Your activity: 4 p.v.

Assessment of disease status and surveillance after treatment in patients with primary brain tumors

Assessment of disease status and surveillance after treatment in patients with primary brain tumors
Author:
Patrick Y Wen, MD
Section Editor:
Jay S Loeffler, MD
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Dec 2022. | This topic last updated: Sep 08, 2021.

INTRODUCTION — For patients with primary brain tumors, appropriate management requires a determination of whether a patient is responding to therapy or is progressing. The integration of improvements in neuroimaging (magnetic resonance imaging [MRI], computed tomography [CT], newer techniques) provides valuable information, but significant issues remain.

Developments in response criteria for both high-grade and low-grade gliomas are reviewed here. The management of these tumors is discussed separately:

(See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas".)

(See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults".)

(See "Radiation therapy for high-grade gliomas".)

(See "Treatment and prognosis of IDH-mutant astrocytomas in adults".)

HIGH-GRADE GLIOMAS — High-grade (grade III or IV) gliomas are best managed with a combined-modality approach, incorporating adjuvant postoperative radiation therapy (RT) and adjuvant chemotherapy following initial surgery. Despite aggressive therapy, most patients eventually develop progressive or recurrent disease, and require multiple courses of treatment to provide optimal care.

For patients on clinical trials, the gold standard is prolongation of overall survival in randomized trials, and this approach has been used with both RT and chemotherapy.

Assessment of overall survival in randomized trials is subject to limitations. Crossover from one treatment to another or the use of subsequent therapy can obscure the benefit derived from one treatment in the original randomization. In addition, overall survival cannot be used as a decision-making tool for individual patients.

An alternative to address some of these issues has been the use of progression-free survival (PFS), either as a median duration or by use of a landmark such as PFS at six months. The use of PFS, both in clinical trials and for individual patients, requires an accurate and consistent definition of progression. Without such a definition, there is a risk that efficacious therapy will be discontinued prematurely or that an ineffective treatment will be continued without benefit. Effective criteria are also important in the conduct of clinical trials for the development of new agents in patients with malignant brain tumors.

The Macdonald criteria for the assessment of response and progression were originally promulgated in 1990 and have been the standard approach for patients with high-grade glial tumors [1]. However, these criteria are subject to a number of significant limitations. Thus, new criteria have been proposed by the Response Assessment in Neuro-Oncology (RANO) Working Group to address these issues [2]. Both of these approaches are discussed here.

Macdonald criteria

Definitions — The Macdonald criteria rely upon changes in two-dimensional tumor area, as defined by contrast enhancement on computed tomography (CT) or magnetic resonance imaging (MRI) [1]. These criteria defined four outcomes:

Complete response – Complete disappearance of all tumor on consecutive CT or MRI scans at least one month apart, off steroids.

Partial response – Greater than or equal to a 50 percent decrease in area of enhancing tumor on consecutive imaging studies at least one month apart. Doses of steroids must be stable or decreased and the patient must be neurologically stable.

Progressive disease – Greater than or equal to a 25 percent increase in size of enhancing tumor or any new tumor on CT or MRI.

Stable disease – All other situations.

Limitations — Increasing experience and improvements in tumor imaging with MRI and the availability of new antiangiogenic agents have helped to highlight a number of important limitations associated with the Macdonald criteria [2]. These include:

Pseudoprogression – The standard approach to treatment of high-grade gliomas includes surgery, followed by RT and concurrent and adjuvant chemotherapy. Approximately one-fourth of patients have evidence of pseudoprogression, which is manifested by increased contrast enhancement at the first reimaging and which then resolves despite continued therapy. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults" and "Radiation therapy for high-grade gliomas" and "Management of recurrent high-grade gliomas", section on 'Early progression versus pseudoprogression'.)

Surgical changes – Surgical changes can result in increased enhancement in the wall of the surgical cavity in the first 48 to 72 hours after surgery [3]. Such areas of contrast enhancement must be distinguished from residual tumor that was not resected. A baseline MRI obtained within 24 to 48 hours after surgery can avoid confusing such enhancement with residual contrast-enhancing tumor.

Antiangiogenic therapy – Antiangiogenic agents such as bevacizumab can normalize tumor vasculature, which can result in decreased contrast enhancement within one to two days of initial treatment. A lack of correlation between response rates and overall survival with these agents suggests that the radiographic changes may not correlate with actual tumor regression. This improvement in contrast enhancement due to diminished vascular permeability does not necessarily reflect a true antitumor effect and has been referred to as a "pseudoresponse" [4]. In addition, a subset of patients who progress on antiangiogenic therapy have nonenhancing tumor that is not taken into account by the Macdonald criteria. (See "Management of recurrent high-grade gliomas", section on 'Bevacizumab'.)

Other issues that are not adequately addressed by the Macdonald criteria include irregularly shaped tumors, multiple tumors, and enhancing lesions in cyst walls following surgery.

