One in five Americans will develop skin cancer in his or her lifetime.1 More than 1 million cases of nonmelanoma skin cancer (NMSC) are estimated to go unreported each year. In 2009, more than 68,720 new cases of melanoma occurred, and melanoma caused 8650 deaths.1
Skin cancer is a costly disease, and its financial burden increases with advanced stages. A 2009 study of melanoma costs documented that the 5-year costs of melanoma when diagnosed at stage IV reached $159,808, which represents a 3438% increase from the costs of melanoma diagnosed in situ ($4648). Costs of stage IIIc and IV melanoma were 23 times greater than costs of earlystage disease.2
The overall burden of skin cancer merits a brief review of recent reports on secondary prevention, prognostic markers, therapies, symptom management, and survivorship. The foundation for this review consists of a selection of large epidemiologic studies, randomized phase 3 clinical trials, systematic reviews, or meta-analyses presented at the 2009 annual meetings of the American Academy of Derm - atology, American Society of Clinical Oncology, European Society for Medical Oncology, and Society for Investigative Dermatology.
The increasing burden of skin cancer has led to more intensive efforts in secondary prevention, which focuses on risk assessment and education, skin surveillance and detection, and removal of suspicious lesions.3 Finding skin cancer in its early stages is critical for favorable prognosis.4 To determine the prevalence and predictors of skin cancer screening among US adults, Lakhani and colleagues analyzed selfreported data from the 2000 and 2005 National Health Interview Surveys.5 Adult respondents (n, not reported) were asked if they had ever had a head-to- toe skin examination for cancer by a dermatologist or other physician. Respondents answering “yes” were asked the date of their most recent total body skin examination (TBSE). Over a 5- year period, TBSE prevalence increased from one in seven to one in six respondents. Significantly higher percentages of women as well as adults aged 50 years and older reported having TBSE. Approximately one in five non-Hispanic white (NHW) participants reported having TBSE, which was significantly higher than TBSE prevalence reported by respondents in other racial/ethnic groups. TBSE prevalence was highest among individuals reporting a personal history of skin cancer (69%). Persons who reported a family history of melanoma were more than twice as likely (odds ratio [OR], 2.42; 95% confidence interval [CI], 1.90-3.08) to have had TBSE, and those with a family history of NMSC were nearly twice as likely (OR, 1.76; 95% CI, 1.40-2.21) than respondents without these histories. Overall, TBSE prevalence increased with more education, physical activity, sun sensitivity, recent sunburn, and sun-protective behaviors.
Other systems-related factors have been associated with differences in the stage of melanoma at diagnosis and in melanoma survival, particularly among ethnic groups. These differences between the two most common types of Medicare healthcare delivery systems, health maintenance organization (HMO) and fee-for-service (FFS), were analyzed in 40,633 patients from 1991 through 2005 using the Surveillance, Epidemiology and End Results (SEER)-Medicare database. Specifically evaluated were differences in melanoma stage at diagnosis and median survival in HMO versus FFS groups by NHW versus Hispanic ethnicity. Among NHWs, the HMO group had an earlier stage at diagnosis than the FFS group when melanoma was the first or subsequent cancer diagnosis. His panic HMO patients were significantly less likely than FFS patients to receive a diagnosis at a later stage versus earlier stages (OR, 0.50; 95% CI, 0.31-0.81). Among HMO patients, there were no statistically significant differences in stage at diagnosis or survival by race/ethnicity. Among FFS patients, Hispanic patients were more than twice as likely to be diagnosed at a later stage (OR, 2.31; CI, 1.75-3.03) than NHW patients; however, median survival for all stages was slightly longer for FFS patients than for HMO patients (45.0 and 43.0 months, respectively; P <.01). This study is a reminder that there are differences in stage at diagnosis and survival between patients in HMOs and those in FFS healthcare plans and by race/ethnicity. Stronger skin cancer educational interventions for Hispanics along with TBSE have the potential to increase diagnosis at an earlier stage.6
Ulceration. Several melanoma studies have focused on prognostic markers, including melanoma ulceration, sentinel node (SN) tumor burden, and molecular biomarkers. Ulcerated melanomas are known to have a worse prognosis than nonulcerated mel anomas. Investigators from the Euro pean Organisation for Research and Treat ment of Cancer (EORTC) Melanoma Group conducted a post hoc meta-analysis of the two largest phase 3 trials (EORTC 18952 and 18991) ever conducted in patients (n = 2644) with stage IIb to III melanoma.7 The goal of this analysis was to determine the predictive value of ulceration on response to adjuvant interferon (IFN) alpha-2b on relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS), both overall and by stage (IIb, IIIN1, or III-N2). In the ulcerated group, the impact of IFN was much greater than in the nonulcerated group for RFS (P = .02), DMFS (P <.001), and OS (P <.001). The greatest reductions occurred in patients with ulceration and stages IIb/III-N1; no reductions occurred in patients without ulceration. The results strongly indicate that patients with an ulcerated primary melanoma are far more sensitive to IFN than patients with nonulcerated primary tumors.
