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Table of Contents
REVIEW
Year : 2018  |  Volume : 1  |  Issue : 3  |  Page : 97-103

Ongoing evolution of response assessment in glioma: Where do we stand?


1 Department of Neurosurgery, Tianjin Medical University General Hospital; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, China
2 Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China

Date of Web Publication29-Jun-2018

Correspondence Address:
Dr. Xuejun Yang
154 An-shan Road, Tianjin 300052
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_13_18

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  Abstract 

The investigation and development of recently introduced agents or radiological measurements caused emergent misunderstandings to the response assessment of glioma. To date, the classical Macdonald criteria and the response assessment of neuro-oncology (RANO) criteria have been used successively for the evaluation of glioma outcome. However, ongoing efforts on complementary assessments are necessary to combat this malignancy. In this review, we highlight the shortcomings of the current criteria and introduce the initiative effort of RANO guideline and its offspring. We also discuss some future barriers for accurate assessment of treatment response in glioma.

Keywords: Assessment, glioma, neuro-oncology, response assessment


How to cite this article:
Yi L, Ming H, Yu S, Ren B, Yang X. Ongoing evolution of response assessment in glioma: Where do we stand?. Glioma 2018;1:97-103

How to cite this URL:
Yi L, Ming H, Yu S, Ren B, Yang X. Ongoing evolution of response assessment in glioma: Where do we stand?. Glioma [serial online] 2018 [cited 2022 Dec 7];1:97-103. Available from: http://www.jglioma.com/text.asp?2018/1/3/97/235648


  Introduction Top


Despite promising preliminary progress made in central nervous system (CNS) tumor, clinical trial expansion, and drug development,[1] especially concerning glioblastoma multiforme (GBM), improvements toward clinical outcomes have been rather modest.[2],[3],[4],[5] The complex heterogeneity, plasticity, and therapeutic resistance of these malignancies may largely account for this disappointing phenomenon.[6],[7],[8] The incomplete response assessment system of clinical outcomes is another underlying cause for the confounding of true prognostic benefits expected in patients with brain tumors. For example, the use of newly introduced drugs or radiologic techniques can lead to unexpected imaging changes that mimic a false progression or remission regarding tumor status. Alternatively, a misleading imaging finding may cause discrepancies in neuro-oncology response assessment and criteria standards in clinical trials, which may eventually impede the process of drug development. Considering these circumstances, the response assessment of neuro-oncology (RANO) has been formed based on the previous Macdonald criteria to offer updated guidelines. It also intends to help relieve the discrepancies between radiographic changes and clinical practices and therefore to translate drug investigation into clinical benefit.


  Limitations of Current Assessments Top


In 1990, Macdonald et al.[9] reported criteria to assess tumor response in patients with high-grade gliomas (HGGs). These criteria, which rely primarily on bi-dimensional tumor measurements made on computed tomography or magnetic resonance imaging (MRI) scans, clinical status, and change in corticosteroid requirement following treatment, marked a transition from a subjective interpretation of clinical and radiologic changes toward more objective radiologically based criteria.[10] The Macdonald criteria consider the enhancing tumor area as the primary measure and also consider the use of steroids and changes in the neurologic status.[11] According to the Macdonald criteria, tumor progression is defined as a 25% increase in the size of the contrast-enhancing lesion.[9] Due to the objectivity of the Macdonald criteria in determining the response to therapy, these criteria were widely accepted in different clinical trials where they were used to make comparisons across different therapeutic interventions.

Nevertheless, with the advent and usage of novel therapeutics, various latent limitations of these criteria began emerging. For example, the Macdonald criteria only addressed the contrast-enhancing component of the tumor, which is only a surrogate to true tumor growth/activity. Specifically, the enhancement may also reflect a disrupted blood–brain barrier (BBB) after corticosteroid administration, as well as inflammation, postsurgical changes, and radiation necrosis.[12],[13],[14],[15],[16] Both pseudoprogression and pseudoresponse (i.e., an increase in the nontumoral enhancing area and a decrease in the enhancing area, respectively) highlighted that enhancement by itself is not a true measurement of tumor activity.[17],[18] As a result, such limitations may lead to premature discontinuation of an actually effective therapeutic agent, thereby producing a “vicious circle” between drug development and clinical practice.


