ADC Values and Prognosis of Malignant Astrocytomas: Does Lower ADC Predict a Worse Prognosis Independent of Grade of Tumor?

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1 Neuroradiology/Head and Neck Imaging Original Research Zulfiqar et al. ADC Values and Prognosis of Malignant Astrocytomas Neuroradiology/Head and Neck Imaging Original Research Maria Zulfiqar 1 David M. Yousem Hong Lai Zulfiqar M, Yousem DM, Lai H Keywords: apparent diffusion coefficient (ADC), astrocytoma, brain tumor, diffusion-weighted MRI, glioblastoma DOI: /AJR Received January 25, 2012; accepted after revision May 9, All authors: The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins Medical Institution, 600 N Wolfe St, Phipps B100F, Baltimore, MD Address correspondence to D. M. Yousem (dyousem1@jhu.edu). AJR 2013; 200: X/13/ American Roentgen Ray Society ADC Values and Prognosis of Malignant Astrocytomas: Does Lower ADC Predict a Worse Prognosis Independent of Grade of Tumor? A Meta-Analysis OBJECTIVE. The purpose of this article is to determine via meta-analysis whether apparent diffusion coefficient (ADC) predicts astrocytoma prognosis independent of grade. MATERIALS AND METHODS. Survival data were subjected to Mantel Haenszel analysis in four qualifying studies. Stratification by tumor grade was also performed. RESULTS. The survival rates of malignant astrocytomas, grade 3 and 4 (p, and < , respectively) were worse below a specific ADC value, independent of grade. CONCLUSION. Low ADC values correlate with poor survival in malignant astrocytomas independent of tumor grade. A strocytomas are the most common primary brain neoplasms in adults and account for more than 70% of all gliomas. The (World Health Organization) WHO Grade III and IV malignant astrocytomas include anaplastic astrocytoma and glioblastoma multiforme (GBM) and are the most prevalent astrocytomas, with an annual incidence of 3 4 per 100,000. At least 80% of malignant gliomas are glioblastomas. Despite aggressive treatments, the overall prognosis of high-grade astrocytomas, especially GBM, is poor, mainly because of their invasive character, mass effect, and high relapse rate compared with low-grade astrocytomas. The median survival is approximately 3 years for patients with anaplastic astrocytoma and 1 year for those with GBM [1, 2]. Well-defined preoperative grading of astrocytomas is therefore crucial because the selection of an appropriate treatment strategy and prognosis differ considerably according to tumor grade. Diffusion-weighted MRI (DWI) is an MRI method that produces in vivo images of biologic tissues based on the detection of a change in the random motion of water protons [3]. MR diffusion imaging evaluates water molecular diffusion over distances that correspond to typical cell sizes. This water diffusion is also impeded by cell membranes that are an integral part of the cell architecture. Apparent diffusion coefficient (ADC) is one of the several parameters calculated from diffusion imaging that can be used to assess the local environment. Calculated ADC maps represent a measure of average diffusion for each voxel [4, 5]. Tumor cellularity increases with increasing grade, and with this increasing cell density, the impeding effect of membranes is expected to increase, thus decreasing the ADC value. Predictably, an inverse correlation exists between tumor cellularity and ADC value [6, 7]. Therefore, in general, the higher the grade of tumor and the more cellular the tumor type in the nucleus-to-cytoplasm ratio, the lower the ADC value [8]. The utility of ADC in the prediction of survival has not been completely explored. A trend that low ADC may independently predict the worst survival has been suggested in some small series of high-grade astrocytomas and oligodendrogliomas [9 13]. Low-grade astrocytomas show little variation in survival according to ADC values [14]. To further look at the role of ADC values and astrocytoma prognosis, we carried out a systematic review and meta-analysis of the studies that address this topic. We sought to determine whether, independent of the influence of the grade of the tumor, ADC values predict prognosis. Materials and Methods Search Strategy A search on MEDLINE using PubMed was conducted for studies using the key words astrocytoma survival/prognosis and ADC values in astrocytomas. We supplemented electronic search by manually searching reference lists, reviews, and abstracts. 624 AJR:200, March 2013

