Phase II neoadjuvant treatment intensification trials in rectal cancer : a systematic review
A partir d'une revue systématique de la littérature publiée entre 2004 et 2016 (92 essais de phase II), cette étude analyse les caractéristiques des essais de phase II évaluant l'intensification d'une radiothérapie néoadjuvante en combinaison ou non avec une chimiothérapie chez les patients atteints d'un cancer rectal de stade II ou III, puis formule des recommandations pour améliorer la qualité des futurs essais
Purpose : Multiple phase II trials of neoadjuvant treatment intensification in locally advanced rectal cancer have reported promising efficacy signals but these have not translated into improved cancer outcomes in phase III trials. Improvements in phase II trial design are needed to reduce these false positive signals. This systematic review evaluated the design of phase II trials of neoadjuvant long-course (chemo)radiotherapy treatment intensification in locally advanced rectal cancer.
Methods and Materials : PubMed, EMBASE, MEDLINE and Cochrane Library were searched for published phase II trials of neoadjuvant treatment intensification from 2004-2016. Trial clinical design and outcomes were assessed, with statistical design and compliance rated using a previously published system. Multivariable meta-regression analysis of pathological complete response (pCR) was conducted.
Results : Ninety-two eligible trials were identified. Patients with AJCC stage II and III equivalent disease were eligible in 87(94.6%) trials. Forty-three(46.7%) trials mandated MRI local staging. Only 12(13.0%) trials were randomised, with eight having a standard treatment control arm. Just 51(55.4%) trials described their statistical design with 21(22.8%) trials failing to report their sample size derivation. The majority of trials (n=84, 91.3%) defined a primary endpoint but 15 different primary endpoints were used. All trials reported pCR rates. Only 38(41.3%) trials adequately reported trial statistical design and compliance. Meta-analysis revealed a pooled pCR rate of 17.5%(95%CI:15.7%-19.4%) across treatment arms of neoadjuvant long-course (chemo)radiotherapy treatment intensification and substantial heterogeneity amongst the reported effect sizes (I2=55.3%, P<0.001). Multivariable meta-regression analysis suggested increased pCR rates with higher radiotherapy doses (adjusted p=0.025).
Conclusions : Improvement in the design of future phase II rectal cancer trials is urgently required. A significant increase in randomised trials is essential to overcome selection bias and determine novel schedules suitable for phase III testing. This systematic review provides key recommendations to guide future treatment intensification trial design in rectal cancer.
International Journal of Radiation Oncology • Biology • Physics , résumé, 2016