  Pseudoprogression After Radiotherapy and Temozolomide Chemotherapy Top


Since the introduction of radiotherapy (RT) plus concomitant and adjuvant temozolomide (TMZ) as the standard-of-care for patients with glioblastoma,[19] there has been an increasing awareness of progressive and enhancing lesions on MRI, noted immediately after the treatment.[20],[21] As these lesions mimic tumor progression, the resulting subacute radiation effects have been termed pseudoprogression.[22],[23],[24],[25] Pseudoprogression is defined as a transient increase in contrast enhancement with or without associated T2-weighted and fluid-attenuated inversion recovery (FLAIR) changes in the absence of true tumor progression. It is seen in up to 50% of patients with glioblastoma who receive RT, both with and without TMZ.[26],[27] Early studies described this occurrence in patients treated with hyperfractionated RT to the brainstem and in cerebral gliomas after intra-arterial carmustine chemotherapy, administered alone or with RT.[28],[29] These findings implied that this event might occur more frequently in patients who are treated intensively. Interestingly, some studies have found an association between the incidence of pseudoprogression and increased survival, perhaps because pseudoprogression represents an active “inflammatory” response against the tumor.[30] Methylation of the O 6-methylguanine-DNA methyltransferase promoter additionally enhances the risk of developing pseudoprogression.[31] Although this phenomenon may be associated with neurological decline and increased steroid requirements, it typically resolves spontaneously within 3 months even if treatment is continued. The physiological mechanisms behind these events have not been fully understood. However, it is likely that chemo-RT prompts a higher degree of tumor cell killing, as well as endothelial cell killing. This increased cell killing might lead to the destruction of the BBB and secondary reactions, including edema and abnormal vessel permeability in the tumor region, mimicking tumor progression, rather than subsequent early treatment-related necrosis in some patients and milder subacute RT reactions in others.[32]


  Pseudoresponse After Antiangiogenic Agent Treatment Top


Targeting angiogenesis in glioblastoma through inhibition of vascular endothelial growth factor (VEGF)-mediated signaling (bevacizumab, aflibercept) or integrin function (cilengitide) has been a major focus in drug development. These agents have shown a rapid decrease in contrast enhancement with a tremendous response rate and increased progression-free survival (PFS). However, there has been only a rather modest effect on overall survival (OS).[33]

Contrast-enhanced MRI was conducted as the basic measurement for determining response in those trials. Improvements were seen as early as 18 days after initiating therapy with bevacizumab and were associated with clinical benefits in some patients.[34] Moreover, in 20%–60% of patients who received VEGF-targeted therapy (i.e., bevacizumab and cediranib), a decrease in the nonenhancing portion of the tumor was identified in T2/FLAIR sequences of the follow-up MRI examinations. This suggested a tumor reduction despite the modest effect on patient outcome. Such phenomenon of a decrease in contrast enhancement without a true reduction of tumor burden is termed as pseudoresponse. The underlying mechanism of pseudoresponse is believed to be attributed to normalization of an abnormally permeable BBB and circumventing effects of angiogenesis inhibition.[18],[35] It has been demonstrated that a very rapid change will occur within hours after antiangiogenic treatment, which produces a normalization of the BBB as shown on MRI. This decreased pattern regarding contrast enhancement will last for just a few days or weeks, after which other routes of tumor compensation may take precedence and even stimulate the so-called vessel co-option. Interestingly, the vascular normalization has been shown to be correlated with increased OS and PFS in glioblastoma patients,[36] while an early postbevacizumab progression would be highly correlated with reduced OS and serve as a useful MRI biomarker for failed anti-VEGF therapy.[37]


