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Background: The chemotherapy regimens recommended for both rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) patients are myelosuppressive and can reduce the absolute neutrophil count (ANC) and subsequently increase the risk of febrile neutropenia (FN). However, only a few studies have focused on the efficacy and safety of granulocyte-colony stimulating factor (G-CSF) drugs in pediatric and adolescent patients with RMS and ES. Our objective was to investigate the efficacy and safety of mecapegfilgrastim, a biosimilar of pegfilgrastim, in prophylaxis of FN for pediatric and adolescent patients with RMS or ES., Methods: In this single-arm, single-center, prospective study, pediatric and adolescent patients with RMS or ES were enrolled to receive either VAC (vincristine, cyclophosphamide, dactinomycin) regimen or VDC (vincristine, cyclophosphamide, doxorubicin) regimen in a 3-week cycle, followed by treatment with mecapegfilgrastim (100 μg/kg, maximum 6 mg) given at 24 h after completing chemotherapy. The primary endpoint was the incidence rate of FN. Secondary endpoints included the incidence rate of grade 4 neutropenia, duration of ANC ≤ 0.5 × 10 9 /L, incidence rate of chemotherapy delay or reduction, use of antibiotics, and safety profile., Results: In total, 2 of the 30 (6.7%, 95% CI: 0.82-22.07) patients experienced FN after the first cycle of chemotherapy. Eight (26.7%, 95% CI: 12.28-45.89) patients experienced grade 4 neutropenia after receiving prophylactic mecapegfilgrastim. Eight patients experienced ANC ≤ 0.5 × 10 9 /L with a median duration of 4.5 days; among them, 6 patients reached the lowest point of their ANC level on day 7, and 5 of them recovered by day 10. No dose reductions, delays, or discontinuation of chemotherapy was reported. Twenty-one (70.0%) patients received antibiotics during the treatment period. No patient experienced FN in the 0-5 years and the 13-18 years groups, and 2 patients experienced FN in the 6-12 years group. Two patients, 6 patients, and no patient experienced grade 4 neutropenia in the 0-5 years, 6-12 years, and 13-18 years groups, respectively., Conclusion: Mecapegfilgrastim showed acceptable efficacy and safety profile in pediatric and adolescent patients with RMS or ES. Further randomized studies with large sample size are warranted., Trial Registration: This clinical trial was registered at Chictr.org.cn (No.ChiCTR1900022249). Registered on March 31, 2019., (© 2024. The Author(s).)

Background: Gestational Trophoblastic Neoplasia (GTN) is a disease of the reproductive age group with an incidence rate of <1% among all tumors involving the female reproductive tract. It occurs because of aberrant fertilization. Patients are diagnosed early because of aggravated symptoms during pregnancy. Moreover, patients also bleed from the tumor sites, which leads to early presentation. A cure rate of 100% can be achieved with adequate treatment., Main Body: In this literature review, the authors have brought to attention the risk factors, classification, and various treatment options in GTN patients according to their stratification as per the WHO scoring system. Patients are categorized into low and high risk based on the FIGO scoring system. Patients with low risk are treated with single-agent methotrexate or actinomycin-D. Despite the superiority of actinomycin-D in terms of efficacy, methotrexate remains the first choice of therapy in low-risk patients due to its better toxicity profile. Multi-agent chemotherapy with etoposide, methotrexate, actinomycin-D, cyclophosphamide and vincristine (EMA-CO) leads to complete remission in 93% of high-risk GTN patients. Around 40% of patients with incomplete responses are salvaged with platinum-based multi-agent chemotherapy. Isolated chemo-resistant clones can be salvaged with surgical interventions., Conclusion: The mortality in patients with GTN has significantly reduced over time. With adequate multi-disciplinary support, patients with GTN can ultimately be cured and can spend every day healthy reproductive life., (© 2023. The Author(s).)

Background: Single-agent chemotherapy using methotrexate or actinomycin D is the first-line treatment for patients with low-risk gestational trophoblastic neoplasia. Various methotrexate-based and actinomycin D-based single-agent regimens can be used. However, there is insufficient evidence to determine the superior regimen. To guide doctors in selecting a single-agent chemotherapy regimen for patients with low-risk gestational trophoblastic neoplasia, we will compare two regimens., Methods: We will conduct a multicentre, randomized, prospective clinical trial. Selected low-risk gestational trophoblastic neoplasia patients (FIGO score 0-4) will be randomized 1:1 to a biweekly single-dose actinomycin D group or a multiday methotrexate therapy group. The actinomycin D group will receive IV pulse actinomycin D (1.25 mg/m 2 ) every 14 days, and the methotrexate group will receive methotrexate (50 mg) intramuscularly on days 1, 3, 5, and 7 (4 doses per cycle) and leucovorin (15 mg) intramuscularly on days 2, 4, 6, and 8. This process will be repeated every 14 days. The primary endpoints will include the complete remission rate by single-agent therapy and the overall complete remission rate. The secondary endpoints will include the duration needed to achieve complete remission after single-agent chemotherapy, number of courses needed to achieve complete remission after single-agent chemotherapy, incidence and severity of adverse effects, effects on menstrual conditions and ovarian function based on the anti-Mullerian hormone level, and patient-reported quality of life., Discussion: Previous clinical trials comparing biweekly single-dose actinomycin D with multiday methotrexate therapy for treating low-risk gestational trophoblastic neoplasia patients failed to meet the expected case number. Through this multicentre study, the complete remission ratio and efficacy difference between biweekly single-dose actinomycin D and multiday methotrexate therapy will be obtained. This study will also provide the basis for formulating a preferred regimen for treating patients with low-risk gestational trophoblastic neoplasia., Trial Registration: ClinicalTrials.gov: NCT04562558, Registered on 13 September 2020 (Protocol version 2020-9-24, version 1.0)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Rationale: 5-Fluorouracil (5-FU) and actinomycin D (ActD) are often used in chemotherapy for various cancers. Side effects are more common in bone marrow suppression, liver function impairment, and gastrointestinal responses. Skin effects are rare and easy to be ignored by doctors and patients, which can lead to life-threatening consequence., Patient Concerns: We reported a 45-year-old woman patient developed skin erythema and fingernail belt in chemotherapy of 5-FU and ActD., Diagnosis: Erythema multiforme drug eruption., Interventions: Laboratory tests including blood and urine routine, liver and kidney function, electrolytes and coagulation function and close observation., Outcomes: The rash was gone and the nail change returned., Lessons: Delays in diagnosis or treatment may lead to serious consequence. We should pay attention to the dosage of 5-FU and ActD, monitor adverse reactions strictly, to reduce occurrence of skin malignant events., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Internationally, a single standard chemotherapy treatment for Ewing sarcoma is not defined. Because different chemotherapy regimens were standard in Europe and the USA for newly diagnosed Ewing sarcoma, and in the absence of novel agents to investigate, we aimed to compare these two strategies., Methods: EURO EWING 2012 was a European investigator-initiated, open-label, randomised, controlled phase 3 trial done in 10 countries. We included patients aged 2-49 years, with any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or Ewing-like sarcomas. The eligibility criteria originally excluded patients with extrapulmonary metastatic disease, but this was amended in the protocol (version 3.0) in September, 2016. Patients were randomly assigned (1:1) to either the European regimen of vincristine, ifosfamide, doxorubicin, and etoposide induction, and consolidation using vincristine, actinomycin D, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1); or the US regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide induction, plus ifosfamide and etoposide, and consolidation using vincristine and cyclophosphamide, or vincristine, actinomycin D, and ifosfamide, with busulfan and melphalan (group 2). All drugs were administered intravenously. The primary outcome measure was event-free survival. We used a Bayesian approach for the design, analysis, and interpretation of the results. Patients who received at least one dose of study treatment were considered in the safety analysis. The trial was registered with EudraCT, 2012-002107-17, and ISRCTN, 54540667., Findings: Between March 21, 2014, and May 1, 2019, 640 patients were entered into EE2012, 320 (50%) randomly allocated to each group. Median follow-up of surviving patients was 47 months (range 0-84). Event-free survival at 3 years was 61% with group 1 and 67% with group 2 (adjusted hazard ratio [HR] 0·71 [95% credible interval 0·55-0·92 in favour of group 1). The probability that the true HR was less than 1·0 was greater than 0·99. Febrile neutropenia as a grade 3-5 treatment toxicity occurred in 234 (74%) patients in group 1 and in 183 (58%) patients in group 2. More patients in group 1 (n=205 [64%]) required at least one platelet transfusion compared with those in group 2 (n=138 [43%]). Conversely, more patients required blood transfusions in group 2 (n=286 [89%]) than in group 1 (n=277 [87%])., Interpretation: Dose-intensive chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide is more effective, less toxic, and shorter in duration for all stages of newly diagnosed Ewing sarcoma than vincristine, ifosfamide, doxorubicin, and etoposide induction and should now be the standard of care for Ewing sarcoma., Funding: The European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration; The National Coordinating Centre in France, Centre Léon Bérard; SFCE; Ligue contre le cancer; Cancer Research UK., Competing Interests: Declaration of interests SS has received honoraria and consulting fees from GSK, Lilly, and Ceridwen Oncology. JM-B reports institutional grants from Adaptimmune, Amgen, AROG, Bayer, Blueprint, Bristol Myers Squibb, Celgene, Daichii-Sankyo, Deciphera, Eisai, FORMA, GSK, IMMIX Biopharma, Karyopharm, Lilly, Nektar, Novartis, Pfizer, and PharmaMar; honoraria from PharmaMar and Tecnofarma; payment for expert testimony from Bayer, Eisai, Lilly, and PharmaMar; support for attending meetings and travel from PharmaMar and Asofarma; and participation on a data safety monitoring board or advisory board for Asofarma, PharmaMar, Boheringer, Tecnofarma, Roche, and Bayer. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Guidelines recommend etoposide, methotrexate, actinomycin D (EMA)/cyclophosphamide, vincristine (CO) as first-line treatment for high-risk gestational trophoblastic neoplasia (GTN). However, the floxuridine, actinomycin D, etoposide and vincristine (FAEV) regimen is commonly used to treat these patients in China. We conducted a randomised controlled trial to compare the efficacies and toxicities of FAEV and EMA/CO., Methods: Ninety-four patients with GTN were enrolled between May 2015 and April 2019 and randomly assigned to the FAEV or EMA/CO regimen. The rates of complete remission and relapse and the toxicities were compared in August 2021., Results: Five patients were excluded from the analysis. There were 46 patients in the FAEV group and 43 patients in the EMA/CO group. The complete remission rates following primary treatment were 89.1% and 79.1% (P = 0.193), respectively. The relapse rates were 8.7% and 9.3% (P = 0.604). The apparent incidences of grade 4 myelosuppression were 60.9% and 32.6% (P = 0.008), respectively; however, they became both 32.6% (P = 0.996) after granulocyte colony-stimulating factor support. Other adverse reactions were similar in the two groups. No patient died of disease., Conclusion: FAEV has comparable efficacy and toxicity to EMA/CO as the primary treatment for high-risk GTN, and may thus be another first-line choice of chemotherapy., Clinical Trial Registration: chictr.org.cn: ChiCTR1800017423., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

