VOLUME
32
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NUMBER
8
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MARCH
10
2014
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Incidence of New Primary Melanomas After Diagnosis of Stage III and IV Melanoma Lisa Zimmer, Lauren E. Haydu, Alexander M. Menzies, Richard A. Scolyer, Richard F. Kefford, John F. Thompson, Dirk Schadendorf, and Georgina V. Long Lisa Zimmer and Dirk Schadendorf, University Hospital, University Duisburg-Essen, Essen, Germany; Lauren E. Haydu, Alexander M. Menzies, Richard A. Scolyer, Richard F. Kefford, John F. Thompson, and Georgina V. Long, Melanoma Institute Australia; Alexander M. Menzies, Richard A. Scolyer, Richard F. Kefford, and Georgina V. Long, Sydney Medical School, The University of Sydney; Richard A. Scolyer and John F. Thompson, Royal Prince Alfred Hospital; Lauren E. Haydu and John F. Thompson, The University of Sydney; John F. Thompson, Mater Hospital, Sydney; Richard F. Kefford and Georgina V. Long, Westmead Institute for Cancer Research, Westmead Hospital, Westmead, New South Wales, Australia. Published online ahead of print at www.jco.org on December 2, 2013. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Lisa Zimmer, MD, Department of Dermatology, University Hospital, University Duisburg-Essen, Hufelandstr 55, 45122 Essen, Germany; e-mail: lisa [email protected].
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Patients and Methods Patients diagnosed with stage III or IV melanoma at Melanoma Institute Australia between 1983 and 2008 were analyzed, and those who received a BRAF inhibitor were excluded. Results Two hundred twenty-nine (5%) of 4,215 patients with stage III melanoma and 43 (1%) of 3,563 patients with stage IV melanoma had at least one NPM after diagnosis of stage III or IV disease. The 6-month, 1-year, and 10-year cumulative incidence rates of developing an NPM after stage III melanoma were 1.2% (95% CI, 0.86% to 1.51%), 1.8% (95% CI, 1.44% to 2.26%), and 5.9% (95% CI, 5.08% to 6.74%), respectively. The 3-month, 6-month, and 1-year cumulative incidence rates of NPM after diagnosis of stage IV melanoma were 0.2% (95% CI, 0.07% to 0.36%), 0.3% (95% CI, 0.15% to 0.51%), and 0.4% (95% CI, 0.25% to 0.7%), respectively. In both patients with stage III and stage IV melanoma, male patients and patients with a prior history of multiple primaries had a higher incidence of NPM. Conclusion Patients with stage III and stage IV melanoma remain at risk for development of further primary melanomas, particularly if they have a history of multiple primary melanomas before stage III or IV disease. The incidence rates are lower than those reported in patients receiving BRAF inhibitors. However, the results must be compared with caution because dermatologic assessment is more frequent in BRAF inhibitor trials. J Clin Oncol 32:816-823. © 2013 by American Society of Clinical Oncology
INTRODUCTION
0732-183X/14/3208w-816w/$20.00
816
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Purpose New primary melanomas (NPMs) have developed in some patients with metastatic melanoma treated with BRAF inhibitors. We sought to determine the background incidence of spontaneous NPMs after a diagnosis of American Joint Committee on Cancer/International Union Against Cancer stage III or IV melanoma in patients not treated with a BRAF inhibitor.
© 2013 by American Society of Clinical Oncology
DOI: 10.1200/JCO.2013.49.5572
R
The incidence of melanoma varies widely among white populations around the world, with the highest incidence in Australia (41.8 per 100,000 for men; 32.1 per 100,000 for women), an intermediate incidence in North America (15.8 per 100,000 for men; 12.5 per 100,000 for women), and the lowest incidence in Western Europe (10.6 per 100,000 for men; 12 per 100,000 for women).1 Patients with a cutaneous melanoma have a 12- to 26-fold increased risk of developing a second primary melanoma compared with the general population.2 This risk remains elevated for more than 20 years after the initial melanoma diagnosis, with a 20-year cumulative risk of 5% to 8.1%.2-5 The risk is greatest in the first year after diagnosis.5-8 Registry-based studies suggest that the cumulative incidence of additional primary
melanomas varies across populations but is correlated with the overall melanoma incidence in the population. At 5 years, the incidence was estimated at 0.6% in Switzerland,4 1.8% in the Netherlands,2 2.1% in the United States,9 and 3.8% in Australia.8 The median overall survival for patients with stage III melanoma is approximately 3.5 years, depending on the substage.10,11 Patients with stage IV metastatic melanoma have a poor prognosis, with a median overall survival of 10 months.11-13 Activating mutations in the BRAF gene occur in approximately 50% of melanomas.14,15 Recently, two type I RAF inhibitors,16 dabrafenib and vemurafenib, have been shown to improve the progression-free and overall survival compared with dacarbazine chemotherapy in phase III clinical trials in patients with advanced-stage V600E BRAF–mutated metastatic melanoma17-19 and are now a standard of care for
© 2013 by American Society of Clinical Oncology
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New Primary Melanomas After Stage III and IV Melanoma
such patients.17-20 The most frequent toxicities from these drugs are cutaneous, including secondary malignancies such as cutaneous squamous cell carcinoma.17,18 The emergence of new primary melanomas (NPMs) in patients treated with BRAF inhibitors was first reported by Dalle et al21 and has been confirmed by others.17-20,22,23 It is currently not known whether the development of NPMs is drug related or simply reflects the natural history because systematic surveillance for NPMs after stage IV diagnosis before BRAF inhibitor treatment in most countries has been nearly nonexistent because of the poor prognosis of this patient population. The incidence of second primary melanomas in patients with stage III and IV melanoma is unknown and would be an important starting point for examining whether NPMs diagnosed during BRAF inhibitor therapy may be drug induced. The objective of this study was to determine the background incidence of spontaneous NPMs after first diagnosis of stage III or IV melanoma in a large cohort of patients who were not treated with a BRAF inhibitor. To represent the same patient population and time frame for the development of NPM as observed in clinical trials of BRAF inhibitors, only patients with stage III or IV melanoma were included and were examined for NPM incidence after their diagnosis of stage III or IV disease.
PATIENTS AND METHODS Patient Selection and Data Collection Patients in the Melanoma Institute Australia (MIA) Melanoma Research Database who were first diagnosed between January 1983 and December 2008 with stage III or IV melanoma either at first presentation or as a recurrence of a previously diagnosed stage I or II primary melanoma were included. Patients diagnosed in a time period before BRAF molecular testing and BRAF inhibitor treatment were included. However, patients with only local recurrence within 5 cm of the primary site and patients with mucosal or uveal primary melanomas were excluded (n ⫽ 117). Patients who subsequently received a BRAF inhibitor (n ⫽ 24) or had no histopathologic confirmation of stage III or IV melanoma (n ⫽ 31) were also excluded. In patients with multiple primary melanomas, before diagnosis of stage III or IV disease, the culprit melanoma was assigned using an algorithm previously described.24 In the Melanoma Research Database, occult primary melanoma is defined as stage III or stage IV melanoma without evidence of a prior invasive cutaneous, mucosal, or ocular primary melanoma. To determine whether a melanoma diagnosed subsequent to the occult primary melanoma was an independent new primary tumor or the culprit primary melanoma, all patients with occult primary melanoma and subsequent primary melanoma were reviewed. A delayed culprit primary melanoma was assigned to the occult disease (as opposed to classifying it as a new primary melanoma) if it drained to the site of regional lymph node occult disease or was in the field of in transit occult disease, and the second primary was recognized within 1 year after diagnosis of the occult disease. For each primary melanoma diagnosed, the date, site, Breslow thickness, Clark level, ulceration, mitotic rate, and American Joint Committee on Cancer 2009 T stage were recorded. Clinical, pathologic, and follow-up data for the patients were retrieved from the MIA database. Follow-Up Patients with stage III melanoma were observed with dermatologic assessment as follows: every 3 months for 2 years, every 6 months for the next 3 years, and yearly thereafter. Patients with stage IV melanoma underwent formal dermatologic assessment rarely; however, patients were reviewed by surgeons and/or medical oncologists on a monthly to yearly basis. Follow-up was defined as the interval between diagnosis of advanced disease and the patient’s death or last follow-up date. Patients with no follow-up information were excluded (n ⫽ 69). www.jco.org
Statistical Analysis The Mann-Whitney U test for medians of continuous values or the 2 test for categorical values was used to compare clinical and pathologic parameters associated with the development of primary melanomas after stage III or IV diagnosis. The characteristics of the culprit and the first subsequent primary melanoma after advanced disease were compared using the Wilcoxon signed rank test for continuous values, the McNemar test for dichotomous categorical values, and the 2 test for all other (nondichotomous) categorical values. Disease-free interval was defined as the interval between diagnosis of the culprit primary melanoma and first diagnosis of stage III or stage IV melanoma. The incidence of a second primary melanoma over time was calculated using a competing risk analysis accounting for death and for the development of stage IV disease as competing risks.25 Incidence over time was calculated from the date of diagnosis of stage III or IV disease to the date of diagnosis of the first NPM after stage III or IV disease, development of stage IV disease, death, or last follow-up. Comparisons of the incidence of NPMs between groups were performed using a Gray’s test for equality while accounting for competing risks. A multivariable proportional hazards model was fit for the subdistribution of competing risks using the competing risks regression function of the cmprsk library using R version 3.0.1 (http://www.r-project.org/). Patients who were first diagnosed between January 1983 and December 2008 with stage III melanoma and who developed distant metastases (stage IV) thereafter where included in both cohorts. In patients who presented initially with stage III disease but then developed metastases, any NPM that developed was assigned as incident to either the stage III cohort or the stage IV cohort depending on the stage of the patient at the time of the NPM diagnosis. Analyses were carried out using SPSS Statistics 19.0 software (SPSS, Chicago, IL) and SAS software, version 9.3 (SAS Institute, Cary, NC).
