Irinotecan for relapsed Wilms tumor in pediatric patients: SIOP experience and review of the literature—A report from the SIOP Renal Tumor Study Group

While irinotecan has been studied in various pediatric solid tumors, its potential role in Wilms tumor (WT) is less clear. We evaluated response and outcome of irinotecan‐containing regimens in relapsed WT and compared our results to the available literature. Among 14 evaluable patients, one complete response (CR) and two partial responses (PRs) were observed in patients with initial intermediate‐risk (CR and PR) and blastemal‐type histologies (PR). Two patients were alive at last follow‐up showing no evidence of disease. Our results and the reviewed literature suggest some effectiveness of irinotecan in the setting of relapsed WT.     

Pretransplant functional imaging and outcome in pediatric patients with relapsed/refractory Hodgkin lymphoma undergoing autologous transplantation

1 Background

Pretransplant functional imaging (FI), particularly a negative positron emission tomography (PET), is a strong predictor of outcome in adults with relapsed or refractory Hodgkin lymphoma (HL), but data in pediatrics are limited.

2 Methods

The medical records of 49 consecutive pediatric patients, who received autologous transplant at a single institution, were retrospectively analyzed. All patients had either gallium or PET scan before transplant and were conditioned with carmustine, etoposide, cytarabine, and melphalan (BEAM). Deauville scores were retrospectively assigned for patients with PET (score ≥ 4 positive).

3 Results

Of the 49 patients (median age, 16.2 years), 41 (84%) were pretransplant FI negative and eight (16%) were pretransplant FI positive, after first‐ to fourth‐line salvage therapy, and a median of two salvage cycles. Eighteen patients (37%) received posttransplant radiation. At a median follow up of 46 months, 45 patients (92%) were alive and disease free, and there were three nonrelapse deaths and only one relapse death (Deauville score of 5). The 4‐year progression‐free survival (PFS) for the entire cohort was 92% (95% confidence interval [CI]: 78–97), and PFS based on pretransplant disease status was 95% (95% CI: 82–99%) in the negative FI group versus 75% (95% CI: 31–93) if positive FI (P = 0.057).

4 Conclusion

Our analysis revealed outstanding outcomes for children and adolescents with relapsed/refractory HL. There were too few relapses to identify the predictive value of pretransplant metabolic status, but pediatric patients with relapsed/refractory HL and a negative pretransplant FI had excellent survival.     

Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma

PURPOSE: This review summarizes the published data on the use of high-dose chemotherapy and hematopoietic stem cell rescue (HSCR) in the treatment of recurrent or metastatic rhabdomyosarcoma (RMS). PATIENTS AND METHODS: Three hundred eighty-nine patients were identified from 22 articles selected by computer generated searching of MEDLINE (1979-present). One hundred seventy-seven patients had stage 4 disease and were treated during first complete remission (CRI). The remaining patients were treated during CR1/first partial remission (PR1) (110 patients), CR2/PR2 (53 patients), CR2 (12 patients), CR3 (1 patient), or treated with disease (36 patients). RESULTS: Patients treated during CR1 or CR1/PR1 had event-free survival (EFS) rates ranging from 24% to 29% at 3 to 6 years from diagnosis and overall survival (OS) rates ranging from 20% to 40% at 2 to 6 years after diagnosis according to data provided as Kaplan-Meier estimates. Studies without Kaplan-Meier estimates (n = 32) indicate that 12 patients (38%) with stage IV RMS treated during CR1 or CR1/PR1 were surviving 7 to 60 months from diagnosis, similar to patients with stage IV RMS treated on Intergroup Rhabdomyosarcoma Studies II or III. Patients treated during CR2, CR3, or with evidence of disease had a worse outcome with an estimated 3 years OS of 12% (n = 51). Studies without Kaplan-Meier estimates (n = 27) indicate that four patients (15%) treated during CR2, CR3, or with disease were surviving 17 to 33 months after transplant. CONCLUSIONS: Based on these data, there does not appear to be a significant advantage to undergoing high-dose chemotherapy with HSCR for patients with relapsed or refractory high-risk RMS. Clearly, there is a need for incorporating new treatment strategies for patients with high-risk RMS.     

