FIGURE 1S: Flowchart:

Among those published as a full paper (n=20), four were not eligible: two trials included patients with GBM and other CNS tumours (data not individualised),1,2 and two, contrary to the NCI recommendation, reported only toxicities that authors considered related to the treatment.3,4 Among abstracts (n=9), 3 were excluded due to duplicate publication.5-7In addition, only 3 investigators answered the e-mail inquiries, and provided additional data.3,8,9A further, four abstracts (n=261 patients, 4 drugs: cetuximab, cilengitide, vandetanib, bevacizumab), were excluded due to insufficient reporting of SAE and/or no information about drug exposure.8-11 Finally, a total of 19 trials were included.

Abbreviations: GBM= Glioblastoma multiforme MTT=Molecularly targeted therapy; RT= radiotherapy

  1. Turner CD, Chi S, Marcus K, et al. Phase II Study of Thalidomide and Radiation in Children with Newly Diagnosed Brain Stem Gliomas and GBM. J Neurooncol 2007;82:95-101
  2. Broniscer A, Baker JN, Tagen M, et al. Phase I Study of Vandetanib During and After Radiotherapy in Children With Diffuse Intrinsic Pontine Glioma. J Clin Oncol 2010;28:4762-8
  3. Nabors LB, Fiveash, Markert JM, et al. A phase I trial of ABT-510 concurrent with standard chemoradiation for patients with newly diagnosed glioblastoma multiforme. Arch Neurol 2010;67:313-9
  4. Vredenburgh JJ 1, Desjardins A, Kirkpatrick JP, et al. Addition Of Bevacizumab To Standard Radiation Therapy And Daily Temozolomide Is Associated With Minimal Toxicity In Newly Diagnosed Glioblastoma Multiforme. Int J Radiat Oncol Biol Phys 2012;82:58-66
  5. Vredenburgh JJ, Desjardins A, Reardon DA, et al. Bevacizumab (BEV) in combination with temozolomide (TMZ) and radiation therapy (XRT) followed by BEV, TMZ, and irinotecan for newly diagnosed glioblastoma multiforme (GBM). J Clin Oncol 2010;28S:abstract2023
  6. Shih KC, Spiegel DR, Burris HA, et al. Phase II trial of radiation therapy/temozolomide/bevacizumab followed by Bevacizumab/Everolimus in the first-line treatment of glioblastoma multiforme (GBM). J Clin Oncol 2010;25S:Abstract2075
  7. Lai A, Fika E, McGibbon B, et al. Phase II Pilot Study of Bevacizumab in Combination with Temozolomide and Regional Radiation Therapy for Up-front Treatment of Patients with Newly Diagnosed GBM: Interim Analysis of Safety and Tolerability. Int J Radiat Oncol Biol Phys 2008;71:1372-80
  8. Quant EC, Batchelor T, Lassman AB, et al. Preliminary results from a multicenter, phase II, randomized, noncomparative clinical trial of radiation and temozolomide with or without Vandetanib in newly diagnosed glioblastoma (GBM). J Clin Oncol 2011;29S:abstract2069
  9. Balana C, Gallego O, Vieitez JM, et al. Phase II randomized study of preradiation treatment with temozolomide (TMZ) and bevacizumab (BEV) previous to TMZ plus radiation plus BEV versus the same treatment without BEV therapy in unresectable glioblastoma (GB): GENOM 009. J Clin Oncol 2011;29S:abstract12519
  10. Combs E, Schulz-Ertner D, Hartmen C, et al. Erbitux® (Cetuximab) Plus Temozolomide as Radiochemotherapy for Primary Glioblastoma (GERT): Interim Results of a Phase I/II Study. Int J Radiat Oncol Biol Phys 2008;72S:S10-S11
  11. Nabors LB, Mikkelsen T, Batchelor T, et al. NABTT 0306: A randomized phaseII trial of EMD 121974 in conjunction with concomitant and adjuvant temozolomide with radiation therapy in patients with newly diagnosed glioblastoma multiforme (GBM).J Clin Oncol 2009; 27 (Suppl):15s (abstr 2001).

FIGURE 2S: Forest plots of incidence rates of overall specific severe adverse events in patients with glioblastoma multiforme included early phase trials of radiotherapy plus targeted therapy or in the Stupp et al. trial (standard treatment): a) thrombocytopenia, b) neutropenia or leucopenia, c) fatigue, d) gastrointestinal events and e) treatment-related deaths. When no event occurred in one trial, we added 0.5 to allow the calculation of the logarithm of the incidence rate. See Legend of figure 1 for more details on the figure contents.

Abbreviations: ln IR = logarithm of the Incidence Rate; CI= Confidence Interval

a)

b)

c)

d)

e)

FIGURE 3S: Forest plots of a) progression-free survival (PFS) b) overall survival (OS) in patients with glioblastoma multiforme included in early phase trials of radiotherapy plus targeted therapy or in the Stupp et al. trial (standard treatment).

Abbreviations: ln median= logarithm of the median; CI= Confidence Interval

a)

b)