Journal of Thoracic Oncology ® • Volume 8, Number 12, December 2013
exon 18 were rare (3%) in concordance with the majority of published studies.3,4,6 In addition, the authors confirmed the Asian and occidental conclusions that EGFR mutation rate was significantly higher in women and in never smokers.3,4,6 However, the study presents several limitations because of numerous biases, and the result presented here should be interpreted with caution3: - The population analyzed was not representative for the overall Moroccan population; as an example, the frequency of EGFR mutation in female patients included was 34% (46 of 137), largely higher than frequencies showed in Rabat and Casablanca registries (the only 2 registries available in Morocco).1,2 According to Casablanca registry, women with AC represent only 16% of lung AC and men with AC represent 84% of lung AC.1 In fact, in Morocco women, lung cancer was a relatively rare condition representing only 8% to 11.5% of all lung cancers versus 33.4% in developed countries.1,2,7,8 And women with lung cancer in Morocco are not smoker in the vast majority of the case (79%).7 - In another hand, the analysis was performed according to specimen available in private laboratories (Nations-Unies Pathology Center, Hassan Pathology Center, and Agdal Pathology Center, at Rabat, Morocco; and Casapath Pathology Center at Casablanca, Morocco.) excluding the majority of specimen available at the most important institutions in Morocco, such as the University Hospitals (National Institute of Oncology at Rabat, Morocco, and Ibn-Rochd University Hospital at Casablanca, Morocco). We do not agree with the author’s conclusion that EGFR mutation frequency in Moroccan patients is higher than that found in whites, but it is the same than that observed in white population. By using the frequency of EGFR mutation in men (7 of 91 = 7.7%) and the frequency of EGFR mutation in women (22 of 46 = 47.8%) calculated from data of the present
article and by using Moroccan statistics (Casablanca registry), we can estimate the true frequency of EGFR mutation in our population; according to Casablanca registry (the most powerful registry), female patients with lung AC represent 16% of lung AC and male patients with lung AC represent 84% of lung AC, the frequency of EGFR mutation will be approximately (16 × 47.8/100 + 7.7 × 84/100 = 7.6% + 6.45%) = 14%. Therefore, we suggest that the incidence of EGFR mutation in Moroccan patients is equivalent than that observed in white population, and we encourage the Moroccan investigators to conduct a multiinstitutional and large study including consecutive patients with AC diagnosed at the most important Cancer Center in Morocco to confirm this suggestion and to refine the result of the present study.3 Nabil Ismaili, MD Rizlane Belbaraka, MD Department of Medical Oncology Oncology Center Mohammed VI University Hospital Marrakech, Morocco REFERENCES 1. Available at: srvweb.sante.gov.ma/.../Registre %20Cancer%20Grand%20Casablanca%2... 2. Tazi MA, Er-Raki A, Benjaafar N. Cancer incidence in Rabat, Morocco: 2006-2008. Ecancermedicalscience. 2013;7:338. 3. Errihani H, Inrhaoun H, Boukir A, et al. Frequency and type of epidermal growth factor receptor mutations in moroccan patients with lung adenocarcinoma. J Thorac Oncol 2013;8:1212–1214. 4. Castro AS, Parente B, Gonçalves I, et al. Epidermal growth factor receptor mutation study for 5 years, in a population of patients with non-small cell lung cancer. Rev Port Pneumol 2013;19:7–12. 5. Smits AJ, Kummer JA, Hinrichs JW, et al. EGFR and KRAS mutations in lung carcinomas in the Dutch population: increased EGFR mutation frequency in malignant pleural effusion of lung adenocarcinoma. Cell Oncol (Dordr) 2012;35:189–196. 6. Bauml J, Mick R, Zhang Y, et al. Frequency of EGFR and KRAS mutations in patients with non small cell lung cancer by racial background: do disparities exist? Lung Cancer 2013;81:347–353. 7. Khouchani M, Selmaji I, Elmorabit B, et al. Female lung cancer in Marrakech. Clin Cancer Investig J 2013;2:128–131 8. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69–90.
