|Ahead of print publication
The role of volumetric method in the assessment of chemotherapy response and predicting survival in malignant pleural mesothelioma
Furkan Erturk Urfali1, Selma Metintas2, Atila Gurgen3, AK Guntulu4, Ragip Ozkan5, Muzaffer Metintas6
1 Department of Radiology, Kutahya Education and Research Hospital, Kutahya, Turkey
2 Eskisehir Osmangazi University Lung and Pleural Cancers Research and Clinical Center; Department of Public Health, Eskisehir Osmangazi University, Medical Faculty, Eskisehir, Turkey
3 Department of Psychiatry, Ordu State Hospital, Ordu, Turkey
4 Eskisehir Osmangazi University Lung and Pleural Cancers Research and Clinical Center; Department of Chest Diseases, Eskisehir Osmangazi University, Medical Faculty, Eskisehir, Turkey
5 Department of Radiology, Medigunes Hospital, Manisa, Turkey
6 Department of Public Health, Eskisehir Osmangazi University, Medical Faculty, Eskisehir; Department of Chest Diseases, Eskisehir Osmangazi University, Medical Faculty, Eskisehir, Turkey
|Date of Submission||28-Mar-2019|
|Date of Acceptance||25-Jun-2019|
|Date of Web Publication||19-Aug-2020|
Furkan Erturk Urfali,
Department of Radiology, Kütahya University of Health Sciences, Kutahya
Source of Support: None, Conflict of Interest: None
Background: Malignant pleural mesothelioma (MPM) is a pleural tumor with high mortality rate and short-term survival expectancy after diagnosis. Assessment of the response to chemotherapy, which is the first choice in treatment of MPM, is important for the transition to alternative chemotherapy protocols and immunotherapy. There is no clarity in the response to chemotherapy treatment.
Objective: Our study aims to compare the assessment of chemotherapy response using the Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria and volumetric measurements and to correlate with median survival.
Materials and Methods: Thirty-two patients (16 females and 16 males) were included in the study, and their ages ranged from 28 to 78 years. Chemotherapy response was determined by both mRECIST and volumetric approach. Tumor volume was measured by linear interpolation and semi-automatic segmentation. Log-rank multiple cutoff analysis was used to determine appropriate cutoff values of volumetric response criteria.
Results: According to both mRECIST and volumetric approach, median survival times in partial response, stable disease, and progressive disease groups were 24, 15, and 9 months, respectively. The survival times of the three groups were different (logrank: 17.76; P < 0.001) by mRECIST. The survival of the progressive disease group was shorter than that of the other groups (logrank: 18.91; P < 0.001) by volumetric approach.
Conclusions: In the assessment of chemotherapy response, even though classifications obtained according to the mRECIST criteria and volumetric measurements are statistically compatible, we think that the measurement of the volumetric values will increase the standardization. In our study, threshold values for volumetric measurements were determined; however, these values should be supported by large-scale multicenter studies.
Keywords: Chemotherapy response evaluation, computed tomography, malignant pleural mesothelioma, Modified Response Evaluation Criteria in Solid Tumor, volumetric tumor measurement
|How to cite this URL:|
Urfali FE, Metintas S, Gurgen A, Guntulu A K, Ozkan R, Metintas M. The role of volumetric method in the assessment of chemotherapy response and predicting survival in malignant pleural mesothelioma. J Can Res Ther [Epub ahead of print] [cited 2021 Jan 25]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=292706
| > Introduction|| |
Malignant pleural mesothelioma (MPM) is the primary tumor of pleura, which originates from the mesothelial cells and covers pleura. The appearance of MPM is observed 20–50 years after the first asbestos exposure, and the age of onset is usually after 65 years of age due to the long latency period. The mean survival time in patients who do not receive any treatment is 6–8 months. In patients receiving 4–6 cycles of cis/carboplatin and antifolate chemotherapy, which are accepted as a standard treatment for MPM, the mean survival time is reported as 11–12 months.,, In patients who do not respond to standard chemotherapy, agents such as vinorelbine,, durvalumab (immune checkpoint inhibitor), and tremelimumab (monoclonal antibodies) are the other options for treatment.
