We did a systematic search of articles in PubMed using combinations of the keywords: “glioma”, “glioblastoma”, “immunotherapy”, “imaging”, “corticosteroid”, and “response criteria”. Articles were also identified through searches of the authors' own files. We included only articles published in English between Jan 1, 1980, and March 31, 2015. The final reference list was generated on the basis of originality and relevance to the broad scope of this Review.
ReviewImmunotherapy response assessment in neuro-oncology: a report of the RANO working group
Introduction
Immunotherapy for cancer has made exciting progress. The US Food and Drug Administration approved the first vaccine against non-viral cancers (sipuleucel-T)1 and blocking monoclonal antibodies to the immune checkpoint molecules CTLA-4 (ipilimumab) and PD-1 (pembroluzimab and nivolumab) for metastatic melanoma and non-small-cell lung cancer.2, 3, 4, 5 Chimeric antigen receptor-engineered autologous T cells have induced durable remissions in patients with leukaemia refractory to conventional therapies, including bone marrow transplantation.6, 7 For patients with primary and metastatic neuro-oncological malignancies, clinical trials assessing various immunotherapeutic approaches are underway, and promising preliminary results are emerging.8, 9, 10
Section snippets
Ongoing evolution of response assessment in neuro-oncology
Traditional imaging response assessment methods, including WHO criteria,11 Response Evaluation in Solid Tumors (RECIST),12 and Macdonald criteria,13 originated in the cytotoxic therapy era when radiographic findings directly represented anti-tumour effect. As oncology treatments have expanded beyond cytotoxic therapy, the effect of therapeutics on tumour imaging findings has become less straightforward. For neuro-oncology, pseudoprogression after radiotherapy and temozolomide chemotherapy,14
Interpretation of worsened radiographic findings after immunotherapy
The interpretation of decreased size of an enhancing lesion is straightforward as such changes indicate a true anti-tumour effect because immunotherapeutics are not associated with pseudoresponse. By contrast, correct interpretation of progressive imaging findings after administration of immunotherapy is essential because early progressive radiographic changes do not always preclude subsequent therapeutic benefit.22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 Two main explanations exist for a
New lesions
Appearance of new lesions is a criterion that defines progression of disease by RANO criteria and the Macdonald criteria. However, transient appearance of new enhancing lesions at either local or distant sites might occur in patients with neuro-oncological malignancies receiving immunotherapy (figure 2).25, 36 For cases of pseudoprogression, histopathology typically shows remarkable immune-cell infiltration, such as CD8+ T lymphocytes, but not mitotically active tumour cells.25 In such
Confirmation of radiographic progression to define progressive disease
The immune-related response criteria were issued to aid the interpretation of imaging changes in patients with cancer undergoing immunotherapy.22, 24, 37 Their intent was to raise awareness that traditional imaging criteria to define progressive disease might be less reliable and could lead to premature discontinuation of potentially beneficial therapy. A key component is the concept of confirmation of radiographic progression. Immune-related response criteria guidelines state that early
When is confirmation of radiographic progression appropriate?
