Lung Cancer 87 (2015) 96–97
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Commentary
Quantification and consequences of lung cancer CT overdiagnosis Jerome M. Reich a,∗ , Jong S. Kim b a b
Thoracic Oncology Program, Earle A Chiles Research Institute, 5251 NE Glisan Ave., Bldg. A, Portland, OR 97213-2967, United States Fariborz Maseeh Department of Mathematics and Statistics, Portland State University, 724 SW Harrison, Portland, OR 97207, United States
a r t i c l e
i n f o
Article history: Received 1 September 2014 Received in revised form 27 November 2014 Accepted 11 December 2014 Keywords: Lung cancer screening NLST Overdiagnosis Surgery CXR Tumor volume doubling time
1. Introduction The term “overdiagnosis” designates screen-identification of cancers which would otherwise have remained inevident within the individual’s lifetime. The authors of the current U.S. Preventive Services Task Force guideline cite a CT-lung cancer screening overdiagnosis estimate of 10–12% (vs. CXR-screened controls) [1]. The chest radiographic (CXR) screening estimate, based on the differential case number identified by CXR vs. null screening is 25% [2]. As many of the CXR trial control cases, considered as clinically relevant, were equally susceptible to overdiagnosis because they were identified by an incidental or a trial-prescribed CXR, 25% may be considered a conservative estimate. The Task Force did not detail their estimate methodology, but the 10–12% range brackets the 11% differential in the number of cases identified in the 6.5year National Lung Screening Trial (NLST) in the CT screened (1060) vs. the CXR screened control group (941) [3]. Net overdiagnosis is the sum of CT (vs. CXR) overdiagnosis, 11% + CXR (vs. null screen) overdiagnosis, 25% = 36%. Because this range excludes control group
∗ Corresponding author. Tel.: +1 5032926027; fax: +1 5032964878. E-mail address: [email protected] (J.M. Reich). http://dx.doi.org/10.1016/j.lungcan.2014.12.002 0169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.
cancers which did not become evident during the trial follow-up, 36% may be considered an upper bound. 2. Discussion Some authors have advanced tumor volume doubling time (TVDT) as a single factor reductionist approach to the quantification of overdiagnosis. Lengthy TVDT, because it implies longer natural history, has been advanced as its defining characteristic. It is however unsatisfactory for this purpose because, in addition, overdiagnosis is a function of age, comorbidity, technology (CT identifies far smaller cancers than CXR, increasing their duration of exposure to lethal comorbidities) and adventitious events (e.g., fatal accidents, and incapacitating illnesses such as a stroke, which diminish the likelihood of lung cancer detection) plus tumor characteristics: histology, dimension, phenotype, and ability to circumvent immunoediting. The likelihood that the course of screen-detected lung cancers will be overtaken by competing lethal morbidities increases with age; the contribution of other morbidities is reflected in the difference between reduction in lung cancer (20%) vs. all cause mortality (6.7%) in the NLST.[3] Actionable nodule dimension is critical in three respects: (1) smaller tumors (due to length time bias) have longer TVDTs; (2) are earlier in their natural history, increasing their duration of exposure to lethal comorbidities; (3) growth rate is a function of dimension. At a constant TVDT,
J.M. Reich, J.S. Kim / Lung Cancer 87 (2015) 96–97
the relative rate of increase in diameter is given by the ratio of the radii, and of volume, by the ratio of the squared radii. For example, the relative rates of diameter and volume increase of a 4 cm vs. a 0.5 cm lung cancer are 8:1 and 64:1 [4]. A plausible estimate of order of magnitude is the most one can hope to achieve, and it will vary by setting and scenario, depending, for example on population age, comorbidity and actionable nodule dimension. Only harm can result from screen identification of overdiagnosed persons whose cancers are, by definition, destined to remain clinically inevident. Brown et al. compared non-cancer mortality of persons with lung cancer to matched persons with non-vital-organcancers and found their relative hazard to be nearly three-fold that in persons with colon and breast cancer [5]. That this marked increase in non-cancer death hazard can be ascribed solely to severe, smoking related, cardiopulmonary morbidities appears incompatible with the belief that this hazard is unaffected by the loss of ca. one-fifth of their lungs. The critical issue is whether the benefit of a screening reduction in lung cancer mortality justifies the harm imposed on a population in which more than one third of cases are overdiagnosed, and which results in the nonbeneficial and decidedly non-trivial intervention of lobectomy. Beyond imposing major surgery, overdiagnosis is harmful to the extent that lung tissue loss may contribute to excess non-cancer death hazard.