  Delayed Responses and Therapy-Induced Inflammation After Immunotherapy Top


In the past few years, immunotherapy has provided promising clinical advances in the treatment of several tumors. The Food and Drug Administration (FDA) approved the first two checkpoint inhibitors that target cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in March 2011 (ipilimumab) and programmed cell death protein 1 (PD-1, pembrolizumab and nivolumab) in the late 2014 and March 2015 for metastatic melanoma and nonsmall cell lung cancer.[38],[39],[40] T-lymphocytes are the most critical immune cell type to infiltrate tumors, and while advances in T-cell checkpoint therapy are beginning to reach clinical relevance in GBM, corresponding improvement in effective monitoring of the immune response is needed.[41],[42],[43],[44] As the immunotherapy of GBM was not associated with pseudoresponse phenomena, the decreased size of an enhancing lesion is a straightforward indication of a true antitumor effect.[45],[46] In contrast, an accurate differentiation of contrast enhancement regarding progressive imaging lesion was frequently found in patients treated with immune-targeted therapies. In addition, the increase in tumor burden was not always true tumor progression as response can occur even after radiological progression.[47],[48] There are two main interpretations that exist for a possible disconnect between early imaging findings and subsequent therapeutic benefit. First, effective immune responses need time to evolve, and early imaging might reflect true progressive disease on the basis of continued tumor growth before the stimulation of the immune response, as well as the development of new lesions.[49] Abnormal imaging findings can also represent successful stimulation of the immune response because movement of tumor-infiltrating lymphocytes into the tumor can induce an apparent increase in the tumor size.[50],[51],[52] Second, the immune-mediated inflammatory response in the areas of macroscopic and microscopic infiltrative tumor may also mimic the radiological features of tumor progression with increased enhancement and edema.[53],[54],[55]


  The Response Assessment of Neuro-Oncology Criteria and Its Offspring in Glioma Top


Recognizing the challenge in determining response to antiangiogenic agents in the treatment of malignant glioma, the response assessment in neuro-oncology (RANO) working group was formed and in 2010 published the updated response assessment criteria for use in clinical trials of HGG. The original effort of RANO was focused on critically appraising the strengths and shortcomings of the Macdonald criteria with the additional goal of updating new criteria specific for the treatment response assessment.[56],[57] Since then, RANO has expanded to create working groups that are focused on other tumors, including brain metastases, leptomeningeal metastases, spinal tumors, meningiomas, and pediatric brain tumors, as well as other clinical trial end points, such as clinical outcome assessments, seizures, corticosteroid use, and positron emission tomography imaging to improve outcome criteria for neuro-oncology over the last 8 years. Although additional refinements might be needed, efforts by RANO have been extensively adopted and are increasingly being used in neuro-oncology trials. To date, the RANO working group is an international volunteer collaboration of neuro-oncologists, medical oncologists, radiation oncologists, neurosurgeons, neuro-radiologists, and regulatory groups (among others), who are dedicated to developing objective and tumor-specific response criteria for various tumor subtypes.[10],[56] Here, we briefly list the major aspects of the updated additional criteria that were included in the response assessment in neuro-glioma [Table 1].
Table 1: Summarize of the response assessment of neuro.oncology response criteria for glioma

Click here to view


Response assessment of neuro-oncology – High-grade gliomas

The RANO criteria built on the Macdonald criteria using two-dimensional tumor measurements, which included a definition of progression for patients being considered for enrolment in clinical trials (≥25% increase in the product of perpendicular diameters compared with baseline or best response); definitions for measurable disease (two perpendicular diameters of at least 10 mm, visible on two or more axial slices that are preferably, at most, 5 mm apart with 0 mm skip); and allowance of up to five target lesions.[10],[61]

To address pseudoprogression, the RANO criteria recommended that within the first 12 weeks (3 months) after irradiation, patients should be excluded from clinical trials for recurrent disease unless progression is clearly outside the radiation field, or there is clear histologic documentation of progression.[33],[62]

