- Email: [email protected]
Determination of the impact of melanoma surgical timing on survival using the National Cancer Database
ORIGINAL
ARTICLE
Determination of the impact of melanoma surgical timing on survival using the National Cancer Database Ruzica Z. Conic, MD,a Claudia I. Cabrera, MD,a Alok A. Khorana, MD,b and Brian R. Gastman, MDa Cleveland, Ohio Background: The ideal timing for melanoma treatment, predominantly surgery, remains undetermined. Patient concern for receiving immediate treatment often exceeds surgeon or hospital availability, requiring establishment of a safe window for melanoma surgery. Objective: To assess the impact of time to definitive melanoma surgery on overall survival. Methods: Patients with stage I to III cutaneous melanoma and with available time to definitive surgery and overall survival were identified by using the National Cancer Database (N = 153,218). The t test and chi-square test were used to compare variables. Cox regression was used for multivariate analysis. Results: In a multivariate analysis of patients in all stages who were treated between 90 and 119 days after biopsy (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.01-1.18) and more than 119 days (HR, 1.12; 95% CI, 1.02-1.22) had a higher risk for mortality compared with those treated within 30 days of biopsy. In a subgroup analysis of stage I, higher mortality risk was found in patients treated within 30 to 59 days (HR, 1.05; 95% CI, 1.01-1.1), 60 to 89 days (HR, 1.16; 95% CI, 1.07-1.25), 90 to 119 days (HR, 1.29; 95% CI, 1.12-1.48), and more than 119 days after biopsy (HR, 1.41; 95% CI, 1.21-1.65). Surgical timing did not affect survival in stages II and III. Limitations: Melanoma-specific survival was not available. Conclusion: Expeditious treatment of stage I melanoma is associated with improved outcomes. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2017.08.039.) Key Words: melanoma; National Cancer Database; stage I melanoma; survival; time to surgery; time to treatment.
C
utaneous malignant melanoma (MM) is the fifth most common cancer among men and seventh among women.1,2 Rates of melanoma continue to rise in the United States and worldwide, and melanoma will be diagnosed in approximately 2.1% of the U.S. population in their lifetime.3-5 Furthermore, approximately 76,380 new cases of melanoma will be diagnosed in 2016, and 10,230 people will die of melanoma.2 The standard of care is surgery, which can include sentinel lymph node biopsy (SLNB) or lymphadenectomy depending on melanoma From the Department of Dermatology and Plastic Surgerya and Department of Hematology and Oncology, Cleveland Clinic.b Funding sources: None. Conflicts of interest: None declared. Accepted for publication August 16, 2017. Reprints not available from the authors.
Abbreviations used: CoC: LVI: MM: NCDB: OS: SLNB: TTI:
Commission on Cancer Lymphovascular invasion Malignant melanoma National Cancer Database Overall survival Sentinel lymph node biopsy Time to treatment initiation
stage.3,6 On diagnosis, the majority of melanomas are confined to a primary site (84%), with occasional spread to regional lymph nodes (9%) and metastasis Correspondence to: Brian R. Gastman, MD, Department of Plastic Surgery, A60 Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: [email protected]. Published online September 27, 2017. 0190-9622/$36.00 Ó 2017 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2017.08.039
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(4%).3 The estimated 5-year relative survival is 98.4% resulting in a time of 0 days to biopsy, and these if confined to a primary site, 62.4% if lymph nodes patients were excluded; this rate was similar are affected, and 17.9% if distantly metastatic.3 between the stages, with 12.5% excluded from stage Intuitively, a more expeditious treatment after I, 12.5% from stage II, and 11.7% from stage III. In cancer diagnosis should lead to better outcome. addition, patients treated after more than 365 days The data analysis of the National Cancer Database were excluded on account of probable existence of (NCDB) showed a better overall survival (OS) if time other factors affecting the decision to postpone to treatment initiation (TTI) surgery. SLNB data before was reduced for head and 2012 were not provided to CAPSULE SUMMARY neck squamous cell carciresearchers; however, this noma and breast cancers.7,8 information was available to Impact of time to treatment on survival the NCDB and used for Despite this likely relationin melanoma remains uncertain. staging.17 In addition, inforship between TTI and Prolonging time to treatment of survival, there are only a mation on compliance with melanoma negatively affects stage I but few small and predominantly National Comprehensive not stage II and III survival. retrospective studies examCancer Network guidelines ining the impact of TTI on was unavailable. Expeditious treatment of stage I melanoma survival.9-11 We identified 419,787 melanoma could improve survival. cases, of which 210,650 Although conclusive data were TNM stage I to III regarding impact of time to (Fig 1). After exclusion of patients without definitive (ie, surgical) treatment on melanoma follow-up, 183,622 cases remained. Lastly, patients survival are lacking, there has been speculation without a time to definitive surgery or a time longer regarding ‘‘ideal’’ TTI. The current recommendation than 365 days were excluded, leaving 153,218 in our for definitive melanoma treatment is within 3 to final cohort, which corresponded to 37% of the initial 4 weeks following diagnosis in the United States and cohort. 4 to 6 weeks in Europe.12,13 To address this issue, we Variables that can influence melanoma treatment used the NCDB to evaluate the effect of time from and outcomes, such as age, sex, comorbidity status, biopsy to definitive surgery on melanoma OS. insurance type, treating facility type and location, primary site, laterality, histologic type, and METHODS AND MATERIALS melanoma stage were analyzed. Follow-up ranged The NCDB is a clinical oncology database between 3 and10 years, and patients who remained established in 1989 as a joint project of the alive once their observation period ended were Commission on Cancer (CoC) of the American censored. Survival data are based on OS. College of Surgeons and American Cancer Society. A business associate agreement, including a data use Statistical analysis agreement, between the American College of Available covariates included age, sex, race, Surgeons and CoC accredited facilities is in place. insurance type, facility location, facility type, The NCDB is a facility-based database, representing comorbidity score, tumor site, laterality, and cancer 48.4% of all melanomas diagnosed in the United stage. Age at diagnosis was categorized as States.14,15 This database contains cases of patients younger than 30, 30 to 39, 40 to 49, 50 to 59, 60 to 18 or older who received all or part of their first 69, 70 to 79, and older than 79 years. Insurance type course therapy at a reporting cancer program.16 was classified as Medicare, Medicaid, private These data were provided to the authors by the insurance, other type of government insurance, no NCDB in a de-identified file, with prior approval insurance, or insurance status unknown. Facility from the Cleveland Clinic Institutional Review type was classified as academic/research Board.14 program, community cancer program, comprehenPatients in whom malignant melanoma had been sive community cancer program, integrated diagnosed from 2004 to 2012 were identified from network cancer program, other, or unknown. The the NCDB by using the International Classification of Charlson-Deyo comorbidity score was designated as Diseases for Oncology codes. Included cases had 0 if patients had no comorbidities, 1 if there was 1 follow-up time, living status, TNM stages I to III, and comorbidity, and 2 if there were 2 or more TTI longer than 0 but no longer than 365 days. comorbidities, with comorbidities defined as We defined TTI as time from biopsy to definitive previously published.18 Tumor site was designated surgery. A small percentage of the patients had excisional biopsy listed as their definitive surgery, as head and neck, upper extremities, trunk, lower d
d
d
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Fig 1. Flowchart presenting selection of patients from the National Cancer Database.
extremities, overlapping, or not specified. Tumor laterality was left, right, midline, or unknown. Breslow depth was categorized as less than 1 mm, 1.01 to 2.0 mm, 2.01 to 4.0 mm, more than 4 mm, or not specified. Ulceration and lymphovascular invasion (LVI) were classified as present, not present, or unknown. TNM stages IA and IB were combined into stage I; stages IIA, IIB and IIC were combined into stage II; and stages IIIA, IIIB and IIIC were combined into stage III. Time of surgery was categorized as 1 to 29, 30 to 59, 60 to 89, 90 to 119, and more than 119 days after biopsy on the basis of current clinical recommendations and knowledge. For univariate analysis, the chi-square test and t test were used. Data were presented as number and percent for categoric variables and as mean and standard deviation for continuous variables. Multivariate analysis was conducted by using a Cox proportional hazards model. Subgroup analysis was performed by stage because of its high impact on survival. Statistical significance was achieved with an a value less than 0.05. The data analysis was performed using R statistical software (version 3.2.4, R Foundation for Statistical Computing, Vienna, Austria).
RESULTS We identified 153,218 patients, of whom 71,950 were treated 30 days or more after biopsy. Specifically, 44.9% of stage I melanomas were treated 29 or more days after biopsy, as were 50.3% of stage II and 51.3% of stage III melanomas (Supplemental Fig 1; available at http://www.jaad.org). Furthermore 9% of stage I melanomas were treated 59 or more days after biopsy, as were 11.8% of stage II and 11.7% of stage III melanomas. Patients with a longer TTI tended to be older, be male, be using Medicare, have more comorbidities, have head and neck melanoma, have a higher Breslow thickness, be less likely to be ulcerated or have LVI, and be at a higher stage compared with those with a shorter TTI (Supplemental Table I; available at http://www.jaad.org). Unadjusted analysis of TTI showed improved survival for patients with shorter waiting times, with patients who were treated 30 to 59 days after biopsy having 14% worse OS, with 40% worse OS for those treated 60 to 89 days after biopsy, 63% worse OS for those treated 90 to 119 days after biopsy, and 70% worse OS for those treated more than 119 days after biopsy compared with patients treated within
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Fig 2. Graphic representation of adjusted and unadjusted hazard ratios by time to treatment initiation. Point estimates represent hazard ratios. Bars represent 95% confidence intervals. A, Unadjusted hazard ratios by time to treatment initiation. B, Unadjusted hazard ratio for days to treatment in stage I. C, Unadjusted hazard ratio for days to treatment in stage II. D, Unadjusted hazard ratio for days to treatment in stage III. Asterisks denote statistical significance.
