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Recurrent Glioblastoma
Given the aggressive nature of glioblastoma, it is nearly a certainty that all patients will need to be evaluated for potential treatment of recurrent disease. There is currently no definitive standard of care for recurrent glioblastoma. Unlike in other solid tumors that have benefited from genomic or molecular profiling and targeted therapy, it is often the case that the recurrent tumor no longer reflects the index tumor. In the pre-bevacizumab era, the meidan overall survival was 30 weeks, and only 10 weeks for median progression-free survival. This chapter discusses the definition of recurrence and gives a further breakdown of the treatment options and surgical and nonsurgical management, with a review of pertinent studies that have led to a better understanding of treatment options for recurrent disease. Other chapters provide expert opinion on the role of antiangiogenic agents (see Chapter 10) and tumor treating fields (See Chapter 17) as they pertain to recurrent glioblastoma and are only briefly discussed here.
Defining recurrence
Before the decision to treat recurrent glioblastoma, it is essential to determine whether or not radiographic evidence of recurrent disease is secondary to glioblastoma progression or to radiographic pseudoprogression. In order to standardize the assessment of response to initial glioblastoma treatment, the MacDonald Criteria organized response based on 4 categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) ( Table 11.1 ).
Table 11.1
MacDonald versus Response Assessment in Neuro-Oncology (RANO) Criteria for response in malignant gliomas
From Roy S, Lahiri D, Maji T, et al. Recurrent glioblastoma: where we stand. South Asian J Cancer 2015;4:164; with permission.
| MacDonald | RANO |
|---|---|
| CR | |
| Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 wk | Disappearance of all enhancing measurable and nonmeasurable disease sustained for a minimum of 4 wk Stable or improved FLAIR/T2-weighted lesions |
| No new lesions | No new lesions |
| Stable or improved clinically | Stable or improved clinically |
| No corticosteroids | Patients cannot be receiving corticosteroids (physiologic replacement doses are acceptable) |
| PR | |
| ≥50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 wk | ≥50% decrease (compared with baseline) in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for a minimum of 4 wk No progression of nonmeasurable disease |
| No new lesions | No new lesions |
| Stable or reduced corticosteroid dose | Stable or improved FLAIR/T2-weighted lesions |
| Stable or improved clinically | Stable or improved clinically Corticosteroid dosage at the time of the scan should be no greater than the dosage at the time of the baseline scan |
| SD | |
| Does not qualify for CR, PR, or PD | Patient does not qualify for CR, PR, or progression Stable FLAIR/T2-weighted lesions on a corticosteroid dose no greater than at baseline |
| Stable clinically | Stable clinically |
| PD | |
| ≥25% increase in sum of the products of perpendicular diameters of enhancing lesions relative to best previous scan | ≥25% increase in sum of the products of perpendicular diameters of all measurable enhancing lesions compared with the smallest tumor measurement obtained either at baseline or best response following the initiation of therapy, while on a stable or increasing dose of corticosteroids. Significant increase in FLAIR T2-weighted lesions compared with baseline or best response following initiation of therapy, not caused by comorbid events (eg, radiation therapy, ischemic injury, seizures, postoperative changes, other treatment effects), while on a stable or increasing dose of corticosteroids |
| Any new lesion | New lesions |
| Clinical deterioration | Clinical deterioration not attributable to any causes apart from the tumor (eg, seizures, medication side effects, complications of therapy, cerebrovascular events, or infection) or decreases in corticosteroid dose. Failure to return for evaluation owing to death or deteriorating condition. Clear progression of nonmeasurable disease |
Abbreviation: FLAIR, fluid-attenuated inversion recovery.
These criteria were initially formulated in 1990, and relied on the enhancing pattern of the tumor, which did not address the effects of chemoradiotherapy and antiangiogenic agents on radiographic imaging. Several factors compound the difficulty in determining pseudoprogression from true progression and include post–radiation treatment effects that increase contrast enhancement and T2 hyperintensity over the first month, which may increase vascular probability, and the use of bevacizumab, which may conversely decrease contrast enhancement. To address this, the Response Assessment in Neuro-Oncology Working Group (RANO) devised criteria for determination of the first progression, which depend on the timing from the initial chemoradiotherapy treatment. In general, these criteria added more restrictive parameters for diagnosing progressive disease within 90 days of chemoradiotherapy completion as well as consideration to corticosteroid use and T2/fluid-attenuated inversion recovery sequencing assessment. At present, the RANO criteria are considered the most appropriate tools for evaluation of progression and response in glioblastoma. Advances in MRI diagnostic capabilities have also been used to differentiate pseudoprogression from true progression, although these tools are suggested for guidance and not definitive diagnosis. Recently, Galldiks and colleagues evaluated a group of 22 patients with glioblastoma with concern for new contrast-enhancing lesions or existing lesions showing increased enhancement on their routine MRI within first 4 months after completion of chemoradiotherapy and compared those findings with O-(2-(18)F-fluoroethyl)- l -tyrosine [(18)F-FET] PET scans done at the same time. In the 11 patients with available histopathologic confirmation, they found significantly lower compound uptake in those with necrosis or pseudoprogression than in those with confirmed tumor recurrence. Although this is promising, this study and others have determined that labeled uptake remains a diagnostic option.
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