To account for pseudoresponses after antiangiogenic therapies, patients who achieved partial or complete responses required a confirmatory scan at least 4 weeks before they were considered as true responses. In addition, the RANO criteria not only defined progression as a 25% increase in contrast-enhancing area over baseline or best response but also included any significant enlargement of nonenhancing T2/FLAIR signal on MRI that was attributed to tumor growth.[63]

Of importance, there were also recommendations for dealing with equivocal imaging changes, which allowed patients to stay in the study with a repeat scan in ≥4 weeks. If progression is subsequently confirmed, the time of progression is backdated to the time point at which the issue was first suspected. This prevents patients from being discontinued prematurely from studies when imaging findings are equivocal.

Response assessment of neuro-oncology – Low-grade gliomas

Low-grade glioma (LGG) refers to WHO Grade I and Grade II tumors, which is a uniformly fatal disease of young adults (mean age, 41 years), with survival averaging approximately 7 years.[64] The prognosis of LGG mainly depends on histology (astrocytic vs. oligodendroglial features), presence/absence of molecular markers (i.e., 1p/19q co-deletion, isocitrate dehydrogenase mutations), and other clinical risk factors (age, performance status, and seizure activity).[65]

Since LGGs represent a benign mass compared to HGGs, the response criteria that are defined for LGG will differ substantially. Unlike HGGs, the LGG response criteria assess T2/FLAIR rather than contrast enhancement as these tumors rarely enhance.[60] In addition, because these tumors grow very slowly, it will take a long time to reach a 25% increased level in lesion size. Furthermore, improved seizure control, symptom burden, and quality of life (QoL) are requisite clinical orders of treatment feedback despite stable imaging findings.[58],[66],[67]

Considering these factors, the RANO-LGG criteria were published. The radiological assessment is mainly based on T2/FLAIR changes although new or increased contrast enhancement is recognized as an indicator of transformation to a higher grade tumor. In addition, the RANO-LGG criteria introduce the category of minor response, which is characterized as a 25%–49% decrease in size of the T2/FLAIR hyperintensive lesion. It also recommended more detailed clinical response criteria using a composite score of neurological function, seizure activity, neurocognitive functioning, symptom burden, and QoL.[67],[68],[69]

Immunotherapy-response assessment in neuro-oncolgy

As a promising area in the treatment of neuro-oncological malignancies, immunotherapy-treated tumors exhibit delayed responses or therapy-induced inflammation-related radiological changes similar to pseudoprogression.[48],[54],[70] In this circumstance, a refinement of the response assessment criteria for patients undergoing immunotherapy is warranted.[45],[71] The immunotherapy response assessment in neuro-oncolgy (iRANO) guidelines incorporate previous criteria defined by the RANO working group to specify complete response, partial response, minor response, stable disease, progressive disease, and nonevaluable disease for patients with malignant gliomas, LGGs, and brain metastases. The critical part of the iRANO criteria is specific additional standards for the confirmation of disease progression in patients with neuro-oncological malignancies undergoing immunotherapy. Moreover, the iRANO criteria advocate for the definition of radiographic progression in appropriate patients determined by clinical status and time from initiation of immunotherapy.

Based on RANO criteria and the Macdonald criteria, the iRANO interpreted the confirmation of radiographic progression to define progressive disease and the appropriate time to confirm radiographic progression. Immune-related response criteria guidelines state that an early increase in lesion size or new lesions cannot define progressive disease unless further progressive changes are confirmed upon follow-up imaging, provided that patients do not have a significant clinical decline.[72],[73],[74] Specifically, the iRANO working group recommends a 6-month immunotherapy window for patients without clinical decline, where early progressive imaging findings do not preclude subsequent clinical benefit. In addition, repeat imaging needs to be performed after 3 months for comparison with the scan of the initial tumor to assess potential disease progression. Only if the repeat assessment confirms disease progression, should the patient then retrospectively be classified as having progressive disease and the treatment should be discontinued. If the repeat imaging shows stabilization or reduction in tumor burden, treatment should be continued.[67] In addition, tissue acquisition is thought to be feasible if there is any difficulty in clarifying the cause of the progressive imaging findings.[45]