SN tumor burden. Despite the lack of clear evidence of survival benefit of sentinel lymph node (SLN) biopsy, this technique has been increasingly applied in the staging of patients with thin (1 mm) melanomas. Findings from a metaanalysis of 3651 patients enrolled in 34 studies reporting rates of SLN positivity were used to estimate the risk, potential predictors, and outcome of SLN positivity.8 Significant heterogeneity (high quality and low quality) among studies was detected (P = .005; test of noncombinability), suggesting high variation among study outcomes. Eighteen studies had a primary focus on SLN biopsy for melanomas 1 mm, with the remainder including all melanomathickness groups. These studies reported selected clinical and histopathologic data on SLN-positive patients only (n = 113). Among the tumors from these patients, six (6.1%) of 698 were ulcerated, 17 (31.5%) of 54 showed regression, and 48 (47.5%) of 101 were invasive to Clark level IV or V. Of 14 (41.2%) studies that provided recurrence and/or survival data, four melanoma-related deaths in SLN-positive patients and four deaths in SLNnegative patients were reported. These findings indicate that relatively few patients with thin melanoma have a positive SLN and that clinical or histopathologic criteria for reliably identifying patients with thin melanoma who might benefit from this intervention remain inadequate.
Also unclear is whether patients with minimal SLN tumor burden, who might be at risk for late recurrences (>5 years), can be managed safely without complete lymph node dissection. The EORTC Melanoma Group reported findings from two large pan- European long-term (5-10 years) follow-up studies of 595 and 663 patients,respectively, with minimal SN tumor burden (<1 mm) as defined by the Rotterdam criteria.9,10
These patients had very low relapse rates and excellent melanoma-specific survival that paralleled that of SLN-negative patients. The authors point out that no increases in relapses of any kind have been seen with 5 to 10 years of follow- up and predict that 10-year survival rates will be excellent.
Given the increasing diagnosis of thin melanomas, in addition to the costs and potential morbidity associated with SLN biopsy, alternative strategies to identify patients at risk for nodal disease, including molecular prognostic factors, are urgently needed.8 However, there is a dearth of validated biomarkers for assessing prognosis and monitoring after complete resection of melanoma in patients with stage IV disease. Two studies addressed this void. In a prospective, multicenter (29 sites) international trial, investigators evaluated the clinical utility of multimarker quantitative reverse-transcription polymerase chain reaction (qRT-PCR) for detecting circulating tumor cells (CTCs).11,12 Pre- and intratreatment serial blood samples from 244 patients enrolled in a phase 3 trial of posto perative adjuvant therapy (bacille Calmette-Guerin [BCG] plus placebo or BCG plus melanoma vaccine) were assessed by qRT-PCR for MART1, MAGEA3, and PAX3 gene messenger ribonucleic acid (mRNA). Median clinical follow-up time was 21.8 and 24.2 months for disease-free survival (DFS) and OS, respectively. MART1, MAGEA3, and PAX3 were detected in 26%, 23%, and 29% of patients, respectively. Biomarker-negative patients had significantly higher DFS than biomarker- positive patients (risk ratio [RR], 1.56; 95% CI, 1.14-2.15; P = .006) and significantly higher OS than patients with one to two (RR, 2.37; CI, 1.14- 4.94; P = .021) or three positive biomarkers (RR, 2.90; 95% CI, 1.28-6.53; P = .01). Having one to two (RR, 2.44; 95% CI, 1.1-5.12; P = .019) or three positive biomarkers was a significant prognostic factor for poor OS (RR, 3.08; 95% CI, 1.36-6.98; P = .007).11
The second study addressed the presence of tumor infiltrating lymphocytes (TIL) as markers for meta static disease in 504 patients who initially presented with local disease.12Of these patients, 370 died of melanoma, with a median survival of 1.4 years after discovery of metastases. The presence of TIL was significantly and independently associated with survival (HR, 0.74; 95% CI, 0.59-0.93, P = .01). These studies suggest that multimarker qRT-PCR analysis of CTC and detection of TIL may have clinical utility as prognostic markers for stage IV melanoma patients.11,12 However, further investigation is needed.
The greatest treatment challenge in melanoma is treatment of advanced disease. This section focuses on medical therapies for advanced melanoma. Patients with metastatic melanoma generally have a poor prognosis, with a median survival of 6 to 9 months. A small proportion of patients achieve long-term survival (LTS); however, it is unclear whether LTS reflects sensitivity to systemic therapy, indolent tumor biology, or host immune factors. There is limited information on the frequency and duration of complete response (CR) following dacarbazine or temozolomide therapy or whether LTS occurs only in patients who achieve CR.