2 ADC Values and Prognosis of Malignant Astrocytomas TABLE 1: Basic Data of the Four Included Studies Year of Publication No. of Subjects Grade of Astrocytoma Observation Period (y) Higano et al. [10] GBM = 20; anaplastic astrocytoma = 15 2 Murakami et al. [11] GBM = 50; anaplastic astrocytoma = 29 2 Yamasaki et al. [12] GBM 1.5 Saksena et al. [13] GBM 0.5 Meta-analysis GBM = 137; anaplastic astrocytoma = Note GBM = glioblastoma multiforme. Inclusion and Exclusion We evaluated each study for inclusion in the meta-analysis on the basis of the following four criteria: target population, patients with histologically proven astrocytoma; availability of ADC data for astrocytomas; division of patients into two groups by an ADC cutoff; and availability of survival rates in the two ADC groups. We included the studies that had ADC data with survival. We excluded some studies because of insufficient survival data [9], dealing with mixed glial tumors [14], using normalized ADC as the DWI parameter, and providing data for groups having high and low volume of tumor with ADC < 1.5 (v[nadc < 1.5]) [9, 15]. After reviewing more than 30 articles on the subject, we found only four that were rigorous enough to be included. Data Extraction Each study was assessed for its number of subjects, the grade of astrocytoma, the DWI b value, and the method for ADC measurement. All four studies used minimum ADC as the parameter and included only the solid tumor component of the tumor for measurements (Tables 1 and 2). The ADC threshold used in each study was mm 2 /s [10], mm 2 /s [11], mm 2 /s [12] and mm 2 /s [13], respectively. An overall survival outcome for all cases obtained was assessed for the respective two groups that had been classified according to the given ADC cutoff value accordingly in each included study (Table 2). Separate survival data for individual grade of tumor (GBMs and anaplastic astrocytomas) were also obtained and analyzed for statistical significance (Table 3). Outcome Measures The four included studies gave prospective data for survival in a given observation period. Higano et al. [10] and Saksena et al. [13] provided progression-free survival data and stratified cases into those labeled stable or progressive. Stable patients did not have tumor recurrence or death within the given observation period. Patients who died or in whom the tumors recurred within the observation period were considered progressive. Murakami et al. [11] and Yamasaki et al. [12] gave overall survival rates. Survival analysis was given as the percentage of patients who survived in the given observation period in the four studies. Characteristics All four studies were prospective and observational with no control group. The four studies yielded 181 qualified patients. Initial MRI ADC values were obtained in all studies for histologically proven, newly diagnosed GBM and anaplastic astrocytoma cases with no therapeutic interventions. Each study had its own cutoff point for ADC. Table 1 shows the baseline characteristics of the included studies. The target was GBM only in Yamasaki et al. [12] and Saksena et al. [13]. Both GBMs and anaplastic astrocytomas were included in Higano et al. [10] and Murakami et al. [11]. Patients were treated with maximum tumor resection, postoperative external-beam radiation therapy, and nitrosurea-based chemotherapy in Higano et al. [10], Murakami et al. [11], and Yamasaki et al. [12]. Saksena et al. [13] used temozolomide therapy in addition to surgery and radiation. However, treatment was not uniform, even among the patients of a single study (Table 4). Statistical Analysis Statistically significant poor survival was found by subjecting the available data to Mantel-Haenszel analysis. The Mantel-Haenszel odds ratio and 95% CI were calculated for each study and meta-analysis was performed on the basis of the survival rates above and below the ADC cutoff value for each included study. The results for the fixed effects model and random effects model were the same. Therefore, only the fixed-effects model was reported, with significantly poorer survival rates for astrocytoma patients below the ADC cutoff compared with otherwise. A p value of < 0.05 was considered statistically