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Merkel cell carcinoma and the controversial role of adjuvant radiation therapy: clinical choices in the absence of statistical evidence
CONTROVERSIES
Merkel cell carcinoma and the controversial role of adjuvant radiation therapy: Clinical choices in the absence of statistical evidence Lynn D. Wilson, MD, MPH,a and Stephen B. Gruber, MD, PhD, MPHb New Haven, Connecticut, and Ann Arbor, Michigan
S
ince Merkel cell carcinoma (MCC) was identified in 19721 there has been significant controversy surrounding management issues, and the use of adjuvant radiation therapy following surgery. Unfortunately, since Merkel cell carcinoma is so rare, there are no randomized controlled trials evaluating the role of adjuvant radiation. Surgery is clearly the cornerstone of therapy for MCC. Many investigators have supported “wide local excision,” and given the propensity for nodal spread in at least 20% of patients at the time of presentation, lymph node dissection is often considered— especially for larger lesions. Recently in the JAAD, Boyer and colleagues2 offered insight into the potential benefit of the Mohs surgical technique in the surgical management of MCC. The information provided by Boyer et al is compelling in favor of use of Mohs for small MCC lesions, and represents one of the larger series endeavoring to evaluate external beam radiotherapy as an adjuvant. The conclusion of the retrospective study of 45 cases was that adjuvant radiotherapy following Mohs “appeared unessential to secure local control.” The statistical evidence from this study, however, is not strong enough to support this conclusion. We endeavor to address this potential controversy from a statistical and clinical perspective.
STATISTICS As is the case with many clinical contributions in the medical literature, rigorous statistical evaluation of the data set tends to add credibility to the findFrom the Departments of Therapeutic Radiology and Dermatology, Yale University School of Medicine,a and the Departments of Internal Medicine and Epidemiology,b Division of Medical Genetics, University of Michigan. Funding sources: None. Conflict of interests: None identified. Reprint requests: Lynn D. Wilson, MD, MPH, Associate Professor, Department of Therapeutic Radiology, Department of Dermatology, Yale University School of Medicine, HRT 136, 333 Cedar St, New Haven, CT 06520. E-mail: [email protected]. J Am Acad Dermatol 2004;50:435-7. 0190-9622/$30.00 © 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2003.09.011
ings. In the medical literature, the use of statistics and a “P-value” of less than 0.05 has become an accepted standard for describing the probability that a result arose by chance, but one needs to have a clear understanding of the meaning of this value and its implications. Sometimes, studies simply are not large enough to demonstrate a statistically validated difference in treatments or means. Type II error or (B error) is the chance of improperly failing to reject a null hypothesis that is false. This type of error is frequently identified in series that are too small to reveal a difference that meets statistical significance. As an example, survival curves that are not significantly different from one another may simply reflect an inability to detect a clinically meaningful difference due to a wide variance of survival estimates from a very small sample population. In the case of the retrospectively evaluated radiation group in the Boyer et al series, the P-value was .12, which was interpreted as representing an insignificant finding with respect to the difference between Mohs only versus Mohs and adjuvant radiation. Clearly the investigators could not reject the null hypothesis that the two treatment groups had equal recurrence rates. This is not the same as proving that adjuvant radiotherapy offers no benefit. Indeed, if one calculates the sample size required to demonstrate a 50% improvement in disease-free recurrence with adjuvant radiotherapy, a randomized clinical trial would require approximately 73 patients per treatment arm with 80% power. The study by Boyer et al, impressive as it is for reporting 45 patients in a multicenter setting, included only 20 and 25 patients per arm, which is less than one third of the necessary sample size for a definitive trial. To detect an even smaller benefit of adjuvant therapy, such as the measurable benefits achieved by adjuvant radiation for breast cancer, one would require a much larger sample size of 275 patients per arm. There are studies in the literature which suggest a clinical local control benefit for patients when radiation is given adjuvantly following surgery for MCC. A variety of investigators have explored this subject 435
436 Wilson and Gruber
in addition to other prognostic issues in MCC.3-23 When evaluating a modality such as radiation, it is important to recognize that there is relatively little documentation available identifying patients who have received radiation in the adjuvant setting for MCC (certainly less than 200 published). The majority of such studies also have involved conventional excision as opposed to Mohs. The weight of the evidence is in favor of considering adjuvant radiation for these patients, albeit based on relatively small, non-controlled trials.
