A phase II study of the farnesyl transferase inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma: a Children's Oncology Group study

BACKGROUND: An open-label Phase II study of tipifarnib was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB)/primitive neuroectodermal tumor (PNET), high-grade glioma (HGG), and diffuse intrinsic brainstem glioma (BSG). METHODS: Between January 2004 and July 2005, patients were enrolled and stratified as follows: Stratum 1, recurrent or refractory MB/PNET; Stratum 2, recurrent or refractory HGG; and Stratum 3, recurrent or refractory BSG. Patients received tipifarnib 200 mg/m2 per dose twice daily for 21 days repeated every 28 days. Patients who received enzyme-inducing anticonvulsants and other CYP3A4/5 inducers or inhibitors were excluded. The primary objective was to estimate the sustained response rate in all strata. RESULTS: Ninety-seven patients with a median age of 11.2 years (range, 3.2-21.9 years) were enrolled on the study, and 81 patients were evaluable for response. One of 35 patients with BSG and 1 of 31 patients with HGG had a sustained partial response. No responses were observed in 15 patients with MB/PNET. Eight patients (3 HGG, 1 MB, and 4 BSG) remained stable for >or=4 courses (range, 4-25 courses). The median number of courses received was 2 (range, 1-25 courses). The most frequent grade 3 and 4 toxicities included neutropenia (18.7%), thrombocytopenia (14.3%), and leukopenia (14.3%). The 6-month progression-free survival rate (+/-standard deviation) was 14%+/-6% for HGG, 6%+/-6% for MB/PNET and 3%+/-3% for BSG. CONCLUSIONS: Tipifarnib tolerated well but had little activity as a single agent in children with recurrent central nervous system malignancies.     

Central nervous system involvement in children with sarcoma

OBJECTIVES: To summarize and analyze the experience in CNS involvement (CNSI) in children with sarcomas treated in the above-mentioned institutions. PATIENTS AND METHODS: From 1990 to 2001, all medical charts were retrospectively reviewed: 19 sarcoma patients (12 boys and 7 girls) were diagnosed with CNSI (4 osteogenic sarcomas, 11 Ewing sarcomas, 2 rhabdomyosarcomas, 1 alveolar soft part sarcoma and 1 mesenchymal chondrosarcoma). Mean age of all patients at the time of initial diagnosis was 14.9 years (range: 4-24 years), mean age at the time when CNSI was diagnosed was 16.9 years (range: 5.5-27 years). RESULTS: The frequency of CNSI among our patients was 6.17%. The following symptoms and signs (sometimes combined) presented: headache (10 patients), nausea and vomiting (6 patients), seizures (11 patients) and focal neurological signs (9 patients). The mean duration of time elapsed since diagnosis of CNSI till death or last follow-up was 5.2 months (SD: +/-5.7 months). Four patients received chemotherapy (CT) alone, 8 CT and radiotherapy (RT), 2 RT alone, 3 supportive treatment only, 1 CT and surgery and 1 surgery alone. Sixteen patients died; there was no significant difference in the duration of survival between those who were treated with RT or surgery (mean +/- SD: 6.77 +/- 6.56 months) and those who received only CT or supportive treatment (mean +/- SD: 2.60 +/- 2.94 months) (p = 0.07). Brain disease was the main cause of death in all but 1 patient who died 4 days after autologous bone marrow transplantation from uncontrolled sepsis. In 16 patients, CNSI was part of a metastatic disease. CONCLUSIONS: Among children with sarcoma, CNSI is encountered in 6.17% of cases. More effective therapy has to be developed in order to improve their outcome.     

Hyperfractionated low-dose radiotherapy for high-risk neuroblastoma after intensive chemotherapy and surgery.

PURPOSE: To assess prognostic factors for local control in high-risk neuroblastoma patients treated with hyperfractionated 21-Gy total dose to consolidate remission achieved by dose-intensive chemotherapy and surgery. PATIENTS AND METHODS: Patients with high-risk neuroblastoma in first remission received local radiotherapy (RT) totaling 21 Gy in twice-daily 1.5-Gy fractions. RT to the primary site followed dose-intensive chemotherapy and tumor resection; the target field encompassed the extent of tumor at diagnosis, plus 3-cm margins and regional lymph nodes. RT to distant sites followed radiologic evidence of response. Local failure was correlated with clinical factors (including other consolidative treatments) and biologic findings. RESULTS: Of 99 consecutively irradiated patients followed for a median of 21.1 months from RT, 10 relapsed in or at margins of RT fields at 1 to 27 months (median, 14 months). At 36 months after RT, the probability of primary-site failure was 10.1% +/- 5.3%. No primary-site relapses occurred among the 23 patients whose tumors were excised at diagnosis, but there were three such relapses among the seven patients who were irradiated with evidence of residual disease in the primary site. Four of 18 patients with MYCN-amplified disease and serum lactate dehydrogenase greater than 1,500 U/L had local failures (23.4% +/- 10.7% risk at 18 months). Acute radiotoxicities were insignificant, but three of 35 patients followed for > or = 36 months had short stature from decreased growth of irradiated vertebra. CONCLUSION: Hyperfractionated 21-Gy RT is well tolerated and, together with dose-intensive chemotherapy and surgery, may help in local control of high-risk neuroblastoma. Extending the RT field to definitively encompass regional nodal groups may improve results. Visible residual disease may warrant higher RT dosing. Patients with biologically unfavorable disease may be at increased risk for local failure. RT to the primary site may not be necessary when tumors are excised at diagnosis.     

