Distinctive Features of Melanoma and Its Management in Elderly Patients A Population-Based Study in France

Transcription

1 Research Original Investigation Distinctive Features of Melanoma and Its Management in Elderly Patients A Population-Based Study in France Dragos Ciocan, MD; Coralie Barbe, MD; Francois Aubin, MD, PhD; Florence Granel-Brocard, MD; Dan Lipsker, MD, PhD; Michel Velten, MD, PhD; Sophie Dalac, MD; François Truchetet, MD; Catherine Michel, MD; Audrey Mitschler, MD; Gwendoline Arnoult, MSc; Antoine Buemi, MD; Stéphane Dalle, MD, PhD; Philippe Bernard, MD, PhD; Anne-Sophie Woronoff, MD; Florent Grange, MD, PhD IMPORTANCE Life expectancy is increasing in most developed countries, and elderly people have the highest incidence of melanoma. Invited Commentary page 1158 OBJECTIVE To identify characteristics of melanoma and its management in the elderly compared with younger patients. DESIGN, SETTING, AND PARTICIPANTS Retrospective population-based study of incident cases of primary melanoma in 1621 patients with stage I or II melanoma in 2004 and Questionnaires administered to physicians and a survey of cancer registries and pathology laboratories were used to obtain data. The study was conducted in 5 regions in northeastern France. MAIN OUTCOMES AND MEASURES Characteristics of patients and tumors, circumstances of diagnosis, and further management in older patients ( 70 years, 487 patients [30.0%]) compared with younger ones (<70 years, 1134 [70.0%]). RESULTS Older patients had more frequent melanomas of the head and neck (29.4% vs 8.7%; P <.001) and of the nodular, lentigo maligna, or acral lentiginous histologic subtypes. They had thicker and more frequently ulcerated tumors, categorized as T3 or T4 in 36.7% of cases vs 20.1% in younger patients. Diagnosis of melanoma occurred more frequently in a general practice setting and less frequently in direct consultation with a dermatologist or regular screening for skin cancer. Time to definitive excision was longer in older patients, and 16.8% of them compared with 5.0% of the younger population had insufficient excision margins (P <.001). A sentinel lymph node biopsy was performed in 23.3% of the older patients with melanoma thicker than 1 mm vs 41.4% in the younger patients (P <.001). Adjuvant therapy was less frequently started in older patients and was prematurely stopped in a higher proportion of that population. CONCLUSIONS AND RELEVANCE Age-related variations are observed at every step of melanoma management. The most important concerns are access of elderly people to settings for early diagnosis and excision with appropriate margins. JAMA Dermatol. 2013;149(10): doi: /jamadermatol Published online August 14, Author Affiliations: Author affiliations are listed at the end of this article. Corresponding Author: Florent Grange, MD, PhD, Service de Dermatologie, Hôpital Robert Debré, Avenue du Général Koenig, Reims Cedex, France (fgrange@chu-reims.fr) jamadermatology.com

2 Management of Melanoma in the Elderly Original Investigation Research The incidence of melanoma and related mortality have been steadily increasing in the past 25 years in most developed countries. 1-4 Despite a recent trend for a decrease in younger populations in northern Europe, incidence rates are still increasing recently in the elderly, particularly in older men. 1-3 In the United States, more than 40% of melanomas are diagnosed in patients older than 65 years. 5 In France, incidence rates exceed 25 per in men and women older than 65 years compared with 7.6 per and 9.5 per in men and women of any age, respectively (world-standardized rates in 2000). 4 In addition to higher incidence rates, older patients have lower diseasespecific survival rates than do younger ones. 6,7 Classical factors associated with a poorer prognosis in older patients are tumors with a higher Breslow thickness, a higher mitotic index, and more advanced stages at diagnosis These factors may result from longer delays to diagnosis in elderly patients because of inadequate screening or lower awareness levels regarding melanoma 13 and from more rapidly growing and/or invasive tumors, possibly related to declining immune function. In addition to tumor- and/or host-related factors, it may be hypothesized that age-related variations in management of melanoma could contribute to the poorer outcome in older patients. Many survival analyses using specific or relative survival as an end point (ie, excluding general agerelated mortality) identified age as an independent prognosis factor after adjustment for initial characteristics of the tumor. 9,14-17 This finding suggests that factors other than stage at diagnosis and initial characteristics of the tumor could play a role in the poorer outcome in older patients. Most studies on melanoma in the elderly have focused on characteristics of patients and tumors; to our knowledge, none has included comprehensive data on the real management of melanoma on a population basis. Previous studies in 2004 and 2008 provided population-based data on different aspects of diagnosis and/or management of melanoma in a large French geographic area. The present study evaluated to what extent characteristics of primary tumors and their management (including excision, surgical margins, sentinel lymph node biopsy [SLNB], adjuvant therapies, and surveillance procedures) differed in older patients compared with younger ones. Methods Study Population The study was approved by the institutional review board of Reims University Hospital, Reims, France. It was performed in northeast France in 5 regions (Alsace, Bourgogne, Champagne-Ardenne, Franche-Comté, and Lorraine), including 8.3 million inhabitants (13% of the French population). 