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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.
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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
LETTERS TO THE EDITOR
apeutic efficacy after transcatheter arterial chemoembolization for hepatocellular carcinoma. Oncol Rep 2010;24(3):727–732. 5. Mannelli L, Kim S, Hajdu CH, et al. Serial diffusion-weighted MRI in patients with hepatocellular carcinoma: prediction and assessment of response to transarterial chemoembolization—preliminary experience. Eur J Radiol 2013;82:577–582. 6. Dong S, Ye XD, Yuan Z, et al. Relationship of apparent diffusion coefficient to survival for patients with unresectable primary hepatocellular carcinoma after chemoembolization. Eur J Radiol 2012;81(3):472–477. 7. Song MJ, Chun HJ, Song do S, et al. Comparative study between doxorubicin-eluting beads and conventional transarterial chemoembolization for treatment of hepatocellular carcinoma. J Hepatol 2012;57(6):1244–1250. 8. Sacco R, Bargellini I, Bertini M, et al. Conventional versus doxorubicin-eluting bead transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2011;22(11):1545–1552.
Response From Vincent Vandecaveye, MD, PhD, Frederik De Keyzer, MSc, and Geert Maleux, MD, PhD Department of Radiology and Medical Imaging Research Center, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium e-mail: vincent.vandecaveye@ uzleuven.be We thank Dr Ye and colleagues for their comments about and interest in our recent article (1). We agree with their comment on the potential reproducibility of the ADC ratio for treatment monitoring as the optimal ADC
ratio cutoff values between good and poor responders seem to be quite robust (13.6%, 14.8%, and 16.2% for the referenced studies). Of course, larger studies are needed to prove this. Dr Ye and colleagues also note that in our study the 1-month response did not correlate with OS, for which they provide two tentative explanations. Their first explanation is the use of two different TACE therapies (conventional vs drug-eluting beads) in our study. However, it is noteworthy to mention that no significant difference in PFS was found between conventional TACE and TACE with drug-eluting beads, leading us to believe that treatment type differences in our study did not contribute to the absent significant correlation with OS. A second possible explanation is the low number of patients in our study, and we agree that the lack of statistical significance between 1-month imaging response and OS may merely reflect low statistical power. However, the patient population to check correlation with OS in our study (n = 30) is similar to that in their previous study (n = 23) (2). Therefore, although OS is often chosen as a primary end point in cancer studies, this may be reconsidered in HCC (3,4). Several reasons for this have been proposed by Memon et al (4). HCC is commonly managed by using multiple, sequential (non)surgical therapies, with crossover between different treatments, making it difficult to attribute survival benefit to a single therapy. Moreover, patients with HCC have competing risks of death, either as
Radiology: Volume 272: Number 3—September 2014 n radiology.rsna.org
a result of their oncologic disease or due to extensive cirrhosis. Also, survival can be significantly prolonged merely with intensive supportive care (4). The redirection of most of the patients included in our study to selective internal radiation or systemic treatment after documentation of disease progression probably made it similarly difficult to correlate initial 1-month response with OS. Therefore, PFS might be more specific to drive early treatment change than OS, as decisions about treatment management are usually based on disease progression. Disclosures of Conflicts of Interest: V.V. disclosed no relevant relationships. F.D.K. disclosed no relevant relationships. G.M. 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. Dong S, Ye XD, Yuan Z, et al. Relationship of apparent diffusion coefficient to survival for patients with unresectable primary hepatocellular carcinoma after chemoembolization. Eur J Radiol 2012;81(3):472–477. 3. Sargent DJ, Hayes DF. Assessing the measure of a new drug: is survival the only thing that matters? J Clin Oncol 2008;26(12):1922–1923. 4. Memon K, Kulik L, Lewandowski RJ, et al. Radiographic response to locoregional therapy in hepatocellular carcinoma predicts patient survival times. Gastroenterology 2011; 141(2):526–535.