Survival and functional outcome of children with hypothalamic/chiasmatic tumors

BACKGROUND: The management of children with hypothalamic (H) and/or chiasmatic (C) tumors remains controversial. We evaluated the impact of clinical and neuroimaging parameters and primary therapy on overall (OS) and progression-free (PFS) survival and on neuroendocrine and neurocognitive outcome in children with H and/or C tumors. METHODS: Records were reviewed for 73 children with H and/or C tumors treated at St. Jude Children's Research Hospital between October 1981 and December 1999. RESULTS: Thirty-six patients received irradiation or chemotherapy immediately postdiagnosis and 37 were observed. The 6-year OS and PFS rates were 86 +/- 5%; and 36 +/- 7%, respectively. The 6-year PFS rates for the irradiation, chemotherapy, and observation groups were 69 +/- 16%, 12 +/- 11%, and 37 +/- 9%, respectively. In multivariate analysis, intracranial NF1 lesions (P = 0.015) and initial irradiation (P = 0.056) led to better PFS rates. There was no difference in OS between those initially treated or observed. Mean serial intelligence quotient (IQ) scores were 86 and 86 at diagnosis and at 6 years later, respectively. Patients younger than 5 years old had a lower mean IQ score at diagnosis (79.1) than older patients (96.3; P = 0.003). Patients who were irradiated at diagnosis had a significantly higher cumulative incidence of endocrinopathy at 3 years (P = 0.008). CONCLUSIONS: Overall survival for children with H and/or C tumors is excellent. Initial treatment with radiation and the presence of intracranial NF1 lesions were positive predictors of PFS. Mean IQ is significantly compromised at diagnosis, but does not change over time or with irradiation. Overall survival is not affected by initial observation. We recommend observation in asymptomatic patients, platinum-based chemotherapy in younger patients, and irradiation in older symptomatic patients.     

Increased risk of lung cancer, non-Hodgkin's lymphoma, and leukemia following Hodgkin's disease

The risk of second cancers (SCs) was assessed in 744 patients with Hodgkin's disease (HD) admitted to The Netherlands Cancer Institute from 1966 to 1983. Sixty-nine SCs were observed one month or more after start of first treatment. These included 14 cases of lung cancer, nine cases of non-Hodgkin's lymphoma (NHL), 16 cases of leukemia, and six cases of the myelodysplastic syndrome (MDS). The median interval between the diagnosis of HD and that of second lung cancer, NHL, and leukemia was 8.1, 13.3, and 5.7 years, respectively. The overall relative risks (RR) (observed/expected [O/E] ratios) of developing lung cancer, NHL, and leukemia were 4.9 (95% confidence limit [CL], 2.7 to 8.2), 31.0 (95% CL, 14.2 to 58.9) and 45.7 (95% CL, 26.1 to 74.2), respectively. At 15 years the cumulative risk of developing an SC amounted to 20.6% +/- 2.9%. The 15-year estimates of lung cancer, NHL, and leukemia were 6.2% +/- 1.9%, 5.9% +/- 2.1% and 6.3% +/- 1.7%, respectively. Increased lung cancer risk following HD has not frequently been clearly demonstrated before; that we were able to demonstrate such risk may be due to the completeness of follow-up over long periods that could be achieved in this study. Excess lung cancer risk was only noted in treatment regimens with radiotherapy (RT); also, all lung cancers arose in irradiation fields. Excess risk of leukemia was only found in treatment regimens involving chemotherapy (CT). For NHL, combined modality treatment was shown to be the most important risk factor. Risk of lung cancer and NHL increased with time since diagnosis. A time-dependent covariate analysis (Cox model) performed on leukemia and MDS showed an increasing risk with intensity of CT, age (greater than 40 years), and a splenectomy.     