22 This area includes 3 of the 11 French population-based general cancer registries, located in 3 different administrative département (Haut-Rhin, Bas-Rhin, and Doubs), and a specific melanoma registry in the Champagne-Ardenne region (Observatoire Melanome en Champagne-Ardenne 8 ). Data Collection Incident cases of clinical stage I or II melanoma (according to the American Joint Committee on Cancer [AJCC] classification 17 ) diagnosed in 2 nonconsecutive years (January 1 to December 31, 2004, and January 1 to December 31, 2008) were identified using surveys of dermatologists, cancer registries, and pathology laboratories, as previously described. 19,21 For each case, data were collected through questionnaires mailed to referent physicians, most of whom were in private practice or hospital dermatologists. Physicians could request the assistance of a clinical research assistant, either by telephone or on site. For 4 patients with more than 1 melanoma during the study period, only the thickest tumor was considered for analysis. The following data were collected for each patient: age, sex, administrative départements, area of residence (urban vs rural), circumstances of diagnosis, anatomic location (divided into 4 locations: head and neck, lower extremity, trunk, and upper extremity), histologic subtype (including superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acral lentiginous melanoma, and other or unclassified subtypes), Breslow thickness, ulceration, modalities of surgery (including excision biopsy, definitive margin excision, and total margins), SLNB, presentation to a multidisciplinary decision committee for a decision on management as recommended by the French Cancer Plan, medical imaging for initial staging, adjuvant therapies, and follow-up procedures. Data on the circumstances of diagnosis were collected from the referent dermatologist for each patient and divided into 5 groups: referral to a dermatologist by a general practitioner (GP) for the tumor, patient-initiated direct consultation with a dermatologist for melanoma, melanoma diagnosed during regular screening for skin cancer, melanoma diagnosed during evaluation for another dermatosis (incidental diagnosis), and referral by another specialist. Excision margins were classified as appropriate, excessive, or insufficient, according to the 2004 French recommendations for total margins. These recommendations were 1 cm for melanomas with a Breslow thickness of 1.0 mm or less, 1 to 2 cm for a Breslow thickness between 1.0 and 2.0 mm, and 2 to 3 cm for a Breslow thickness of 2.0 mm or greater. 23 Statistical Analysis Quantitative variables were described as mean (SD) or median (range) according to their distribution, and qualitative data were described as number and percentage. Older patients were defined as individuals aged 70 years or older and were compared with those younger than 70 years (ie, the younger group) for every study variable. Comparisons between the older and younger groups were performed using a 2-tailed unpaired t test, Wilcoxon rank test, χ 2 test, or Fisher exact test, as appropriate. Multivariate analyses were performed to investigate the adjusted role of age on different management features (time to definitive excision, margins, and medical imaging for initial staging) using logistic regression with ascending stepwise selection and entry and exit threshold set at P <.05 was considered statistically significant. Statistical analyses jamadermatology.com JAMA Dermatology October 2013 Volume 149, Number

3 Research Original Investigation Management of Melanoma in the Elderly Table 1. Initial Patient and Tumor Characteristics in the Whole Study Population and Comparison According to Age No. (%) Age, y Total <70 70 Characteristic (N = 1621) (n = 1134) (n = 487) Age, y Mean Median (range) 58 (6-97) 51 (6-69) 77 (70-97) Sex a Female 842 (52.0) 601 (53.0) 241 (49.6) Male 778 (48.0) 533 (47.0) 245 (50.4) Area of residence b Rural 632 (40.1) 437 (39.7) 195 (41.1) Urban 943 (59.9) 664 (60.3) 279 (58.9) Location c Head and neck 241 (14.9) 98 (8.7) 143 (29.4) Upper limb 277 (17.1) 192 (17.0) 85 (17.5) Trunk 609 (37.6) 469 (41.5) 140 (28.6) Lower limb 491 (30.3) 372 (32.8) 119 (24.5) Histologic subtype d SSM 1108 (70.9) 847 (77.4) 261 (55.9) Nodular 222 (14.2) 120 (11.0) 102 (21.8) ALM 51 (3.3) 26 (2.4) 25 (5.4) LMM 73 (4.7) 23 (2.0) 50 (10.7) P Value Not classified 108 (6.9) 79 (7.2) 29 (6.2) Breslow thickness, mm e Mean Median (range) 0.78 ( ) 0.7 ( ) 1.08 ( ) Breslow thickness, mm (60.4) 725 (65.4) 224 (48.4) (77.8) 918 (82.9) 305 (65.9) >2 348 (22.2) 190 (17.1) 158 (34.1) Ulceration f 225 (14.9) 132 (12.4) 93 (20.9) Tumor stage g,h T1-T (75.0) 835 (79.9) 271 (63.3) T3-T4 368 (25.0) 211 (20.1) 157 (36.7) Abbreviations: ALM, acral lentiginous melanoma; LMM, lentigo maligna melanoma; SSM, superficial spreading melanoma. a Data were unknown in 1 case (0.1%). b Data were unknown in 46 cases (2.8%). c Data were unknown in 3 cases (0.2%). d Data were unknown in 59 cases (3.6%). e Data were unknown in 50 cases (3.1%). f Data were unknown in 107 cases (6.6%). g According to the 2001 American Joint Committee on Cancer classification. 