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.     

Response of Orbital and Central Nervous System Metastases of Retinoblastoma Following Treatment with Cyclophosphamide/Doxorubicin

A 3.5-year-old boy with orbital and central nervous system extension of unilateral retinoblastoma received chemotherapy consisting of intravenous cyclophosphamide and doxorubicin and intrathecal methotrexate. Complete shrinkage of orbital tumor, phthisis bulbi,'and disappearance of intracranial metastases occurred following chemotherapy. Response of the intra-cranial tumors reflected the combined effects of cyclophosphamide and doxorubicin; the contribution of each agent could not be assessed. Cerebrospinal fluid tumor cells persisted prior to delivery of craniospinal irradiation, and were detected again 6 weeks after completion of irradiation.     

Children's Oncology Group's 2013 blueprint for research: Bone tumors

In the US, approximately 650 children are diagnosed with osteosarcoma and Ewing sarcoma (ES) each year. Five‐year survival ranges from 65% to 75% for localized disease and <30% for patients with metastases. Recent findings include interval‐compressed five drug chemotherapy improves survival with localized ES. In osteosarcoma a large international trial investigating the addition of ifosfamide/etoposide or interferon to standard therapy has completed accrual. For ES an ongoing trial explores the addition of cyclophosphamide/topotecan to interval‐compressed chemotherapy. Trials planned by the Children's Oncology Group will investigate new target(s) including IGF‐1R and mTOR in ES, and RANKL and GD2 in osteosarcoma. Pediatr Blood Cancer 2013; 60: 1009–1015. © 2012 Wiley Periodicals, Inc.     

Success of chemotherapy and a liver transplant in a pediatric patient with hepatic angiosarcoma: A case report

Hepatic angiosarcoma is an extremely rare diagnosis in children, with fewer than 50 pediatric cases reported in the literature worldwide. This aggressive vascular sarcoma carries a very dismal prognosis and is known to be resistant to radiation, chemotherapy, and other vascular‐targeted agents. Complete surgical resection is felt to provide the best chance for long‐term survival. In patients with tumors not amenable to resection, a liver transplant can be considered. However, very few such transplants have been reported, given that they remain controversial due to high cancer recurrence and mortality post‐transplant. Herein, we report the unique case of a 2‐year‐old child with localized hepatic angiosarcoma not amendable to resection who successfully underwent a liver transplant and received chemotherapy with six cycles of doxorubicin, docetaxel, and ifosfamide.     

Hyperbaric oxygen therapy improves early posttransplant islet function

Sakata N, Chan NK, Ostrowski RP, Chrisler J, Hayes P, Kim S, Obenaus A, Zhang JH, Hathout E. Hyperbaric oxygen therapy improves early posttransplant islet function. Objective: This study investigates the therapeutic potential of hyperbaric oxygen therapy (HBO) in reducing hypoxia and improving engraftment of intraportal islet transplants by promoting angiogenesis. Methods: Diabetic BALB/c mice were transplanted with 500 syngeneic islets intraportally and received six consecutive twice‐daily HBO treatments (n = 9; 100% oxygen for 1 h at 2.5 atmospheres absolute) after transplantation. Dynamic contrast‐enhanced magnetic resonance imaging (DCE MRI) was used to assess new vessel formation at postoperative days (POD) 3, 7, and 14. Liver tissue was recovered at the same time points for correlative histology, including: hematoxylin and eosin, hypoxia‐inducible factor (HIF1α), Terminal deoxynucleotidyl transferase (TdT)‐mediated dUTP‐biotin nick end labeling (TUNEL), vascular endothelial growth factor (VEGF), and von Willebrand Factor immunohistochemistry. Results: HBO therapy significantly reduced HIF‐1α, TUNEL and VEGF expression in islets at POD 7. In the non‐HBO transplants, liver enhancement on DCE MRI peaked at POD 7 consistent with less mature vasculature but this enhancement was suppressed at POD 7 in the HBO‐treated group. The number of new peri‐islet vessels at POD 7 was not significantly different between HBO and control groups. Conclusion: These results are consistent with a hyperbaric oxygen‐mediated decrease in hypoxia that appeared to enhance vessel maturation in the critical days following intraportal islet transplantation.     