significant (Table 5). The mean observation period and mean survival rate of the groups above and below the ADC cutoff for all the included studies were calculated (Table 2). Results The mean observation period for the included studies was 1.5 years. The mean survival rate above the respective ADC cutoff points used in the four studies (n = 91) was %. The mean survival rate below the respective ADC cutoff points (n = 90) was % (Table 2). Statistical significance was achieved for the poor survival rates below the ADC cutoff value therefore, improved survival rate above the ADC cutoff value. Stratifying the data according to tumor grade, we were able TABLE 2: Apparent Diffusion Coefficient (ADC) Parameters for the Four Selected Studies ADC Parameter Used Cystic, Necrotic, Hemorrhagic Areas Excluded b Values Used (s/mm 2 ) Cutoff Value Used (10 3 mm 2 /s) Survival Rate Above ADC Cutoff Value (%) Survival Rate Below ADC Cutoff Value (%) Higano et al. [10] Minimum ADC Yes 0, Murakami et al. [11] Minimum ADC Yes 0, Yamasaki et al. [12] Minimum ADC Yes 0, Saksena et al. [13] Minimum ADC Yes 0, Meta-analysis Minimum ADC (mean of all four values) Note Dash indicates not available. AJR:200, March

3 Zulfiqar et al. TABLE 3: Stratification of Survival Rate Data According to Available Astrocytoma Tumor Grades (n = 137) Statistical Significance (p < 0.05) Survival Rate (%) Higano et al. [10] (n = 20) Murakami et al. [11] (n = 50) Yamasaki et al. [12] (n = 33) Saksena et al. [13] (n = 34) Mean Grade Above, 64.8; below, 19.3 Mantel-Haenszel odds ratio, 6.690; 95% CI, ; z = 4.335; p < Above ADC cutoff, 68; below ADC cutoff, 23 Above ADC cutoff, 60; below ADC cutoff, 30.4 Above ADC cutoff, 64; below ADC cutoff, 13 Above ADC cutoff, 57.1; below ADC cutoff, 15.4 Glioblastoma multiforme Above, 94.6; below, 43 Mantel-Haenszel odds ratio,23.204; 95% CI, ; z = 2.880; p = Above ADC cutoff, 92; below ADC cutoff, 33 Above ADC cutoff, 100; below ADC cutoff, 50% Anaplastic astrocytoma Note Survival rates with respect to tumor grade above and below the respective ADC cutoffs used in the four studies are also calculated. Group with ADC values below the cutoff corresponds with poor survival in both glioblastoma multiforme and anaplastic astrocytoma. ADC = apparent diffusion coefficient. Dash indicates not available. to obtain 137 GBM cases and 44 anaplastic astrocytoma cases (Table 3). Although different treatment modalities used in the included studies may affect the survival data (Table 4), one can see from the table that 168 underwent maximal surgical resection, with only 15 undergoing a biopsy only. In three of the series, postoperative radiation and chemotherapy were provided and this accounted for all but seven of 181 patients in the meta-analysis. Salvage surgery and additional chemoradiotherapy were included in two studies. No patients refused surgery. The treatment did not vary by grade. The Mantel-Haenszel odds ratio was with a 95% CI of (z = 6.710, and p = ), thus showing ADC value has an inverse relationship with malignant astrocytoma survival (Table 5 and Fig. 1). The survival of WHO grade IV GBMs with ADC below the cutoff was significantly poorer than above the ADC value (Mantel- Haenszel odds ratio, 6.690; 95% CI, ; z = 4.335; p < ) (Tables 5 and 6). This was also true for WHO grade III anaplastic astrocytomas (Mantel-Haenszel odds ratio, ; 95% CI, ; z = 2.880; p = 0.004) (Table 7). Because the follow-up in the study by Saksena et al. [13] was limited to 6 months, we reanalyzed the data excluding the 34 patients in this group. We found no difference in the conclusions previously noted. Therefore low ADC values may be an independent measure of poor prognosis in malignant astrocytomas, independent of tumor grade. Discussion The findings of this systemic review and meta-analysis of prospective studies support the view that low ADC values of malignant astrocytomas correlate with poor survival, independent of their relationship with grade of tumor by WHO classification. In the past, ADC has been found to have an inverse relation with the grade of astrocytomas [8, 16 19]. Lower ADC values suggest a malignant high-grade astrocytoma, whereas higher ADCs suggest low-grade astrocytoma. On the basis of specific histologic features of the tumor, such as cellularity, nuclear atypia, mitosis, pleomorphism, vascular