Correspondence
Harm reduction and e-cigarettes: not evidence-based We read with interest your Editorial about the need to regulate e-cigarettes,1 and the response by Riccardo Polosa and Pasquale Caponnetto,2 calling for regulations to be evidencebased. US figures from the Centers for Disease Control and Prevention’s National Youth Tobacco Survey3 are mentioned in both pieces. In 2012, 20·3% of middle-school students (aged 11–14 years) and 7·2% of high-school students (aged 14–18 years) who had ever tried e-cigarettes reported that they had never smoked conventional cigarettes.3 So a notable proportion of individuals might be at risk of nicotine addiction from e-cigarettes alone, even at this early stage of their take-up. As more young people are drawn to e-cigarettes’ product design, promotional activities, associated safety claims, and cheap price, the number will only increase. Many flavours of e-cigarettes are available, and they are marketed with several colours, by celebrities, on the internet, and through social media, which leaves little doubt about which age group is being targeted.4,5 The numbers of users will also grow as e-cigarettes’ popularity increases in young people as a result of peer influence; it might take only a few exposures to nicotine for an adolescent to become hooked for life.6,7 Polosa and Caponnetto2 state that e-cigarettes should be endorsed because they will reduce the numbers of smokers and therefore the health burden of smoking, and that it is “irresponsible” to discourage their use to consumers and young people without any evidence. However, no evidence is available to support their claim that e-cigarettes will help smokers to quit or reduce their harm without unintentional societal effects through large increases in nicotine addiction. Polosa and Caponneto are mindful of the risks of individuals developing a www.thelancet.com/oncology Vol 15 March 2014
nicotine addiction through e-cigarette use, but, at the same time, realise that e-cigarettes need to compete with traditional cigarettes, so those who can benefit will use them.2 To try to reconcile these conflicting needs, they call for strict regulations of e-cigarettes for young people (eg, with restriction of sales and marketing), but relaxed ones for adults (eg, no regulation as pharmaceutical products, so that e-cigarettes can be attractive and be priced competitively).2 This policy variation would implicitly suggest that we live in a society of silos, with little contamination between different groups of the population, even for broad-based policy and behavioural issues. Polosa and Caponneto also seem to imply that, in the face of a seemingly safe product that is reminiscent of a popular one, young people will apply the necessary judgment not to try it and get addicted to nicotine as a result. Their final implicit assumption is that somehow a for-profit industry will follow a public health agenda— voluntarily or through regulations— and target only adult smokers who find it hard to quit, even if this approach runs against its business model. Supporters of e-cigarettes need to be reminded that nicotine causes a real addiction with lifelong psychosocial, economic, and health effects.8 We declare that we have no conflicts of interest.
*Ziyad Ben Taleb, Wasim Maziak zbent002@fiu.edu Department of Epidemiology, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL 33199, USA (ZBT, WM); and Syrian Center for Tobacco Studies, Aleppo, Syria (WM) 1 2
3
4
The Lancet Oncology. Time for e-cigarette regulation. Lancet Oncol 2013; 14: 1027. Polosa R, Caponnetto P. Time for evidence-based e-cigarette regulation. Lancet Oncol 2013; 14: e582–83. Centers for Disease Control and Prevention. Notes from the field: electronic cigarette use among middle and high school students— United States, 2011–12. MMWR Morb Mortal Wkly Rep 2013; 62: 729–30. McKee M. E-cigarettes and the marketing push that surprised everyone. BMJ 2013; 347: f5780.
5
6 7
8
Grana RA, Glantz SA, Ling PM. Electronic nicotine delivery systems in the hands of Hollywood. Tob Control 2011; 20: 425–26. Kobus K. Peers and adolescent smoking. Addiction 2003; 98 (suppl 1): 37–55. DiFranza JR, Savageau JA, Fletcher K, et al. Symptoms of tobacco dependence after brief intermittent use: the Development and Assessment of Nicotine Dependence in Youth-2 study. Arch Pediatr Adolesc Med 2007; 161: 704–10. US Department of Health and Human Services. The health consequences of smoking: nicotine addiction. A report of the Surgeon General. 1988. http://profiles.nlm.nih.gov/NN/B/B/ Z/D/ (accessed Jan 20, 2014).
