Correspondence
from the New EPOC trial, these fundamental questions should also be answered. We declare no competing interests.
Kiyoshi Hasegawa, Masaru Oba, *Norihiro Kokudo [email protected] Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan 1
Primrose J, Falk S, Finch-Jones M, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol 2014; 15: 601–11.
Author’s reply We thank Kiyoshi Hasegawa, Masaru Oba, and Norihiro Kokudo for their comments. We have not assessed overall survival or its causes in any detail because this was not the primary outcome of the study, and the data were immature at the time the study was stopped in November, 2012. We do know that there were few treatment-related deaths, and we have assessed in detail the causes of the difference in the early progressionfree survival: these are documented in the report. Overall survival will be the subject of a later analysis. I have attended advisory boards for Merck, Bayer, and Sanofi-Aventis.
John Neil Primrose [email protected] University Surgery, Southampton General Hospital, Southampton SO16 6YD, UK
Addressing overdiagnosis and overtreatment in cancer Mass screening for solid cancers or precancerous lesions is based on the belief that if cancers can be found early—ie, before presentation with clinical symptoms—therapy is more likely to be successful. Unfortunately, screening can also sometimes lead www.thelancet.com/oncology Vol 15 July 2014
to the discovery of lesions that pathologists call cancer, but these diagnoses are too early—ie, they are lesions that would never progress to clinically apparent disease if simply left alone. Aggressive treatment of these lesions is the major source of patient harm that can be attributed to cancer screening, producing diagnosis survivors who are mistakenly regarded as cancer survivors. Until now, opposition to the status quo of labelling these too-early lesions as cancer has been from a small number of vocal advocates1 and scientists who have generated alarming, but largely ignored epidemiological data. Laura Esserman and colleagues2 propose to revolutionise the debate by advocating a workable pathway to diagnostic reform. Of interest, no diagnostic pathologist is an author on this report, which proposes major changes to the diagnostic terminology used in pathology. However, lack of involvement by diagnostic pathologists is to be expected because the specialty of pathology never challenged an expertopinion-based gold standard that too often conflates risk of cancer with the clinical disease cancer. Pathologists’ indifference to readily available patient outcomes data is difficult to explain because pathologists were in the best position to quickly recognise and modify hazardous diagnostic criteria for cancer. When screening radically changed biopsy specimens, the traditional gold standard of expert opinion did not adapt, becoming progressively distanced from its effect on patient populations. Experts in pathology promoted their ability to interpret cellular minutia, leaving it to non-pathologists such as Esserman and colleagues to notice the harm that these interpretations were causing to the pathologists’ patients. Although I hope that the investigators are successful in their terminology reform efforts, I encourage them to include among their goals the search for a better understanding
of why the specialty of pathology was unable to escape from its stubborn devotion to turning lesions with a low or poorly defined risk into cancer. Also, why is there no backup mechanism analogous to the US Food and Drug Administration’s review to detect and respond in a timely fashion to a systemic problem like hazardous diagnostic criteria becoming the standard of care? Was it not clear that if self-correction failed, histopathological diagnosis would be too recondite for effective informal monitoring by non-pathologists? The damage caused by pathologists’ overdiagnosis of cancer is being addressed only after there is overt evidence of a problem that is so long term and so serious that it demands intervention by non-pathology specialties. This would suggest that although we have made great progress in understanding medical error, specialty-wide error might have received too little attention. Inevitably, there will be future instances of specialty error, and it would be a missed opportunity not to learn from this particular example. Although the need for terminology reform is urgent, I would caution Esserman and colleagues that they could be underestimating the challenges they will face when extending their reform efforts beyond examples of clear-cut misuse of malignant terminology (eg, low grade ductal carcinoma in situ). Developing an evidence-based approach that links tissue-derived cancer risk to ever evolving therapeutic options could require use of complex and expensive methods not previously applied to the establishment of the risk associated with focal or low-grade morphological aberrations. Esserman and colleagues are optimistic that some challenges to assigning risk will be overcome with scientific advances, but these advances might be difficult to achieve. Also, reformers should remain aware of the danger of increasing underdiagnosis when decreasing overdiagnosis. If terminology changes such as e306
Correspondence
indolent lesions of epithelial origin increase the number of patients who perceive themselves to be victims of underdiagnosis, this perception will occur in the context of a harsh legal system that thrives on lay juries listening to paid experts who excel at retrospectively identifying missed cancer diagnoses. By contrast, the many current victims of overdiagnosis are not regarded as potential plaintiffs, but instead as cancer survivors who exist anonymously in the epidemiology data of Esserman and colleagues. I declare no competing interests.