Comparison of results of a pilot study of alternating vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide with IRS-IV in intermediate risk rhabdomyosarcoma: a report from the Children's Oncology Group

Background

Over 50% of patients with rhabdomyosarcoma (RMS) have intermediate risk disease, with a 3‐year failure‐free survival (FFS) of 50%–70% depending on histology. Doxorubicin is active against RMS, but its role in improving outcome remains controversial. Ifosfamide is as active as cyclophosphamide in RMS, with the Fourth Intergroup RMS Study (IRS‐IV) showing equivalent outcomes for patients treated with ifosfamide for the first 28 weeks compared to cyclophosphamide. Treatment with alternating cycles of non‐cross‐resistant chemotherapy has been used in a number of diseases with good results.

Procedure

The results of a pilot study utilizing alternating courses of vincristine, doxorubicin, cyclophosphamide, and etoposide/ifosfamide (VDC/IE) were compared for outcome and patient characteristics to a group of similar matched patients treated on IRS‐IV.

Results

The 5‐year FFS for patients with parameningeal (PM) primaries on IRS‐IV and the VDC/IE study were 72% and 82%, respectively (P = 0.26); for patients with non‐PM primaries, the estimated risk of failure for VDC/IE study versus IRS‐IV was 0.54. Combining all disease sites and performing analysis for relative risk of failure for 46 VDC/IE patients and 342 IRS‐IV patients, the relative risk of failure for the VDC/IE study compared to the IRS‐IV study is 0.5 (P = 0.06).

Conclusions

VDC/IE is as effective therapy for intermediate risk RMS as IRS‐IV therapy. It is being explored along with irinotecan in relapsed patients and newly diagnosed high‐risk patients. Pediatr Blood Cancer 2008;50:33–36. © 2006 Wiley‐Liss, Inc.     

Combination of clofarabine,cyclophosphamide, and etoposide for relapsed or refractory childhood and adolescent acute myeloid leukemia

Relapsed/refractory acute myeloid leukemia (AML) has an extremely poor prognosis. We describe 17 children and adolescents with relapsed/refractory AML who received clofarabine, cyclophosphamide, and etoposide. Seven patients (41%) responded: 4 with a complete response (CR); 1 with CR with incomplete platelet recovery; and 2 with a partial response. Additionally, 4 developed hypocellular marrow without evidence of leukemia; 5 patients had resistant disease; and 1 suffered early toxic death. After further therapy including transplantation, 4 patients (24%) are alive without evidence of disease at a median of 60 months. This anthracycline-free regimen may be studied for relapsed or refractory AML, but due to the high risk of marrow aplasia reduced doses of clofarabine and cyclophosphamide should be used.     

Immunosuppressive Therapy in Aplastic Anemia

Objective

To assess the response to antithymocyte globulin based immunosuppressive therapy (IST) in pediatric patients with idiopathic aplastic anemia.

Methods

Thirty patients (19 boys and 11 girls) with aplastic anemia received antithymocyte globulin and cyclosporine. Twenty-two patients had severe and 8 had very severe aplastic anemia.

Results

Mean age of the patients was 9.19?±?2.56?y. Three patients died within 1?mo of therapy, two due to sepsis and one due to intracranial hemorrhage. Twenty-seven patients were analyzed for response to therapy. Eight patients (29.7%) responded at 3?mo: 3 complete response (CR) and 5 partial response (PR). Six mo after the therapy, overall response (OR) was seen in 9/27 (33.3%), with one more patient in no response group achieving partial response. At 1?year, patients in CR maintained their status and 1 patient in PR group relapsed. He again achieved partial response with repeat course of ATG. Responders had significantly shorter duration of illness and higher absolute neutrophil count as compared to non responders to IST. None of the patients developed acute leukemia in the follow up.

Conclusions

The treatment of aplastic anemia in pediatric patients is a challenging task. One third of the patients achieved overall response which included both complete and partial response.     