大剂量化疗结合外周血干细胞移植治疗横纹肌肉瘤疗效分析

目的对采用大剂量化疗结合自体外周血造血干细胞移植及免疫治疗的3例横纹肌肉瘤患儿的疗效进行观察。方法 3例横纹肌肉瘤患儿,年龄为3、10、14岁,强烈化疗5、6、11个周期,平均(7.33±3.21)个疗程;期间进行外周血造血干细胞采集、手术切除,然后进行自体外周血造血干细胞移植,术后行白介素-2治疗,复发者行普通化疗及局部放疗,定期随访。结果均顺利度过移植后骨髓抑制期,造血重建时间为13、14、15d,平均(13.33±0.58)d。术后随访8、12、17个月,3例患儿无病生存2/3,总生存率3/3。结论大剂量化疗、自体外周血造血干细胞移植及白介素-2相结合治疗横纹肌肉瘤,在移植前达到部分缓解时可取得较好疗效,长期生存率较高。     

Long‐term survival after autologous peripheral blood stem cell transplantation in two patients with malignant rhabdoid tumor of the kidney

A 5‐month‐old male with stage II malignant rhabdoid tumor of the kidney (MRTK) and a 24‐month‐old male with stage III MRTK were treated with surgical resection of tumors and chemotherapy of alternating ICE (ifosfamide, carboplatin, and etoposide) and VDC (vincristine, doxorubicin, and cyclophosphamide), followed by high‐dose chemotherapy using etoposide, carboplatin, and melphalan with autologous hematopoietic stem cell transplantation (SCT). Two patients have been alive without any evidence of disease for 30 and 37 months after diagnosis, respectively, and require no medication. Consolidation with SCT should be further studies for selected patients with high‐risk MRTK. Pediatr Blood Cancer 2009;52:888–890. © 2009 Wiley‐Liss, Inc.     

Germ cell tumors in children: Gonadal and extragonadal

Sixty-three pediatric patients with germ cell tumors are presented with details of symptoms, histological findings, staging, serological markers, treatment, and response to therapy. The primary sites were: ovarian 32, testicular 17, presacral 7, mediastinal 3, intraabdominal 2, vaginal 1, and right inguinal canal 1. These patients were treated with T2 (sequential use of dactinomycin, doxorubicin, vincristine, and cyclophosphamide, with or without radiation), T6 (combination chemotherapy with cyclo-phosphamide, bleomycin, dactinomycin, doxorubicin, methotrexate, vincristine), or VAB treatment protocols (velban, dactinomycin, bleomycin, cisplatin). The cure rate for stage I ovarian and testicular germ cell tumors was 100%; for stage III, all primary sites, 82% and for stage IV, all primary sites, 75%. Histology was prognostic in ovarian tumors of the immature malignant teratoma type; the neural type immature teratoma, grades II and III, had the worst prognosis. Initial debulking surgery in combination with chemotherapy and radiation plays an important role in germ cell tumors. Stages II, III, and IV germ cell tumors require aggressive treatment with surgery, radiation, and chemotherapy. For stage I patients, with primary ovarian malignant tumor, cure with surgery alone can be achieved in 50% of the cases and in testicular tumors in about 70% of the patients. For those with stage I and elevated serological markers, it is feasible to follow these markers and give no treatment until there is evidence of persistent elevation or a rise in titers after an initial fall. In those without elevated serological markers, one should take into consideration the size of the tumor and the histological type before taking the “wait and see” approach. These stage I tumors are highly curable when they first present but, if allowed to recur, chemotherapy may not offer the patient such a favorable response and cure rate.     

Germ cell tumors in children: gonadal and extragonadal.

Sixty-three pediatric patients with germ cell tumors are presented with details of symptoms, histological findings, staging, serological markers, treatment, and response to therapy. The primary sites were: ovarian 32, testicular 17, presacral 7, mediastinal 3, intraabdominal 2, vaginal 1, and right inguinal canal 1. These patients were treated with T2 (sequential use of dactinomycin, doxorubicin, vincristine, and cyclophosphamide, with or without radiation), T6 (combination chemotherapy with cyclophosphamide, bleomycin, dactinomycin, doxorubicin, methotrexate, vincristine), or VAB treatment protocols (velban, dactinomycin, bleomycin, cisplatin). The cure rate for stage I ovarian and testicular germ cell tumors was 100%; for stage III, all primary sites, 82% and for stage IV, all primary sites, 75%. Histology was prognostic in ovarian tumors of the immature malignant teratoma type; the neural type immature teratoma, grades II and III, had the worst prognosis. Initial debulking surgery in combination with chemotherapy and radiation plays an important role in germ cell tumors. Stages II, III, and IV germ cell tumors require aggressive treatment with surgery, radiation, and chemotherapy. For stage I patients, with primary ovarian malignant tumor, cure with surgery alone can be achieved in 50% of the cases and in testicular tumors in about 70% of the patients. For those with stage I and elevated serological markers, it is feasible to follow these markers and give no treatment until there is evidence of persistent elevation or a rise in titers after an initial fall. In those without elevated serological markers, one should take into consideration the size of the tumor and the histological type before taking the "wait and see" approach. These stage I tumors are highly curable when they first present but, if allowed to recur, chemotherapy may not offer the patient such a favorable response and cure rate.     