Elliott Foucar [email protected] University of New Mexico School of Medicine, Albuquerque, NM 87131, USA 1
2
Page DL, Simpson JF, Jensen RA. Re: When and to what end do pathologists disagree? J Natl Cancer Inst 1998; 90: 1014–16. Esserman LJ, Thompson IM, Reid B, et al. Addressing overdiagnosis and overtreatment in cancer: a prescription for change. Lancet Oncol 2014; 15: e234–42.
We believe that the labelling of non-melanoma skin cancers as an indolent lesion of epithelial origin and not as cancer, as suggested by Laura Esserman colleagues,1 sends a potentially dangerous message to patients and their families. We do not think the authors have considered the ramifications of their comments. Published data suggest a watchand-wait approach for patients with non-melanoma skin cancer is often harmful to patients.2 Basal cell carcinoma grows rapidly—on average, doubling in size yearly. Squamous cell carcinoma grows even more rapidly, has a 2·1% fatality rate, and metastasises in up to 3·7% of patients within 4 years of initial treatment. Of course, the numbers would be much higher with a watch-and-wait approach.
e307
Although basal cell carcinoma rarely metastasises, if left untreated, it can commonly invade local structures, causing haemorrhage, blindness, infection, and disability. Prediction (even in patients with significant comorbidities) of who will and will not die of their skin cancer is impossible. It is cruel to deny patients treatment when we, as physicians, know it can save their lives. We cannot understand why anyone would oppose such treatments, particularly when dermatologists render treatments inexpensively, under local anaesthesia, and in the office setting. Additionally, there are now 263 000 patients immunocompromised after solid organ transplants who are alive in the USA. These patients typically develop several aggressive skin cancers. It is irrational to spend billions of dollars on these transplants only to let these patients—if left untreated— die of skin cancer. Having markers predictive of clinical outcome might be useful, but they do not exist at present. The costs of treating skin cancer, when detected early, are low. The costs of finding such a predictive marker profile would almost certainly be at least as much as the currently proven and timehonoured treatments, thus resulting in little cost savings. We are also alarmed with the suggestion that dermatologists should do fewer skin cancer screenings. Lives are saved by screening.3 Melanoma has been increasing at a rate of 4% per year and is detected frequently during screening. Non-melanoma skin cancers are increasing in the USA at epidemic proportions.4 Recent estimates also suggest that the number of fatalities per year from cutaneous squamous cell carcinoma in the USA is approaching that of
melanoma, and screening also has a positive effect on the early detection of these carcinomas.5 We dermatologists take very seriously our obligation to provide the highest standard of care by using appropriate, cost-effective treatment. The decision of how to approach and treat a skin cancer should rest with the patient in consultation with their dermatologist. Renaming a destructive and sometimes fatal disease—to make it sound harmless—is a disservice to our patients. Rather than suggesting a semantic change that is potentially harmful, it would be more constructive to start planning how to best manage the epidemic at hand. We declare no competing interests.
*Brett M Coldiron, J Ramsey Mellette Jr, George J Hruza, Thomas N Helm, Carlos A Garcia [email protected] American Academy of Dermatology, 930 East Woodfield Road, Schaumburg, IL, 60173, USA (BMC); American College of Mohs Surgery, Milwaukee, WI, USA (JRM); American Society for Dermatologic Surgery, Rolling Meadows, IL, USA (GJH); American Society of Dermatopathology, Deerfield, IL, USA (TNH); and American Society for Mohs Surgery, Huntington Beach, CA, USA (CAG) 1
2
3
4
5
Esserman LJ, Thompson IM, Reid B, et al. Addressing overdiagnosis and overtreatment in cancer: a prescription for change. Lancet Oncol 2014; 15: e234–42. Kricker A, Armstrong B, Hansen V, et al. Basal cell carcinoma and squamous cell carcinoma growth rates and determinants of size in community patients. J Am Acad Dermatol 2014; 70: 456–64. Katalinic A, Waldmann A, Weinstock MA, et al. Does skin cancer screening save lives?: an observational study comparing trends in melanoma mortality in regions with and without screening. Cancer 2012; 118: 5395–402. Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States 2006. Arch Dermatol 2010; 146: 283–87. Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol 2013; 68: 957–66.
www.thelancet.com/oncology Vol 15 July 2014
from the New EPOC trial, these fundamental questions should also be answered. We declare no competing interests.