We aimed to evaluate the effectiveness and safety of single-course initial regimens in patients with low-risk gestational trophoblastic neoplasia (GTN). In this trial (NCT01823315), 276 patients were analyzed. Patients were allocated to three initiated regimens: single-course methotrexate (MTX), single-course MTX + dactinomycin (ACTD), and multi-course MTX (control arm). The primary endpoint was the complete remission (CR) rate by initial drug(s). The primary CR rate was 64.4% with multi-course MTX in the control arm. For the single-course MTX arm, the CR rate was 35.8% by one course; it increased to 59.3% after subsequent multi-course MTX, with non-inferiority to the control (difference -5.1%,95% confidence interval (CI) -19.4% to 9.2%, P = 0.014). After further treatment with multi-course ACTD, the CR rate (93.3%) was similar to that of the control (95.2%, P = 0.577). For the single-course MTX + ACTD arm, the CR rate was 46.7% by one course, which increased to 89.1% after subsequent multi-course, with non-inferiority (difference 24.7%, 95% CI 12.8%-36.6%, P < 0.001) to the control. It was similar to the CR rate by MTX and further ACTD in the control arm (89.1% vs. 95.2%, P =0.135). Four patients experienced recurrence, with no death, during the 2-year follow-up. We demonstrated that chemotherapy initiation with single-course MTX may be an alternative regimen for patients with low-risk GTN., (© 2021. Higher Education Press.)

This study reports the treatment feasibility and efficacy of a novel multiagent intensive treatment program for young patients with desmoplastic small round cell tumor. This small series includes three patients and should be seen as a first suggestion of integration of the dose density and the maintenance chemotherapy concept. The IrIVA regimen (irinotecan, ifosfamide, vincristine, and actinomycin-D) is added-used at a short interval between chemotherapy administrations-at more classic intensive ifosfamide-based regimens. The vinorelbine and low-dose oral cyclophosphamide maintenance therapy is added at the end of conventional chemotherapy to achieve an antiangiogenic effect.

Background: Gestational trophoblastic neoplasia (GTN) are a spectrum of tumors that develop from placental tissue. We aimed to evaluate the management and treatment outcome of GTN., Methods: Patients diagnosed with GTN presented to Kasr Alainy Center of Clinical Oncology between 2008 and 2017 were included in this study. Patients were assigned to low or high-risk according to the World Health Organization (WHO) scoring system. All data were tabulated and statistically studied by descriptive analysis; comparison between the two groups was done using student t-test for continuous data and Chi-square test for categorical data., Results: A total of 111 patients were studied; the majority of them had WHO low-risk score. In low-risk group, the overall response rate to methotrexate-folinic acid (MTX- FA) or actinomycin D (ActD) was 48.5%, comparable response rate observed between MTX and ActD was 48.2% vs 50%, respectively. Those who received MTX-FA 8-day regimen had higher response rate compared to a weekly schedule, however, no statistical significant difference was observed (51.6% vs 44.4%, respectively, P = 0.586), all low-risk patients who failed MTX or ActD achieved complete remission (CR) with subsequent chemotherapy. Patients with WHO score 5-6 had a significantly lower CR rate compared to patients with scores <5, (28% and 60%, respectively; P = 0.01). Five-years overall survival was significantly lower in high-risk than low-risk patients (79.3% vs 100%, respectively, P = <0.001)., Conclusion: Low-risk patients have a survival rate of 100% even if they did not respond to first-line chemotherapy, MTX-FA 8-day regimen seems to be more effective than MTX weekly regimen., Competing Interests: None

Background: 5-fluorouracil-based multiagent chemotherapy has been used as the primary treatment for high-risk gestational trophoblastic neoplasia (GTN) in China for a few decades. This study aims to assess the efficacy and toxicity of floxuridine, actinomycin D, etoposide, and vincristine (FAEV) as a primary treatment for patients with GTN who had International Federation of Gynecology and Obstetrics (FIGO) scores ≥5., Materials and Methods: A total of 207 patients with GTN who had FIGO scores ≥5 were treated with FAEV as first-line chemotherapy at Peking Union Medical College Hospital between January 2002 and December 2017. Complete remission (CR), resistance, survival, toxicity, and reproductive outcomes were analyzed., Results: Of the 207 patients treated with FAEV, 9 (4.3%) required a change of chemotherapy owing to toxicity and 1 (0.5%) died of cerebral hernia 5 weeks after commencing treatment. The remaining 197 patients were assessable to determine the response to FAEV; among them, 168 (85.3%) achieved CR with FAEV and 29 (14.7%) developed resistance to FAEV. The 5-year overall survival rate of the entire cohort was 97.4%. Grade 3-4 neutropenia, thrombocytopenia, and anemia occurred in 28.4%, 6.8%, and 6.2% of cycles, respectively. No acute toxicity-related deaths occurred. Five patients developed acute myeloid leukemia 10-50 months after exposure to chemotherapy; another patient developed duodenal cancer 2 years after completing therapy. Sixty-one patients who preserved fertility wanted to become pregnant; 56 of them conceived., Conclusion: The FAEV regimen is an effective primary treatment for patients with GTN who have FIGO scores ≥5 and has predictable and manageable toxicity., Implications for Practice: The most commonly used multiagent chemotherapy for high-risk gestational trophoblastic neoplasia (GTN) is etoposide, methotrexate and actinomycin D/cyclophosphamide and vincristine (EMA/CO) worldwide. However, 5-fluorouracil-based multiagent chemotherapy has been used as a primary treatment for high-risk GTN in China for a few decades. This study evaluated the efficacy and toxicity of floxuridine, actinomycin D, etoposide, and vincristine (FAEV) as a primary treatment for patients with GTN who have International Federation of Gynecology and Obstetrics (FIGO) scores ≥5. The study's data demonstrated that FAEV as a primary treatment achieved favorable outcomes for patients with FIGO scores ≥5. Toxicities that result from the FAEV regimen are predictable and manageable. The FAEV regimen may provide another option for the treatment of GTN., (© 2021 AlphaMed Press.)

Background: Actinomycin-D (Act-D) and Methotrexate (MTX) are both effective first-line agents for low-risk gestational trophoblastic neoplasia (LRGTN) with no consensus regarding which is more effective or less toxic. The primary objective of this meta-analysis is to compare Act-D with MTX in the treatment of LRGTN., Methods: We systematically searched electronic databases, conferences abstracts and trial registries for randomized controlled trials (RCTs) and high-quality non-randamized controlled trials (non-RCTs), comparing Act-D with MTX for patients with LRGTN. Studies were full-text screened for quality assessment and data extraction. Eligible studies must have reported complete remission rate. A fixed-effects meta-analysis was conducted to quantify the efficacy and safety of Act-D and MTX on odds ratios (ORs) and 95% confidence intervals (95%CIs), respectively., Results: A total of 8 RCTs and 9 non-RCTs (1674 patients) were included. In terms of efficacy, Act-D is superior to MTX in complete remission (80.2% [551/687] vs 65.1% [643/987]; OR 2.15, 95%CI 1.70 to 2.73). In the stratified analysis, patients from RCTs and non-RCTs both had a better complete remission from Act-D-based regimen (RCTs: 81.2% [259/319] vs 66.1% [199/301], OR 2.17, 95%CI 1.49 to 3.16; non-RCTs: 79.3% [292/368] vs 65.0% [444/686], OR 2.14, 95%CI 1.57 to 2.92). In terms of safety, patients receiving Act-D had higher risks of suffering nausea (OR 2.35, 95%CI 1.68 to 3.27), vomiting (OR 2.40, 95%CI 1.63 to 3.54), and alopecia (OR 2.76, 95%CI 1.60 to 4.75). Notably, liver toxicity (OR 0.38, 95%CI 0.19 to 0.76) was the only one that was conformed to have a higher risk for patients receiving MTX. In addition, the pooled results showed no significant difference of anaemia, leucocytopenia, neutropenia, thrombocytopnia, constipation, diarrhea, anorexia, and fatigue between Act-D and MTX., Conclusions: Our meta-analysis suggests that Act-D had better efficacy profile in general, and MTX had less toxicities in LRGTN. Future clinical trials should be better orchestrated to provide more valid data on efficacy and toxicity., (© 2021. The Author(s).)

