Recurrent disease is different from newly diagnosed GBM. Patients had exposer to RT/TMZ already. The patients who had a Pseudoprogression response would need to be confirmed not to be within the recurrent data. And again Avastin causes pseudo response which is the opposite of Pseudoprogression. In theory if Avastin is working at all there should be NO increase in TUMOR mass. None. If there was it would indicate TUMOR mass. Definitely no need to wait given that drugs mechanism of action, and so yes, it makes no sense to do a next scan. If there is TUMOR on Avastin that gets larger in the recurrent ITT patient population than the patient is a progression patient.
Again it is important to understand the drug's mechanism of action and adjust imaging criteria to capture response or failure of response. Avastin can mimic response on an MRI but it does not mean a response. It is why the study was not approved on the the basis of the PFS gains in the newly diagnosed setting, as it did not translate to OS. The investigators hypothesized that Avastin showed false response.
"The CHMP noted that the effectiveness of Avastin in combination with radiotherapy and temozolomide had not been sufficiently demonstrated. Although there was an improvement in progression-free survival, it could not be considered clinically relevant because of limitations in the methods available to measure the size of brain tumours. In addition, there was no benefit in terms of overall survival. Therefore, at that point in time, the CHMP was of the opinion that the benefits of Avastin in the treatment of glioblastoma did not outweigh its risks. Hence, the CHMP recommended that the change to the marketing authorisation be refused." — Regulatory decision [/quote]
There are nuances to the MRI data regulators looked at that skeptics have ignored, and it pertains to Bevacizumab’s mechanism of action (MOA). It further explain how regulators came to their “NO” decision.
A drug like Bevacizumab can cause a pseudoresponse response to appear. This iHub discusses pseudoprogression almost daily. But, we rarely discuss pseudoresponse. The discussion does not come up because it is not a condition that would show up in this trial, as it is not a “mechanism of action” response that is associated with any of the newly diagnosed agents being used in this Phase III trial. But what is Pseudoresponse exactly? It’s the opposite of Psuedoprogression essentially. Pseduoresponse is the condition that shows up that can “mimic” the signs of tumor “regression” response. But, it is not always response.
"Tumor pseudoresponse, also known just as pseudoresponse, refers tumours appearing to respond to a specific treatment on imaging criteria, when the lesion actually remains stable or has even progressed.
The term is largely used in brain tumours imaging follow-up, especially for high grade gliomas (e.g. glioblastoma) in which a rapid decrease in contrast enhancement and oedema can be observed in a short period of time after administration of antiangiogenic agents (e.g, bevacizumab and cediranib), often without any significative change in actual tumour size (as visualised by T2 (non-enhancing tumour) or diffusion / perfusion studies 1-3.
Bevacizumab (trade name Avastin) for example, is an inhibitor of vascular endothelial growth factor (VEGF), aimed at inhibiting the formation of new blood vessels within the tumour (neoangiogenesis). VEGF is produced by the tumours, and not only promotes neoangiogenesis but also reduces effectiveness of gap junction and creates fenestrations in the endothelium of existing brain capillaries, leading to oedema and enhancement 4. The amount of VEGF produced has been shown to correlate with tumour grade.
The changes seen in pseudoresponse (rapid reduction in enhancement and vasogenic oedema) are largely mediated by changes in blood brain barrier permeability rather than antiangiogenic effects, meaning that relying on enhancement and T2 signal change can be misleading when interpreting follow up MRI studies 4. "
As for the image criteria, in the newly diagnosed setting with Avastin there was a Pseudoprogression decision tree, as in that setting it was appropriate to capture RT/TMZ responders. We went over this many times.
"Assessment of Pseudoprogression in AVAglio
The AVAglio protocol also standardizes the assessment of possible pseudoprogression. The potential occurrence of pseudoprogression is evaluated at the first disease assessment after radiotherapy (ie, 4 weeks after radiotherapy; see Table 2). If the investigator observes a ≥25% increase in index lesions and/or unequivocal progression of existing nonindex lesions relative to the baseline disease assessment, then the recommended assessment is pseudoprogression, and treatment is continued under the provision that a confirmatory scan be performed 2 months later (ie, 12 weeks after radiotherapy) (Fig. 3). If the confirmatory scan shows further tumor progression as compared to the previous MRI, the assessment is PD, and the patient is discontinued from further treatment. In such cases, the date of the first disease assessment after radiotherapy is considered to be the date of PD. Conversely, if the confirmatory scan shows SD or PR as compared to the previous MRI, the initial assessment is confirmed to be pseudoprogression, and the patient is continued on treatment. In cases of confirmed pseudoprogression, the measurements of first MRI after radiotherapy are used as the new baseline (Fig. 4) but as a consequence, patients with confirmed pseudoprogression are excluded from the response analysis population." -- off the AVAglio paper
Figure 3: Pseudoprogression confirmed on AVAglio's study's third MRI (the first being done at randomization; the second to at 4 weeks after RT (w/concurrent Bev + TMZ) to find suspected Psuedoprogression; and the third at 12 weeks after RT to confirm Pseudoprogression (responders) or Progressive Disease PATIENTS.
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