RESULTS
Cohort Characteristics The study included 5,963 patients who were first diagnosed with American Joint Committee on Cancer/International Union Against Cancer stage III (n ⫽ 4,215) or stage IV (n ⫽ 1,748) melanoma between January 1983 and December 2008. Forty-three percent (n ⫽ 1,815) of patients with stage III disease developed stage IV disease, and these patients were added to the stage IV cohort for analyses of NPM after stage IV (n ⫽ 3,563). Two hundred twenty-nine patients (5%) developed an NPM after diagnosis of stage III disease. Forty-three patients (1%) developed an NPM after stage IV diagnosis. The median follow-up time for the patients with stage III disease was 36.8 months (range, 0.1 to 343.9 months; Table 1), and for the patients with stage IV disease, it was 7.9 months (range, 0.03 to 315.4 months; Table 2). The 5-year cumulative overall survival for patients with stage III disease was 47.7%, and the 1-year cumulative overall survival for patients with stage IV disease was 38.0% (Data Supplement). Of the 229 patients with stage III disease (5%) who had an NPM after stage III diagnosis, 184 patients (80%) had one NPM, 28 (12%) had two NPMs, and 13 (6%) had three NPMs (Data Supplement). Two patients had five and 12 NPMs each after diagnosis of stage III melanoma. Of the 43 patients with stage IV disease (1%) who had an NPM after stage IV diagnosis, 34 patients (79%) had one NPM, seven (16%) had two NPMs, and two (5%) had three NPMs (Data Supplement). The number of primary melanomas before and after stage III or IV disease according to the substage showed no specific trend (Data Supplement). © 2013 by American Society of Clinical Oncology
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Table 1. Demographics and Clinicopathologic Characteristics of Patients With Stage III Melanoma With and Without an NPM After Stage III Diagnosis No NPM After Stage III Diagnosis %
NPM After Stage III Diagnosis
Characteristic
No. of Patients
No. of Patients
%
Total patients Sex Female Male Age at metastatic presentation, years Median Range Follow-up from metastasis, months Median Range Follow-up from culprit melanoma, months Median Range Disease-free interval, months Median Range Culprit primary melanoma Site Head and neck Trunk Arm Leg Occult Other† Breslow thickness, mm Median Range T1 (ⱕ 1 mm) T2 (1.01-2.00 mm) T3 (2.01-4.00 mm) T4 (ⱖ 4.00 mm) Occult Tx (unable to assess) Mitotic rate, per mm2 Median Range Absent Present Occult Not known Ulceration Absent Present Occult Not known
3,986
100
229
100
1,505 2,481
38 62
56 173
24 76
Total Cohort (No. of patients)
P Not tested ⬍ .001
4,215 1,561 2,654
.032 59 4-96
60 19-86
35.0 0.1-343.9
86.3 0.7-318.5
54.9 0.4-594.2
103.9 1.9-467.7
6.1 ⫺10.8-494.3ⴱ
3.8 0-324.5
59 4-96 ⬍ .001 36.8 0.1-343.9 ⬍ .001 57.5 0.4-594.2 .711 6.0 ⫺10.8-494.3ⴱ ⬍ .001
649 1,308 339 1,185 501 4
16.3 32.8 8.5 29.7 12.6 0.1
2.3 0.1-50.0 519 921 1,124 754 501 167
42 97 22 40 28 0
18.3 42.4 9.6 17.5 12.2 0.0 1.9 0.2-13.0
13.0 23.1 28.2 18.9 12.6 4.2
34 69 50 39 28 9
4‡ 1-98
Not tested .015
14.8 30.1 21.8 17.0 12.2 3.9
.035
Not tested Not tested .497
4‡ 1-30
200 2,692 501 593
5.0 67.5 12.6 14.9
14 149 28 38
6.1 65.1 12.2 16.6
1,734 1,193 501 558
43.5 29.9 12.6 14.0
94 71 28 36
41.0 31.0 12.2 15.7
.415 Not tested Not tested .564 Not tested Not tested
691 1,405 361 1,225 529 4 2.3 0.1-50.0 553 990 1,174 793 529 176 4‡ 1-98 214 2,841 529 631 1,828 1,264 529 594
Abbreviation: NPM, new primary melanoma. ⴱ Patients (n ⫽ 5) in whom the culprit melanoma was identified after occult metastatic presentation had a negative disease-free interval. †Includes other and not known. ‡Includes only patients with mitotic rate greater than 0.
Clinicopathologic Characteristics of NPM After Stage III or IV Diagnosis Tables 1 and 2 show the clinicopathologic characteristics of stage III and IV patients with and without an NPM after advanced disease, respectively. Factors correlating with NPM after stage III or IV disease were male sex, longer duration of follow-up, and site of culprit lesion (Tables 1 and 2). In addition, for those with an NPM after stage III 818
© 2013 by American Society of Clinical Oncology
melanoma, the median Breslow thickness of the culprit primary melanoma was less than that in patients without an NPM (1.9 mm v 2.3 mm, respectively; P ⫽ .015; Table 1). The characteristics of the culprit melanoma and the first NPM after stage III and IV disease were compared (Data Supplement). Seventy-nine percent (n ⫽ 180) of the NPMs in the stage III cohort (n ⫽ 229) and 74% (n ⫽ 32) in the stage IV cohort (n ⫽ 43) were JOURNAL OF CLINICAL ONCOLOGY
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New Primary Melanomas After Stage III and IV Melanoma
Table 2. Demographics and Clinicopathologic Characteristics of Patients With Stage IV Melanoma With and Without an NPM After Stage IV Diagnosis No NPM After Stage IV Diagnosis Characteristic Total patients Sex Female Male Age at metastatic presentation, years Median Range Follow-up from metastasis, months Median Range Follow-up from culprit melanoma, months Median Range Disease-free interval, months Median Range Culprit primary melanoma Site Head and neck Trunk Arm Leg Occult Other† Breslow thickness, mm Median Range T1 (ⱕ 1 mm) T2 (1.01-2.00 mm) T3 (2.01-4.00 mm) T4 (ⱖ 4.00 mm) Occult Tx (unable to assess) Mitotic rate, per mm2 Median Range Absent Present Occult Not known Ulceration Absent Present Occult Not known
No. of Patients
%
NPM After Stage IV Diagnosis No. of Patients
%
3,520
100
43
100
1,176 2,344
33 67
5 38
12 88
P
Total Cohort (No. of patients)
Not tested .003
3,563 1,181 2,382
.376 60 16-96
60 36-86
7.8 0.03-315.4
50.4 7.4-290.0
44.7 0.2-569.3
81.0 8.6-533.0
29.7 ⫺5.5-482.5ⴱ
32.7 0-296.4
60 16-96 ⬍ .001 7.9 0.03-315.4 ⬍ .001 45.2 0.2-569.3 .555 29.8 ⫺5.5-482.5ⴱ .031
650 1,293 319 764 488 6
18.5 36.7 9.1 21.7 13.9 0.2
16 13 3 5 6 0
2.3‡ 0.2-50.0 502 725 942 676 488 187
37.2 30.2 7.0 11.6 14.0 0.0
666 1,306 322 769 494 6
Not tested .160
2.3 0.4-6.3 14.3 20.6 26.8 19.2 13.9 5.3
10 6 16 5 6 0
4‡ 1-98
23.3 14.0 37.2 11.6 14.0 0.0
2.3 0.2-50.0 512 731 958 681 494 187
.122
Not tested Not tested .669
4‡ 1-36
4‡ 1-98
187 2,224 488 621
5.3 63.2 13.9 17.6
4 28 6 5
9.3 65.1 14.0 11.6
1,388 1,065 488 579
39.4 30.3 13.9 16.5
19 9 6 9
44.2 20.9 14.0 20.9
.321 Not tested Not tested .231 Not tested Not tested
191 2,252 494 626 1,407 1,074 494 588
Abbreviation: NPM, new primary melanoma. ⴱ Patients (n ⫽ 2) in whom the culprit melanoma was identified after occult metastatic presentation had a negative disease-free interval. †Includes other and not known. ‡Including only cases with Breslow thickness or mitotic rate greater than 0.
