High-dose Chemotherapy With Autologous Stem Cell Rescue for Children With Recurrent Malignant Brain Tumors

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1 1345 High-dose Chemotherapy With Autologous Stem Cell Rescue for Children With Recurrent Malignant Brain Tumors Chie-Schin Shih, MD 1 Gregory A. Hale, MD 2 Lindsey Gronewold, MSc 1 Xin Tong, MPH 1,3 Fred H. Laningham, MD 4 Elizabeth A. Gilger, RN, PNP 1 Deo Kumar Srivastava, PhD 1,3 Larry E. Kun, MD 4 Amar Gajjar, MD 1 Maryam Fouladi, MD 1 1 Department of Oncology, St. Jude Children s Research Hospital, Memphis, Tennessee. 2 Division of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children s Research Hospital, Memphis, Tennessee. 3 Department of Biostatistics, St. Jude Children s Research Hospital, Memphis, Tennessee. 4 Division of Radiation Oncology, Department of Radiological Sciences, St. Jude Children s Research Hospital, Memphis, Tennessee. Maryam Fouladi s current address: Division of Hematology/Oncology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio. Supported in part by the National Cancer Institute (Grant CA 21765), Musicians Against Childhood Cancer (MACC), The Noyes Brain Tumor Foundation, and the American Lebanese Syrian Associated Charities (ALSAC). We thank Dr. Richard Heideman for contributions to the care of patients and the conduct of clinical trials, Chenghong Li for biostatistical assistance, David Galloway for editorial assistance, and Patsy Burnside for assistance with figures and tables. Address for reprints: Maryam Fouladi, MD, Division of Hematology/Oncology, Cincinnati Children s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229; Fax: (513) ; maryam.fouladi@cchmc.org Received August 13, 2007; accepted September 26, BACKGROUND. High-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) has been reported to be effective in treating children with recurrent central nervous system (CNS) malignancies. METHODS. To evaluate the efficacy and toxicities of HDCT and ASCR, the medical records of 27 children with recurrent CNS malignancies who received such therapy at St. Jude Children s Research Hospital between 1989 and 2004 were reviewed. RESULTS. The median age at diagnosis was 4.5 years (range, years) and that at ASCR was 6.7 years (range, years). Diagnoses included medulloblastoma (13 patients), primitive neuroectodermal tumor (3 patients), pineoblastoma (2 patients), atypical teratoid rhabdoid tumor (2 patients), ependymoma (3 patients), anaplastic astrocytoma (2 patients), and glioblastoma multiforme (2 patients). The 5-year overall and progression-free survival (PFS) rates were 28.2% and 18.5%, respectively. The 5-year PFS rate for patients aged <3 years at diagnosis (57.1%) was significantly better than older patients (5.0%) (P 5.019). Among the 6 long-term survivors (5 with M0 disease and 1 with M3 disease at diagnosis), 5 received both radiotherapy and HDCT as part of their salvage regimen; 4 were aged <3 years at diagnosis and had received chemotherapy only as part of frontline therapy. Two patients died of transplant-related toxicities; 44% experienced grade 3 or 4 transplant-related toxicities (toxicities were graded according to the National Cancer Institute Common Toxicity Criteria). CONCLUSIONS. HDCT with ASCR is not an effective salvage strategy for older children with recurrent CNS malignancies. The significantly better outcome in the younger cohort was most likely related to the use of radiotherapy as part of the salvage strategy. Cancer 2008;112: Ó 2008 American Cancer Society. KEYWORDS: high-dose chemotherapy, recurrent, central nervous system neoplasms, salvage therapy, autologous stem cell transplantation. The outcome for patients with recurrent central nervous system (CNS) malignancies after radiotherapy remains dismal, with a median survival after disease progression of only 5 to 20 months. 1,2 Long-term neurocognitive and neuroendocrine sequelae associated with neuraxis radiotherapy 3 6 and ototoxicity 7 9 from platinum therapy also remain major concerns. Thus, achieving cure with minimal long-term morbidity for all children with CNS malignancies remains a major goal of pediatric neuro-oncology. High-dose chemotherapy (HDCT) followed by autologous stem cell rescue (ASCR) has been used as frontline as well as salvage therapy in children with a variety of CNS malignancies, based on the ability of this strategy to allow better penetration of the blood- ª 2008 American Cancer Society DOI /cncr Published online 25 January 2008 in Wiley InterScience (