17 h Data were unknown in 147 cases (9.1%). were performed using commercial software (SAS, version 9.0; SAS Institute, Inc). Results Patient and Melanoma Characteristics A total of 1621 patients with a primary cutaneous melanoma diagnosed in 2004 or 2008 were included in the study; 487 individuals (30.0%) constituted the older group and 1134 patients (70.0%) composed the younger group. The median age in the older and younger groups was 77 years and 51 years, respectively. No significant differences were observed for sex distribution (Table 1). 17 Tumor location and type differed between older and younger patients. Older patients had a higher proportion of head and neck melanomas (29.4% vs 8.7%; P <.001) and a lower proportion of melanomas located on the trunk (28.6% vs 41.5%; P <.001) and the lower limbs (24.5% vs 32.8%; P <.001). Superficial spreading melanoma was the most frequent histologic subtype found in both older (55.9%) and younger (77.4%) patients, but older patients developed nodular melanoma, lentigo maligna melanoma, or acral lentiginous melanoma more frequently (37.9% vs 15.4%; P <.001). Patients in the older group had thicker melanomas (mean Breslow thickness, 2.34 vs 1.35 mm; P <.001) and a higher frequency of ulcerated lesions (20.9% vs 12.4%; P <.001), resulting in tumors of more advanced AJCC stages (stages T3 and T4: 36.7% vs 20.1%; P <.001). No significant difference between groups was observed for ulceration after stratifying for Breslow thickness. In the older group, the proportion of AJCC stages T3 and T4 melanomas was higher in patients living in a rural area than in patients living in an urban area (42.3% vs 33.1%; P =.05), whereas no relationship between stage and area of residence was observed in the younger group JAMA Dermatology October 2013 Volume 149, Number 10 jamadermatology.com

4 Management of Melanoma in the Elderly Original Investigation Research Table 2. Circumstances of Diagnosis of Melanoma According to Age Age, No. (%), y <70 70 Circumstances of Diagnosis of Melanoma a (n = 1134) (n = 487) P Value Patient referred by a general practitioner 353 (33.8) 196 (43.6) Patient directly consulting for melanoma 354 (33.9) 125 (27.8).03 Patient diagnosed with melanoma during regular 152 (14.5) 16 (3.5) screening for skin cancer Patient diagnosed with melanoma when consulting for 132 (12.6) 84 (18.7) another dermatosis.002 Patient referred to a dermatologist by another specialist 54 (5.2) 29 (6.4).30 a Circumstances of diagnosis, as indicated by the referent dermatologist, were unknown in 126 cases (7.8%). Table 3. Initial Surgical Management of Cutaneous Melanoma According to Age Age, No. (%), y <70 70 Characteristic (n = 1134) (n = 487) P Value Physician performing the initial excision a Private dermatologist 830 (75.1) 257 (54.0) Hospital dermatologist 85 (7.7) 62 (13.1) Surgeon 159 (14.4) 149 (31.4) Other physician 31 (2.8) 7 (1.5) Patients undergoing definitive margin excision b 1049 (92.9) 375 (77.8) Physician performing the definitive excision c Private dermatologist 227 (22.1) 53 (14.4) Surgeon 599 (58.4) 252 (68.7) Hospital dermatologist 193 (18.8) 61 (16.6).002 Other physician 7 (0.7) 1 (0.3) Time to definitive margin excision, wk d (78.0) 243 (67.9) >6 215 (22.0) 115 (32.1) Excision margin e Adequate 800 (80.7) 268 (70.3) Narrow 49 (5.0) 64 (16.8) Excessive 142 (14.3) 49 (12.7) SLNB for Breslow thickness 1 mm (n = 656) f 170 (41.4) 57 (23.3) Abbreviation: SLNB, sentinel lymph node biopsy. a Data were unknown in 41 cases (2.5%). b Data were unknown in 10 cases (0.6%). c Data were unknown in 228 cases (14.1%). d Data were unknown in 284 cases (17.5%). e Data were unknown in 249 cases (15.4%). f Data were unknown in 7 cases (1.1%). Circumstances of Diagnosis Older patients more often received a diagnosis of melanoma in a general practice setting. They less frequently consulted a dermatologist directly for their tumor. In addition, older patients received the diagnosis less frequently during a regular screening for skin cancer (Table 2). Initial Management of Cutaneous Melanomas Presentation to a multidisciplinary decision committee in a referral center for management was more frequent in the older than in the younger group (49.5% vs 43.1%; P =.02). However, this difference disappeared after stratifying for Breslow thickness, the rate of presentation being similar in both groups for melanoma thicker than 1 mm (58.4% vs 57.4%; P =.80). Initial excision was performed by a surgeon more often in older patients (31.4% vs 14.4%; P <.001) (Table 3). Some 22.2% of patients in the older group, compared with 7.1% in the younger one, did not undergo a definitive excision with additional margins after initial excision (P <.001). Definitive excision was more often performed by a surgeon in older patients (68.7% vs 58.4%; P <.001). The time to definitive excision was more often longer than 6 weeks in older patients (32.1% vs 22.0%; P <.001). After taking into account Breslow thickness (odds ratio [OR], 1.4; 95% CI, ; P =.05) and performance of an SLNB (OR, 3.6; 95% CI, ; P <.001), older age still had