- Email: [email protected]
Properly Selected Skin Cancer Treatments Are Very Effective
HW Rogers et al. Properly Selected Skin Cancer Treatments
banding pattern seen by immunoblot. The lower amounts of Ki-67 staining when p16INK4A expression is high suggests that downregulation of proliferation is occurring. This decrease is likely a consequence of its increased inhibitory effects on CDK4/6 and the retinoblastoma pathway, resulting in cell cycle arrest (Ortega et al., 2002) and increased senescence (Alcorta et al., 1996). Unexpectedly, we observed that the level of endogenous p16INK4A expression appeared higher in the p16INK4A overexpression model. We speculate that the presence of recombinant p16INK4A protein might indirectly upregulate endogenous p16INK4A protein through various detrimental factors excreted from an increased number of senescent cells. On the basis of these observations, we decided to explore the biological consequences of silencing p16INK4A in the aged donor LSE model. Here, we saw a dramatic improvement in the morphology of the aged donor LSE, which now resembled that of a much younger donor (Figure 2c and d). A striking difference between these LSEs and the atrophic, non–silenced controls was the substantial increase of Ki-67positive cells in the p16INK4A-silenced cultures with a consequent normalization of terminal differentiation, as detected by the restoration of filaggrin, loricrin, and caspase expression. This was repeated in at least three other aged donor models with similar results. In accordance with the conditional knockout model of Baker et al. (2011), in which senescent p16INK4A-expressing
cells were selectively eliminated, and as evidenced by this model’s morphology and biomarkers, our results indicate that the atrophic phenotype can be significantly improved in vitro by selectively silencing the expression of p16INK4A. Collectively, these results further substantiate p16INK4A as a major regulator of aging in the epidermis, thus lending strong support for furthering our knowledge on the function and appearance of aged skin. For human cells obtained from donors, the Declaration of Helsinki protocols were followed; donors gave written, informed consent; and the Stony Brook University IRB approved of the study. CONFLICT OF INTEREST The authors state no conflict of interest.
ACKNOWLEDGMENTS This work was fully supported by Unilever R&D.
Jean Adamus1, Sirpa Aho1, Helen Meldrum1, Carol Bosko1 and Jian-Ming Lee1 1
Skin Biosciences, Unilever R&D, Trumbull, Connecticut, USA E-mail: [email protected] or [email protected]
SUPPLEMENTARY MATERIAL Supplementary material is linked to the online version of the paper at http://www.nature.com/jid
REFERENCES Aho S, Harding CR, Lee J et al. (2012) Regulatory role for the profilaggrin N-terminal domain in epidermal homeostasis. J Invest Dermatol 132:2376–85 Alcorta DA, Xiong Y, Phelps D et al. (1996) Involvement of the cyclin-dependent kinase
inhibitor p16(INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci 93:13742–7 Baker DJ, Wijshake T, Tchkonia T et al. (2011) Clearance of p16 Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–6 Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: When bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–40 Di Nunzio F, Maruggi G, Ferrari S et al. (2008) Correction of laminin-5 deficiency in human epidermal stem cells by transcriptionally targeted lentiviral vectors. Mol Ther 16:1977–85 Giangreco A, Goldie SJ, Failla V et al. (2010) Human skin aging is associated with reduced expression of the stem cell markers b1 integrin and MCSP. J Invest Dermatol 130:604–8 Gilhar A, Ullmann Y, Karry R et al. (2004) Ageing of human epidermis: the role of apoptosis, fas and telomerase. Br J Dermatol 150:56–63 Krishnamurthy J, Torrice C, Ramsey MR et al. (2004) Ink4a/Arf expression is a biomarker of aging. J Clin Invest 114:1299–307 Ortega S, Malumbres M, Barbacid M (2002) Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim et Biophys Acta 1602: 73–87 Ressler S, Bartkova J, Niederegger H et al. (2006) p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging Cell 5: 379–89 Sharpless NE (2004) Ink4a/Arf links senescence and aging. Exp Gerontol 39(11–12 Spec. Iss.): 1751–59 Waaijer ME, Parish WE, Strongitharm BH et al. (2012) The number of p16INK4A positive cells in human skin reflects biological age. Aging Cell 11:722–5
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons. org/licenses/by-nc-nd/3.0/