Outcomes of a pediatric surgical oncology fellowship in a pediatric cancer institution

Surgery plays an important role as part of the treatment plan in most children with malignant solid tumors in regards to initial biopsy, upfront resection, and delayed resection. Surgeons also play a critical role in the treatment of surgical complications that may arise during medical treatment. The pediatric surgical oncologist should be familiar with the current treatment guidelines, histology implications, chemotherapy and radiation side effects, tumor staging, and overall care of the child with cancer. Specific training in pediatric surgical oncology is not widespread internationally and it represents a potential undervalued intervention for improving global pediatric cancer care.     

A phase II trial of a multi‐agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer

Background

Preclinical models show that an antiangiogenic regimen at low‐dose daily (metronomic) dosing may be effective against chemotherapy‐resistant tumors. We undertook a prospective, open‐label, single‐arm, multi‐institutional phase II study to evaluate the efficacy of a “5‐drug” oral regimen in children with recurrent or progressive cancer.

Procedure

Patients ≤21 years old with recurrent or progressive tumors were eligible. Treatment consisted of continuous oral celecoxib, thalidomide, and fenofibrate, with alternating 21‐day cycles of low‐dose cyclophosphamide and etoposide. Primary endpoint was to assess, within eight disease strata, activity of the 5‐drug regimen over 27 weeks. Blood and urine angiogenesis markers were assessed.

Results

One hundred one patients were enrolled; 97 began treatment. Median age was 10 years (range: 191 days–21 years); 47 (49%) were female. Disease strata included high‐grade glioma (HGG, 21 patients), ependymoma (19), low‐grade glioma (LGG, 12), bone tumors (12), medulloblastoma/primitive neuroectodermal tumor (PNET, 8), leukemia (4), neuroblastoma (3), and miscellaneous tumors (18). Treatment was generally well tolerated; most common toxicities were hematologic. Twenty‐four (25%) patients completed 27 weeks therapy without progression, including HGG: 1 (5%), ependymoma: 7 (37%), LGG: 7 (58%), medulloblastoma/PNET: 1, neuroblastoma: 1, and miscellaneous tumors: 7 (39%). Best response was complete response (one patient with medulloblastoma), partial response (12), stable disease (36), progressive disease (47), and inevaluable (1). Baseline serum thrombospondin levels were significantly higher in patients successfully completing therapy than in those who progressed (P = 0.009).

Conclusion

The 5‐drug regimen was well tolerated. Clinical activity was demonstrated in some but not all tumor strata. Pediatric Blood Cancer 2014;61:636–642. © 2013 The Authors Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.     

Renal cell carcinoma in children

Renal cell carcinoma is a rare tumor in childhood, however, rare tumors must be kept in mind if tumor therapy protocols like the SIOP-9 or SIOP 93-01 Wilms' tumor trial include preoperative chemotherapy based on clinical and radiologic findings without further histologic tumor confirmation. We present a 12-year-old boy initially believed to have a stage IV Wilms' tumor with pulmonary metastasis. Following chemotherapy with doxorubicin, vincristine, and actinomycin D, subsequent tumor nephrectomy revealed a highly differentiated renal cell carcinoma (pT₂pN₀). Wedge resection of the lung showed no evidence of a pulmonary metastasis (M₀). The benefit of preoperative chemotherapy with regard to downstaging of the tumor must be considered carefully, taking into account the risk of incorrect tumor diagnosis.     