2 1346 CANCER March 15, 2008 / Volume 112 / Number 6 brain barrier and to increase the dose-response effect for drugs such as cyclophosphamide, carboplatin, and melphalan. 15 Early attempts with escalation of nitrosourea-containing regimens resulted in unacceptable neurologic and pulmonary toxicities and little improvement in survival or response rates Subsequent trials have used cyclophosphamide, melphalan, thiotepa, and carboplatin, often combined with etoposide. The strategy of using HDCT followed by ASCR has proven to be feasible and led to improved survival in patients with newly diagnosed, high-risk medulloblastoma, 11 ATRT, 12 pineoblastoma, 13 and in children aged <3 years with newly diagnosed embryonal tumors. 10,14 There is also some evidence that HDCT used in conjunction with radiotherapy may be an effective salvage regimen in younger children with recurrent embryonal tumors. 20,21 The data in the literature regarding the benefits of HDCT for older patients with recurrent CNS malignancies are conflicting, 19,21 27 making the role of HDCT difficult to interpret, especially in light of the high morbidity and mortality associated with this strategy. 19,21 23,28 In the current study, we report our institutional experience using HDCT and ASCR for the treatment of children with recurrent or refractory CNS malignancies. MATERIALS AND METHODS Patient Population Patients were considered for ASCR if they had tumors that were refractory or had recurred after primary therapy. Patients included in the study had recurrent or refractory medulloblastoma, primitive neuroectodermal tumor (PNET), atypical teratoid rhabdoid tumor (ATRT), ependymoma, pineoblastoma, anaplastic astrocytoma, or glioblastoma multiforme. Patients were eligible for treatment regimens if they had Karnofsky or Lansky scores 50 and did not have evidence of organ dysfunction. Patients had to have adequate bone marrow function, defined as a peripheral absolute neutrophil count (ANC) 1000/mL, platelet counts 100,000/mL (transfusion-independent), and hemoglobin 8.0 g/dl; adequate renal function (serum creatinine normal for age or a glomerular filtration rate 70 ml/min/1.73 m 2 ); adequate liver function (total bilirubin the institutional upper limit of normal for age and alanine aminotransferse and aspartate aminotransferase levels the institutional upper limit of normal for age); adequate cardiac function (shortening fraction of 27% by echocardiogram or a left ventricular ejection fraction of 50% by gated radionucleotide study); and adequate pulmonary function, defined as no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry >94% if there were clinical indication for determination. All patients and/or their parents provided informed consent. All treatment protocols were approved by the St. Jude Institutional Review Board. Data Collection Medical records were retrospectively reviewed for patient data, including patient age at diagnosis; sex; initial diagnosis; HDCT regimen; extent of disease at diagnosis and at the time of ASCR; extent of surgery at all resections; salvage therapy after recurrence or refractory status; chemotherapeutic regimen at ASCR; dose, volume, and timing of radiotherapy; disease status before ASCR; all chemotherapeutic regimens before and after ASCR; toxicity of ASCR regimen; and engraftment of neutrophils and platelets after ASCR. Evaluations Before ASCR and During Therapy Institutional guidelines for evaluations before ASCR were followed. Pretreatment evaluations included a history; physical examination; determination of performance status; echocardiogram; pulmonary function test or pulse oximetry (if too young for a pulmonary function test); complete blood count (CBC); serum electrolytes; renal and liver function tests; serum protein and albumin; prothrombin time; international normalized ratio; partial thromboplastin time; fibrinogen; 24-hour urine creatinine clearance (or technetium-99 measurement); and serologic studies including human immunodeficiency virus, hepatitis B virus, hepatitis C virus, rapid plasma reagent, and cytomegalovirus. CBCs were obtained daily during and after ASCR until neutrophil engraftment. Physical examinations and laboratory studies were obtained weekly until bone marrow recovery was noted. Neuroimaging consisting of magnetic resonance imaging of the brain and spine and clinical assessments were performed before ASCR, approximately 1 month after ASCR, and every 3 months for the first 2 years, every 6 months until 5 years after diagnosis, and then annually thereafter or when symptoms suggested progressive or recurrent disease. Patients with embryonal tumors and ependymomas also had cerebral spinal fluid (CSF) cytology assessment at the time of neuroimaging. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria. All neuroimaging of patients obtained immediately before HDCT and ASCR was retrospectively reviewed by a neuroradiologist (F.L.) to assess extent of disease.

