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COMMUNICATIONS n
Letters to the Editor
follows the Zelen method; the further analysis uses other assumptions.
From Felicitas Richter, MSc, and Marc Dewey, MD, PhD Department of Radiology, CharitéUniversitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany e-mail: [email protected]
Disclosures of Conflicts of Interest: F.R. disclosed no relevant relationships. M.D. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems. Financial activities not related to the present article: is a paid consultant for Guerbet; institution has grants/grants pending from the European Regional Development Fund, the German Heart Foundation/German Foundation of Heart Research, GE Healthcare, Bracco, Guerbet, Toshiba Medical Systems, the German Research Foundation and the German Federal Ministry of Education and Research, the German Research Foundation (for a Heisenberg professorship to M.D.), and European Union, FP7; receives payment for development of educational presentations including service on speakers’ bureaus from Toshiba Medical Systems, Bayer-Schering, Guerbet, and Cardiac MR Academy Berlin; institution receives travel/ accommodations expenses from Toshiba Medical Systems and Guerbet. Other relationships: institution has master research agreements with Siemens Medical Solutions, Philips Medical Systems, and Toshiba Medical Systems; receives royalties from Springer.
Editor: We read with great interest the article by Dr Gao and colleagues in the March 2014 issue of Radiology (1) regarding benign prostatic hyperplasia. According to the description given in the Materials and Methods section, the trial was planned with use of the Zelen design (2), in which patients are randomized to either a treatment or control group before providing informed consent. In this way, the physician and patient already know which treatment to expect before the patient gives consent. However, Dr Gao and colleagues actually used a modified double-consent version of the Zelen design (3,4). Patients in each treatment group who refused to give consent for their allocated treatment were offered the alternative therapy, but their examination results were excluded from further analysis (1). This is not what Zelen initially proposed in 1979. He wanted all patients from the first randomization group to be compared with the second one, irrespective of the allocated treatment. This means that a patient who was initially randomized to group A but received treatment B because the patient refused assignment to group A should be analyzed together with all other patients in group A. Zelen proposed this design to avoid exclusion of patients in trials. He aimed to increase the number of patients even at the price of a loss of statistical efficiency (1). The approach chosen by Dr Gao and colleagues should therefore not be designated as Zelen design because only the way of seeking consent Radiology: Volume 272: Number 3—September 2014 n radiology.rsna.org
References 1. Gao Y, Huang Y, Zhang R, et al. Benign prostatic hyperplasia: prostatic arterial embolization versus transurethral resection of the prostate—a prospective, randomized, and controlled clinical trial. Radiology 2014;270(3):920–928. 2. Zelen M. A new design for randomized clinical trials. N Engl J Med 1979;300(22):1242–1245. 3. Homer CSE. Using the Zelen design in randomized controlled trials: debates and controversies. J Adv Nurs 2002;38(2):200–207. 4. Torgerson DJ, Roland M. What is Zelen’s design? BMJ 1998;316(7131):606.
Response From Yi Wang, MD, PhD, and Yuan-an Gao, MD Department of Radiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China e-mail: [email protected] We thank Richter and Dewey for their interest in our article (1). We agree, as we described in our Materials and 919
LETTERS TO THE EDITOR
Zelen Design in Randomized Controlled Clinical Trials
LETTERS TO THE EDITOR
Methods section, that we used a double-consent Zelen design in the random assignment of patients (1). The double-consent version of the Zelen design differs because participants allocated to the control group are asked for their consent to the standard treatment, and those who decline may receive the experimental (or some other) treatment. Participants allocated to the experimental group are asked whether they consent to the new treatment. If they decline, they receive the standard treatment as in a single-consent version (2,3). We also agree that, in the standard Zelen design, results from patients in each treatment group who refuse consent to the allocated treatment and undergo the alternative therapy should be included in the analysis (2–4). However, in practice, these patients may be unwilling to undergo regular follow-up. In our study, although all patients allocated to the experimental group received the new treatment and the subsequent follow-up, four patients in the control group declined the assigned treatment and failed to participate in the follow-up regularly; thus, their results had to be excluded from the data analysis, as described in our Materials and Methods section. For this reason, we think the further analysis in our study is also in accord with the Zelen design. Disclosures of Conflicts of Interest: Y.W. disclosed no relevant relationships. Y.G. disclosed no relevant relationships.
