is becoming more commonplace, with further success on the horizon. With this increasing survival rate comes the responsibility to evaluate closely the subtle and more overt long-term effects on the children themselves—not only physical and functional effects, but behavioral, neuropsychological, and intellectual effects as well. Long-term physical and hormonal effects are easily evaluated and quantitated, and early intervention may modify the long-term effects on the child. Other long-term sequelae, however, are less easily defined and can require a comprehensive range of tests to even establish a general area of deficiency, let alone to determine the cause and effect mechanisms.