Brain magnetic resonance imaging after high-dose chemotherapy and radiotherapy for childhood brain tumors

PURPOSE: Brain necrosis or other subacute iatrogenic reactions has been recognized as a potential complication of radiotherapy (RT), although the possible synergistic effects of high-dose chemotherapy and RT might have been underestimated. METHODS AND MATERIALS: We reviewed the clinical and radiologic data of 49 consecutive children with malignant brain tumors treated with high-dose thiotepa and autologous hematopoietic stem cell rescue, preceded or followed by RT. The patients were assessed for neurocognitive tests to identify any correlation with magnetic resonance imaging (MRI) anomalies. RESULTS: Of the 49 children, 18 (6 of 25 with high-grade gliomas and 12 of 24 with primitive neuroectodermal tumors) had abnormal brain MRI findings occurring a median of 8 months (range, 2-39 months) after RT and beginning to regress a median of 13 months (range, 2-26 months) after onset. The most common lesion pattern involved multiple pseudonodular, millimeter-size, T1-weighted unevenly enhancing, and T2-weighted hyperintense foci. Four patients with primitive neuroectodermal tumors also had subdural fluid leaks, with meningeal enhancement over the effusion. One-half of the patients had symptoms relating to the new radiographic findings. The MRI lesion-free survival rate was 74%+/-6% at 1 year and 57%+/-8% at 2 years. The number of marrow ablative courses correlated significantly to the incidence of radiographic anomalies. No significant difference was found in intelligent quotient scores between children with and without radiographic changes. CONCLUSION: Multiple enhancing cerebral lesions were frequently seen on MRI scans soon after high-dose chemotherapy and RT. Such findings pose a major diagnostic challenge in terms of their differential diagnosis vis-à-vis recurrent tumor. Their correlation with neurocognitive results deserves further investigation.     

Long-term follow-up of patients treated with primary radiotherapy for supradiaphragmatic Hodgkin's disease at St. Jude Children's Research Hospital.

OBJECTIVE: To assess disease control, patterns of relapse, factors predictive of relapse, and late effects of treatment, we reviewed all cases of supradiaphragmatic (SD) Hodgkin's disease (HD) treated with primary radiation therapy (RT) at our institution. METHODS: We retrospectively reviewed the disease characteristics, treatment history, and long-term outcome of the 106 patients with Stage I and II supradiaphragmatic HD who received definitive irradiation at St. Jude Children's Research Hospital between 1970 and 1995. As of the date of analysis, 95 patients are alive, with a median follow-up of 13.3 years (range, 1.9-24.2 years). RESULTS: The median age at diagnosis was 14.7 years (range, 3.7-22.7). Involved-field RT was given to 13 patients (12%), whereas 37 (35%) had mantle RT, 51 patients (48%) had subtotal nodal irradiation, and 5 (5%) had total nodal irradiation. Relapsed disease developed in 26 patients at a median of 1.8 years (range, 0.2-9.3 years). The 5- and 10-year estimated cumulative incidences of relapse were 20.9% +/- 4.0% and 25.1% +/- 4.3%, respectively. With a median dose of 36 Gy (range, 32-40), in-field failure rate was 6.2%, whereas subdiaphragmatic relapse in sites irradiated prophylactically was 1.5%. There was a trend toward an increased incidence of relapse with higher ESR (p = 0.088) and greater number of sites of disease (p = 0.087). Age, stage, histology, nodal disease > or = 6 cm, the presence of bulky mediastinal disease, and the method of staging did not affect the incidence of relapse. The pattern of failure could not be predicted based on the stage of disease, the extent of subdiaphragmatic staging, the extent of radiation therapy, or the sequence of RT fields-"ping pong" vs. sequential. Subset analysis of Stage II patients revealed significantly more relapses in clinically staged patients. Excluding Stage IA patients with high cervical disease or peripheral nodal disease, nodal extension failures were more common for patients undergoing limited-volume RT, whereas extranodal relapses were likely after STNI or TNI. The estimated 10- and 15-year cumulative incidences of second malignancies were 2.9% +/- 1.6% and 7.9% +/- 3.3%, respectively. Our patients are at increased risk of second malignancies (11-fold), and fatal cardiac (68-fold) and infectious (33-fold) complications. Overall survival at 10 years was 90.8% +/- 3.2%; event-free survival was 72.1% +/- 5.0%. CONCLUSIONS: The current analysis confirms the curative potential of RT for HD in children and adolescents. Despite successful salvage therapy, relapsed disease remained the principal cause of death in our cohort. Excess risk of septic death in asplenic patients, fatal heart disease, and second malignancies may further compromise the ultimate cure of HD in long-term survivors.     