3 High-dose Chemotherapy for Recurrent CNS Tumors/Shih et al Treatment Regimens Institutional guidelines for minimum stem cell collection guidelines were followed, including total nucleated cells (TNC)/kg for bone marrow collection and CD34 1 TNC cells/kg for peripheral blood stem cell (PBSC) collection. Bone marrow was collected and cryopreserved in dimethylsulfoxide in the standard fashion without purging. The HDCT regimens varied during the time period of the study. Nine patients received carboplatin (2100 mg/m 2 ) plus etoposide (1500 mg/m 2 ), 6 patients received cyclophosphamide (6 g/m 2 ) plus thiotepa (900 mg/m 2 ), 4 patients received cyclophosphamide (3 g/m 2 ) plus topotecan (pharmcokinetically adjusted to ng-hr/m 2 per day for 10 days), 3 patients received cyclophosphamide (6 g/m 2 ) plus melphalan (180 mg/m 2 ), 3 patients received busulfan (16 mg/kg) plus thiotepa (900 mg/m 2 ), and 2 patients received busulfan (16 mg/kg) plus melphalan (180 mg/m 2 ). Granulocyte colony-stimulating factor was administered after stem cell infusion until neutrophil engraftment, defined as the first of 3 consecutive days of an ANC 500/mm 3. Pneumocystis prophylaxis with cotrimoxazole was initiated at the time of neutrophil engraftment. No other prophylaxis was administered for bacterial, viral, or fungal pathogens. No veno-occlusive disease prophylaxis was administered. Seventeen patients received bone marrow grafts containing a median of TNC/kg (range, TNC/kg), and 4 patients received PBSC products containing a median of CD 341 /kg (range, CD 341 /kg). Statistical Analysis Overall survival (OS) was measured from the date of ASCR to the date of death or last contact. Progression-free survival (PFS) was measured from the date of ASCR to the date of disease progression or death from any cause. The date of the first event was used in calculating PFS. Distributions of PFS and OS were estimated using the method of Kaplan and Meier. Differences in OS and PFS distributions based on patient age at diagnosis were assessed by exact logrank tests. The criterion for significance for all analyses was P.05. All statistical analyses were performed with SAS Release 9.1 software (Cary, NC). RESULTS From March 1989 to May 2004, 27 children (17 boys and 10 girls), with recurrent or refractory malignant CNS tumors were treated with HDCT regimens requiring ASCR at St. Jude Children s Research Hospital. The median age at diagnosis was 4.5 years (range, years) and the median age at ASCR was 6.7 years (range, years). Diagnoses included medulloblastoma (13 patients), PNET (3 patients), pineoblastoma (2 patients), ATRT (2 patients), ependymoma (3 patients), anaplastic astrocytoma (2 patients), and glioblastoma multiforme (2 patients). Seven patients were aged 3 years at diagnosis (6 of whom were aged 3 years at the time of ASCR), and 20 were aged >3 years at diagnosis. The median follow-up was 325 days (range, days). Table 1 summarizes the clinical characteristics, therapy, and outcome for all 27 patients. Disease Status Before ASCR Whenever possible, there was an attempt to decrease tumor burden by surgical resection or further chemotherapy before HDCT and ASCR. Before ASCR, 9 patients had bulky disease (defined as residual tumor >2 cm 3 ), 4 had a residual nodule with or without a positive CSF result for tumor cells, 5 had only CSF evidence of tumor, and 9 had no evidence of disease. Among those with measurable disease, the tumor ranged in size from 0.5 cm cm cm 3 to 7 cm 3 4cm3 4cm 3. Response to Therapy and Patient Outcome Two patients had a partial response to HDCT. One patient was a 4-year-old with medulloblastoma who had received craniospinal irradiation (CSI) only as primary therapy and went on to receive high-dose carboplatin and etoposide followed by ASCR. The