The clinical characteristics and treatment outcome of 57 children and adolescents with primary central nervous system germ cell tumors

Primary central nervous system germ cell tumors （CNS-GCTs） in children and adolescents have unique clinical features and methods of treatment compared with those in adults. There is little information about Chinese children and adolescents with CNS-GCTs. Therefore, in this study we retrospectively analyzed the clinical features and treatment outcome of Chinese children and adolescents with primary CNS-GCTs. Between January 2002 and December 2012, 57 untreated patients from a single institution were enrolled. They were diagnosed with CNS-GCTs after pathologic or clinical assessment. Of the 57 patients, 41 were males and 16 were females, with a median age of 12.8 years （range, 2.7 to 18.0 years） at diagnosis; 43 （75.4%） had non-germinomatous germ cell tumors （NGGCTs） and 14 （24.6%） had germinomas; 44 （77.2%） had localized disease and 13 （22.8%） had extensive lesions. Fifty-three patients completed the prescribed treatment, of which 18 underwent monotherapy of surgery, radiotherapy, or chemotherapy, and 35 underwent multimodality therapies that included radiotherapy combined with chemotherapy or surgery combined with chemotherapy and/or radiotherapy. PEB （cisplatin, etoposide, and bleomycin） protocol was the major chemotherapy regimen. The median follow-up time was 32.3 months （range, 1.2 to 139 months）. Fourteen patients died of relapse or disease progression. The 3-year event-free survival （EFS） and overall survival rates for all patients were 72.2% and 73.8%, respectively. The 3-year EFS was 92.9% for germinomas and 64.8% for NGGCTs （P = 0.064）. The 3-year EFS rates for patients with NGGCTs who underwent monotherapy and multimodality therapies were 50.6% and 73.5%, respectively （P = 0.042）. Our results indicate that multimodality therapies including chemotherapy plus radiotherapy were better treatment option for children and adolescents with CNS-GCTs.     

Treatment and outcomes of UK and German patients with relapsed intracranial germ cell tumors following uniform first‐line therapy

We aimed to retrospectively assess treatments/outcomes, including the value of high‐dose‐chemotherapy and autologous‐stem‐cell‐rescue (HDC + AuSCR) and re‐irradiation, in a large, European patient‐cohort with relapsed intracranial germ‐cell‐tumors (GCTs) receiving uniform first‐line therapy, including radiotherapy as standard‐of‐care. Fifty‐eight UK/German patients (48 male/10 female) with relapsed intracranial‐GCTs [13 germinoma/45 non‐germinomatous GCT (NGGCT)] treated 1996–2010 as per the SIOP‐CNS‐GCT‐96 protocol were evaluated. For germinoma, six patients relapsed with germinoma and five with NGGCT (one palliative, one teratoma patient excluded). Five‐year overall‐survival (OS) for the whole‐group (n = 11) was 55%. Four of six germinoma relapses and two of five relapsing with NGGCT were salvaged; patients were salvaged with either standard‐dose‐chemotherapy (SDC) and re‐irradiation or HDC + AuSCR with/without re‐irradiation. Of 45 relapsed NGGCT patients, 13 were excluded (three non‐protocol adherence, five teratoma, five palliation). Five‐year OS for the remaining 32 relapsed malignant NGGCT patients treated with curative intent was 9% (95%CI: 2–26%). By treatment received, 5‐year OS for the 10 patients receiving SDC and 22 patients treated with intention for HDC + AuSCR was 0% (0–0%) and 14% (3–36%), respectively. The three relapsed NGGCT survivors had raised HCG markers alone; two received additional irradiation. Patients with relapsed germinoma had better 5‐year OS than those with relapsed NGGCT (55 vs. 9%; p = 0.007). Patients with relapsed germinoma were salvaged both with SDC and re‐irradiation or HDC + AuSCR with/without re‐irradiation; both represent valid treatment options. Outcomes for malignant relapse following initial diagnosis of NGGCT were exceptionally poor; the few survivors received thiotepa‐based HDC + AuSCR, which is a treatment option at first malignant relapse for such patients, with further surgery/irradiation where feasible.     

