GAMEC – a new intensive protocol for untreated poor prognosis and relapsed or refractory germ cell tumours

Shamash, Jonathan; Powles, Tom; Ansell, Wendy; Stebbing, Justin; Mutsvangwa, Katherine; Wilson, Peter; Asterling, S.; Liu, S; Wyatt, Philip; Joel, S P; Oliver, R. T. D.

doi:10.1038/sj.bjc.6603865

Cited by 25 publications

(19 citation statements)

References 31 publications

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“…This review was initiated 4 years ago due to the authors' clinical and pathological experience, gained in phase 2 trials of novel treatments for relapsed germ cell tumours, 6 that elderly men with germ cell tumours tended to present late, and responded more poorly to chemotherapy when compared with younger men. Due to their rarity, even in referral practice, a retrospective cohort has been collected from a number of sources.…”

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Malignant germ cell tumours in the elderly: a histopathological review of 50 cases in men aged 60 years or over

et al. 2008

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Malignant testicular germ cell tumours in the elderly are extremely rare with anecdotal accounts of their aggressive behaviour. Fifty cases of germ cell tumour, diagnosed at the age of 60 years or above, were pathologically reviewed. The oldest patient was 86 years of age, with 78% of cases presenting in men in their 60s. Forty-one (82%) of the tumours were seminomas with only nine cases (18%) of mixed or nonseminomatous germ cell tumour. However, all non-seminomatous types of tumour were represented in the series. The macroscopic tumour size was significantly larger (median ¼ 6 cm, range ¼ 2-11 cm) than comparable series in younger men. They were also of higher stage with more frequent vascular invasion and rete testis invasion than is typically seen in a younger population. The tumours were less associated with intratubular germ cell neoplasia than in younger men as it was present in only 47% of assessable cases. We conclude that germ cell tumours, in man aged 60 years or above, present at a later stage than in younger men, and although most are seminomas, non-seminomatous tumours may occur with a wide spectrum of morphology.

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Malignant germ cell tumours in the elderly: a histopathological review of 50 cases in men aged 60 years or over

et al. 2008

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“…The fold variability compared to observed values ranged from 1.2‐fold to 1.6‐fold, depending on dose group (Figure B). The model prediction was compared to data obtained from an adult PK study dataset . The visual predictive check (Figure ) showed that the simulated mean concentration–time profile fell within the observed results; however, the simulation failed to capture the full variability of the observed data (observed AUC 0‐26h SD: 595.33 ng h ml −1 , simulated AUC 0‐26h SD: 9.04 ng h ml −1 ).…”

Section: Resultsmentioning

confidence: 90%

“…The data for patients in the 1–<6 and 6–<10 year age bands were utilized for comparison with the simulated data obtained from the model. PK data for 30 adult patients were provided by St Bart's Hospital, London, for further assessment of the model .…”

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confidence: 99%

Development of a physiologically based pharmacokinetic model of actinomycin D in children with cancer

Walsh

Bonner

Johnson

et al. 2016

Brit J Clinical Pharma

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AimsUse 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.MethodsAssays 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.ResultsThe 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.ConclusionsThe 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.

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“…Salvage therapy: patient 001: Granulocyte colony stimulating factor (GCSF), actinomycin D, methotrexate, etoposide, cisplatin (GAMEC) chemotherapy (Shamash et al , 2007b) followed by RPLND showing no viable tumour. Remains progression free 6 years later.Patient 005: GAMEC chemotherapy (Shamash et al , 2007b) followed by RPLND showing no viable tumour. Relapsed in abdomen.…”

Section: Figurementioning

confidence: 99%

Accelerated BEP: a phase I trial of dose-dense BEP for intermediate and poor prognosis metastatic germ cell tumour

et al. 2011

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Background:We used bleomycin, etoposide, cisplatin (BEP), the most effective regimen in the treatment of germ cell tumours (GCTs) and increased dose-density by using pegfilgrastim to shorten cycle length. Our aim was to assess safety and tolerability.Methods:Sixteen male patients with intermediate or poor prognosis metastatic GCT were treated with four cycles of 3-day BEP with G-CSF on a 14-day cycle for a planned relative dose-density of 1.5 compared with standard BEP.Results:Eleven intermediate and five poor prognosis patients were treated. In all, 14 of 16 patients completed the study treatment. Toxicities were comparable to previous studies using standard BEP, except for mucositis and haematological toxicity that were more severe. The overall relative dose-density for all 16 patients was mean 1.38 (range 0.72–1.5; median 1.46). Complete response was achieved after chemotherapy alone in two patients (13%) and following chemotherapy plus surgery in nine additional patients (56%). Four patients (25%) had a partial response and normalised their marker levels. At a median follow-up of 4.4 years (range 2.1–6.8) the estimated 5-year progression-free survival probability is 81% (95% CI 64–100%).Conclusion:Accelerated BEP is tolerable without major additional toxicity. A randomised controlled trial will be required to obtain comparative efficacy data.

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GAMEC – a new intensive protocol for untreated poor prognosis and relapsed or refractory germ cell tumours

Cited by 25 publications

References 31 publications

Malignant germ cell tumours in the elderly: a histopathological review of 50 cases in men aged 60 years or over

Malignant germ cell tumours in the elderly: a histopathological review of 50 cases in men aged 60 years or over

Development of a physiologically based pharmacokinetic model of actinomycin D in children with cancer

Accelerated BEP: a phase I trial of dose-dense BEP for intermediate and poor prognosis metastatic germ cell tumour

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