Properly Selected Skin Cancer Treatments Are Very Effective Journal of Investigative Dermatology (2014) 134, 1133–1135; doi:10.1038/jid.2013.449; published online 21 November 2013
TO THE EDITOR We read with interest Chren et al.’s study on the recurrence rates of nonmelanoma skin cancer (NMSC)
treatments and the accompanying commentary by Dr Stern entitled Cost Effectiveness of Mohs Micrographic Surgery (Chren et al., 2013, Stern, 2013). Dr
Abbreviation: NMSC, nonmelanoma skin cancer Accepted article preview online 12 November 2013; published online 21 November 2013
Chren described the recurrence rates for NMSCs diagnosed and treated at the San Francisco VA and UCSF dermatology clinics. The biopsying dermatologists selected the skin cancer treatment method (destruction, excision, or Mohs surgery.) The authors concluded that these treatments for NMSC were at www.jidonline.org 1133
HW Rogers et al. Properly Selected Skin Cancer Treatments
least 95% effective. Moreover, the rates of recurrence for the three different treatments were similar, even after adjustment for tumor and patient risk factors. There are important limitations that affect Dr Chren’s conclusions. Notably, this study pools two distinctly different populations (University setting and the VA). Review of Table 1 illustrates a number of key measured differences between the populations (age, gender, level of provider training, etc.). Some of these differences undermine the generalizability of the findings beyond the University and VA settings. Also, the addition of the VA to the University sample, although convenient, distorts the sample and therefore the conclusions drawn from the results. For example, the University site contributes more than two times as many Mohs cases to the study population than the VA, and its study population may be more representative of typical US practice population. Within the University site, recurrence rates for tumors treated by Mohs were lower (1.9% Mohs vs. 2.6% excision vs. 6.2% destruction). Per Table 2, the P-value for this difference was between 0.05 and 0.1. When the University and VA sites were pooled for the entire sample, this potential signal of Mohs’ benefit was squelched, and contributed to a conclusion that all treatments were equivalent in terms of the recurrence rate outcome measure. The next major limitation of this study is that in addition to differences between the cohorts, the treatment groups differ substantially. This is an observational study, in which the dermatologists decided on the skin cancer treatment, not based on any specific criteria. Not surprisingly, the tumors with aggressive clinical and histologic features were mainly referred for Mohs surgery and away from excisions and destructions (used more for low-risk tumors.) For example, the Mohs treatment group had 68% tumors present in the H zone of the face, while only 26% of the excision group included tumors in this location. Despite this large difference in an indicator of tumor recurrence risk, Mohs reached similar recurrence outcomes to excision in the pooled group and better outcome (1.2% vs. 6.3%,
P ¼ 0.05) in the University group. For this subgroup, we can conclude that Mohs was more effective than excision in recurrence risk reduction. The authors do attempt to overcome the differences in treatment groups with a statistical technique, propensity matching. However, the referral bias intrinsic to the dermatologists’ decision-making process in determining proper treatment method cannot be measured by the study criteria and makes this study’s comparison of treatment types an ‘‘apples to oranges’’ comparison that cannot be reconciled by propensity-adjusted analysis, and the authors do concede that ‘‘unmeasured characteristics may have affected the risk of recurrence.’’ In the accompanying editorial, Dr Stern makes the case that Mohs surgery is not cost-effective for most primary NMSCs because surgical excision is equally effective to Mohs surgery (from a recurrence standpoint) and because Mohs surgery is more expensive than excision. Dr Stern bases his effectiveness argument on Chren et al.’s study (that we have commented on above) and on the study of Mosterd et al. (2008) from the Netherlands. Although Mosterd et al. describe a randomized study comparing excision and Mohs surgery for basal cell carcinoma of the face, there were numerous problems with the study randomization and technique that may have confounded the results (Otley, 2006). Moreover, none of the surgeons that participated in the Dutch study were Mohs fellowship trained. Of note, Dr Stern in his editorial states that nonfellowship-trained Mohs surgeons provide ‘‘what they call Mohs surgery,’’ suggesting a different, possibly inferior or less consistent service than that provided by Mohs college members. Dr Stern also ignores some other benefits of Mohs surgery over excision that have not been added to effectiveness measures including same day closure of even complex defects because of confirmed clear histologic margins, decreased patient anxiety while awaiting permanent sections, and avoidance of multiple secondary excisions for positive margins. In terms of increased costs of Mohs surgery over excision, Dr Stern again bases his arguments on the Dutch study (Essers et al., 2006) and the same study
1134 Journal of Investigative Dermatology (2014), Volume 134
cohort described in Chren et al. above (Wilson et al., 2012). Despite the report that Mohs surgery resulted in increased usage of resources over excision in micro-costing analysis in the Dutch health system, this study employed excision with delayed closure and frozen sections in many of its patients. In the US system of relative value units and multiple surgery reductions, these methods would have resulted in total reimbursements higher than for Mohs surgery (Rogers and Coldiron, 2009). Moreover, as previously described, the reimbursements for procedures in the San Francisco series do not compare the treatment of similar tumors (Rogers et al., 2012). Dr Stern’s comments do not account for the effect of referral bias, which directs more complex tumors to Mohs surgery. The limitations of direct comparison of excision and destruction to Mohs seem to be understated. As Dr Stern states, a US-based, multicenter, randomized study of Mohs surgery versus excision would be invaluable in directly comparing the costs and effectiveness of these two treatments. However, we believe it would be unethical to deny Mohs surgery, which has been proven effective in treatment of high-risk tumors, for many who would benefit from the procedure. Moreover, power analysis simulation (to achieve 80% power to detect a difference between Mohs and excision yielding a hazard ratio of 1.5 from the recurrence rates described by Dr Chren) indicate a minimum required sample size of 5,456 tumors (Chren’s sample was 1,488 tumors). The sheer size, cost, and ethical constraints of such a project without industry sponsorship make its performance unlikely. In conclusion, we agree wholeheartedly with Chren et al. that properly selected skin cancer treatments are very effective. However, the study design and the profound differences in the treatment groups do not allow direct comparison of recurrence rates between these treatments. We disagree with Dr Stern’s conclusion that Mohs surgery is not cost-effective for most primary skin cancers treated with this method in the USA. The bulk of available data indicate that Mohs surgery is more effective than traditional surgical excision, with
M-M Chren Response to Rogers et al.
numerous other benefits, for cases typically referred for Mohs surgery. Moreover, Mohs surgery has been shown to be either cost comparable or slightly more expensive than excision with permanent sections and immediate reconstruction but less costly when frozen sections, delayed reconstruction, or surgical facilities are employed. CONFLICT OF INTEREST Dr Fosko discloses that he is a consultant, investigator, and speaker for Genentech. The remaining authors state no conflict of interest. 1
2
Howard W. Rogers , Eric Armbrecht , Brett M. Coldiron3, John Albertini4, Michel McDonald5, Scott M. Dinehart6, Ali Hendi7, George Hruza8, Scott W. Fosko8 and Brent R. Moody9 1
Advanced Dermatology, Norwich, Connecticut, USA; 2St Louis University Center for Outcomes Research, St Louis, Missouri,