KRAS Mutation in Pediatric Intracranial Germ Cell Tumors

Background: Intracranial germ cell tumors (IGCTs) are rare, highly curable neoplasms. KRAS is a gene in the KIT/RAS signaling pathway, and KRAS mutations have been reported in patients diagnosed with IGCTs. Objectives: To describe the clinicopathologic and molecular features of KRAS mutation and the treatment outcome of children diagnosed with IGCTs. Methods: Patients diagnosed with IGCTs at the Department of Pediatrics, King Chulalongkorn Memorial Hospital from 2007 to 2016 were retrospectively reviewed. DNA was extracted from formalin-fixed, paraffin-embedded tissue and used for molecular study. Mutations in codons 12, 13, and 61 of the KRAS gene were detected using the cobas® KRAS mutation test and pyrosequencing. Results: Eighteen patients were diagnosed with IGCTs (11 males and 7 females): nine with germinomas and nine with non-germinomatous GCTs (NGGCTs). The age range of the patients was 5–14 years (median 10.5 years). Elevated markers were revealed in approximately 25% of the patients. Four patients (two with germinomas and two with NGGCTs) had leptomeningeal involvement. All patients underwent tumor biopsy and received neoadjuvant chemotherapy. Radiotherapy was administered in 16 patients, and craniospinal radiation was administered only in patients with leptomeningeal metastasis. With a median follow-up of 26 months, overall survival was 88.9% in the patients with germinomas and 37% in the patients with NGGCTs. Mutation of the KRAS gene was detected using pyrosequencing in one patient. The mutation located at codon 61, with frequency 38.3% units, nucleotide substitution CAA > CTA, and amino acid substitution, was Q61L. The patient carrying the mutant gene was diagnosed with germinoma with cerebrospinal fluid metastasis and eventually died from treatment-related toxicity. Conclusion: Our study revealed the treatment outcomes of IGCTs in Thai children. The metastatic germinoma patient with KRAS codon 61 mutation had a poor outcome, supporting that Q61L has a clinical correlation with IGCTs.     

Salvage high-dose chemotherapy for children with extragonadal germ-cell tumours

We reviewed the European Group for Blood and Marrow Transplantation (EBMT) experience with salvage high-dose chemotherapy (HDC) in paediatric patients with extragonadal germ-cell tumour (GCT). A total of 23 children with extragonadal GCT, median age 12 years (range 1-20), were treated with salvage HDC with haematopoietic progenitor cell support. The GCT primary location was intracranial site in nine cases, sacrococcyx in eight, retroperitoneum in four, and mediastinum in two. In all, 22 patients had a nongerminomatous GCT and one germinoma. Nine patients received HDC in first- and 14 in second- or third-relapse situation. No toxic deaths occurred. Overall, 16 of 23 patients (70%) achieved a complete remission. With a median follow-up of 66 months (range 31-173 months), 10 (43%) are continuously disease-free. Of six patients who had a disease recurrence after HDC, one achieved a disease-free status with surgical resection followed by chemotherapy and radiotherapy. In total, 11 patients (48%) are currently disease-free. Eight of 14 patients (57%) with extracranial primary and three of nine patients (33%) with intracranial primary GCT are currently disease-free. HDC induced impressive long-term remissions as salvage treatment in children with extragonadal extracranial GCTs. Salvage HDC should be investigated in prospective trials in these patients.     

Pediatric central nervous system germ cell tumors: a review

Central nervous system (CNS) germ cell tumors (GCTs) represent approximately 3% of primary pediatric brain tumors and encompass a wide pathologic spectrum. CNS GCTs are most commonly located in the pineal and suprasellar regions of the brain and can be divided into major groups including germinomas and nongerminomatous GCTs (NGGCTs), with teratomas often considered a separate category. The clinical presentation varies by location and size, and it frequently includes endocrine abnormalities, visual changes, and signs of increased intracranial pressure. Neuroimaging studies cannot differentiate GCTs from other tumors, and therefore, the diagnosis usually requires histologic confirmation. The rare exceptions are the cases where characteristic elevations of tumor markers, including alpha-fetoprotein and/or beta-human chorionic gonadotropin are documented in the serum and/or cerebrospinal fluid. In these cases, the imaging findings along with the tumor marker elevation may be diagnostic in themselves without the need for tissue confirmation. Treatment and prognosis differ greatly between groups. Germinomas have a superior prognosis than NGGCTs. Five-year overall survival rates >90% were reported initially with the use of craniospinal irradiation. More recently, the use of chemotherapy in addition to radiation therapy has afforded the ability to decrease the dose and volume of radiation therapy without affecting survival rates. NGGCTs are less radiosensitive than germinomas, but the use of adjuvant chemotherapy has improved survival rates in this group as well. The standard management for CNS GCTs remains controversial. Treatment regimens aimed to improve progression-free and overall survival times are ongoing.     