the first 29 days (Fig 2, A). In addition, unadjusted analysis of stage based on TTI showed worse prognosis with longer TTI, which was most apparent in stage I (Fig 2, B to D). Multivariate adjustment for age, race, sex, comorbidities, year of diagnosis, hospital location, laterality, primary site, histologic type, Breslow depth, ulceration, LVI, insurance status, and stage was used for all models. All-stage model After adjustment, there were no differences in survival for patients with a TTI less than 90 days (Supplemental Table II [available at http://www. jaad.org] and Fig 3, A). Patients who were treated within 90 to 119 days and after 119 days were 9% and 12% more likely to die, respectively, than were those treated within 30 days. Patients with a Breslow depth of 1.01 to 2.00 mm, 2.01 to 4.00 mm, and more than 4.0 mm had a 12%, 25%, and 80% greater chance of death, respectively, than those with a Breslow depth less than 1.0 mm regardless of other factors. Worse outcomes were present with increasing age, male sex, head and neck melanoma, ulceration, LVI, and more comorbidities. Stage I model Following adjustment, patients who waited between 30 and 59 days after biopsy had 5% worse
survival; those who waited 60 to 89 days had 16% worse survival; those who waited 90 to 119 days had 29% worse survival; and those who waited longer than 119 days had 41% worse survival (Supplemental Table III [available at http://www.jaad.org] and Fig 3, B). Patients with a Breslow depth of 1.01 to 2.0 mm had 35% worse survival than those with a Breslow depth less than 1.0 mm independent of other factors. Additional factors that negatively affected survival were older age, male sex, more comorbidities, nodular or acral melanoma, a diagnosis of head and neck melanoma, midline tumors, and ulceration or LVI. Factors that positively affected survival were having private insurance, lower extremity melanoma, and desmoplastic melanoma. In an effort to pinpoint the breakpoint at which TTI starts to significantly affect survival, we analyzed TTI in 2-week intervals, with the breakpoint being between 43 and 56 days. The exact day at which TTI becomes important for survival could not be identified, likely because of an insufficient number of events. Stage 2 model After adjustment, there were no differences in survival times between the 5 TTI categories (Supplemental Table IV [available at http://www. jaad.org] and Fig 3, C ). Younger age, female sex, lack of comorbidities, desmoplastic or spindle histologic type of melanoma, upper or lower extremity
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Fig 3. Graphic representation of adjusted hazard ratios by time to treatment initiation. Point estimates represent hazard ratios. Bars represent 95% confidence intervals. A, Adjusted hazard ratios by time to treatment initiation. B, Adjusted hazard ratio for days to treatment in stage I. C, Adjusted hazard ratio for days to treatment in stage II. D, Adjusted hazard ratio for days to treatment in stage III. Asterisks denote statistical significance.
melanoma, and lower Breslow depth favorably affected survival. Factors that negatively affected survival were Medicaid, acral melanoma, head and neck melanoma, and ulceration or LVI. Stage 3 model As in stage II, there were no differences in survival between the 5 TTI categories after adjustment (Supplemental Table V [available at http://www. jaad.org], Fig 3, D). Older age at diagnosis, male sex, Medicaid, acral melanoma, higher Breslow depth, and presence of ulceration or LVI negatively affected survival. Patients with fewer comorbidities, melanoma on the extremities, and desmoplastic melanoma had better survival.
DISCUSSION In this study, we were, to the best of our knowledge, the first to show that OS decreases in patients waiting longer than 90 days for definitive surgical treatment of melanoma regardless of stage. Moreover, we believe that we are reporting for the first time that delay of surgery beyond the first 29 days for stage I melanoma negatively OS when 30-day intervals are used. Furthermore, when TTI was analyzed in 2-week intervals for stage I, we found that the critical time point at which TTI in the 30- to 59-day group leads to worse outcomes is between 43 and 56 days. The finding that increasing TTI negatively affects survival of patients with earlier stages of cancer is similar to the findings of several nonmelanoma studies.
In a recent report, Bleicher et al used the NCDB to examine the impact of TTI on breast cancer OS by stage, concluding that there is a 16% mortality increase for each 30-day increase in waiting time in stage I and a 9% increase in stage II but no effect on stage III.8 Similarly, an analysis of head and neck squamous cell carcinoma found that patients with stage I and II squamous cell carcinoma who waited 31 to 60 days had a 17% increase in mortality, whereas those waiting 61 to 90 days had a 54% increase in mortality; in comparison, there was no effect on mortality for those with stage III or IV disease who waited 31 to 60 days and an 8% increase for those who waited 61 to 90 days.7 Because of the much smaller cohort size, and thus lower statistical power, prior studies examining the impact of TTI on melanoma survival were not able to examine their data in the same level of granularity as ours, which explains why these outcomes have not been previously reported. For example, McKenna et al found no impact of TTI in OS or disease-specific survival regardless of melanoma stage, in a cohort of 986 patients.9 Similarly, Carpenter et al concluded that there was no difference in OS or disease-specific survival in 473 patients who waited less than or more than 28 days for treatment.19 Lastly, Parret et al found no difference in OS after analyzing TTI on the basis of groups of patients who waited less than or more than 40 days.20 We hypothesize that the negative effect of prolonging TTI on early-stage melanoma is visible
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as a result of the lower baseline mortality found in these patients. However in stages II and III, the potential benefits of a shorter TTI are likely overshadowed by a higher metastatic potential and baseline mortality. In other words, it appears that prompt initiation of definitive treatment is beneficial in stage I melanoma but likely not in stage II or III. Stages II and III melanoma are likely influenced by time to diagnosis, the importance of which is illustrated by several national studies and programs created to increase patient suspicion and physician recognition, leading to a decreasing incidence and mortality.5,21-24 For example, the state of Israel had the second highest incidence and mortality due to melanoma in the world; however, following prevention and detection efforts, its incidence rate dropped to 13th place for men and 20th place for women, whereas mortality dropped to eight and 10th place, respectively.22,23,25 Furthermore, rates of melanoma in situ increased, indicating a higher awareness and increase in early detection.22,25 Next, in an effort to improve waiting time after identification of a suspicious lesion, the United Kingdom implemented a ‘‘2-week’’ rule, according to which patients needed to see a specialist within 2 weeks of being referred by their general practitioner for any suspicion of cancer. Following implementation of this rule, detected melanomas were lower in stage and OS was significantly improved.21 Finally, following implementation of a new systematic skin cancer screening program in Germany, rates of mortality due to melanoma decreased.5 The findings of these studies support our hypothesis and indicate that detection in early stages and prompt treatment initiation following identification likely result in decreased mortality. Our study comes at a critical time in melanoma treatment. Stage I melanoma is typically treated by various specialties, including general practitioners, dermatologists, otorhinolaryngologists, general surgeons, surgical oncologists, and plastic surgeons, leading to high variability in approach and treatment.26-29 Furthermore, even in a single specialty, there is a high variability in physicians’ treatment approach for stage I melanoma; this includes controversy in performing SLNB.30 Finally, as a larger variety of physicians can treat stage I melanoma, a disproportionate number of cases may not be captured in the NCDB, which could have influenced our data. This fact may limit the applicability of our conclusions to CoC reporting facilities. However this concern is likely balanced by the fact that the database contains almost half of all melanomas treated in the United States. In contrast, stage II and III melanomas tend to be treated by
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specialists who perform SLNB and lymphadenectomy; given many guidelines such as those from the National Comprehensive Cancer Network, this coalesced group of surgeons likely deal with these advanced stages by using a more algorithmic approach. Our data highlight the need for stricter adherence to recommended TTI and standardization of the treatment approach for physicians who treat stage I melanoma. Lastly, our data provide critical information for ensuring safety in managing and planning neoadjuvant trials for melanoma. Neoadjuvant treatment, in which patients are treated before definitive surgical treatment, is used primarily in stage II and III melanoma and may result in delay of surgery.31-33 Despite current controversies in neoadjuvant therapy, currently there are 26 active neoadjuvant trials for MM, indicating that neoadjuvant trials will continue as a scientific endeavor.34,35 According to our data, TTI does not affect OS in these stages, allowing temporal freedom to maximize preoperative/‘‘neo’’ components.
CONCLUSION In conclusion, we found that definitive surgical treatment for stage I melanoma should be expeditious, whereas definitive surgical treatment for stage II and III may not affect OS in the current milieu of melanoma. Furthermore, expeditious patient identification and biopsy could migrate would-be stage II and III patients to stage I, where TTI optimization can be used to further improve their OS. On the basis of the available literature combined with our data, it is likely that these times are underoptimized and greater efforts to improve the entire process from suspicion of melanoma to its ultimate treatment should be implemented. We thank Katherine Glass for assistance with accessing data. REFERENCES 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7-30. 2. American Cancer Society. Cancer Facts & Figures 2016. Atlanta, Georgia: American Cancer Society; 2016. Available at: https:// www.cancer.org/content/dam/cancer-org/research/cancer-factsand-statistics/annual-cancer-facts-and-figures/2016/cancer-factsand-figures-2016.pdf. Accessed July 6, 2016. 3. Howlader N, Noone AM, Krapcho M, et al., eds. SEER Cancer Statistics Review. Bethesda, MD: National Cancer Institute; 1975-2013. Available at: https://seer.cancer.gov/csr/ 1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016. Accessed June 10, 2016. 4. Nikolaou V, Stratigos AJ. Emerging trends in the epidemiology of melanoma. Br J Dermatol. 2014;170:11-19.
