Pseudoprogression of Brain Tumors Seen With Temozolomide

Becky McCall

March 11, 2011

March 11, 2011 (Vienna, Austria) — The use of chemoradiotherapy with temozolomide (Temodar and Temodal, Schering-Plough) as the new standard of care for patients with glioblastoma has led to an increasing awareness of progressive and enhanced lesions that are evident on magnetic resonance imaging during and after treatment.

According to new research presented here at the European Congress of Radiology 2011, these lesions might be representative of pseudoprogression related to a treatment effect, rather than real tumor growth.

Pseudoprogression and pseudoresponse have made conventional imaging with gadolinium-based contrast agents almost obsolete. There is a need for methods that use biomarkers, which would allow radiologists to differentiate a pseudophenomenon from real progression or response, noted presenter Meng Law, MD, FRACR, professor of radiology and neurological surgery, director of neuroradiology, Keck School of Medicine, University of Southern California–Los Angeles, who presented his work.

According to Dr. Law, pseudoprogression is found in 20% to 40% of patients with glioblastoma treated with temozolomide. "This can explain about half of all cases of increasing lesions and enhancement during and after treatment. The key is to differentiate between true progression and pseudoprogression. It is very difficult to know what sort of treatment triage should occur in these patients. Should we continue therapy, stop therapy, or carry out surgery?" Dr. Law asked.

In one study, patients with pseudoprogression demonstrated a consistent pattern of low permeability on the signal-intensity curve and permeability maps and low cerebral blood volume (<1.75). Magnetic resonance spectroscopy demonstrated an increase in Cho/Cho(n) and an increase in lipid and lactate. In patients with pseudoprogression, these results appeared in the first 2 to 6 months of treatment, and the tumors usually regressed 6 to 12 months after the commencement of temozolomide and radiation therapy.

"In true disease progression, there is elevated perfusion or increased vascularity, as well as damage to the blood–brain barrier. This makes sense biologically, but in pseudoprogression, there is no elevation in perfusion, just damage to the blood–brain barrier caused by temozolomide. There's no increased vascularity," Dr. Law explained.

In the same session, Pia C. Maly Sundgren, MD, PhD, professor of radiology, Lund University, Sweden, presented the findings of her study in which she monitored physiological and environmental changes in tumor volume during treatment as a means of identifying patients with a poor treatment response or who suffer from tumor recurrence early.

"Ideally, we'd like to know if a patient is responding to treatment early on, rather than waiting 10 weeks . . ., to spare patient exposure to ineffective treatment and to avoid a delay in the trial of potentially useful second-line treatments," said Dr. Sundgren.

Dr. Sundgren's work extends previous research conducted by a team led by Brian Ross, PhD, and Thomas Chenevert, PhD, from the University of Michigan Medical School, Ann Arbor. She presented additional data from that cohort, which shows how pseudoprogression can be identified from tumor recurrence, as described in a recent study by the same research group (J Clin Oncol. 2010;28:2293-2299).

Using parametric response maps in a cohort of patients with high-grade glioma who received concurrent chemoradiotherapy, the researchers were able to determine which patients actually had real progressive disease and which had pseudoprogression early in treatment. This aided clinical decision-making about whether to continue or stop treatment. Parametric response mapping revealed a significantly lower blood volume at week 3 in patients with progressive disease than in those with pseudoprogression (P < .01).

Parametric response mapping is a novel voxel-by-voxel analytical method of monitoring physiological and environmental changes in tumor volume during treatment. Parametric response mapping "strives to address the needs of early indication of pseudoprogression or true tumor progression, is quantitatively designed to mitigate tumor heterogeneity effects, and is applicable to functional changes, such as perfusion indices or cellularity changes, as seen by perfusion and diffusion parameters within the tumor and its surroundings," said Dr. Sundgren.

Performing parametric response mapping using the initial pretreatment images, repeated imaging during treatment, and performing voxel-by-voxel analysis have resulted in a spatial map of suspected responding and suspected nonresponding tissue. "These results have been shown to correlate well with outcome data, as defined by conventional [magnetic resonance images] at 10 weeks and clinical follow-up," added Dr. Sundgren. Eventually, this will enable the individualization of treatment and allow the therapist to revise treatment, if needed.

Dr. Law has disclosed relationships with the Accelerate Brain Cancer Cure, National Institutes of Health/National Cancer Institute, Prism Clinical Imaging, Siemens Medical Solutions, Bayer Healthcare/Bracco Diagnostics, Radiological Society of North America, and the Zumberge Foundation. Dr. Sundgren has disclosed no relevant financial relationships.

European Congress of Radiology (ECR) 2011: Abstracts A-163 an A-164. Presented March 4, 2011.

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