Copyright © 2013 by the International Association for the Study of Lung Cancer
Letters to the Editor
Spectrum of EGFR Mutation in Lung Adenocarcinoma in Morocco In Response: On behalf of the author group, we thank Dr. Ismaili for his interest in our article Spectrum of EGFR Mutation in Lung Adenocarcinoma in Morocco1 and his insightful comments. With regard to his comments, we think the following points should be clarified. First, our series was a retrospective study and therefore some potential sources of bias cannot be ruled out. Despite this, our results provide some information about the frequency of epidermal growth factor receptor (EGFR) mutation in lung adenocarcinoma in Morocco, and as indicated in our article, have to be confirmed in larger prospective studies. Second, data analysis was performed according to the availability of specimens in private pathology laboratories because these laboratories perform more than 90% of all tests requested in Morocco, and EGFR mutation testing is not available for specimens that could be found in public institutions. We do not fully agree with suggestion made by Dr. Ismaili that the incidence of EGFR mutation in Moroccan patients would be equivalent than that observed in white population. In our series, the EGFR mutation rate was higher than that found in other studies conducted in whites despite similar sex distribution.2,3 For example, Rosell et al.2, in a large prospective Spanish study, reported EGFR mutation in only 16% of patients with lung cancer including 39% of female patients. In such situation, extrapolation as done by Dr. Ismaili should be avoided, and we believe that the best way to provide an accurate EGFR mutation rate in Moroccan patients is to Address for correspondence: Ibrahim Elghissassi, MD, Medical Oncology Department, National Institute of Oncology, Allal Elfassi Street, Rabat 62000, Morocco. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0812-e115
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Letters to the Editor
conduct a large prospective study (currently ongoing in our institution). Finally, we once again thank Dr. Ismaili for his thoughtful comments and we are grateful to get the opportunity to clarify some points from our work. Ibrahim Elghissassi, MD Hassan Errihani, MD Medical Oncology Department National Institute of Oncology Rabat, Morocco REFERENCES 1. Errihani H, Inrhaoun H, Boukir A, et al. Frequency and type of epidermal growth factor receptor mutations in moroccan patients with lung adenocarcinoma. J Thorac Oncol 2013;8:1212–1214. 2. Rosell R, Moran T, Queralt C, et al; Spanish Lung Cancer Group. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958–967. 3. Castro AS, Parente B, Gonçalves I, et al. Epidermal growth factor receptor mutation study for 5 years, in a population of patients with non-small cell lung cancer. Rev Port Pneumol 2013;19:7–12.
To the Editor: In their article, Barraclough et al. provide important insights into the interpretation of hazard ratio (HR) estimates from Cox models and Kaplan–Meier curves from clinical trials. Unfortunately, the authors provide a particular interpretation of the HR, which can distort both statistical and clinical interpretations. Specifically, the authors interpret (see ref.,1 p. 981, Box 2) a 0.75 HR for overall survival (OS), comparing treatment E (experimental) versus C (control), as either (1) a 25% lower risk of death (via 100 × (1 − HR)%, denoted 1 − HR), or (2) a 33% increase in the survival time (via 100 × (1/HR − 1)%, denoted 1/HR − 1). The interpretation provided by (1) is 1
Disclosure: All authors are employed by Genentech, Inc., South San Francisco. Address for correspondence: Larry Frank Leon, PhD, Genentech, 1 DNA Way, South San Francisco, CA 94070. E-mail: leon.larry@ gene.com Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0812-e116
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Journal of Thoracic Oncology ® • Volume 8, Number 12, December 2013
appropriate and is standard throughout the statistical and medical literature. The interpretation provided by (2), however, is not sound and can cause considerable miscommunication of study results. Statement (2) suggests that treatment E extends the survival times of patients after treatment E by 33% compared with the survival times of patients after treatment C. For example, 1-year OS under treatment C is extended to 1.33 years under treatment E, 2-year OS extended to 2.66 years, and so on. The degree of improvement in OS times or probabilities cannot by itself be summarized by a single value as survival differences will vary across time. Although the HR is generally considered the most important comprehensive summary of survival comparisons, its interpretation should not be taken out of context. The authors’ interpretation assumes that survival times follow an exponential distribution. In this case, when both treatment groups follow exponential distributions, then the ratio of medians, me/mc (say), is equal to 1/HR. The