USA; 3Department of Dermatology, University of Cincinnati Medical School, Cincinnati, Ohio, USA; 4Department of Dermotology, Wake Forest Baptist Health, Winston-Salem, North Carolina, USA; 5Department of Dermotology, Vanderbilt University, Nashville, Tennessee, USA; 6Department of Dermatology, University of Arkansas, Little Rock, Arkansas, USA; 7 Private Practice, Chevy Chase, Maryland, USA; 8 Department of Dermatology, St Louis University, St Louis, Missouri, USA and 9 Private Practice, Nashville, Tennessee, USA E-mail: [email protected] REFERENCES Chren MM, Linos E, Torres JS et al. (2013) Tumor recurrence 5 years after treatment of cutaneous basal cell carcinoma and squamous cell carcinoma. J Invest Dermatol 133:1188–96 Essers BA, Dirksen CD, Nieman FH et al. (2006) Cost-effectiveness of Mohs micrographic surgery vs surgical excision for basal cell carcinoma of the face. Arch Dermatol 142:187–94 Mosterd K, Krekels GA, Nieman FH et al. (2008) Surgical excision versus Mohs’ micrographic
surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up. Lancet Oncol 9:1149–56 Otley CC (2006) Cost-effectiveness of Mohs micrographic surgery vs surgical excision for basal cell carcinoma of the face. Arch Dermatol 142:1235 Rogers HW, Coldiron BM (2009) A relative value unit-based cost comparison of treatment modalities for nonmelanoma skin cancer: effect of the loss of the Mohs multiple surgery reduction exemption. J Am Acad Dermatol 61:96–103 Rogers HW, Coldiron BM, Dinehart SM et al. (2012) Skin cancer treatment fee comparisons inaccurate. Dermatol Surg 38:2038–9. author reply 2039–41 Stern RS (2013) Cost effectiveness of Mohs micrographic surgery. J Invest Dermatol 133: 1129–31 Wilson LS, Pregenzer M, Basu R et al. (2012) Fee comparisons of treatments for nonmelanoma skin cancer in a private practice academic setting. Dermatol Surg 38:570–84
Response to Rogers et al. Journal of Investigative Dermatology (2014) 134, 1135–1136; doi:10.1038/jid.2013.450; published online 21 November 2013
TO THE EDITOR There is no basis for the assertion by Dr Rogers and his colleagues (2014) that our conclusions were erroneous or affected by the study design. We meticulously studied every patient with basal cell carcinoma or cutaneous squamous cell carcinoma diagnosed over a 2-year period at two busy hospitals at our academic medical center. We had excellent follow-up on virtually all patients, and we analyzed patients at the two hospitals separately before pooling them. We could find no evidence that long-term recurrence was lower after Mohs surgery than after excision, even with multiple analyses that adjusted for differences in patient, tumor, and care characteristics. We conclude that any difference in recurrence rates could be determined only in a randomized controlled trial in which similar patients with similar tumors are randomized to receive one treatment or another.
It is clear that for most nonmelanoma skin cancers, there is insufficient evidence— from our large prospective cohort study and the European randomized controlled trial in facial basal cell carcinomas (Mosterd et al., 2008)—to guide choices between therapies. What this means for our specialty is that we have no data to justify the dramatic increase in Mohs surgery utilization in the USA over the last decades given that Mohs surgery is not the less expensive treatment (Wilson et al., 2012). Because they are costly, randomized controlled trials often are conducted after observational studies demonstrate clinical equipoise in important, targeted situations. This is precisely the situation in which we find ourselves for many nonmelanoma skin cancers. The results of our studies strongly support a focused randomized controlled trial of surgical treatments for nonmelanoma skin cancer, and I urge Dr Rogers and colleagues, as respected Mohs surgeons and leaders, to join me in supporting this next scientific
Accepted article preview online 12 November 2013; published online 21 November 2013
approach to studying the comparative efficacy of these treatments. In my experience, arguments against such a trial typically fall into three types. First is the conviction that a trial is not indicated and may be unethical because the result would be obvious, since a therapy that eliminates every visible tumor cell and spares normal tissue will of course be curative and therefore superior. Such a belief is wrong in, for example, prostate cancer (Wilt and Ahmed, 2013), and the consistency of our findings and those of the European study for both clinical (Mosterd et al., 2008) and patient-reported (Essers et al., 2006; Chren et al., 2007) outcomes demonstrates that it may be wrong for basal cell carcinoma and cutaneous squamous cell carcinoma. Second is the perspective that since nonmelanoma skin cancer is typically nonfatal, the care of these tumors is too trivial to warrant further study. In fact, of course, these tumors are a burden for the public health; for example, the Global Burden of Disease www.jidonline.org 1135