SURVIVAL VERSUS LOCAL CONTROL What is really clinically significant? How much statistical significance is important in deciding the first question? Is it local control, survival, both? Boyer et al noted 4 failures out of 25 patients (16%) in the Mohs only group. There were zero failures in the adjuvant radiation group, but yet these differences were thought not to be significantly different based on the statistical analysis. Given the rare nature of MCC, it will be difficult to show significant differences between treatment groups when series have limited follow up with small numbers of patients. Adjuvant radiation also did not impact on survival in this series of patients. This should not be considered a viable argument for supporting its lack of utility either. In fact, Boyer et al comment on the lack of survival advantage with radiation, but do not develop this as a theme in support of it not being utilized. Most recently, the 20-year follow-up of the National Surgical Adjuvant Breast and Bowel Project-06 breast cancer study was published in the New England Journal of Medicine.24 The series studied the outcomes for 2163 women with invasive breast tumors 4 cm or less, who were randomized to one of three treatment groups. The treatment arms were: total mastectomy, lumpectomy, or lumpectomy and radiation. There were no “significant” differences in disease-free or overall survival, but there was a “significant” decrease in local recurrence for those women treated with lumpectomy and radiation compared to those who did not receive radiation. Radiation had no impact on survival, but did have clinically meaningful, and “statistically” significant results with respect to preventing local failure. It is this large randomized trial that serves as one of several supporting the use of adjuvant radiation in the treatment of breast cancer today. Such treatment has no benefit with respect to survival, but yet the local control issue is deemed important enough, that adjuvant radiation following lumpectomy has become a standard of care for women choosing breast conservation therapy. Hence, we must all be careful in assigning value to therapies based on survival alone as an endpoint. The issue of local control is a valuable one, especially when contemplating the
J AM ACAD DERMATOL MARCH 2004
complexities of management and emotional concerns of patients faced with recurrence of cancer.
SUMMATION Boyer et al provide an excellent review of MCC, and its management, and confirm the utility of Mohs surgery in the local management of MCC. The authors do discuss potential bias as it may have related to their evaluation of the patient groups. The presentation is balanced, but the final message regarding lack of benefit from radiation needs to be consumed cautiously. This data set certainly adds important new information in the search for answers regarding this rare disease for which the clarity in the application of postoperative radiation is not yet available. Further follow-up of this clinical cohort will add even more data to the small numbers of patients that have been reported in the literature. MCC is a disease that may recur years later, and the total number of events (recurrences or deaths) may still accrue over time. Despite the apparent lack of statistical evidence supporting adjuvant radiation for local control at the “.05 level,” we need to keep in mind that negative statistical findings may not always confer “lack of clinical meaning,” especially in non-controlled, small retrospective series which are subject to bias by definition. Given the lack of clear evidence to guide us in decision-making regarding adjuvant radiation, it would be reasonable to at least have patients with MCC seen in consultation by a radiation oncologist, so that a multidisciplinary team approach can be applied. The indications regarding postoperative radiation for MCC continue to remain unclear. There are no controlled trials to further elucidate its role, nor are there likely to be. Therefore, it is likely in the patient’s best interest to have a multidisciplinary management team, and for decisions to be based on clinical factors as they pertain to each individual patient—as opposed to uniform application of therapeutic policy. In our view, the risks and benefits of adjuvant radiotherapy should be discussed with each patient. Although definitive evidence from a randomized clinical trial is unlikely to be achieved, it would be helpful to accumulate the collective experience of the published MCC series within a metaanalysis. Until then, clinical judgment will be required in the absence of statistical evidence. REFERENCES 1. Toker C. Trabecular carcinoma of the skin. Arch Dermatol 1972; 105:107-10. 2. Boyer JD, Zitelli JA, Brodland DG, D’Angelo G. Local control of primary Merkel cell carcinoma: review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation. J Am Acad Dermatol 2002;47:885-92.
