Recently Wen* and his colleagues made a case in JCO for why patients with brain tumors should be included in phase I clinical trials. They are argued that most of the reasons that led to the exclusion of these patients in the past were obsolete and should be reconsidered. Below is a summary on why these patients should be considered for phase I trials.
- They are no longer treated with EIAEDs (drugs that usually induced P450 enzyme and affected hepatic metabolism of the agents being tested), and when they rarely are, they are excluded from studies.
- The MTD or maximum tolerated dose determined in phase I trials for systemic cancers is also the maximum-tolerated dose for brain tumors
- The condition of the patients: patients with brain tumors often younger, have generally less co-morbidities, have taken less prior treatments and have an overall better organ function than patients with systemic cancers.
- Their performance status is acceptable and their life expectancy of 4 to 7 months which is often better than most of the other patients participating in phase I that have exhausted all treatment options.
- Studies have shown that there was not an increase risk of CNS hemorrhage even with the use of biologics or the risk was very modest.
- It is possible to differentiate between neurologic symptoms associated with the tumors and neurotoxicity associated with the investigational product.
- The issue of crossing the BBB (blood brain barrier) remains, which is a valid point. However, based on preclinical studies, if there is evidence that the drug can pass through the BBB, there is no reason to exclude patients with primary brain tumors from the phase I study. Conversely, if preclinical studies suggest that drug penetration may be limited, it may be reasonable to consider excluding patients with brain tumors from the phase I study.
The authors concluded that excluding patients with brain tumors will slow our ability to find better treatments for these patients for whom so few effective therapies exist, and potentially means a lost opportunity to identify a responsive tumor type. Temozolomide is one of the few drugs approved for high-grade gliomas, and inclusion of patients with brain tumors into the phase I trial determined the fate of this important agent. Activity was seen in patients with high-grade gliomas, and eventually the drug received approval from the US Food and Drug Administration. If this drug had been evaluated only in systemic cancers, it is unlikely that its activity against primary brain tumors would have been identified, and as a result, one of the few outcome-changing drugs in glioma treatment would not have become an option for patients.
*Patrick Y. Wen, et al, JCO Aug 20, 2011:3211-3213; published online on July 18, 2011; 10.1200/JCO.2011.36.6328.