other patient was a 7-year-old with anaplastic astrocytoma who was treated with CSI as primary therapy at another institution and at the time of disease recurrence went on to receive HDCT and local radiotherapy. Both patients experienced disease progression 175 days and 259 days, respectively, after ASCR and ultimately died of their disease. Twenty-two patients (81%) experienced disease recurrence at a median of 127 days after HDCT (range, days); all but 1 patient among this group died of their disease. One patient was alive at the time of last follow-up with progressive disease. The 5-year OS and PFS rates for all patients were 28.2% 9.8% (Fig. 1) and 18.5% 8.4%, respectively (Fig. 1) (Table 2). The 5-year PFS rate for children aged <3 years at the time of diagnosis was 57.1% 21.6%. In contrast, children aged 3 years had a PFS rate of 5.0% 3.4% (P 5.019) (Table 2) (Fig. 2). In patients with embryonal tumors (medulloblastoma, pineoblastoma, PNET, and ATRT), the PFS rate for children aged <3 years at the time of diagnosis was

4 1348 CANCER March 15, 2008 / Volume 112 / Number 6 TABLE 1 Clinical Characteristics, Treatment, and Outcome for 27 Patients With Recurrent or Refractory Malignant CNS Tumors Age, years Dx Rx at initial Dx Recurrence Rx pre-hdct Status before HDCT Salvage therapy* HDCT Response to HDCT TTP, days Final status Survival, days 0.4 EPD Chemotherapy Nodule HDCT Bu/Thiotepa PD 29 DOD ATRT Chemotherapy Nodule, CSF1 HDCT Cyclo/Topo PD 39 DOD ATRT Chemotherapy NED local RT1HDCT Cyclo/Topo NED NED NED Pineb Chemotherapy CSF1 CSI1HDCT Thiotepa/Cyclo NED 156 DOD PNET Chemotherapy NED HDCT1CSI Bu/Thiotepa NED NED NED MB Chemotherapy Nodule CSI1HDCT Cyclo/Topo SD NED NED MB Chemotherapy Chemotherapy Bulky HDCT1CSI Bu/Mel NED NED NED PNET Chemotherapy 1 CSI Nodule HDCT Thiotepa/Cyclo PD 265 DOD MB Chemotherapy 1 CSI Chemotherapy 33 Bulky HDCT Cyclo/Mel PD 27 DOD EPD Local RT 1 chemotherapy Bulky HDCT Thiotepa/Cyclo PD 29 DOD MB Chemotherapy 1 local RT Chemotherapy 32 NED HDCT Cyclo/Mel NED 148 DOD MB CSI 1 chemotherapy NED HDCT Thiotepa/Cyclo NED NA DOD MB CSI None Bulky HDCT Carbo/etoposide PR 175 DOD AA Chemotherapy 1 local RT NED HDCT Thiotepa/Cyclo PD 44 DOD AA CSI Bulky HDCT 1 local RT Thiotepa/Cyclo PR 259 DOD MB CSI Chemotherapy Bulky HDCT Carbo/etoposide PD 15 Died of toxicity MB CSI 1 chemotherapy Chemotherapy 32 Bulky CSI1HDC Carbo/etoposide NA 435 DOD MB CSI 1 HDCT NED HDCT 1 local RT Cyclo/Topo NED 1065 NED MB CSI 1 chemotherapy Chemotherapy 32 NED HDCT Carbo/etoposide NED 214 DOD GBM Chemotherapy 1 CSI Chemotherapy Bulky HDCT Carbo/etoposide PD 29 DOD MB CSI 1 chemotherapy Chemotherapy NED HDCT Cyclo/Mel SD 187 DOD Pineb CSI 1 HDCT Chemotherapy CSF 1 HDCT Bu/Thiotepa SD 43 NED MB CSI 1 chemotherapy Chemotherapy Bulky HDCT Carbo/etoposide PD 104 DOD PNET CSI 1 chemotherapy Chemotherapy CSF1 HDCT Bu/Thiotepa NED 127 DOD EPD Local RT Chemotherapy NED HDCT Carbo/etoposide PD 43 Died of toxicity MB CSI 1 chemotherapy None CSF1 HDCT Cyclo/IT MTX SD 316 DOD GBM CSI NED HDCT Thiotepa/Cyclo PD 126 DOD 3104 CNS indicates central nervous system; Dx, diagnosis; Rx, treatment; HDCT, high-dose chemotherapy; TTP, time to disease progression; EPD, ependymoma; Bu, busulfan; PD, progressive disease; DOD, died of disease; ATRT, atypical teratoid rhabdoid tumor; CSF, cerebrospinal fluid; 1, positive; Cyclo, cyclophosphamide; Topo, topotecan; NED, no evidence of disease; Pineb, pineoblastoma; CSI, craniospinal irradiation; PNET, primitive neuroectodermal tumor; MB, medulloblastoma; SD, stable disease; Bulky, bulky disease; Mel, melphalan; RT, radiotherapy; NA, not available; Carbo, carboplatin; PR, partial response; AA, anaplastic astrocytoma; GBM, glioblastoma multiforme; IT MTX, intrathecal methotrexate. * Sequence of RT and HDCT is as shown.