invasive. The first NPMs after stage III diagnosis, compared with the culprit melanomas, were thinner (48% v 15% were ⱕ 1.0 mm, respectively; P ⬍ .001), were more likely to have absent mitoses (26% v 6%, respectively; P ⬍ .001), and were less likely to be ulcerated (59% v 41%, respectively; P ⬍ .001; Data Supplement). In the stage IV group, the only significant finding was that the first NPMs were thinner than the culprit melanomas (median, 0.8 mm v 2.3 mm, respectively; P ⫽ .009; Data Supplement). www.jco.org
Cumulative Risk The 6-month, 1-year, and 10-year cumulative incidence rates of an NPM after diagnosis of stage III melanoma were 1.2% (95% CI, 0.86% to 1.51%), 1.8% (95% CI, 1.44% to 2.26%), and 5.9% (95% CI, 5.08% to 6.74%), respectively, with nearly half the risk accumulating within the first 2 years (Table 3, Fig 1A). Diagnosis of stage IV disease or death was more common than the diagnosis of an NPM after stage III melanoma. The 3-month, 6-month, and 1-year cumulative © 2013 by American Society of Clinical Oncology
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Table 3. Cumulative Incidence of New Primary Melanoma After Stage III or IV Melanoma Diagnosis Including Death as a Competing Risk Melanoma Stage and Interval To Advanced Primary
Cumulative Incidence (%)
Standard Error (%)
95% CI (%)
0.762 1.149 1.813 2.550 4.234 5.871
0.134 0.165 0.208 0.247 0.326 0.421
0.533 to 1.064 0.860 to 1.509 1.440 to 2.255 2.098 to 3.068 3.628 to 4.907 5.083 to 6.735
0.170 0.285 0.431 0.707 0.950 1.283
0.070 0.090 0.111 0.144 0.171 0.212
0.073 to 0.361 0.148 to 0.513 0.254 to 0.697 0.467 to 1.037 0.659 to 1.333 0.917 to 1.753
Stage IIIⴱ 3 months 6 months 1 year 2 years 5 years 10 years Stage IV 3 months 6 months 1 year 2 years 5 years 10 years
Male patients and patients with a prior history of multiple primary melanoma before or at stage III or IV diagnosis had a higher incidence of NPMs after stage III or stage IV (Figs 1B and 1C; Figs 2B and 2C; Data Supplement). This result was confirmed in a multivariable competing risks regression analysis (Table 4). In the stage III cohort, the 1-year incidence was 6% in those with a prior history of multiple primaries compared with 2% for patients with only a single primary (P ⬍ .001; Fig 1C, Data Supplement); similarly, in the stage IV cohort, the 1-year incidence rates were 1% and 0.4%, respectively (P ⬍ .002; Fig 2C, Data Supplement). Age was not associated with the incidence of NPMs after stage IV diagnosis. Patients age ⱖ 60 years had a higher incidence of NPMs after stage III melanoma compared with younger patients (3% v 1%, respectively; P ⬍ .028; Figs 1D and 2D, Data Supplement); however, this result lost significance in multivariable competing risks regression (Table 4). DISCUSSION
ⴱ
Crossover to stage IV diagnosis also counted as a competing risk.
incidence rates of developing an NPM after diagnosis of stage IV melanoma were 0.2% (95% CI, 0.07% to 0.36%), 0.3% (95% CI, 0.15% to 0.51%), and 0.4% (95% CI, 0.25% to 0.7%), respectively, with most of the risk occurring within the first 6 months (Table 3, Fig 2A).
Cumulative Incidence
1.0
New primary melanoma after stage III Diagnosis of stage IV or death without a new primary
0.8
0.6
0.4
0.2
0
B Cumulative Incidence
A
This is the first report, to our knowledge, of the cumulative incidence of NPMs after diagnosis of stage III or IV melanoma. In contrast to previous studies2,3,6-8,26 that have assessed incidence in earlier stage melanoma or the overall incidence regardless of stage (Data Supplement), we report the incidence of NPM from date of stage III or IV disease to death or last follow-up, focusing on the same time frame as
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
.150
Female Male
.125 .100 .075 .050 .025
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Time (years)
Cumulative Incidence
.25
D
Single primary Multiple primaries
Cumulative Incidence
C
.20
.15
.10
.05
0
Time (years)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Time (years)
.150
Age < 60 years Age ≥ 60 years
.100
.075
.050
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Time (years)
Fig 1. The cumulative incidence of a new primary melanoma after diagnosis of stage III melanoma. (A) Incidence of new primary melanoma versus incidence of death or diagnosis of stage IV disease without a new primary melanoma. (B) Incidence in males versus females. (C) Incidence in patients with multiple primaries at or before stage III diagnosis versus patients with only a single primary before stage III diagnosis. (D) Incidence in older patients (ⱖ 60 years) versus younger patients (⬍ 60 years). 820
© 2013 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
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New Primary Melanomas After Stage III and IV Melanoma
B
Cumulative Incidence
1.0
0.8
0.6 Death without a new primary New primary melanoma after stage IV
0.4
0.2
0
Cumulative Incidence
A
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
.030
Female Male
.025 .020 .015 .010 .005
0
1
2
3
4
5
6
Time (years)
Cumulative Incidence
.03
D
Single primary Multiple primaries
.02
.01
0
1
2
3
4
5
6
7
8
8
9 10 11 12 13 14 15 16 17
Time (years)
Cumulative Incidence
C
7
9 10 11 12 13 14 15 16 17
Time (years)
.025
Age < 60 years Age ≥ 60 years
.020
.015
.010
.005
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17
Time (years)
Fig 2. The cumulative incidence of a new primary melanoma after diagnosis of stage IV melanoma. (A) Incidence of new primary melanoma versus incidence of death without a new primary melanoma. (B) Incidence in males versus females. (C) Incidence in patients with multiple primaries at or before stage IV diagnosis versus patients with only a single primary before stage IV diagnosis. (D) Incidence in older patients (ⱖ 60 years) versus younger patients (⬍ 60 years).
in clinical trials in patients undergoing therapy with BRAF inhibitors. This study included a large cohort of patients with stage III and IV melanoma who had detailed follow-up data and had not been treated with a BRAF inhibitor, with similar overall survival as that reported by Balch et al.11
Table 4. Multivariable Competing Risks Regression of Time to Development of NPM After Diagnosis of Stage III or IV Melanoma Factor Stage III cohort (n ⫽ 4,215) Male Age ⱖ 60 years at diagnosis with stage III Positive history of multiple primary melanoma Stage IV cohort (n ⫽ 3,563) Male Positive history of multiple primary melanomasⴱ
Hazard Ratio
95% CI
P
1.72 1.14
1.28 to 2.32 ⬍ .001 0.88 to 1.49 .320
3.19
2.24 to 4.52 ⬍ .001
3.71
1.46 to 9.44
.006
2.64
1.27 to 5.52
.010
Abbreviation: NPM, new primary melanoma. ⴱ A history of multiple primary melanomas at or before the diagnosis of stage III or IV disease includes the culprit melanoma and any primary melanoma diagnosed before stage III or IV disease.
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The major limitation of this study is the lack of rigorous and regular protocol-driven dermatologic surveillance for NPMs, particularly in patients with stage IV melanoma. This was because of their poor prognosis and the lack of effective therapies during that time period. Other limitations include the referral bias associated with MIA, a large quaternary referral center, although the demographics and primary features of the patients were consistent with the general Australian population3,8; the possibility of misclassification of satellite nodules, in-transit metastases, or subcutaneous nodules as NPMs or vice versa, although several clinical and pathologic features assist accurate classification27; the different follow-up time between those with an NPM and those without an NPM after diagnosis of stage III or IV melanoma; and the underlying Australian population with a genetic background (CDKN2A mutations)28 and incidence rates specific to Australia.1,3,8 In this study, the 1-year cumulative incidence rates of NPMs after diagnosis of stage III or IV disease were 1.8% and 0.4%, respectively. Consistent with previous findings,2,6,7 the NPMs after stage III and IV melanoma were thinner compared with the culprit melanoma. This trend toward thinner melanomas is likely a result of surveillance and early detection of any additional melanoma as well as less aggressive tumor biology in patients with multiple primary melanomas.7 However, given the lack of surveillance in patients with stage IV disease in © 2013 by American Society of Clinical Oncology
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this study, the stage III incidence rate may be a more accurate measure of the incidence of NPMs after metastasis. Because the NPMs after stage III diagnosis were thinner, less likely to be ulcerated, and more likely to have absent mitoses than the initial culprit melanoma, this suggests that most patients in this study were actively surveyed as per protocol (ie, thorough dermatologic assessment at least once a year, in addition to more frequent surgical oncology reviews). The development of NPMs in patients treated with BRAF inhibitors in phase III trials17-20 of vemurafenib and dabrafenib has been reported, at rates of 2.4% (eight of 337 patients) and 1.6% (three of 187 patients), respectively, with a median follow-up time of 13 and 10.5 months, respectively. It is not known whether the development of NPMs is drug related, perhaps caused by paradoxical activation of the MAP kinase pathway via CRAF in BRAF wild-type cells,29,30 or simply reflects the natural history that was not previously apparent because of the frequent lack of dermatologic surveillance in patients with stage IV disease before BRAF inhibitor treatment and outside of clinical trials. However, the degree of discordance between primary and NPM BRAF genotypes observed in patients treated with BRAF inhibitors (100%)21-23 compared with those not treated (36%),31 as well as the timing of NPMs,22 would further support that NPMs after BRAF inhibitor treatment may be drug induced. Furthermore, there is emerging evidence that BRAF inhibitors may induce other noncutaneous malignancies.32,33 In our study, the 1-year incidence of NPMs after stage III or IV melanoma was higher in those with a history of multiple