RANO criteria — The RANO Working Group is an international, multidisciplinary group that is developing criteria that can address the limitations that are present in the Macdonald criteria [1,2].

Key features of the proposed RANO criteria that differ from the Macdonald criteria include [2]:

During the first 12 weeks after completion of chemoradiotherapy, progressive disease requires contrast enhancement outside the RT field or histologic evidence of viable tumor on a biopsy sample in order to avoid confusing progressive disease with pseudoprogression. Clinical deterioration alone is not adequate to define progression during this initial period.

After the first 12 weeks, criteria for progressive disease include new contrast enhancement outside the radiation field or an increase in size of the original lesion. For patients receiving an antiangiogenic agent such as bevacizumab, the diagnosis of progressive disease can also be based upon an increase in size of a nonenhancing lesion, as visualized using T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI sequences.

The definitions for complete response, partial response, and stable disease are similar to those for the Macdonald criteria. However, these now incorporate the results obtained from T2 or FLAIR images for nonenhancing lesions.

The RANO criteria have been formulated for incorporation into clinical trials, and further validation of these guidelines is required [2,5]. However, the issues raised by these criteria, particularly concerns about pseudoprogression and the evidence for progressive disease in situations not meeting the Macdonald criteria, are also applicable to clinical practice. Accurate assessment of nonenhancing tumor burden and tumor progression is perhaps the most difficult aspect of the RANO criteria for high-grade gliomas, and there is ongoing debate as to whether it provides added value [6]. RANO criteria for patients treated with immunotherapies have also been proposed [7].

Modified RANO criteria — Modified RANO criteria have been proposed to address some of the limitations of the original RANO criteria [8]. These criteria propose the use of volumetric response evaluation, use of contrast-enhanced T1 subtraction maps to increase lesion conspicuity, removal of qualitative nonenhancing tumor assessment requirements, use of the postradiation time point as the baseline for newly diagnosed glioblastoma response assessment, and "treatment-agnostic" response assessment for identifying pseudoprogression, pseudoresponse, and a confirmed durable response in newly diagnosed and recurrent glioblastoma trials. While the original RANO criteria continue to be the main response criteria used for clinical trials, an increasing number of studies are incorporating variations of the modified RANO criteria for secondary endpoint analysis.

LOW-GRADE GLIOMAS — Assessment of response and progression in patients with low-grade gliomas is more difficult than for high-grade gliomas [9]. Key issues include:

Slow growth rate of these tumors until they undergo malignant transformation

Lack of contrast enhancement in the majority of cases

Poor correlation between tumor imaging findings and clinical parameters of cognition and health-related quality of life

Overall survival is limited as a tool in assessing treatment efficacy in low-grade glioma clinical trials because of the prolonged median survival (five years or more) and because of the confounding effects due to salvage therapies.

Progression-free survival (PFS) has often been used in assessing the efficacy of investigational agents. However, assessment of progression can be subjective and is particularly difficult because of the difficulties in accurately imaging low-grade gliomas. PFS has not been validated as an endpoint, and its correlation with overall survival is uncertain.

Imaging criteria — In the vast majority of cases, low-grade gliomas do not exhibit contrast enhancement [9]. Thus, the Macdonald criteria that are used in patients with high-grade gliomas usually cannot be applied. The diagnosis and subsequent assessment of low-grade gliomas is based upon T2 or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) sequences for nonenhancing lesions, which are relatively poor in assessing small changes. Supplemental approaches such as positron emission tomography [PET] and magnetic resonance spectroscopy may eventually help to improve upon tumor size measurement by MRI or computed tomography (CT), but currently these remain experimental.

Clinical issues — There is a relatively poor correlation between imaging findings and clinical relevant endpoints. These include cognitive function, symptom burden, seizure activity, and the need for glucocorticoids, all of which contribute significantly to the overall health-related quality of life. Each of these parameters needs to be considered and assessed prospectively both in the clinical trial setting and in the management of an individual patient.

RANO criteria — The Response Assessment in Neuro-Oncology (RANO) Working Group has proposed specific criteria for patients with low-grade gliomas [9]:

Complete response – Complete disappearance of the original lesion on T2 or FLAIR MRI sequences and the absence of any new lesions or imaging abnormalities other than those attributable to treatment. Patients should be clinically improved or stable and off steroids or on physiologic replacement doses only. Complete response status should be sustained for at least four weeks.

Partial response – A greater than 50 percent decrease in the product of the perpendicular diameters on T2 or FLAIR MRI sequences without new lesions, sustained for at least four weeks. Clinically, a patient should be stable or improved and there should be no increase in baseline steroid requirements.

Minor response – A response of greater than 25 but less than 50 percent in the product of the perpendicular diameters on T2/FLAIR MRI sequences without new lesions. Clinically, a patient should be stable or improved and there should be no increase in baseline steroid requirements.