Kiyoshi Hasegawa, Masaru Oba, *Norihiro Kokudo [email protected] Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan 1
Primrose J, Falk S, Finch-Jones M, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol 2014; 15: 601–11.
Author’s reply We thank Kiyoshi Hasegawa, Masaru Oba, and Norihiro Kokudo for their comments. We have not assessed overall survival or its causes in any detail because this was not the primary outcome of the study, and the data were immature at the time the study was stopped in November, 2012. We do know that there were few treatment-related deaths, and we have assessed in detail the causes of the difference in the early progressionfree survival: these are documented in the report. Overall survival will be the subject of a later analysis. I have attended advisory boards for Merck, Bayer, and Sanofi-Aventis.
John Neil Primrose [email protected] University Surgery, Southampton General Hospital, Southampton SO16 6YD, UK
Addressing overdiagnosis and overtreatment in cancer Mass screening for solid cancers or precancerous lesions is based on the belief that if cancers can be found early—ie, before presentation with clinical symptoms—therapy is more likely to be successful. Unfortunately, screening can also sometimes lead www.thelancet.com/oncology Vol 15 July 2014
to the discovery of lesions that pathologists call cancer, but these diagnoses are too early—ie, they are lesions that would never progress to clinically apparent disease if simply left alone. Aggressive treatment of these lesions is the major source of patient harm that can be attributed to cancer screening, producing diagnosis survivors who are mistakenly regarded as cancer survivors. Until now, opposition to the status quo of labelling these too-early lesions as cancer has been from a small number of vocal advocates1 and scientists who have generated alarming, but largely ignored epidemiological data. Laura Esserman and colleagues2 propose to revolutionise the debate by advocating a workable pathway to diagnostic reform. Of interest, no diagnostic pathologist is an author on this report, which proposes major changes to the diagnostic terminology used in pathology. However, lack of involvement by diagnostic pathologists is to be expected because the specialty of pathology never challenged an expertopinion-based gold standard that too often conflates risk of cancer with the clinical disease cancer. Pathologists’ indifference to readily available patient outcomes data is difficult to explain because pathologists were in the best position to quickly recognise and modify hazardous diagnostic criteria for cancer. When screening radically changed biopsy specimens, the traditional gold standard of expert opinion did not adapt, becoming progressively distanced from its effect on patient populations. Experts in pathology promoted their ability to interpret cellular minutia, leaving it to non-pathologists such as Esserman and colleagues to notice the harm that these interpretations were causing to the pathologists’ patients. Although I hope that the investigators are successful in their terminology reform efforts, I encourage them to include among their goals the search for a better understanding
of why the specialty of pathology was unable to escape from its stubborn devotion to turning lesions with a low or poorly defined risk into cancer. Also, why is there no backup mechanism analogous to the US Food and Drug Administration’s review to detect and respond in a timely fashion to a systemic problem like hazardous diagnostic criteria becoming the standard of care? Was it not clear that if self-correction failed, histopathological diagnosis would be too recondite for effective informal monitoring by non-pathologists? The damage caused by pathologists’ overdiagnosis of cancer is being addressed only after there is overt evidence of a problem that is so long term and so serious that it demands intervention by non-pathology specialties. This would suggest that although we have made great progress in understanding medical error, specialty-wide error might have received too little attention. Inevitably, there will be future instances of specialty error, and it would be a missed opportunity not to learn from this particular example. Although the need for terminology reform is urgent, I would caution Esserman and colleagues that they could be underestimating the challenges they will face when extending their reform efforts beyond examples of clear-cut misuse of malignant terminology (eg, low grade ductal carcinoma in situ). Developing an evidence-based approach that links tissue-derived cancer risk to ever evolving therapeutic options could require use of complex and expensive methods not previously applied to the establishment of the risk associated with focal or low-grade morphological aberrations. Esserman and colleagues are optimistic that some challenges to assigning risk will be overcome with scientific advances, but these advances might be difficult to achieve. Also, reformers should remain aware of the danger of increasing underdiagnosis when decreasing overdiagnosis. If terminology changes such as e306
Correspondence
indolent lesions of epithelial origin increase the number of patients who perceive themselves to be victims of underdiagnosis, this perception will occur in the context of a harsh legal system that thrives on lay juries listening to paid experts who excel at retrospectively identifying missed cancer diagnoses. By contrast, the many current victims of overdiagnosis are not regarded as potential plaintiffs, but instead as cancer survivors who exist anonymously in the epidemiology data of Esserman and colleagues. I declare no competing interests.