References 1. Gao Y, Huang Y, Zhang R, et al. Benign prostatic hyperplasia: prostatic arterial embolization versus transurethral resection of the prostate—a prospective, randomized, and controlled clinical trial. Radiology 2014; 270(3):920–928. 2. Zelen M. A new design for randomized clinical trials. N Engl J Med 1979;300(22):1242– 1245. 3. Zelen M. Randomized consent designs for clinical trials: an update. Stat Med 1990; 9(6):645–656. 4. Homer CS. Using the Zelen design in ran domized controlled trials: debates and controversies. J Adv Nurs 2002;38(2):200–207.
920
Apparent Diffusion Coefficients at Diffusion-weighted MR Imaging: Potential Predictors of Survival in Patients with Hepatocellular Carcinoma Treated with Chemoembolization From Xiao-Dan Ye, MD,* Wen-Tao Li, MD,† and Zheng Yuan, MD†‡ Department of Radiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China* Department of Radiology, Shanghai Cancer Hospital, Fudan University, 270 Dong An Rd, Shanghai 200032, China† e-mail: [email protected] Department of Radiology, Shanghai No. 85 Hospital, Shanghai, China‡
Editor: We read with great interest the article by Dr Vandecaveye and colleagues (1), “Chemoembolization for Hepatocellular Carcinoma: 1-Month Response Determined with Apparent Diffusion Coefficient is an Independent Predictor of Outcome,” which appeared in the March 2014 issue of Radiology. The results showed that the apparent diffusion coefficient (ADC) ratio 1 month after transcatheter arterial chemoembolization (TACE) was an independent predictor of progressive-free survival (PFS), which showed a stronger association with tumor response than did Response Evaluation Criteria in Solid Tumors (RECIST), European Association for the Study of the Liver criteria, and modified RECIST. No response variables showed correlation with overall survival (OS). Recent studies have shown that ADC is an imaging biomarker for the prediction of response to chemoembolization in hepatocellular carcinoma (HCC) (2–5). Our previous retrospective study (3) showed that, following TACE, the optimum ADC ratio threshold of 16.2% could be used as a significant predictor of treatment response. Dr Vandecaveye and colleagues prospectively used an ADC ratio threshold of 13.6% and an optimum threshold of 14.8% as a significant predictor of
5-month PFS (1). The similarity between this result and ours (3) illustrates the potential reproducibility of the technique. Furthermore, in our previously published study (6), prechemoembolization lesion ADC values or ADC ratio after chemoembolization had a significant influence on the overall cumulative survival. In the study by Dr Vandecaveye and colleagues (1), 1-month response assessment did not correlate with OS. The authors think two factors, a single therapy and the limited number of patients, may have resulted in the lack of significance in the association between imaging response and OS. We think another factor may also have contributed to the above result. In the study by Dr Vandecaveye and colleagues, patients received different therapy procedures, including conventional TACE and TACE with drug-eluting beads loaded with doxorubicin. Recent studies showed that TACE with drug-eluting beads resulted in better treatment response and delayed tumor progression compared with conventional TACE (7). However, no differences were observed in survival (8). It may affect the relationship of 1-month response assessment and OS based on these patients’ data. Disclosures of Conflicts of Interest: X.D.Y. disclosed no relevant relationships. W.T.L. disclosed no relevant relationships. Z.Y. disclosed no relevant relationships.
References 1. Vandecaveye V, Michielsen K, De Keyzer F, et al. Chemoembolization for hepatocellular carcinoma: 1-month response determined with apparent diffusion coefficient is an independent predictor of outcome. Radiology 2014;270(3):747–757. 2. Yuan Z, Li WT, Peng WJ. Pre-treatment apparent diffusion coefficient is imaging biomarker for prediction of response to chemoembolization in hepatocellular carcinoma. Eur J Radiol 2013;82(12):e901–e902. 3. Yuan Z, Ye XD, Dong S, et al. Role of magnetic resonance diffusion-weighted imaging in evaluating response after chemoembolization of hepatocellular carcinoma. Eur J Radiol 2010;75(1):e9–e14. 4. Kubota K1, Yamanishi T, Itoh S, et al. Role of diffusion-weighted imaging in evaluating ther-
radiology.rsna.org n Radiology: Volume 272: Number 3—September 2014
COMMUNICATIONS n
Letters to the Editor
follows the Zelen method; the further analysis uses other assumptions.