The objective of this study is to assess the effect of anthracyclines/ifosfamide-based adjuvant chemotherapy for soft tissue sarcoma (STS) and provide a relative ranking of regimens for STS. We pooled the hazard ratios of overall survival (OS) and relapse free survival (RFS) by conventional meta-analysis to appraise whether adjuvant chemotherapy benefits STS and performed a network meta-analysis using a Bayesian model to establish the relative ranking of regimens. Nine studies were included in our meta-analysis. The pooled hazard ratios were 0.68 (95%CI: 0.53-0.86) and 0.65 (95%CI: 0.52-0.83) for OS and RFS, respectively. Doxorubicin was indicated as best regimen to benefit OS (probability: 30.2%), while cyclophosphamide + vincristine + doxorubicin + dactinomycin was indicated as the best regimen for RFS (probability: 37.1%). This meta-analysis confirms the positive effect of anthracyclines/ifosfamide-based adjuvant chemotherapy in STS for both OS and RFS.

Actinomycin-D and vincristine are cytotoxic drugs commonly used to treat cancers in children. This prospective study assessed pharmacokinetic variability and toxicity of these drugs in children. Blood samples were collected in 158 patients. Actinomycin-D or vincristine concentrations were quantified using high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using non-compartmental methods. Target toxicities were collected prospectively. Actinomycin-D pharmacokinetics (n = 52 patients) were highly variable. The median (coefficient of variation, CV%) area under the concentration-time curve (AUC) was 332 ng/mL·h. (110%); clearance was 4.6 L/h/m 2 (90%); half-life was 25 h (60%). No patient met the defined criteria for myelosuppression. In multivariate analysis, none of the demographic nor pharmacokinetic parameters was predictors of acute hepatotoxicity. Vincristine pharmacokinetics (n = 132 patients) demonstrated substantial variability. The median (CV%) AUC was 78 ng/mL·h (98%); clearance was 17.2 L/h/m 2 (67%); half-life was 14.6 h (73%). In multivariate analysis, the effect of increasing age for a given BSA was an increase in neuropathy while the effect of increasing BSA for a given age was a decrease in neuropathy. Conclusion: Pharmacokinetics of both drugs were highly variable. For actinomycin-D, there was no correlation between demographic or pharmacokinetic parameters and target toxicities. For vincristine, the correlations of age and BSA and neuropathy are confounded by the correlation between age and BSA in children and the ability to ascertain neuropathy in infants. Variability may be attributed to dose reductions and capped doses for both drugs. Investigation of BSA-based dosing in young children is warranted to decrease variability of exposure.

Background: A human chorionic gonadotropin (hCG) cut-off of ≤300 IU/l for starting actinomycin D (ActD) in post-molar gestational trophoblastic neoplasia (GTN) patients developing methotrexate resistance (MTX-R) reduced the number of women needing toxic multi-agent chemotherapy (etoposide, MTX and ActD alternating weekly with cyclophosphamide and vincristine; EMA/CO) without affecting survival. Here we assess whether an increased hCG cut-off of ≤1000 IU/l spares more women EMA/CO., Patients and Methods: All post-molar GTN patients treated with first-line methotrexate and folinic acid (MTX/FA) were identified in a national cohort between 2009 and 2016. Data collected included age, FIGO score, the hCG levels at MTX-R, and treatment outcomes., Results: In total, 609 GTN patients commenced treatment with MTX/FA achieving a complete response in 57% (348/609). Resistance developed in 25.1% (153/609) at an hCG ≤ 1000 IU/l and switching to ActD achieved remission in 92.8% without any major toxicity with the remaining 7.2% remitting on EMA/CO. Comparative analysis of patients switching at an hCG <100 versus 100-300 versus 300-1000 IU/l revealed a significant fall in the cure rate with second-line ActD from 97% (93/96) to 87% (34/39) to 78% (14/18), respectively, P = 0.009. However, by increasing the hCG cut-off from ≤300 to ≤1000 IU/l, 14 patients were spared EMA/CO chemotherapy. Moreover, in the present series, all post-molar GTN remain in remission., Conclusion: This study demonstrates that increasing the hCG cut-off from ≤300 to ≤1000 IU/l for choosing patients for ActD following MTX-R spares more women with GTN from the greater toxicity of EMA/CO without compromising 100% survival outcomes., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Methotrexate and actinomycin-D are both effective first-line drugs for low-risk (WHO score 0-6) Gestational Trophoblastic Neoplasia (GTN) with considerable debate about which is more effective, less toxic, and better tolerated. The primary trial objective was to test if treatment with multi-day methotrexate (MTX) was inferior to pulse actinomycin-D (ACT-D). Secondary objectives included evaluation of severity and frequency of adverse events, and impact on quality of life (QOL)., Methods: This was a prospective international cooperative group randomized phase III two arm non-inferiority study (Clinical Trials Identifier: (NCT01535053). The control arm was ACT-D; the experimental arm was multi-day MTX regimen (institutional preference of 5 or 8 day). Outcome measures included complete response rate, recurrence rate, toxicity, and QOL as measured by FACT-G and FACIT supplemental items., Results: The complete response rates for multi-day methotrexate and pulse actinomycin-D were 88% (23/26 patients) and 79% (22/28 patients) (p = NS) respectively, there were two recurrences in each arm, and 100% of patients survived. Significant toxicity was minimal, but mouth sores (mucositis), and eye pain were significantly more common in the MTX arm (p = 0.001 and 0.01 respectively). Quality of life showed no significant difference in overall quality of life, body image, sexual function, or treatment related side effects. The study was closed for low accrual rate (target 384, actual accrual 57), precluding statistical analysis of the primary objective., Conclusions: The complete response rate for multi-day methotrexate was higher than actinomycin-D, but did not reach statistical significance. The multi-day MTX regimens were associated with significantly more mucositis and were significantly less convenient., Competing Interests: Declaration of competing interest Dr. Julian Schink, Dr. Jeanne Carter, Dr. Matthew Winter, Dr. Nancy Anderson, Dr. Katherine Moxley, Dr. Akira Yabucoa, Dr. Sarah Taylor, Dr. Christina Kushnir, Dr. Neil Horowitz and Ms. Helen Huang have nothing to disclose. Dr. Virginia Filiaci reports grants from NIH, during the conduct of the study; grants from GOG Foundation, Inc., from null, outside the submitted work. Dr. Tidy reports personal fees from Zilico Ltd., outside of the submitted work. Dr. David Miller reports personal fees received as consultant for Tesaro, Eisai, Incyte, Karyopharm and Genentech. Dr. Miller also reports money was paid to his institution by Merck and grants received from nVision Medical, Advenchen, Forty Seven, Merck and Syros, (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To compare experiences with EMA versus EMACO in the treatment of gestational trophoblastic neoplasia., Methods: The medical records of women diagnosed with GTN at the New England Trophoblastic Disease Center from 1986 to 2019 were reviewed, and women receiving EMA or EMACO as their first multiagent regimen were eligible. Clinical characteristics, treatment, outcomes, and adverse events were compared between the two groups., Results: We identified 44 and 39 patients who received EMA and EMACO, respectively. The complete remission rate was significantly higher in the EMA group (97.7%) than in the EMACO group (71.8%) (p = 0.001). However, patients receiving EMACO were more likely to have adverse prognostic factors such as higher median prognostic risk score (8 vs 4, p < 0.001), non-molar antecedent pregnancy (59 vs 27.3%, p = 0.014) and distant metastasis (64.1 vs 47.7%, p = 0.017). Time to complete remission was also similar (p = 0.947) with a median of 12 weeks with EMA and 13.1 weeks with EMACO. There was no significant difference in treatment delays or use of adjuvant surgery. After multivariate analysis, chemotherapy regimen (EMA or EMACO) did not retain prognostic significance for remission. Overall toxicities were more frequent in EMA (60.2 vs 32.7%, p < 0.001), especially neutropenia, but this did not delay treatment and likely resulted from less growth factor support (18.2 vs 48.7%, p = 0.003)., Conclusions: When controlling for other prognostic factors, outcomes with EMA appear similar to EMACO. It may be worthwhile to investigate whether EMA, a simpler and less costly regimen, may be as effective as EMACO in the treatment of GTN., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Clinical trials have tested different chemotherapy regimens to improve outcome for patients with rhabdomyosarcoma (RMS), but therapy duration has never been explicitly evaluated. North American trials evolved from longer (104 weeks) to shorter duration (24-42 weeks). In Europe, treatment duration similarly evolved from 35 to 48 to 22 weeks for lower risk patients and from 56 to 72 to 27 weeks for higher risk patients. There was no evidence that chemotherapy duration influenced outcome over time. The recent RMS2005 trial showed an improved survival with the addition of 24 weeks of low-dose chemotherapy. Treatment duration remains a question to be addressed in future trials., (© 2020 Wiley Periodicals, Inc.)