An epidemiologic study of 397 patients treated with either dacarbazine or temozolomide over an 18-year period sought to document LTS (defined as 18 months posttherapy).13 Specific outcomes were CR (no evidence of disease by diagnostic imaging), progressive disease (PD; any tumor growth), and partial response (PR) or stable disease (SD). Of the 45 patients who met the criterion of LTS, the best response to dacarbazine or temozolomide was CR, 18%; PR/SD, 67%; and PD, 13%. The 5-year OS and progression-free survival (PFS) rates were 33% and 12%, respectively. Eleven patients survived more than 5 years (range, 5-27.5 years), and six patients remained in remission (5 CR, 1 PR). Disease progression occurred in five patients in less than 1 year; however, they remained alive for at least 5 years (range, 5.2-17.9 years). The authors concluded that although LTS occurs in patients with metastatic melanoma treated with dacarbazine or temozolomide, few patients have a sustained response to chemotherapy; most cases of LTS are likely the result of indolent disease or host biology.
PFS (defined as >90% power to detect a 2-month improvement) was the end point in a 2-year study of 651 patients with stage IV metastatic melanoma who were randomized to receive either 213 mg/m2 of elesclomol (an investigative drug that increases oxidative stress in cancer cells leading to mitochondria-induced apoptosis) in combination with 80 mg/m2 of paclitaxel (ELPAC) or 80 mg/m2 of paclitaxel alone.14 Both regimens were given weekly for 3 weeks followed by 1 week of rest, until disease progression. Patients were stratified by prior noncytotoxic treatment, M1 grade, and lactate dehydrogenase. Median PFS in the ELPAC arm was 3.5 months (95% CI, 2.7-3.7) compared with 1.9 months (95% CI, 1.9-3.3) in the paclitaxel alone arm (HR, 0.88; 95% CI, 0.67- 1.16; P = .3695). Improved PFS in the ELPAC arm did not achieve statistical significance, however. The median number of cycles was three in the ELPAC arm and two in the paclitaxel alone arm. In February 2009, the study was halted after increased deaths occurred on the ELPAC arm, which may or may not have been related to the treatment. The investigators continue to collect OS data to determine whether the observed imbalance in OS persists as the data mature.
A prospective, randomized phase 3 trial of high-dose (HD) interleukin (IL)-2 alone (arm 1) versus gp100:209- 217(210M) synthetic peptide cancer vaccine plus Montanide ISA followed by HD IL-2 (arm 2) was conducted in 185 patients with stage IV or locally advanced stage III melanoma treated at 21 centers.15 The primary outcome was clinical response; secondary outcomes included toxicity and PFS. Numbers of patients enrolled, treated, and evaluable for response in arm 1 were 94, 93, and 93, respectively; in arm 2, 91, 86, and 86. Toxicities were consistent with those that were seen with HD IL-2 ± vaccine. Arm 2 demonstrated significant im provement in overall response rate (22.1% vs 9.7%, P = .0223, chisquare) and PFS (2.9 months [1.7-4.5] vs 1.6 [1.5-1.8], P = .0101). Median OS was 17.6 months (11.8-26.6) in arm 2 versus 12.8 months (8.7-16.3) in arm 1 (P = .0964). The authors concluded that response rate and PFS were superior with peptide vaccine plus HD IL-2 compared with HD IL-2 alone, and stated that this study represents the first evidence of clinical benefit of vaccination in patients with melanoma.
HD IFN for patients with melanoma has consistently demonstrated benefits as an adjuvant treatment. Side effects and impaired quality of life (QOL) affect patients’ motivation to continue treatment. A 4-year evaluation of selfreported QOL in 300 patients enrolled in an adjuvant, randomized, controlled phase 3 trial of pulsed, HD intravenous (IV) IFN alpha-2b and subcutaneous (SC) IFN treatment revealed that HD IV IFN treatment led to a globally decreased QOL score in 84% of patients.16 Im paired QOL during HD IV IFN was caused mainly by physical symptoms. During SC IFN treatment, global QOL remained reduced by an average of 24% in a majority of patients, despite dose adjustments. Fatigue was the most important determinant of reduced QOL, especially during continuous treatment. Depression was minor and rated as less important than physical and cognitive impairment. These findings demonstrate that fatigue remains the symptom that most affects QOL in patients receiving IFN.