exponential model, however, should not be the basis for general interpretation. For example, suppose that treatment C survival times follow a Weibull model with shape parameter ν and scale parameter θ (cf. ref.2), and that the hazard function for treatment E is equal to threefourths the hazard function for treatment C. We note that the exponential model is a special case of the Weibull model with shape parameter ν=1. Then HR=0.75 and the ratio of medians is equal to 1/ HR=1.33 if and only if ν=1. However, if ν=0.25, for example, then the ratio of medians is equal to 3.16, and if ν=4, then the ratio is 1.07. These examples illustrate the pitfalls of interpreting 1/HR as the “increase in survival time.” Here we clarify that for HR=0.75, 1 − HR = 0.25 means that “treatment E reduces the risk of death by 25% relative to treatment C,” whereas 1/HR − 1 = 0.33 means that “treatment C increases the risk of death by 33% relative to treatment E.” In other words, converting the interpretation from 1 − HR to 1/HR − 1 simply changes the reference group; from E versus C to C versus E. This can be seen from the definition of the HR. Let λe denote the hazard of death for treatment E, and λc denote the
hazard of death for treatment C. If the ratio of hazards r(t)=λe(t)/λc(t) does not depend on time t then the proportional hazards assumption holds. Denoting this ratio by HR we can interpret HR = 0.75 (without reference to time) as “patients on treatment E have a 25% reduced risk of death relative to treatment C.” If we switch the interpretation to be in terms of C relative to E then this is λc(t)/λe(t)=1/HR, which means that the hazard for C is (1/0.75) or 133% the hazard of E. Note that [λc(t)–λe(t)]/ λe(t)=1/HR − 1, where λc(t)–λe(t) represents how much treatment C increases the hazard of death compared with E. Then 1/HR − 1 = 33% is the percentage increase in the hazard of death for treatment C relative to treatment E. Because survival probabilities (OS curves) are an explicit mathematical expression of the hazard function, that “treatment E reduces the risk (hazard) of death” already directly translates into prolonged OS for E relative to C. As we design trials to assess whether an experimental regimen prolongs OS relative to a control, the interpretation given by 1 − HR (E versus C) is what is needed. Larry Frank Leon, PhD Bann-Mo Day, PhD Xiaoping Sylvia Hu, PhD Genentech South San Francisco, California REFERENCES 1. Barraclough H, Simms L, Govindan R. (2011). What a clinician ought to know: Hazard ratios. J Thorac Oncol, 978–982. 2. Kalbfleisch J, Prentice R. The Statistical Analysis of Failure Time Data. Hoboken, NJ: John Wiley & Sons, 2002.
In Response: We appreciate the opportunity to reply to the letter by Leon et al. in response to our article on Hazard Address for correspondence: Ramaswamy Govindan, MD, Department of Medicine, Division of Oncology, Washington University School of Medicine, 4960 Children's Place, St Louis, MO 63021. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0812-e116
Copyright © 2013 by the International Association for the Study of Lung Cancer
exon 18 were rare (3%) in concordance with the majority of published studies.3,4,6 In addition, the authors confirmed the Asian and occidental conclusions that EGFR mutation rate was significantly higher in women and in never smokers.3,4,6 However, the study presents several limitations because of numerous biases, and the result presented here should be interpreted with caution3: - The population analyzed was not representative for the overall Moroccan population; as an example, the frequency of EGFR mutation in female patients included was 34% (46 of 137), largely higher than frequencies showed in Rabat and Casablanca registries (the only 2 registries available in Morocco).1,2 According to Casablanca registry, women with AC represent only 16% of lung AC and men with AC represent 84% of lung AC.1 In fact, in Morocco women, lung cancer was a relatively rare condition representing only 8% to 11.5% of all lung cancers versus 33.4% in developed countries.1,2,7,8 And women with lung cancer in Morocco are not smoker in the vast majority of the case (79%).7 - In another hand, the analysis was performed according to specimen available in private laboratories (Nations-Unies Pathology Center, Hassan Pathology Center, and Agdal Pathology Center, at Rabat, Morocco; and Casapath Pathology Center at Casablanca, Morocco.) excluding the majority of specimen available at the most important institutions in Morocco, such as the University Hospitals (National Institute of Oncology at Rabat, Morocco, and Ibn-Rochd University Hospital at Casablanca, Morocco). We do not agree with the author’s conclusion that EGFR mutation frequency in Moroccan patients is higher than that found in whites, but it is the same than that observed in white population. By using the frequency of EGFR mutation in men (7 of 91 = 7.7%) and the frequency of EGFR mutation in women (22 of 46 = 47.8%) calculated from data of the present