Young age may predict a better outcome for children with diffuse pontine glioma

BACKGROUND: Because diffuse pontine glioma (DPG) is rare among young children, the outcome of affected patients is unknown. METHODS: The authors reviewed clinical and radiologic characteristics of all children aged <3 years with DPG who were evaluated at their institution. Inclusion followed standard magnetic resonance imaging criteria for the diagnosis of DPG. RESULTS: The median age at diagnosis in 10 patients was 2.2 years (range, 0.8-2.7 years). The median interval between the onset of symptoms and diagnosis was 2.5 months. All patients presented with cranial nerve palsy with (n = 7) or without (n = 3) other neurologic deficits attributable to brainstem involvement. All patients had pons-based tumors involving >50% of this brainstem segment. Histologic confirmation was attempted in 2 patients who had atypical radiologic features at diagnosis. Four patients initially were observed only. All patients received therapy, which consisted of radiation therapy (RT) (n = 2), RT and chemotherapy (n = 6), or chemotherapy only (n = 2). Four patients died of tumor progression after a median of 0.7 years (range, 0.5-3.7 years). Six patients have survived for a median of 2.3 years (range, 0.9-8 years). The 3-year progression-free and overall survival rates were 45% +/- 19% and 69% +/- 19%, respectively. CONCLUSIONS: Children aged <3 years with DPG potentially may fare better than older patients with the same diagnosis despite the use of similar therapy. The current results suggested that DPG in younger children may be distinct biologically from similar tumors in older age groups.     

Racial differences in the survival of childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group Study.

PURPOSE: We conducted a historic cohort study to test the hypothesis that, after adjustment for biologic factors, African-American (AA) children and Spanish surname (SS) children with newly diagnosed B-precursor acute lymphoblastic leukemia had lower survival than did comparable white children. PATIENTS AND METHODS: From 1981 to 1994, 4,061 white, 518 AA, and 507 SS children aged 1 to 20 years were treated on three successive Pediatric Oncology Group multicenter randomized clinical trials. RESULTS: AA and SS patients were more likely to have adverse prognostic features at diagnosis and lower survival than were white patients. The 5-year cumulative survival rates were (probability +/- SE) 81.9% +/- 0.6%, 68.6% +/- 2.1%, and 74.9% +/- 2.0% for white, AA, and SS children, respectively. Adjusting for age, leukocyte count, sex, era of treatment, and leukemia blast cell ploidy, we found that AA children had a 42% excess mortality rate compared with white children (proportional hazards ratio [PHR] = 1.42; 95% confidence interval [CI], 1.12 to 1. 80), and SS children had a 33% excess mortality rate compared with white children (PHR = 1.33; 95% CI, 1.19 to 1.49). CONCLUSION: Clinical presentation, tumor biology, and deviations from prescribed therapy did not explain the differences in survival and event-free survival that we observed, although differences seem to be diminishing over time with improvements in therapy. The disparity in outcome for AA and SS children is most likely related to variations in chemotherapeutic response to therapy and not to compliance. Further improvements in outcome may require individualized dosing based on specific pharmacogenetic profiles, especially for AA and SS children.     

Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a children's cancer group study.

PURPOSE: To determine prospectively whether surgery alone is sufficient therapy for Evans stages I and II neuroblastoma and to define biologic and clinical features having prognostic potential for this group. PATIENTS AND METHODS: Between June 1989 and August 1995, 374 eligible children (age range, 0 to 18 years) with newly diagnosed stage I (n = 141) and stage II (n = 233) neuroblastoma were registered onto Children's Cancer Group trial 3881. Surgical resection was the only primary therapy except in cases with spinal cord compression, where radiation therapy was allowed. Event-free survival (EFS) and overall survival (OS) were analyzed by life-table methods according to clinical and biologic features. RESULTS: EFS and OS (mean +/- SE) for all stage I patients were 93% +/- 3.0% and 99% +/- 1.0%, respectively, compared with 81% +/- 4.0% and 98% +/- 2. 0%, respectively, for stage II patients. The significantly higher recurrence rate among stage II patients was managed successfully in 38 of 43 children with either surgery or multimodality treatment. There was one death among stage I patients and six among stage II. For stage II patients tumor MYCN gene amplication, unfavorable histopathology, an age greater than 2 years, and positive lymph nodes predicted a lower OS (P <.05). CONCLUSION: Children with stages I and II neuroblastoma have 98% survival with surgery alone as primary therapy. Supplemental treatment was necessary in only 10% of stage I patients and 20% of stage II patients. In children with localized neuroblastoma, a subset of patients that are at higher risk for death can be defined as those with stage II disease who have tumor MYCN amplification or who are >/= 2 years of age with either unfavorable histopathology or positive lymph nodes.     

Localized childhood Hodgkin's disease: response-adapted chemotherapy with etoposide, bleomycin, vinblastine, and prednisone before low-dose radiation therapy-results of the French Society of Pediatric Oncology Study MDH90.