High-dose chemotherapy with autologous stem-cell rescue in children and adults with newly diagnosed pineoblastomas.

PURPOSE: We evaluated the usefulness of a treatment regimen that included high-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) in patients with newly diagnosed pineoblastoma (PBL). PATIENTS AND METHODS: Twelve patients with PBL were initially treated with surgery and induction chemotherapy. All but two patients underwent radiotherapy. Subsequently, all patients received HDC using cyclophosphamide (CTX) + melphalan (MEL) or busulfan (Bu) + MEL regimens and ASCR. RESULTS: A total of six children and six adults with median ages of 4.2 (range, 0.3 to 19.8 years) and 23 years (range, 23 to 43.7 years), respectively, were treated according to this strategy. Four patients had metastatic disease confined to the neuraxis. Five of 12 patients (42%) had a complete tumor resection at diagnosis. Ten patients received radiotherapy at median doses of 36.0 and 59.4 Gy to the neuraxis and pineal region, respectively. Eleven patients received HDC with CTX + MEL, and one patient received BU + MEL followed by ASCR. Nine patients are alive with no evidence of disease recurrence at a median of 62 months from diagnosis (range, 28 to 125 months), including three patients with metastatic disease and two infants who did not receive any radiotherapy. Three patients have died of progressive disease at 19, 32, and 37 months from diagnosis, respectively. The actuarial 4-year progression-free and overall survivals are 69% (95% confidence interval [CI], 39% to 99%) and 71% (95% CI, 43% to 99%), respectively. CONCLUSION: The use of HDC in addition to radiotherapy seems to be an effective treatment for patients with newly diagnosed pineoblastoma.     

High-dose carboplatin,thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma

Recurrent medulloblastoma is highly lethal in previously irradiated patients. Previously irradiated patients with M-0–M-3 recurrences who achieved a minimal disease state prior to protocol enrollment received carboplatin (Calvert formula with area under the curve = 7 mg/mL min, maximum 500 mg/m²/day) on days −8 to −6, and thiotepa (300 mg/m²/day) and etoposide (250 mg/m²/day) on days −5 to −3, followed by autologous stem cell rescue (ASCR) on day 0. Twenty-five patients, aged 7.6–44.7 years (median 13.8 years) at ASCR, were treated. Three (12%) died of treatment-related toxicities within 30 days of ASCR, due to multiorgan system failure (n = 2) and aspergillus infection with veno-occlusive disease (n = 1). Tumor recurred in 16 at a median of 8.5 months (range 2.3–58.5 months). Six are event-free survivors at a median of 151.2 months post-ASCR (range 127.2–201.6 months). The Kaplan–Meier estimate of median overall survival is 26.8 months (95% CI: 11.9–51.1 months) and of event-free survival (EFS) and overall survival are both 24% (95% CI: 9.8%–41.7%) at 10 years post-ASCR. M-0 (vs M-1 + ) recurrence prior to protocol, lack of tissue confirmation of relapse, and initial therapy of radiation therapy (RT) alone (vs RT + chemotherapy) were not significantly associated with better EFS (P = .33, .34, and .27, respectively). Trends toward better EFS were noted in patients (n = 5) who received additional RT as part of their retrieval therapy (P = .07) and whose recurrent disease was demonstrated to be sensitive to reinduction chemotherapy (P = .09). This retrieval strategy provides long-term EFS for some patients with previously irradiated recurrent medulloblastoma. The use of additional RT may be associated with better outcome.     