Basal-cell carcinoma: no response versus relapse We read with interest the report of the large multicentre, non-inferiority, randomised controlled trial of surgical excision versus imiquimod for basalcell carcinoma.1 Fiona Bath-Hextall and colleagues conclude that imiquimod (5% cream once daily for 6 weeks for superficial tumours or for 12 weeks for nodular tumours) is inferior to surgery according to the number of participants with evidence of clinical success at 3 years. However, this finding probably resulted exclusively from a substantial difference in the proportion of patients who failed treatment during the first year (29 [14%] of 212 patients assigned to imiquimod vs two [1%] of 188 assigned to surgery).1 In the subsequent 2 years of follow-up when examining the data presented in table 3, almost no difference in frequency of recurrence was reported between the two therapeutic modalities—ie, once cleared with imiquimod, patients were not at a higher risk of recurrence than were those whose tumours had been surgically removed. Should this trend be confirmed in the 5-year assessment, it would certainly favour non-surgical approaches, because it supports their emerging role as therapeutic alternatives to surgery for primary basal-cell carcinoma. In the treatment of basal-cell carcinoma, discrimination between e104
Correspondence
failure to induce initial tumour clearance and relapse after clinical clearance is crucial if the role of pathophysiologically designed nonsurgical approaches is to be compared with surgery. In the 18-month follow-up assessment of our trial of the treatment of histologically verified non-superficial basal-cell carcinoma with immunocryosurgery (ie, 5-week cycles of daily imiquimod with a cryosurgery session at day 14; NCT01212562),2 three of the six patients with treatment failure after one cycle were deemed to be initial treatment failures (ie, the treatment did not induce tumour clearance), and the other three were recurrences after complete clinical response (six [5%] of 119 had overall treatment failure). Because Bath-Hextall and colleagues defined treatment success collectively as “no initial treatment failure or signs of subsequent local recurrence”,1 we suppose that initial treatment failure affecting treatment outcome solely during the first year of follow-up could have overwhelmingly affected the patients who received imiquimod in their trial. Compared with surgery, nonsurgical modalities are more sensitive to tumour type, and need detailed tumour diagnosis before treatment selection to ensure effectiveness. However, tumour clearance should be the primary treatment objective of selective non-surgical modalities for basal-cell carcinoma, because they have to consistently induce complete tumour responses to be competitive with surgery. Until then, the design of cornerstone studies, like that of BathHextall and colleagues,1 will need to be adapted to the individual biology of the target tumours. Knowledge of the exact nature of treatment failures will mean that the use of these non-surgical modalities either alone or in combinations can be optimised.3,4 Additionally, management measures for treatment failures after non-surgical interventions need to be investigated, particularly e105
for non-responders, much as is done for incompletely excised tumours.5 Along these lines, Bath-Hextall and colleagues would appreciably contribute to the design of future studies if they amended their report1 to give the frequency of initial failure to induce tumour clearance. We declare that we have no conflicts of interest.
*Ioannis D Bassukas, Georgios Gaitanis [email protected] Division of Skin and Venereal Diseases, Department of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece 1
2
3
4
5
Bath-Hextall F, Ozolins M, Armstrong SJ, et al, on behalf of the Surgery versus Imiquimod for Nodular and Superficial basal cell carcinoma (SINS) study group. Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial. Lancet Oncol 2014; 15: 96–105. Gaitanis G, Bassukas ID. Immunocryosurgery for non-superficial basal cell carcinoma: a prospective, open-label phase III study for tumours ≤2 cm in diameter. Acta Derm Venereol 2014; 94: 38–44. van der Geer S, Martens J, van Roij J, et al. Imiquimod 5% cream as pretreatment of Mohs micrographic surgery for nodular basal cell carcinoma in the face: a prospective randomized controlled study. Br J Dermatol 2012; 167: 110–15. Gaitanis G, Bassukas ID. Intralesional bevacizumab as in-add adjuvant to immunocryosurgery for locally advanced basal cell carcinoma. J Eur Acad Dermatol Venereol 2013; published online Nov 29. DOI:10.1111/jdv.12327. Telfer NR, Colver GB, Morton CA. Guidelines for the management of basal cell carcinoma. Br J Dermatol 2008; 159: 35–48.