Patients with melanoma are at high risk for subsequent primary cancers. An epidemiologic study evaluated 79,901 white patients who survived at least 2 months after melanoma diagnosis and reported to one of nine population-based cancer registries in the SEER program between 1973 and 2004.17 Of those patients, 7943 developed one or more subsequent primary tumors; 24% of which were cutaneous melanoma. Patients aged 30 years and younger had a markedly higher relative risk of developing subsequent melanoma (observed to expected ratio [O/E], 14.44; 95% CI, 12.40-16.71) as did female patients (O/E, 14.04; 95% CI, 12.00-16.33) or patients with their initial melanoma on the head and neck (O/E, 10.04; 95% CI, 9.21- 10.92). Risk of subsequent cancers did not vary substantially by histology. The authors concluded that patients with cutaneous melanoma have an approximate ninefold increased risk of developing a subsequent melanoma compared with the general population and require active surveillance for future melanoma.
With the increasing incidence of skin cancer and costs associated with it, we must focus on risk assessment and education as well as skin surveillance and detection. To do this, we must keep abreast of the latest studies on prognostic markers and QOL for patients receiving adjuvant therapies and those who are survivors of the disease. !
1. Cancer Facts and Figures, 2009. American Cancer Society. www.cancer.org/downloads/STT/500809web.pdf. Accessed February 19, 2010.
2. Alexandrescu DT. Melanoma costs: a dynamic model comparing estimated overall costs of various clinical stages. Dermatol Online J. November 15, 2009. dermatology.cdlib.org/1511/originals/melanoma_costs/alexandrescu.html. Accessed February 22, 2010.
3. Rigel DS, Friedman RJ, Kopf AW, Polsky D. ABCDE—an evolving concept in the early detection of melanoma. Arch Dermatol. 2005; 141:1032-1034.
4. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19:3635-3648.
5. Lakhani N, Shaw K, Saraiya M. Skin cancer screening among US adults: 2000 and 2005 national health interview surveys. J Am Acad Dermatol. 2009;60(suppl 1):Abstract P1900.
6. Rouhani P, Kirsner R. Health care delivery system effect on disparities in melanoma outcomes among Medicare-aged Hispanic patients. J Am Acad Dermatol. 2009;60(suppl 1):Abstract P604.
7. Eggermont AM, Suciu S, Testori A, Patel P, Spatz A, for the EORTC Melanoma Group. Ulceration of primary melanoma and responsiveness to adjuvant interferon therapy: analysis of the adjuvant trials EORTC18952 and EORTC18991 in 2,644 patients. J Clin Oncol. 2009;27(15S):Abstract 9007.
8. Warycha M, Polsky D, Osman I, Mazumdar M. Metaanalysis of sentinel lymph node positivity in thin melanoma (1 mm). J Am Acad Dermatol. 2009;60(suppl 1):Abstract P601.
9. van Akkooi AC, Rutkowski P, van der Ploeg IM, et al. Long-term follow-up of patients with minimal sentinel node tumor burden (<0.1 mm) according to Rotterdam criteria: a study of the EORTC Melanoma Group. J Clin Oncol. 2009;27(15S):Abstract 9005.
10. van Akkooi ACJ, Rutkowski P, van der Ploeg IM, et al. Excellent long-term survival of patients with minimal sentinel node tumor burden (<0.1 mm) according to Rotterdam criteria: a study of the EORTC melanoma group. Eur J Cancer Supplements. 2009;7:Abstract 9302.
11. Hoshimoto S, Shingai T, Wang H, et al. MMAIT-IV Clinical Trial Group Centers. Validation of a multimarker blood assay for postoperative assessment of stage IV melanoma patients in a prospective international phase III trial. J Clin Oncol. 2009;27(15S):9045.
12. Wriston CC, Troxel DB, Shin A, et al. Tumor infiltrating lymphocytes are a prognostic marker for survival in patients who develop melanoma metastases. J Invest Dermatol. 2009;129(S1): Abstract 363.
13. Kim C, Lee CW, Klasa R, Shah A, Savage KJ. Long-term survival of patients with metastatic melanoma (MM) treated with dacarbazine (DTIC) or temozolomide (TMZ). J Clin Oncol. 2009;27(15S):Abstract 9054.
14. Hauschild A, Eggermont AM, Jacobson E, O’Day SJ. Phase III, randomized, double-blind study of elesclomol and paclitaxel versus paclitaxel alone in stage IV metastatic melanoma (MM). J Clin Oncol. 2009;27(18S):Abstract LBA9012.
15. Schwartzentruber DJ, Lawson D, Richards J, et al. A phase III multi-institutional randomized study of immunization with the gp100: 209- 217(210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma. J Clin Oncol. 2009;27(18S):Abstract CRA9011.
16. Mohr P, Hauschild A, Rass K, et al; for the DeCOG Melanoma Study Group. Quality-oflife (QoL) impairment in melanoma patients receiving high-dose interferon alpha 2b (IFNa2b). J Clin Oncol. 2009;27(15S):e20011.
17. Bradford PT, Freedman DM, Goldstein AM, Tucker MA. Increased risk of second primary cancers after diagnosis of melanoma. J Invest Dermatol. 2009;129(S1):S138.
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