a statistically significant effect on time to definitive excision (OR, 1.4; 95% CI, ; P =.02). The total excision margins were insufficient in 16.8% of the older patients compared with 5.0% in younger patients (P <.001). Factors independently associated with an insufficient margin in multivariate analysis were age older than 70 years (OR, 2.2; 95% CI, ; P <.001), the head and neck location (OR, 4.4; 95% CI, ; P <.001), and Breslow thickness greater than 2 mm (OR, 5.0; 95% CI, ; P <.001). In the group of melanoma with a Breslow thickness of 1 mm or more, SLNB was less often performed in older patients than in younger ones (23.3% vs 41.4%; P <.001). No significant difference was observed for the rate of positive SLNB results between the 2 groups (22.4% in the older group vs 19.8% in the younger group; P =.70). jamadermatology.com JAMA Dermatology October 2013 Volume 149, Number

5 Research Original Investigation Management of Melanoma in the Elderly Table 4. Nonsurgical Management of Cutaneous Melanoma According to Age After Surgery Age, No. (%), y <70 70 Characteristic (n = 1134) (n = 487) P Value Adjuvant therapy a Proposed b 140 (58.8) 32 (18.9) Instituted (when proposed) c 87/139 (62.6) 16/30 (53.3).35 Completed (when instituted) d 54/82 (65.9) 4/15 (26.7).004 Initial staging e,f Clinical examination only 221 (21.4) 121 (27.4).01 Including lymph node US 14 (4.2) 8 (4.5).80 Including chest radiography and abdominal US 489 (59.6) 166 (48.3) Including CT 275 (25.1) 127 (27.0).40 Including PET 38 (3.4) 16 (3.3).95 Frequency of follow-up visits g 3-mo Interval 60 (15.5) 40 (26.0) 6-mo Interval 175 (45.3) 71 (46.1).01 Other interval 151 (39.2) 43 (27.9) Modalities of surveillance h Clinical examination only 578 (58.9) 238 (58.7).96 Including chest radiography and abdominal US 281 (27.4) 108 (24.8).30 Including CT 104 (9.2) 47 (9.7).70 Including PET 4 (0.4) 4 (0.8).30 Abbreviations: CT, computed tomography; PET, positron emission tomography; US, ultrasonography. a Adjuvant therapy was considered only in the group of patients with Breslow thickness of 1.5 mm or greater and sentinel lymph node biopsy that had a negative result or was not done (n = 407). b Data were available for 391 cases. c Data were available for 388 cases. d Data were available for 382 cases. e Data were available for 1475 cases. f The former French recommendations for melanoma management in force between 1995 and 2005 still proposed chest radiography and abdominal US as optional staging procedures for melanoma. g Data were available for 1417 cases. h Data were available for 1386 cases. Further Management Despite more advanced tumors in the older group, systematic medical imaging for initial staging was less frequently carried out in this group than in the younger one (72.6% vs 78.6%; P =.01). In multivariate analysis, factors independently associated with the use of medical imaging for initial staging were age younger than 70 years (OR, 1.7; 95% CI, ; P <.001) and a Breslow thickness of 1 mm or greater (OR, 4.1; 95% CI, ; P <.001). For these analyses, patients with a positive SLNB result (n = 54) were excluded. In the group of patients (n = 407) with a melanoma thicker than 1.5 mm (a cutoff size corresponding to the approval of adjuvant low-dose interferon alfa in France), adjuvant therapy was less frequently proposed (18.9% vs 58.8%; P <.001) to older patients than to younger ones and was started less frequently. Only 16 of 169 older patients (9.5%) compared with 87 of 238 younger ones (36.6%), started adjuvant therapy (P <.001) (Table 4). Adjuvant therapy was most often lowdose interferon alfa (74.3%) or high-dose interferon alfa (10.1%), without any significant difference between the age 2 groups. Adjuvant therapy was prematurely stopped in 73.3% of older patients vs 34.1% of younger ones (P =.004). Reasons for stopping adjuvant therapy in older patients included disease progression (30.0% of patients), adverse effects (50.0%), and patient s choice or unspecified reasons (20.0%). During follow-up, no significant difference was observed for the use of systematic medical imaging between the 2 groups (41.3% in the older group vs 41.1% in the younger one; P =.96). Older patients were more often monitored with a 3-month interval than were younger patients (Table 4), but this difference disappeared after stratifying for Breslow thickness. Discussion This population-based comparative study included comprehensive data on the management of 1621 melanomas diagnosed in 2004 and 2008 in 5 regions of northeast France. No significant difference was observed between these 2 nonconsecutive years for the characteristics of patients, melanomas, and main features of management (data not shown) except for an increasing role of GPs in diagnosis from 2004 to 2008, as reported in a previous study. 21 In contrast, major differences were identified in both years of the study period between older and younger patients concerning the initial characteristics and the subsequent management of their melanoma. Our results confirm and extend those of previous reports on the presentation and characteristics of melanoma in the elderly. 9,24 In accordance with previous series, 6,9,24 we observed that the head and neck was the most frequent location in older patients (29.4% of all melanoma cases vs 8.7% in younger ones). Previous authors 9,25 have demonstrated that the head and neck location of melanoma increases with age and becomes the most common site after age 70 years. It was suggested that this high incidence of head and neck melanoma might be attributable to cumulative photo damage, resulting notably in numerous lentigo malignant melanoma. This predominant site may have a significant clinical impact. Because the head and neck location has been shown to have an independent adverse prognostic effect on survival, 17,26 this topographic characteristic could play a role in the poorer prognosis of melanoma in the elderly JAMA Dermatology October 2013 Volume 149, Number 10 jamadermatology.com