PURPOSE: The French Society of Pediatric Oncology MDH82 study demonstrated the effectiveness of 20 Gy irradiation of involved fields after doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or mechlorethamine, vincristine, procarbazine, and prednisone/ABVD chemotherapy in children with localized Hodgkin's disease (HD). The response to primary chemotherapy was the only predictor of survival. To reduce long-term treatment complications without compromising efficacy, the MDH90 study was based on a new chemotherapy regimen devoid of both alkylating agents and anthracycline, followed by 20 Gy of radiotherapy (RT) for good responders. PATIENTS AND METHODS: From January 1990 to July 1996, 202 children were enrolled from 30 institutions. Good responders to four cycles of vinblastine, bleomycin, etoposide (VP16), and prednisone (VBVP) were given 20 Gy of RT and no further therapy. Poor responders were given vincristine, procarbazine, prednisone, and doxorubicin. After a second evaluation, good responders were given 20 Gy of RT, and poor responders were given 40 Gy of RT. RESULTS: One hundred seventy-one patients (85%) were good responders to VBVP, 27 (15%) were poor responders, and four did not respond. With a median follow-up of 74 months (range, 25 to 117 months), the 5-year overall survival rate (mean +/- SD) is 97.5% +/- 2.1%, and the event-free survival rate (mean +/- SD) is 91.1% +/- 1.8%. Significant predictors of worse event-free survival in multivariate analysis were hemoglobin < 10.5 g/L, "b" biologic class, and nodular sclerosis. CONCLUSION: These results suggest that most children with clinical stage I and II HD can be treated with chemotherapy devoid of alkylating agents and anthracycline, followed by low-dose RT.     

Primary rectal carcinoma in patients with stage IV resectable disease at diagnosis

BACKGROUND: Rectal cancer is commonly diagnosed at a precocious stage, but for patients presenting at diagnosis with stage IV disease the best treatment is still undefined. The purpose of this study was to review the feasibility and outcome of multimodality treatment of rectal cancer patients metastatic at diagnosis. PATIENTS AND METHODS: From January 2000 to December 2005, 40 patients with histologically proven stage IV rectal adenocarcinoma (< 12 cm from the anal verge) were examined. Variables considered were age (under or over 65 years), tumour grade, presence of peritoneal carcinomatosis, type of surgery (palliative versus resection). RESULTS: The median age was 61 years (range, 32-83) and 27 were male and 13 female. Seventeen patients with unresectable or potentially resectable metastatic disease received neoadjuvant chemoradiotherapy (CHT-RT) with 5-fluorouracil (5FU) (plus oxaliplatin in 11 cases), radical surgery was performed in almost half of the cases; only in two patients were metastases also resected. If the patient is a candidate for radical surgical resection, the primary tumour should initially be treated as in a patient without metastatic disease and subsequently the primary tumour and metastases should be treated surgically. If the metastases are unresectable, the treatment of the primary lesion, according to the patient's symptoms, should be by palliative CHT. It is still not determined whether RT should be reserved for the symptomatic cases as an alternative to local surgery. In five patients treated with neoadjuvant CHT alone, radical local surgery was performed in two cases. Eighteen symptomatic patients were resected primarily; all of them received a postoperative CHT but only five of them also received postoperative RT. Nevertheless, after a multimodality treatment (neoadjuvant CHT +/- RT) 22.5% achieved a response rate (RR) (one complete remission (CR) and eight partial remission (PR)). Considering that all except two of the patients were locally radically resected and two of them also underwent metastases surgery, the overall RR was 17.5% (four CR and three PR). All of the CR were disease-free and alive after a median follow-up of 19.3 months. Age > or = 65 years had no impact on overall survival (OS), but the presence of peritoneal carcinosis in five patients showed a trend towards diminished survival, although it was not statistically significant (p = 0.08). CONCLUSION: The best treatment on diagnosis of metastatic rectal cancer is a multimodality CHT-RT approach. New prospective studies should evaluate non cross-resistant regimens as additional therapy for those patients with a systemic residual disease after common CHT-RT.     

Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group.

PURPOSE: To evaluate response rate, event-free survival (EFS), and toxicity of two chemotherapeutic regimens for treatment of children younger than 36 months with malignant brain tumors and to estimate control intervals without irradiation in children with no residual tumor after initial surgery and induction chemotherapy and with delayed irradiation in patients with residual tumor or metastatic disease at diagnosis. PATIENTS AND METHODS: Patients were randomly assigned to one of two regimens of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide v vincristine, carboplatin, ifosfamide, and etoposide). Maintenance chemotherapy began after induction in children without progressive disease. Children with no residual tumors after induction therapy and no metastatic disease at diagnosis were not to receive radiation therapy unless their tumors progressed. RESULTS: Two hundred ninety-nine infants were enrolled. Forty-two percent of patients responded to induction chemotherapy. At 5 years from study entry, the EFS rate was 27% +/- 3%, and the survival rate was 43% +/- 3%. There was no significant difference between the two arms in terms of response rate or EFS. For medulloblastoma, supratentorial primitive neuroectodermal tumor, ependymoma, and rhabdoid tumors, 5-year EFS rates were 32% +/- 5%, 17% +/- 6%, and 32% +/- 6%, and 14% +/- 7%, respectively. Fifty-eight percent of patients who were alive 5 years after study entry had not received radiation therapy. CONCLUSION: Intensified induction chemotherapy resulted in a high response rate of malignant brain tumors in infants. Survival was comparable to that of previous studies, and most patients who survived did not receive radiation therapy.     