儿童淋巴母细胞型淋巴瘤40例临床特征及近期疗效观察

目的分析40例儿童淋巴母细胞淋巴瘤(Lymphoblastic lymphonma,LBL)的临床特点和预后,总结BFM-90方案的BCH-2003-LBL方案治疗的近期疗效。方法对LBL患儿的临床资料进行总结和分析。结果40例中T细胞型31例,B细胞型9例。临床Ⅱ期4例,Ⅲ期10例,Ⅳ期26例。于诱导缓解33天、诱导结束时(约化疗3个月)评估,骨髓完全缓解(CR)率均为100%;同时评估瘤灶,CR率分别为67.5%、87.5%,部分缓解(PR)率分别为32.5%、12.5%,总有效率100%。全组中位随访时间23.2月(6~52)月,7例复发,6例死亡。1、2年无事件生存率(EFS)分别为89.3%、79.9%,预计3年EFS(pEFS)为68.9%。3年总生存率(OS)71.1%。采用Kaplan-meier法单因素分析显示不良预后因素包括:诱导结束时未达完全缓解、纵隔病变、巨大瘤块。结论儿童淋巴母细胞型淋巴瘤属于高度恶性非霍奇金氏淋巴瘤,本组现有资料显示T-LBL较B-LBL更易复发,预后较差。本组采用BCH-2003-LBL方案化疗近期疗效良好,但中枢神经系统、骨髓及原发肿瘤部位复发是治疗失败的主要原因,复发后单纯化疗效果不佳,应尽早采取造血干细胞移植(HSCT)。     

Busulfan, melphalan, and thiotepa with or without total marrow irradiation with hematopoietic stem cell rescue for poor-risk Ewing-Sarcoma-Family tumors

BACKGROUND: Survival following metastatic or recurrent Ewing sarcoma family tumors (ESFT) remains <25%. Myeloablative therapy with hematopoietic stem cell transplantation (HSCT) may improve survival for poor-risk ESFT. We describe the toxicity and efficacy of a myeloablative chemotherapy regimen, followed by a second myeloablative radiotherapy regimen as consolidation treatment for poor-risk ESFT. PROCEDURE: Sixteen patients with poor-risk ESFT were treated with myeloablative therapy followed by HSCT. All patients received busulfan, melphalan, and thiotepa (BuMelTT) as chemotherapy conditioning. Nine patients received total marrow irradiation (TMI) as a second myeloablative therapy, also followed by HSCT. Seven patients were excluded from TMI because of inadequate peripheral blood stem cell harvest, extensive prior radiation therapy, early disease progression, orpatient refusal. The disease status prior to my eloablative therapy was first complete response (CR1) in three patients, CR2 in nine, second partial response (PR2) in one, CR3 in one, and progressive disease (PD) in two. RESULTS: One patient died of regimen-related toxicity, one from late pulmonary toxicity, and one following allogeneic transplantation for myelodysplasia. Eight developed recurrent disease (median time to progression 6.8 months). Six survive without relapse from 27 to 66 months following BuMelTT (median follow-up 42 months), all of whom received both BuMelTT and TMI patients (3-year event-free survival 36%). CONCLUSIONS: Dual myeloablative therapy with BuMelTT and TMI was a feasible and promising treatment approach for patients with poor-risk ESFT. Inability to collect sufficient PBSC and extensive previous radiation therapy limit the ability to deliver TMI as a second HSCT conditioning regimen.     

Efficacy of ifosfamide and doxorubicin given as a phase II "window" in children with newly diagnosed metastatic rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study Group.

BACKGROUND: The cure rate for children/adolescents with localized rhabdomyosarcoma (RMS) has tripled over the past 25 years, but patients with metastatic disease at presentation have not benefited similarly, and urgently need new therapy. We evaluated a new drug pair, ifosfamide + doxorubicin, for such patients. PROCEDURE: We estimated the complete and partial response rates (i.e., CR and PR) of 152 previously untreated children/adolescents with metastatic RMS entered on the IRS-IV pilot from July 1988 to October 1991 who received an "up-front window" of ifosfamide (1.8 gm/m(2)/day for 5 days) and doxorubicin (30 mg/m(2)/day for 2 days) given every 3 weeks for 12 weeks. This was followed by combination chemotherapy with vincristine, actinomycin D, and cyclophosphamide (VAC), given every 3 weeks for an additional 36 weeks. RESULTS: Of 115 patients evaluable for early response at 12 weeks, 28 (20%) had CR and 66 (43%) had PR. The ultimate CR rate was 52%. Overall, about one-third of patients survived. Prognostic factor analysis revealed that patients < 10 years old (P < 0.001), those with embryonal tumors (P = 0.002), or a GU primary site (P = 0.010), and those who lacked nodal disease (P = 0.041), and those who lacked bone or bone marrow metastasis (P < 0.001) fared better than did others. CONCLUSIONS: The 63% CR + PR rate achieved at 12 weeks and overall 5-year FFS seen with this drug pair is similar to that achieved with previously evaluated drug combinations. We conclude that ifosfamide/doxorubicin is highly active in advanced RMS, and should be considered for inclusion in frontline therapy for children with intermediate or high-risk RMS.     