Objectives: The purpose of this study was to evaluate both the outcomes and toxicity of second-line actinomycin D (ActD) chemotherapy in methotrexate (MTX) - resistant low-risk postmolar gestational trophoblastic neoplasia (GTN) with 5-day ActD versus pulsed ActD., Methods: This retrospective cohort study included patients with MTX-resistant low-risk postmolar GTN from 1974 to 2016. Second-line chemotherapy consisted of 5-day ActD (10-12 μg/kg per day for 5 days every 14 days) or biweekly ActD (1.25 mg/m 2 every 2 weeks). Data on patient characteristics, disease presentation, treatment outcome, and toxicity were collected., Results: Sixty-eight MTX-resistant patients receiving ActD as second-line chemotherapy were identified (5-day ActD, 53 patients; pulsed ActD, 15 patients). No significant differences were observed in patient/disease characteristics and sustained remission (overall rate 72%) between second-line ActD regimens. Time to hCG remission was significantly faster (median 21 vs 47 days, p = .04) and required fewer treatment cycles (median 1 vs 2, p < .001) with 5-day ActD. Thrombocytopenia was only observed with 5-day ActD (64.6 vs 0%, p < .001). The frequency (60.4 vs 16.7%, p = .009) and severity (grade 3: 37.9 vs 0%, p = .045) of oral mucositis was significantly higher with 5-day ActD. Grade 2 alopecia was significantly more frequent (70.6 vs 16.7%, p = .02) with 5-day ActD., Conclusions: While 5-day ActD and pulsed ActD achieve comparable remission rates, due to its reduced toxicity, ease of administration, and patient convenience, pulsed ActD should be the treatment of choice for MTX-resistant postmolar low-risk GTN., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: In the fifth National Wilms Tumor Study (NWTS-5), the 4-year event-free survival (EFS) and overall survival (OS) estimates for 29 patients with stage I focal (n = 10) or diffuse (n = 19) anaplastic Wilms' tumour (AWT) treated with vincristine and dactinomycin without flank radiation were 69.5% and 82.6%, respectively. The Children's Oncology Group AREN0321 study evaluated whether adding doxorubicin and flank radiation improves survival for these patients., Patients and Methods: Tumour histology and stage were confirmed by real-time central pathology, surgery and radiology review. The patients received 25 weeks of vincristine, dactinomycin and doxorubicin (cumulative dose 150 mg/m 2 ) with flank radiation (1080 cGy). We retrospectively analysed outcomes of all patients with stage I AWT enrolled in NWTSs 1-5 and AREN0321 with respect to treatment regimens., Results: Eighteen patients with stage I AWT (8 focal and 10 diffuse) were enrolled on AREN0321. With a median follow-up of 4.6 years, the 4-year EFS and OS were 100%. One patient with diffuse AWT had pulmonary relapse 4.12 years after diagnosis. In the 112 patients with stage I AWT treated in NWTSs 1-5 and AREN0321, the EFS was significantly improved with doxorubicin treatment (p = 0.01; 4-year EFS: 97.2% [95% confidence interval {CI}: 91.3-100] vs. 77.5% [95% CI: 67.6-87.4]) but not by flank radiation (p = 0.15)., Conclusions: Treatment of stage I AWT with vincristine, dactinomycin, doxorubicin and flank radiation in AREN0321 yielded excellent survival outcomes. Retrospective analysis of AREN0321 and NWTS patients suggests that doxorubicin had a greater contribution to the excellent outcomes than radiation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: We aimed to identify an optimal regimen for low-risk gestational trophoblastic neoplasia (LR-GTN) providing reduction in dosage and toxicity/side effects, enhancement of therapeutic efficacy, and a shorter treatment duration., Methods: A total of 149 LR-GTN patients were enrolled in the affiliated Beijing Maternity Hospital of Capital Medical University from January 2014 to January 2017 and randomly divided into 3 groups with 50 cases in the methotrexate (MTX) group, 49 in actinomycin D (ACT-D) group, and 50 in ACT-D+MTX group. Follow-up recorded symptoms, physical and bimanual gynecological examinations, routine blood test, serum β-HCG level, liver and renal functions, electrolytes, electrocardiogram before each treatment course, and pelvic and abdominal B-mode ultrasound or pelvic/abdominal/chest computed tomography., Results: Serum complete remission (SCR) was 96.0, 87.8, and 83.7% for the ACT-D+MTX, ACT-D, and MTX groups, respectively, with SCR being highest in the ACT-D+MTX group, statistically higher than in the MTX group. Vomiting was the only side effect differing significantly by chemotherapy regimen, with a distinctly higher incidence in the ACT-D+MTX group compared with the MTX group (p = 0.028). The reduction rate of serum β-HCG in the ACT-D+MTX group was significantly greater than in the other 2 groups., Conclusion: Combined ACT-D+MTX chemotherapy achieved overall better efficacy and showed less toxicity than ACT-D or MTX alone, and thus can be prioritized for the treatment of LR-GTN., (© 2019 S. Karger AG, Basel.)

Objective: To compare the treatment outcome and cost-effectiveness of pulsed actinomycin D (Act-D) and 5-day Act-D in patients with low-risk gestational trophoblastic neoplasia (GTN)., Method: The present retrospective study included patients with low-risk GTN who received pulsed Act-D or 5-day Act-D as first-line chemotherapy at West China Second Hospital, Chengdu, China, between January 1, 2016, and December 31, 2017. Complete remission rates, mean number of treatment courses, and adverse events were compared, and a cost-effectiveness analysis was performed., Results: The study included 34 patients treated with pulsed Act-D and 26 patients treated with 5-day Act-D. Overall complete remission was observed in 21 (62%) patients in the pulsed Act-D group and 19 (73%) patients in the 5-day Act-D group (P=0.355); the mean number of treatment courses were 5.1 and 5.3, respectively (P=0.686). When Act-D failed, patients in each group required 4.9 and 4.6 courses, respectively, of a multi-agent regimen (P=0.545). No major adverse events were observed but moderate adverse events were more frequent in the pulsed Act-D group (P=0.011). The 5-day Act-D regimen was more expensive compared with pulsed Act-D regimen (US$7504.33 vs $5541.79), with an incremental cost-effectiveness ratio of $64 557.08 per avoidance of treatment failure., Conclusion: Pulsed Act-D was more cost-effective than 5-day Act-D and could be preferred when considering Act-D as chemotherapy for low-risk GTN., (© 2018 International Federation of Gynecology and Obstetrics.)

Objectives: The aim of this study was to review the treatment and outcomes of low-risk gestational trophoblastic neoplasia (GTN) in Manitoba over more than 3 decades, with a focus on those treated with alternating methotrexate and dactinomycin, a protocol that has only rarely been described., Materials and Methods: We retrospectively reviewed all patients with GTN referred to CancerCare Manitoba from January 1977 to December 2012. Cases were classified as low risk as per the modified WHO-FIGO prognostic scoring system (score, ≤6). Demographic, treatment, and outcomes data were abstracted, and descriptive statistics and time-to-event analysis were performed. The low-risk protocol used at CancerCare Manitoba consists of alternating single-agent use of methotrexate and dactinomycin, each for 5 days, on a 14-day cycle., Results: Sixty-seven cases of GTN were identified, of which 52 were low risk. Thirty-nine patients were initiated on alternating methotrexate and dactinomycin. Thirty-four (87.2%) achieved primary cure on this regimen, with a median of 4.4 cycles administered (range, 2-7). Median time to response was 56 days. One patient achieved cure after receiving a repeat course of methotrexate as their final cycle. Second-line multiagent chemotherapy was required by 4 patients. Two patients experienced grade 3 toxicities, and none greater than grade 3. There were no recurrences., Conclusions: Alternating methotrexate and dactinomycin is an effective treatment protocol for low-risk GTN, with high rates of primary cure and acceptable toxicity.

Purpose Intermediate-risk rhabdomyosarcoma (RMS) includes patients with either nonmetastatic, unresected embryonal RMS (ERMS) with an unfavorable primary site or nonmetastatic alveolar RMS (ARMS). The primary aim of this study was to improve the outcome of patients with intermediate-risk RMS by substituting vincristine and irinotecan (VI) for half of vincristine, dactinomycin, and cyclophosphamide (VAC) courses. All patients received a lower dose of cyclophosphamide and earlier radiation therapy than in previous trials. Patients and Methods Patients were randomly assigned at study entry to either VAC (cumulative cyclophosphamide dose, 16.8 g/m 2 ) or VAC/VI (cumulative cyclophosphamide dose, 8.4 g/m 2 ) for 42 weeks of therapy. Radiation therapy started at week 4, with individualized local control plans permitted for patients younger than 24 months. The primary study end point was event-free survival (EFS). The study design had an 80% power (5% one-sided α-level) to detect an improved long-term EFS from 65% (with VAC) to 76% (with VAC/VI). Results A total of 448 eligible patients were enrolled in the study. At a median follow-up of 4.8 years, the 4-year EFS was 63% with VAC and 59% with VAC/VI ( P = .51), and 4-year overall survival was 73% for VAC and 72% for VAC/VI ( P = .80). Within the ARMS and ERMS subgroups, no difference in outcome by treatment arm was found. Severe hematologic toxicity was less common with VAC/VI therapy. Conclusion The addition of VI to VAC did not improve EFS or OS for patients with intermediate-risk RMS. VAC/VI had less hematologic toxicity and a lower cumulative cyclophosphamide dose, making VAC/VI an alternative standard therapy for intermediate-risk RMS.