Efficacy of irradiation and external hyperthermia in locally advanced, hormone-refractory or radiation recurrent prostate cancer: a preliminary report

PURPOSE: To present a preliminary report on the feasibility, efficacy, and toxicity of irradiation (RT) and hyperthermia (HT) in patients with locally advanced, hormone-refractory prostate cancer (LAHRPC) who may or may not have received prior RT. METHODS AND MATERIALS: Between 1997 and 2002, 13 consecutive patients with LAHRPC or RT-recurrent prostate cancer were treated with RT and HT on a Phase I-II protocol. Eight patients had RT-recurrent LAHRPC (Group A) and 5 had LAHRPC without prior RT (Group B). All patients had large and clinically symptomatic tumors. The median RT dose was 39.6 Gy and 66.6 Gy in Groups A and B, respectively. External deep HT was delivered using a BSD-2000 Sigma-60 applicator. The median number of HT treatments was 8 in group A and 10 in group B. RESULTS: The median follow-up was 14 and 13 months for Groups A and B, respectively. All patients achieved a complete or partial response (CR/PR) and complete palliation of symptoms. Eleven patients had follow-up CT scans that demonstrated a CR in six and a PR in five. Two patients, who died of metastasis, did not have CT scans and had a PR on digital rectal examination. Two patients demonstrated a biochemical CR. The median duration of the CR/PR among Group A patients was 12 months after therapy. Three patients in Group A developed tumor recurrence at 9, 17, and 27 months after repeat RT to doses of 39.6, 36, and 50 Gy, respectively. At last follow-up, no Group B patient developed local recurrence. Grade 1-2 rectal bleeding was noted in 3 patients. RT and HT were generally well tolerated by all patients who had not previously undergone RT. Of the 8 patients who had, 6 (75%) tolerated retreatment well with minimal or no complications. Two patients in the repeat RT group had severe complications. One patient with lymphoma and factor XI deficiency developed Grade 4 hemorrhagic cystitis. Another previously irradiated patient developed a rectovesical fistula 4 months after retreatment, after disappearance of a large, invasive, and necrotic tumor. CONCLUSION: This preliminary report demonstrates the feasibility and efficacy of RT and HT in patients with LAHRPC, who may or may not have received prior RT. Presently, such patients who have undergone previous RT have no effective treatment options. RT and HT were generally well tolerated by patients who were not previously undergone RT. Of those who had been, most (6 of 8) tolerated retreatment well with minimal or no complications. The high-risk factors for treatment- and tumor regression-related side effects include the presence of large necrotic tumors, previous RT with a large dose/fraction, and the presence of bleeding disorders. Despite the size of these large tumors, RT and HT resulted in significant tumor shrinkage, rapid serum prostate-specific antigen decline, durable treatment responses, and durable palliation of symptoms. Additional clinical studies are warranted.     

Analysis of carina position as surrogate marker for delivering phase-gated radiotherapy

PURPOSE: Respiratory gating can mitigate the effect of tumor mobility in radiotherapy (RT) for lung cancer. Because the tumor is generally not visualized, external surrogates of tumor position are used to trigger respiration-gated RT. We evaluated the suitability of the carina position as a surrogate in respiration-gated RT. METHODS AND MATERIALS: A total of 30 four-dimensional (4D) computed tomography (CT) scans from 14 patients with lung cancer were retrospectively analyzed. Both uncoached (free breathing) and audio-coached 4D-CT scans were acquired from 9 patients, and 12 uncoached 4D-CT scans were acquired from 5 other patients during a 2-4-week period of stereotactic RT. The repeat scans were co-registered. The carina position was identified on the coronal cut planes in all 4D-CT phases. The correlation between the carina position and the total lung volume for each phase was determined, and the reproducibility of the carina position was studied in the 5 patients with repeat uncoached 4D-CT scans. RESULTS: The mean extent of carina motion in 21 uncoached scans was 5.3 +/- 1.6 mm in the craniocaudal (CC), 2.3 +/- 1.4 mm in the anteroposterior, and 1.5 +/- 0.7 mm in the mediolateral direction. Audio coaching resulted in a twofold increase in carina mobility in all directions. The CC carina position correlated with changes in the total lung volume (R = 0.89 +/- 0.14), but the correlation was better for the audio-coached than for the uncoached 4D-CT scans (R = 0.93 +/- 0.08 vs. R = 0.85 +/- 0.17; paired t test, p = 0.034). Preliminary data from the 5 patients indicated that the CC carina motion correlated better with tumor motion than did the motion of the diaphragm. CONCLUSIONS: The CC position of the carina correlated well with the total lung volume, indicating that the carina is a good surrogate for verifying the total lung volume during respiration-gated RT.     