Since the computed tomography (CT) scans can show the anatomic details, it is a primary imaging method for diagnosis, staging, and response assessment, and its high availability is the main advantage of this imaging modality.,,, For assessing the response to treatment, the bidimensional criteria of the World Health Organization (WHO) and then the unidimensional criteria of Response Evaluation Criteria in Solid Tumors (RECIST) have been widely used in clinical practice and studies. It is very important that standards of RECIST can be used in all solid tumor types as well as they are easily and quickly applicable. However, MPM typically spreads around the pleura in circular form; therefore, the use of standard linear tumor measurements in the assessment of response to treatment is a matter of debate. Depending on the tumor morphology and the difference in axis, in which the tumor growth is prominent, it is difficult to determine the response to treatment with unidimensional standard measurements. The previous studies revealed that the RECIST criteria were unsatisfactory for assessing the response to treatment in MPM.,, The studies evaluating the response to MPM therapy encouraged the research on new medications/approaches in order to improve the survival rates of patients. For this reason, appropriate evaluation of the response to these therapies is of great clinical importance. The aim of this study was to determine the chemotherapy response of MPM patients with volumetric measurements by computer-assisted semi-automatic segmentation and compare the results with the Modified RECIST (mRECIST) criteria based on median survival.
| > Materials and Methods|| |
A total of 32 patients, who have pathologically proven MPM and were treated with chemotherapy in 2012–2013, were included in the present study. The age, gender, radiological findings of asbestos exposure, side of disease, histology, stage, and Karnofsky Performance Status were obtained from database of our unit. All patients underwent a platinum-based pemetrexed regimen. The staging of patients was carried out according to the staging system proposed by the International Mesothelioma Interest Group in conjunction with the thoracic multislice CT (MSCT) findings. The study was approved by Eskisehir Osmangazi University Ethical Committee (2012/34).
MSCT (Aquilion 64, Toshiba, Tokyo, Japan) scan was performed in supine position using parameters including 64 × 0.5 collimation, 0.75-s rotation time, table motion with 2.24 cm/s gantry rotation, 300 effective mAs, and 120 kV. After determining the contrast agent transit time using the smart prep bolus technique, we acquired image data during an intravenous injection of 75-ml iodinated contrast agent at a rate of 2 ml/s. The contrast-enhanced thoracic MSCT images of patients prior to and 4 weeks after the second or fourth cycles of chemotherapy were examined. CT images were evaluated by a senior thoracic radiologist with 20 years of experience in thorax radiology. mRECIST and volume evaluations were performed at different times, blinded and independent of patient information.
The chemotherapy response was assessed using computer-assisted tumor volumetry and linear unidimensional measurements, in which mRECIST criteria were used. Pleural fluid was excluded from the evaluation. For mRECIST evaluation, a total of six measurements were made from three different levels and two different regions which were spaced at least 1 cm apart from each other and perpendicular to the mediastinum and chest wall. In follow-up CT examinations, (i) the disappearance of all lesions was classified as complete response, (ii) more than 30% volume reduction was classified as partial response, and (iii) more than 20% increase in volume was classified as progression. A large group of patients between partial response and progression was defined as stable disease.
Volumetric approach was performed using Vitrea FX version 6.1 (Vital Images Inc., a Canon Group Company, Minnetonka, Minnesota, USA). Tumor volume was measured with linear interpolation and semi-automatic segmentation; in addition, manual adjustments were made when needed. In this method, a typographical segmentation combining various image processing techniques including chest-rib interpolation was used in order to distinguish MPM from the chest wall, liver, spleen, and adjacent normal organs/tissues [Figure 1]. The tumor tissue image obtained by semi-automatic segmentation and manual correction can be reconstructed in three dimensions [Figure 2]. In the segmentation process, lung tissue, pleural effusion, and atelectatic lung parenchyma were semiautomatically marked by density equalization and area expansion firstly. After normal lung tissue, pleural effusion, and atelectatic lung were detected, the outer portion of the pleura was semiautomatically segmented. In order to achieve accurate MPM volumes, computer-generated tumor contours of the baseline and follow-up images were examined side by side and reanalyzed. Corrections were made manually when necessary. Then, the obtained volume was recorded as image [Figure 3].
|Figure 1: (a) In the images obtained before the manual correction, the adjacent liver parenchyma (L) and intercostal musculature planes (ICC) in the dentition similar to mesothelioma were selected incorrectly. (b) In the upper sections, it is noticed that the vascular structures and atelectatic lung parenchyma (A) are successfully distinguished by the software, but the neighboring pleural fluid is marked as cancerous tissue in some places|
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|Figure 2: (a) Computer-assisted semi-automatic segmentation image of tumor of a patient in Image 1 before the chemotherapy (tumor is coded in blue color). (b) Volumetric comparisons after the chemotherapy|
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|Figure 3: The tumor tissue scattered in the hemithoracic cavity is differentiated from the surrounding the anatomical structures and adjacent intact tissue by computer-assisted semi-automatic segmentation, and then, the volumetric measurements are performed automatically by the software|
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Statistical analyses were performed using IBM SPSS Statistic (IBM Corp., Armonk, NY, USA) 15.0 program. The suitability to normal distribution of tumor volume variable was examined by the Shapiro–Wilk test and graphs. The volume variable did not show normal distribution. Mann–Whitney U-test or Kruskal–Wallis test with Bonferroni correction was performed to compare tumor volume of patients in terms of age, gender, radiological findings of asbestos exposure, side of disease, histology, stage, and Karnofsky Performance Status. Log-rank multiple cutoff analysis was used to determine appropriate cutoff values of volumetric response criteria. Partial response was defined by a ≥20% decrease in the tumor volume; progressive disease was defined by a ≥40% increase of tumor volume; stable disease was defined by a <20% decrease or <40% increase. Median survivals with 95% confidence intervals (CIs) were estimated according to the Kaplan–Meier method. Differences in time distributions between groups were tested for statistical significance using the log-rank test. Kappa analysis was performed to determine the correspondence between the two methods. Kappa values were defined as: 0, no correspondence; 0–0.2, slight; 0.2–0.4, fair; 0.4–0.6, moderate; 0.6–0.8, substantial; and 0.8–1.0, almost perfect correspondence. P < 0.05 was considered statistically significant.