Autologous bone marrow transplantation for pediatric Wilms' tumor: The experience of the European bone marrow transplantation solid tumor registry

This survey includes 25 children with Wilms' tumor undergoing high-dose chemotherapy associated with autologous bone marrow transplantation (ABMT) in the period June 1984-December 1991 and enrolled in the European Bone Marrow Transplantation Registry for Solid Tumors. At diagnosis, 12 children presented stage IV disease, 5 stage III, 3 stage II, and 5 stage I. Before ABMT, 21 children had 1 to 4 relapses (median 1); 13 achieved a second or subsequent complete remission (CR), four stage IV children failed to respond to first line treatment and achieved either CR (3 patients), or partial remission (PR) after second line therapy. At high-dose chemotherapy, 17 children were in CR and 8 had measurable disease. Seven different high-dose regimens were administered, even if 20 children received melphalan mostly associated with vincristine and 8 involved field radiotherapy. Three children died early of pneumonitis; 2 developed an acute transient renal failure, 1 a chronic renal failure. Out of the 8 children with target disease at graft, 2 died of toxicity, 5 achieved CR, 1 obtained PR, and only 1 is presently alive in CCR at 39 months after ABMT. Of the 17 children grafted in CR, 8 are alive event-free at 14-90 months (median 34) from ABMT; 7 relapsed at 3-23 months (median 7 months); 1 died of toxicity and 1 was lost to follow-up in CR at 12 months. A salvage attempt with high-dose chemotherapy in children with resistant or poor prognosis recurrent Wilms' tumor seems to be justified. An international cooperative protocol taking into account the increased risk of lung and renal toxicity is necessary. © 1994 Wiley-Liss, Inc.     

Antithymocyte globulin and cyclosporin in children with acquired aplastic anemia

Objective  To assess the responses to ATG and cyclosporin combination in patients of aplastic anemia. Methods  Twenty three (17M: 6F) patients of aplastic anemia (11 very severe aplastic anemia (VSAA) and 12 severe aplastic anemia (SAA), were administered antithymocyte globulin and cyclosporin. Results  The median age of patents was 8 years (range 6–12 years). Three patients died within 2 months of therapy. Twenty children (11 SAA and 9 VSAA) were finally analysed. Six months after the start of treatment, 8/20 (40%) patients responded-2 complete (CR) and 6 partial responses (PR). At the end of 1 year; 2 patients maintained CR and seven patients continued PR (overall responders 45%). The response was better in SAA (54.5%) with 2 CR and 4 PR; than in VSAA (33%) with 3 PR. Eleven (55%) children were alive without response. One patient developed AML 13 months later. Conclusion  We conclude that antithymocyte globulin and cyclosporin combination is an effective treatment for aplastic anemia patients who are ineligible for bone marrow transplantation.     

Cisplatin,bleomycin, and vinblastine combination therapy of testicular tumors: An analysis

A combination regimen consisting of cisplatin, bleomycin, and vinblastine was evaluated in 86 patients with metastatic testicular tumors. Prior therapy included surgical resection of primary tumor (84 patients), radiotherapy (21 patients), chemotherapy (33 patients). Thirteen patients received prior bleomycin and vincristine or vinblastine. Of 80 evaluable patients 51 achieved complete response (CR) and 26 achieved partial response (PR), for an overall response rate 96.5%. There was no significant difference in response rates or survival with respect to prior therapy, sites of metastatic lesions, and tumor histology. The median survival time was not reached in an observation period of 44+ months. Sixty patients were alive 11+–44+ months, and 57 of these were free of disease. Thirty-two of the 60 patients (53%) had a survival time greater than 20 months. Toxicities included nephrotoxicity (18 patients) leukopenia, (69 patients), thrombocytopenia (nine patients), and anemia (56 patients). Bleomycin-induced pulmonary toxicity was fatal in one patient. Other toxicities included nausea and vomiting, stomatitis, fever, alopecia, and neurological effects.     

Cisplatin, bleomycin, and vinblastine combination therapy of testicular tumors: an analysis.