primary melanomas, a group of patients who are less likely to have the BRAF mutation15 and who are more likely to have a better overall survival from diagnosis of distant metastases.24 This suggests that the cumulative incidence could be even lower than our reported figure in those with a BRAF mutation, and thus the difference compared with the BRAF inhibitor trials even greater. When the analysis was adjusted for other predictive factors, a history of multiple primary melanomas retained its strong prognostic utility (Table 4). This is consistent with the reported higher risk of a third primary melanoma after a second primary melanoma.6,7 Given the fact that patients with multiple primaries may harbor germline CDKN2A mutations, ideally these patients should be excluded from analysis because the risk in these individuals is determined by a known genotype. However, in the Australian population, the proportion of such patients is lower than in other populations. In the international, multicenter, population-based, case-control study of melanoma, the Genes Environment and Melanoma (GEM) Study,28 the rates of CDKN2A mutations in patients from New South Wales were 1.0% for single primary melanoma and 2.0% for multiple primary melanomas. Referring to those rates, it can be concluded that an exclusion of patients with CDKN2A mutations will lead to similar overall results. In conclusion, patients with stage III or IV melanoma, especially those with a prior history of multiple primaries, remain at risk for development of further primary melanomas after the diagnosis of stage III or IV melanoma. Whether patients with stage IV melanoma REFERENCES 1. International Agency for Research on Cancer: Cancer incidence in five continents. Vol IX. CANCERMondial. Lyon, France, IARC Cancer822
© 2013 by American Society of Clinical Oncology
should undergo surveillance for NPMs remains arguable at this point in time because of improved17-20,34-36 but still poor overall survival in this patient cohort. Although the incidence rates are lower than those observed in the studies of dabrafenib and vemurafenib, the results must be compared with caution because of the more frequent and thorough dermatologic assessments in the BRAF inhibitor studies. The true effect of BRAF inhibitors on the incidence of NPMs will be assessed prospectively in the randomized, placebo-controlled, adjuvant clinical trial of vemurafenib (NCT01667419). AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Lisa Zimmer, Bristol-Myers Squibb (C); Richard A. Scolyer, Roche (C), GlaxoSmithKline (C); Richard F. Kefford, Roche (C), GlaxoSmithKline (C); John F. Thompson, Roche (C), GlaxoSmithKline (C); Dirk Schadendorf, Roche (C), GlaxoSmithKline (C), Novartis (C), Amgen (C), AstraZeneca (C), Morphotek (C), Merck Sharp & Dohme (C), Bristol-Myers Squibb (C); Georgina V. Long, Roche (C), GlaxoSmithKline (C), Novartis (C) Stock Ownership: None Honoraria: Lisa Zimmer, Roche, Bristol-Myers Squibb, Amgen; Alexander M. Menzies, Roche; Richard A. Scolyer, Abbott Molecular; Richard F. Kefford, Roche, GlaxoSmithKline; Dirk Schadendorf, Roche, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Morphotek, AstraZeneca; Georgina V. Long, Roche Research Funding: Dirk Schadendorf, Merck Sharp & Dohme Expert Testimony: None Patents: None Other Remuneration: Lisa Zimmer, Bristol-Meyers Squibb, Merck Sharp & Dohme, Roche; Alexander M. Menzies, GlaxoSmithKline, Roche; Richard F. Kefford, GlaxoSmithKline; Dirk Schadendorf, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme
AUTHOR CONTRIBUTIONS Conception and design: Lisa Zimmer, Lauren E. Haydu, Dirk Schadendorf, Georgina V. Long Provision of study materials or patients: Lauren E. Haydu, Alexander M. Menzies, Richard F. Kefford, John F. Thompson, Georgina V. Long Collection and assembly of data: Lisa Zimmer, Lauren E. Haydu, Richard A. Scolyer, Georgina V. Long Data analysis and interpretation: Lisa Zimmer, Lauren E. Haydu, Alexander M. Menzies, Richard A. Scolyer, Richard F. Kefford, John F. Thompson, Dirk Schadendorf, Georgina V. Long Manuscript writing: All authors Final approval of manuscript: All authors
Base, No 160, 2007; (France) Vol IX. http://www .dep.iarc.fr/ 2. van der Leest RJ, Liu L, Coebergh JW, et al: Risk of second primary in situ and invasive melanoma in Dutch population-based cohort: 1989-2008. Br J Dermatol 167:1321-1330, 2012
3. Karahalios E, English D, Thursfield V, et al: Second primary cancers in Victoria, Victorian Cancer Registry 1982-2005. http:// www.cancervic.org.au/about-our-research/ registry-statistics/cancer-in-victoria/secondprimary-cancers-victoria JOURNAL OF CLINICAL ONCOLOGY
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New Primary Melanomas After Stage III and IV Melanoma
4. Levi F, Randimbison L, Te VC, et al: High constant incidence rates of second cutaneous melanomas. Int J Cancer 117:877-879, 2005 5. Bradford PT, Freedman DM, Goldstein AM, et al: Increased risk of second primary cancers after a diagnosis of melanoma. Arch Dermatol 146:265272, 2010 6. Hwa C, Price LS, Belitskaya-Levy I, et al: Single versus multiple primary melanomas: Old questions and new answers. Cancer 118:41844192, 2012 7. Ferrone CR, Ben Porat L, Panageas KS, et al: Clinicopathological features of and risk factors for multiple primary melanomas. JAMA 294:1647-1654, 2005 8. McCaul KA, Fritschi L, Baade P, et al: The incidence of second primary invasive melanoma in Queensland, 1982-2003. Cancer Causes Control 19: 451-458, 2008 9. Goggins WB, Tsao H: A population-based analysis of risk factors for a second primary cutaneous melanoma among melanoma survivors. Cancer 97:639-643, 2003 10. Lee CC, Faries MB, Wanek LA, et al: Improved survival after lymphadenectomy for nodal metastasis from an unknown primary melanoma. J Clin Oncol 26:535-541, 2008 11. Balch CM, Gershenwald JE, Soong SJ, et al: Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27:6199-6206, 2009 12. Atkins M, Long G, Warneke C, et al: Unraveling the prognostic heterogeneity in patients with advanced melanoma between Australia (OZ) and the United States (US): Preliminary report of the PHAMOUS study. J Clin Oncol 28, 2010 (suppl 15S; abstr 8516) 13. Lee CC, Faries MB, Wanek LA, et al: Improved survival for stage IV melanoma from an unknown primary site. J Clin Oncol 27:3489-3495, 2009 14. Davies H, Bignell GR, Cox C, et al: Mutations of the BRAF gene in human cancer. Nature 417:949954, 2002 15. Long GV, Menzies AM, Nagrial AM, et al: Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 29:1239-1246, 2011
16. Ribas A, Flaherty KT: BRAF targeted therapy changes the treatment paradigm in melanoma. Nat Rev Clin Oncol 8:426-433, 2011 17. Hauschild A, Grob JJ, Demidov LV, et al: Dabrafenib in BRAF-mutated metastatic melanoma: A multicentre, open-label, phase 3 randomised controlled trial. Lancet 380:358-365, 2012 18. Chapman PB, Hauschild A, Robert C, et al: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364: 2507-2516, 2011 19. Hauschild A, Grob JJ, Demidov LV, et al: An update on BREAK-3, a phase III, randomized trial: Dabrafenib (DAB) versus dacarbazine (DTIC) in patients with BRAF V600E-positive mutation metastatic melanoma (MM). J Clin Oncol 31, 2013 (suppl; abstr 9013) 20. Chapman PB, Hauschild A, Robert C, et al: Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. J Clin Oncol 30, 2012 (suppl; abstr 8502) 21. Dalle S, Poulalhon N, Thomas L: Vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 365:1448-1449, 2011 22. Zimmer L, Hillen U, Livingstone E, et al: Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J Clin Oncol 30:2375-2383, 2012 23. Haenssle HA, Kraus SL, Brehmer F, et al: Dynamic changes in nevi of a patient with melanoma treated with vemurafenib: Importance of sequential dermoscopy. Arch Dermatol 148:11831185, 2012 24. Murali R, Brown PT, Kefford RF, et al: Number of primary melanomas is an independent predictor of survival in patients with metastatic melanoma. Cancer 118:4519-4529, 2012 25. Sherif BN: A comparison of Kaplan-Meier and cumulative incidence estimate in the presence or absence of competing risks in breast cancer data. Submitted to the Graduate Faculty of Graduate School of Public Health in partial fulfillment of the requirements for the degree of Master of Science, University of Pittsburgh, Pittsburgh, PA, 2007.
http://d-scholarship.pitt.edu/9986/1/BintuSherif_ thesis%5B1%5D.pdf 26. DiFronzo LA, Wanek LA, Elashoff R, et al: Increased incidence of second primary melanoma in patients with a previous cutaneous melanoma. Ann Surg Oncol 6:705-711, 1999 27. Orlow I, Tommasi DV, Bloom B, et al: Evaluation of the clonal origin of multiple primary melanomas using molecular profiling. J Invest Dermatol 129:1972-1982, 2009 28. Berwick M, Orlow I, Hummer AJ, et al: The prevalence of CDKN2A germ-line mutations and relative risk for cutaneous malignant melanoma: An international population-based study. Cancer Epidemiol Biomarkers Prev 15:1520-1525, 2006 29. Poulikakos PI, Zhang C, Bollag G, et al: RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464:427430, 2010 30. Hatzivassiliou G, Song K, Yen I, et al: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464:431-435, 2010 31. Palmieri G, Sini M, De Giorgi V, et al: Assessment of germ-line and somatic alterations in main candidate genes among patients with multiple primary melanoma. J Clin Oncol 30, 2012 (suppl; abstr 8581) 32. Chapman P, Metz D, Sepulveda A, et al: Development of colonic adenomas and gastric polyps in BRAF mutant melanoma patients treated with vemurafenib. Pigment Cell Melanoma Res 25:847, 2012 (abstr) 33. Callahan MK, Rampal R, Harding JJ, et al: Progression of RAS-mutant leukemia during RAF inhibitor treatment. N Engl J Med 367:2316-2321, 2012 34. Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364: 2517-2526, 2011 35. Flaherty KT, Infante JR, Daud A, et al: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367:16941703, 2012 36. Flaherty KT, Robert C, Hersey P, et al: Improved survival with MEK inhibition in BRAFmutated melanoma. N Engl J Med 367:107-114, 2012
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Acknowledgment We thank the staff at Melanoma Institute Australia.