A crucial issue is identification of patients who develop early progressive imaging findings but still derive therapeutic benefit from immunotherapy from those patients who are truly resistant to therapy and unlikely to benefit clinically from immunotherapy. According to most response assessment criteria, including RANO, patients with substantial neurological decline, irrespective of imaging findings, are deemed to have progressive disease, provided that their decline is not attributable to
3-month period to confirm radiographic progression
Another crucial unanswered question regarding the significance of early progressive imaging findings is how long such changes can evolve before clinicians can confidently conclude that they indicate true underlying tumour progression. Is there a period of time in which imaging findings might continue to worsen but a patient might still derive clinical benefit? Alternatively, how long should progressive imaging continue after starting immunotherapy to confidently conclude that ultimate clinical
Tissue acquisition to aid response assessment
In uncertain cases in which acquisition of tumour histopathology by biopsy or resection is thought to be feasible, pathological assessment might be considered to clarify the cause of progressive imaging findings. If pathology confirms a predominance of recurrent tumour, the cause should be considered to be true progression. For cases where there is no evidence of a viable tumour, or where a prominence of gliosis or inflammation with restricted viable tumour is reported, the cause should be
Immunotherapy continuation pending confirmation of progression
Whether continued immunotherapy after initial disease progression would provide treatment efficacy or harm to patients has not yet been established and further study of this important question is warranted. A decision of whether a patient should continue immunotherapy pending confirmation of radiographic disease progression should be established based on perceived benefits and risks. Continuation of immunotherapy might be considered pending follow-up imaging as long as patients are deriving
iRANO criteria
The iRANO guidelines incorporate criteria previously defined by the RANO working committee to define complete response, partial response, minor response, stable disease, progressive disease, and non-evaluable disease for patients with malignant glioma,16 low-grade glioma,40 and brain metastases.18 The key component of the iRANO criteria is specific additional guidance for the determination of progressive disease in patients with neuro-oncological malignancies undergoing immunotherapy (table 1,
Corticosteroids
Patients with brain tumours frequently develop peritumoral oedema needing treatment with corticosteroids. Dexamethasone is the most commonly used corticosteroid.41, 42 In addition to the systemic side-effects, dexamethasone can have profound effects on contrast enhancement for neuroimaging studies and on the immune system, especially T cells.43 In preclinical studies, administration of dexamethasone to rats with intracranial C6 glioblastomas dose-dependently decreased intratumoral infiltration
Conclusion
We propose updated response assessment criteria for the assessment of patients with neuro-oncological malignancies undergoing immunotherapy. These recommendations integrate the framework of response assessment established by the RANO working group for malignant glioma,16 low-grade glioma,40 and brain metastases18 with guidance for confirmation of disease progression as originally advocated by the immune-related response criteria to guide clinical decision making. The iRANO guidelines
Search strategy and selection criteria
This online publication has been
References (52)
- et al.
Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial
Lancet
(2014) - et al.
Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas
Lancet Oncol
(2008) - 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) - et al.
Response assessment criteria for brain metastases: proposal from the RANO group
Lancet Oncol
(2015) Evolution of end points for cancer immunotherapy trials
Ann Oncol
(2012)- 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) - et al.
The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy
Blood
(2011) - et al.
Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial
Lancet Oncol
(2012) - et al.
Sipuleucel-T immunotherapy for castration-resistant prostate cancer
N Engl J Med
(2010) - et al.
Improved survival with ipilimumab in patients with metastatic melanoma
N Engl J Med
(2010)
Nivolumab in previously untreated melanoma without BRAF mutation
N Engl J Med
Nivolumab in NSCLC: latest evidence and clinical potential
Ther Adv Med Oncol
Chimeric antigen receptor T cells for sustained remissions in leukemia
N Engl J Med
Chimeric antigen receptor-modified T cells for acute lymphoid leukemia
N Engl J Med
Immunotherapy advances for glioblastoma
Neuro Oncol
Recent developments on immunotherapy for brain cancer
Expert Opin Emerg Drugs
Immunotherapy for brain cancer: recent progress and future promise
Clin Cancer Res
Reporting results of cancer treatment
Cancer
New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada
J Natl Cancer Inst
Response criteria for phase II studies of supratentorial malignant glioma
J Clin Oncol
Response assessment criteria for glioblastoma: practical adaptation and implementation in clinical trials of antiangiogenic therapy
Curr Neurol Neurosci Rep
Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group
J Clin Oncol
Pseudoprogression in patients with glioblastoma: clinical relevance despite low incidence
Neuro Oncol
Immediate post-radiotherapy changes in malignant glioma can mimic tumor progression
Neurology
MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients
J Clin Oncol
Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria
Clin Cancer Res
Cited by (542)
REVOLUMAB: A phase II trial of nivolumab in recurrent IDH mutant high-grade gliomas
2024, European Journal of CancerPost-treatment imaging of gliomas: challenging the existing dogmas
2024, Clinical RadiologyNaGdF<inf>4</inf>-based magnetic resonance nanoprobes for qualitative inflammation imaging in glioma: Hot or cold?
2024, Chemical Engineering Journal
- †
Contributed equally