A combination regimen consisting of cisplatin, bleomycin, and vinblastine was evaluated in 86 patients with metastatic testicular tumors. Prior therapy included surgical resection of primary tumor (84 patients), radiotheapy (21 patients), chemotherapy (33 patients). Thirteen patients received prior bleomycin and vincristine or vinblastine. Of 80 evaluable patients 51 achieved complete response (CR) and 26 achieved partial response (PR), for an overall response rate 96.5%. There was no significant difference in response rates or survival with respect to prior therapy, sites of metastatic lesions, and tumor histology. The median survival time was not reached in an observation period of 44+ months. Sixty patients were alive 11+--44+ months, and 57 of these were free of disease. Thirty-two of the 60 patients (53%) had a survival time greater than 20 months. Toxicities included nephrotoxicity (18 patients) leukopenia, (69 patients), thrombocytopenia (nine patients), and anemia (56 patients). Bleomycin-induced pulmonary toxicity was fatal in one patient. Other toxicities included nausea and vomiting, stomatitis, fever, alopecia, and neurological effects.     

High-dose chemoradiotherapy with bone marrow transplantation as a consolidation treatment of neuroblastoma. Results in 49 unselected patients with stage IV cancer and older than 1 year. Report of the LMCE neuroblastoma group

65 consecutive children over one year of age presenting with neuroblastoma stage IV were unselectively treated with an induction regimen alternating Cis-Platinum/VM 26 and Cyclophosphamide/Adriamycin/Vincristin. After primary surgery two to four months post diagnosis, consolidation consisted of continuous Vincristin, high dose Melphalan and fractionated total body irradiation, followed by bone marrow transplantation (autologous except for 3 allogeneic). Of the 49 children transplanted up to evaluation date, 31 were in partial remission (PR) and 18 in "very good partial remission" (VGPR) or complete remission (CR) at the time of transplantation. The toxic mortality was 20% (14% early, 6% late), the relapse rate 29% and the progressive disease rate 6%. The event-free survival from graft (events being relapse, progression or death) was 33% after a median of 17 months (range: 2-45) without a significant difference between a status at transplantation of PR versus VGPR/CR. The overall actuarial progression-free survival of the complete group of children with neuroblastoma stage IV was 24% after 27 months, including 10 patients who died or relapsed before massive therapy as well as 6 children still in induction. This result must be compared with 6% survival in a similar group diagnosed at the same institutions and treated with conventional chemotherapy before the onset of this trial.     

Oxaliplatin, irinotecan, and gemcitabine: a novel combination in the therapy of progressed, relapsed, or refractory tumors in children

Therapeutic options for unresectable neuroendocrine carcinomas and relapsed or refractory solid tumors are still limited in pediatric patients. We present a retrospective review of 12 children (3 to 16 y) in a case series treated with a novel combination of oxaliplatin, irinotecan, and gemcitabine (triple therapy). We defined its feasibility in a mainly outpatient setting and assessed its toxicity and effectiveness. Three patients with unresectable neuroendocrine carcinomas received triple therapy as first-line treatment; 9 children with relapsed or refractory solid tumors of different entities were assigned after failure of standard treatment protocols. The treatment schedule comprised oxaliplatin (85 mg/m2), irinotecan (175 mg/m2), and gemcitabine (1,000 mg/m2), the latter to be repeated on day 8. A median of 7 cycles was applied. Nine of 12 patients showed hematotoxicity 0-III degrees. Gastrointestinal toxicity I-II degrees were handled satisfactorily by supportive drugs. Tumor response was defined as partial response in 1 of 12 children, stable disease in 8 of 12 children, and progressive disease in 3 of 12 children with a median time of disease control of 7 months. We regard triple therapy as a well-tolerated outpatient treatment option offering children a high quality of life and showing considerable effectiveness in delaying tumor progress.     

Improved care of rhabdomyosarcoma in Jordan using less intensive therapy

Background

The care of rhabdomyosarcoma (RMS) is complex due to its multimodal nature. By following standard protocols with acceptable toxicity and building local expertise, better outcome should be achievable.