hyperplasia, and necrosis, the revised WHO classification subdivides gliomas into four grades [18]. Of these features, tumor cellularity is the main correlate of quantitative assessment with DWI [18, 20]. With increasing cell density as seen with increasing grade of tumors, the impeding effects of cellular membranes and reduced intracellular and extracellular fluid are expected to result in low values of ADC in high-grade tumors and therefore high values of ADC in low-grade tumors [4]. In short, the ADC value of an astrocytoma may aid conventional MRI in characterizing the tumor and therefore help to plan treatment and assess prognosis accordingly. ADC may be considered an independent predictor of outcome in patients with highgrade astrocytomas. An inverse relation has been identified between ADC values and prognosis for GBM and anaplastic astrocytomas in the meta-analysis of prospective studies reviewed here. Murakami et al. [11] showed an overall poor survival rate of highgrade astrocytoma (grades III and IV) having low ADC values. In the study by Oh et al. [9], the ADC values within the T1 contrast enhancement and T2 regions of interest were normalized relative to contralateral normalappearing white matter. Thus, the study evaluated the mean normalized ADCs of GBMs seen on MR images obtained before surgery and radiation therapy and found that the patients with low normalized ADCs had noticeably shorter survival independent of tumor grade III or IV. Even though this study gave statistically significant results for the inverse relation between normalized ADC and GBM prognosis, it failed to elicit the same for relative cerebral blood volume for the same groups of patients. Perfusion weighted MRI can be used to calculate relative cerebral blood volume associated with tumor microvascularity and to distinguish residual or recurrent tumor from treatment-induced necrosis. Among mean ADC, minimum ADC, and maximum ADC values, minimum ADC was the strongest prognostic factor in GBM patients for overall survival in the study by Yamasaki et al. [12]. This was also true for those GBMs in which total surgical resection was not possible. Saksena et al. [13] also found that low ADCs in GBMs corresponded to a lower 6-month progression-free survival rate. Higano et al. [10] preoperatively assessed minimum ADC of each tumor (grades III and IV) followed by surgery and radiation therapy. Significantly better 2-year outcomes were observed for tumors with high ADC values than for those with relatively low ADCs. This study also showed that minimum ADC values of malignant astrocytomas are negatively correlated with the Ki- 67 labeling index, an immunohistochemical 626 AJR:200, March 2013

4 ADC Values and Prognosis of Malignant Astrocytomas TABLE 4: Treatment Modalities and Postoperative Measures Taken in the Included Studies That Might Have Affected Survival Rates Higano et al. [10] Maximal Surgical Resection: Stereotactic Biopsy 30:7 (two patients died of pneumonia with no tumor recurrence and were excluded from final classification) Postoperative External-Beam Irradiation Postoperative Chemotherapy Postoperative Clinical Complications Salvage Surgery and Additional Radiation and Chemotherapy in Case of Progression or Recurrence Refusal of Treatment by Patient All All Murakami et al. [11] 79:0 All All Yes Yamasaki et al. [12] 33:0 All All Yes Saksena et al. [13] 26:8 29 patients 27 patients Note Dash indicates not available. TABLE 5: Forest Plot Comparing Survival Rates Above and Below Apparent Diffusion Coefficient (ADC) Cutoff Value for Each Statistics Mantel-Haenszel Odds Ratio Lower Limit Upper Limit z p Higano et al. [10] Murakami et al. [11] Yamasaki, et al. [12] Saksena, et al. [13] Fixed-model Mantel Haenszel analysis Mantel-Haenszel Odds Ratio and 95% CI Favors A Favors B Note Mantel-Haenszel odds ratio, 95% CI, and p value for each of the included studies without stratification by tumor grade. Fixed-model meta-analysis shows very significant poor survival for astrocytoma patients having ADC values below the cutoff point. Area A favors better survival. Area B favors detrimental survival. Each study is depicted by a square and the size of the square correlates with the sample size and therefore weight of that study in the meta-analysis. The pooled metaanalytical data are depicted by the diamond