© 2013 by American Society of Clinical Oncology
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Incidence of New Primary Melanomas After Diagnosis of Stage III and IV Melanoma Lisa Zimmer, Lauren E. Haydu, Alexander M. Menzies, Richard A. Scolyer, Richard F. Kefford, John F. Thompson, Dirk Schadendorf, and Georgina V. Long Lisa Zimmer and Dirk Schadendorf, University Hospital, University Duisburg-Essen, Essen, Germany; Lauren E. Haydu, Alexander M. Menzies, Richard A. Scolyer, Richard F. Kefford, John F. Thompson, and Georgina V. Long, Melanoma Institute Australia; Alexander M. Menzies, Richard A. Scolyer, Richard F. Kefford, and Georgina V. Long, Sydney Medical School, The University of Sydney; Richard A. Scolyer and John F. Thompson, Royal Prince Alfred Hospital; Lauren E. Haydu and John F. Thompson, The University of Sydney; John F. Thompson, Mater Hospital, Sydney; Richard F. Kefford and Georgina V. Long, Westmead Institute for Cancer Research, Westmead Hospital, Westmead, New South Wales, Australia. Published online ahead of print at www.jco.org on December 2, 2013. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Lisa Zimmer, MD, Department of Dermatology, University Hospital, University Duisburg-Essen, Hufelandstr 55, 45122 Essen, Germany; e-mail: lisa [email protected].
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Patients and Methods Patients diagnosed with stage III or IV melanoma at Melanoma Institute Australia between 1983 and 2008 were analyzed, and those who received a BRAF inhibitor were excluded. Results Two hundred twenty-nine (5%) of 4,215 patients with stage III melanoma and 43 (1%) of 3,563 patients with stage IV melanoma had at least one NPM after diagnosis of stage III or IV disease. The 6-month, 1-year, and 10-year cumulative incidence rates of developing an NPM after stage III melanoma were 1.2% (95% CI, 0.86% to 1.51%), 1.8% (95% CI, 1.44% to 2.26%), and 5.9% (95% CI, 5.08% to 6.74%), respectively. The 3-month, 6-month, and 1-year cumulative incidence rates of NPM after diagnosis of stage IV melanoma were 0.2% (95% CI, 0.07% to 0.36%), 0.3% (95% CI, 0.15% to 0.51%), and 0.4% (95% CI, 0.25% to 0.7%), respectively. In both patients with stage III and stage IV melanoma, male patients and patients with a prior history of multiple primaries had a higher incidence of NPM. Conclusion Patients with stage III and stage IV melanoma remain at risk for development of further primary melanomas, particularly if they have a history of multiple primary melanomas before stage III or IV disease. The incidence rates are lower than those reported in patients receiving BRAF inhibitors. However, the results must be compared with caution because dermatologic assessment is more frequent in BRAF inhibitor trials. J Clin Oncol 32:816-823. © 2013 by American Society of Clinical Oncology
INTRODUCTION
0732-183X/14/3208w-816w/$20.00
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Purpose New primary melanomas (NPMs) have developed in some patients with metastatic melanoma treated with BRAF inhibitors. We sought to determine the background incidence of spontaneous NPMs after a diagnosis of American Joint Committee on Cancer/International Union Against Cancer stage III or IV melanoma in patients not treated with a BRAF inhibitor.
© 2013 by American Society of Clinical Oncology
DOI: 10.1200/JCO.2013.49.5572
R
The incidence of melanoma varies widely among white populations around the world, with the highest incidence in Australia (41.8 per 100,000 for men; 32.1 per 100,000 for women), an intermediate incidence in North America (15.8 per 100,000 for men; 12.5 per 100,000 for women), and the lowest incidence in Western Europe (10.6 per 100,000 for men; 12 per 100,000 for women).1 Patients with a cutaneous melanoma have a 12- to 26-fold increased risk of developing a second primary melanoma compared with the general population.2 This risk remains elevated for more than 20 years after the initial melanoma diagnosis, with a 20-year cumulative risk of 5% to 8.1%.2-5 The risk is greatest in the first year after diagnosis.5-8 Registry-based studies suggest that the cumulative incidence of additional primary
melanomas varies across populations but is correlated with the overall melanoma incidence in the population. At 5 years, the incidence was estimated at 0.6% in Switzerland,4 1.8% in the Netherlands,2 2.1% in the United States,9 and 3.8% in Australia.8 The median overall survival for patients with stage III melanoma is approximately 3.5 years, depending on the substage.10,11 Patients with stage IV metastatic melanoma have a poor prognosis, with a median overall survival of 10 months.11-13 Activating mutations in the BRAF gene occur in approximately 50% of melanomas.14,15 Recently, two type I RAF inhibitors,16 dabrafenib and vemurafenib, have been shown to improve the progression-free and overall survival compared with dacarbazine chemotherapy in phase III clinical trials in patients with advanced-stage V600E BRAF–mutated metastatic melanoma17-19 and are now a standard of care for
© 2013 by American Society of Clinical Oncology
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New Primary Melanomas After Stage III and IV Melanoma
such patients.17-20 The most frequent toxicities from these drugs are cutaneous, including secondary malignancies such as cutaneous squamous cell carcinoma.17,18 The emergence of new primary melanomas (NPMs) in patients treated with BRAF inhibitors was first reported by Dalle et al21 and has been confirmed by others.17-20,22,23 It is currently not known whether the development of NPMs is drug related or simply reflects the natural history because systematic surveillance for NPMs after stage IV diagnosis before BRAF inhibitor treatment in most countries has been nearly nonexistent because of the poor prognosis of this patient population. The incidence of second primary melanomas in patients with stage III and IV melanoma is unknown and would be an important starting point for examining whether NPMs diagnosed during BRAF inhibitor therapy may be drug induced. The objective of this study was to determine the background incidence of spontaneous NPMs after first diagnosis of stage III or IV melanoma in a large cohort of patients who were not treated with a BRAF inhibitor. To represent the same patient population and time frame for the development of NPM as observed in clinical trials of BRAF inhibitors, only patients with stage III or IV melanoma were included and were examined for NPM incidence after their diagnosis of stage III or IV disease.
PATIENTS AND METHODS Patient Selection and Data Collection Patients in the Melanoma Institute Australia (MIA) Melanoma Research Database who were first diagnosed between January 1983 and December 2008 with stage III or IV melanoma either at first presentation or as a recurrence of a previously diagnosed stage I or II primary melanoma were included. Patients diagnosed in a time period before BRAF molecular testing and BRAF inhibitor treatment were included. However, patients with only local recurrence within 5 cm of the primary site and patients with mucosal or uveal primary melanomas were excluded (n ⫽ 117). Patients who subsequently received a BRAF inhibitor (n ⫽ 24) or had no histopathologic confirmation of stage III or IV melanoma (n ⫽ 31) were also excluded. In patients with multiple primary melanomas, before diagnosis of stage III or IV disease, the culprit melanoma was assigned using an algorithm previously described.24 In the Melanoma Research Database, occult primary melanoma is defined as stage III or stage IV melanoma without evidence of a prior invasive cutaneous, mucosal, or ocular primary melanoma. To determine whether a melanoma diagnosed subsequent to the occult primary melanoma was an independent new primary tumor or the culprit primary melanoma, all patients with occult primary melanoma and subsequent primary melanoma were reviewed. A delayed culprit primary melanoma was assigned to the occult disease (as opposed to classifying it as a new primary melanoma) if it drained to the site of regional lymph node occult disease or was in the field of in transit occult disease, and the second primary was recognized within 1 year after diagnosis of the occult disease. For each primary melanoma diagnosed, the date, site, Breslow thickness, Clark level, ulceration, mitotic rate, and American Joint Committee on Cancer 2009 T stage were recorded. Clinical, pathologic, and follow-up data for the patients were retrieved from the MIA database. Follow-Up Patients with stage III melanoma were observed with dermatologic assessment as follows: every 3 months for 2 years, every 6 months for the next 3 years, and yearly thereafter. Patients with stage IV melanoma underwent formal dermatologic assessment rarely; however, patients were reviewed by surgeons and/or medical oncologists on a monthly to yearly basis. Follow-up was defined as the interval between diagnosis of advanced disease and the patient’s death or last follow-up date. Patients with no follow-up information were excluded (n ⫽ 69). www.jco.org
Statistical Analysis The Mann-Whitney U test for medians of continuous values or the 2 test for categorical values was used to compare clinical and pathologic parameters associated with the development of primary melanomas after stage III or IV diagnosis. The characteristics of the culprit and the first subsequent primary melanoma after advanced disease were compared using the Wilcoxon signed rank test for continuous values, the McNemar test for dichotomous categorical values, and the 2 test for all other (nondichotomous) categorical values. Disease-free interval was defined as the interval between diagnosis of the culprit primary melanoma and first diagnosis of stage III or stage IV melanoma. The incidence of a second primary melanoma over time was calculated using a competing risk analysis accounting for death and for the development of stage IV disease as competing risks.25 Incidence over time was calculated from the date of diagnosis of stage III or IV disease to the date of diagnosis of the first NPM after stage III or IV disease, development of stage IV disease, death, or last follow-up. Comparisons of the incidence of NPMs between groups were performed using a Gray’s test for equality while accounting for competing risks. A multivariable proportional hazards model was fit for the subdistribution of competing risks using the competing risks regression function of the cmprsk library using R version 3.0.1 (http://www.r-project.org/). Patients who were first diagnosed between January 1983 and December 2008 with stage III melanoma and who developed distant metastases (stage IV) thereafter where included in both cohorts. In patients who presented initially with stage III disease but then developed metastases, any NPM that developed was assigned as incident to either the stage III cohort or the stage IV cohort depending on the stage of the patient at the time of the NPM diagnosis. Analyses were carried out using SPSS Statistics 19.0 software (SPSS, Chicago, IL) and SAS software, version 9.3 (SAS Institute, Cary, NC).