banding pattern seen by immunoblot. The lower amounts of Ki-67 staining when p16INK4A expression is high suggests that downregulation of proliferation is occurring. This decrease is likely a consequence of its increased inhibitory effects on CDK4/6 and the retinoblastoma pathway, resulting in cell cycle arrest (Ortega et al., 2002) and increased senescence (Alcorta et al., 1996). Unexpectedly, we observed that the level of endogenous p16INK4A expression appeared higher in the p16INK4A overexpression model. We speculate that the presence of recombinant p16INK4A protein might indirectly upregulate endogenous p16INK4A protein through various detrimental factors excreted from an increased number of senescent cells. On the basis of these observations, we decided to explore the biological consequences of silencing p16INK4A in the aged donor LSE model. Here, we saw a dramatic improvement in the morphology of the aged donor LSE, which now resembled that of a much younger donor (Figure 2c and d). A striking difference between these LSEs and the atrophic, non–silenced controls was the substantial increase of Ki-67positive cells in the p16INK4A-silenced cultures with a consequent normalization of terminal differentiation, as detected by the restoration of filaggrin, loricrin, and caspase expression. This was repeated in at least three other aged donor models with similar results. In accordance with the conditional knockout model of Baker et al. (2011), in which senescent p16INK4A-expressing
cells were selectively eliminated, and as evidenced by this model’s morphology and biomarkers, our results indicate that the atrophic phenotype can be significantly improved in vitro by selectively silencing the expression of p16INK4A. Collectively, these results further substantiate p16INK4A as a major regulator of aging in the epidermis, thus lending strong support for furthering our knowledge on the function and appearance of aged skin. For human cells obtained from donors, the Declaration of Helsinki protocols were followed; donors gave written, informed consent; and the Stony Brook University IRB approved of the study. CONFLICT OF INTEREST The authors state no conflict of interest.
ACKNOWLEDGMENTS This work was fully supported by Unilever R&D.
Jean Adamus1, Sirpa Aho1, Helen Meldrum1, Carol Bosko1 and Jian-Ming Lee1 1
Skin Biosciences, Unilever R&D, Trumbull, Connecticut, USA E-mail: [email protected] or [email protected]
SUPPLEMENTARY MATERIAL Supplementary material is linked to the online version of the paper at http://www.nature.com/jid
REFERENCES Aho S, Harding CR, Lee J et al. (2012) Regulatory role for the profilaggrin N-terminal domain in epidermal homeostasis. J Invest Dermatol 132:2376–85 Alcorta DA, Xiong Y, Phelps D et al. (1996) Involvement of the cyclin-dependent kinase
inhibitor p16(INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci 93:13742–7 Baker DJ, Wijshake T, Tchkonia T et al. (2011) Clearance of p16 Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–6 Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: When bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–40 Di Nunzio F, Maruggi G, Ferrari S et al. (2008) Correction of laminin-5 deficiency in human epidermal stem cells by transcriptionally targeted lentiviral vectors. Mol Ther 16:1977–85 Giangreco A, Goldie SJ, Failla V et al. (2010) Human skin aging is associated with reduced expression of the stem cell markers b1 integrin and MCSP. J Invest Dermatol 130:604–8 Gilhar A, Ullmann Y, Karry R et al. (2004) Ageing of human epidermis: the role of apoptosis, fas and telomerase. Br J Dermatol 150:56–63 Krishnamurthy J, Torrice C, Ramsey MR et al. (2004) Ink4a/Arf expression is a biomarker of aging. J Clin Invest 114:1299–307 Ortega S, Malumbres M, Barbacid M (2002) Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim et Biophys Acta 1602: 73–87 Ressler S, Bartkova J, Niederegger H et al. (2006) p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging Cell 5: 379–89 Sharpless NE (2004) Ink4a/Arf links senescence and aging. Exp Gerontol 39(11–12 Spec. Iss.): 1751–59 Waaijer ME, Parish WE, Strongitharm BH et al. (2012) The number of p16INK4A positive cells in human skin reflects biological age. Aging Cell 11:722–5
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons. org/licenses/by-nc-nd/3.0/
