Response Assessment in Neuro-Oncology

Accuracy and reproducibility in determining response to therapy and tumor progression can be difficult to achieve for nervous system tumors. Current response criteria vary depending on the pathology and have several limitations. Until recently, the most widely used criteria for gliomas were “Macdonald criteria,” based on two-dimensional tumor measurements on neuroimaging studies. However, the Response Assessment in Neuro-Oncology (RANO) Working Group has published new recommendations in high-grade gliomas and is working on recommendations for other nervous system tumors. This article reviews current response criteria for high-grade glioma, low-grade glioma, brain metastasis, meningioma, and schwannoma.     

Response criteria in prostatic carcinoma

Assessment of response in advanced prostate cancer is hampered by the preponderance of nonmeasurable, "bone-only" disease. Although bone scans are accurate in assessing new lesions, they are frequently unreliable in evaluating tumor regression. Alternatively, evaluation of response based on changes in prostate-specific antigen (PSA), a biochemical marker, is now routinely incorporated into clinical trials as a surrogate end point for response. However, despite general acceptance of its use as an end point in clinical trials, there is no standardized definition of PSA response. Furthermore, changes in PSA do not always correlate with regression of measurable tumor, especially in response to noncytotoxic agents. PSA changes are most defensibly used to define initial hints of a drug's potential usefulness, rather than as a validation of benefit. Improvement in quality of life has emerged as a clinically relevant endpoint, especially in the setting of hormone-refractory disease, in which therapy has yet to have an impact on survival. There is a current trend toward reporting response to therapy as reflecting changes in biochemical markers, measurable disease, bone-only disease, and quality of life separately, rather than trying to pigeon-hole "response" into traditional categories of "complete" and "partial." This independent reporting of outcome parameters provides a more accurate picture of the potential therapeutic benefit of the assessed new treatments, and allows more informed decision-making by physicians and their patients.     

Radiologic Response to Neoadjuvant Treatment Predicts Histologic Response in Thymic Epithelial Tumors

IntroductionNeoadjuvant treatment might increase resectability of thymic epithelial tumors (TETs). No standardized pathologic grading scheme for tumor response is available. Also, it is unclear whether radiologic treatment response can predict pathologic response.MethodsPatients with unresectable TETs who underwent neoadjuvant treatment before surgery at Mayo Clinic Rochester (1942–2014) were included. The pathologic tumor response grade (TRG) was based on Mandard grading (1994), ranging from TRG 1 (no viable tumor) to TRG 5 (no regression). TRG was compared with response by computed tomography, including with the Response Evaluation Criteria in Solid Tumors, version 1.1 (Byrne modification).ResultsA total of 49 patients, including 29 men, with a median age of 47.6 years and thymomas (n = 28) or thymic carcinomas (n = 21) were included. In five cases, pretreatment tumor type differed from posttreatment diagnosis. Thymic carcinomas had a greater morphologic response to neoadjuvant treatment than did thymomas with a lower percent viable tumor (p < 0.0001) and lower TRG (p<0.0001). Agreement for TRG by three reviewers was good (Krippendorff α = 0.838). By imaging (n = 24), partial response and larger reduction in tumor longest diameter and volume were associated with lower TRG (p = 0.0093, p = 0.0042, and p = 0.0021, respectively) and lower percent viable tumor (p = 0.0041, p = 0.0034, and p =0.0019). TRG correlated with radiologic change in tumor longest diameter and volume (Spearman correlation coefficient = 0.59 and 0.61, respectively). Radiologic change in tumor longest diameter and volume reasonably predicted pathologic TRG of 3 to 5 versus 1 or 2 (area under the curve 0.73 and 0.71, respectively). Sixty-seven percent of patients' tumors were completely resected.ConclusionsOur proposed histologic TRG for TETs appears easy and reproducible and correlates with radiologic response. Radiologic response is useful to predict pathologic response.     

Response assessment in gastrointestinal stromal tumor

Imatinib is standard first-line treatment for patients with advanced gastrointestinal stromal tumor (GIST). Initial responses are not always accompanied by reductions in tumor size; consequently, other parameters should be considered in response assessments. Conventional size-based criteria such as Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate responses to imatinib and have poor predictive value for outcome. Imatinib-responding tumors demonstrate decreased metabolic activity on positron emission tomography within the first weeks of treatment, often showing reduced density and greater homogeneity on computed tomography (CT) scans regardless of initial changes in tumor size. New criteria, based on reductions in tumor size or in tumor density on CT, seem more sensitive and specific for detecting early responses to imatinib, and more predictive of time to tumor progression and disease-specific survival. Compared with conventional size-based criteria, new CT-based criteria may potentially offer improved response assessment and be predictive of outcome in GIST. However, such emerging criteria should be further explored and validated in large, multicenter trials with imatinib and other kinase inhibitors in GIST and in other solid tumors.     

Response Kinetics and Clinical Benefits of Nonintensive AML Therapies in the Absence of Morphologic Response

The ultimate goal of treatment for acute myeloid leukemia (AML) is to improve survival, and the best means of doing so is through the induction of morphologic remission, which is historically most reliably achieved with intensive chemotherapy regimens. Older patients with AML are less likely to be candidates for or to benefit from intensive chemotherapy. Patients deemed ineligible for intensive therapy may nevertheless benefit from lower-intensity therapies and from newly available targeted AML treatments. Recently approved lower-intensity treatments for AML include enasidenib, ivosidenib, glasdegib, venetoclax, midostaurin, and gilteritinib, and additional promising agents are in later stages of clinical development. Noncytotoxic agents may result in slower kinetics of therapeutic activity compared to intensive regimens, and although they are generally better tolerated than intensive chemotherapy, bone marrow responses are less frequent and may take longer to achieve. Notably, newer therapies might have been considered ineffective had they been judged solely by 2003 International Working Group response criteria for AML, which were based on experience with intensive regimens in predominantly younger patients. Lower-intensity therapies may require several treatment cycles to induce responses, and failure to achieve rapid morphologic remission may not signal the need for treatment cessation or transition to alternative therapies. Additionally, even in the absence of a conventional complete remission, lower-intensity therapies may provide meaningful clinical benefit, including improved survival and quality of life, by inducing hematologic improvement and transfusion independence. Reviewed here are the mechanisms of activity and response kinetics of lower-intensity AML therapies, as well as the clinical benefits resulting from nontraditional AML responses.     

Response to radiation

Computed tomography (CT) has traditionally been the standard radiographic modality for diagnosing and monitoring non-small cell; lung cancer (NSCLC) after treatment. Given the limitations of CT, the utility of 18F-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) has been investigated for the management of NSCLC, with promising findings. Its adjunctive role with CT in diagnosing and staging disease is well established. FDG-PET also has been found to be a valuable tool for radiation treatment planning because it improves the precision of lesion definition. More recently, its value for determining clinical response both during and after treatment has been explored. This review highlights the various applications of FDG-PET in the diagnosis and management of NSCLC as corroborated by clinical data, with considerations of future directions.