RESULTS
Cohort Characteristics The study included 5,963 patients who were first diagnosed with American Joint Committee on Cancer/International Union Against Cancer stage III (n ⫽ 4,215) or stage IV (n ⫽ 1,748) melanoma between January 1983 and December 2008. Forty-three percent (n ⫽ 1,815) of patients with stage III disease developed stage IV disease, and these patients were added to the stage IV cohort for analyses of NPM after stage IV (n ⫽ 3,563). Two hundred twenty-nine patients (5%) developed an NPM after diagnosis of stage III disease. Forty-three patients (1%) developed an NPM after stage IV diagnosis. The median follow-up time for the patients with stage III disease was 36.8 months (range, 0.1 to 343.9 months; Table 1), and for the patients with stage IV disease, it was 7.9 months (range, 0.03 to 315.4 months; Table 2). The 5-year cumulative overall survival for patients with stage III disease was 47.7%, and the 1-year cumulative overall survival for patients with stage IV disease was 38.0% (Data Supplement). Of the 229 patients with stage III disease (5%) who had an NPM after stage III diagnosis, 184 patients (80%) had one NPM, 28 (12%) had two NPMs, and 13 (6%) had three NPMs (Data Supplement). Two patients had five and 12 NPMs each after diagnosis of stage III melanoma. Of the 43 patients with stage IV disease (1%) who had an NPM after stage IV diagnosis, 34 patients (79%) had one NPM, seven (16%) had two NPMs, and two (5%) had three NPMs (Data Supplement). The number of primary melanomas before and after stage III or IV disease according to the substage showed no specific trend (Data Supplement). © 2013 by American Society of Clinical Oncology
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Table 1. Demographics and Clinicopathologic Characteristics of Patients With Stage III Melanoma With and Without an NPM After Stage III Diagnosis No NPM After Stage III Diagnosis %
NPM After Stage III Diagnosis
Characteristic
No. of Patients
No. of Patients
%
Total patients Sex Female Male Age at metastatic presentation, years Median Range Follow-up from metastasis, months Median Range Follow-up from culprit melanoma, months Median Range Disease-free interval, months Median Range Culprit primary melanoma Site Head and neck Trunk Arm Leg Occult Other† Breslow thickness, mm Median Range T1 (ⱕ 1 mm) T2 (1.01-2.00 mm) T3 (2.01-4.00 mm) T4 (ⱖ 4.00 mm) Occult Tx (unable to assess) Mitotic rate, per mm2 Median Range Absent Present Occult Not known Ulceration Absent Present Occult Not known
3,986
100
229
100
1,505 2,481
38 62
56 173
24 76
Total Cohort (No. of patients)
P Not tested ⬍ .001
4,215 1,561 2,654
.032 59 4-96
60 19-86
35.0 0.1-343.9
86.3 0.7-318.5
54.9 0.4-594.2
103.9 1.9-467.7
6.1 ⫺10.8-494.3ⴱ
3.8 0-324.5
59 4-96 ⬍ .001 36.8 0.1-343.9 ⬍ .001 57.5 0.4-594.2 .711 6.0 ⫺10.8-494.3ⴱ ⬍ .001
649 1,308 339 1,185 501 4
16.3 32.8 8.5 29.7 12.6 0.1
2.3 0.1-50.0 519 921 1,124 754 501 167
42 97 22 40 28 0
18.3 42.4 9.6 17.5 12.2 0.0 1.9 0.2-13.0
13.0 23.1 28.2 18.9 12.6 4.2
34 69 50 39 28 9
4‡ 1-98
Not tested .015
14.8 30.1 21.8 17.0 12.2 3.9
.035
Not tested Not tested .497
4‡ 1-30
200 2,692 501 593
5.0 67.5 12.6 14.9
14 149 28 38
6.1 65.1 12.2 16.6
1,734 1,193 501 558
43.5 29.9 12.6 14.0
94 71 28 36
41.0 31.0 12.2 15.7
.415 Not tested Not tested .564 Not tested Not tested
691 1,405 361 1,225 529 4 2.3 0.1-50.0 553 990 1,174 793 529 176 4‡ 1-98 214 2,841 529 631 1,828 1,264 529 594
Abbreviation: NPM, new primary melanoma. ⴱ Patients (n ⫽ 5) in whom the culprit melanoma was identified after occult metastatic presentation had a negative disease-free interval. †Includes other and not known. ‡Includes only patients with mitotic rate greater than 0.
Clinicopathologic Characteristics of NPM After Stage III or IV Diagnosis Tables 1 and 2 show the clinicopathologic characteristics of stage III and IV patients with and without an NPM after advanced disease, respectively. Factors correlating with NPM after stage III or IV disease were male sex, longer duration of follow-up, and site of culprit lesion (Tables 1 and 2). In addition, for those with an NPM after stage III 818
© 2013 by American Society of Clinical Oncology
melanoma, the median Breslow thickness of the culprit primary melanoma was less than that in patients without an NPM (1.9 mm v 2.3 mm, respectively; P ⫽ .015; Table 1). The characteristics of the culprit melanoma and the first NPM after stage III and IV disease were compared (Data Supplement). Seventy-nine percent (n ⫽ 180) of the NPMs in the stage III cohort (n ⫽ 229) and 74% (n ⫽ 32) in the stage IV cohort (n ⫽ 43) were JOURNAL OF CLINICAL ONCOLOGY
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New Primary Melanomas After Stage III and IV Melanoma
Table 2. Demographics and Clinicopathologic Characteristics of Patients With Stage IV Melanoma With and Without an NPM After Stage IV Diagnosis No NPM After Stage IV Diagnosis Characteristic Total patients Sex Female Male Age at metastatic presentation, years Median Range Follow-up from metastasis, months Median Range Follow-up from culprit melanoma, months Median Range Disease-free interval, months Median Range Culprit primary melanoma Site Head and neck Trunk Arm Leg Occult Other† Breslow thickness, mm Median Range T1 (ⱕ 1 mm) T2 (1.01-2.00 mm) T3 (2.01-4.00 mm) T4 (ⱖ 4.00 mm) Occult Tx (unable to assess) Mitotic rate, per mm2 Median Range Absent Present Occult Not known Ulceration Absent Present Occult Not known
No. of Patients
%
NPM After Stage IV Diagnosis No. of Patients
%
3,520
100
43
100
1,176 2,344
33 67
5 38
12 88
P
Total Cohort (No. of patients)
Not tested .003
3,563 1,181 2,382
.376 60 16-96
60 36-86
7.8 0.03-315.4
50.4 7.4-290.0
44.7 0.2-569.3
81.0 8.6-533.0
29.7 ⫺5.5-482.5ⴱ
32.7 0-296.4
60 16-96 ⬍ .001 7.9 0.03-315.4 ⬍ .001 45.2 0.2-569.3 .555 29.8 ⫺5.5-482.5ⴱ .031
650 1,293 319 764 488 6
18.5 36.7 9.1 21.7 13.9 0.2
16 13 3 5 6 0
2.3‡ 0.2-50.0 502 725 942 676 488 187
37.2 30.2 7.0 11.6 14.0 0.0
666 1,306 322 769 494 6
Not tested .160
2.3 0.4-6.3 14.3 20.6 26.8 19.2 13.9 5.3
10 6 16 5 6 0
4‡ 1-98
23.3 14.0 37.2 11.6 14.0 0.0
2.3 0.2-50.0 512 731 958 681 494 187
.122
Not tested Not tested .669
4‡ 1-36
4‡ 1-98
187 2,224 488 621
5.3 63.2 13.9 17.6
4 28 6 5
9.3 65.1 14.0 11.6
1,388 1,065 488 579
39.4 30.3 13.9 16.5
19 9 6 9
44.2 20.9 14.0 20.9
.321 Not tested Not tested .231 Not tested Not tested
191 2,252 494 626 1,407 1,074 494 588
Abbreviation: NPM, new primary melanoma. ⴱ Patients (n ⫽ 2) in whom the culprit melanoma was identified after occult metastatic presentation had a negative disease-free interval. †Includes other and not known. ‡Including only cases with Breslow thickness or mitotic rate greater than 0.