Primary CNS germ cell tumors: current epidemiology and update on treatment

Primary central nervous system (CNS) germ cell tumors (GCTs) are a heterogeneous group of lesions that account for 0.5 % of all primary brain and CNS tumors, occurring at an incidence rate of 0.10 per 100,000 person-years in the United States with approximately 90 % of the cases before the age of 20 years. Primary CNS GCTs demonstrate a remarkable difference in incidence based on gender and location within the brain with males having a 15:1 incidence in the pineal region while the gender incidence is nearly 1:1 in the rest of the brain. Also, historically the incidence was noted to be significantly higher in Japan and East Asia, but recent studies in Japan demonstrate similar incidence as in the United States. They are broadly classified as germinomas and non-germinomatous germ cell tumors (NGGCTs) based on clinicopathologic features. Germinomas are sensitive to treatment with radiotherapy and chemotherapy with high cure rates and carry an excellent prognosis, while NGGCTs display various forms of differentiation, have a poorer prognosis and are refractory to therapy. Standard management of CNS GTCs remains unsettled and ongoing research aims to achieve best possible survival rates and post-treatment quality of life by reduction in treatment intensity.     

Treatment outcomes of female germ cell tumors: The Egyptian National Cancer Institute experience

IntroductionFemale germ cell tumors (GCTS) are rare tumors that carry a good prognosis.AimTo report the experience of the Egyptian National Cancer Institute (ENCI) in managing female GCTs.MethodsThis retrospective study included 19 females with ovarian GCTs presenting to the ENCI between 2006 and 2010.ResultsThe median age was 23 years. Ovaries were the primary site in all patients. Dysgerminoma and teratoma were the predominant pathologies followed by mixed GCT in females. Unilateral ovariectomy or ovarian tumorectomy were the classic surgical procedures with R0 resection being feasible in most cases. Surveillance was adopted in six patients with stage I disease. Chemotherapy was administered in 63% of ovarian GCTs with BEP being the commonest regimen with reasonable tolerability and good response rates. The median OS and EFS were not reached. The projected 5-year OS rate was 93.8%. Both OS and EFS were better in patients responding to chemotherapy than non-responders (p < 0.002). Stage of disease did not significantly affect OS or EFS.ConclusionsFemale GCTs rarely affect Egyptian females. They have good prognosis.     

23例原发中枢神经系统生殖细胞瘤综合治疗的疗效分析

背景与目的:原发中枢神经系统生殖细胞瘤(primary central nervoussystem germ cell tumors,CNS GCTs)是较罕见的恶性肿瘤,病理类型多样。除纯生殖细胞瘤和成熟畸胎瘤外,其它类型预后较差。目前的研究多联合包括化疗在内的综合治疗以改善生存。本文分析PEB方案化疗联合放疗/手术的综合治疗的疗效及不良反应。方法:2002年5月至2006年6月期间中山大学肿瘤防治中心收治的23例CNS GCTs患者入组,中位年龄16岁,82.6%的患者AFP和/或β-HCG升高。所有患者均采用PEB方案化疗结合手术/放射治疗。PEB方案:顺铂20mg/m2d1～5或80～100mg/m2d1,足叶乙甙或替尼泊甙60～100mg/m2d1～5,博来霉素10mg/m2,d1,d5,每3周重复。结果:17例初治患者采用诱导化疗后放射治疗或手术/放疗后辅助化疗;6例复发患者行挽救化疗,其中3例肿瘤播散的患者挽救化疗后补充全中枢放疗。23例患者共完成61个周期的PEB方案化疗,中位化疗3周期,单纯化疗的客观有效率为87.0%,完全缓解率为30.4%。全中枢放疗14例,局部放疗8例,1例未放疗。13例接受过手术治疗但均未能完全切除肿瘤。综合治疗后60.9%(14/23)的患者持续完全缓解至今生存未复发。中位随访24个月,死亡6例,均死于肿瘤进展。全组2年生存率为67.4%。主要不良反应为迟发性放射性损伤:继发性再生障碍性贫血并下丘脑综合征1例,放射性脑病1例,垂体功能减退2例。结论:对CNS GCTs特别是伴有肿瘤标记物升高的患者,PEB方案化疗联合放疗/手术的综合治疗可获得较好的疗效和生存率,但全中枢放疗的远期副作用不容忽视。     

Outcome and prognostic factors in advanced Hodgkin's disease treated with high-dose chemotherapy and autologous stem cell transplantation: a study of 341 patients.