Ewing sarcoma/primitive neuroectodermal tumor of the kidney treated with chemotherapy including ifosfamide

Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) of the kidney is extremely rare, and is usually diagnosed after nephrectomy without neoadjuvant chemotherapy. Although ifosfamide and etoposide improve survival to a great extent in ES/PNET, the use of nephrotoxic agent, particularly ifosfamide, is a concern after nephrectomy. We describe the case of a 14‐year‐old female patient with abdominal mass who was diagnosed with ES/PNET of the right kidney after nephrectomy. Adjuvant chemotherapy including ifosfamide and etoposide were given. The estimated glomerular filtration rate decreased to 75% after the end of therapy. There was no evidence of recurrence 70 months after initial diagnosis.     

Long-term survival of pancreatoblastoma in children

Pancreatoblastoma is an extremely rare pancreatic tumor of childhood. We report our experience in 2 patients with pancreatoblastoma who had long-term survival and review the literature with a focus on chemotherapy in pancreatoblastoma with vascular invasion. The cases were 7-year-old and 4-year-old girls who complained of an abdominal mass without jaundice. Laboratory findings including serum alpha-fetoprotein were within normal limits. Radiologic investigations revealed a mass in the pancreas with vascular invasion. After surgical resection, postoperative chemotherapy included cisplatin, doxorubicin, ifosfamide, and etoposide. They have now been well for 7 years without recurrence.     

Treatment of metastatic Ewing sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy--a report from the Children's Oncology Group

BACKGROUND: The outcome for patients with Ewing sarcoma family of tumors (ESFTs) of bone with metastases at diagnosis remains poor despite new approaches to treatment. We evaluated whether a dose-intensity chemotherapy regimen improved survival for patients with ESFTs of bone with metastases at diagnosis. METHODS: We entered 60 patients with metastatic ESFTs of bone onto a single arm trial of a new intensive therapy. Treatment consisted of 51-weeks of chemotherapy and local control of the primary with radiation, surgery, or both. The chemotherapeutic protocol included two alternating blocks: one with vincristine (2 mg/m(2)), doxorubicin (90 mg/m(2)), and cyclophosphamide (2,200 mg/m(2)); and the second with ifosfamide (2,800 mg/m(2)/day x 5 days) and etoposide (100 mg/m(2)/day x 5 days). RESULTS: Of the 60 patients with metastatic ESFTs of bone enrolled onto this single arm trial, 12 had metastasis to lung only, 7 to bone marrow or bone only, 38 to multiple sites, 2 in other sites and 3 not specified. There were three toxic deaths. Six patients (6-year cumulative incidence: 9%) developed second malignant neoplasms and died. The 6-year overall event-free survival (EFS) was 28% (standard error (SE) 6%) and survival (S) was 29% (SE 6%). CONCLUSION: An intensified treatment regimen using higher doses of cyclophosphamide, ifosfamide, and doxorubicin increased toxicity and risk of second malignancy without improving EFS and S.     

Preliminary experience with arterial chemoembolization for hepatoblastoma and hepatocellular carcinoma in children

The objective of this work was to test feasibility and efficacy of hepatic artery chemoembolization (HACE) in unresectable malignant liver tumors. Five patients aged from 1-12 years were treated in the Medical University of Gdansk from 1999 to 2002. All had locally advanced tumors, which did not respond to systemic chemotherapy: four, hepatoblastoma (HB) and one, hepatocellular carcinoma (HCC). Arteriography was performed and chemoembolization suspension (cisplatin + doxorubicin + mitomycin mixed with lipiodol) was injected, followed by gelatin foam particles. The procedure was performed one to three times in each patient. In four patients (three, HB, one, fibrolamellar HCC), tumor response was observed, with decrease in the diameter of the mass of 25-33% and fall in the AFP level of 83-99%. One child with HB was non-evaluable due to early death caused by systemic myelotoxicity. Two patients (2 HB) underwent macroscopically complete tumor resection, 1 is alive and well, and 1 died at the end of surgery for an unknown reason (possibly related to cardiotoxicity of earlier systemic chemotherapy). One HB patient was successfully transplanted after two HACE courses. The only HCC patient died because of pulmonary oil embolism immediately after the third HACE course. HACE can lead to tumor regression in most cases and may be considered an alternative for patients with unresectable liver tumors who do not respond to primary systemic chemotherapy and are not candidates for liver transplantation for various reasons.     