invasive. The first NPMs after stage III diagnosis, compared with the culprit melanomas, were thinner (48% v 15% were ⱕ 1.0 mm, respectively; P ⬍ .001), were more likely to have absent mitoses (26% v 6%, respectively; P ⬍ .001), and were less likely to be ulcerated (59% v 41%, respectively; P ⬍ .001; Data Supplement). In the stage IV group, the only significant finding was that the first NPMs were thinner than the culprit melanomas (median, 0.8 mm v 2.3 mm, respectively; P ⫽ .009; Data Supplement). www.jco.org
Cumulative Risk The 6-month, 1-year, and 10-year cumulative incidence rates of an NPM after diagnosis of stage III melanoma were 1.2% (95% CI, 0.86% to 1.51%), 1.8% (95% CI, 1.44% to 2.26%), and 5.9% (95% CI, 5.08% to 6.74%), respectively, with nearly half the risk accumulating within the first 2 years (Table 3, Fig 1A). Diagnosis of stage IV disease or death was more common than the diagnosis of an NPM after stage III melanoma. The 3-month, 6-month, and 1-year cumulative © 2013 by American Society of Clinical Oncology
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Table 3. Cumulative Incidence of New Primary Melanoma After Stage III or IV Melanoma Diagnosis Including Death as a Competing Risk Melanoma Stage and Interval To Advanced Primary
Cumulative Incidence (%)
Standard Error (%)
95% CI (%)
0.762 1.149 1.813 2.550 4.234 5.871
0.134 0.165 0.208 0.247 0.326 0.421
0.533 to 1.064 0.860 to 1.509 1.440 to 2.255 2.098 to 3.068 3.628 to 4.907 5.083 to 6.735
0.170 0.285 0.431 0.707 0.950 1.283
0.070 0.090 0.111 0.144 0.171 0.212
0.073 to 0.361 0.148 to 0.513 0.254 to 0.697 0.467 to 1.037 0.659 to 1.333 0.917 to 1.753
Stage IIIⴱ 3 months 6 months 1 year 2 years 5 years 10 years Stage IV 3 months 6 months 1 year 2 years 5 years 10 years
Male patients and patients with a prior history of multiple primary melanoma before or at stage III or IV diagnosis had a higher incidence of NPMs after stage III or stage IV (Figs 1B and 1C; Figs 2B and 2C; Data Supplement). This result was confirmed in a multivariable competing risks regression analysis (Table 4). In the stage III cohort, the 1-year incidence was 6% in those with a prior history of multiple primaries compared with 2% for patients with only a single primary (P ⬍ .001; Fig 1C, Data Supplement); similarly, in the stage IV cohort, the 1-year incidence rates were 1% and 0.4%, respectively (P ⬍ .002; Fig 2C, Data Supplement). Age was not associated with the incidence of NPMs after stage IV diagnosis. Patients age ⱖ 60 years had a higher incidence of NPMs after stage III melanoma compared with younger patients (3% v 1%, respectively; P ⬍ .028; Figs 1D and 2D, Data Supplement); however, this result lost significance in multivariable competing risks regression (Table 4). DISCUSSION
ⴱ
Crossover to stage IV diagnosis also counted as a competing risk.
incidence rates of developing an NPM after diagnosis of stage IV melanoma were 0.2% (95% CI, 0.07% to 0.36%), 0.3% (95% CI, 0.15% to 0.51%), and 0.4% (95% CI, 0.25% to 0.7%), respectively, with most of the risk occurring within the first 6 months (Table 3, Fig 2A).
Cumulative Incidence
1.0
New primary melanoma after stage III Diagnosis of stage IV or death without a new primary
0.8
0.6
0.4
0.2
0
B Cumulative Incidence
A
This is the first report, to our knowledge, of the cumulative incidence of NPMs after diagnosis of stage III or IV melanoma. In contrast to previous studies2,3,6-8,26 that have assessed incidence in earlier stage melanoma or the overall incidence regardless of stage (Data Supplement), we report the incidence of NPM from date of stage III or IV disease to death or last follow-up, focusing on the same time frame as
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
.150
Female Male
.125 .100 .075 .050 .025
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Time (years)
Cumulative Incidence
.25
D
Single primary Multiple primaries
Cumulative Incidence
C
.20
.15
.10
.05
0
Time (years)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Time (years)
.150
Age < 60 years Age ≥ 60 years
.100
.075
.050
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Time (years)
Fig 1. The cumulative incidence of a new primary melanoma after diagnosis of stage III melanoma. (A) Incidence of new primary melanoma versus incidence of death or diagnosis of stage IV disease without a new primary melanoma. (B) Incidence in males versus females. (C) Incidence in patients with multiple primaries at or before stage III diagnosis versus patients with only a single primary before stage III diagnosis. (D) Incidence in older patients (ⱖ 60 years) versus younger patients (⬍ 60 years). 820
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New Primary Melanomas After Stage III and IV Melanoma
B
Cumulative Incidence
1.0
0.8
0.6 Death without a new primary New primary melanoma after stage IV
0.4
0.2
0
Cumulative Incidence
A
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
.030
Female Male
.025 .020 .015 .010 .005
0
1
2
3
4
5
6
Time (years)
Cumulative Incidence
.03
D
Single primary Multiple primaries
.02
.01
0
1
2
3
4
5
6
7
8
8
9 10 11 12 13 14 15 16 17
Time (years)
Cumulative Incidence
C
7
9 10 11 12 13 14 15 16 17
Time (years)
.025
Age < 60 years Age ≥ 60 years
.020
.015
.010
.005
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17
Time (years)
Fig 2. The cumulative incidence of a new primary melanoma after diagnosis of stage IV melanoma. (A) Incidence of new primary melanoma versus incidence of death without a new primary melanoma. (B) Incidence in males versus females. (C) Incidence in patients with multiple primaries at or before stage IV diagnosis versus patients with only a single primary before stage IV diagnosis. (D) Incidence in older patients (ⱖ 60 years) versus younger patients (⬍ 60 years).
in clinical trials in patients undergoing therapy with BRAF inhibitors. This study included a large cohort of patients with stage III and IV melanoma who had detailed follow-up data and had not been treated with a BRAF inhibitor, with similar overall survival as that reported by Balch et al.11
Table 4. Multivariable Competing Risks Regression of Time to Development of NPM After Diagnosis of Stage III or IV Melanoma Factor Stage III cohort (n ⫽ 4,215) Male Age ⱖ 60 years at diagnosis with stage III Positive history of multiple primary melanoma Stage IV cohort (n ⫽ 3,563) Male Positive history of multiple primary melanomasⴱ
Hazard Ratio
95% CI
P
1.72 1.14
1.28 to 2.32 ⬍ .001 0.88 to 1.49 .320
3.19
2.24 to 4.52 ⬍ .001
3.71
1.46 to 9.44
.006
2.64
1.27 to 5.52
.010
Abbreviation: NPM, new primary melanoma. ⴱ A history of multiple primary melanomas at or before the diagnosis of stage III or IV disease includes the culprit melanoma and any primary melanoma diagnosed before stage III or IV disease.
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The major limitation of this study is the lack of rigorous and regular protocol-driven dermatologic surveillance for NPMs, particularly in patients with stage IV melanoma. This was because of their poor prognosis and the lack of effective therapies during that time period. Other limitations include the referral bias associated with MIA, a large quaternary referral center, although the demographics and primary features of the patients were consistent with the general Australian population3,8; the possibility of misclassification of satellite nodules, in-transit metastases, or subcutaneous nodules as NPMs or vice versa, although several clinical and pathologic features assist accurate classification27; the different follow-up time between those with an NPM and those without an NPM after diagnosis of stage III or IV melanoma; and the underlying Australian population with a genetic background (CDKN2A mutations)28 and incidence rates specific to Australia.1,3,8 In this study, the 1-year cumulative incidence rates of NPMs after diagnosis of stage III or IV disease were 1.8% and 0.4%, respectively. Consistent with previous findings,2,6,7 the NPMs after stage III and IV melanoma were thinner compared with the culprit melanoma. This trend toward thinner melanomas is likely a result of surveillance and early detection of any additional melanoma as well as less aggressive tumor biology in patients with multiple primary melanomas.7 However, given the lack of surveillance in patients with stage IV disease in © 2013 by American Society of Clinical Oncology
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this study, the stage III incidence rate may be a more accurate measure of the incidence of NPMs after metastasis. Because the NPMs after stage III diagnosis were thinner, less likely to be ulcerated, and more likely to have absent mitoses than the initial culprit melanoma, this suggests that most patients in this study were actively surveyed as per protocol (ie, thorough dermatologic assessment at least once a year, in addition to more frequent surgical oncology reviews). The development of NPMs in patients treated with BRAF inhibitors in phase III trials17-20 of vemurafenib and dabrafenib has been reported, at rates of 2.4% (eight of 337 patients) and 1.6% (three of 187 patients), respectively, with a median follow-up time of 13 and 10.5 months, respectively. It is not known whether the development of NPMs is drug related, perhaps caused by paradoxical activation of the MAP kinase pathway via CRAF in BRAF wild-type cells,29,30 or simply reflects the natural history that was not previously apparent because of the frequent lack of dermatologic surveillance in patients with stage IV disease before BRAF inhibitor treatment and outside of clinical trials. However, the degree of discordance between primary and NPM BRAF genotypes observed in patients treated with BRAF inhibitors (100%)21-23 compared with those not treated (36%),31 as well as the timing of NPMs,22 would further support that NPMs after BRAF inhibitor treatment may be drug induced. Furthermore, there is emerging evidence that BRAF inhibitors may induce other noncutaneous malignancies.32,33 In our study, the 1-year incidence of NPMs after stage III or IV melanoma was higher in those with a history of multiple primary melanomas, a group of patients who are less likely to have the BRAF mutation15 and who are