Properly Selected Skin Cancer Treatments Are Very Effective Journal of Investigative Dermatology (2014) 134, 1133–1135; doi:10.1038/jid.2013.449; published online 21 November 2013
TO THE EDITOR We read with interest Chren et al.’s study on the recurrence rates of nonmelanoma skin cancer (NMSC)
treatments and the accompanying commentary by Dr Stern entitled Cost Effectiveness of Mohs Micrographic Surgery (Chren et al., 2013, Stern, 2013). Dr
Abbreviation: NMSC, nonmelanoma skin cancer Accepted article preview online 12 November 2013; published online 21 November 2013
Chren described the recurrence rates for NMSCs diagnosed and treated at the San Francisco VA and UCSF dermatology clinics. The biopsying dermatologists selected the skin cancer treatment method (destruction, excision, or Mohs surgery.) The authors concluded that these treatments for NMSC were at www.jidonline.org 1133
HW Rogers et al. Properly Selected Skin Cancer Treatments
least 95% effective. Moreover, the rates of recurrence for the three different treatments were similar, even after adjustment for tumor and patient risk factors. There are important limitations that affect Dr Chren’s conclusions. Notably, this study pools two distinctly different populations (University setting and the VA). Review of Table 1 illustrates a number of key measured differences between the populations (age, gender, level of provider training, etc.). Some of these differences undermine the generalizability of the findings beyond the University and VA settings. Also, the addition of the VA to the University sample, although convenient, distorts the sample and therefore the conclusions drawn from the results. For example, the University site contributes more than two times as many Mohs cases to the study population than the VA, and its study population may be more representative of typical US practice population. Within the University site, recurrence rates for tumors treated by Mohs were lower (1.9% Mohs vs. 2.6% excision vs. 6.2% destruction). Per Table 2, the P-value for this difference was between 0.05 and 0.1. When the University and VA sites were pooled for the entire sample, this potential signal of Mohs’ benefit was squelched, and contributed to a conclusion that all treatments were equivalent in terms of the recurrence rate outcome measure. The next major limitation of this study is that in addition to differences between the cohorts, the treatment groups differ substantially. This is an observational study, in which the dermatologists decided on the skin cancer treatment, not based on any specific criteria. Not surprisingly, the tumors with aggressive clinical and histologic features were mainly referred for Mohs surgery and away from excisions and destructions (used more for low-risk tumors.) For example, the Mohs treatment group had 68% tumors present in the H zone of the face, while only 26% of the excision group included tumors in this location. Despite this large difference in an indicator of tumor recurrence risk, Mohs reached similar recurrence outcomes to excision in the pooled group and better outcome (1.2% vs. 6.3%,
P ¼ 0.05) in the University group. For this subgroup, we can conclude that Mohs was more effective than excision in recurrence risk reduction. The authors do attempt to overcome the differences in treatment groups with a statistical technique, propensity matching. However, the referral bias intrinsic to the dermatologists’ decision-making process in determining proper treatment method cannot be measured by the study criteria and makes this study’s comparison of treatment types an ‘‘apples to oranges’’ comparison that cannot be reconciled by propensity-adjusted analysis, and the authors do concede that ‘‘unmeasured characteristics may have affected the risk of recurrence.’’ In the accompanying editorial, Dr Stern makes the case that Mohs surgery is not cost-effective for most primary NMSCs because surgical excision is equally effective to Mohs surgery (from a recurrence standpoint) and because Mohs surgery is more expensive than excision. Dr Stern bases his effectiveness argument on Chren et al.’s study (that we have commented on above) and on the study of Mosterd et al. (2008) from the Netherlands. Although Mosterd et al. describe a randomized study comparing excision and Mohs surgery for basal cell carcinoma of the face, there were numerous problems with the study randomization and technique that may have confounded the results (Otley, 2006). Moreover, none