BCOR‐CCNB3 fusion‐positive clear cell sarcoma of the kidney

Clear cell sarcoma of the kidney (CCSK) is the second most common malignant pediatric renal tumor. Two of the recurrent somatic alterations reported in CCSK are BCL‐6 corepressor (BCOR) internal tandem duplication (ITD) and YWHAE‐NUTM2B/E gene fusion. A minority of patients with CCSKs have other rare somatic alterations. We report two patients with CCSK showing BCOR‐CCNB3 (where CCNB3 is cyclin B3) fusion, who had similar clinical presentation of a large renal mass with tumor thrombus extending through the inferior vena cava into the right atrium and a favorable response to chemotherapy. We recommend BCOR‐CCNB3 fusion testing for all patients with CCSK who lack BCOR‐ITD or YWHAE‐NUTM2B/E gene fusions.     

Cardioprotective effect of dexrazoxane during treatment with doxorubicin: a study using low-dose dobutamine stress echocardiography

AIM: To assess the late cardioprotective effect of dexrazoxane associated with doxorubicin during treatment of osteosarcoma by means of low-dose dobutamine stress echocardiography (LDDSE) in non-relapsed asymptomatic children and teenagers. PATIENTS AND METHODS: The study population included 58 patients with osteosarcoma divided in three groups, with equivalent age range, gender proportion and body surface area. Group I (21 patients, 14 males, 15 +/- 4 years) was analyzed before chemotherapy and considered the control group; Group II (19 patients, 11 males, 19.7 +/- 4 years) was treated with 348.4 +/- 18 mg/m2 of doxorubicin only and Group III (18 patients, 14 male, 16.8 +/- 5 years) treated with 396.5 +/- 55 mg/m2 of doxorubicin with dexrazoxane in the ratio 10:1. The patients were submitted to LDDSE (maximal dose 5 microg/kg/min). No major side effects were observed. Heart rate, blood pressure, left ventricular diameters, end systolic wall stress (ESWS), and other diastolic and systolic function indexes were assessed at rest conditions and during LDDSE and compared between the three groups. RESULTS: Group III received a doxorubicin dose significantly greater than Group II (P = 0.001). During LDDSE there were no significant changes in the diastolic function indexes in any of the groups, but there was a significant increase of systolic indexes and a decrease of ESWS in Group III compared to group II. There was no significant difference of any systolic functional parameters between Group I and III. Considering the ejection fraction (EF) at rest or at LDDSE, 13 patients (69.4%) in Group II and 5 patients (27.7%) in Group III were considered to have systolic dysfunction. (P = 0.02). CONCLUSION: Myocardial response to LDDSE in patients treated with doxorubicin and dexrazoxane was similar to patients without chemotherapy and better than those treated with doxorubicin only, suggesting less cardiotoxicity.     

Adult type vs. Childhood hepatocellular carcinoma--are they the same or different lesions? Biology,natural history,prognosis, and treatment

BACKGROUND: Differences in the biology, natural history, and treatment results of hepatocellular carcinoma (HCC) in children and adults were sought based on the literature and experience resulting from SIOPEL 1 trial. PROCEDURE: In the SIOPEL1 study, 40 children with HCC were registered from January 1990 to February 1994. Outcome was analyzed in 39. In most cases, disease was advanced at diagnosis: 31% had metastases and 39% had extrahepatic tumor extension and/or vascular invasion. More than 50% of patients had multifocal tumors; 39% of tumors were associated with hepatic cirrhosis. All, but two patients, received preoperative chemotherapy (PLADO--cisplatin and doxorubicin). Outcome, response to treatment, and prognostic factors were analyzed using the SAS statistical package. RESULTS: Overall survival (OS) at 5 years is 28% and EFS is 17% at median follow-up of 75 months (49-90). Partial response to chemotherapy was observed in 18 of 37 cases evaluated (49%). Complete tumor resection was achieved in 14 of the 39 patients (36%). Twenty (51%) never became operable. Multifocality of the tumor, presence of metastases, and PRETEXT grouping adversely influenced OS. A large number of "de novo" HCC cases, fairly high response rate to preoperative chemotherapy (49%) and 54% survival after complete resection constitute a significant difference in comparison with adult HCC series. CONCLUSIONS: Survival for pediatric HCC patients is below 30%. Radical tumor resection remains the only chance for survival. New multi-center prospective studies in children with HCC are required to better results and to allow further study of differences between adult and pediatric HCC should they exist.