at the bottom. Both glioblastoma multiforme and anaplastic astrocytoma have significantly poorer survival below ADC cutoff value (area B) compared with survival above ADC value (area A). Patient Survival (%) Higano et al. [10] Murakami et al. [11] 60.0 Yamasaki et al. [12] Saksena et al. [13] Meta-Analysis Fig. 1 Graph shows survival rates for patients above and below apparent diffusion coefficient cutoff value for included studies (n = 4) and meta-analysis. Observation period was 2 years for studies by Higano et al. [10] and Murakami et al. [11], 1.5 years for study by Yamasaki et al. [12], and 0.5 year for study by Saksena et al. [13] factor, with higher rates of Ki-67 positive cells corresponding with greater malignancy of brain tumors. Although a reliable prognostic marker, Ki-67 is only applicable to tumor specimens after surgery. Crawford et al. [15] showed that the patients with portions of GBM having normalized ADC less than 1.5 ml had worse survival. Although ADC has proven to be a useful predictor of patient survival in high-grade astrocytomas, Brasil Caseiras et al. [14] distinguished low-grade gliomas (grade II astrocytomas) as having no effect on prognosis with respect to ADC values. None of the ADC parameters proved to be a useful predictor of malignant transformation in low-grade gliomas. Our meta-analysis for combined survival data in malignant astrocytomas (grades III and IV) yielded a significantly poorer survival for patients with low ADC values, supporting the predictive power of ADC for malignant astrocytoma prognosis. Separate analysis AJR:200, March

5 Zulfiqar et al. TABLE 6: Stratification of Data by Tumor Grade for Glioblastoma Multiforme Statistics Mantel-Haenszel Odds Ratio Odds Ratio Lower Limit Upper Limit z p and 95% CI Higano et al. [10] Murakami et al. [11] Yamasaki et al. [12] Saksena et al. [13] Fixed-model Mantel Haenszel analysis Favors A Favors B Note Mantel-Haenszel analysis by tumor stratification shows poor survival for glioblastoma multiformes having ADC values below cutoff value (area B) compared with those with ADCs above cutoff value (area A). Each study is depicted by a square and the size of the square correlates with the sample size and therefore weight of that study in the meta-analysis. The pooled meta-analytical data are depicted by the diamond at the bottom. TABLE 7: Stratification of Data by Tumor Grade for Anaplastic Astrocytoma Statistics Mantel-Haenszel Odds Ratio Odds Ratio Lower Limit Upper Limit z p and 95% CI Higano et al. [10] Murakami et al. [11] Fixed-model Mantel Haenszel analysis Favors A Favors B Note Mantel-Haenszel analysis by tumor stratification shows poor survival for anaplastic astrocytomas having ADC values below cutoff (area B) value compared with those with ADCs above cutoff value (area A). Area B favors detrimental survival. Each study is depicted by a square and the size of the square correlates with the sample size and therefore weight of that study in the meta-analysis. The pooled meta-analytical data are depicted by the diamond at the bottom. conducted for the survival and tumor grade on the basis of an ADC cutoff value also held this relation for high-grade astrocytomas (GBMs and anaplastic astrocytomas). The quality of included studies should be considered in the interpretation of our findings. Variable treatment or no available treatment might have affected the survival of the patients. The approaches used to obtain the ADC values and the selected ADC cutoffs in the included studies are variable and sensitive to user bias. For example, Higano et al. [10] and Murakami et al. [11] used two neuroradiologists for reading the data who were blinded to the clinical and histopathologic information. No comparison is available for the remaining two included studies. The use of variable MRI scanners and selected field strengths and sequence parameters especially the b value might have led to diverse ADC values in the different studies. Absence of accordance of the areas of ADC measurement in the studies is an important factor that might have led to different survival rate. ADC values of the peripheral portion might show a better relationship with the prognosis of astrocytomas. Some have suggested that peripheral regions of a tumor are the growing edge of the tumor, thus making it a more important factor than