5 High-dose Chemotherapy for Recurrent CNS Tumors/Shih et al Among the 20 patients aged 3 years, all patients received radiotherapy as part of their frontline therapy (Table 1). Only 3 patients received radiotherapy (local in 2 patients and CSI in 1 patient) as well as HDCT as part to their salvage regimen; 1 patient is a long-term survivor. Among the 17 patients who did not undergo radiotherapy as part of their salvage strategy, the only long-term survivor did not respond to HDCT, as described earlier, and received further investigational therapy to achieve a long-term remission. FIGURE 1. Overall survival (OS) and progression-free survival (PFS) in all patients. 66.7% 22.2%, compared with 7.1% 4.9% (P 5.019) for those aged 3 years at diagnosis (Table 3). Patients who received radiotherapy as part of their salvage regimen, either immediately before or after HDCT, were found to have a significantly better 5-year PFS ( %) than those who did not ( %) (P ). Patients with bulky residual tumor (defined as >2 cm 3 ) before HDCT had a trend toward a worse PFS than those who did not (P 5.067). Among the 6 long-term survivors (median age, 2.2 years; range, years), 5 had M0 disease and 1 had M3 disease at diagnosis; 5 received both radiotherapy (CSI in 3 patients and local in 2 patients) and HDCT as part of their salvage regimen. Four were aged <3 years at diagnosis and had received chemotherapy only as part of their frontline therapy. The 2 survivors aged 3 years at the time of diagnosis had M0 disease; 1 developed a local recurrence, underwent a macroscopic total resection, and received HDCT and radiotherapy as part of his salvage therapy; the other had CSF positivity only at the time of disease recurrence, did not have clear CSF after HDCT, and went on to receive further therapy (Table 1). Among the 7 patients aged <3 years, 5 received local radiotherapy (1 patient) or CSI (4 patients) as part of their salvage regimen, and 4 remained longterm survivors (Table 1). One patient with recurrent pineoblastoma who received CSI and HDCT developed disease progression at 156 days after transplantation and later died of his disease. Two patients underwent only HDCT at the time of disease recurrence because their young age precluded the use of radiotherapy at recurrence and experienced progressive disease at 29 days and 39 days, respectively, after transplantation and ultimately died of their disease. Toxicity All patients developed panctyopenia requiring blood products transfusion, mucositis requiring total parental nutrition (TPN), and fever. These adverse events, as well as electrolyte abnormalities, are omitted from Table 4. Twelve patients (44.4%) experienced other grade 3 and 4 toxicities based on National Cancer Institute toxicity criteria. Two toxic deaths occurred: 1 because of a-streptococcal sepsis on Day 15 after ASCR, the other because of multiorgan failure on Day 43 after ASCR with evidence of progressive disease at autopsy. Engraftment Engraftment data were collected, including days to an ANC >500/mL after HDCT and days to platelet independence (>20,000/mL) in the first 100 days. Neutrophil engraftment and platelet engraftment occurred at a median of 16 days (range, 9 33 days) and 28 days (range, days) after HDCT, respectively. Eleven patients (41%) were not able to maintain platelet independence within 100 days. DISCUSSION The results of the current study demonstrate that HDCT with ASCR is not an effective salvage strategy for older children with recurrent CNS malignancies. The significantly better outcome in the younger cohort is most likely related to the use of radiotherapy as part of the salvage strategy. In this series, the 7 children aged <3 years had a significantly better PFS (57.1% 21.6%) than the 20 children who were aged 3 years (5.0% 3.4%) (P 5.02). Despite the clearly recognized benefits of early radiotherapy in the treatment of older children, the neurocognitive sequelae associated with radiotherapy in younger patients have prevented oncologists from using irradiation in children aged <3 years until recently. 3,28 In the current study, none of the 7 patients aged <3 years received any irradiation at diagnosis, but the 4 long-term survivors in this group all underwent irradiation (CSI in 3 patients and local