article and by using Moroccan statistics (Casablanca registry), we can estimate the true frequency of EGFR mutation in our population; according to Casablanca registry (the most powerful registry), female patients with lung AC represent 16% of lung AC and male patients with lung AC represent 84% of lung AC, the frequency of EGFR mutation will be approximately (16 × 47.8/100 + 7.7 × 84/100 = 7.6% + 6.45%) = 14%. Therefore, we suggest that the incidence of EGFR mutation in Moroccan patients is equivalent than that observed in white population, and we encourage the Moroccan investigators to conduct a multiinstitutional and large study including consecutive patients with AC diagnosed at the most important Cancer Center in Morocco to confirm this suggestion and to refine the result of the present study.3 Nabil Ismaili, MD Rizlane Belbaraka, MD Department of Medical Oncology Oncology Center Mohammed VI University Hospital Marrakech, Morocco REFERENCES 1. Available at: srvweb.sante.gov.ma/.../Registre %20Cancer%20Grand%20Casablanca%2... 2. Tazi MA, Er-Raki A, Benjaafar N. Cancer incidence in Rabat, Morocco: 2006-2008. Ecancermedicalscience. 2013;7:338. 3. Errihani H, Inrhaoun H, Boukir A, et al. Frequency and type of epidermal growth factor receptor mutations in moroccan patients with lung adenocarcinoma. J Thorac Oncol 2013;8:1212–1214. 4. Castro AS, Parente B, Gonçalves I, et al. Epidermal growth factor receptor mutation study for 5 years, in a population of patients with non-small cell lung cancer. Rev Port Pneumol 2013;19:7–12. 5. Smits AJ, Kummer JA, Hinrichs JW, et al. EGFR and KRAS mutations in lung carcinomas in the Dutch population: increased EGFR mutation frequency in malignant pleural effusion of lung adenocarcinoma. Cell Oncol (Dordr) 2012;35:189–196. 6. Bauml J, Mick R, Zhang Y, et al. Frequency of EGFR and KRAS mutations in patients with non small cell lung cancer by racial background: do disparities exist? Lung Cancer 2013;81:347–353. 7. Khouchani M, Selmaji I, Elmorabit B, et al. Female lung cancer in Marrakech. Clin Cancer Investig J 2013;2:128–131 8. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69–90.
Copyright © 2013 by the International Association for the Study of Lung Cancer
Letters to the Editor
Spectrum of EGFR Mutation in Lung Adenocarcinoma in Morocco In Response: On behalf of the author group, we thank Dr. Ismaili for his interest in our article Spectrum of EGFR Mutation in Lung Adenocarcinoma in Morocco1 and his insightful comments. With regard to his comments, we think the following points should be clarified. First, our series was a retrospective study and therefore some potential sources of bias cannot be ruled out. Despite this, our results provide some information about the frequency of epidermal growth factor receptor (EGFR) mutation in lung adenocarcinoma in Morocco, and as indicated in our article, have to be confirmed in larger prospective studies. Second, data analysis was performed according to the availability of specimens in private pathology laboratories because these laboratories perform more than 90% of all tests requested in Morocco, and EGFR mutation testing is not available for specimens that could be found in public institutions. We do not fully agree with suggestion made by Dr. Ismaili that the incidence of EGFR mutation in Moroccan patients would be equivalent than that observed in white population. In our series, the EGFR mutation rate was higher than that found in other studies conducted in whites despite similar sex distribution.2,3 For example, Rosell et al.2, in a large prospective Spanish study, reported EGFR mutation in only 16% of patients with lung cancer including 39% of female patients. In such situation, extrapolation as done by Dr. Ismaili should be avoided, and we believe that the best way to provide an accurate EGFR mutation rate in Moroccan patients is to Address for correspondence: Ibrahim Elghissassi, MD, Medical Oncology Department, National Institute of Oncology, Allal Elfassi Street, Rabat 62000, Morocco. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0812-e115
e115
Letters to the Editor
conduct a large prospective study (currently ongoing in our institution). Finally, we once again thank Dr. Ismaili for his thoughtful comments and we are grateful to get the opportunity to clarify some points from our work. Ibrahim Elghissassi, MD Hassan Errihani, MD Medical Oncology Department National Institute of Oncology Rabat, Morocco REFERENCES 1. Errihani H, Inrhaoun H, Boukir A, et al. Frequency and type of epidermal growth factor receptor mutations in moroccan patients with lung adenocarcinoma. J Thorac Oncol 2013;8:1212–1214. 2. Rosell R, Moran T, Queralt C, et al; Spanish Lung Cancer Group. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958–967. 3. Castro AS, Parente B, Gonçalves I, et al. Epidermal growth factor receptor mutation study for 5 years, in a population of patients with non-small cell lung cancer. Rev Port Pneumol 2013;19:7–12.