Author’s reply We thank Ioannis Bassukas and Georgios Gaitanis for highlighting that frequency of recurrence did not differ substantially between patients in our trial1 who received topical 5% imiquimod cream and those who underwent excisional surgery once initial treatment failures had been taken into account. We defined clinically successful treatment as no initial treatment failure or signs of subsequent local recurrence at 3 years. Of the 29 topical imiquimod treatment failures at 1 year, 25 were due to initial treatment failure rather than recurrence, whereas both early surgery failures were initial treatment failures. We remained faithful to
presentation of our primary composite outcome to avoid outcome reporting bias, but we agree that data for initial treatment failures and recurrences should be presented separately, which we will do in our forthcoming 5-year data analysis. In terms of clinical implications, it was reassuring that topical imiquimod was not associated with substantial recurrences after the first year, because our team initially had concerns that imiquimod might result in apparent clinical clearance due to superficial improvement, only to cause problems as deeper portions of so-called submarine lesions resurface after 2–3 years.2 Another issue is how to explain the two pieces of information about early treatment failure and subsequent recurrences to a patient making a treatment decision. Most patients choosing a treatment for a skin cancer will want something that works, not something that works well as long as it does not fail initially. Formal research, such as discrete choice experiments, could be best placed to elicit patient preferences in such complex decisions.3 I declare that I have no conflicts of interest.
Hywel C Williams, on behalf of the Surgery versus Imiquimod for Nodular and Superficial basal cell carcinoma (SINS) writing team [email protected] Centre for Evidence Based Dermatology, University of Nottingham, Nottingham NG7 2NR, UK 1
2
3
Bath-Hextall F, Ozolins M, Armstrong SJ, et al, on behalf of the Surgery versus Imiquimod for Nodular and Superficial basal cell carcinoma (SINS) study group. Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial. Lancet Oncol 2014; 15: 96–105. Roozeboom MH, Aardoom MA, Nelemans PJ, et al. Fractionated 5-aminolevulinic acid photodynamic therapy after partial debulking versus surgical excision for nodular basal cell carcinoma: a randomized controlled trial with at least 5-year follow-up. J Am Acad Dermatol 2013; 69: 280–87. Tinelli M, Ozolins M, Bath-Hextall F, Williams HC. What determines patient preferences for treating low risk basal cell carcinoma when comparing surgery vs imiquimod? A discrete choice experiment survey from the SINS trial. BMC Dermatol 2012; 12: 19.
www.thelancet.com/oncology Vol 15 March 2014
Harm reduction and e-cigarettes: not evidence-based We read with interest your Editorial about the need to regulate e-cigarettes,1 and the response by Riccardo Polosa and Pasquale Caponnetto,2 calling for regulations to be evidencebased. US figures from the Centers for Disease Control and Prevention’s National Youth Tobacco Survey3 are mentioned in both pieces. In 2012, 20·3% of middle-school students (aged 11–14 years) and 7·2% of high-school students (aged 14–18 years) who had ever tried e-cigarettes reported that they had never smoked conventional cigarettes.3 So a notable proportion of individuals might be at risk of nicotine addiction from e-cigarettes alone, even at this early stage of their take-up. As more young people are drawn to e-cigarettes’ product design, promotional activities, associated safety claims, and cheap price, the number will only increase. Many flavours of e-cigarettes are available, and they are marketed with several colours, by celebrities, on the internet, and through social media, which leaves little doubt about which age group is being targeted.4,5 The numbers of users will also grow as e-cigarettes’ popularity increases in young people as a result of peer influence; it might take only a few exposures to nicotine for an adolescent to become hooked for life.6,7 Polosa and Caponnetto2 state that e-cigarettes should be endorsed because they will reduce the numbers of smokers and therefore the health burden of smoking, and that it is “irresponsible” to discourage their use to consumers and young people without any evidence. However, no evidence is available to support their claim that e-cigarettes will help smokers to quit or reduce their harm without unintentional societal effects through large increases in nicotine addiction. Polosa and Caponneto are mindful of the risks of individuals developing a www.thelancet.com/oncology Vol 15 March 2014
nicotine addiction through e-cigarette use, but, at the same time, realise that e-cigarettes need to compete with traditional cigarettes, so those who can benefit will use them.2 To try to reconcile these conflicting needs, they call for strict regulations of e-cigarettes for young people (eg, with restriction of sales and marketing), but relaxed ones for adults (eg, no regulation as pharmaceutical products, so that e-cigarettes can be attractive and be priced competitively).2 This policy variation would implicitly suggest that we live in a society of silos, with little contamination between different groups of the population, even for broad-based policy and behavioural issues. Polosa and Caponneto also seem to imply that, in the face of a seemingly safe product that is reminiscent of a popular one, young people will apply the necessary judgment not to try it and get addicted to nicotine as a result. Their final implicit assumption is that somehow a for-profit industry will follow a public health agenda— voluntarily or through regulations— and target only adult smokers who find it hard to quit, even if this approach runs against its business model. Supporters of e-cigarettes need to be reminded that nicotine causes a real addiction with lifelong psychosocial, economic, and health effects.8 We declare that we have no conflicts of interest.