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5. Breitbart EW, Waldmann A, Nolte S, et al. Systematic skin cancer screening in northern Germany. J Am Acad Dermatol. 2012;66:201-211. 6. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370:599-609. 7. Murphy CT, Galloway TJ, Handorf EA, et al. Survival impact of increasing time to treatment initiation for patients with head and neck cancer in the United States. J Clin Oncol. 2016;34:169-178. 8. Bleicher RJ, Ruth K, Sigurdson ER, et al. Time to surgery and breast cancer survival in the United States. JAMA Oncol. 2016; 2:330-339. 9. McKenna DB, Lee RJ, Prescott RJ, Doherty VR. The time from diagnostic excision biopsy to wide local excision for primary cutaneous malignant melanoma may not affect patient survival. Br J Dermatol. 2002;147:48-54. 10. Baade PD, English DR, Youl PH, McPherson M, Elwood JM, Aitken JF. The relationship between melanoma thickness and time to diagnosis in a large population-based study. Arch Dermatol. 2006;142:1422-1427. 11. Torring ML, Frydenberg M, Hansen RP, Olesen F, Vedsted P. Evidence of increasing mortality with longer diagnostic intervals for five common cancers: a cohort study in primary care. Eur J Cancer. 2013;49:2187-2198. 12. Hajdarevic S, Hornsten A, Sundbom E, Isaksson U, Schmitt-Egenolf M. Health-care delay in malignant melanoma: various pathways to diagnosis and treatment. Dermatol Res Pract. 2014;2014:294287. 13. Garbe C, Peris K, Hauschild A, et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guidelinedupdate 2016. Eur J Cancer. 2016;63: 201-217. 14. Bilimoria KY, Stewart AK, Winchester DP, Ko CY. The National Cancer Data Base: a powerful initiative to improve cancer care in the United States. Ann Surg Oncol. 2008;15:683-690. 15. Neal RD, Tharmanathan P, France B, et al. Is increased time to diagnosis and treatment in symptomatic cancer associated with poorer outcomes? Systematic review. Br J Cancer. 2015; 112(suppl 1):S92-S107. 16. Survival NSCB. NCDB survival reports. Available at: https:// www.facs.org/;/media/files/quality%20programs/cancer/ncdb/ survival_help_07172015.ashx. Accessed January 7, 2017. 17. Scope of regional lymph node surgery. Available at: http:// ncdbpuf.facs.org/sites/default/files/FORDS%20Scope%20of% 20Regional%20LN%20Surgery.pdf. Accessed January 7, 2017. 18. Quan H, Li B, Couris CM, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011;173:676-682. 19. Carpenter S, Pockaj B, Dueck A, et al. Factors influencing time between biopsy and definitive surgery for malignant melanoma: do they impact clinical outcome? Am J Surg. 2008;196:834-842 [discussion 842-843]. 20. Parrett BM, Accortt NA, Li R, et al. The effect of delay time between primary melanoma biopsy and sentinel lymph node
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Supplemental Fig 1. Distribution of time to treatment by stage.
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Supplemental Table I. Demographic characteristics Characteristic
Age at diagnosis, y \30 30-39 40-49 50-59 60-69 70-79 $80 Sex Female Male Race White Black Asian Pacific Islander American Indian, Aleutian, Eskimo Other Unknown Charlson-Deyo comorbidity score 0 1 $2 Insurance type/status Medicare Medicaid Private insurance/managed care Other government Not insured Insurance status unknown Distance from hospital Facility type Academic/research program Community cancer program Comprehensive community cancer program Integrated network cancer program Other Unknown Facility location East north central East south central Middle Atlantic Mountain New England Pacific South Atlantic West North Central West South Central Unknown Primary site Head and neck Upper extremities Trunk
\30 d (n = 81,268)
30-59 d (n = 56,246)
60-89 d (n = 10,967)
90-119 d (n = 2779)
[119 d (n = 1958)
P value
\.001 4529 7455 13,379 17,792 17,282 13,750 7081
(5.6) (9.2) (16.5) (21.9) (21.3) (16.9) (8.7)
2754 4544 8679 11,795 12,200 10,423 5851
(4.9) (8.1) (15.4) (21.0) (21.7) (18.5) (10.4)
530 813 1468 2294 2373 2126 1363
(4.8) (7.4) (13.4) (20.9) (21.6) (19.4) (12.4)
109 198 350 549 612 565 396
(3.9) (7.1) (12.6) (19.8) (22.0) (20.3) (14.2)
105 154 231 394 398 387 289
(5.4) (7.9) (11.8) (20.1) (20.3) (19.8) (14.8) \.001
35,607 (43.8) 45,661 (56.2)
23,879 (42.5) 32,367 (57.5)
79,335 318 113 25 68 297 1112
54,845 312 92 9 57 190 741
4500 (41.0) 6467 (59.0)
1124 (40.4) 1655 (59.6)
826 (42.2) 1132 (57.8)
2676 39 10 1 4 8 41
1883 32 10 1 3 10 19
\.001 (97.6) (0.4) (0.1) (0.0) (0.1) (0.4) (1.4)
(97.5) (0.6) (0.2) (0.0) (0.1) (0.3) (1.3)
10,676 90 28 1 10 41 121
(97.3) (0.8) (0.3) (0.0) (0.1) (0.4) (1.1)
(96.3) (1.4) (0.4) (0.0) (0.1) (0.3) (1.5)
(96.2) (1.6) (0.5) (0.1) (0.2) (0.5) (1.0) \.001
72,267 (88.9) 7717 (9.5) 1284 (1.6) 27,466 1323 48,124 653 1870 1832 32.28
49,286 (87.6) 5822 (10.4) 1138 (2.0)
(33.8) 20,811 (37.0) (1.6) 1174 (2.1) (59.2) 31,103 (55.3) (0.8) 559 (1.0) (2.3) 1462 (2.6) (2.3) 1137 (2.0) (112.93) 34.98 (99.96)
9523 (86.8) 1202 (11.0) 242 (2.2) 4359 361 5463 125 377 282 39.48
2345 (84.4) 357 (12.8) 77 (2.8)
1677 (85.6) 229 (11.7) 52 (2.7) \.001 (41.9) (5.0) (44.2) (1.7) (3.9) (3.2) (109.60) \.001 \.001 998 (51.0) 94 (4.8) 532 (27.2)
(39.7) 1183 (42.6) 820 (3.3) 124 (4.5) 98 (49.8) 1270 (45.7) 866 (1.1) 36 (1.3) 34 (3.4) 109 (3.9) 77 (2.6) 57 (2.1) 63 (107.76) 38.21 (91.61) 41.73
29,153 (35.9) 5329 (6.6) 30,504 (37.5)
26,784 (47.6) 2831 (5.0) 16,713 (29.7)
6001 (54.7) 455 (4.1) 2682 (24.5)
1498 (53.9) 130 (4.7) 715 (25.7)
5217 (6.4)
3219 (5.7)
590 (5.4)
159 (5.7)
96 (4.9)
52 (0.1) 11,013 (13.6)
24 (0.0) 6675 (11.9)
6 (0.1) 1233 (11.2)
1 (0.0) 276 (9.9)
1 (0.1) 237 (12.1)
1847 428 2052 398 591 1497 2147 428 346 1233
428 121 513 112 170 455 497 99 108 276
291 79 337 72 110 331 340 83 78 237
\.001 11,169 6190 7978 3744 4117 8130 16,808 7821 4298 11,013
(13.7) (7.6) (9.8) (4.6) (5.1) (10.0) (20.7) (9.6) (5.3) (13.6)
8442 3027 9330 2258 3502 6326 11,692 3085 1909 6675
(15.0) (5.4) (16.6) (4.0) (6.2) (11.2) (20.8) (5.5) (3.4) (11.9)
(16.8) (3.9) (18.7) (3.6) (5.4) (13.7) (19.6) (3.9) (3.2) (11.2)
(15.4) (4.4) (18.5) (4.0) (6.1) (16.4) (17.9) (3.6) (3.9) (9.9)
(14.9) (4.0) (17.2) (3.7) (5.6) (16.9) (17.4) (4.2) (4.0) (12.1) \.001
14,776 (18.2) 21,891 (26.9) 27,507 (33.8)
12,645 (22.5) 14,270 (25.4) 17,864 (31.8)
3134 (28.6) 2508 (22.9) 3186 (29.1)
878 (31.6) 612 (22.0) 744 (26.8)
645 (32.9) 439 (22.4) 483 (24.7) Continued
J AM ACAD DERMATOL
7.e3 Conic et al
n 2017
Supplemental Table I. Cont’d Characteristic
Lower extremities Not specified Laterality Left Midline Right Unknown Histologic type Superficial spreading Nodular Lentigo maligna Acral lentiginous Desmoplastic Spindle Amelanotic Other Unspecified Breslow depth \1 mm 1.01-2.00 mm 2.01-4 mm [4 mm Not specified Ulceration Not present Present Unknown Lymphovascular invasion Not present Present Unknown TNM pathologic stage Stage I Stage II Stage III Living status Alive Dead Year of diagnosis 2004 2005 2006 2007 2008 2009 2010 2011 2012
\30 d (n = 81,268)
30-59 d (n = 56,246)
60-89 d (n = 10,967)
90-119 d (n = 2779)
[119 d (n = 1958)
16,620 (20.5) 474 (0.6)
11,146 (19.8) 321 (0.6)
2054 (18.7) 85 (0.8)
524 (18.9) 21 (0.8)
369 (18.8) 22 (1.1)
35,123 8486 32,326 5333
(43.2) (10.4) (39.8) (6.6)
24,023 6525 22,377 3321
(42.7) (11.6) (39.8) (5.9)
4600 1426 4309 632
(41.9) (13.0) (39.3) (5.8)
1124 390 1128 137
(40.4) (14.0) (40.6) (4.9)
779 291 790 98
(39.8) (14.9) (40.3) (5.0)
26,264 8140 3487 1023 980 919 102 630 39,723
(32.3) (10.0) (4.3) (1.3) (1.2) (1.1) (0.1) (0.8) (48.9)
18,058 6350 2635 1004 1068 958 74 501 25,598
(32.1) (11.3) (4.7) (1.8) (1.9) (1.7) (0.1) (0.9) (45.5)
3125 1341 622 250 297 219 15 110 4988
(28.5) (12.2) (5.7) (2.3) (2.7) (2.0) (0.1) (1.0) (45.5)
736 331 174 72 78 65 3 22 1298
(26.5) (11.9) (6.3) (2.6) (2.8) (2.3) (0.1) (0.8) (46.7)
498 239 132 55 64 51 2 17 900
(25.4) (12.2) (6.7) (2.8) (3.3) (2.6) (0.1) (0.9) (46.0)
45,525 1,7350 10,289 5969 2135
(56.0) (21.3) (12.7) (7.3) (2.6)
29,018 12,548 7893 5410 1377
(51.6) (22.3) (14.0) (9.6) (2.4)
5183 2395 1651 1429 309
(47.3) (21.8) (15.1) (13.0) (2.8)
1259 603 402 415 100
(45.3) (21.7) (14.5) (14.9) (3.6)
925 373 274 301 85
