Safety, efficacy and survival of patients with primary malignant brain tumours (PMBT) in phase I (Ph1) trials: the 12-year Royal Marsden experience

  • Niamh Coleman
  • Vasiliki Michalarea
  • Scheryll Alken
  • Karim Rihawi
  • Raquel Perez Lopez
  • Nina Tunariu
  • Ann Petruckevitch
  • L. R. Molife
  • Udai Banerji
  • Johann S. De Bono
  • Liam Welsh
  • Frank Saran
  • Juanita Lopez
Clinical Study

Abstract

Background

Primary malignant brain tumours (PMBT) constitute less than 2% of all malignancies and carry a dismal prognosis. Treatment options at relapse are limited. First-in-human solid tumour studies have historically excluded patients with PMBT due to the poor prognosis, concomitant drug interactions and concerns regarding toxicities.

Methods

Retrospective data were collected on clinical and tumour characteristics of patients referred for consideration of Ph1 trials in the Royal Marsden Hospital between June 2004 and August 2016. Survival analyses were performed using the Kaplan–Meier method, Cox proportional hazards model. Chi squared test was used to measure bivariate associations between categorical variables.

Results

100pts with advanced PMBT were referred. At initial consultation, patients had a median ECOG PS 1, median age 48 years (range 18–70); 69% were men, 76% had glioblastoma; 68% were on AEDs, 63% required steroid therapy; median number of prior treatments was two. Median OS for patients treated on a Ph1 trials was 9.3 months (95% CI 5.9–12.9) versus 5.3 months (95% CI 4.1–6.1) for patients that did not proceed with a Ph1 trial, p = 0.0094. Steroid use, poor PS, neutrophil-to-lymphocyte ratio and treatment on a Ph1 trial were shown to independently influence OS.

Conclusions

We report a survival benefit for patients with PMBT treated on Ph1 trials. Toxicity and efficacy outcomes were comparable to the general Ph1 population. In the absence of an internationally recognized standard second line treatment for patients with recurrent PMBT, more Ph1 trials should allow enrolment of patients with refractory PMBT and Ph1 trial participation should be considered at an earlier stage.

Keywords

Malignant brain tumour High grade glioma Glioblastoma Drug development Phase I 

Notes

Compliance with ethical standards

Conflict of interest

There are no conflict of interest for all authors.