BACKGROUND: The reported probability of survival of patients with Hodgkin's disease (HD) following high-dose chemotherapy with autologous stem cell transplantation (HDC/ASCT) is 35-65% at 5 years. The Polish Lymphoma Research Group investigated retrospectively prognostic factors for overall survival (OS) and event-free survival (EFS), and the risk of secondary malignancies in a large series of patients who underwent HDC/ASCT. PATIENTS AND METHODS: The data of 341 consecutive patients treated in 10 centers from 1990 to 2002 were collected and analyzed. RESULTS: The actuarial 5-year OS and EFS were 64% [95% confidence interval (CI) 57% to 71%] and 45% (95% CI 39% to 51%), respectively. In the multivariate model, unfavorable prognostic factors for EFS were less than partial response at the time of ASCT [relative risk (RR), 2.92 (95% CI 1.68-5.08); P<0.001] and three or more previous chemotherapy lines (RR, 2.16; 95% CI 1.42-3.30; P<0.001). These two factors were also associated with unfavorable OS (RR, 3.32; 95% CI 1.90-5.79; P<0.001 and RR, 2.34, 95% CI 1.51-3.64; P<0.001). Five-year cumulative risk of secondary malignancy was 8.4% (95% CI 2% to 13%) and the only identified risk factor was splenectomy (P=0.02). CONCLUSIONS: HDC/ASCT should be considered early in the course of disease for patients with a response after standard therapy.     

High-dose chemotherapy with autologous stem cell transplantation in adults with recurrent embryonal tumors of the central nervous system

BACKGROUND: Embryonal central nervous system (CNS) tumors (medulloblastoma, cerebral neuroblastoma, pineoblastoma, and primitive neuroectodermal tumors) are rare in adults. Recurrent disease has an extremely poor outcome. The use of high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has demonstrated promising results in children with recurrent disease, but there are only limited data regarding its role in adults. The purpose of the current study was to evaluate adult patients with embryonal CNS tumors who were treated with HDC with ASCT and compare their outcomes with those of patients who received conventional-dose chemotherapy. METHODS: The authors reviewed the medical records of 23 adult patients (age >or= 18 years) who were treated at the Mayo Clinic for recurrent embryonal CNS tumors between 1976 and 2004. The authors compared treatment with HDC with ASCT (10 patients) with an historic control of patients treated with conventional-dose chemotherapy (nitrosourea based, cisplatin based, or both) (13 patients). RESULTS: HDC with ASCT was associated with increased survival (P= .044) and a longer time to disease progression (TTP) (P= .028). The conventional-dose chemotherapy group had a median TTP of 0.58 years and a median survival of 2.00 years. The HDC with ASCT group had a median TTP of 1.25 years and a median survival of 3.47 years. When restricted to patients receiving ASCT after first disease recurrence, the median TTP was 2.5 years and the median survival was 4.16 years. Toxicities were similar in both groups. CONCLUSIONS: Improvements in the median TTP and survival noted with the administration of HDC with ASCT, as well as the acceptable toxicity of this regimen, supports consideration of its use in adults with recurrent embryonal CNS tumors.     

Induction chemotherapy followed by low-dose involved-field radiotherapy for intracranial germ cell tumors.

PURPOSE: To investigate the efficacy of chemotherapy followed by low-dose involved-field radiotherapy for the treatment of intracranial germ cell tumors (GCTs). PATIENTS AND METHODS: Thirty-three patients with GCTs, including 16 pure germinomas, 11 human chorionic gonadotropin-beta (HCG-beta)-secreting germinomas, three mixed GCTs composed of immature teratomas plus germinomas (IMT/G), and three highly malignant mixed GCTs, were treated. Etoposide and cisplatin (EP) were used for the treatment of solitary pure germinomas, and ifosfamide, cisplatin, and etoposide (ICE) were used for the treatment of other GCTs. The dose schedule was 24 Gy for germinomas and 40 to 54 Gy for other GCTs. An involved-field set-up was used except for highly malignant GCTs, in which craniospinal irradiation was used. The median follow-up was 58 months (range, 18 to 102 months). RESULTS: Disease-related, overall, and relapse-free survival rates at 5 years were 100%, 93%, and 69% for all patients, 100%, 100%, and 86% for patients with pure germinomas, and 100%, 75%, and 44% for patients with HCG-beta-secreting germinomas, respectively. All six patients with nongerminomatous GCTs were alive at the last follow-up. All eight relapses (one pure germinoma, five HCG-beta-secreting germinomas, and two IMT/G), except one in a course of salvage treatment, were salvaged and free of disease at the last follow-up. No decline was observed in the full-scale, verbal, or performance intelligence quotient at 12 to 51 months after the treatment in 11 patients. CONCLUSION: Our results support an excellent prognosis after EP and ICE regimens followed by radiotherapy. Dose and volume can be reduced to 24 Gy in 12 fractions and involve a field set-up after EP chemotherapy for the treatment of pure germinomas.     