Boyer et al 437
J AM ACAD DERMATOL VOLUME 50, NUMBER 3
3. Gruber S, Wilson L. Merkel cell carcinoma. In: Miller SJ, Maloney ME, editors. Cutaneous oncology. Malden (MA): Blackwell Science; 1998. p. 710-21. 4. Morrison WH, Peters IJ, Silva EG, Wendt CD, Ang KK, Goepfert H. The essential role of radiation therapy in securing locoregional control of Merkel cell carcinoma. Int J Radiat Biol Phys 1990;19: 583-91. 5. Meeuwissen JA, Bourne RG, Kearsley JH. The importance of postoperative radiation in the treatment of Merkel cell carcinoma. Int J Radiat Oncol Biol Phys 1995;31:325-31. 6. Cotlar AM, Gates JO, Gibbs FA. Merkel cell carcinoma: combined surgery and radiation therapy. Am Surg 1986;52:159-64. 7. Pacella J, Ashby M, Ainslie J, Minty C. The role of radiotherapy in the management of primary cutaneous neuroendocrine tumors (Merkel cell or trabecular carcinoma): experience at the Peter MacCallum Cancer Institute. Int J Radiat Oncol Biol Phys 1988; 14:1077-84. 8. Fenig E, Brenner B, Katz A, Rakovosky E, Bar Hanna M, Sulkes A. The role of radiation therapy and chemotherapy in the treatment of Merkel cell carcinoma. Cancer 1997;80:881-5. 9. Wilder RB, Harari PM, Graham AR, Skimm DS, Cassady JR. Merkel cell carcinoma improved locoregional control with postoperative radiation therapy. Cancer 1991;68:1004-8. 10. Gillenwater AM, Hessel AC, Morrison WH, Burgess A, Silva EG, Roberts D, et al. Merkel cell carcinoma of the head and neck: effect of surgical excision and radiation on recurrence and survival. Arch Otolaryngol Head Neck Surg 2001;127:149-54. 11. O’Connor WJ, Roenigk RK, Brodland DG. Merkel cell carcinoma: comparison of Mohs micrographic surgery and wide excision in 86 patients. Dermatol Surg 1997;23:929-23. 12. Ott MJ, Tanabe KK, Gadd MA, Stark P, Smith BL, Finkelstein DM, et al. Multimodality management of Merkel cell carcinoma. Arch Surg 1999;134:388-93. 13. Gollard R, Weber R, Kosty MP, Greenway HT, Massullo V, Hum-
14.
15.
16.
17.
18. 19.
20. 21.
22.
23. 24.
berson C. Merkel cell carcinoma: a review of 22 cases with surgical, pathologic, and therapeutic considerations. Cancer 2000; 88:1842-51. Sibley RK, Dehner LP, Rosai J. Primary neuroendocrine (Merkel cell?) carcinoma of the skin. A clinicopathologic and ultrastructural study of 43 cases. Am J Surg Pathol 1985;9:95-108. Hitchcock CL, Bland KL, Laney RG, Franzini D, Harris B, Copeland EM. Neuroendocrine (Merkel cell) carcinoma of the skin. Ann Surg 1988;207:201-7. Brierley JD, Stockdale AD, Rostom AY. Merkel cell (trabecular) carcinoma of the skin treated by radiotherapy. Clin Oncol (R Coll Radiol) 1991;3:117-8. Hasle H. Merkel cell carcinoma: the role of primary treatment with radiotherapy. Review. Clin Oncol (R Coll Radiol) 1991;3:114-6. Westgate SJ. Radiation therapy for skin tumors. Otolaryngol Clin North Am 1993;26:295-309. Goepfert H, Rammler D, Silva EG, Wheeler B. Merkel cell carcinoma (endocrine carcinoma of the skin) of the head and neck. Arch Otolaryngol Head Neck Surg 1984;110:707-12. Marks ME, Kim RY, Salter MM. Radiotherapy as an adjunct in the management of Merkel cell carcinoma. Cancer 1990;65:60-4. Yiengpruksawan A, Coit DG, Thaler HT, Urmacher C, Knapper WK. Merkel cell carcinoma. Prognosis and management. Arch Surg 1991;126:1514-9. Pitale M, Sessions RB, Husain S. An analysis of prognostic factors in cutaneous neuroendocrine carcinoma [review]. Laryngoscope 1992;102:244-9. Shaw JH, Rumball E. Merkel cell tumour: clinical behaviour and treatment. Review. Br J Surg 1991;78:138-42. Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus radiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-41.