*Ziyad Ben Taleb, Wasim Maziak zbent002@fiu.edu Department of Epidemiology, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL 33199, USA (ZBT, WM); and Syrian Center for Tobacco Studies, Aleppo, Syria (WM) 1 2
3
4
The Lancet Oncology. Time for e-cigarette regulation. Lancet Oncol 2013; 14: 1027. Polosa R, Caponnetto P. Time for evidence-based e-cigarette regulation. Lancet Oncol 2013; 14: e582–83. Centers for Disease Control and Prevention. Notes from the field: electronic cigarette use among middle and high school students— United States, 2011–12. MMWR Morb Mortal Wkly Rep 2013; 62: 729–30. McKee M. E-cigarettes and the marketing push that surprised everyone. BMJ 2013; 347: f5780.
5
6 7
8
Grana RA, Glantz SA, Ling PM. Electronic nicotine delivery systems in the hands of Hollywood. Tob Control 2011; 20: 425–26. Kobus K. Peers and adolescent smoking. Addiction 2003; 98 (suppl 1): 37–55. DiFranza JR, Savageau JA, Fletcher K, et al. Symptoms of tobacco dependence after brief intermittent use: the Development and Assessment of Nicotine Dependence in Youth-2 study. Arch Pediatr Adolesc Med 2007; 161: 704–10. US Department of Health and Human Services. The health consequences of smoking: nicotine addiction. A report of the Surgeon General. 1988. http://profiles.nlm.nih.gov/NN/B/B/ Z/D/ (accessed Jan 20, 2014).
Basal-cell carcinoma: no response versus relapse We read with interest the report of the large multicentre, non-inferiority, randomised controlled trial of surgical excision versus imiquimod for basalcell carcinoma.1 Fiona Bath-Hextall and colleagues conclude that imiquimod (5% cream once daily for 6 weeks for superficial tumours or for 12 weeks for nodular tumours) is inferior to surgery according to the number of participants with evidence of clinical success at 3 years. However, this finding probably resulted exclusively from a substantial difference in the proportion of patients who failed treatment during the first year (29 [14%] of 212 patients assigned to imiquimod vs two [1%] of 188 assigned to surgery).1 In the subsequent 2 years of follow-up when examining the data presented in table 3, almost no difference in frequency of recurrence was reported between the two therapeutic modalities—ie, once cleared with imiquimod, patients were not at a higher risk of recurrence than were those whose tumours had been surgically removed. Should this trend be confirmed in the 5-year assessment, it would certainly favour non-surgical approaches, because it supports their emerging role as therapeutic alternatives to surgery for primary basal-cell carcinoma. In the treatment of basal-cell carcinoma, discrimination between e104
Correspondence
failure to induce initial tumour clearance and relapse after clinical clearance is crucial if the role of pathophysiologically designed nonsurgical approaches is to be compared with surgery. In the 18-month follow-up assessment of our trial of the treatment of histologically verified non-superficial basal-cell carcinoma with immunocryosurgery (ie, 5-week cycles of daily imiquimod with a cryosurgery session at day 14; NCT01212562),2 three of the six patients with treatment failure after one cycle were deemed to be initial treatment failures (ie, the treatment did not induce tumour clearance), and the other three were recurrences after complete clinical response (six [5%] of 119 had overall treatment failure). Because Bath-Hextall and colleagues defined treatment success collectively as “no initial treatment failure or signs of subsequent local recurrence”,1 we suppose that initial treatment failure affecting treatment outcome solely during the first year of follow-up could have overwhelmingly affected the patients who received imiquimod in their trial. Compared with surgery, nonsurgical modalities are more sensitive to tumour type, and need detailed tumour diagnosis before treatment selection to ensure effectiveness. However, tumour clearance should be the primary treatment objective of selective non-surgical modalities for basal-cell carcinoma, because they have to consistently induce complete tumour responses to be competitive with surgery. Until then, the design of cornerstone studies, like that of BathHextall and colleagues,1 will need to be adapted to the individual biology of the target tumours. Knowledge of the exact nature of treatment failures will mean that the use of these non-surgical modalities either alone or in combinations can be optimised.3,4 Additionally, management measures for treatment failures after non-surgical interventions need to be investigated, particularly e105
for non-responders, much as is done for incompletely excised tumours.5 Along these lines, Bath-Hextall and colleagues would appreciably contribute to the design of future studies if they amended their report1 to give the frequency of initial failure to induce tumour clearance. We declare that we have no conflicts of interest.