6 Management of Melanoma in the Elderly Original Investigation Research The most relevant difference in terms of baseline prognostic characteristics between older and younger patients in our study, as in previous ones, 8,10,11,27 was a higher Breslow thickness in the older group. Among factors that could explain this difference, the frequency of the nodular histologic subtype may play an important role. In the present study, nodular melanoma occurred twice as frequently in the older group as in the younger one. Nodular melanomas have been consistently reported 8,11,18,28-30 to be associated with more advanced clinical stages at diagnosis and poorer prognosis than other types of melanoma. This may be explained mainly by a more biologically aggressive behavior, including the absence of an initial radial growth phase, an increased number of mitoses, and a more aggressive growth rate. 31 In addition, delayed diagnosis is frequent for nodular melanoma, which often lacks the ABCD criteria (asymmetry, border irregularity, color variation, and diameter >6 mm) and is often misdiagnosed at first consultation. 10,32,33 In addition to nodular melanoma with clinical characteristics not typical of melanoma, more typical tumors according to the ABCD rule, including superficial spreading melanoma, may also have a delayed diagnosis in older individuals as a consequence of location in scarcely visible areas (ie, scalp and back), absence of a partner for home examination, poor vision, ignorance of clinical changes, and/or confusion between melanoma and seborrheic keratoses. 9,34 Finally, a simple explanation for increased tumor thickness in older patients is that melanoma originated at a younger age and progressed over time. 35 Thus, tumors with a long radial growth phase lasting many years enter a vertical growth phase later in life, frequently resulting in advanced lesions in older patients. In addition to intrinsic characteristics of tumors, sociodemographic factors and patients living conditions played a role in melanoma stage at diagnosis. 11,21,30,36 Whereas no relationship between area of residence and stage at diagnosis was observed in the younger group, older patients living in a rural area received diagnoses of more advanced AJCC stages of melanoma than did those living in an urban area. Geographic inequalities in health have been observed frequently between areas with contrasting socioeconomic conditions, and studies in industrialized countries have found higher overall mortality rates in rural populations. 37,38 More specifically, cancer mortality has been shown to be higher in rural areas. 37 Although the incidence of melanoma as a whole is higher in populations with a high socioeconomic level, 39 including those of metropolitan areas compared with rural ones, 40 lower socioeconomic status has been associated with later stages at diagnosis and a higher mortality rate. 28,39 Our study suggests that such inequalities could be more prominent in older individuals than in younger ones. In addition to characteristics of tumors and sociodemographic characteristics of patients, our study provides comprehensive data on circumstance of diagnosis and subsequent management of melanoma. In France, no systematic skin cancer screening has been organized. The recognition of individuals at risk by GPs and regular follow-up by dermatologists have been encouraged. However, despite a much higher incidence of melanoma and other skin cancers in the elderly, no special attention has been provided for older patients. In our study, older patients were more often diagnosed with melanoma in a GP setting and were rarely receiving regular skin cancer screening when they developed melanoma. Previous studies found that melanomas diagnosed by GPs were thicker than those diagnosed by dermatologists 18,21,30 and that the thinnest tumors were observed in the group of patients regularly screened by dermatologists. 