| > Results|| |
A total of 32 patients were included in the study. All of the patients had environmental asbestos exposure in rural area, and all of them were dead. The median age was 59 – 50 in males and 64 in females. The characteristics of the patients are shown in [Table 1]. The median tumor volume of the patients was 85.7 cm3 (1.1–1405.7) at diagnosis. There was no difference between median tumor volumes at diagnosis in terms of age (<65 vs. ≥65; P = 0.301), gender (M vs. F; P = 0.724), radiological findings of asbestos exposure (pleural plaque, diffuse pleural thickening, and round atelectasis) (yes vs. no; P = 0.677), disease side (left vs. right; P = 0.669), and Karnofsky Performance Status (≤80 vs. ≥90; P = 0.388). However, median tumor volume was higher in patients with epithelioid histology and Stage IV disease than others at diagnosis (for histology 88.0 cm3 vs. 33.4 cm3; P = 0.003) (for stage 296.6 cm3 vs. 27.3 cm3; P = 0.003). There was no relationship between median tumor volume at diagnosis and median survival of patients (P = 0.684).
The percent change of tumor volume was significantly different between the partial response group and others of mRECIST criteria but not between the progressive disease and stable disease groups. Tumor volume before and after chemotherapy and percentage change of tumor volume according to mRECIST response groups are shown in [Table 2]. Median survival time ± standard error (95% confidence interval [CI]) was 17.0 ± 4.24 (95% CI: 8.69–25.32) months. There were survival differences between the mRECIST response groups (logrank: 17.76; P < 0.001). Median survival times for progressive disease, stable disease, and partial response were 9, 15, and 24 months, respectively. Median survivals were also different between the volumetric response groups (logrank = 18.91; P < 0.001). Median survivals for progressive disease, stable disease, and partial response were 9, 15, and 24 months, respectively. Patients with progressive disease had shorter survival than those with partial and stable diseases. However, patients with partial response and stable disease had similar median survival (logrank = 2.48; P = 0.12). Median survivals of patients according to mRECIST and volumetric response criteria are shown in [Table 3]. Survival curves for volumetric criteria and mRECIST criteria are shown in [Figure 4] and [Figure 5]. Two methods classified 26 patients in the same group according to chemotherapy response. The agreement between mRECIST and volumetric approach was substantial (K = 0.71; P < 0.001) [Table 4].
|Table 2: Tumor volume before and after chemotherapy and percent change of tumor volume according to mRECIST response groups|
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|Table 3: Median survivals of patients according to mRECIST and volumetric response criteria|
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|Figure 5: Kaplan–Meier survival curves for modified response evaluation criteria in solid tumor criteria|
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| > Discussion|| |
MPM is an aggressive malignant tumor of pleura and primarily related with the exposure to asbestos. Approximately 80% of patients diagnosed for MPM have a history of exposure to asbestos., All 32 patients in our study group exposed to asbestos. Different from the literature data, the ratio of females and males was same in the present study, and this suggests that, rather than the occupational exposure, the asbestos originates from the use in daily life in our rural region. There is environmental asbestos exposure in rural area of Turkey, and asbestos is used for whitewashing and insulation of the roofs and furnaces.