  Neurologic Assessment In Neuro-Oncology Top


Clinical status is also a major assessment that measures the benefits of the treatment based on the patients' QoL, neurologic status, or function. The current clinical status assessment includes the Karnofsky performance status, MD Anderson Symptom Inventory brain tumor module, and Mini-Mental State Examination.[75],[76],[77] However, while these assessment tools were used globally and might correlate with OS, they lack specificity and reproducibility and may not accurately capture the neurologic changes of patients. In this context, the Neurologic Assessment in Neuro-Oncology (NANO) working group formed and developed specific parameters to measure the clinical status of patients with brain tumors. The NANO scale evaluates nine major domains of neurologic function that are most relevant to patients with supratentorial, infratentorial, and brainstem tumors. Tests include gait, strength, upper extremity ataxia, sensation, visual fields, facial strength, language, level of consciousness, and behavior.[59],[78]

The neurological scale integrated into the RANO and the classical Macdonald criteria specifies the priority of clinical status in overall assessment and provides a much more comprehensive assessment system of treatment outcome. To confirm its repeatability, a prospective multinational study was conducted to assess routine office visits to determine the interobserver variability and feasibility. An interobserver agreement rate ranging from 90.7% to 96.4% and a median assessment time of 4 min were observed. Further efforts aim to assess its validity and utility relative to radiographic and overall outcome.[10],[59]


  End Point Selection Top


To identify more effective therapies for these tumors, there is an increasing number of clinical trials being developed and conducted. Nonetheless, the most appropriate study end points to be used in these studies remain subject to further debate, whereas early-phase trials might focus on the identification of a therapeutic signal to guide decisions on further development, and late-phase trials might focus on the confirmation of therapeutic impact by considering clinically meaningful end points.[1],[79],[80],[81] OS is considered the gold standard and most objective study end point. However, its use is limited in studies that investigate tumors characterized by a longer clinical lifespan (e.g., LGG, meningioma), and subsequent salvage treatments that may have an influence on OS could confound the true effect of the investigated agent.[82],[83],[84],[85] Whether PFS can be an appropriate primary end point in phase III trials – or whether OS should be the primary end point in these trials as a matter of principle – is an ongoing discussion in oncology.[86] A recent novel statistical model study found that compared to using either end point alone, considering both OS and earlier events such as PFS would be more robust and efficient for glioblastoma trials.[87],[88],[89]


  Future Expectations Top


Given the emergence of newly advanced imaging modalities such as volumetric tumor measurements, digital subtraction maps, and magnetic resonance spectroscopy, detecting changes in tumor size is becoming more accurate. However, confirmation of these expectations will require time. Moreover, the RANO proposals regarding the immunotherapy, neurological assessment, brain metastases, and leptomeningeal metastases criteria need to be validated in clinical practice and the outcomes must be compared between studies. In addition, it is inevitable that novel therapies and combined medical treatment strategies might cause substantial confusion in the definition of the radiological imaging assessments of clinical status. As to biopsy samples, the gold standard for diagnosis can be difficult to interpret due to the potential heterogeneity of these lesions and the findings of mixed tissues. Nonetheless, it is believed that the different published RANO guidelines, to date, based on the best currently available evidence and updates, would increase the accuracy and efficiency of the early valuation of novel therapies and therefore improve the outcome of CNS malignancies.[90]

Financial support and sponsorship

The research is funded by the National Natural Science Foundation of China (No. 81472352) and Natural Science Foundation of Tianjin City (No. 15JCZDJC36200).

Conflicts of interest

There are no conflicts of interest.



 
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