Phase II study of high-dose chemotherapy before radiation in children with newly diagnosed high-grade astrocytoma: final analysis of Children's Cancer Group Study 9933

BACKGROUND: High-grade astrocytomas (HGA) carry a dismal prognosis and compose nearly 20% of all childhood brain tumors. The role of high-dose chemotherapy (HDCT) in the treatment of HGA remains unclear. METHODS: In a nationwide study, The Children's Cancer Group (CCG) prospectively evaluated 102 children with HGA and postoperative residual disease for efficacy and toxicity of four courses of HDCT before radiotherapy (RT). Patients were randomly assigned to one of three couplets of drugs: carboplatin/etoposide (Regimen A), ifosfamide/etoposide (Regimen B), or cyclophosphamide/etoposide (Regimen C). After HDCT, all patients were to receive local RT followed by lomustine and vincristine. Twenty-six patients were excluded after central neuroradiographic review (n = 8) or pathology review (n = 18). RESULTS: Of 76 evaluable patients (median age, 11.95 yrs; range, 3-20 yrs), 30 patients relapsed during HDCT, and 11 others did not complete HDCT because of toxicity. Nonhematologic serious toxicities were common (29%), and 21% of patients did not receive RT. Objective response rates were not associated with amount of residual disease and did not statistically differ between regimens: 27% (Regimen A), 8% (Regimen B), and 29% (Regimen C). Overall survival (OS) was 24% +/- 5% at 5 years and did not differ between groups. Median time to an event was longest for Regimen A (283 days compared with 83 and 91 days for Regimens B and C, respectively). The five-year, event-free survival (EFS) rate for all patients was 8% +/- 3% and 14% +/- 7% for Regimen A (P = 0.07). CONCLUSIONS: OS and EFS were not affected by histologic grade. Patients who responded to HDCT had a nominally higher survival rate (P = 0.03 for trend). The authors conclude that these commonly used HDCT regimens provide no additional clinical benefit to conventional treatment in HGA, regardless of the amount of measurable residual tumor.     

Scintigraphic response by 123I-metaiodobenzylguanidine scan correlates with event-free survival in high-risk neuroblastoma.

PURPOSE: To investigate whether response to induction therapy, evaluated by metaiodobenzylguanadine (MIBG) and bone scintigraphy, correlates with event-free survival (EFS) in children with high-risk neuroblastoma (NB). PATIENTS AND METHODS: Twenty-nine high-risk NB patients were treated prospectively with an intensive induction regimen and consolidated with three cycles of high-dose therapy with peripheral blood stem-cell rescue. The scintigraphic response was evaluated by MIBG and bone scans using a semi-quantitative scoring system. The prognostic significance of the imaging scores at diagnosis and following induction therapy was evaluated. RESULTS: A trend associating worse 4-year EFS rates for patients with versus without osteomedullary uptake on MIBG scintigraphs at diagnosis was seen (35% +/- 11% v 80% +/- 18%, respectively; P =.13). Similarly, patients with positive bone scans at diagnosis had worse EFS than those with negative scans, although the difference did not receive statistical significance (34% +/- 10% v 83% +/- 15%, respectively; P =.06). However, significantly worse EFS was observed in patients with a postinduction MIBG score of >/= 3 compared to those with scores of less than 3 (0% v 58% +/- 11%; P =.002). There was no correlation between bone scan scores and outcome following induction therapy. CONCLUSION: MIBG scores >/= 3 following induction therapy identifies a subset of NB patients who are likely to relapse following three cycles of high-dose therapy with peripheral blood stem-cell rescue, local radiotherapy, and 13-cis-retinoic acid. Alternative therapeutic strategies should be considered for patients with a poor response to induction therapy.     

Influence of tumor grade on time to progression after irradiation for localized ependymoma in children