Median survival time of the patients was 17.0 ± 4.24 months, and median tumor volume was 85.7 cm3 at diagnosis in this study. There was no relationship between prechemotherapy tumor volume and survival time (P = 0.684). We also examined the relationship between prechemotherapy tumor volume and clinical characteristics of patients in this study. Epithelioid type histology and Stage IV disease showed higher tumor volume than others at diagnosis. The prognosis of MPM is generally poor, and the survival varies between 6 and 17 months in large case series (mean value of 12 months).,, Recently, studies are carried out on the prognostic importance of solely the pretreatment tumor volume. In order to categorize the pretreatment small-volume and large-volume diseases, the threshold value of tumor volume was evaluated., Pass et al. reported that patients who had a preoperative tumor volume of <100 cm3 had a median overall survival of 22 months, whereas those with a larger tumor volume had a median overall survival of 11 months. Rusch et al. reported that tumor volume correlated with stage and overall survival, average volumes of 91.2, 245.3, and 511.3 cm3 associated with median overall survival 37, 18, and 8 months, respectively. These studies included surgically treated patients. It is expected that effective resection will be more difficult in patients with high tumor burden and the risk of possible surgical complications will be higher. At this point, it is expected that the prognosis is worse in patients with high tumor burden. In the chemotherapy series, the prognosis depends mainly on the response to chemotherapy. Therefore, tumor burden may have less effect on prognosis of patients treated with chemotherapy than on prognosis of patients treated with surgery. In our study, we did not find the relationship between pretreatment tumor volume and survival.
In a study of Liu et al., the radiological response to chemotherapy was reported to be the best determinant of survival. The authors reported that if the tumor volume can be accurately measured in MSCT images, then the volumetric measurements could better represent the tumor response to the treatment in comparison to the unidimensional measurements. In their study, the authors declared that the changes in tumor volume were in significant relationship with the survival and that the mRECIST measurements conducted at the same while did not show such a correlation. In our study, both volumetric measurements and mRECIST represent the chemotherapy response. We observed that the classification of volumetric measurements and mRECIST criteria was compatible with survival and the classification was consistent (kappa compliance value: 0, 71).
In their study, Sensakovic et al. reported that the MPM segmentation errors most frequently occur in hemithoracic base and intercostal spaces. In the present study, moreover, we observed that the highest level of time in manual corrections and retouching was spent to these locations. Some of the computed-assisted segmentation errors are the unequal distribution of contrast material, high-density/high-content pleural liquid, and the partial volume effect creating the pixels having density values such as atelectasis and mesothelioma adjacent to tumor. In studies on the tumor volumetry, it was reported that generally 10–15 min is spent for volume measurement and less than the first for mRECIST method in pre- and posttreatment examinations of the patient. Frauenfelder et al. reported that the semi-automatic segmentation can be improved using segmentation algorithms (object-based segmentation) and the time spent decreases. In our study, the time spent for volume measurements and mRECIST classification was not calculated, but we think that it was shorter for mRECIST than volumetric measurement.
In a study of Labby et al. on 78 patients, the minor axis-unidimensional measurements were optimized with survival analysis. 64% regression and 50% progression values were obtained in assessing the response to treatment. They used Harrell's C statistic to find best response criteria. In the present study, we aimed to find the threshold values in accordance with the survival for three-dimensional volumetric values. We used log-rank multiple cutoff analysis to determine the best cutoff values of volumetric response criteria in this study. We found that 20% regression and 40% progression in posttreatment tumor volume were the best cutoff values for the volumetric assessment. According to these criteria, we found that patients with partial response and stable disease had similar median survival. In our present study, different threshold values were obtained when compared to a previous study which was based on the Cavalieri's principle and performed with transparent films marked with fixed intervals in the same center. We think that these are not the best criteria for volumetry because of the limited number of patients. It is a fact that larger studies are needed to achieve ideal volumetric criteria.
In a study of Frauenfelder et al., the tumor volume measurements and the mRECIST classifications were examined between different observers. The interobserver correlation in response classifications with volumetric measurements was found to be better than those with linear measurements. Moreover, the tumor volume measurement has a higher accuracy level when compared to mRECIST method. Besides, in a study of Armato et al., the systematic bias was observed among the observers in minimum measurable lesions (mean thickness of tumor: 7.5 mm), and the difference between the measurements was reported to be approximately 20%.
The limitations of the present study: (1) we did not evaluate interobserver variability and (2) we have the relatively insufficient number of patients for obtaining adequate statistical significance. No statistically significant threshold could be determined between pretreatment tumor volume and survival. The stable disease group is quite broad by volumetric response criteria based on the WHO and mRECIST, and most of the patients are interpreted having stable response. We think that the most important deficiency in the volumetric evaluation is the lack of determined appropriate response criteria rather than the measurement techniques. Multicenter studies involving more patients are required to determine the best volumetric criteria independent of the WHO and mRECIST criteria.
The advancements in computer software will offer faster and more sufficient segmentation. We believe that the direct measurement of tumor volume for irregularly shaped solid tumors such as MPM will be commonly conducted in daily practice in the future. In parallel with the advancements in tumor volume calculation, the criteria for response to the treatment should be arranged with the survival analyses in large patient groups for each histological subtype.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4]