Rationale: Familial hydatidiform mole is extremely rare while familial gestational trophoblastic neoplasia (GTN) has never been reported. Inspired by 2 biological sisters with postmolar GTN and liver toxicity, we reviewed susceptible maternal-effect genes and explored the role of possible drug transporter genes in the development of GTN., Patient Concerns: We reported one Chinese family where the two sisters developed postmolar GTN while experiencing fast remission and significant hepatic toxicity from actinomycin D chemotherapy., Diagnoses: The index pregnancy was diagnosed with curettage. The following GTN was confirmed when there was a rise in beta-hCG for three consecutive weekly measurements over at least a period of 2 weeks. Computed tomography was used to identify lung metastasis. The elder sister was diagnosed with gestational trophoblastic neoplasia (III: 2) while the younger sister was diagnosed as III: 3 according to WHO scoring system., Interventions: Patients were treated with actinomycin D of 10 μg/kg intravenously for 5 days every 2 weeks. When hepatic toxicity was indicated, polyene phosphatidyl choline and magnesium isoglycyrrhizinate were prescribed., Outcomes: Both patients responded extremely well to the 5-day actinomycin D regimen. Beta-hCG remained less than 2 mIU/ml after 5 cycles while computed tomography scan showed downsized pulmonary nodules. Both experienced significant rise in ALT and AST levels that could be ameliorated with corresponding medication. Monthly followed-up showed negative beta-hCG levels and normal liver enzyme levels., Lessons: We speculated that the known or unknown NLRP7 and KHDC3L mutations might be correlated with drug disposition in liver while liver drug transporters such as P-glycoprotein family that are also expressed in trophoblasts might be correlated to GTN susceptibility. Future genomic profiles of large samples alike using next generation sequencing are needed to confirm our hypothesis and discover yet unknown genes.

Preclinical Research & Development Pancreatic cancer is the third leading cause of death in the US with a poor 5-year survival rate of 8.5%. A novel anti-cancer drug, dimethylamino parthenolide (DMAPT), is the water-soluble analog of the natural sesquiterpene lactone, parthenolide. The putative modes of action of DMAPT are inhibition of the Nuclear chain factor kappa-light-chain enhancer of activated B cells (NFκB) pathway and depletion of glutathione levels; the latter causing cancer cells to be more susceptible to oxidative stress-induced cell death. Actinomycin-D (ActD) is a polypeptide antibiotic that binds to DNA, and inhibits RNA and protein synthesis by inhibiting RNA polymerase II. A phase 2 clinical trial indicated that ActD could be a potent drug against pancreatic cancer; however, it was not a favored drug due to toxicity issues. New drug entities and methods of drug delivery, used alone or in combination, are needed to treat pancreatic cancer more effectively. Thus, it was postulated that combining DMAPT and ActD would result in synergistic inhibition of Panc-1 pancreatic cancer cell growth because DMAPT's inhibition of NFκB would enhance induction of apoptosis by ActD, via phosphorylation of c-Jun, by minimizing NFκB inhibition of c-Jun phosphorylation. Combining these two drugs induced a higher level of cell death than each drug alone. A fixed drug ratio of DMAPT: ActD (1,200:1) was used. Data from metabolic (MTT) and colony formation assays were analyzed for synergism with CompuSyn software, which utilizes the Chou-Talalay equation. The analyses indicated synergism and moderate synergism at combination concentrations of DMAPT/ActD of 12/0.01 and 18/0.015 μM, respectively., (© 2018 Wiley Periodicals, Inc.)

Microdontia is one of the late effects of antineoplastic therapy in children. This study is based on the comparative histological examination of abnormal, peg-shaped premolars, erupted in a patient treated for neuroblastoma, and of non-affected teeth, extracted in a healthy child. Apart from the size, the teeth vary in tissue morphology. The number of dentinal tubules, dependent on the number of odontoblasts, is smaller in the microdontal sample when observation in the same-sized field of view is conducted. Moreover, the youngest, more than 100-micrometer-thick layer of the microdontal dentin seems to be the secondary dentin, with crispy-shaped tubules and empty spaces between them. No irregular dentin is deposited in the samples of physiologically developed teeth. The structure of cementum is different as well. Unlike regularly shaped premolars, in which typical 2-layer tissue is seen, in sections of microdontal teeth, only acellular tissue with cementoblasts overlying its surface is present. Thorough analysis of drug administration effects, which are visible in microscopic sections, and of time of anticancer treatment could provide insight into the developmental mechanisms of tooth germ formation.

We review and summarize the highlights of almost five decades of cooperative group trials in rhabdomyosarcoma on both sides of the Atlantic, concentrating on chemotherapy regimens, what has been learned, and where remaining challenges are. The most important achievements have been to decrease or omit the dose of alkylator therapy for many patients, to clarify after much controversy that doxorubicin does not improve the outcome of patients even in the highest risk groups, and to show that high dose chemotherapy and stem cell rescue do not improve the outcome of the highest risk patients. In North America, vincristine/actinomycin/cyclophosphamide (VAC) remains an important part of therapy, whereas in Europe the alkylating agent of choice is ifosfamide. The highest risk patients, namely those with the poorest prognostic score, have had no improvement in outcome since the first cooperative group trial in 1972 and remain the greatest challenge. Philosophical differences between European and North American strategies still revolve somewhat around the total burden of therapy received, that is should certain groups of patients be spared aggressive local control in order to reduce late effects, recognizing that it is not possible to identify priori the children that can be cured with this approach exposing the whole population to a higher risk of relapse. Collaboration and joining resources may help answer some difficult questions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Using a questionnaire to evaluate different regimens of chemotherapy on ovarian function and quality of life of patients with gestational trophoblastic neoplasia (GTN) . Methods: At least 6 months after completion of chemotherapy, 200 patients with GTN treated in Peking Union Medical College Hospital from January 2010 to June 2017 were randomly selected to fill up the questionnaire. The questionnaire items were included the patient's menstrual cycles, sexual life, gestational issues and common health. The patients were divided into 3 groups by chemotherapy regimens: actinomycin D (Act-D) group, floxuridine+Act-D+vincristine (FAV) or floxuridine+Act-D+etoposide+vincristine (FAEV) group (FAV-FAEV group) , and etoposide+methotrexate+Act-D (EMA) /vincristine+cyclophosphamide (CO) or EMA/ etoposide+cisplatin (EP) group (EMA/CO-EMA/EP group) . Chi-square test was used with a significance level of P -value less than 0.05. Results: One hundred and seventy-three (86.5%,173/200) of the patients completed the questionnaire. Forty three point two percent (43.2%, 19/44) in the EMA/CO-EMA/EP group had a normal menstrual cycle, which were significantly lower than those of Act-D group (84.6%,22/26) and FAV-FAEV group (71.2%, 37/52; all P< 0.05) . Amenorrhea rate was also significantly higher in EMA/CO-EMA/EP group (25.0%, 11/44) than in Act-D group (0) and FAV-FAEV group (17.3%, 9/52; all P< 0.05) . The sexual life parameters were comparable among 3 groups. Ten out of thirty-two patients conceived after chemotherapy, 2 had miscarriages and 8 had full-term delivery of healthy babies. The common health and labor capacity were significantly decreased after chemotherapy (all P< 0.05) . Conclusions: EMA/CO or EMA/EP regimen have a worse impact on ovarian function than Act-D and FAV or FAEV regimen. Gynecologic oncologist should be concerned about the ovarian function and quality of life of GTN patients.