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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
LETTERS TO THE EDITOR
apeutic efficacy after transcatheter arterial chemoembolization for hepatocellular carcinoma. Oncol Rep 2010;24(3):727–732. 5. Mannelli L, Kim S, Hajdu CH, et al. Serial diffusion-weighted MRI in patients with hepatocellular carcinoma: prediction and assessment of response to transarterial chemoembolization—preliminary experience. Eur J Radiol 2013;82:577–582. 6. Dong S, Ye XD, Yuan Z, et al. Relationship of apparent diffusion coefficient to survival for patients with unresectable primary hepatocellular carcinoma after chemoembolization. Eur J Radiol 2012;81(3):472–477. 7. Song MJ, Chun HJ, Song do S, et al. Comparative study between doxorubicin-eluting beads and conventional transarterial chemoembolization for treatment of hepatocellular carcinoma. J Hepatol 2012;57(6):1244–1250. 8. Sacco R, Bargellini I, Bertini M, et al. Conventional versus doxorubicin-eluting bead transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2011;22(11):1545–1552.
Response From Vincent Vandecaveye, MD, PhD, Frederik De Keyzer, MSc, and Geert Maleux, MD, PhD Department of Radiology and Medical Imaging Research Center, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium e-mail: vincent.vandecaveye@ uzleuven.be We thank Dr Ye and colleagues for their comments about and interest in our recent article (1). We agree with their comment on the potential reproducibility of the ADC ratio for treatment monitoring as the optimal ADC
ratio cutoff values between good and poor responders seem to be quite robust (13.6%, 14.8%, and 16.2% for the referenced studies). Of course, larger studies are needed to prove this. Dr Ye and colleagues also note that in our study the 1-month response did not correlate with OS, for which they provide two tentative explanations. Their first explanation is the use of two different TACE therapies (conventional vs drug-eluting beads) in our study. However, it is noteworthy to mention that no significant difference in PFS was found between conventional TACE and TACE with drug-eluting beads, leading us to believe that treatment type differences in our study did not contribute to the absent significant correlation with OS. A second possible explanation is the low number of patients in our study, and we agree that the lack of statistical significance between 1-month imaging response and OS may merely reflect low statistical power. However, the patient population to check correlation with OS in our study (n = 30) is similar to that in their previous study (n = 23) (2). Therefore, although OS is often chosen as a primary end point in cancer studies, this may be reconsidered in HCC (3,4). Several reasons for this have been proposed by Memon et al (4). HCC is commonly managed by using multiple, sequential (non)surgical therapies, with crossover between different treatments, making it difficult to attribute survival benefit to a single therapy. Moreover, patients with HCC have competing risks of death, either as
Radiology: Volume 272: Number 3—September 2014 n radiology.rsna.org
a result of their oncologic disease or due to extensive cirrhosis. Also, survival can be significantly prolonged merely with intensive supportive care (4). The redirection of most of the patients included in our study to selective internal radiation or systemic treatment after documentation of disease progression probably made it similarly difficult to correlate initial 1-month response with OS. Therefore, PFS might be more specific to drive early treatment change than OS, as decisions about treatment management are usually based on disease progression. Disclosures of Conflicts of Interest: V.V. disclosed no relevant relationships. F.D.K. disclosed no relevant relationships. G.M. 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. Dong S, Ye XD, Yuan Z, et al. Relationship of apparent diffusion coefficient to survival for patients with unresectable primary hepatocellular carcinoma after chemoembolization. Eur J Radiol 2012;81(3):472–477. 3. Sargent DJ, Hayes DF. Assessing the measure of a new drug: is survival the only thing that matters? J Clin Oncol 2008;26(12):1922–1923. 4. Memon K, Kulik L, Lewandowski RJ, et al. Radiographic response to locoregional therapy in hepatocellular carcinoma predicts patient survival times. Gastroenterology 2011; 141(2):526–535.
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