To the Editor: In their article, Barraclough et al. provide important insights into the interpretation of hazard ratio (HR) estimates from Cox models and Kaplan–Meier curves from clinical trials. Unfortunately, the authors provide a particular interpretation of the HR, which can distort both statistical and clinical interpretations. Specifically, the authors interpret (see ref.,1 p. 981, Box 2) a 0.75 HR for overall survival (OS), comparing treatment E (experimental) versus C (control), as either (1) a 25% lower risk of death (via 100 × (1 − HR)%, denoted 1 − HR), or (2) a 33% increase in the survival time (via 100 × (1/HR − 1)%, denoted 1/HR − 1). The interpretation provided by (1) is 1
Disclosure: All authors are employed by Genentech, Inc., South San Francisco. Address for correspondence: Larry Frank Leon, PhD, Genentech, 1 DNA Way, South San Francisco, CA 94070. E-mail: leon.larry@ gene.com Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0812-e116
e116
Journal of Thoracic Oncology ® • Volume 8, Number 12, December 2013
appropriate and is standard throughout the statistical and medical literature. The interpretation provided by (2), however, is not sound and can cause considerable miscommunication of study results. Statement (2) suggests that treatment E extends the survival times of patients after treatment E by 33% compared with the survival times of patients after treatment C. For example, 1-year OS under treatment C is extended to 1.33 years under treatment E, 2-year OS extended to 2.66 years, and so on. The degree of improvement in OS times or probabilities cannot by itself be summarized by a single value as survival differences will vary across time. Although the HR is generally considered the most important comprehensive summary of survival comparisons, its interpretation should not be taken out of context. The authors’ interpretation assumes that survival times follow an exponential distribution. In this case, when both treatment groups follow exponential distributions, then the ratio of medians, me/mc (say), is equal to 1/HR. The exponential model, however, should not be the basis for general interpretation. For example, suppose that treatment C survival times follow a Weibull model with shape parameter ν and scale parameter θ (cf. ref.2), and that the hazard function for treatment E is equal to threefourths the hazard function for treatment C. We note that the exponential model is a special case of the Weibull model with shape parameter ν=1. Then HR=0.75 and the ratio of medians is equal to 1/ HR=1.33 if and only if ν=1. However, if ν=0.25, for example, then the ratio of medians is equal to 3.16, and if ν=4, then the ratio is 1.07. These examples illustrate the pitfalls of interpreting 1/HR as the “increase in survival time.” Here we clarify that for HR=0.75, 1 − HR = 0.25 means that “treatment E reduces the risk of death by 25% relative to treatment C,” whereas 1/HR − 1 = 0.33 means that “treatment C increases the risk of death by 33% relative to treatment E.” In other words, converting the interpretation from 1 − HR to 1/HR − 1 simply changes the reference group; from E versus C to C versus E. This can be seen from the definition of the HR. Let λe denote the hazard of death for treatment E, and λc denote the
hazard of death for treatment C. If the ratio of hazards r(t)=λe(t)/λc(t) does not depend on time t then the proportional hazards assumption holds. Denoting this ratio by HR we can interpret HR = 0.75 (without reference to time) as “patients on treatment E have a 25% reduced risk of death relative to treatment C.” If we switch the interpretation to be in terms of C relative to E then this is λc(t)/λe(t)=1/HR, which means that the hazard for C is (1/0.75) or 133% the hazard of E. Note that [λc(t)–λe(t)]/ λe(t)=1/HR − 1, where λc(t)–λe(t) represents how much treatment C increases the hazard of death compared with E. Then 1/HR − 1 = 33% is the percentage increase in the hazard of death for treatment C relative to treatment E. Because survival probabilities (OS curves) are an explicit mathematical expression of the hazard function, that “treatment E reduces the risk (hazard) of death” already directly translates into prolonged OS for E relative to C. As we design trials to assess whether an experimental regimen prolongs OS relative to a control, the interpretation given by 1 − HR (E versus C) is what is needed. Larry Frank Leon, PhD Bann-Mo Day, PhD Xiaoping Sylvia Hu, PhD Genentech South San Francisco, California REFERENCES 1. Barraclough H, Simms L, Govindan R. (2011). What a clinician ought to know: Hazard ratios. J Thorac Oncol, 978–982. 2. Kalbfleisch J, Prentice R. The Statistical Analysis of Failure Time Data. Hoboken, NJ: John Wiley & Sons, 2002.
In Response: We appreciate the opportunity to reply to the letter by Leon et al. in response to our article on Hazard Address for correspondence: Ramaswamy Govindan, MD, Department of Medicine, Division of Oncology, Washington University School of Medicine, 4960 Children's Place, St Louis, MO 63021. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0812-e116
Copyright © 2013 by the International Association for the Study of Lung Cancer