Reply a
John D. Boyer, MD, John A. Zitelli, MD,b David G. Brodland, MD,b and Gina M. D’Angelo, ScMc Honolulu, Hawaii
W
ilson and Gruber raise important issues regarding the statistical analysis reported in our recent manuscript.1 In rare tumors, such as Merkel cell carcinoma (MCC), where pro-
From the Department of Medicine (Dermatology), John A. Burns School of Medicine, University of Hawaii at Manoaa, Shadyside Hospital,b and UPCI Biostatistics Facility.c Funding sources: None. Conflict of interest: None identified. Reprints not available from authors. Correspondence to: John D. Boyer, MD, Associate Professor, Department of Medicine (Dermatology), John A. Burns School of Medicine, University of Hawaii at Manoa, 1329 Lusitana Street, Suite 207, Honolulu, HI 96813. E-mail: [email protected]. 0190-9622/$30.00 J Am Acad Dermatol 2004;50:437-8. © 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2003.09.012
spective trials are lacking, clinicians must rely upon existing studies, with its spectrum of variable quality, to guide patient management. Therefore, it is appropriate to discuss the clinical implications of our study and the controversy of adjuvant radiation for local control of MCC.
STATISTICS Strength of statistical evidence would have been enhanced by a larger study size. As acknowledged in the section, Study Limitations, small study size, referral bias, and short interval follow-up require cautious statistical interpretation.1 Confidence intervals should have been provided (Table I). However, an ideal randomized clinical trial would require almost half of the published cases of MCC accumulated since 1972.
Merkel cell carcinoma and the controversial role of adjuvant radiation therapy: Clinical choices in the absence of statistical evidence Lynn D. Wilson, MD, MPH,a and Stephen B. Gruber, MD, PhD, MPHb New Haven, Connecticut, and Ann Arbor, Michigan
S
ince Merkel cell carcinoma (MCC) was identified in 19721 there has been significant controversy surrounding management issues, and the use of adjuvant radiation therapy following surgery. Unfortunately, since Merkel cell carcinoma is so rare, there are no randomized controlled trials evaluating the role of adjuvant radiation. Surgery is clearly the cornerstone of therapy for MCC. Many investigators have supported “wide local excision,” and given the propensity for nodal spread in at least 20% of patients at the time of presentation, lymph node dissection is often considered— especially for larger lesions. Recently in the JAAD, Boyer and colleagues2 offered insight into the potential benefit of the Mohs surgical technique in the surgical management of MCC. The information provided by Boyer et al is compelling in favor of use of Mohs for small MCC lesions, and represents one of the larger series endeavoring to evaluate external beam radiotherapy as an adjuvant. The conclusion of the retrospective study of 45 cases was that adjuvant radiotherapy following Mohs “appeared unessential to secure local control.” The statistical evidence from this study, however, is not strong enough to support this conclusion. We endeavor to address this potential controversy from a statistical and clinical perspective.