6 1350 CANCER March 15, 2008 / Volume 112 / Number 6 TABLE 2 Survival for All Patients With Central Nervous System Tumors Survival rate estimate Survival Group No. 3-Year 5-Year Exact log-rank P Overall All patients % 8.9% 28.2% 9.8% Age at DX <3 y % 16.7% 57.1% 21.6%.26 Age at DX 3 y % 9.5% 20.2% 8.9% Age at ASCR <3 y % 17.7% 50.0% 20.4%.51 Age at ASCR 3 y % 9.6% 22.2% 9.8% Progression-free All patients % 6.8% 18.5% 8.4% Age at DX <3 y % 16.7% 57.1% 21.6%.019 Age at DX 3 y % 3.4% 5.0% 3.4% Age at ASCR <3 y % 17.7% 50.0% 20.4%.13 Age at ASCR 3 y % 5.2% 9.5% 6.4% DX indicates diagnosis; ASCR, autologous stem cell rescue. FIGURE 2. Progression-free survival of all patients by age at diagnosis (Dx). radiotherapy in 1 patient) as part of salvage therapy with HDCT. Of the 3 patients aged <3 years who died of their disease, 2 did not receive radiotherapy as part of their salvage regimen. Among the 20 patients aged 3 years, all received radiotherapy as part of their frontline therapy (CSI in 16 patients and local radiotherapy in 4 patients); only 2 patients were long-term survivors after HDCT. One had stable disease with persistent CSF positivity after HDCT and went on to receive other investigational therapy to achieve a long-term disease remission; the other received local conformal radiotherapy and HDCT as part of his salvage therapy for a local recurrence. A careful review of the literature demonstrates that encouraging reports of long-term survival in children with recurrent CNS malignancies after HDCT generally involve patients whose salvage regimen included irradiation either before or immediately after HDCT. Kalifa et al. 29 initially reported that, in children with recurrent CNS malignancies, highdose chemotherapy with busulfan and thiotepa led to a response rate of 26%, with partial responses achieved in 4 patients with medulloblastoma/pnet and 1 patient with an ependymoma. Six of 20 patients remained alive at the time of last follow-up with a short follow-up of 2 to 24 months. Five of the survivors received post-hdct radiotherapy as part of their salvage regimen. The sixth survivor had a follow-up of only 2 months. In a follow-up study from the same group, Dupuis-Girod et al. 20 reported that, among medulloblastoma patients aged <3 years who developed disease recurrence after chemotherapy alone, high-dose chemotherapy with busulfan and thiotepa followed by local radiotherapy led to an event-free survival (EFS) rate of 50%, with a median follow-up of 31 months. However, only 1 of 7 patients with M1 disease was a long-term survivor. These results are very similar to the PFS rate of 57% reported in the cohort of patients aged <3 years in the current study. In contrast, Valteau-Couanet et al. 24 studied 15 previously irradiated older medulloblastoma patients and reported that high-dose chemotherapy with busulfan and thiotepa led to a high toxic death rate (26.6%) and a poor outcome. These findings, similar to those of the current study, suggest that patients who are most likely to benefit from HDCT are younger, previously unirradiated children with local disease recurrence whose salvage regimen includes radiotherapy. In fact, Bowers et al. 30 recently reported that, in patients with recurrent medulloblastoma, patients who received radiotherapy as a salvage regimen had a significantly better PFS than those who did not (P 5.015). Dunkel et al. 25 reported an EFS of 24 to 78 months among 7 of 23 patients with recurrent medulloblastoma who were treated with a high-dose combination of carboplatin, thiotepa, and etoposide.