Elliott Foucar [email protected] University of New Mexico School of Medicine, Albuquerque, NM 87131, USA 1
2
Page DL, Simpson JF, Jensen RA. Re: When and to what end do pathologists disagree? J Natl Cancer Inst 1998; 90: 1014–16. Esserman LJ, Thompson IM, Reid B, et al. Addressing overdiagnosis and overtreatment in cancer: a prescription for change. Lancet Oncol 2014; 15: e234–42.
We believe that the labelling of non-melanoma skin cancers as an indolent lesion of epithelial origin and not as cancer, as suggested by Laura Esserman colleagues,1 sends a potentially dangerous message to patients and their families. We do not think the authors have considered the ramifications of their comments. Published data suggest a watchand-wait approach for patients with non-melanoma skin cancer is often harmful to patients.2 Basal cell carcinoma grows rapidly—on average, doubling in size yearly. Squamous cell carcinoma grows even more rapidly, has a 2·1% fatality rate, and metastasises in up to 3·7% of patients within 4 years of initial treatment. Of course, the numbers would be much higher with a watch-and-wait approach.
e307
Although basal cell carcinoma rarely metastasises, if left untreated, it can commonly invade local structures, causing haemorrhage, blindness, infection, and disability. Prediction (even in patients with significant comorbidities) of who will and will not die of their skin cancer is impossible. It is cruel to deny patients treatment when we, as physicians, know it can save their lives. We cannot understand why anyone would oppose such treatments, particularly when dermatologists render treatments inexpensively, under local anaesthesia, and in the office setting. Additionally, there are now 263 000 patients immunocompromised after solid organ transplants who are alive in the USA. These patients typically develop several aggressive skin cancers. It is irrational to spend billions of dollars on these transplants only to let these patients—if left untreated— die of skin cancer. Having markers predictive of clinical outcome might be useful, but they do not exist at present. The costs of treating skin cancer, when detected early, are low. The costs of finding such a predictive marker profile would almost certainly be at least as much as the currently proven and timehonoured treatments, thus resulting in little cost savings. We are also alarmed with the suggestion that dermatologists should do fewer skin cancer screenings. Lives are saved by screening.3 Melanoma has been increasing at a rate of 4% per year and is detected frequently during screening. Non-melanoma skin cancers are increasing in the USA at epidemic proportions.4 Recent estimates also suggest that the number of fatalities per year from cutaneous squamous cell carcinoma in the USA is approaching that of
melanoma, and screening also has a positive effect on the early detection of these carcinomas.5 We dermatologists take very seriously our obligation to provide the highest standard of care by using appropriate, cost-effective treatment. The decision of how to approach and treat a skin cancer should rest with the patient in consultation with their dermatologist. Renaming a destructive and sometimes fatal disease—to make it sound harmless—is a disservice to our patients. Rather than suggesting a semantic change that is potentially harmful, it would be more constructive to start planning how to best manage the epidemic at hand. We declare no competing interests.
*Brett M Coldiron, J Ramsey Mellette Jr, George J Hruza, Thomas N Helm, Carlos A Garcia [email protected] American Academy of Dermatology, 930 East Woodfield Road, Schaumburg, IL, 60173, USA (BMC); American College of Mohs Surgery, Milwaukee, WI, USA (JRM); American Society for Dermatologic Surgery, Rolling Meadows, IL, USA (GJH); American Society of Dermatopathology, Deerfield, IL, USA (TNH); and American Society for Mohs Surgery, Huntington Beach, CA, USA (CAG) 1
2
3
4
5
Esserman LJ, Thompson IM, Reid B, et al. Addressing overdiagnosis and overtreatment in cancer: a prescription for change. Lancet Oncol 2014; 15: e234–42. Kricker A, Armstrong B, Hansen V, et al. Basal cell carcinoma and squamous cell carcinoma growth rates and determinants of size in community patients. J Am Acad Dermatol 2014; 70: 456–64. Katalinic A, Waldmann A, Weinstock MA, et al. Does skin cancer screening save lives?: an observational study comparing trends in melanoma mortality in regions with and without screening. Cancer 2012; 118: 5395–402. Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States 2006. Arch Dermatol 2010; 146: 283–87. Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol 2013; 68: 957–66.
www.thelancet.com/oncology Vol 15 July 2014