central portions (especially if there is necrosis) when survival is being considered. Recurrence generally occurs in the peripheral regions that tend to be at risk after surgery [10]. Moreover, although there is a known correlation between increasing tumor cellularity and decreasing ADC values, this relationship is somewhat complex and incompletely understood. Astrocytomas may have increasing edema and necrosis as their grade and malignancy increase, two factors (necrosis and vasogenic edema) that conversely would increase the ADC value [21]. For this reason, all the included studies excluded areas of cystic degeneration, necrosis, and hemorrhage with reference to conventional MR images when measuring the ADC values. It is important that the initial ADC value is obtained before any intervention is measured. Antiangiogenesis agents, such as bevacizumab, are now commonly used and therefore can change the ADC values of tumors [22]. Absent or insufficient survival data available for analysis was a major factor restricting our meta-analysis to just four studies of 30 published on DWI and astrocytomas. Because there was an absence of individual case data and very low numbers of subjects studied prospectively for low-grade astrocytomas, we were forced to limit our approach to malignant WHO grade III and IV astrocytomas. Different treatment modalities used in the included studies may affect the survival data (Table 4). For example, usage of maximal surgical removal versus stereotactic biopsy might show improved survival in the former. Occurrence of postoperative complications salvage surgery, radiation, and chemotherapy in case of tumor recurrence and patient refusal of treatment are factors that invariably could affect patient survival. In addition, different methods of data collection and analysis (ADC cutoff of mm 2 /s by Saksena et al. [13] compared with mm 2 /s and mm 2 /s used by other studies) and variable observation periods (6 months for Saksena et al. [13] vs 2 years and 1.5 years in the remaining three studies) used by the included studies may have affected the recorded survival rates. However, even though the study by Saksena et al. [13] had limited follow-up of GBM cases (6 months) compared with the other three studies, we reached the same conclusions when calculations were performed excluding data 628 AJR:200, March 2013

6 ADC Values and Prognosis of Malignant Astrocytomas from Saksena et al. [13]. Despite these shortcomings, the strength of the present analysis is that it was limited to studies of malignant astrocytomas (grades III and IV), and it accumulated a large number of homogeneous cases compared with smaller sample studies. Moreover, while performing a retrospective meta-analysis, there are inevitable variables for which one cannot control. Fortunately, the mainstays of treatment of GBM, surgery and radiation, are universally applied. Other chemotherapeutic agents have shown limited effect on survival. Additionally, the parameters for ADC determination varied little. The survival data were in a form that was transparent enough to assess the value of ADC as a predictor of prognosis as shown. No other meta-analysis on the matter is available. Our meta-analysis underscores the importance of measuring ADC values in assessing prognosis of astrocytoma. It is recommended that ADC be measured in all brain tumors so that an effective ADC cutoff can be identified, separating malignant astrocytomas of any specific grade with a worse prognosis. Conclusion Low ADC values, independent of tumor grade, correlate with poor survival in malignant astrocytomas. Pretreatment DWI with calculation of ADC values may be helpful for planning therapy and in prognostication for patients with high-grade astrocyotomas. References 1. DeAngelis LM. Brain Tumors. N Engl J Med 2001; 344: Radhakrishnan K, Mokri B, Parisi JE, O Fallon WM, Sunku J, Kurland LT. The trends in incidence of primary brain tumors in the population of Rochester, Minnesota. Ann Neurol 1995; 37: Bammer R, Stollberger R, Augustin M, et al. Diffusion-weighted Imaging with navigated interleaved echo-planar imaging and a conventional gradient system. Radiology 1999; 211: Maier SE, Sun Y, Mulkern RV. Diffusion imaging of brain tumors. NMR Biomed 2010; 23: Rowley HA, Grant PE, Roberts TP. 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