The United Kingdom Children's Cancer Study Group's second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity.

PURPOSE: To evaluate carboplatin, etoposide, and bleomycin (JEB) in children with malignant extracranial germ cell tumors (GCTs). PATIENTS AND METHODS: Malignant GCTs in children aged 0 to 16 years were excised without major morbidity or otherwise biopsied. Stage I testicular and some ovarian GCTs were resected and monitored with alpha-fetoprotein (AFP) ("watch-and-wait" approach). Patients with recurrent stage I disease and all other patients received JEB (etoposide 120 mg/m(2) on days 1 through 3, carboplatin 600 mg/m(2) on day 2, and bleomycin 15 mg/m(2) on day 3). Courses were administered every 3 to 4 weeks until remission, and then two more courses were given. Chemotherapy toxicities were assessed using World Health Organization or Brock grading. RESULTS: Between January 1989 and December 1997, 192 patients were registered. Eight were excluded because either there was no histologic diagnosis (n = 3) or chemotherapy was given off-study (n = 5). The remaining 184 patients had germinoma (n = 20), malignant teratoma (n = 55), embryonal carcinoma (n = 1), yolk sac tumor (n = 107), or choriocarcinoma (n = 1). Forty-seven patients were treated with surgery alone, and 137 patients received JEB. The 5-year survival rate in March 1999 for all 184 patients was 93.2% (95% confidence interval [CI], 87.9% to 96.3%); for the 137 JEB-treated patients, it was 90.9% (95% CI, 83.9% to 95.0%), with an event-free survival rate of 87.8% (95% CI, 81.1% to 92.4%). The median follow-up after JEB treatment was 53 months (range, 0 to 109 months); the median number of courses was five (range, three to eight). Site, stage, and AFP level had prognostic significance. Nonfatal hematologic toxicity was common, but deafness and pulmonary and renal toxicities were rare. One child died of a thoracic tumor and bronchopulmonary dysplasia, and another died of acute myeloid leukemia. CONCLUSION: Conservative surgery, a watch-and-wait approach after complete excision, and JEB for those requiring chemotherapy produced high cure rates and few serious complications.     

Long term outcomes in patients with intracranial germinomas: a single institution experience of irradiation with or without chemotherapy

Complete remission can be achieved soon after irradiation in patients with intracranial germinoma. This study aimed to analyze the follow-up outcome of intracranial germinoma patients. About 39 intracranial germinoma patients (29 males and 10 females; average age, 15 years; range, 7–27 years) treated at Kyoto University Hospital from 1978 to 2004 were included in the study group. Six patients had multifocal disease at initial diagnosis, and 10 had human chorionic gonadotropin (HCG)-producing tumors. Thirteen patients were treated with craniospinal axis irradiation, 6 with whole-brain irradiation, 17 with whole-ventricle irradiation, and 3 with local field irradiation. Since 1997, 15 patients were treated with reduced–dose whole-ventricle irradiation (median, 23.4 Gy; range, 20.4–27 Gy) followed by a local boost (median, 40.8 Gy; range, 36–54 Gy) combined with chemotherapy. The median follow-up was 94 months (18 months to 25 years). The 5- and 10-year overall survival (OS) rates of the entire group were 97 and 90%, respectively. The 5- and 10-year progression-free survival (PFS) rates of the entire group were 91 and 87%, respectively. The 8-year OS and PFS in 15 patients treated by whole-ventricle irradiation combined with chemotherapy were 100% and 92%, respectively. Four patients had recurrences within a median period of 59.5 months (51–85 months). All relapses occurred outside the radiation fields. Tumor site, tumor size, HCG production, multifocal disease and radiation dose to the primary site or whole ventricle did not significantly affect PFS. All initial recurrences of intracranial germinoma occurred at the distant site out of the radiation field. Our data suggested that reduced doses to the whole ventricle, combined with chemotherapy, should be sufficiently effective in patients with intracranial germinoma.     