Procedure

A retrospective study was conducted of records of patients (n = 45; 31 males; median age 26 months) with RMS treated at King Hussein Cancer Center in Jordan from January 2004 to December 2008. Patient demographics, tumor characteristics, risk stratification, treatment plan, and outcomes were studied. In June 2006, the cyclophosphamide dose was lowered from 2.2 g/m² to 1.2 g/m² per cycle because of the significant toxicity with higher dose. Survival rates, hematological toxicities, period of hospitalization due to febrile neutropenia (FN), and response rate at week 12 of treatment were compared between low‐ and high‐dose cyclophosphamide groups.

Results

Four‐year progression‐free survival (PFS) and overall survival (OS) rates were 61% ± 7.5% and 72% ± 6.9%, respectively. There was a significant difference in outcome by risk group in 4‐year PFS (low‐risk, 88% ± 12%; intermediate‐risk 63% ± 9.3%; high‐risk, 14% ± 13%; P = 0.0001) and OS (low‐risk, 88% ± 12%; intermediate‐risk 79% ± 7.5%; high‐risk, 17% ± 15%; P = 0.0011). There was significant reduction in hematological toxicities, incidence of FN, and period of hospitalization for FN in patients given low‐dose cyclophosphamide but no significant difference in PFS between low‐ and high‐dose cyclophosphamide groups.

Conclusions

Survival rates of patients with RMS in some developing countries can be improved by following or modifying evidence‐based approaches successful in developed countries and establishing multidisciplinary strategies. Therapy intensity should be increased in developing countries only when evidence supports its utility. Pediatr Blood Cancer 2013; 60: 53–58. © 2012 Wiley Periodicals, Inc.     

Outcomes in childhood AML in the absence of transplantation in first remission--Children's Cancer Group (CCG) studies 2891 and CCG 213

Background

The majority of childhood acute myeloid leukemia (AML) patients lack a matched‐related bone marrow transplant (BMT) donor in first remission.

Procedure

Disease‐free survival (DFS), overall survival (OS), relapse‐free survival (RFS), and post‐relapse outcome were evaluated for children with de novo AML on CCG 213 and the standard timing (ST) and intensive timing (IT) induction arms of CCG 2891 who were randomized to (intent‐to‐treat, ITT) or who received (as‐treated, AT) only chemotherapy intensification.

Results

Outcomes at 8 years post‐induction in ITT analysis of chemotherapy intensification were as follows: 31% DFS, 43% OS on CCG 213; 34% DFS, 51% OS on CCG 2891 ST; 48% DFS, 56% OS on CCG 2891 IT. All toxic deaths during and following Capizzi II chemotherapy intensification on both protocols were in patients >3 years of age (P ≤ 0.001). Black race was a significant poor prognostic factor for OS (P = 0.008, hazard ratio: 1.74, 95% CI: 1.15–2.61). Overall 48% of patients on both trials relapsed and 19.1% of patients who relapsed on these trials survived. CR1 >12 months portends a much better OS for patients who relapse. Post‐relapse treatment included BMT in 47% of patients.

Conclusions

OS on CCG 2891 was superior to CCG 213 but equivalent between ST and IT arms due to better salvage rates post‐relapse in ST patients. Overall survival for childhood AML in the absence of BMT in CR1 is influenced by duration of CR1 and by race. Pediatr Blood Cancer 2008;50:9–16. © 2007 Wiley‐Liss, Inc.     

Central nervous system relapse of rhabdomyosarcoma

1 Purpose

The optimal management of central nervous system (CNS) relapse of rhabdomyosarcoma (RMS) is unclear. We examined diagnosis, management, and outcomes of patients with RMS developing CNS relapse.

2 Methods

Records of 23 patients diagnosed with CNS relapse between 1999 and 2016 were reviewed. Median age at presentation of CNS relapse was 15 years (range, 1–34 years). High‐risk features at initial presentation were as follows: 16 alveolar patients, 13 Stage IV, and 13 with primary tumor in parameningeal locations.

3 Results

CNS relapse occurred at a median 12 months (range, 1–23 months) from diagnosis and most common presenting symptoms were headache (n = 9), nausea/vomiting (n = 8), visual difficulty (n = 5), and none (n = 5). Leptomeningeal metastases were detected in 21 patients while only 2 developed parenchymal metastases without leptomeningeal involvement. Fifteen patients received CNS‐directed radiation therapy (RT), including craniospinal irradiation to a median 36 Gy (range, 18–36 Gy) and/or whole brain radiotherapy to a median 30 Gy (range, 6–41.4 Gy). Three patients received concurrent chemotherapy. Follow‐up magnetic resonance imaging was conducted in 13 patients after RT initiation with 8 demonstrating improvement, 2 with stable disease, and 3 with progression. Twelve patients were tested for reactivity to I‐131‐labeled monoclonal antibody 8H9, and three tested positive and received at least one intra‐Ommaya dose; all three lived >12 months post‐CNS relapse. Twenty‐one patients died of CNS disease and two of metastatic disease at other sites. Median survival post‐CNS relapse was 5 months (range, 0.1–49 months).