Objective: There is no consensus regarding what should be the optimal single-agent regimen in low-risk gestational trophoblastic neoplasia(LRGTN). we performed this network meta-analysis(NMA) and our aim is to synthesize all efficacy evidence, enabling a comparison of all single-agent methotrexate(MTX)-based or actinomycin-d(Act-D)-based regimens in LRGTN., Methods: We performed a literature search of PubMed, Embase, and the Cochrane Library for all relevant articles. Seven randomized controlled trials and four retrospective studies met the study eligibility criteria. Overall, 987 patients were included. Treatments were grouped into weekly intramuscular MTX(w-IM MTX), five-day intramuscular MTX(5d-IM MTX), five-day intravenous MTX(5d-IV MTX), eight-day intramuscular MTX with folinic acid(MTX-FA), five-day intravenous Act-D(5d-IV Act-D), and bi-weekly pulsed intravenous Act-D (pulsed IV Act-D) treatments. P-score was used to rank the treatments., Results: Values of P-score indicated that the Act-D-based regimens had superior efficacy compared with the MTX-based regimens. Namely, 5d-IV Act-D had the highest probability of being the best treatment arm for CR, followed by pulsed IV Act-D and 5d-IV MTX. Similar results were observed in the subgroup analysis from the prospective studies. Toxicity analysis indicated that 5d-IM MTX showed increased toxicity in nausea and vomiting, as measured by their P-scores. In contrast, 5d-IV Act-D had the highest probability of being the least toxic regimen in terms of nausea and vomiting. Grade 3/4 adverse events (AEs), though infrequent, were more frequently observed in 5d-IM MTX, followed by 5d-IV Act-D and 5d-IV MTX., Conclusions: Our NMA provides a systematic evaluation of the relative efficacy of available single-agent MTX-based and Act-D-based regimes in LRGTN. Until new evidence becomes available, 5d-IV Act-D and pulsed IV Act-D appear to be the best treatment options in LRGTN., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Gestational trophoblastic neoplasia (GTN) is classified as a highly curable group of pregnancy-related malignancies; however, approximately 15% will be persistent and require chemotherapy. Up to 25% of these women will develop resistance and 2% will develop disease relapse after initial chemotherapy. Despite the need for further chemotherapy in these women, cure rates are high., Objective: To evaluate the outcomes of women diagnosed with low-risk GTN, assessing the type of treatment, the number of chemotherapy cycles received, development of resistance or disease relapse, survival, and to assess the feasibility of changing to a new drug regimen., Methods: From March 2012 until February 2015, a retrospective study was conducted and 38 cases with low-risk GTN were reviewed. The number of cycles, type of treatment received, duration of treatment, development of resistance and disease relapse, and adverse side effects were analysed., Results: The median duration of follow-up was 12 months. Disease-free survival was 100% and primary complete remission rates were achieved in 85.3% of patients who were treated with actinomycin D and 25% patients who were treated with methotrexate (MTX). A change in chemotherapy was required for nine patients. One patient developed disease relapse. Nausea, fatigue and constipation were the most frequent adverse events reported with actinomycin D. All women were cured of their disease., Conclusion: All women were successfully treated and achieved complete remission. Changing from MTX to actinomycin D as first-line chemotherapy for women with low-risk GTN was feasible and safe., (© 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

In this study, we describe a 2-year-old boy patient with nephroblastoma who has developed toxic epidermal necrolysis (TEN) associated with the combination chemotherapy administration of dactinomycin and vincristine. A skin biopsy confirmed the diagnosis of TEN, and with methylprednisolone pulse therapy, intravenous immunoglobulin (IVIG), and supportive care, the patient improved significantly.

Objectives: Gynecologic Oncology Group (GOG) 0174 compared weekly intramuscular methotrexate (MTX) with biweekly pulsed intravenous dactinomycin (Act-D) as single-agent chemotherapy for low-risk gestational trophoblastic neoplasia (GTN). Act-D had a higher rate of initial complete response (CR) (70% vs. 53%, p=0.01), but multi-day regimens of MTX have higher historic success rates. We assessed the cost-effectiveness of Act-D vs. MTX per GOG 0174 and explored multi-day MTX regimens., Methods: A cost effectiveness decision model was constructed with data from GOG 0174. Outcome was cost per first-line treatment success expressed in terms of incremental cost-effectiveness ratio (ICER). Front-line failures were assumed to receive cross-over single agent therapy, second line failures; multi-agent chemotherapy. GOG 0174 had no quality of life (QOL) evaluation, so equal QOL (utility 1.0) was assumed but varied in sensitivity analysis. A second exploratory model included 5-day and 8-day MTX regimens., Results: Act-D ($18,505) was more expensive compared to weekly MTX ($8950) with an ICER of $56,215 per first-line treatment success compared to weekly MTX. Small decreases in QOL dramatically increased the ICER during sensitivity analysis. Models with multi-day MTX regimens were also more cost-effective than Act-D. If effectiveness was redefined as avoidance of multi-agent chemotherapy, weekly MTX was more effective., Conclusions: With a complete cure rate for low-risk GTN regardless of initial agent, our model supports provider hesitation toward first line Act-D for low risk GTN. While Act-D is more effective for first line treatment success, it is more costly, and does not decrease rate of multi-agent chemotherapy use., (Published by Elsevier Inc.)

Hepatic sinusoidal obstruction syndrome (SOS) is a life-threatening syndrome that generally occurs as a complication after hematopoietic stem cell transplantation or, less commonly, after conventional chemotherapy. Regarding SOS in rhabdomyosarcoma patients who received conventional chemotherapy, the doses of chemotherapeutic agents are associated with the development of SOS. Several cases of SOS in rhabdomyosarcoma patients after receiving chemotherapy with escalated doses of cyclophosphamide have been reported. Here, we report on a 9-year-old female with rhabdomyosarcoma who developed severe SOS after receiving chemotherapy consisting of vincristine, actinomycin-D, and a moderate dose of cyclophosphamide. She was treated successfully with defibrotide without sequelae to the liver., Competing Interests: relevant to this article was not reported.

Objective: To evaluate the efficacy and toxicity profile of floxuridine, dactinomycin, etoposide and vincristine (FAEV) regimen as primary treatment in stage IV gestational trophoblastic neoplasia (GTN)., Methods: From 2004 to 2014, FAEV was given to 30 stage IV GTNs as the primary treatment (at least two cycles) in Peking Union Medical College Hospital. Remission/resistance/recurrence rate, the cause of treatment failure, and the toxicity profile were analyzed., Results: A total of 190cycles of FAEV were administered to 30 patients; the median number of the cycles was 6 (range 3-11). The median follow up was 52.3months (range 8-120). Of all the patients received FAEV primarily, 24 achieved complete remission after only received FAEV, with no recurrence; 6 patients later switched to EMA-CO treatment due to FAEV resistance. Among the 6 patients, 2 died of progressive disease after multiple lines of chemotherapy, the other 4 achieved complete remission after second-line or third-line chemotherapy and 1 of them relapsed 15months later. FAEV was well tolerated. No one died from toxicity. Severe grade 4 neutropenia and thrombocytopenia were noted in 8 (26.7%) and 2 (6.7%) cases. No secondary malignancy was observed with follow-ups from 8 to120 months. Patients treated with FAEV showed good reproductive outcomes., Conclusions: FAEV regimen might be considered as an alternative to other chemotherapy regimen in the primary treatment of stage IV GTN, where it had a high rate of remission and a tolerable toxicity., (Copyright © 2016. Published by Elsevier Inc.)

Radiation recall dermatitis (RRD) is an uncommon reaction typically triggered by the use of chemotherapeutic agents in the months after treatment with radiation therapy. It usually presents as dermatitis in the irradiated field with prominent intertriginous involvement, and because internal involvement occurs in up to one-third of cases, early recognition is important. RRD has rarely been reported in the pediatric literature. We report the case of a 15-month-old boy with RRD to dactinomycin., (© 2016 Wiley Periodicals, Inc.)

Background: This is the second update of a Cochrane review that was first published in 2009, Issue 1, . Gestational trophoblastic neoplasia (GTN) is a rare but curable disease arising in the fetal chorion during pregnancy. Most women with low-risk GTN will be cured by evacuation of the uterus with or without single-agent chemotherapy. However, chemotherapy regimens vary between treatment centres worldwide and the comparable benefits and risks of these different regimens are unclear., Objectives: To determine the efficacy and safety of first-line chemotherapy in the treatment of low-risk GTN., Search Methods: We electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase in September 2008, February 2012, and January 2016. In addition, we searched online trial registers for protocols and ongoing trials., Selection Criteria: For the original review, we included randomised controlled trials (RCTs), quasi-RCTs and non-RCTs that compared first-line chemotherapy for the treatment of low-risk GTN. For this updated versions of the review, we included only RCTs., Data Collection and Analysis: Two review authors independently assessed studies for inclusion and extracted data to a pre-designed data extraction form. Meta-analysis was performed using the random-effects model., Main Results: We included seven RCTs (667 women) in this updated review. Most studies were at a low or moderate risk of bias and all compared methotrexate with actinomycin D. Three studies compared weekly intramuscular (IM) methotrexate with bi-weekly pulsed intravenous (IV) actinomycin D (393 women), one study compared five-day IM methotrexate with bi-weekly pulsed IV actinomycin D (75 women), one study compared eight-day IM methotrexate-folinic acid (MTX-FA) with five-day IV actinomycin D (49 women), and one study compared eight-day IM MTX-FA with bi-weekly pulsed IV actinomycin D. One study contributed no data. Moderate-certainty evidence indicates that actinomycin D is probably more likely to lead to primary cure than methotrexate (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.57 to 0.75; six trials, 577 participants; I(2) = 26%), and first-line methotrexate treatment is probably more likely to fail than actinomycin D treatment (RR 3.55, 95% CI 1.81 to 6.95; six trials, 577 participants; I(2) = 61%; moderate-certainty evidence) Low-certainty evidence suggests that there may be little or no difference between methotrexate and actinomycin D treatment with respect to nausea (four studies, 466 women; RR 0.61, 95% CI 0.29 to 1.26) or any of the other individual side-effects reported, although data for all of these outcomes were insufficient and too inconsistent to be conclusive. Low-certainty evidence suggests that there may be little or no difference in the risk of severe adverse events (SAEs) between the groups overall (five studies, 515 women; RR 0.35, 95% CI 0.08 to 1.66; I² = 60%); however, the direction of effect favours methotrexate and more evidence is needed. Furthermore, evidence from subgroup analyses suggests that actinomycin D may be associated with a greater risk of SAEs than methotrexate (low-certainty evidence). We found no evidence on the effect of these treatments on future fertility., Authors' Conclusions: Actinomycin D is probably more likely to achieve a primary cure in women with low-risk GTN, and less likely to result in treatment failure, than a methotrexate regimen. There may be little or no difference between the pulsed actinomycin D regimen and the methotrexate regimen with regard to side-effects. However, actinomycin D may be associated with a greater risk of severe adverse events (SAEs) than a methotrexate regimen. Higher-certainty evidence is still needed on treating low-risk GTN and the four ongoing trials are likely to make a significant contribution to this field. Given the variety of treatment regimens, findings from these trials could facilitate a network meta-analysis in the next version of this review to help women and clinicians determine the best treatment options for low-risk GTN.