(47.2) (19.1) (14.0) (15.4) (4.3)
P value
\.001
\.001
\.001
\.001 63,033 (77.6) 1319 (1.6) 16,916 (20.8)
43,423 (77.2) 1005 (1.8) 11,818 (21.0)
8243 (75.2) 256 (2.3) 2468 (22.5)
2014 (72.5) 64 (2.3) 701 (25.2)
1404 (71.7) 44 (2.2) 510 (26.0)
22,525 (27.7) 1212 (1.5) 57,531 (70.8)
16,374 (29.1) 968 (1.7) 38,904 (69.2)
3088 (28.2) 236 (2.2) 7643 (69.7)
777 (28.0) 62 (2.2) 1940 (69.8)
521 (26.6) 46 (2.3) 1391 (71.0)
55,309 (68.1) 15,725 (19.3) 10,234 (12.6)
36,167 (64.3) 12,194 (21.7) 7885 (14.0)
6478 (59.1) 2600 (23.7) 1889 (17.2)
1518 (54.6) 685 (24.6) 576 (20.7)
1082 (55.3) 464 (23.7) 412 (21.0)
67,635 (83.2) 1,3633(16.8)
45,913 (81.6) 10,333(18.4)
8591 (78.3) 2376 (21.7)
2103 (75.7) 676 (24.3)
1453 (74.2) 505 (25.8)
\.001
\.001
\.001 \.001 7732 8344 8864 8629 8441 8777 9560 10,286 10,635
(9.5) (10.3) (10.9) (10.6) (10.4) (10.8) (11.8) (12.7) (13.1)
4653 5488 5757 6027 6229 6261 6534 7219 8078
(8.3) (9.8) (10.2) (10.7) (11.1) (11.1) (11.6) (12.8) (14.4)
875 1047 1127 1204 1204 1311 1249 1346 1604
(8.0) (9.5) (10.3) (11.0) (11.0) (12.0) (11.4) (12.3) (14.6)
219 254 313 288 305 318 302 377 403
(7.9) (9.1) (11.3) (10.4) (11.0) (11.4) (10.9) (13.6) (14.5)
168 186 213 216 208 220 218 266 263
(8.6) (9.5) (10.9) (11.0) (10.6) (11.2) (11.1) (13.6) (13.4)
J AM ACAD DERMATOL
Conic et al 7.e4
VOLUME jj, NUMBER j
Supplemental Table II. Multivariate analysis of overall survival across all stages
Supplemental Table II. Cont’d
Characteristic
Laterality Left Midline Right Unknown Histologic type Superficial spreading Lentigo maligna Acral lentiginous Amelanotic Nodular Desmoplastic Spindle Other Unspecified Breslow depth \1 mm 1.01-2.00 mm 2.01-4.00 mm [4 mm Unknown Ulceration Not present Present Unknown Lymphovascular invasion Not present Present Unknown TNM pathologic stage Stage I Stage II Stage III Time to surgery 1-29 d 30-59 d 60-89 d 90-119 d $120 d
Age at diagnosis \30 30-39 40-49 50-59 60-69 70-79 $80 Sex Female Male Charlson-Deyo comorbidity score 0 1 $2 Insurance type/status Unknown Medicaid Medicare Not insured Other government Private insurance/ managed care Facility type (%) Academic/research program Community cancer program Comprehensive community cancer program Integrated network cancer program Other Facility location (%) East north central East south central Middle Atlantic Mountain New England Pacific South Atlantic West north central West south central Unknown Primary site Head and neck Lower extremities Overlapping Trunk Upper extremities Not specified
Hazard Ratio
95% CI
P value
Reference 1.22 1.34 1.61 2.03 3.24 6.31
1.08-1.38 1.08-1.65 1.31-1.98 1.64-2.49 2.63-4.00 5.11-7.78
Reference 1.37
1.33-1.41 \.001
Reference 1.29 2.08
1.24-1.33 \.001 1.96-2.20 \.001
Reference 1.64 1.13 1.35 1.18 0.83
.001 .007 \.001 \.001 \.001 \.001
1.46-1.83 \.001 1.04-1.24 .03 1.21-1.51 \.001 1.01-1.38 .14 0.76-0.90 \.001
Reference 1.18
1.13-1.24 \.001
1.06
1.03-1.09 \.001
1.11
1.05-1.16 \.001
0.88
0.47-1.63
.62
Reference 1.18 0.94 1.00 0.92 0.92 1.01 0.99 1.10 0.81
1.12-1.24 \.001 0.90-0.99 .02 0.94-1.06 .97 0.87-0.97 .007 0.88-0.97 \.001 0.97-1.05 .77 0.94-1.04 .47 1.04-1.17 \.001 0.67-0.98 .03
Reference 0.71 0.71 0.85 0.77 0.88
0.68-0.74 0.56-1.11 0.82-0.89 0.74-0.80 0.77-1.02
\.001 \.001 \.001 \.001 .03
Continued
Characteristic
CI, Confidence interval.
Hazard Ratio
95% CI
P value
Reference 1.12 1.00 1.1
1.07-1.17 \.001 0.97-1.03 .9 1.05-1.16 \.001
Reference 1.07 1.30 0.82 1.13 0.79 0.91 1.03 1.06
1.01-1.14 1.20-1.42 0.56-1.19 1.09-1.18 0.72-0.86 0.83-0.99 0.90-1.18 1.03-1.09
.04 \.001 .3 \.001 \.001 .01 .69 \.001
Reference 1.12 1.25 1.80 1.24
1.08-1.16 1.19-1.30 1.72-1.88 1.16-1.33
\.001 \.001 \.001 \.001
Reference 5.69 1.28
5.40-5.99 \.001 1.24-1.31 \.001
Reference 1.74 1.11
1.60-1.88 \.001 1.11-1.16 \.001
Reference 1.57 3.28
1.51-1.64 \.001 3.15-3.41 \.001
Reference 1.02 1.03 1.09 1.12
0.99-1.04 0.99-1.08 1.01-1.18 1.02-1.22
.12 .09 .03 .02
J AM ACAD DERMATOL
7.e5 Conic et al
n 2017
Supplemental Table III. Multivariate analysis of melanoma for TNM stage I
Supplemental Table III. Cont’d
Characteristic
Laterality Left Midline Right Unknown Histologic type Superficial spreading Acral lentiginous Amelanotic Desmoplastic Lentigo maligna Nodular Spindle Other Unspecified Breslow depth \1 mm 1.01-2.00 mm Ulceration Not present Present Unknown Lymphovascular invasion Not present Present Unknown Time to treatment 1-29 d 30-59 d 60-89 d 90-119 d $120 d
Age at diagnosis \30 30-39 40-49 50-59 60-69 70-79 $80 Sex Female Male Charlson-Deyo comorbidity score 0 1 $2 Insurance type/status Medicare Medicaid Private insurance/ managed care Other government Not insured Insurance status unknown Facility type Academic/research program Community cancer program Comprehensive community cancer program Integrated network cancer program Other Facility location East north central East south central Middle Atlantic Mountain New England Pacific South Atlantic West north central West south central Primary site Head and neck Trunk Upper extremities Lower extremities Not specified
Hazard ratio
95% CI
P value
Reference 1.52 2.23 3.35 4.75 8.68 21.66
1.13-2.04 1.7-2.93 2.57-4.36 3.65-6.18 6.66-11.32 16.6-28.26
.005 \.001 \.001 \.001 \.001 \.001
Reference 1.48
1.41-1.55
\.001
Reference 1.45 2.51
1.37-1.54 2.27-2.77
\.001 \.001
Reference 1.6 0.65
1.34-1.91 0.61-0.69
\.001 \.001
0.94 1.11 0.74
0.74-1.21 0.93-1.33 0.63-0.87
.648 .264 \.001
Reference 1.19
1.1-1.29
\.001
1.06
1.01-1.11
.017
1.13
1.04-1.23
.004
0.78
0.25-2.43
.671
Reference 1.16 0.92 1 0.92 0.87 0.96 0.96 1.08
1.06-1.26 0.86-1 0.9-1.12 0.84-1.01 0.81-0.95 0.9-1.03 0.88-1.05 0.97-1.2
.001 .042 .942 .091 .001 .292 .42 .165
Reference 0.77 0.76 0.63 1
0.73-0.82 0.71-0.8 0.58-0.68 0.77-1.3
\.001 \.001 \.001 .982
Characteristic
CI, Confidence interval.
Continued
Hazard ratio
95% CI
P value
Reference 1.11 0.99 1.15
1.03-1.19 0.95-1.04 1.06-1.24
.007 .74 .001
Reference 1.25 1.26 0.83 1 1.27 1 0.65 1.04
1.03-1.51 0.57-2.82 0.67-1.04 0.93-1.08 1.15-1.4 0.82-1.21 0.47-0.88 0.99-1.09
.022 .568 .104 .931 \.001 .973 .005 .107
Reference 1.35
1.29-1.41
\.001
Reference 7.11 1.22
5.9-8.58 1.14-1.31
\.001 \.001
Reference 1.41 1.02
0.94-2.09 0.94-1.11
.093 .597
Reference 1.05 1.16 1.29 1.41
1.01-1.1 1.07-1.25 1.12-1.48 1.21-1.65
.029 \.001 \.001 \.001
J AM ACAD DERMATOL
Conic et al 7.e6
VOLUME jj, NUMBER j
Supplemental Table IV. Multivariate analysis of melanoma by TNM stage II
Supplemental Table IV. Cont’d
Characteristic
Laterality Left Midline Right Unknown Histologic type Superficial spreading Acral lentiginous Amelanotic Desmoplastic Lentigo maligna Nodular Spindle Other Unspecified Breslow depth 1.01-2.00 2.01-4 [4 Ulceration Not present Present Unknown Lymphovascular invasion Not present Present Unknown Time to treatment 1-29 d 30-59 d 60-89 d 90-119 d $120 d
Age at diagnosis \30 30-39 40-49 50-59 60-69 70-79 $80 Sex Female Male Charlson-Deyo comorbidity score 0 1 $2 Insurance type/status Medicare Medicaid Private insurance/ managed care Other government Not insured Insurance status unknown Facility type Academic/research program Community cancer program Comprehensive community cancer program Integrated network cancer program Other Facility location East north central East south central Middle Atlantic Mountain New England Pacific South Atlantic West north central West south central Primary site Head and neck Trunk Upper extremities Lower extremities Not specified
Hazard ratio
95% CI
P value
Reference 1.26 1.39 1.6 1.88 2.87 5.26
0.94-1.68 1.07-1.82 1.24-2.07 1.45-2.43 2.21-3.73 4.05-6.82
.115 .015 \.001 \.001 \.001 \.001
Reference 1.26
1.2-1.33
\.001
Reference 1.25 1.95
1.17-1.33 \.001 1.75-2.16 \.001
Reference 1.24 0.79
1.04-1.48 .015 0.73-0.84 \.001
1.05 1.13 0.93
0.81-1.36 0.96-1.34 0.76-1.14
.726 .136 .488
Reference 1.23
1.12-1.34 \.001
1.06
1.01-1.11
.028
1.17
1.07-1.28
.001
1.41
0.53-3.76
.495
Reference 1.13 0.96 1.01 0.92 0.95 1.03 0.95 1.18
1.02-1.24 0.88-1.04 0.9-1.13 0.82-1.02 0.87-1.04 0.96-1.11 0.86-1.05 1.04-1.32
.017 .33 .879 .113 .248 .44 .328 .008
Reference 0.95 0.85 0.79 0.86
0.89-1.03 .203 0.79-0.91 \.001 0.72-0.86 \.001 0.65-1.15 .316 Continued
Characteristic
CI, Confidence interval.