PURPOSE: To investigate the influence of histologic grade on progression-free survival (PFS) after irradiation (RT) for pediatric patients with localized ependymoma. METHODS AND MATERIALS: Fifty patients with localized ependymoma (median age 3.6 years, range 1-18 years at the time of RT) were treated with RT between December 1982 and June 1999. Anaplastic features were identified in 14 of 50 patients. The extent of resection was characterized as gross-total in 36 patients, near-total in 5, and subtotal in 9. The median dose to the primary site was 54 Gy. Of the 50 patients, 23 received pre-RT chemotherapy. RESULTS: Thirty-nine patients were alive at a median follow-up of 46 months (range 21-214) from diagnosis. Thirty-four patients remained progression free at a median follow-up of 35 months (range 13-183) after the initiation of RT. Progression occurred in 16 patients (12 local and 4 local and distant), with a median time to failure of 21.2 months (range 4.6-65.0). The tumor grade significantly influenced the PFS after RT (p < 0.0005). The estimated 3-year PFS rate was 28% +/- 14% for patients with anaplastic ependymoma compared with 84% +/- 8% for patients with differentiated ependymoma. These results remained significant when corrected for age at diagnosis (<3 years), pre-RT chemotherapy, and extent of resection. Patients who received pre-RT chemotherapy had an inferior 3-year PFS estimate after RT (49 +/- 12%) compared with those who did not (84% +/- 10%; p = 0.056). Anaplastic ependymoma was found more frequently in the supratentorial brain (p = 0.002). Six of 12 patients with supratentorial tumor developed recurrence; recurrence was restricted to patients with anaplastic ependymoma. CONCLUSION: Tumor grade influences outcome for patients with ependymoma independent of other factors and should be considered in the design and analysis of prospective trials involving pediatric patients treated with RT. Chemotherapy before RT influences the PFS and overall survival after RT. The effect is more pronounced when progression occurs during chemotherapy.     

Second malignancy after treatment of childhood non-Hodgkin lymphoma.

BACKGROUND: The objective of this report was to determine the cumulative incidence of and risk factors for second malignancy and the competing risk of death due to any other cause among patients who were treated for childhood non-Hodgkin lymphoma (NHL). METHODS: The authors retrospectively reviewed a cohort of 497 patients with NHL who were treated at St. Jude Children's Research Hospital between 1970 and 1997. RESULTS: A second malignancy developed in 16 patients (9 patients with solid tumors and 7 patients with secondary acute myeloid leukemia [AML]). This number was 10.8-fold (95% confidence interval, 6.1-16.9) higher than the 1.48 patients projected for the general population by SEER Cancer Statistics. The estimated cumulative incidence rate of second malignancy was 2.1% +/- 0.7% at 10 years after diagnosis of NHL and increased to 4.8% +/- 1.3% at 20 years after diagnosis. The cumulative incidence rate of second malignancy was least among patients with small noncleaved cell lymphoma (0.5% +/- 0.5% at 20 years), higher among patients with large cell lymphoma (5.8% +/- 3.3% at 20 years), and highest among patients with lymphoblastic lymphoma (10.9% +/- 3.6% at 20 years; P = 0.002 for overall comparison). Exposure to epipodophyllotoxins was a risk factor for the development of secondary AML (P < 0.001). The cumulative incidence rate of death due to other causes was significantly less for patients who were treated after June 1978 (19.9% +/- 2.2% at 10 years) compared with patients who were treated earlier (55.6% +/- 4.2% at 10 years; P < 0.001), whereas the risk of second malignancy was similar for these two eras. CONCLUSIONS: Survivors of childhood NHL, especially those with lymphoblastic histology, are at a greater risk of developing a second malignancy compared with the general population. The incidence rate of second malignancy has remained unchanged despite a recent decline in the risk of death related to primary NHL or earlier treatment complications.     

Asymptomatic dermatophyte scalp carriage in school children in Adana, Turkey

The aim of this study was to determine the prevalence of asymptomatic dermatophyte scalp carriage and symptomatic tinea capitis in Adana Province, Cukurova region, Turkey. For this purpose, a screening study was performed in five schools, between January 2004 and May 2005, covering a total of 5143 children with 2740 (53.3%) boys and 2403 (46.7%) girls, aged 7-14 years (9.6 +/- 2.0). The diagnosis was made using the cotton swab method with inoculation onto Sabouraud glucose agar amended with cycloheximide, chloramphenicol and gentamicin. Among 10 (0.2%) cases, six asymptomatic carriers (mean age 10.7 +/- 2.3) and four symptomatic cases (mean age 8.3 +/- 0.5) were detected, all of whom were boys and had immigrated from the south-eastern and eastern region of Anatolia, Turkey. The mean age differences were found to be statistically significant (Mann-Whitney U=3.000, P=0.046). Boys were found to be more prone to asymptomatic carriage (P=0.033), but not tinea capitis (P>0.05). Zoophilic dermatophytes, namely Microsporum canis (40%) and Trichophyton mentagrophytes var. mentagrophytes (40%) were the most commonly isolated species, followed by anthropophilic Trichophyton tonsurans (10%), while no causative agent was detected in a case (10%) with tinea capitis superficialis. Scalp cultures were found to be dermatophyte-negative after 3- to 8-month follow-up in cases with asymptomatic carriage. As a conclusion, the prevalence of asymptomatic carrier state was similar with the prevalence of symptomatic cases, and we found a predominance of zoophilic species.