STATISTICS As is the case with many clinical contributions in the medical literature, rigorous statistical evaluation of the data set tends to add credibility to the findFrom the Departments of Therapeutic Radiology and Dermatology, Yale University School of Medicine,a and the Departments of Internal Medicine and Epidemiology,b Division of Medical Genetics, University of Michigan. Funding sources: None. Conflict of interests: None identified. Reprint requests: Lynn D. Wilson, MD, MPH, Associate Professor, Department of Therapeutic Radiology, Department of Dermatology, Yale University School of Medicine, HRT 136, 333 Cedar St, New Haven, CT 06520. E-mail: [email protected]. J Am Acad Dermatol 2004;50:435-7. 0190-9622/$30.00 © 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2003.09.011
ings. In the medical literature, the use of statistics and a “P-value” of less than 0.05 has become an accepted standard for describing the probability that a result arose by chance, but one needs to have a clear understanding of the meaning of this value and its implications. Sometimes, studies simply are not large enough to demonstrate a statistically validated difference in treatments or means. Type II error or (B error) is the chance of improperly failing to reject a null hypothesis that is false. This type of error is frequently identified in series that are too small to reveal a difference that meets statistical significance. As an example, survival curves that are not significantly different from one another may simply reflect an inability to detect a clinically meaningful difference due to a wide variance of survival estimates from a very small sample population. In the case of the retrospectively evaluated radiation group in the Boyer et al series, the P-value was .12, which was interpreted as representing an insignificant finding with respect to the difference between Mohs only versus Mohs and adjuvant radiation. Clearly the investigators could not reject the null hypothesis that the two treatment groups had equal recurrence rates. This is not the same as proving that adjuvant radiotherapy offers no benefit. Indeed, if one calculates the sample size required to demonstrate a 50% improvement in disease-free recurrence with adjuvant radiotherapy, a randomized clinical trial would require approximately 73 patients per treatment arm with 80% power. The study by Boyer et al, impressive as it is for reporting 45 patients in a multicenter setting, included only 20 and 25 patients per arm, which is less than one third of the necessary sample size for a definitive trial. To detect an even smaller benefit of adjuvant therapy, such as the measurable benefits achieved by adjuvant radiation for breast cancer, one would require a much larger sample size of 275 patients per arm. There are studies in the literature which suggest a clinical local control benefit for patients when radiation is given adjuvantly following surgery for MCC. A variety of investigators have explored this subject 435
436 Wilson and Gruber
in addition to other prognostic issues in MCC.3-23 When evaluating a modality such as radiation, it is important to recognize that there is relatively little documentation available identifying patients who have received radiation in the adjuvant setting for MCC (certainly less than 200 published). The majority of such studies also have involved conventional excision as opposed to Mohs. The weight of the evidence is in favor of considering adjuvant radiation for these patients, albeit based on relatively small, non-controlled trials.
SURVIVAL VERSUS LOCAL CONTROL What is really clinically significant? How much statistical significance is important in deciding the first question? Is it local control, survival, both? Boyer et al noted 4 failures out of 25 patients (16%) in the Mohs only group. There were zero failures in the adjuvant radiation group, but yet these differences were thought not to be significantly different based on the statistical analysis. Given the rare nature of MCC, it will be difficult to show significant differences between treatment groups when series have limited follow up with small numbers of patients. Adjuvant radiation also did not impact on survival in this series of patients. This should not be considered a viable argument for supporting its lack of utility either. In fact, Boyer et al comment on the lack of survival advantage with radiation, but do not develop this as a theme in support of it not being utilized. Most recently, the 20-year follow-up of the National Surgical Adjuvant Breast and Bowel Project-06 breast cancer study was published in the New England Journal of Medicine.24 The series studied the outcomes for 2163 women with invasive breast tumors 4 cm or less, who were randomized to one of three treatment groups. The treatment arms were: total mastectomy, lumpectomy, or lumpectomy and radiation. There were no “significant” differences in disease-free or overall survival, but there was a “significant” decrease in local recurrence for those women treated with lumpectomy and radiation compared to those who did not receive radiation. Radiation had no impact on survival, but did have clinically meaningful, and “statistically” significant results with respect to preventing local failure. It is this large randomized trial that serves as one of several supporting the use of adjuvant radiation in the treatment of breast cancer today. Such treatment has no benefit with respect to survival, but yet the local control issue is deemed important enough, that adjuvant radiation following lumpectomy has become a standard of care for women choosing breast conservation therapy. Hence, we must all be careful in assigning value to therapies based on survival alone as an endpoint. The issue of local control is a valuable one, especially when contemplating the
J AM ACAD DERMATOL MARCH 2004
complexities of management and emotional concerns of patients faced with recurrence of cancer.