Hazard ratio
95% CI
P value
Reference 1.21 1.04 1.11
1.12-1.31 \.001 0.98-1.09 .19 1-1.22 .048
Reference 1.14 0.43 0.71 0.85 0.99 0.74 1.1 0.94
0.97-1.33 .109 0.19-0.96 .039 0.63-0.8 \.001 0.72-1 .048 0.92-1.06 .716 0.65-0.84 \.001 0.87-1.4 .434 0.88-1 .068
Reference 1.35 2
1.26-1.45 \.001 1.85-2.15 \.001
Reference 6.2 1.2
5.71-6.74 \.001 1.14-1.26 \.001
Reference 1.73 1.1
1.46-2.05 \.001 1.02-1.2 .02
Reference 0.99 0.96 1.03 1.06
0.94-1.04 0.88-1.04 0.89-1.2 0.89-1.26
.771 .296 .647 .548
J AM ACAD DERMATOL
7.e7 Conic et al
n 2017
Supplemental Table V. Multivariate analysis of melanoma by TNM stage III
Supplemental Table V. Cont’d
Characteristic
Histologic type Superficial spreading Acral lentiginous Amelanotic Desmoplastic Lentigo maligna Nodular Spindle Other Unspecified Breslow depth \1 mm 1.01-2.00 mm 2.01-4.00 mm [4 mm Not specified Ulceration Not present Present Unknown Lymphovascular invasion Not present Present Unknown Time to treatment 1-29 d 30-59 d 60-89 d 90-119 d $120 d
Age at diagnosis \30 30-39 40-49 50-59 60-69 70-79 $80 Sex Female Male Charlson-Deyo comorbidity score 0 1 $2 Insurance type/status Medicaid Medicare Not insured Other government Private insurance/ managed care Facility type Academic/research program Community cancer program Comprehensive community cancer program Integrated network cancer program Facility location East north central East south central Middle Atlantic Mountain New England Pacific South Atlantic West north central West south central Primary site Head and neck Trunk Upper extremities Lower extremities Not specified Laterality Left Midline Right Unknown
Hazard ratio
95% CI
Characteristic
P value
Reference 1.32 1.65 1.79 2.03 2.47 3.74
1.12-1.56 1.41-1.94 1.53-2.1 1.73-2.38 2.09-2.92 3.15-4.44
Reference 1.28
1.21-1.34 \.001
Reference 1.16 1.7
1.09-1.24 \.001 1.51-1.9 \.001
Reference 1.32 1.09 1.13 1.18 0.86
1.09-1.6 0.92-1.28 0.94-1.37 0.92-1.52 0.73-1.01
.001 \.001 \.001 \.001 \.001 \.001
.004 .313 .187 .2 .069
Reference 1.08
0.98-1.18
.13
0.99
0.94-1.05
.781 CI, Confidence interval.
1.02
0.92-1.13
.661
Reference 1.16 0.96 0.96 0.91 0.97 1.01 1.02 1
1.04-1.28 0.89-1.05 0.86-1.08 0.81-1.02 0.88-1.06 0.93-1.08 0.92-1.12 0.9-1.12
.007 .377 .521 .101 .455 .888 .732 .979
Reference 0.89 0.77 0.79 0.74
0.82-0.97 .007 0.71-0.84 \.001 0.72-0.86 \.001 0.6-0.92 .006
Reference 1.12 0.99 1.04
1.02-1.22 0.94-1.04 0.95-1.15
.021 .619 .381
Continued
Hazard ratio
95% CI
P value
Reference 1.25 0.81 0.65 0.92 1.05 0.85 0.98 1.05
1.09-1.43 0.42-1.57 0.51-0.83 0.74-1.16 0.98-1.13 0.69-1.04 0.77-1.24 0.98-1.12
Reference 0.82 1.09 1.62 1.18
0.76-0.89 \.001 1.01-1.17 .024 1.51-1.73 \.001 1.05-1.32 .005
Reference 1.65 1.51
1.48-1.84 \.001 1.44-1.59 \.001
Reference 1.57 1.2
1.4-1.76 \.001 1.11-1.31 \.001
Reference 1.03 1.03 0.97 0.98
0.98-1.09 0.95-1.12 0.85-1.12 0.85-1.14
.001 .534 .001 .484 .142 .114 .85 .152
.201 .436 .703 .836
ARTICLE
Determination of the impact of melanoma surgical timing on survival using the National Cancer Database Ruzica Z. Conic, MD,a Claudia I. Cabrera, MD,a Alok A. Khorana, MD,b and Brian R. Gastman, MDa Cleveland, Ohio Background: The ideal timing for melanoma treatment, predominantly surgery, remains undetermined. Patient concern for receiving immediate treatment often exceeds surgeon or hospital availability, requiring establishment of a safe window for melanoma surgery. Objective: To assess the impact of time to definitive melanoma surgery on overall survival. Methods: Patients with stage I to III cutaneous melanoma and with available time to definitive surgery and overall survival were identified by using the National Cancer Database (N = 153,218). The t test and chi-square test were used to compare variables. Cox regression was used for multivariate analysis. Results: In a multivariate analysis of patients in all stages who were treated between 90 and 119 days after biopsy (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.01-1.18) and more than 119 days (HR, 1.12; 95% CI, 1.02-1.22) had a higher risk for mortality compared with those treated within 30 days of biopsy. In a subgroup analysis of stage I, higher mortality risk was found in patients treated within 30 to 59 days (HR, 1.05; 95% CI, 1.01-1.1), 60 to 89 days (HR, 1.16; 95% CI, 1.07-1.25), 90 to 119 days (HR, 1.29; 95% CI, 1.12-1.48), and more than 119 days after biopsy (HR, 1.41; 95% CI, 1.21-1.65). Surgical timing did not affect survival in stages II and III. Limitations: Melanoma-specific survival was not available. Conclusion: Expeditious treatment of stage I melanoma is associated with improved outcomes. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2017.08.039.) Key Words: melanoma; National Cancer Database; stage I melanoma; survival; time to surgery; time to treatment.
C
utaneous malignant melanoma (MM) is the fifth most common cancer among men and seventh among women.1,2 Rates of melanoma continue to rise in the United States and worldwide, and melanoma will be diagnosed in approximately 2.1% of the U.S. population in their lifetime.3-5 Furthermore, approximately 76,380 new cases of melanoma will be diagnosed in 2016, and 10,230 people will die of melanoma.2 The standard of care is surgery, which can include sentinel lymph node biopsy (SLNB) or lymphadenectomy depending on melanoma From the Department of Dermatology and Plastic Surgerya and Department of Hematology and Oncology, Cleveland Clinic.b Funding sources: None. Conflicts of interest: None declared. Accepted for publication August 16, 2017. Reprints not available from the authors.