From Felicitas Richter, MSc, and Marc Dewey, MD, PhD Department of Radiology, CharitéUniversitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany e-mail: [email protected]
Disclosures of Conflicts of Interest: F.R. disclosed no relevant relationships. M.D. Financial activities related to the present article: institution received a grant from Toshiba Medical Systems. Financial activities not related to the present article: is a paid consultant for Guerbet; institution has grants/grants pending from the European Regional Development Fund, the German Heart Foundation/German Foundation of Heart Research, GE Healthcare, Bracco, Guerbet, Toshiba Medical Systems, the German Research Foundation and the German Federal Ministry of Education and Research, the German Research Foundation (for a Heisenberg professorship to M.D.), and European Union, FP7; receives payment for development of educational presentations including service on speakers’ bureaus from Toshiba Medical Systems, Bayer-Schering, Guerbet, and Cardiac MR Academy Berlin; institution receives travel/ accommodations expenses from Toshiba Medical Systems and Guerbet. Other relationships: institution has master research agreements with Siemens Medical Solutions, Philips Medical Systems, and Toshiba Medical Systems; receives royalties from Springer.
Editor: We read with great interest the article by Dr Gao and colleagues in the March 2014 issue of Radiology (1) regarding benign prostatic hyperplasia. According to the description given in the Materials and Methods section, the trial was planned with use of the Zelen design (2), in which patients are randomized to either a treatment or control group before providing informed consent. In this way, the physician and patient already know which treatment to expect before the patient gives consent. However, Dr Gao and colleagues actually used a modified double-consent version of the Zelen design (3,4). Patients in each treatment group who refused to give consent for their allocated treatment were offered the alternative therapy, but their examination results were excluded from further analysis (1). This is not what Zelen initially proposed in 1979. He wanted all patients from the first randomization group to be compared with the second one, irrespective of the allocated treatment. This means that a patient who was initially randomized to group A but received treatment B because the patient refused assignment to group A should be analyzed together with all other patients in group A. Zelen proposed this design to avoid exclusion of patients in trials. He aimed to increase the number of patients even at the price of a loss of statistical efficiency (1). The approach chosen by Dr Gao and colleagues should therefore not be designated as Zelen design because only the way of seeking consent Radiology: Volume 272: Number 3—September 2014 n radiology.rsna.org
References 1. Gao Y, Huang Y, Zhang R, et al. Benign prostatic hyperplasia: prostatic arterial embolization versus transurethral resection of the prostate—a prospective, randomized, and controlled clinical trial. Radiology 2014;270(3):920–928. 2. Zelen M. A new design for randomized clinical trials. N Engl J Med 1979;300(22):1242–1245. 3. Homer CSE. Using the Zelen design in randomized controlled trials: debates and controversies. J Adv Nurs 2002;38(2):200–207. 4. Torgerson DJ, Roland M. What is Zelen’s design? BMJ 1998;316(7131):606.
Response From Yi Wang, MD, PhD, and Yuan-an Gao, MD Department of Radiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China e-mail: [email protected] We thank Richter and Dewey for their interest in our article (1). We agree, as we described in our Materials and 919
LETTERS TO THE EDITOR
Zelen Design in Randomized Controlled Clinical Trials
LETTERS TO THE EDITOR
Methods section, that we used a double-consent Zelen design in the random assignment of patients (1). The double-consent version of the Zelen design differs because participants allocated to the control group are asked for their consent to the standard treatment, and those who decline may receive the experimental (or some other) treatment. Participants allocated to the experimental group are asked whether they consent to the new treatment. If they decline, they receive the standard treatment as in a single-consent version (2,3). We also agree that, in the standard Zelen design, results from patients in each treatment group who refuse consent to the allocated treatment and undergo the alternative therapy should be included in the analysis (2–4). However, in practice, these patients may be unwilling to undergo regular follow-up. In our study, although all patients allocated to the experimental group received the new treatment and the subsequent follow-up, four patients in the control group declined the assigned treatment and failed to participate in the follow-up regularly; thus, their results had to be excluded from the data analysis, as described in our Materials and Methods section. For this reason, we think the further analysis in our study is also in accord with the Zelen design. Disclosures of Conflicts of Interest: Y.W. disclosed no relevant relationships. Y.G. disclosed no relevant relationships.