SUMMATION Boyer et al provide an excellent review of MCC, and its management, and confirm the utility of Mohs surgery in the local management of MCC. The authors do discuss potential bias as it may have related to their evaluation of the patient groups. The presentation is balanced, but the final message regarding lack of benefit from radiation needs to be consumed cautiously. This data set certainly adds important new information in the search for answers regarding this rare disease for which the clarity in the application of postoperative radiation is not yet available. Further follow-up of this clinical cohort will add even more data to the small numbers of patients that have been reported in the literature. MCC is a disease that may recur years later, and the total number of events (recurrences or deaths) may still accrue over time. Despite the apparent lack of statistical evidence supporting adjuvant radiation for local control at the “.05 level,” we need to keep in mind that negative statistical findings may not always confer “lack of clinical meaning,” especially in non-controlled, small retrospective series which are subject to bias by definition. Given the lack of clear evidence to guide us in decision-making regarding adjuvant radiation, it would be reasonable to at least have patients with MCC seen in consultation by a radiation oncologist, so that a multidisciplinary team approach can be applied. The indications regarding postoperative radiation for MCC continue to remain unclear. There are no controlled trials to further elucidate its role, nor are there likely to be. Therefore, it is likely in the patient’s best interest to have a multidisciplinary management team, and for decisions to be based on clinical factors as they pertain to each individual patient—as opposed to uniform application of therapeutic policy. In our view, the risks and benefits of adjuvant radiotherapy should be discussed with each patient. Although definitive evidence from a randomized clinical trial is unlikely to be achieved, it would be helpful to accumulate the collective experience of the published MCC series within a metaanalysis. Until then, clinical judgment will be required in the absence of statistical evidence. REFERENCES 1. Toker C. Trabecular carcinoma of the skin. Arch Dermatol 1972; 105:107-10. 2. Boyer JD, Zitelli JA, Brodland DG, D’Angelo G. Local control of primary Merkel cell carcinoma: review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation. J Am Acad Dermatol 2002;47:885-92.
Boyer et al 437
J AM ACAD DERMATOL VOLUME 50, NUMBER 3
3. Gruber S, Wilson L. Merkel cell carcinoma. In: Miller SJ, Maloney ME, editors. Cutaneous oncology. Malden (MA): Blackwell Science; 1998. p. 710-21. 4. Morrison WH, Peters IJ, Silva EG, Wendt CD, Ang KK, Goepfert H. The essential role of radiation therapy in securing locoregional control of Merkel cell carcinoma. Int J Radiat Biol Phys 1990;19: 583-91. 5. Meeuwissen JA, Bourne RG, Kearsley JH. The importance of postoperative radiation in the treatment of Merkel cell carcinoma. Int J Radiat Oncol Biol Phys 1995;31:325-31. 6. Cotlar AM, Gates JO, Gibbs FA. Merkel cell carcinoma: combined surgery and radiation therapy. Am Surg 1986;52:159-64. 7. Pacella J, Ashby M, Ainslie J, Minty C. The role of radiotherapy in the management of primary cutaneous neuroendocrine tumors (Merkel cell or trabecular carcinoma): experience at the Peter MacCallum Cancer Institute. Int J Radiat Oncol Biol Phys 1988; 14:1077-84. 8. Fenig E, Brenner B, Katz A, Rakovosky E, Bar Hanna M, Sulkes A. The role of radiation therapy and chemotherapy in the treatment of Merkel cell carcinoma. Cancer 1997;80:881-5. 9. Wilder RB, Harari PM, Graham AR, Skimm DS, Cassady JR. Merkel cell carcinoma improved locoregional control with postoperative radiation therapy. Cancer 1991;68:1004-8. 10. Gillenwater AM, Hessel AC, Morrison WH, Burgess A, Silva EG, Roberts D, et al. Merkel cell carcinoma of the head and neck: effect of surgical excision and radiation on recurrence and survival. Arch Otolaryngol Head Neck Surg 2001;127:149-54. 11. O’Connor WJ, Roenigk RK, Brodland DG. Merkel cell carcinoma: comparison of Mohs micrographic surgery and wide excision in 86 patients. Dermatol Surg 1997;23:929-23. 12. Ott MJ, Tanabe KK, Gadd MA, Stark P, Smith BL, Finkelstein DM, et al. Multimodality management of Merkel cell carcinoma. Arch Surg 1999;134:388-93. 13. Gollard R, Weber R, Kosty MP, Greenway HT, Massullo V, Hum-
14.