Abbreviations used: CoC: LVI: MM: NCDB: OS: SLNB: TTI:
Commission on Cancer Lymphovascular invasion Malignant melanoma National Cancer Database Overall survival Sentinel lymph node biopsy Time to treatment initiation
stage.3,6 On diagnosis, the majority of melanomas are confined to a primary site (84%), with occasional spread to regional lymph nodes (9%) and metastasis Correspondence to: Brian R. Gastman, MD, Department of Plastic Surgery, A60 Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: [email protected]. Published online September 27, 2017. 0190-9622/$36.00 Ó 2017 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2017.08.039
1
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(4%).3 The estimated 5-year relative survival is 98.4% resulting in a time of 0 days to biopsy, and these if confined to a primary site, 62.4% if lymph nodes patients were excluded; this rate was similar are affected, and 17.9% if distantly metastatic.3 between the stages, with 12.5% excluded from stage Intuitively, a more expeditious treatment after I, 12.5% from stage II, and 11.7% from stage III. In cancer diagnosis should lead to better outcome. addition, patients treated after more than 365 days The data analysis of the National Cancer Database were excluded on account of probable existence of (NCDB) showed a better overall survival (OS) if time other factors affecting the decision to postpone to treatment initiation (TTI) surgery. SLNB data before was reduced for head and 2012 were not provided to CAPSULE SUMMARY neck squamous cell carciresearchers; however, this noma and breast cancers.7,8 information was available to Impact of time to treatment on survival the NCDB and used for Despite this likely relationin melanoma remains uncertain. staging.17 In addition, inforship between TTI and Prolonging time to treatment of survival, there are only a mation on compliance with melanoma negatively affects stage I but few small and predominantly National Comprehensive not stage II and III survival. retrospective studies examCancer Network guidelines ining the impact of TTI on was unavailable. Expeditious treatment of stage I melanoma survival.9-11 We identified 419,787 melanoma could improve survival. cases, of which 210,650 Although conclusive data were TNM stage I to III regarding impact of time to (Fig 1). After exclusion of patients without definitive (ie, surgical) treatment on melanoma follow-up, 183,622 cases remained. Lastly, patients survival are lacking, there has been speculation without a time to definitive surgery or a time longer regarding ‘‘ideal’’ TTI. The current recommendation than 365 days were excluded, leaving 153,218 in our for definitive melanoma treatment is within 3 to final cohort, which corresponded to 37% of the initial 4 weeks following diagnosis in the United States and cohort. 4 to 6 weeks in Europe.12,13 To address this issue, we Variables that can influence melanoma treatment used the NCDB to evaluate the effect of time from and outcomes, such as age, sex, comorbidity status, biopsy to definitive surgery on melanoma OS. insurance type, treating facility type and location, primary site, laterality, histologic type, and METHODS AND MATERIALS melanoma stage were analyzed. Follow-up ranged The NCDB is a clinical oncology database between 3 and10 years, and patients who remained established in 1989 as a joint project of the alive once their observation period ended were Commission on Cancer (CoC) of the American censored. Survival data are based on OS. College of Surgeons and American Cancer Society. A business associate agreement, including a data use Statistical analysis agreement, between the American College of Available covariates included age, sex, race, Surgeons and CoC accredited facilities is in place. insurance type, facility location, facility type, The NCDB is a facility-based database, representing comorbidity score, tumor site, laterality, and cancer 48.4% of all melanomas diagnosed in the United stage. Age at diagnosis was categorized as States.14,15 This database contains cases of patients younger than 30, 30 to 39, 40 to 49, 50 to 59, 60 to 18 or older who received all or part of their first 69, 70 to 79, and older than 79 years. Insurance type course therapy at a reporting cancer program.16 was classified as Medicare, Medicaid, private These data were provided to the authors by the insurance, other type of government insurance, no NCDB in a de-identified file, with prior approval insurance, or insurance status unknown. Facility from the Cleveland Clinic Institutional Review type was classified as academic/research Board.14 program, community cancer program, comprehenPatients in whom malignant melanoma had been sive community cancer program, integrated diagnosed from 2004 to 2012 were identified from network cancer program, other, or unknown. The the NCDB by using the International Classification of Charlson-Deyo comorbidity score was designated as Diseases for Oncology codes. Included cases had 0 if patients had no comorbidities, 1 if there was 1 follow-up time, living status, TNM stages I to III, and comorbidity, and 2 if there were 2 or more TTI longer than 0 but no longer than 365 days. comorbidities, with comorbidities defined as We defined TTI as time from biopsy to definitive previously published.18 Tumor site was designated surgery. A small percentage of the patients had excisional biopsy listed as their definitive surgery, as head and neck, upper extremities, trunk, lower d
d
d
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Fig 1. Flowchart presenting selection of patients from the National Cancer Database.
extremities, overlapping, or not specified. Tumor laterality was left, right, midline, or unknown. Breslow depth was categorized as less than 1 mm, 1.01 to 2.0 mm, 2.01 to 4.0 mm, more than 4 mm, or not specified. Ulceration and lymphovascular invasion (LVI) were classified as present, not present, or unknown. TNM stages IA and IB were combined into stage I; stages IIA, IIB and IIC were combined into stage II; and stages IIIA, IIIB and IIIC were combined into stage III. Time of surgery was categorized as 1 to 29, 30 to 59, 60 to 89, 90 to 119, and more than 119 days after biopsy on the basis of current clinical recommendations and knowledge. For univariate analysis, the chi-square test and t test were used. Data were presented as number and percent for categoric variables and as mean and standard deviation for continuous variables. Multivariate analysis was conducted by using a Cox proportional hazards model. Subgroup analysis was performed by stage because of its high impact on survival. Statistical significance was achieved with an a value less than 0.05. The data analysis was performed using R statistical software (version 3.2.4, R Foundation for Statistical Computing, Vienna, Austria).
RESULTS We identified 153,218 patients, of whom 71,950 were treated 30 days or more after biopsy. Specifically, 44.9% of stage I melanomas were treated 29 or more days after biopsy, as were 50.3% of stage II and 51.3% of stage III melanomas (Supplemental Fig 1; available at http://www.jaad.org). Furthermore 9% of stage I melanomas were treated 59 or more days after biopsy, as were 11.8% of stage II and 11.7% of stage III melanomas. Patients with a longer TTI tended to be older, be male, be using Medicare, have more comorbidities, have head and neck melanoma, have a higher Breslow thickness, be less likely to be ulcerated or have LVI, and be at a higher stage compared with those with a shorter TTI (Supplemental Table I; available at http://www.jaad.org). Unadjusted analysis of TTI showed improved survival for patients with shorter waiting times, with patients who were treated 30 to 59 days after biopsy having 14% worse OS, with 40% worse OS for those treated 60 to 89 days after biopsy, 63% worse OS for those treated 90 to 119 days after biopsy, and 70% worse OS for those treated more than 119 days after biopsy compared with patients treated within
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Fig 2. Graphic representation of adjusted and unadjusted hazard ratios by time to treatment initiation. Point estimates represent hazard ratios. Bars represent 95% confidence intervals. A, Unadjusted hazard ratios by time to treatment initiation. B, Unadjusted hazard ratio for days to treatment in stage I. C, Unadjusted hazard ratio for days to treatment in stage II. D, Unadjusted hazard ratio for days to treatment in stage III. Asterisks denote statistical significance.
the first 29 days (Fig 2, A). In addition, unadjusted analysis of stage based on TTI showed worse prognosis with longer TTI, which was most apparent in stage I (Fig 2, B to D). Multivariate adjustment for age, race, sex, comorbidities, year of diagnosis, hospital location, laterality, primary site, histologic type, Breslow depth, ulceration, LVI, insurance status, and stage was used for all models. All-stage model After adjustment, there were no differences in survival for patients with a TTI less than 90 days (Supplemental Table II [available at http://www. jaad.org] and Fig 3, A). Patients who were treated within 90 to 119 days and after 119 days were 9% and 12% more likely to die, respectively, than were those treated within 30 days. Patients with a Breslow depth of 1.01 to 2.00 mm, 2.01 to 4.00 mm, and more than 4.0 mm had a 12%, 25%, and 80% greater chance of death, respectively, than those with a Breslow depth less than 1.0 mm regardless of other factors. Worse outcomes were present with increasing age, male sex, head and neck melanoma, ulceration, LVI, and more comorbidities. Stage I model Following adjustment, patients who waited between 30 and 59 days after biopsy had 5% worse
survival; those who waited 60 to 89 days had 16% worse survival; those who waited 90 to 119 days had 29% worse survival; and those who waited longer than 119 days had 41% worse survival (Supplemental Table III [available at http://www.jaad.org] and Fig 3, B). Patients with a Breslow depth of 1.01 to 2.0 mm had 35% worse survival than those with a Breslow depth less than 1.0 mm independent of other factors. Additional factors that negatively affected survival were older age, male sex, more comorbidities, nodular or acral melanoma, a diagnosis of head and neck melanoma, midline tumors, and ulceration or LVI. Factors that positively affected survival were having private insurance, lower extremity melanoma, and desmoplastic melanoma. In an effort to pinpoint the breakpoint at which TTI starts to significantly affect survival, we analyzed TTI in 2-week intervals, with the breakpoint being between 43 and 56 days. The exact day at which TTI becomes important for survival could not be identified, likely because of an insufficient number of events. Stage 2 model After adjustment, there were no differences in survival times between the 5 TTI categories (Supplemental Table IV [available at http://www. jaad.org] and Fig 3, C ). Younger age, female sex, lack of comorbidities, desmoplastic or spindle histologic type of melanoma, upper or lower extremity
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Fig 3. Graphic representation of adjusted hazard ratios by time to treatment initiation. Point estimates represent hazard ratios. Bars represent 95% confidence intervals. A, Adjusted hazard ratios by time to treatment initiation. B, Adjusted hazard ratio for days to treatment in stage I. C, Adjusted hazard ratio for days to treatment in stage II. D, Adjusted hazard ratio for days to treatment in stage III. Asterisks denote statistical significance.
melanoma, and lower Breslow depth favorably affected survival. Factors that negatively affected survival were Medicaid, acral melanoma, head and neck melanoma, and ulceration or LVI. Stage 3 model As in stage II, there were no differences in survival between the 5 TTI categories after adjustment (Supplemental Table V [available at http://www. jaad.org], Fig 3, D). Older age at diagnosis, male sex, Medicaid, acral melanoma, higher Breslow depth, and presence of ulceration or LVI negatively affected survival. Patients with fewer comorbidities, melanoma on the extremities, and desmoplastic melanoma had better survival.
DISCUSSION In this study, we were, to the best of our knowledge, the first to show that OS decreases in patients waiting longer than 90 days for definitive surgical treatment of melanoma regardless of stage. Moreover, we believe that we are reporting for the first time that delay of surgery beyond the first 29 days for stage I melanoma negatively OS when 30-day intervals are used. Furthermore, when TTI was analyzed in 2-week intervals for stage I, we found that the critical time point at which TTI in the 30- to 59-day group leads to worse outcomes is between 43 and 56 days. The finding that increasing TTI negatively affects survival of patients with earlier stages of cancer is similar to the findings of several nonmelanoma studies.