References 1. Gao Y, Huang Y, Zhang R, et al. Benign prostatic hyperplasia: prostatic arterial embolization versus transurethral resection of the prostate—a prospective, randomized, and controlled clinical trial. Radiology 2014; 270(3):920–928. 2. Zelen M. A new design for randomized clinical trials. N Engl J Med 1979;300(22):1242– 1245. 3. Zelen M. Randomized consent designs for clinical trials: an update. Stat Med 1990; 9(6):645–656. 4. Homer CS. Using the Zelen design in ran domized controlled trials: debates and controversies. J Adv Nurs 2002;38(2):200–207.
920
Apparent Diffusion Coefficients at Diffusion-weighted MR Imaging: Potential Predictors of Survival in Patients with Hepatocellular Carcinoma Treated with Chemoembolization From Xiao-Dan Ye, MD,* Wen-Tao Li, MD,† and Zheng Yuan, MD†‡ Department of Radiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China* Department of Radiology, Shanghai Cancer Hospital, Fudan University, 270 Dong An Rd, Shanghai 200032, China† e-mail: [email protected] Department of Radiology, Shanghai No. 85 Hospital, Shanghai, China‡
Editor: We read with great interest the article by Dr Vandecaveye and colleagues (1), “Chemoembolization for Hepatocellular Carcinoma: 1-Month Response Determined with Apparent Diffusion Coefficient is an Independent Predictor of Outcome,” which appeared in the March 2014 issue of Radiology. The results showed that the apparent diffusion coefficient (ADC) ratio 1 month after transcatheter arterial chemoembolization (TACE) was an independent predictor of progressive-free survival (PFS), which showed a stronger association with tumor response than did Response Evaluation Criteria in Solid Tumors (RECIST), European Association for the Study of the Liver criteria, and modified RECIST. No response variables showed correlation with overall survival (OS). Recent studies have shown that ADC is an imaging biomarker for the prediction of response to chemoembolization in hepatocellular carcinoma (HCC) (2–5). Our previous retrospective study (3) showed that, following TACE, the optimum ADC ratio threshold of 16.2% could be used as a significant predictor of treatment response. Dr Vandecaveye and colleagues prospectively used an ADC ratio threshold of 13.6% and an optimum threshold of 14.8% as a significant predictor of
5-month PFS (1). The similarity between this result and ours (3) illustrates the potential reproducibility of the technique. Furthermore, in our previously published study (6), prechemoembolization lesion ADC values or ADC ratio after chemoembolization had a significant influence on the overall cumulative survival. In the study by Dr Vandecaveye and colleagues (1), 1-month response assessment did not correlate with OS. The authors think two factors, a single therapy and the limited number of patients, may have resulted in the lack of significance in the association between imaging response and OS. We think another factor may also have contributed to the above result. In the study by Dr Vandecaveye and colleagues, patients received different therapy procedures, including conventional TACE and TACE with drug-eluting beads loaded with doxorubicin. Recent studies showed that TACE with drug-eluting beads resulted in better treatment response and delayed tumor progression compared with conventional TACE (7). However, no differences were observed in survival (8). It may affect the relationship of 1-month response assessment and OS based on these patients’ data. Disclosures of Conflicts of Interest: X.D.Y. disclosed no relevant relationships. W.T.L. disclosed no relevant relationships. Z.Y. disclosed no relevant relationships.
References 1. Vandecaveye V, Michielsen K, De Keyzer F, et al. Chemoembolization for hepatocellular carcinoma: 1-month response determined with apparent diffusion coefficient is an independent predictor of outcome. Radiology 2014;270(3):747–757. 2. Yuan Z, Li WT, Peng WJ. Pre-treatment apparent diffusion coefficient is imaging biomarker for prediction of response to chemoembolization in hepatocellular carcinoma. Eur J Radiol 2013;82(12):e901–e902. 3. Yuan Z, Ye XD, Dong S, et al. Role of magnetic resonance diffusion-weighted imaging in evaluating response after chemoembolization of hepatocellular carcinoma. Eur J Radiol 2010;75(1):e9–e14. 4. Kubota K1, Yamanishi T, Itoh S, et al. Role of diffusion-weighted imaging in evaluating ther-
radiology.rsna.org n Radiology: Volume 272: Number 3—September 2014