18 Therefore, our present results show that older persons have the most disadvantageous diagnosis pattern for early detection. Although it has been previously suggested that not only a follow-up by dermatologists but also a periodic full-body skin examination by GPs may be associated with early melanoma detection, 41 a previous study 21 found that full-body skin examination by GPs was very rarely performed in daily practice in France. Together, these data suggest that diagnosis patterns for melanoma in older individuals could be considerably improved in France. Following initial diagnosis, the management of melanoma also appears to be a challenging issue. Chang et al 42 emphasized that older patients should be treated according to the characteristics and prognostic factors of their tumors and not according to their more advanced age. In contrast to this statement, we observed that 16.8% of elderly people, compared with 5.0% of younger ones, had insufficient excision margins (due to either absence of definitive margin excision or inadequate safety excision). Furthermore, using multivariate analysis, we found that age contributed to insufficient margins independently of other factors frequently identified in older patients, ie, the head and neck location and a greater Breslow thickness. In addition to a higher rate of insufficient margins, older patients experienced longer delays to definitive excision. Age had an independent effect on time to definitive excision after taking into account other factors associated with longer delays, ie, greater Breslow thickness and the performance of SLNB. Among patients typically eligible for SLNB (ie, having a melanoma with Breslow thickness 1 mm), only 23.3% in the older group (vs 41.4% in the younger one) underwent this procedure. This may partly be the result of the limited practical value of SLNB in older patients for whom interferon alfa or other adjuvant therapies are not an option. In addition, the prognostic value of SLNB may appear to be reduced in very old patients with limited life expectancy. However, our results contrast with data recently reported from Germany by Livingstone et al. 43 Although these authors also observed a significant effect of age on the use of SLNB, more than 82% of a total of 419 patients with a melanoma thicker than 1 mm had an SLNB. Since more than 50% of patients in the Livingstone et al study were older than 60 years, it is probable that most elderly subjects as defined in the present study (ie, 70 years) also had an SLNB in the German investigation. Another major difference between older and younger patients was the rate of adjuvant therapy proposed and completed. During this study period, both low-dose interferon alfa-2a and high-dose interferon alfa-2b were approved as adjuvant therapies in France for melanomas 1.5 mm or more in thickness and those at high risk of recurrence ( 4 mm or stage III), respectively. Most of the patients given adjuvant inter- jamadermatology.com JAMA Dermatology October 2013 Volume 149, Number

7 Research Original Investigation Management of Melanoma in the Elderly feron alfa in the present study received the low-dose regimen. However, only 2.4% of older patients (4 of 169) compared with 22.7% of younger ones (54 of 238) eligible for adjuvant therapy underwent a full course of interferon alfa (ie, 1 year). This may be the result partly of good clinical practices, as many older patients have poor health, making it difficult to prescribe adjuvant therapies. In addition, older patients may be reluctant to accept a treatment with significant adverse effects and little benefit. However, this contrasts again with the study of Livingstone et al, 43 which found that adjuvant therapy was initiated in 114 of the 330 German patients (34.5%) of all ages eligible for an adjuvant therapy according to the same criteria as in France. There are some limitations to this study. First, it was retrospective. Second, what we observed in the northeast part of France may not be generalized to the whole French territory. Third, factors such as skin type, number of nevi, family history of melanoma, and history of nonmelanoma skin cancer or noncutaneous cancer were not collected, and further studies are required to compare such risk factors and characteristics between older and younger patients. In summary, compared with the younger group, older patients had thicker melanomas of more aggressive subtypes that were more often diagnosed coincidentally in a GP setting. They also had a higher rate of insufficient surgical margin, a longer delay to definitive excision, and lower rates of SLNB and adjuvant therapies. Because different studies failed to show any significant effect on survival associated with surgical margins and performance of SLNB, 47 and 2 meta-analyses noted only a low effect of adjuvant interferon alfa on overall survival, 48,49 it remains questionable whether specific differences observed in the present study played a role in a poorer outcome of melanoma in the elderly. However, it has been suggested previously that specific variations in management of melanoma, although with uncertain impact when studied individually in clinical trials, could have a significant effect on mortality when taking place together in a population setting. 