In a recent report, Bleicher et al used the NCDB to examine the impact of TTI on breast cancer OS by stage, concluding that there is a 16% mortality increase for each 30-day increase in waiting time in stage I and a 9% increase in stage II but no effect on stage III.8 Similarly, an analysis of head and neck squamous cell carcinoma found that patients with stage I and II squamous cell carcinoma who waited 31 to 60 days had a 17% increase in mortality, whereas those waiting 61 to 90 days had a 54% increase in mortality; in comparison, there was no effect on mortality for those with stage III or IV disease who waited 31 to 60 days and an 8% increase for those who waited 61 to 90 days.7 Because of the much smaller cohort size, and thus lower statistical power, prior studies examining the impact of TTI on melanoma survival were not able to examine their data in the same level of granularity as ours, which explains why these outcomes have not been previously reported. For example, McKenna et al found no impact of TTI in OS or disease-specific survival regardless of melanoma stage, in a cohort of 986 patients.9 Similarly, Carpenter et al concluded that there was no difference in OS or disease-specific survival in 473 patients who waited less than or more than 28 days for treatment.19 Lastly, Parret et al found no difference in OS after analyzing TTI on the basis of groups of patients who waited less than or more than 40 days.20 We hypothesize that the negative effect of prolonging TTI on early-stage melanoma is visible
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as a result of the lower baseline mortality found in these patients. However in stages II and III, the potential benefits of a shorter TTI are likely overshadowed by a higher metastatic potential and baseline mortality. In other words, it appears that prompt initiation of definitive treatment is beneficial in stage I melanoma but likely not in stage II or III. Stages II and III melanoma are likely influenced by time to diagnosis, the importance of which is illustrated by several national studies and programs created to increase patient suspicion and physician recognition, leading to a decreasing incidence and mortality.5,21-24 For example, the state of Israel had the second highest incidence and mortality due to melanoma in the world; however, following prevention and detection efforts, its incidence rate dropped to 13th place for men and 20th place for women, whereas mortality dropped to eight and 10th place, respectively.22,23,25 Furthermore, rates of melanoma in situ increased, indicating a higher awareness and increase in early detection.22,25 Next, in an effort to improve waiting time after identification of a suspicious lesion, the United Kingdom implemented a ‘‘2-week’’ rule, according to which patients needed to see a specialist within 2 weeks of being referred by their general practitioner for any suspicion of cancer. Following implementation of this rule, detected melanomas were lower in stage and OS was significantly improved.21 Finally, following implementation of a new systematic skin cancer screening program in Germany, rates of mortality due to melanoma decreased.5 The findings of these studies support our hypothesis and indicate that detection in early stages and prompt treatment initiation following identification likely result in decreased mortality. Our study comes at a critical time in melanoma treatment. Stage I melanoma is typically treated by various specialties, including general practitioners, dermatologists, otorhinolaryngologists, general surgeons, surgical oncologists, and plastic surgeons, leading to high variability in approach and treatment.26-29 Furthermore, even in a single specialty, there is a high variability in physicians’ treatment approach for stage I melanoma; this includes controversy in performing SLNB.30 Finally, as a larger variety of physicians can treat stage I melanoma, a disproportionate number of cases may not be captured in the NCDB, which could have influenced our data. This fact may limit the applicability of our conclusions to CoC reporting facilities. However this concern is likely balanced by the fact that the database contains almost half of all melanomas treated in the United States. In contrast, stage II and III melanomas tend to be treated by
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specialists who perform SLNB and lymphadenectomy; given many guidelines such as those from the National Comprehensive Cancer Network, this coalesced group of surgeons likely deal with these advanced stages by using a more algorithmic approach. Our data highlight the need for stricter adherence to recommended TTI and standardization of the treatment approach for physicians who treat stage I melanoma. Lastly, our data provide critical information for ensuring safety in managing and planning neoadjuvant trials for melanoma. Neoadjuvant treatment, in which patients are treated before definitive surgical treatment, is used primarily in stage II and III melanoma and may result in delay of surgery.31-33 Despite current controversies in neoadjuvant therapy, currently there are 26 active neoadjuvant trials for MM, indicating that neoadjuvant trials will continue as a scientific endeavor.34,35 According to our data, TTI does not affect OS in these stages, allowing temporal freedom to maximize preoperative/‘‘neo’’ components.
CONCLUSION In conclusion, we found that definitive surgical treatment for stage I melanoma should be expeditious, whereas definitive surgical treatment for stage II and III may not affect OS in the current milieu of melanoma. Furthermore, expeditious patient identification and biopsy could migrate would-be stage II and III patients to stage I, where TTI optimization can be used to further improve their OS. On the basis of the available literature combined with our data, it is likely that these times are underoptimized and greater efforts to improve the entire process from suspicion of melanoma to its ultimate treatment should be implemented. We thank Katherine Glass for assistance with accessing data. REFERENCES 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7-30. 2. American Cancer Society. Cancer Facts & Figures 2016. Atlanta, Georgia: American Cancer Society; 2016. Available at: https:// www.cancer.org/content/dam/cancer-org/research/cancer-factsand-statistics/annual-cancer-facts-and-figures/2016/cancer-factsand-figures-2016.pdf. Accessed July 6, 2016. 3. Howlader N, Noone AM, Krapcho M, et al., eds. SEER Cancer Statistics Review. Bethesda, MD: National Cancer Institute; 1975-2013. Available at: https://seer.cancer.gov/csr/ 1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016. Accessed June 10, 2016. 4. Nikolaou V, Stratigos AJ. Emerging trends in the epidemiology of melanoma. Br J Dermatol. 2014;170:11-19.
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5. Breitbart EW, Waldmann A, Nolte S, et al. Systematic skin cancer screening in northern Germany. J Am Acad Dermatol. 2012;66:201-211. 6. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370:599-609. 7. Murphy CT, Galloway TJ, Handorf EA, et al. Survival impact of increasing time to treatment initiation for patients with head and neck cancer in the United States. J Clin Oncol. 2016;34:169-178. 8. Bleicher RJ, Ruth K, Sigurdson ER, et al. Time to surgery and breast cancer survival in the United States. JAMA Oncol. 2016; 2:330-339. 9. McKenna DB, Lee RJ, Prescott RJ, Doherty VR. The time from diagnostic excision biopsy to wide local excision for primary cutaneous malignant melanoma may not affect patient survival. Br J Dermatol. 2002;147:48-54. 10. Baade PD, English DR, Youl PH, McPherson M, Elwood JM, Aitken JF. The relationship between melanoma thickness and time to diagnosis in a large population-based study. Arch Dermatol. 2006;142:1422-1427. 11. Torring ML, Frydenberg M, Hansen RP, Olesen F, Vedsted P. Evidence of increasing mortality with longer diagnostic intervals for five common cancers: a cohort study in primary care. Eur J Cancer. 2013;49:2187-2198. 12. Hajdarevic S, Hornsten A, Sundbom E, Isaksson U, Schmitt-Egenolf M. Health-care delay in malignant melanoma: various pathways to diagnosis and treatment. Dermatol Res Pract. 2014;2014:294287. 13. Garbe C, Peris K, Hauschild A, et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guidelinedupdate 2016. Eur J Cancer. 2016;63: 201-217. 14. Bilimoria KY, Stewart AK, Winchester DP, Ko CY. The National Cancer Data Base: a powerful initiative to improve cancer care in the United States. Ann Surg Oncol. 2008;15:683-690. 15. Neal RD, Tharmanathan P, France B, et al. Is increased time to diagnosis and treatment in symptomatic cancer associated with poorer outcomes? Systematic review. Br J Cancer. 2015; 112(suppl 1):S92-S107. 16. Survival NSCB. NCDB survival reports. Available at: https:// www.facs.org/;/media/files/quality%20programs/cancer/ncdb/ survival_help_07172015.ashx. Accessed January 7, 2017. 17. Scope of regional lymph node surgery. Available at: http:// ncdbpuf.facs.org/sites/default/files/FORDS%20Scope%20of% 20Regional%20LN%20Surgery.pdf. Accessed January 7, 2017. 18. Quan H, Li B, Couris CM, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011;173:676-682. 19. Carpenter S, Pockaj B, Dueck A, et al. Factors influencing time between biopsy and definitive surgery for malignant melanoma: do they impact clinical outcome? Am J Surg. 2008;196:834-842 [discussion 842-843]. 20. Parrett BM, Accortt NA, Li R, et al. The effect of delay time between primary melanoma biopsy and sentinel lymph node
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dissection on sentinel node status, recurrence, and survival. Melanoma Res. 2012;22:386-391. Pacifico MD, Pearl RA, Grover R. The UK government two-week rule and its impact on melanoma prognosis: an evidence-based study. Ann R Coll Surg Engl. 2007;89:609-615. Israel Cancer Association. 2015 Skin Cancer Prevention and Detection Awareness Week. Available at: http://en.cancer.org. il/template_e/default.aspx?PageId=8925. Accessed August 16, 2016. Haaretz. Israel’s skin cancer rate second highest in the world. Available at: http://www.haaretz.com/israel-s-skin-cancer-ratesecond-highest-in-the-world-1.10250. Accessed September 28, 2016. Watts CG, Cust AE, Menzies SW, Coates E, Mann GJ, Morton RL. Specialized surveillance for individuals at high risk for melanoma: a cost analysis of a high-risk clinic. JAMA Dermatol. 2015;151:178-186. Sella T, Goren I, Shalev V, et al. Incidence trends of keratinocytic skin cancers and melanoma in Israel 2006-11. Br J Dermatol. 2015;172:202-207. McKenna DB, Marioni JC, Lee RJ, Prescott RJ, Doherty VR. A comparison of dermatologists’, surgeons’ and general practitioners’ surgical management of cutaneous melanoma. Br J Dermatol. 2004;151:636-644. DeFazio JL, Marghoob AA, Pan Y, Dusza SW, Khokhar A, Halpern A. Variation in the depth of excision of melanoma: a survey of US physicians. Arch Dermatol. 2010;146: 995-999. Corbo MD, Vender R, Wismer J. Comparison of dermatologists’ and nondermatologists’ diagnostic accuracy for malignant melanoma. J Cutan Med Surg. 2012;16:272-280. Martinka MJ, Crawford RI, Humphrey S. Clinical recognition of melanoma in dermatologists and nondermatologists. J Cutan Med Surg. 2016;20:532-535. Charles CA, Yee VS, Dusza SW, et al. Variation in the diagnosis, treatment, and management of melanoma in situ: a survey of US dermatologists. Arch Dermatol. 2005;141:723-729. van Zeijl MC, van den Eertwegh AJ, Haanen JB, Wouters MW. (Neo)adjuvant systemic therapy for melanoma. Eur J Surg Oncol. 2017;43:534-543. Davar D, Tarhini AA, Kirkwood JM. Adjuvant immunotherapy of melanoma and development of new approaches using the neoadjuvant approach. Clin Dermatol. 2013;31:237-250. Moschos SJ, Edington HD, Land SR, et al. Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J Clin Oncol. 2006;24:3164-3171. Raigani S, Cohen S, Boland GM. The role of surgery for melanoma in an era of effective systemic therapy. Curr Oncol Rep. 2017;19:17. Clinical Trials.gov. Search results: 24 studies found for neoadjuvant trials on melanoma. Available at: https://clinicaltrials. gov/ct2/results?term=neoadjuvant1trials1on1melanoma &pg=2. Accessed February 28, 2017.