of the surgeons that participated in the Dutch study were Mohs fellowship trained. Of note, Dr Stern in his editorial states that nonfellowship-trained Mohs surgeons provide ‘‘what they call Mohs surgery,’’ suggesting a different, possibly inferior or less consistent service than that provided by Mohs college members. Dr Stern also ignores some other benefits of Mohs surgery over excision that have not been added to effectiveness measures including same day closure of even complex defects because of confirmed clear histologic margins, decreased patient anxiety while awaiting permanent sections, and avoidance of multiple secondary excisions for positive margins. In terms of increased costs of Mohs surgery over excision, Dr Stern again bases his arguments on the Dutch study (Essers et al., 2006) and the same study
1134 Journal of Investigative Dermatology (2014), Volume 134
cohort described in Chren et al. above (Wilson et al., 2012). Despite the report that Mohs surgery resulted in increased usage of resources over excision in micro-costing analysis in the Dutch health system, this study employed excision with delayed closure and frozen sections in many of its patients. In the US system of relative value units and multiple surgery reductions, these methods would have resulted in total reimbursements higher than for Mohs surgery (Rogers and Coldiron, 2009). Moreover, as previously described, the reimbursements for procedures in the San Francisco series do not compare the treatment of similar tumors (Rogers et al., 2012). Dr Stern’s comments do not account for the effect of referral bias, which directs more complex tumors to Mohs surgery. The limitations of direct comparison of excision and destruction to Mohs seem to be understated. As Dr Stern states, a US-based, multicenter, randomized study of Mohs surgery versus excision would be invaluable in directly comparing the costs and effectiveness of these two treatments. However, we believe it would be unethical to deny Mohs surgery, which has been proven effective in treatment of high-risk tumors, for many who would benefit from the procedure. Moreover, power analysis simulation (to achieve 80% power to detect a difference between Mohs and excision yielding a hazard ratio of 1.5 from the recurrence rates described by Dr Chren) indicate a minimum required sample size of 5,456 tumors (Chren’s sample was 1,488 tumors). The sheer size, cost, and ethical constraints of such a project without industry sponsorship make its performance unlikely. In conclusion, we agree wholeheartedly with Chren et al. that properly selected skin cancer treatments are very effective. However, the study design and the profound differences in the treatment groups do not allow direct comparison of recurrence rates between these treatments. We disagree with Dr Stern’s conclusion that Mohs surgery is not cost-effective for most primary skin cancers treated with this method in the USA. The bulk of available data indicate that Mohs surgery is more effective than traditional surgical excision, with
M-M Chren Response to Rogers et al.
numerous other benefits, for cases typically referred for Mohs surgery. Moreover, Mohs surgery has been shown to be either cost comparable or slightly more expensive than excision with permanent sections and immediate reconstruction but less costly when frozen sections, delayed reconstruction, or surgical facilities are employed. CONFLICT OF INTEREST Dr Fosko discloses that he is a consultant, investigator, and speaker for Genentech. The remaining authors state no conflict of interest. 1
2
Howard W. Rogers , Eric Armbrecht , Brett M. Coldiron3, John Albertini4, Michel McDonald5, Scott M. Dinehart6, Ali Hendi7, George Hruza8, Scott W. Fosko8 and Brent R. Moody9 1
Advanced Dermatology, Norwich, Connecticut, USA; 2St Louis University Center for Outcomes Research, St Louis, Missouri,
USA; 3Department of Dermatology, University of Cincinnati Medical School, Cincinnati, Ohio, USA; 4Department of Dermotology, Wake Forest Baptist Health, Winston-Salem, North Carolina, USA; 5Department of Dermotology, Vanderbilt University, Nashville, Tennessee, USA; 6Department of Dermatology, University of Arkansas, Little Rock, Arkansas, USA; 7 Private Practice, Chevy Chase, Maryland, USA; 8 Department of Dermatology, St Louis University, St Louis, Missouri, USA and 9 Private Practice, Nashville, Tennessee, USA E-mail: [email protected] REFERENCES Chren MM, Linos E, Torres JS et al. (2013) Tumor recurrence 5 years after treatment of cutaneous basal cell carcinoma and squamous cell carcinoma. J Invest Dermatol 133:1188–96 Essers BA, Dirksen CD, Nieman FH et al. (2006) Cost-effectiveness of Mohs micrographic surgery vs surgical excision for basal cell carcinoma of the face. Arch Dermatol 142:187–94 Mosterd K, Krekels GA, Nieman FH et al. (2008) Surgical excision versus Mohs’ micrographic
surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up. Lancet Oncol 9:1149–56 Otley CC (2006) Cost-effectiveness of Mohs micrographic surgery vs surgical excision for basal cell carcinoma of the face. Arch Dermatol 142:1235 Rogers HW, Coldiron BM (2009) A relative value unit-based cost comparison of treatment modalities for nonmelanoma skin cancer: effect of the loss of the Mohs multiple surgery reduction exemption. J Am Acad Dermatol 61:96–103 Rogers HW, Coldiron BM, Dinehart SM et al. (2012) Skin cancer treatment fee comparisons inaccurate. Dermatol Surg 38:2038–9. author reply 2039–41 Stern RS (2013) Cost effectiveness of Mohs micrographic surgery. J Invest Dermatol 133: 1129–31 Wilson LS, Pregenzer M, Basu R et al. (2012) Fee comparisons of treatments for nonmelanoma skin cancer in a private practice academic setting. Dermatol Surg 38:570–84
Response to Rogers et al. Journal of Investigative Dermatology (2014) 134, 1135–1136; doi:10.1038/jid.2013.450; published online 21 November 2013
TO THE EDITOR There is no basis for the assertion by Dr Rogers and his colleagues (2014) that our conclusions were erroneous or affected by the study design. We meticulously studied every patient with basal cell carcinoma or cutaneous squamous cell carcinoma diagnosed over a 2-year period at two busy hospitals at our academic medical center. We had excellent follow-up on virtually all patients, and we analyzed patients at the two hospitals separately before pooling them. We could find no evidence that long-term recurrence was lower after Mohs surgery than after excision, even with multiple analyses that adjusted for differences in patient, tumor, and care characteristics. We conclude that any difference in recurrence rates could be determined only in a randomized controlled trial in which similar patients with similar tumors are randomized to receive one treatment or another.
It is clear that for most nonmelanoma skin cancers, there is insufficient evidence— from our large prospective cohort study and the European randomized controlled trial in facial basal cell carcinomas (Mosterd et al., 2008)—to guide choices between therapies. What this means for our specialty is that we have no data to justify the dramatic increase in Mohs surgery utilization in the USA over the last decades given that Mohs surgery is not the less expensive treatment (Wilson et al., 2012). Because they are costly, randomized controlled trials often are conducted after observational studies demonstrate clinical equipoise in important, targeted situations. This is precisely the situation in which we find ourselves for many nonmelanoma skin cancers. The results of our studies strongly support a focused randomized controlled trial of surgical treatments for nonmelanoma skin cancer, and I urge Dr Rogers and colleagues, as respected Mohs surgeons and leaders, to join me in supporting this next scientific
Accepted article preview online 12 November 2013; published online 21 November 2013
approach to studying the comparative efficacy of these treatments. In my experience, arguments against such a trial typically fall into three types. First is the conviction that a trial is not indicated and may be unethical because the result would be obvious, since a therapy that eliminates every visible tumor cell and spares normal tissue will of course be curative and therefore superior. Such a belief is wrong in, for example, prostate cancer (Wilt and Ahmed, 2013), and the consistency of our findings and those of the European study for both clinical (Mosterd et al., 2008) and patient-reported (Essers et al., 2006; Chren et al., 2007) outcomes demonstrates that it may be wrong for basal cell carcinoma and cutaneous squamous cell carcinoma. Second is the perspective that since nonmelanoma skin cancer is typically nonfatal, the care of these tumors is too trivial to warrant further study. In fact, of course, these tumors are a burden for the public health; for example, the Global Burden of Disease www.jidonline.org 1135