Stable disease – No change in imaging that meets the requirements for response (complete, partial, or minor) or progression. Clinically, a patient should be stable and there should be no increase in baseline steroid requirements.

Progression – Progression based upon imaging requires the development of new lesions, radiologic evidence of transformation to a high-grade glioma (increase in contrast enhancement), or a 25 percent increase in size on T2 or FLAIR MRI sequences of a nonenhancing lesion on stable or increasing doses of corticosteroids that is not attributable to treatment effect. Alternatively, progression is defined based upon clinical criteria that include definite clinical deterioration that is not due to other causes or to decreasing doses of corticosteroids.

NEUROLOGIC ASSESSMENT (NANO) SCALE — Radiographic response assessment must be integrated with neurologic function to best determine overall disease status. The Neurologic Assessment in Neuro-Oncology (NANO) scale has been proposed as a quantifiable evaluation of nine neurologic domains assessed during a routine clinical visit and examination [10]. The scale's validity and utility have not yet been validated in clinical trials.

SURVEILLANCE AFTER TREATMENT — There are no formal clinical trials that define the optimal frequency for follow-up after treatment. A standardized brain tumor imaging protocol should be used if possible to reduce variability in technique from scan to scan [11]. The following guidelines are consistent with those from the National Comprehensive Cancer Network (NCCN) for follow-up imaging [12]:

For patients with high-grade gliomas, a repeat magnetic resonance imaging (MRI) should be obtained four weeks after completion of radiation therapy (RT), then every two to four months for two to three years, and less frequently thereafter.

For patients with low-grade gliomas, a repeat MRI should be obtained every three to six months for five years, and then at least annually thereafter.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary brain tumors".)

SUMMARY

For patients with a high-grade glioma, the assessment of disease status depends upon multiple factors, including the characteristics of the tumor on imaging (magnetic resonance imaging [MRI], computed tomography [CT]), overall clinical status, and use of steroids. (See 'High-grade gliomas' above.)

The Macdonald criteria have a number of limitations and have generally been replaced by the Response Assessment in Neuro-Oncology (RANO) criteria. (See 'Macdonald criteria' above.)

The RANO criteria attempt to address the limitations of the Macdonald criteria. Although the RANO criteria have been developed with a primary focus on clinical trials, the issues raised in these criteria need to be considered in the care of patients with high-grade gliomas outside of clinical trials as well. (See 'RANO criteria' above.)

For patients with low-grade gliomas, assessment of response and progression is difficult because of the slow growth rate of these tumors, their prolonged natural history, and the limited ability of imaging studies, including T2 and FLAIR MRI sequences, to accurately define response and progression. Proposed criteria from the RANO Working Group integrate both imaging and clinical criteria in assessing response. (See 'Low-grade gliomas' above.)

  1. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990; 8:1277.
  2. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: Response assessment in neuro-oncology working group. J Clin Oncol 2010; 28:1963.
  3. Cairncross JG, Pexman JH, Rathbone MP, DelMaestro RF. Postoperative contrast enhancement in patients with brain tumor. Ann Neurol 1985; 17:570.
  4. Reardon DA, Galanis E, DeGroot JF, et al. Clinical trial end points for high-grade glioma: the evolving landscape. Neuro Oncol 2011; 13:353.
  5. Wen PY, Cloughesy TF, Ellingson BM, et al. Report of the Jumpstarting Brain Tumor Drug Development Coalition and FDA clinical trials neuroimaging endpoint workshop (January 30, 2014, Bethesda MD). Neuro Oncol 2014; 16 Suppl 7:vii36.
  6. Ellingson BM, Wen PY, van den Bent MJ, Cloughesy TF. Pros and cons of current brain tumor imaging. Neuro Oncol 2014; 16 Suppl 7:vii2.
  7. Okada H, Weller M, Huang R, et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol 2015; 16:e534.
  8. Ellingson BM, Wen PY, Cloughesy TF. Modified Criteria for Radiographic Response Assessment in Glioblastoma Clinical Trials. Neurotherapeutics 2017; 14:307.
  9. van den Bent MJ, Wefel JS, Schiff D, et al. Response assessment in neuro-oncology (a report of the RANO group): Assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol 2011; 12:583.
  10. Nayak L, DeAngelis LM, Brandes AA, et al. The Neurologic Assessment in Neuro-Oncology (NANO) scale: a tool to assess neurologic function for integration into the Response Assessment in Neuro-Oncology (RANO) criteria. Neuro Oncol 2017; 19:625.
  11. Ellingson BM, Bendszus M, Boxerman J, et al. Consensus recommendations for a standardized Brain Tumor Imaging Protocol in clinical trials. Neuro Oncol 2015; 17:1188.
  12. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf (Accessed on March 17, 2021).
Topic 5208 Version 20.0