*Ioannis D Bassukas, Georgios Gaitanis [email protected] Division of Skin and Venereal Diseases, Department of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece 1
2
3
4
5
Bath-Hextall F, Ozolins M, Armstrong SJ, et al, on behalf of the Surgery versus Imiquimod for Nodular and Superficial basal cell carcinoma (SINS) study group. Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial. Lancet Oncol 2014; 15: 96–105. Gaitanis G, Bassukas ID. Immunocryosurgery for non-superficial basal cell carcinoma: a prospective, open-label phase III study for tumours ≤2 cm in diameter. Acta Derm Venereol 2014; 94: 38–44. van der Geer S, Martens J, van Roij J, et al. Imiquimod 5% cream as pretreatment of Mohs micrographic surgery for nodular basal cell carcinoma in the face: a prospective randomized controlled study. Br J Dermatol 2012; 167: 110–15. Gaitanis G, Bassukas ID. Intralesional bevacizumab as in-add adjuvant to immunocryosurgery for locally advanced basal cell carcinoma. J Eur Acad Dermatol Venereol 2013; published online Nov 29. DOI:10.1111/jdv.12327. Telfer NR, Colver GB, Morton CA. Guidelines for the management of basal cell carcinoma. Br J Dermatol 2008; 159: 35–48.
Author’s reply We thank Ioannis Bassukas and Georgios Gaitanis for highlighting that frequency of recurrence did not differ substantially between patients in our trial1 who received topical 5% imiquimod cream and those who underwent excisional surgery once initial treatment failures had been taken into account. We defined clinically successful treatment as no initial treatment failure or signs of subsequent local recurrence at 3 years. Of the 29 topical imiquimod treatment failures at 1 year, 25 were due to initial treatment failure rather than recurrence, whereas both early surgery failures were initial treatment failures. We remained faithful to
presentation of our primary composite outcome to avoid outcome reporting bias, but we agree that data for initial treatment failures and recurrences should be presented separately, which we will do in our forthcoming 5-year data analysis. In terms of clinical implications, it was reassuring that topical imiquimod was not associated with substantial recurrences after the first year, because our team initially had concerns that imiquimod might result in apparent clinical clearance due to superficial improvement, only to cause problems as deeper portions of so-called submarine lesions resurface after 2–3 years.2 Another issue is how to explain the two pieces of information about early treatment failure and subsequent recurrences to a patient making a treatment decision. Most patients choosing a treatment for a skin cancer will want something that works, not something that works well as long as it does not fail initially. Formal research, such as discrete choice experiments, could be best placed to elicit patient preferences in such complex decisions.3 I declare that I have no conflicts of interest.
Hywel C Williams, on behalf of the Surgery versus Imiquimod for Nodular and Superficial basal cell carcinoma (SINS) writing team [email protected] Centre for Evidence Based Dermatology, University of Nottingham, Nottingham NG7 2NR, UK 1
2
3
Bath-Hextall F, Ozolins M, Armstrong SJ, et al, on behalf of the Surgery versus Imiquimod for Nodular and Superficial basal cell carcinoma (SINS) study group. Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial. Lancet Oncol 2014; 15: 96–105. Roozeboom MH, Aardoom MA, Nelemans PJ, et al. Fractionated 5-aminolevulinic acid photodynamic therapy after partial debulking versus surgical excision for nodular basal cell carcinoma: a randomized controlled trial with at least 5-year follow-up. J Am Acad Dermatol 2013; 69: 280–87. Tinelli M, Ozolins M, Bath-Hextall F, Williams HC. What determines patient preferences for treating low risk basal cell carcinoma when comparing surgery vs imiquimod? A discrete choice experiment survey from the SINS trial. BMC Dermatol 2012; 12: 19.
www.thelancet.com/oncology Vol 15 March 2014