Aims: Use of the anti-tumour antibiotic actinomycin D is associated with development of hepatotoxicity, particularly in young children. A paucity of actinomycin D pharmacokinetic data make it challenging to develop a sound rationale for defining dosing regimens in younger patients. The study aim was to develop a physiologically based pharmacokinetic (PBPK) model using a combination of data from the literature and generated from experimental analyses., Methods: Assays to determine actinomycin D Log P, blood:plasma partition ratio and ABCB1 kinetics were conducted. These data were combined with physiochemical properties sourced from the literature to generate a compound file for use within the modelling-simulation software Simcyp (version 14 release 1). For simulation, information was taken from two datasets, one from 117 patients under the age of 21 and one from 20 patients aged 16-48., Results: The final model incorporated clinical renal and biliary clearance data and an additional systemic clearance value. The mean AUC0-26h of simulated subjects was within 1.25-fold of the observed AUC0-26h (84 ng h ml(-1) simulated vs. 93 ng h ml(-1) observed). For the younger age ranges, AUC predictions were within two-fold of observed values, with simulated data from six of the eight age/dose ranges falling within 15% of observed data. Simulated values for actinomycin D AUC0-26h and clearance in infants aged 0-12 months ranged from 104 to 115 ng h ml(-1) and 3.5-3.8 l h(-1) , respectively., Conclusions: The model has potential utility for prediction of actinomycin D exposure in younger patients and may help guide future dosing. However, additional independent data from neonates and infants is needed for further validation. Physiological differences between paediatric cancer patients and healthy children also need to be further characterized and incorporated into PBPK models., (© 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

The study aimed to compare the efficacy of methotrexate (MTX) cervical injections + actinomycin-D (ACT-D)(MACT) and 5-fluorouracil (5-Fu) + actinomycin-D (5-Fu plus ACT-D) chemotherapy regimens for low-risk gestational trophoblastic neoplasia (LR-GTN). Clinical data from 66 LR-GTN patients, admitted to the Beijing Obstetrics and Gynecology Hospital from January 2010 to April 2012, were analysed retrospectively. In total, 32 patients were treated with a MACT therapeutic regimen and the remaining 34 with a 5Fu + ACT-D therapeutic regimen. Complete remission rates (CR), duration of treatment, hospital stay and toxicity effects were compared. There was no statistical difference in CR for the MACT (90.63%) or the 5-Fu plus ACT-D (100%) therapeutic regimens (p = 0.0676) or in the duration of treatment [MACT (3.50) or 5-Fu plus ACT-D (3.71; p = 0.2021)]. Moreover, the hospital stay in the 5-Fu plus ACT-D group (32.88 days) was significantly longer than for the MACT group (22.09 days; p ＜ 0.001). Furthermore, the degree of myelosuppression, nausea and vomiting, diarrhoea, stomatitis and alopecia was more severe in the 5Fu + ACT-D group (p ＜ 0.01). However, there was no statistical difference in the severity of liver function damage between the two groups. A shorter hospital stay, lower hospitalization cost and slightly more toxic effects were observed in LR-GTN patients treated with the MACT therapeutic regimen. We suggest that the MACT regimen should be used as first-line chemotherapy for LR-GTN.

The antitumor agent actinomycin D has been used in the treatment of Wilms tumor for the past 40 years. Actinomycin D-induced hepatopathy-thrombocytopenia syndrome (HTS) is characterized as a rare syndrome. The mechanism underlying HTS may differ with individual multidrug resistance protein-1 (MDR1) genotype. The relationship between actinomycin D-related HTS and MDR1 gene mutations is presented in this case study of a pediatric patient with Wilms tumor. Our findings revealed that the girl had (-)1G>A, 1236C>T, 2677G>T, 3435C>T, and 61A>G MDR1 gene mutations. Understanding the function of genetic variants of MDR1 is an important aim for personalized cancer management.

We have investigated a number of complexes of 7-aminoactinomycin D (7AAMD), with its potential carriers: caffeine, folic acid (FA), purine bases-guanine and adenine, pyrimidine base-thymine and with fragmented DNA to determine more stable and suitable complex. The process of binding of the fluorescent antibiotic with clusters of caffeine, guanine, adenine, thymine and with fragmented DNA was accompanied by a considerable long-wavelength shift in excitation spectrum. The energy of interaction between phenoxazine hetero-cycle of 7AAMD and chromophores of the carriers studied has been found. In the case of 7AAMD with guanine, adenine, thymine and caffeine, the energy is about of 7 kcal/mol, which is a little lower than in the case with DNA (7.7 kcal/mol). On the basis of emission spectra, in all examined compounds, with the exception DNA, the 7AAMD molecule emits photons from water phase, not from a cluster, since photo-excitation leads to desorption of the antibiotic from a cluster surface. We observed also the mutual fluorescence quenching of 7AAMD and FA in their complex. It may well be that this complex forms due to interaction of peptide-lactone rings of 7AAMD with system of FA. In the case of DNA, the complex with 7AAMD has very high stability that is determined not only by interaction between phenoxazine of 7AAMD and the DNA bases, but it is largely owing to the interaction between two peptide-lactone rings of 7AAMD and the DNA deoxyribose-phosphate chains., (© The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Background: Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation., Methods: For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m(2) at weeks 1-8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 μg/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m(2) given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants., Findings: Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8-79·8). 2 year event-free survival was 92·6% (95% CI 89·6-95·7) for treatment including doxorubicin and 88·2% (84·5-92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4-9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3-98·8) for treatment including doxorubicin and 95·8% (93·3-98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (<1%) of 291 receiving treatment including doxorubicin died of sepsis, three (1%) of 292 receiving treatment excluding doxorubicin died of varicella, metabolic seizure, and sepsis during treatment for relapse. 17 patients (3%) had hepatic veno-occlusive disease. Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin. 12 children receiving treatment including doxorubicin, and ten children receiving treatment excluding doxorubicin, died, with the remaining deaths from tumour recurrence., Interpretation: Doxorubicin does not need to be included in treatment of stage II-III intermediate risk Wilms' tumour when the histological response to preoperative chemotherapy is incorporated into the risk stratification., Funding: See Acknowledgments for funders., (Copyright © 2015 Pritchard-Jones et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To assess the risks of second malignancy and early menopause in a large cohort of patients with gestational trophoblastic tumor who were treated with chemotherapy., Patients and Methods: A survey of patients treated at Charing Cross Hospital between 1958 and 2000 was performed in 2006 to assemble incidence data for subsequent malignancies and the age at menopause. Treatment records were reviewed for the regimens and durations, and the incidence of subsequent malignancies was compared with that in the national age-matched population., Results: Data were obtained for 1,903 patients, with a mean follow-up of 16.9 years. Eighty-six patients developed a subsequent malignancy compared with an expected number of 79 (standardized incidence ratio [SIR], 1.1; 95% CI, 0.9 to 1.3). The overall risk was low for patients treated with single-agent methotrexate and folinic acid (MTX-FA; SIR, 0.7; 95% CI, 0.5 to 1.1) and also for patients treated with etoposide, methotrexate, and dactinomycin followed by cyclophosphamide and vincristine on alternating weeks (EMA-CO) with an SIR of 0.9 (95% CI, 0.4 to 2.2), but there were significantly increased risks of oral cancer, melanoma, meningioma, and leukemia. The cumulative risk of early menopause was low after MTX-FA but was substantial after EMA-CO, reaching 13% by age 40 years and 36% by age 45 years., Conclusion: Subsequent cancer risks for patients cured of gestational trophoblastic tumors with modern chemotherapy appear similar to those of the normal population with no overall increased risk of malignancy after MTX-FA or EMA-CO. However, there was evidence of an increased risk of leukemia after EMA-CO and some evidence of other site-specific increased risks based on small patient numbers. All major treatments except MTX-FA increased the risk of early menopause., (© 2014 by American Society of Clinical Oncology.)