High-dose chemotherapy and autologous stem cell rescue for metastatic breast cancer: superior survival for tandem compared with single transplants

During 1990-1999, we treated 60 patients with breast cancer who had distant metastases with high-dose chemotherapy and autologous stem cell rescue (HDC) after they had responded to induction chemotherapy. HDC regimens were MiTepa (60 mg/m2 mitoxantrone by continuous intravenous infusion over 3 days plus 300 mg/m2 thiotepa intravenously over 2 hours daily x 3 days) and ICE (12 g/m2 ifosfamide, 1800 mg/m2 carboplatin, 2 g/m2 etoposide; all 3 by continuous intravenous over 4 days). At a median follow up >8 years, the median failure-free survival (FFS) was 13.9 months, median overall survival (OS) 29.1 months, 5-year FFS 12%s and 5-year OS 25%. Thirty-three patients underwent tandem (T) transplants; 27 underwent a single (S) HDC. Median ages for these 2 groups were 45 and 48 years; bone and liver metastases were more prevalent in the T cohort, whereas lung metastases were more prevalent in the S cohort. At a median follow up of 6.5 years for the S group and >9 years for the T group, there were 52 deaths. FFS was better for T: median 15.7 versus 7.7 months (p2 = 0.010) as was OS: median 32.7 versus 17.7 months, 2-year survival 68% versus 41%, and 5-year survival 32% versus 15% (p2 = 0.010). As a group, patients with distant metastatic breast cancer who underwent tandem transplants had a better posttransplant survival than patients who underwent a single HDC.     

So-called bifocal tumors with diabetes insipidus and negative tumor markers: are they all germinoma?

BackgroundThe Delphi consensus statements on the management of germ cell tumors (GCTs) failed to reach agreements on the statement that the cases with (i) pineal and neurohypophyseal bifocal lesion, (ii) with diabetes insipidus, and (iii) with negative tumor markers can be diagnosed as germinoma without histological verification. To answer this, multicenter retrospective analysis was performed.MethodsA questionnaire on clinical findings, histological diagnosis, and details of surgical procedures was sent to 86 neurosurgical and 35 pediatrics departments in Japan.ResultsFifty-one institutes reported 132 cases that fulfilled the 3 criteria. Tissue sampling was performed in 91 cases from pineal (n = 44), neurohypophyseal (n = 32), both (n = 6), and distant (n = 9) lesions. Histological diagnosis was established in 89 cases: pure germinoma or germinoma with syncytiotrophoblastic giant cells in 82 (92.1%) cases, germinoma and mature teratoma in 2 cases, and granulomatous inflammation in 2 cases. Histological diagnosis was not established in 2 cases. Although no tumors other than GCTs were identified, 3 (3.4%) patients had non-germinomatous GCTs (NGGCTs). None of the patients developed permanent complications after endoscopic or stereotactic biopsy. Thirty-nine patients underwent simultaneous procedure for acute hydrocephalus without permanent complications, and hydrocephalus was controlled in 94.9% of them.ConclusionAll patients who fulfilled the 3 criteria had GCTs or granulomatous inflammation, but not other types of tumors. However, no fewer than 3.4% of the patients had NGGCTs. Considering the safety and the effects of simultaneous procedures for acute hydrocephalus, biopsy was recommended in such patients.     

Intracranial Germ Cell Tumors: A Single Institution Experience and Review of the Literature