7 High-dose Chemotherapy for Recurrent CNS Tumors/Shih et al TABLE 3 Survival Rates for Patients With Central Nervous System Embryonal Tumors* Survival rate estimate Survival Group No. 3-Year 5-Year Exact log-rank P Overall All patients % 10.6% 32.8% 12.0% Age at DX <3 y % 17.2% 66.7% 22.2%.18 Age at DX 3 y % 11.7% 21.4% 11.0% Age at ASCR <3 y % 19.0% 60.0% 21.9%.38 Age at ASCR 3 y % 11.7% % 12.1% Progression-free All patients % 8.8% 25.5% 10.8% Age at DX <3 y % 17.2% 66.7% 22.2%.019 Age at DX >3 y % 4.9% 7.1% 4.9% Age at ASCR <3 y % 19.0% 60.0% 21.9%.12 Age at ASCR 3 y % 7.2% 13.3% 8.8% DX indicates diagnosis; ASCR, autologous stem cell rescue. * Includes medulloblastoma, pineoblastoma, primary neuroectodermal tumor, and atypical teratoid rhabdoid tumor. TABLE 4 Type and Degree of Grade 3 and 4 Toxicity (n 5 12)* Toxicity Grade 3 4 Acute renal failure 1 0 Adult respiratory distress syndrome 0 1 a-strep sepsis 1 0 CNS hemorrhage 1 0 Congestive heart failure 1 1 Creatinine, abnormal level 0 1 Fungal pneumonia 1 0 Hallucination 1 0 Hemorrhagic cystitis 1 0 Hypertension 2 0 Infection: coagulase-negative staphylococcus, blood 1 0 Infection: Pseudomonas aeruginosa, blood 1 0 Infection: Streptococcus viridans sepsis, blood 1 0 Infection: septic shock 0 1 Interstitial pulmonary disease 1 0 Shingles 1 0 Supraglottitis 0 1 Veno-occlusive disease 2 0 Toxicity: maximum grade noted 8 4 CNS indicates central nervous system. * Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria. Five of these survivors underwent radiotherapy either immediately before or after HDCT. Two other longterm survivors were chemotherapy-naive and had only received prior radiotherapy. Broniscer et al. 26 also reported that 5 of 7 patients with cortical PNETs (median age of 2.1 years; range, years) were long-term survivors, 4 of whom had received irradiation after HDCT as part of their salvage regimen. It is No. No. interesting to note that Broniscer et al reported that both surgery at the time of disease recurrence and the use of irradiation after HDCT (P 5.01) were favorable prognostic factors. Similarly, in the current series, patients with minimal disease at the time of ASCR had a trend toward a better PFS (P 5.067); therefore, we recommend a second resection, if possible, for local recurrence. Finlay et al. 31 reported that, among 45 patients with recurrent CNS malignancies who were treated with high-dose thiotepa and etoposide, the only long-term survivors were 5 patients with high-grade glioma (HGG), 4 of whom had received prior radiotherapy. Although the age of these surviving children is unclear from the report (the median age for the entire cohort is 8 years, with a range of 8 months-36 years), reports in the literature have demonstrated that children aged <3 years of age at the time of diagnosis with HGG are more chemosensitive and have a better outcome than older children with the same disease ; the reasons for this difference remain unclear, but may be related to biologic differences in HGGs developing in younger children. 35 A subsequent randomized phase 2 trial of HDCT in children aged >3 years with newly diagnosed high-grade astrocytomas did not demonstrate a survival advantage compared with conventional therapy, 36 suggesting that the better outcome with this approach in younger patients may be related to biologic factors that render HGGs more sensitive to chemotherapy in general. Finally, Grill et al. 21 reported that among 16 patients with recurrent ependymoma undergoing HDCT, the only long-term survivors were 3 patients who underwent macroscopic total resection and local radiotherapy as part of their salvage therapy.

8 1352 CANCER March 15, 2008 / Volume 112 / Number 6 The time to disease progression of 127 days (4.2 months) in the current study is similar to that reported for other HDCT regimens and, indeed, conventional-dose chemotherapy regimens in general. In fact, studies using chronic oral etoposide as palliative therapy for patients with recurrent CNS malignancies including medulloblastomas 37,38 and ependymomas 39 have reported similar median times to disease progression of 5 months to 8 months, with much less associated toxicity. The lack of a clear survival advantage with HDCT alone for older children with recurrent CNS malignancies and toxic mortality rates as high as 27% (11% in the current series), 19,21 23,31,40 as well as severe transplant-related toxicities reported in the literature have dampened our enthusiasm for HDCT salvage strategies for children with recurrent CNS malignancies in recent years. The findings of the current study are particularly important in light of the wide array of promising novel agents and approaches that are rapidly becoming available in this group of patients. The enrollment of patients with recurrent CNS malignancies in investigational trials of novel agents such as antiangiogenic agents and small molecule inhibitors may be associated with less toxicity and some benefit and will certainly advance our understanding of the biology of pediatric CNS tumors. Although a uniform treatment regimen for HDCT was not examined in the current study and the number of patients is rather small, we conclude that children aged 3 years who have received multimodality therapy including radiotherapy as part of their frontline treatment regimen and subsequently experience disease recurrence do not benefit from HDCT alone as salvage therapy. 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