97
3. Conclusion We recommend caution in advocating population screening pending lengthier follow-up of the NLST and replication of its results in the European trials which employed null-screened controls. Conflict of interest The authors declare that there is no conflict of interest. References [1] Moyer VA, on behalf of the U.S Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014;160:330–8. [2] Reich JM. A critical appraisal of overdiagnosis: estimates of its magnitude and implications for lung cancer screening. Thorax 2008;63:377–83 (review). [3] The National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365(5):395–409. [4] Reich JM, Kim JS. Lung cancer growth dynamics. Eur J Radiol 2011;80(3):e458–61, http://dx.doi.org/10.1016/j.ejrad.2010.08.006. [5] Brown BW, Brauner C, Minnotte MC. Noncancer deaths in white adult cancer patients. J Natl Cancer Inst 1993;85:979–87.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Commentary
Quantification and consequences of lung cancer CT overdiagnosis Jerome M. Reich a,∗ , Jong S. Kim b a b
Thoracic Oncology Program, Earle A Chiles Research Institute, 5251 NE Glisan Ave., Bldg. A, Portland, OR 97213-2967, United States Fariborz Maseeh Department of Mathematics and Statistics, Portland State University, 724 SW Harrison, Portland, OR 97207, United States
a r t i c l e
i n f o
Article history: Received 1 September 2014 Received in revised form 27 November 2014 Accepted 11 December 2014 Keywords: Lung cancer screening NLST Overdiagnosis Surgery CXR Tumor volume doubling time
1. Introduction The term “overdiagnosis” designates screen-identification of cancers which would otherwise have remained inevident within the individual’s lifetime. The authors of the current U.S. Preventive Services Task Force guideline cite a CT-lung cancer screening overdiagnosis estimate of 10–12% (vs. CXR-screened controls) [1]. The chest radiographic (CXR) screening estimate, based on the differential case number identified by CXR vs. null screening is 25% [2]. As many of the CXR trial control cases, considered as clinically relevant, were equally susceptible to overdiagnosis because they were identified by an incidental or a trial-prescribed CXR, 25% may be considered a conservative estimate. The Task Force did not detail their estimate methodology, but the 10–12% range brackets the 11% differential in the number of cases identified in the 6.5year National Lung Screening Trial (NLST) in the CT screened (1060) vs. the CXR screened control group (941) [3]. Net overdiagnosis is the sum of CT (vs. CXR) overdiagnosis, 11% + CXR (vs. null screen) overdiagnosis, 25% = 36%. Because this range excludes control group
∗ Corresponding author. Tel.: +1 5032926027; fax: +1 5032964878. E-mail address: [email protected] (J.M. Reich). http://dx.doi.org/10.1016/j.lungcan.2014.12.002 0169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.
cancers which did not become evident during the trial follow-up, 36% may be considered an upper bound. 2. Discussion Some authors have advanced tumor volume doubling time (TVDT) as a single factor reductionist approach to the quantification of overdiagnosis. Lengthy TVDT, because it implies longer natural history, has been advanced as its defining characteristic. It is however unsatisfactory for this purpose because, in addition, overdiagnosis is a function of age, comorbidity, technology (CT identifies far smaller cancers than CXR, increasing their duration of exposure to lethal comorbidities) and adventitious events (e.g., fatal accidents, and incapacitating illnesses such as a stroke, which diminish the likelihood of lung cancer detection) plus tumor characteristics: histology, dimension, phenotype, and ability to circumvent immunoediting. The likelihood that the course of screen-detected lung cancers will be overtaken by competing lethal morbidities increases with age; the contribution of other morbidities is reflected in the difference between reduction in lung cancer (20%) vs. all cause mortality (6.7%) in the NLST.[3] Actionable nodule dimension is critical in three respects: (1) smaller tumors (due to length time bias) have longer TVDTs; (2) are earlier in their natural history, increasing their duration of exposure to lethal comorbidities; (3) growth rate is a function of dimension. At a constant TVDT,
J.M. Reich, J.S. Kim / Lung Cancer 87 (2015) 96–97
the relative rate of increase in diameter is given by the ratio of the radii, and of volume, by the ratio of the squared radii. For example, the relative rates of diameter and volume increase of a 4 cm vs. a 0.5 cm lung cancer are 8:1 and 64:1 [4]. A plausible estimate of order of magnitude is the most one can hope to achieve, and it will vary by setting and scenario, depending, for example on population age, comorbidity and actionable nodule dimension. Only harm can result from screen identification of overdiagnosed persons whose cancers are, by definition, destined to remain clinically inevident. Brown et al. compared non-cancer mortality of persons with lung cancer to matched persons with non-vital-organcancers and found their relative hazard to be nearly three-fold that in persons with colon and breast cancer [5]. That this marked increase in non-cancer death hazard can be ascribed solely to severe, smoking related, cardiopulmonary morbidities appears incompatible with the belief that this hazard is unaffected by the loss of ca. one-fifth of their lungs. The critical issue is whether the benefit of a screening reduction in lung cancer mortality justifies the harm imposed on a population in which more than one third of cases are overdiagnosed, and which results in the nonbeneficial and decidedly non-trivial intervention of lobectomy. Beyond imposing major surgery, overdiagnosis is harmful to the extent that lung tissue loss may contribute to excess non-cancer death hazard.
97
3. Conclusion We recommend caution in advocating population screening pending lengthier follow-up of the NLST and replication of its results in the European trials which employed null-screened controls. Conflict of interest The authors declare that there is no conflict of interest. References [1] Moyer VA, on behalf of the U.S Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014;160:330–8. [2] Reich JM. A critical appraisal of overdiagnosis: estimates of its magnitude and implications for lung cancer screening. Thorax 2008;63:377–83 (review). [3] The National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365(5):395–409. [4] Reich JM, Kim JS. Lung cancer growth dynamics. Eur J Radiol 2011;80(3):e458–61, http://dx.doi.org/10.1016/j.ejrad.2010.08.006. [5] Brown BW, Brauner C, Minnotte MC. Noncancer deaths in white adult cancer patients. J Natl Cancer Inst 1993;85:979–87.