4 Conclusions

The prognosis for patients with RMS developing CNS relapse remains poor. Treatment including CNS‐directed RT should be considered and investigation into preventative therapies is warranted.     

Temozolomide in resistant or relapsed pediatric solid tumors

PURPOSE: We report the off-label study aimed at investigating the use of temozolomide (TMZ) as single agent in relapsed or resistant pediatric solid tumors. The drug was administered at the dose of 215 mg/m2/day x 5 days or 180 mg/m2/day x 5 days in patients with prior craniospinal irradiation (CSI) or autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Fifty two patients, median age 127.6 months, with resistant or relapsed solid tumors were enrolled. Tumor types were: neuroblastoma (NB; n = 17), medulloblastoma (MB; 8), brain stem glioma (BSG; 8), extraosseous Ewing's sarcoma/peripheral neuroectodermal tumor (EOES; 4), Ewing's sarcoma (ES; 4), anaplastic astrocytoma (AA; 3), rhabdomyosarcoma (RMS; 2), ependymoma (EP; 2), cerebral primitive neuroectodermal tumor (cPNET; 2), hepatocarcinoma (HC; 1), and osteosarcoma (OS; 1). All patients were pre-treated. Two outpatient courses were administered, with a median of 4.8 courses/pt. RESULTS: Objective response-rate (CR + PR + MR) in our series was 13.4% (1.9% CR, 3.8% PR, and 7.7% MR), SD occurred in 38.4% of patients and 48% had PD. The median survival was 7.8 months (range 1-37) and median time to progression was 3.4 months (range 1-20); these data were significantly correlated with histology and previous nitrosureas administration in multivariate analysis. Haematological toxicity grade 3-4 (mainly thrombocytopenia) was observed in 21.4% of administered courses, nausea was reported in 3.1% and respiratory distress in 0.7%. CONCLUSION: Oral TMZ was well tolerated in children with resistant or relapsed solid tumors and showed activity in NB and CNS tumours refractory to standard chemotherapy.     

Survival after recurrence of osteosarcoma: a 20-year experience at a single institution

BACKGROUND: Approximately one-third of patients with osteosarcoma who have a complete response to their initial treatment can be expected to relapse. It is important to define what host, tumor, or treatment characteristics determine outcome after relapse. We present findings in 59 patients treated at our institution from 1974 to 1996 who have relapsed one or more times after their initial response. METHODS: Host and tumor characteristics at diagnosis and relapse, therapeutic interventions and survival outcomes were determined from examination of medical records and a follow-up questionnaire. RESULTS: Of the 59 patients, 37 initially presented with localized disease of the extremity, 11 with localized non-extremity disease, and 11 with metastatic disease. This report focuses on those with localized disease of the extremity. For these patients, median time from original diagnosis to first recurrence was 14 months. Median survival after first recurrence was 31 months. The median post initial relapse survival was the same for patients whose first relapse occurred before or after 14 months from original diagnosis. Seventeen of 29 patients with systemic metastasis at first recurrence had complete removal of their disease and had a median post-op survival of 2.5 years, while the remaining 12 patients with no surgery, had a median survival of 2 years. Of the 37 patients who presented with primary disease only in the extremities and relapsed: 31 died (2 more than 6 years from first recurrence) and 6 are alive from 6 to 24 years from first recurrence (5 without disease and 1 with disease). Three of the five disease-free survivors had three or more relapses. CONCLUSION: With a long follow-up time, we found 15% of patients with relapsed osteosarcoma who originally presented with localized disease in the extremity are alive with no evidence of disease at 10 years from first recurrence (Kaplan-Meier estimate). Even patients with multiple relapses may have long-term disease-free survival after salvage therapy. Chemotherapy and time to first recurrence were unrelated to survival after relapse in this study. Complete surgical removal of metastatic disease may be important for long-term survival.