50 It may therefore be hypothesized that age-related variations in the management of melanoma observed in the present study might contribute to a poorer overall prognosis in the elderly. Stage at diagnosis remains the most important difference between younger and older patients. Further public health campaigns regarding melanoma should focus on access of elderly people to early diagnosis and excision with appropriate margins. ARTICLE INFORMATION Accepted: January 22, Published Online: August 14, doi: /jamadermatol Author Affiliations: Unité d Aide Méthodologique, Hôpital Robert Debré, Reims, France (Ciocan, Barbe); Service de Dermatologie, Hôpital Saint Jacques, Besançon, France (Aubin); Service de Dermatologie, Hôpitaux de Brabois, Vandoeuvre Les Nancy, France (Granel-Brocard); Clinique Dermatologique, Hôpital Civil, Strasbourg, France (Lipsker); Registre des Cancers du Bas-Rhin, Strasbourg, France (Velten); Réseau Français des Registres de Cancers FRANCIM (France Cancer Incidence et Mortalité), France (Velten, Buemi, Woronoff); Service de Dermatologie, Hôpital du Bocage, Dijon, France (Dalac); Service de Dermatologie, Hôpital Beauregard, Thionville, France (Truchetet); Service de Dermatologie, Hôpital du Moenschberg, Mulhouse, France (Michel); Service de Dermatologie, Hôpital Louis Pasteur, Colmar, France (Mitschler); Centre de Recherche et d Investigation Clinique, Hôpital Maison Blanche, Reims, France (Arnoult); Registre des Cancers du Haut-Rhin, Mulhouse, France (Buemi); Service de Dermatologie du Centre Hospitalier Lyon-Sud, Lyon, France (Dalle); Hospices Civils de Lyon, Lyon, France (Dalle); Service de Dermatologie, Hôpital Robert Debré, Reims, France (Bernard, Grange); Registre des tumeurs du Doubs, CHU de Besançon, Besançon, France (Woronoff). Author Contributions: Study concept and design: Ciocan, Grange. Acquisition of data: Aubin, Granel-Brocard, Lipsker, Velten, Dalac, Truchetet, Michel, Mitschler, Arnoult, Buemi, Dalle, Bernard, Woronoff, Grange. Analysis and interpretation of data: Ciocan, Barbe, Grange. Drafting of the manuscript: Ciocan, Barbe, Grange. Critical revision of the manuscript for important intellectual content: Barbe, Aubin, Granel-Brocard, Lipsker, Velten, Dalac, Truchetet, Michel, Mitschler, Arnoult, Buemi, Dalle, Bernard, Woronoff. Statistical analysis: Ciocan. Obtained funding: Grange Study supervision: Grange. Conflict of Interest Disclosures: None reported Funding/Support: This study was supported by grants from the Ligue Contre le Cancer, the Société Française de Dermatologie, and the Fondation de France. Role of the Sponsors: The funding organizations had no role in the design and conduct of the study, preparation, review, or approval of the manuscript. Additional Contributions: We thank the physicians and dermatologists who provided data for this study and the following associations of dermatologists: Association d Enseignement Post-Universitaire en Dermato-Vénérologie de Champagne-Ardenne, Association des Dermatologues de Bourgogne, Association d Information Post-Universitaire des Dermato-Vénérologues de Strasbourg, Association de Formation des Dermatologues de Franche-Comté, and Association Lorraine Post-Universitaire de Dermatologie. REFERENCES 1. MacKie RM, Hauschild A, Eggermont AMM. Epidemiology of invasive cutaneous melanoma. Ann Oncol. 2009;20(suppl 6):vi1-vi7. 2. Tsai S, Balch C, Lange J. Epidemiology and treatment of melanoma in elderly patients. Nat Rev Clin Oncol. 2010;7(3): de Vries E, Bray FI, Coebergh JWW, Parkin DM. Changing epidemiology of malignant cutaneous melanoma in Europe : rising trends in incidence and mortality but recent stabilizations in western Europe and decreases in Scandinavia. Int J Cancer. 2003;107(1): Grange F. Epidemiology of cutaneous melanoma: descriptive data in France and Europe [in French]. Ann Dermatol Venereol. 2005;132(12, pt 1): Surveillance epidemiology and end results. Accessed August 6, Chao C, Martin RCG II, Ross MI, et al. Correlation between prognostic factors and increasing age in melanoma. Ann Surg Oncol. 2004;11(3): Austin PF, Cruse CW, Lyman G, Schroer K, Glass F, Reintgen DS. Age as a prognostic factor in the malignant melanoma population. Ann Surg Oncol. 1994;1(6): Barbe C, Hibon E, Vitry F, Le Clainche A, Grange F. Clinical and pathological characteristics of melanoma: a population-based study in a French regional population. J Eur Acad Dermatol Venereol. 2012;26(2): Macdonald JB, Dueck AC, Gray RJ, et al. Malignant melanoma in the elderly: different regional disease and poorer prognosis. J Cancer. 2011;2: Geller AC, Elwood M, Swetter SM, et al. Factors related to the presentation of thin and thick nodular melanoma from a population-based cancer registry in Queensland Australia.Cancer. 2009;115(6): Baumert J, Plewig G, Volkenandt M, Schmid-Wendtner M-H. Factors associated with a high tumour thickness in patients with melanoma. Br J Dermatol. 2007;156(5): Chamberlain AJ, Fritschi L, Giles GG, Dowling JP, Kelly JW. Nodular type and older age as the most significant associations of thick melanoma in Victoria, Australia. Arch Dermatol. 2002;138(5): Hanrahan PF, Hersey P, D Este CA. Factors involved in presentation of older people with thick melanoma.med J Aust. 1998;169(8): JAMA Dermatology October 2013 Volume 149, Number 10 jamadermatology.com