There is little literature to guide therapy in children and young adults with intracranial germ cell tumors. We present 17 consecutively diagnosed intracranial germ cell tumors at The Children's Hospital, Denver, from 1995 to 2001. Of 17 patients, 3 had considerable delay in diagnosis. Two with suprasellar tumors presented with dementia, blindness and pan-hypopituitarism and another with recurrent subarachnoid hemorrhage. Seven had germinoma, three were metastatic at diagnosis. Ten had non-germinomatous germ cell tumors (NGGCT), 5/10 were alpha feto-protein (AFP) positive only, one beta-human chorionic growth (betaHCG) factor positive only, 3 positive for AFP and betaHCG, and 1 malignant teratoma. Therapy for metastatic patients consisted of chemotherapy followed by craniospinal radiation (CSI). Patients with localized disease received chemotherapy followed by focal radiation. Two patients received chemotherapy only, one because she died of sepsis while receiving chemotherapy and one because of neurologic injury incurred during surgery parents elected for no therapy. Three patients have died, one of tumor recurrence, one from a remote complication of surgery and one of sepsis. Twelve patients are alive without evidence of disease from 10 to 68 months (median 31.5 months). All five children with only AFP positivity, treated with chemotherapy and focal radiation are alive without evidence of disease at 10, 16, 22, 41 and 41 months. Thus, there is little evidence that CSI is necessary in non-metastatic germinomas and AFP positive NGGCTs when combined chemotherapy and radiation therapy is used. However, complications of delayed diagnosis, surgery and chemotherapy are important causes of mortality, with only one patient dying of tumor.     

Treatment of children and adolescents with stage II testicular and stages I and II ovarian malignant germ cell tumors: A Pediatric Intergroup Study--Pediatric Oncology Group 9048 and Children's Cancer Group 8891.

PURPOSE: To determine whether children with localized gonadal malignant germ cell tumors (MGCT) stage II testicular and stages I and II ovarian treated with four cycles of standard-dose cisplatin combined with etoposide and low-dose bleomycin (PEB) have an event-free survival (EFS) of at least 85% without significant toxicity. PATIENTS AND METHODS: Between May 1990 and July 1995, eligible pediatric patients with stage II or recurrent from stage I (as a stage II) testicular MGCT and stages I and II ovarian MGCT were enrolled onto this Pediatric Oncology Group and Children's Cancer Group study. PEB chemotherapy consisted of bleomycin 15 U/m2 on day 1, cisplatin 20 mg/m2/d on days 1 to 5, and etoposide 100 mg/m2/d on days 1 to 5. Patients received four cycles of therapy at 21-day intervals. RESULTS: Seventy-four patients with a median age of 10.5 years (range, 8.7 months to 16.7 years) were enrolled. Primary sites included: stage II testicular (n = 17), stage I ovarian (n = 41), and stage II ovarian MGCT (n = 16). Treatment with standard PEB resulted in 6-year EFS of 95% and overall survival (OS) of 95.7%. EFS and OS by primary site were as follows: stage II testicular, 100% and 100%; stage I ovarian, 95.1% and 95.1%; and stage II ovarian, 87.5% and 93.8%, respectively. Two patients died from recurrent disease, and one patient died of secondary acute myelocytic leukemia. Infrequent grade 3 to 4 hematologic toxicity was reported. No grade 3 to 4 renal, pulmonary, or ototoxicity was observed. CONCLUSION: Combination chemotherapy with PEB results in excellent EFS and OS with minimal toxicity in children and adolescents with localized gonadal MGCT.     

Late recurrence and salvage therapy of CNS germinomas

Central nervous system (CNS) germinoma is a curable tumor and its recurrence rate after initial therapy may be approximately 10% or higher. This study elucidates the time-course of recurrence and results of salvage therapy. Twenty-five patients with recurrent germinoma treated at Hokkaido University Hospital were retrospectively reviewed. The median age at initial treatment was 12 years (range: 8–37). All patients had been tumor-free for at least 6 months after the initial treatment. The median follow-up period was 134 months (range: 44–338). The median age at first recurrence was 18 years and the median time to the first recurrence was 50 months. Among the patients, 9 (36%) had the first recurrence at 60 months or later. The latest recurrence in a patient occurred 230 months after the initial treatment. The results of salvage therapy were estimated in all 25 patients. Seventeen patients (68%) were salvaged and were tumor-free at the final observation. The remaining 8 patients died of disease. At first recurrence, 11 patients were treated using radiation therapy with or without surgery and 7 out of the 11 patients died due to the recurrent tumor. On the other hand, 13 patients who received salvage chemotherapy and radiotherapy were tumor-free at the last follow-up. In conclusion, late recurrence is not a rare event in patients with CNS germinoma. To identify a true cure rate of this disease, a 10-year or longer observation period may be required. As a salvage therapy, platinum-based chemotherapy followed by wide-field low-dose radiation therapy appears to be effective.