15.
16.
17.
18. 19.
20. 21.
22.
23. 24.
berson C. Merkel cell carcinoma: a review of 22 cases with surgical, pathologic, and therapeutic considerations. Cancer 2000; 88:1842-51. Sibley RK, Dehner LP, Rosai J. Primary neuroendocrine (Merkel cell?) carcinoma of the skin. A clinicopathologic and ultrastructural study of 43 cases. Am J Surg Pathol 1985;9:95-108. Hitchcock CL, Bland KL, Laney RG, Franzini D, Harris B, Copeland EM. Neuroendocrine (Merkel cell) carcinoma of the skin. Ann Surg 1988;207:201-7. Brierley JD, Stockdale AD, Rostom AY. Merkel cell (trabecular) carcinoma of the skin treated by radiotherapy. Clin Oncol (R Coll Radiol) 1991;3:117-8. Hasle H. Merkel cell carcinoma: the role of primary treatment with radiotherapy. Review. Clin Oncol (R Coll Radiol) 1991;3:114-6. Westgate SJ. Radiation therapy for skin tumors. Otolaryngol Clin North Am 1993;26:295-309. Goepfert H, Rammler D, Silva EG, Wheeler B. Merkel cell carcinoma (endocrine carcinoma of the skin) of the head and neck. Arch Otolaryngol Head Neck Surg 1984;110:707-12. Marks ME, Kim RY, Salter MM. Radiotherapy as an adjunct in the management of Merkel cell carcinoma. Cancer 1990;65:60-4. Yiengpruksawan A, Coit DG, Thaler HT, Urmacher C, Knapper WK. Merkel cell carcinoma. Prognosis and management. Arch Surg 1991;126:1514-9. Pitale M, Sessions RB, Husain S. An analysis of prognostic factors in cutaneous neuroendocrine carcinoma [review]. Laryngoscope 1992;102:244-9. Shaw JH, Rumball E. Merkel cell tumour: clinical behaviour and treatment. Review. Br J Surg 1991;78:138-42. Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus radiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-41.
Reply a
John D. Boyer, MD, John A. Zitelli, MD,b David G. Brodland, MD,b and Gina M. D’Angelo, ScMc Honolulu, Hawaii
W
ilson and Gruber raise important issues regarding the statistical analysis reported in our recent manuscript.1 In rare tumors, such as Merkel cell carcinoma (MCC), where pro-
From the Department of Medicine (Dermatology), John A. Burns School of Medicine, University of Hawaii at Manoaa, Shadyside Hospital,b and UPCI Biostatistics Facility.c Funding sources: None. Conflict of interest: None identified. Reprints not available from authors. Correspondence to: John D. Boyer, MD, Associate Professor, Department of Medicine (Dermatology), John A. Burns School of Medicine, University of Hawaii at Manoa, 1329 Lusitana Street, Suite 207, Honolulu, HI 96813. E-mail: [email protected]. 0190-9622/$30.00 J Am Acad Dermatol 2004;50:437-8. © 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2003.09.012
spective trials are lacking, clinicians must rely upon existing studies, with its spectrum of variable quality, to guide patient management. Therefore, it is appropriate to discuss the clinical implications of our study and the controversy of adjuvant radiation for local control of MCC.
STATISTICS Strength of statistical evidence would have been enhanced by a larger study size. As acknowledged in the section, Study Limitations, small study size, referral bias, and short interval follow-up require cautious statistical interpretation.1 Confidence intervals should have been provided (Table I). However, an ideal randomized clinical trial would require almost half of the published cases of MCC accumulated since 1972.