8 Management of Melanoma in the Elderly Original Investigation Research 14. Eisemann N, Jansen L, Holleczek B, et al. Up-to-date results on survival of patients with melanoma in Germany. Br J Dermatol. 2012;167(3): Page AJ, Li A, Hestley A, Murray D, Carlson GW, Delman KA. Increasing age is associated with worse prognostic factors and increased distant recurrences despite fewer sentinel lymph node positives in melanoma. Int J Surg Oncol. 2012;2012: doi: /2012/ Lasithiotakis K, Leiter U, Meier F, et al. Age and gender are significant independent predictors of survival in primary cutaneous melanoma. Cancer. 2008;112(8): Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19(16): Durbec F, Vitry F, Granel-Brocard F, et al. The role of circumstances of diagnosis and access to dermatological care in early diagnosis of cutaneous melanoma: a population-based study in France. Arch Dermatol. 2010;146(3): Grange F, Vitry F, Granel-Brocard F, et al. Variations in management of stage I to stage III cutaneous melanoma: a population-based study of clinical practices in France. Arch Dermatol. 2008;144(5): Lévy-Sitbon C, Barbe C, Granel-Brocard F, et al. Diagnosis and management of melanoma with regional lymph node metastases: a population-based study in France [published online July 30, 2012]. J Eur Acad Dermatol Venereol. Accessed August 6, Grange F, Barbe C, Mas L, et al. The role of general practitioners in diagnosis of cutaneous melanoma: a population-based study in France. Br J Dermatol. 2012;167(6): National Institute of Statistics and Economic Studies. Accessed August 6, Saiag P, Bosquet L, Guillot B, et al; Société Française de Dermatologie. Management of adult patients with cutaneous melanoma without distant metastasis: 2005 update of the French Standards, Options and Recommendations guidelines: summary report. Eur J Dermatol. 2007;17(4): Tragos C, Hieken TJ. Optimizing the management of cutaneous melanoma in the elderly. Surgery.2011;150(4): Cohen HJ, Cox E, Manton K, Woodbury M. Malignant melanoma in the elderly. J Clin Oncol. 1987;5(1): Callender GG, Egger ME, Burton AL, et al. Prognostic implications of anatomic location of primary cutaneous melanoma of 1 mm or thicker. Am J Surg. 2011;202(6): de Vries E, Nijsten TEC, Visser O, et al. Superior survival of females among 10,538 Dutch melanoma patients is independent of Breslow thickness, histologic type and tumor site. Ann Oncol. 2008;19(3): Geller AC, Swetter SM, Oliveria S, Dusza S, Halpern AC. Reducing mortality in individuals at high risk for advanced melanoma through education and screening. J Am Acad Dermatol. 2011;65(5)(suppl 1):S87-S Demierre M-F, Chung C, Miller DR, Geller AC. Early detection of thick melanomas in the United States: beware of the nodular subtype. Arch Dermatol. 2005;141(6): Grange F, Barbe C, Aubin F, et al. Clinical and sociodemographic characteristics associated with thick melanomas: a population-based, case-case study in France. Arch Dermatol. 2012;148(12): Liu W, Dowling JP, Murray WK, et al. Rate of growth in melanomas: characteristics and associations of rapidly growing melanomas. Arch Dermatol. 2006;142(12): Kalkhoran S, Milne O, Zalaudek I, et al. Historical, clinical, and dermoscopic characteristics of thin nodular melanoma. Arch Dermatol. 2010;146(3): Chamberlain AJ, Fritschi L, Kelly JW. Nodular melanoma: patients perceptions of presenting features and implications for earlier detection. JAm Acad Dermatol. 2003;48(5): Adams J, Audisio RA, White M, Forman D. Age-related variations in progression of cancer at diagnosis and completeness of cancer registry data. Surg Oncol. 2004;13(4): Christos PJ, Oliveria SA, Berwick M, et al. Signs and symptoms of melanoma in older populations. J Clin Epidemiol. 2000;53(10): Van Durme DJ, Ferrante JM, Pal N, Wathington D, Roetzheim RG, Gonzalez EC. Demographic predictors of melanoma stage at diagnosis. Arch Fam Med. 2000;9(7): Eberhardt MS, Pamuk ER. The importance of place of residence: examining health in rural and nonrural areas. Am J Public Health. 2004;94(10): Pampalon R, Martinez J, Hamel D. Does living in rural areas make a difference for health in Québec? Health Place. 2006;12(4): Reyes-Ortiz CA, Goodwin JS, Freeman JL, Kuo Y-F. Socioeconomic status and survival in older patients with melanoma. J Am Geriatr Soc. 2006;54(11): Singh SD, Ajani UA, Johnson CJ, et al. Association of cutaneous melanoma incidence with area-based socioeconomic indicators United States, J Am Acad Dermatol. 2011;65(5)(suppl 1):S58-S Swetter SM, Pollitt RA, Johnson TM, Brooks DR, Geller AC. Behavioral determinants of successful early melanoma detection: role of self and physician skin examination. Cancer. 2012;118(15): Chang CK, Jacobs IA, Vizgirda VM, Salti GI. Melanoma in the elderly patient. Arch Surg. 2003;138(10): Livingstone E, Windemuth-Kieselbach C, Eigentler TK, et al. A first prospective population-based analysis investigating the actual practice of melanoma diagnosis, treatment and follow-up. Eur J Cancer. 2011;47(13): Thomas JM, Newton-Bishop J, A Hern R, et al; United Kingdom Melanoma Study Group; British Association of Plastic Surgeons; Scottish Cancer Therapy Network. Excision margins in high-risk malignant melanoma. N Engl J Med. 2004;350(8): Balch CM, Soong SJ, Smith T, et al; Investigators from the Intergroup Melanoma Surgical Trial. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol. 2001;8(2): Veronesi U, Cascinelli N. Narrow excision (1-cm margin): a safe procedure for thin cutaneous melanoma. Arch Surg. 1991;126(4): Morton DL, Thompson JF, Cochran AJ, et al; MSLT Group. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355(13): Wheatley K, Ives N, Hancock B, Gore M, Eggermont A, Suciu S. Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit? a meta-analysis of the randomised trials. Cancer Treat Rev. 2003;29(4): Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010;102(7): Lasithiotakis KG, Leiter U, Eigentler T, et al. Improvement of overall survival of patients with cutaneous melanoma in Germany, : which factors contributed? Cancer. 2007;109(6): jamadermatology.com JAMA Dermatology October 2013 Volume 149, Number