more likely to have a better overall survival from diagnosis of distant metastases.24 This suggests that the cumulative incidence could be even lower than our reported figure in those with a BRAF mutation, and thus the difference compared with the BRAF inhibitor trials even greater. When the analysis was adjusted for other predictive factors, a history of multiple primary melanomas retained its strong prognostic utility (Table 4). This is consistent with the reported higher risk of a third primary melanoma after a second primary melanoma.6,7 Given the fact that patients with multiple primaries may harbor germline CDKN2A mutations, ideally these patients should be excluded from analysis because the risk in these individuals is determined by a known genotype. However, in the Australian population, the proportion of such patients is lower than in other populations. In the international, multicenter, population-based, case-control study of melanoma, the Genes Environment and Melanoma (GEM) Study,28 the rates of CDKN2A mutations in patients from New South Wales were 1.0% for single primary melanoma and 2.0% for multiple primary melanomas. Referring to those rates, it can be concluded that an exclusion of patients with CDKN2A mutations will lead to similar overall results. In conclusion, patients with stage III or IV melanoma, especially those with a prior history of multiple primaries, remain at risk for development of further primary melanomas after the diagnosis of stage III or IV melanoma. Whether patients with stage IV melanoma REFERENCES 1. International Agency for Research on Cancer: Cancer incidence in five continents. Vol IX. CANCERMondial. Lyon, France, IARC Cancer822
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should undergo surveillance for NPMs remains arguable at this point in time because of improved17-20,34-36 but still poor overall survival in this patient cohort. Although the incidence rates are lower than those observed in the studies of dabrafenib and vemurafenib, the results must be compared with caution because of the more frequent and thorough dermatologic assessments in the BRAF inhibitor studies. The true effect of BRAF inhibitors on the incidence of NPMs will be assessed prospectively in the randomized, placebo-controlled, adjuvant clinical trial of vemurafenib (NCT01667419). AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Lisa Zimmer, Bristol-Myers Squibb (C); Richard A. Scolyer, Roche (C), GlaxoSmithKline (C); Richard F. Kefford, Roche (C), GlaxoSmithKline (C); John F. Thompson, Roche (C), GlaxoSmithKline (C); Dirk Schadendorf, Roche (C), GlaxoSmithKline (C), Novartis (C), Amgen (C), AstraZeneca (C), Morphotek (C), Merck Sharp & Dohme (C), Bristol-Myers Squibb (C); Georgina V. Long, Roche (C), GlaxoSmithKline (C), Novartis (C) Stock Ownership: None Honoraria: Lisa Zimmer, Roche, Bristol-Myers Squibb, Amgen; Alexander M. Menzies, Roche; Richard A. Scolyer, Abbott Molecular; Richard F. Kefford, Roche, GlaxoSmithKline; Dirk Schadendorf, Roche, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Morphotek, AstraZeneca; Georgina V. Long, Roche Research Funding: Dirk Schadendorf, Merck Sharp & Dohme Expert Testimony: None Patents: None Other Remuneration: Lisa Zimmer, Bristol-Meyers Squibb, Merck Sharp & Dohme, Roche; Alexander M. Menzies, GlaxoSmithKline, Roche; Richard F. Kefford, GlaxoSmithKline; Dirk Schadendorf, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme
AUTHOR CONTRIBUTIONS Conception and design: Lisa Zimmer, Lauren E. Haydu, Dirk Schadendorf, Georgina V. Long Provision of study materials or patients: Lauren E. Haydu, Alexander M. Menzies, Richard F. Kefford, John F. Thompson, Georgina V. Long Collection and assembly of data: Lisa Zimmer, Lauren E. Haydu, Richard A. Scolyer, Georgina V. Long Data analysis and interpretation: Lisa Zimmer, Lauren E. Haydu, Alexander M. Menzies, Richard A. Scolyer, Richard F. Kefford, John F. Thompson, Dirk Schadendorf, Georgina V. Long Manuscript writing: All authors Final approval of manuscript: All authors
Base, No 160, 2007; (France) Vol IX. http://www .dep.iarc.fr/ 2. van der Leest RJ, Liu L, Coebergh JW, et al: Risk of second primary in situ and invasive melanoma in Dutch population-based cohort: 1989-2008. Br J Dermatol 167:1321-1330, 2012
3. Karahalios E, English D, Thursfield V, et al: Second primary cancers in Victoria, Victorian Cancer Registry 1982-2005. http:// www.cancervic.org.au/about-our-research/ registry-statistics/cancer-in-victoria/secondprimary-cancers-victoria JOURNAL OF CLINICAL ONCOLOGY
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New Primary Melanomas After Stage III and IV Melanoma
4. Levi F, Randimbison L, Te VC, et al: High constant incidence rates of second cutaneous melanomas. Int J Cancer 117:877-879, 2005 5. Bradford PT, Freedman DM, Goldstein AM, et al: Increased risk of second primary cancers after a diagnosis of melanoma. Arch Dermatol 146:265272, 2010 6. Hwa C, Price LS, Belitskaya-Levy I, et al: Single versus multiple primary melanomas: Old questions and new answers. Cancer 118:41844192, 2012 7. Ferrone CR, Ben Porat L, Panageas KS, et al: Clinicopathological features of and risk factors for multiple primary melanomas. JAMA 294:1647-1654, 2005 8. McCaul KA, Fritschi L, Baade P, et al: The incidence of second primary invasive melanoma in Queensland, 1982-2003. Cancer Causes Control 19: 451-458, 2008 9. Goggins WB, Tsao H: A population-based analysis of risk factors for a second primary cutaneous melanoma among melanoma survivors. Cancer 97:639-643, 2003 10. Lee CC, Faries MB, Wanek LA, et al: Improved survival after lymphadenectomy for nodal metastasis from an unknown primary melanoma. J Clin Oncol 26:535-541, 2008 11. Balch CM, Gershenwald JE, Soong SJ, et al: Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27:6199-6206, 2009 12. Atkins M, Long G, Warneke C, et al: Unraveling the prognostic heterogeneity in patients with advanced melanoma between Australia (OZ) and the United States (US): Preliminary report of the PHAMOUS study. J Clin Oncol 28, 2010 (suppl 15S; abstr 8516) 13. Lee CC, Faries MB, Wanek LA, et al: Improved survival for stage IV melanoma from an unknown primary site. J Clin Oncol 27:3489-3495, 2009 14. Davies H, Bignell GR, Cox C, et al: Mutations of the BRAF gene in human cancer. Nature 417:949954, 2002 15. Long GV, Menzies AM, Nagrial AM, et al: Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 29:1239-1246, 2011
16. Ribas A, Flaherty KT: BRAF targeted therapy changes the treatment paradigm in melanoma. Nat Rev Clin Oncol 8:426-433, 2011 17. Hauschild A, Grob JJ, Demidov LV, et al: Dabrafenib in BRAF-mutated metastatic melanoma: A multicentre, open-label, phase 3 randomised controlled trial. Lancet 380:358-365, 2012 18. Chapman PB, Hauschild A, Robert C, et al: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364: 2507-2516, 2011 19. Hauschild A, Grob JJ, Demidov LV, et al: An update on BREAK-3, a phase III, randomized trial: Dabrafenib (DAB) versus dacarbazine (DTIC) in patients with BRAF V600E-positive mutation metastatic melanoma (MM). J Clin Oncol 31, 2013 (suppl; abstr 9013) 20. Chapman PB, Hauschild A, Robert C, et al: Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. J Clin Oncol 30, 2012 (suppl; abstr 8502) 21. Dalle S, Poulalhon N, Thomas L: Vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 365:1448-1449, 2011 22. Zimmer L, Hillen U, Livingstone E, et al: Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J Clin Oncol 30:2375-2383, 2012 23. Haenssle HA, Kraus SL, Brehmer F, et al: Dynamic changes in nevi of a patient with melanoma treated with vemurafenib: Importance of sequential dermoscopy. Arch Dermatol 148:11831185, 2012 24. Murali R, Brown PT, Kefford RF, et al: Number of primary melanomas is an independent predictor of survival in patients with metastatic melanoma. Cancer 118:4519-4529, 2012 25. Sherif BN: A comparison of Kaplan-Meier and cumulative incidence estimate in the presence or absence of competing risks in breast cancer data. Submitted to the Graduate Faculty of Graduate School of Public Health in partial fulfillment of the requirements for the degree of Master of Science, University of Pittsburgh, Pittsburgh, PA, 2007.
http://d-scholarship.pitt.edu/9986/1/BintuSherif_ thesis%5B1%5D.pdf 26. DiFronzo LA, Wanek LA, Elashoff R, et al: Increased incidence of second primary melanoma in patients with a previous cutaneous melanoma. Ann Surg Oncol 6:705-711, 1999 27. Orlow I, Tommasi DV, Bloom B, et al: Evaluation of the clonal origin of multiple primary melanomas using molecular profiling. J Invest Dermatol 129:1972-1982, 2009 28. Berwick M, Orlow I, Hummer AJ, et al: The prevalence of CDKN2A germ-line mutations and relative risk for cutaneous malignant melanoma: An international population-based study. Cancer Epidemiol Biomarkers Prev 15:1520-1525, 2006 29. Poulikakos PI, Zhang C, Bollag G, et al: RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464:427430, 2010 30. Hatzivassiliou G, Song K, Yen I, et al: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464:431-435, 2010 31. Palmieri G, Sini M, De Giorgi V, et al: Assessment of germ-line and somatic alterations in main candidate genes among patients with multiple primary melanoma. J Clin Oncol 30, 2012 (suppl; abstr 8581) 32. Chapman P, Metz D, Sepulveda A, et al: Development of colonic adenomas and gastric polyps in BRAF mutant melanoma patients treated with vemurafenib. Pigment Cell Melanoma Res 25:847, 2012 (abstr) 33. Callahan MK, Rampal R, Harding JJ, et al: Progression of RAS-mutant leukemia during RAF inhibitor treatment. N Engl J Med 367:2316-2321, 2012 34. Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364: 2517-2526, 2011 35. Flaherty KT, Infante JR, Daud A, et al: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367:16941703, 2012 36. Flaherty KT, Robert C, Hersey P, et al: Improved survival with MEK inhibition in BRAFmutated melanoma. N Engl J Med 367:107-114, 2012
■ ■ ■
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Acknowledgment We thank the staff at Melanoma Institute Australia.
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![[Primary Figo stage III melanoma of the uterine cervix].](/assets/img/hold.png)