References

  1. 1.
    Thakkar JP et al (2014) Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomark Prev 23(10):1985–1996CrossRefGoogle Scholar
  2. 2.
    Ostrom QT et al (2014) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro Oncol 16(Suppl 4, no. suppl_4):iv1–iv63CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Eisenhauer EA, Twelves C, Buyse ME (2006) Phase I cancer clinical trials: a practical guide. Oxford University Press, OxfordGoogle Scholar
  4. 4.
    Spriggs DR, Gounder MM (2011) Inclusion of Patients with brain metastases in phase I trials: an unmet need. Clin Cancer Res 17(12):3855–3857CrossRefPubMedGoogle Scholar
  5. 5.
    Wen PY et al (2011) It is time to include patients with brain tumors in phase I trials in oncology. J Clin Oncol 29(24):3211–3213CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Garrido-Laguna I et al (2012) Validation of the Royal Marsden Hospital prognostic score in patients treated in the phase i clinical trials program at the MD Anderson Cancer Center. Cancer 118(5):1422–1428CrossRefPubMedGoogle Scholar
  7. 7.
    Brennan CW et al (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Papadatos-Pastos D, Banerji U (2011) Revisiting the role of molecular targeted therapies in patients with brain metastases. J Neurooncol 105(3):467–474CrossRefPubMedGoogle Scholar
  9. 9.
    Lamborn KR et al (2008) Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol 10(2):162–170CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Wick W et al (2010) Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol 28(7):1168–1174CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Glantz MJ et al (2000) Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors—report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 54(10):1886–1893CrossRefPubMedGoogle Scholar
  12. 12.
    Hellmann A et al (2011) Effect of cytochrome P450 3A4 inducers on the pharmacokinetic, pharmacodynamic and safety profiles of Bortezomib in patients with multiple myeloma or non-Hodgkinʼs lymphoma. Clin Pharmacokinet 50(12):781–791CrossRefPubMedGoogle Scholar
  13. 13.
    Prados MD et al (2004) Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study. Neuro Oncol 6(1):44–54CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Relat Cancer 16(4):1103–1123CrossRefPubMedGoogle Scholar
  15. 15.
    Derr RL, Ye X, Islas MU, Desideri S, Saudek CD, Grossman SA (2009) Association between hyperglycemia and survival in patients with newly diagnosed glioblastoma. J Clin Oncol 27(7):1082–1086CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Chambless LB, Parker SL, Hassam-Malani L, McGirt MJ, Thompson RC (2012) Type 2 diabetes mellitus and obesity are independent risk factors for poor outcome in patients with high-grade glioma. J Neurooncol 106(2):383–389CrossRefPubMedGoogle Scholar
  17. 17.
    McGirt MJ et al (2008) Persistent outpatient hyperglycemia is independently associated with decreased survival after primary resection of malignant brain astrocytomas. Neurosurgery 63(2):286–291CrossRefPubMedGoogle Scholar
  18. 18.
    Bachelot T et al (2000) Multivariable analysis of prognostic factors for toxicity and survival for patients enrolled in phase I clinical trials. Ann Oncol 11(2):151–156CrossRefPubMedGoogle Scholar
  19. 19.
    Roberts TG et al (2004) Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. JAMA 292(17):2130–2140CrossRefPubMedGoogle Scholar
  20. 20.
    Molife LR et al (2012) Defining the risk of toxicity in phase I oncology trials of novel molecularly targeted agents: a single centre experience. Ann Oncol 23(8):1968–1973CrossRefPubMedGoogle Scholar
  21. 21.
    Templeton AJ et al (2014) Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst 106(6):dju124CrossRefPubMedGoogle Scholar
  22. 22.
    van Soest RJ et al (2014) Neutrophil to lymphocyte ratio as a prognostic biomarker for men with metastatic castration-resistant prostate cancer receiving first-line chemotherapy: data from two randomized phase III trials. Ann Oncol 2014:743–749Google Scholar
  23. 23.
    Gu X et al (2016) Prognostic significance of neutrophil-to-lymphocyte ratio in prostate cancer: evidence from 16,266 patients. Sci Rep 6:22089CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Pinato DJ, Shiner RJ, Seckl MJ, Stebbing J, Sharma R, Mauri FA (2014) Prognostic performance of inflammation-based prognostic indices in primary operable non-small cell lung cancer. Br J Cancer 110(8):1930–1935CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Gu L et al (2016) Prognostic value of preoperative inflammatory response biomarkers in patients with sarcomatoid renal cell carcinoma and the establishment of a nomogram. Sci Rep 6:23846CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Bambury RM et al (2013) The association of pre-treatment neutrophil to lymphocyte ratio with overall survival in patients with glioblastoma multiforme. J Neurooncol 114(1):149–154CrossRefPubMedGoogle Scholar
  27. 27.
    Medical Research Council (1990) Prognostic factors for high-grade malignant glioma: development of a prognostic index. A report of the medical research council brain tumour working party. J Neurooncol 9(1):47–55CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Niamh Coleman
    • 1
  • Vasiliki Michalarea
    • 1
  • Scheryll Alken
    • 1
  • Karim Rihawi
    • 1
  • Raquel Perez Lopez
    • 2
  • Nina Tunariu
    • 2
  • Ann Petruckevitch
    • 1
  • L. R. Molife
    • 1
  • Udai Banerji
    • 1
  • Johann S. De Bono
    • 1
  • Liam Welsh
    • 3
  • Frank Saran
    • 3
  • Juanita Lopez
    • 1
  1. 1.Drug Development UnitThe Royal Marsden Hospital Trust and Institute of Cancer ResearchLondonUK
  2. 2.Radiology DepartmentThe Royal Marsden Hospital Trust and Institute of Cancer ResearchLondonUK
  3. 3.Neuro-oncology DepartmentThe Royal Marsden Hospital Trust and Institute of Cancer ResearchLondonUK

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