Background: High-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) is a treatment option for pediatric patients with relapsed nephroblastoma. We present long term results of 9 patients treated between 1993 and 2013 at our center., Procedure: Reinduction therapy was carried out according to GPOH and SIOP recommendations. The conditioning regimen consisted of carboplatin (1 200 mg/m²), etoposide (800 mg/m² or 40 mg/kg) and melphalan (180 mg/m²). Purging of the grafts with immunomagnetic CD34 positive selection was performed in 5 patients., Results: 8 of 9 Patients (90%) are alive without evidence of disease after a median follow-up of 8.5 years. Leukocyte engraftment occurred after a median of 10 days (range 8-12). Median numbers of 667/µl CD3+, 329/µl CD4+, 369/µl CD8+T cells and 949/µl B cells were reached after 180 days. No negative impact of CD34 selection was observed. No transplantation-related death occurred. Acute toxicity comprised mucositis III°-IV° in all and veno-occlusive disease in one patient. Long term effects probably related to treatment occurred in 3/7 evaluable patients and comprised hearing impairment, reduced renal phosphate reabsorption, mild creatinine elevation and hypothyroidism (n=1, each)., Conclusion: Thus, in our experience HDC with ASCR is an effective treatment of recurrent or refractory nephroblastoma with acceptable side effects. However, a randomized trial proving its efficiency with a high level of evidence is needed., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Relative efficacy and toxicity of cyclophosphamide compared with ifosfamide are debatable. The Euro-EWING99-R1 trial asked whether cyclophosphamide may replace ifosfamide in combination with vincristine and dactinomycin (vincristine, dactinomycin, and cyclophosphamide [VAC] v vincristine, dactinomycin, and ifosfamide [VAI]) after an intensive induction chemotherapy containing vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in standard-risk localized disease (NCT00020566)., Methods: Standard-risk Ewing sarcomas were localized tumors with either a good histologic response to chemotherapy (< 10% cells) or small tumors (< 200 mL) resected at diagnosis or receiving radiotherapy alone as local treatment. Patients entered the trial after six VIDE+1 VAI courses. Allocated treatment was either 7 VAC courses with 1.5 g/m(2) of cyclophosphamide or seven VAI-courses with 6 g/m(2) ifosfamide. The limit of noninferiority was set at -8.5% for the 3-year event-free survival rate (EFS), equivalent to 1.43 in terms of the hazard ratio of event (HR(event))., Results: This large international trial recruited 856 patients between February 2000 and March 2010 (n = 431 receiving VAC and n = 425 receiving VAI). With a median follow-up of 5.9 years, the 3-year EFSs were 75.4% and 78.2%, respectively, the 3-year EFS difference was -2.8% (91.4% CI, -7.8 to 2.2%), the HR(event) was 1.12 (91.4% CI, 0.89 to 1.41), and the HR(death) was 1.09 (91.4% CI, 0.84 to 1.42; intention-to-treat). The HR(event) was 1.22 (91.4% CI, 0.96 to 1.54) on the per-protocol population. Major treatment modifications were significantly less frequent in the VAC arm (< 1%) than in the VAI arm (7%), mainly resulting from toxicity. Patients experienced more frequent thrombocytopenia in the VAC arm (45% v 35%) but fewer grade 2 to 4 acute tubular toxicities (16% v 31%)., Conclusion: Cyclophosphamide may be able to replace ifosfamide in consolidation treatment of standard-risk Ewing sarcoma. However, some uncertainty surrounding the noninferiority of VAC compared with VAI remains at this stage. The ongoing comparative evaluation of long-term renal and gonadal toxicity is crucial to decisions regarding future patients., (© 2014 by American Society of Clinical Oncology.)

Background: Patients with high-risk gestational trophoblastic neoplasia (GTN) need multi-agent chemotherapy to be cured. The most common regimen is etoposide (E), methotrexate (M) and actinomycin D (A), alternating weekly with cyclophosphamide (C) plus vincristine (O) (EMA/CO). Cisplatin (P) is a very active drug, but it is usually restricted to second-line therapies. Herein, we report the results of a cisplatin-based therapy: APE (actinomycin D, cisplatin, and etoposide)., Patients and Methods: The efficacy and safety of APE for high-risk GTN (defined by Institut Gustave-Roussy (IGR) criteria and/or an International Federation of Gynaecology and Obstetrics (FIGO) score >6) are reported. Patients with brain metastasis or placental-site trophoblastic tumour were excluded., Results: Between 1985 and 2013, 95 patients were treated with APE for high-risk GTN: 59 patients as first-line, 36 as ⩾ 2nd-line therapy. There was 94.7% complete remission, though five patients relapsed. One patient died from GTN after multiple lines of chemotherapy. The five-year overall survival rate (median follow-up 5.7 years) was 97% (95% confidence interval (CI): 91-99%). No death from toxicity occurred. Long-term, six grade-1 neuro-toxicities, three grade-1 and two grade-2 oto-toxicities, and one grade-1 renal toxicity were recorded. One patient developed AML-M4 after APE and EMA/CO. Thirty-four of 35 women, who wished to become pregnant, succeeded and all had at least one live birth., Conclusion: With a 97% long-term overall survival rate, limited long-term toxicity, and an excellent reproductive outcome, APE could be regarded as an alternative option to EMA/CO as a standard therapy for high-risk GTN., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Wilms' tumor (WT) is a common childhood renal cancer. A 25-year single center UK experience is reported. During 1985-2010, 97 children underwent immediate nephrectomy or delayed resection of tumor after chemotherapy. Survival, morbidity, and late effects following treatment are described. Tumor distribution was: Stage I, 25.7% (n = 25); Stage II, 24.7% (n = 24); Stage III, 26.8% (n = 26); Stage IV, 17.5% (n = 17); and Stage V, 5.2% (n = 5). Immediate nephrectomy was performed in 39% (n = 38) patients with elective delayed resection in 61% (n = 59) cases. Ten patients had cavotomy to excise tumor involving vena cava territory. Two cases required cardiopulmonary bypass. Tumor rupture was recorded in eight (8.5%) total operated cases-after immediate (n = 5/37), 13.5% vs delayed nephrectomy-(n = 3/57), 5.2%; X(2) P = .154. From 2001 onwards, one case of tumor rupture was recorded at this center after the universal adoption of UKW3 and SIOP guidelines advocating preoperative chemotherapy and delayed nephrectomy for all WT. Three treatment-related deaths occurred-hepatic veno-occlusive disease (n = 2) with actinomycin D and a single WT fatality due to vascular injury. Overall survival was 84.5% (82/97 cases). Two patients developed "late malignancies" -thyroid cancer and a basal cell carcinoma. This study demonstrates excellent survival for WT comparable with national outcomes and international cooperative studies. Adverse events with chemotherapy and surgery, including "late onset," second malignancies deserve special consideration.

Background: Treatment of stage V nephroblastoma is less established and more complex than in unilateral nephroblastoma., Methods: Retrospective analysis of 121 consecutive patients with stage V nephroblastoma registered from January 1989 to May 2005. Registration, prospective data collection and treatment were carried out within the framework of 3 consecutive SIOP/GPOH-nephroblastoma-trials., Results: 19 patients had metastasis and 29 syndromes at diagnosis. 13 patients had been pretreated for bilateral nephroblastomatosis. 1 patient was not treated and 17 patients had upfront surgery. Preoperative treatment duration ranged from 1-12 weeks (n=103). 1-3 preoperative treatment-cycles resulted in average tumor-volume-reduction of 45%. 1 patient underwent bilateral nephrectomy. 52% of the patients had 2 functioning kidneys after the end of treatment. 20 patients had died after mean follow-up of 8.6 years. 5y-Progression-Free (PFS) and Overall-Survival (OS) were excellent for patients having a localized disease without pretreatment for nephroblastomatosis (5yPFS/OS: 80±4%/93±3%). Metastasis at diagnosis (51±12%/56±12%; p=0.003) and pretreatment for nephroblastomatosis (37±14%/67±13%; p<0.001) were associated with significantly poorer outcome. Cox-regression analysis revealed an independent influence of pretreatment for nephroblastomatosis, metastasis and syndromes on PFS. The latter 2 as well as anaplasia and age (<2 years or >3 years) had an independent influence on OS., Conclusions: Pretreatment for nephroblastomatosis, metastasis and syndromes are independent risk factors. 1-3 preoperative treatment-cycles are sufficient to achieve save nephron-sparing-surgery in most patients., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To analyze the reproductive outcomes of women with high-risk gestational trophoblastic neoplasia (GTN) treated with multiagent EMA-CO chemotherapy., Study Design: Of 212 patients treated with chemotherapy for GTN between 1986 and 2012, 65 (31%) could be contacted by telephone or mail and consented to participate in a questionnaire designed to assess their menstrual and reproduction outcomes., Results: Twenty-four high-risk (HR) and 41 low-risk (LR) patients consented to the study. Fifteen (63%) HR and 34 (83%) LR women had not undergone hysterectomy (p = 0.08). Of the 12 HR and 33 LR women who could recall their menstrual history, all 12 (100%) HR and 32 (97%) LR women resumed menses after chemotherapy. Both groups also had a similar age of menopause (HR, 43.8 years; LR, 48.5 years) (p = 0.19). Although fewer women in the HR group desired to become pregnant after chemotherapy (HR 5/15 [33%] vs. LR 25/34 [74%]) (p = 0.01), 8 HR women (53%) and 29 LR women (85%) eventually became pregnant (p = 0.03), with equivalent live birth rates of 74% and 76%, respectively., Conclusion: Multiagent EMA-CO chemotherapy did not significantly alter menstrual or reproductive outcomes compared to single-agent methotrexate chemotherapy for GTN.