Defining the endpoints: how to measure the efficacy of drugs that are active against central nervous system metastases

Abstract

Brain metastases (BMs) are the most common cause of malignant central nervous system (CNS) tumors in adults. In the recent past, patients with BMs were excluded from clinical trials, but now, with the advent of new biological and immunological drugs, their inclusion is more common. In the last era response and progression criteria used across clinical trials have defined the importance to consider not only measurement changes of brain lesions but also the modification of parameters related to the metastases such as metabolism of tissue and its pathological features. Magnetic resonance imaging (MRI) represents the first choice in the evaluation of BMs; the computed tomography (CT) scan will be made only in case of MRI's contraindication. CT, MRI and positron emission tomography (PET-CT), may be used to monitor response to treatment as part of clinical and radiological follow up. In the evaluation of response to treatment, MRI shows superior accuracy in comparison to CT; PET-CT is useful in particularly in cases of BMs underwent to locoregional therapies in the differential diagnosis between recurrence or radionecrosis. Now is possible to use functional imaging as CT-perfusion, dynamic susceptibility contrast (DSC) MR imaging, dynamic contrast-enhanced (DCE) MR imaging, diffusion-weighted MR imaging and MR-Spectroscopy in the evaluation of treatment response; these imaging techniques can provide qualitative and quantitative imaging parameters that allow pathophysiologic correlation. In the evaluation of the response to immunotherapy treatments, the immune-related response criteria (irRC) are considered as the gold standard. The irRC utilizes bidimensional measurements, quantifying the tumor dimension using a product of the longest diameter and the longest perpendicular diameter. We analyze clinical and radiological criteria to better define outcome of drugs for BMs from solid tumors in the new era of biological and immunological therapies.

Keywords: Brain metastases (BMs); brain metastases measurement; efficacy outcome.

Figure 1

Patient affected by non-small cell lung cancer. (A) MRI with contrast medium shows a metastases in the left cerebellum; (B,C) in the next controls, MRI with c.m. shows the progressive reduction of the dimension; (D) in the control after 18 months MRI with cm shows the disappearance of the lesion. MRI, magnetic resonace imaging.

Figure 2

Volumetric evaluation of the left cerebellum metastases on MRI in patients with lung cancer. MRI, magnetic resonace imaging.

Figure 3

MRI with contrast medium (cm) shows a metastasis in the left cerebellum (A); in the first control after radiosurgery MRI with cm shows a reduction of the dimension of the lesion (B); after 12 months MRI with cm shows an increase both of lesion dimension and of vasogenic oedema (C); PET-CT, with FDG shows a moderate area of uptake of FDG (D); after 16 months MRI with cm shows an improving of the dimension (E); DCE-MR perfusion shows low Ktrans (permeability) (F), low nIAUGC (blow volume and blood flow) (G) and high Ve (extracellular-extravascular space) (H) as a possible consequence of radionecrosis; after 20 months MRI with cm shows a reduction of the size of the lesion and the vasogenic oedema (I); PET-CT with methionine does not evidence the area of increase uptake in the left cerebellum (J). MRI, magnetic resonance imaging; PET-CT, positron emission tomography; FDG, 2-deoxy-[F]fluoro-D-glucose.