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Supplemental Fig 1. Distribution of time to treatment by stage.
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Supplemental Table I. Demographic characteristics Characteristic
Age at diagnosis, y \30 30-39 40-49 50-59 60-69 70-79 $80 Sex Female Male Race White Black Asian Pacific Islander American Indian, Aleutian, Eskimo Other Unknown Charlson-Deyo comorbidity score 0 1 $2 Insurance type/status Medicare Medicaid Private insurance/managed care Other government Not insured Insurance status unknown Distance from hospital Facility type Academic/research program Community cancer program Comprehensive community cancer program Integrated network cancer program Other Unknown Facility location East north central East south central Middle Atlantic Mountain New England Pacific South Atlantic West North Central West South Central Unknown Primary site Head and neck Upper extremities Trunk
\30 d (n = 81,268)
30-59 d (n = 56,246)
60-89 d (n = 10,967)
90-119 d (n = 2779)
[119 d (n = 1958)
P value
\.001 4529 7455 13,379 17,792 17,282 13,750 7081
(5.6) (9.2) (16.5) (21.9) (21.3) (16.9) (8.7)
2754 4544 8679 11,795 12,200 10,423 5851
(4.9) (8.1) (15.4) (21.0) (21.7) (18.5) (10.4)
530 813 1468 2294 2373 2126 1363
(4.8) (7.4) (13.4) (20.9) (21.6) (19.4) (12.4)
109 198 350 549 612 565 396
(3.9) (7.1) (12.6) (19.8) (22.0) (20.3) (14.2)
105 154 231 394 398 387 289
(5.4) (7.9) (11.8) (20.1) (20.3) (19.8) (14.8) \.001
35,607 (43.8) 45,661 (56.2)
23,879 (42.5) 32,367 (57.5)
79,335 318 113 25 68 297 1112
54,845 312 92 9 57 190 741
4500 (41.0) 6467 (59.0)
1124 (40.4) 1655 (59.6)
826 (42.2) 1132 (57.8)
2676 39 10 1 4 8 41
1883 32 10 1 3 10 19
\.001 (97.6) (0.4) (0.1) (0.0) (0.1) (0.4) (1.4)
(97.5) (0.6) (0.2) (0.0) (0.1) (0.3) (1.3)
10,676 90 28 1 10 41 121
(97.3) (0.8) (0.3) (0.0) (0.1) (0.4) (1.1)
(96.3) (1.4) (0.4) (0.0) (0.1) (0.3) (1.5)
(96.2) (1.6) (0.5) (0.1) (0.2) (0.5) (1.0) \.001
72,267 (88.9) 7717 (9.5) 1284 (1.6) 27,466 1323 48,124 653 1870 1832 32.28
49,286 (87.6) 5822 (10.4) 1138 (2.0)
(33.8) 20,811 (37.0) (1.6) 1174 (2.1) (59.2) 31,103 (55.3) (0.8) 559 (1.0) (2.3) 1462 (2.6) (2.3) 1137 (2.0) (112.93) 34.98 (99.96)
9523 (86.8) 1202 (11.0) 242 (2.2) 4359 361 5463 125 377 282 39.48
2345 (84.4) 357 (12.8) 77 (2.8)
1677 (85.6) 229 (11.7) 52 (2.7) \.001 (41.9) (5.0) (44.2) (1.7) (3.9) (3.2) (109.60) \.001 \.001 998 (51.0) 94 (4.8) 532 (27.2)
(39.7) 1183 (42.6) 820 (3.3) 124 (4.5) 98 (49.8) 1270 (45.7) 866 (1.1) 36 (1.3) 34 (3.4) 109 (3.9) 77 (2.6) 57 (2.1) 63 (107.76) 38.21 (91.61) 41.73
29,153 (35.9) 5329 (6.6) 30,504 (37.5)
26,784 (47.6) 2831 (5.0) 16,713 (29.7)
6001 (54.7) 455 (4.1) 2682 (24.5)
1498 (53.9) 130 (4.7) 715 (25.7)
5217 (6.4)
3219 (5.7)
590 (5.4)
159 (5.7)
96 (4.9)
52 (0.1) 11,013 (13.6)
24 (0.0) 6675 (11.9)
6 (0.1) 1233 (11.2)
1 (0.0) 276 (9.9)
1 (0.1) 237 (12.1)
1847 428 2052 398 591 1497 2147 428 346 1233
428 121 513 112 170 455 497 99 108 276
291 79 337 72 110 331 340 83 78 237
\.001 11,169 6190 7978 3744 4117 8130 16,808 7821 4298 11,013
(13.7) (7.6) (9.8) (4.6) (5.1) (10.0) (20.7) (9.6) (5.3) (13.6)
8442 3027 9330 2258 3502 6326 11,692 3085 1909 6675
(15.0) (5.4) (16.6) (4.0) (6.2) (11.2) (20.8) (5.5) (3.4) (11.9)
(16.8) (3.9) (18.7) (3.6) (5.4) (13.7) (19.6) (3.9) (3.2) (11.2)
(15.4) (4.4) (18.5) (4.0) (6.1) (16.4) (17.9) (3.6) (3.9) (9.9)
(14.9) (4.0) (17.2) (3.7) (5.6) (16.9) (17.4) (4.2) (4.0) (12.1) \.001
14,776 (18.2) 21,891 (26.9) 27,507 (33.8)
12,645 (22.5) 14,270 (25.4) 17,864 (31.8)
3134 (28.6) 2508 (22.9) 3186 (29.1)
878 (31.6) 612 (22.0) 744 (26.8)
645 (32.9) 439 (22.4) 483 (24.7) Continued
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Supplemental Table I. Cont’d Characteristic
Lower extremities Not specified Laterality Left Midline Right Unknown Histologic type Superficial spreading Nodular Lentigo maligna Acral lentiginous Desmoplastic Spindle Amelanotic Other Unspecified Breslow depth \1 mm 1.01-2.00 mm 2.01-4 mm [4 mm Not specified Ulceration Not present Present Unknown Lymphovascular invasion Not present Present Unknown TNM pathologic stage Stage I Stage II Stage III Living status Alive Dead Year of diagnosis 2004 2005 2006 2007 2008 2009 2010 2011 2012
\30 d (n = 81,268)
30-59 d (n = 56,246)
60-89 d (n = 10,967)
90-119 d (n = 2779)
[119 d (n = 1958)
16,620 (20.5) 474 (0.6)
11,146 (19.8) 321 (0.6)
2054 (18.7) 85 (0.8)
524 (18.9) 21 (0.8)
369 (18.8) 22 (1.1)
35,123 8486 32,326 5333
(43.2) (10.4) (39.8) (6.6)
24,023 6525 22,377 3321
(42.7) (11.6) (39.8) (5.9)
4600 1426 4309 632
(41.9) (13.0) (39.3) (5.8)
1124 390 1128 137
(40.4) (14.0) (40.6) (4.9)
779 291 790 98
(39.8) (14.9) (40.3) (5.0)
26,264 8140 3487 1023 980 919 102 630 39,723
(32.3) (10.0) (4.3) (1.3) (1.2) (1.1) (0.1) (0.8) (48.9)
18,058 6350 2635 1004 1068 958 74 501 25,598
(32.1) (11.3) (4.7) (1.8) (1.9) (1.7) (0.1) (0.9) (45.5)
3125 1341 622 250 297 219 15 110 4988
(28.5) (12.2) (5.7) (2.3) (2.7) (2.0) (0.1) (1.0) (45.5)
736 331 174 72 78 65 3 22 1298
(26.5) (11.9) (6.3) (2.6) (2.8) (2.3) (0.1) (0.8) (46.7)
498 239 132 55 64 51 2 17 900
(25.4) (12.2) (6.7) (2.8) (3.3) (2.6) (0.1) (0.9) (46.0)
45,525 1,7350 10,289 5969 2135
(56.0) (21.3) (12.7) (7.3) (2.6)
29,018 12,548 7893 5410 1377
(51.6) (22.3) (14.0) (9.6) (2.4)
5183 2395 1651 1429 309
(47.3) (21.8) (15.1) (13.0) (2.8)
1259 603 402 415 100
(45.3) (21.7) (14.5) (14.9) (3.6)
925 373 274 301 85
(47.2) (19.1) (14.0) (15.4) (4.3)
P value
\.001
\.001
\.001
\.001 63,033 (77.6) 1319 (1.6) 16,916 (20.8)
43,423 (77.2) 1005 (1.8) 11,818 (21.0)
8243 (75.2) 256 (2.3) 2468 (22.5)
2014 (72.5) 64 (2.3) 701 (25.2)
1404 (71.7) 44 (2.2) 510 (26.0)
22,525 (27.7) 1212 (1.5) 57,531 (70.8)
16,374 (29.1) 968 (1.7) 38,904 (69.2)
3088 (28.2) 236 (2.2) 7643 (69.7)
777 (28.0) 62 (2.2) 1940 (69.8)
521 (26.6) 46 (2.3) 1391 (71.0)
55,309 (68.1) 15,725 (19.3) 10,234 (12.6)
36,167 (64.3) 12,194 (21.7) 7885 (14.0)
6478 (59.1) 2600 (23.7) 1889 (17.2)
1518 (54.6) 685 (24.6) 576 (20.7)
1082 (55.3) 464 (23.7) 412 (21.0)
67,635 (83.2) 1,3633(16.8)
45,913 (81.6) 10,333(18.4)
8591 (78.3) 2376 (21.7)
2103 (75.7) 676 (24.3)
1453 (74.2) 505 (25.8)
\.001
\.001
\.001 \.001 7732 8344 8864 8629 8441 8777 9560 10,286 10,635
(9.5) (10.3) (10.9) (10.6) (10.4) (10.8) (11.8) (12.7) (13.1)
4653 5488 5757 6027 6229 6261 6534 7219 8078
(8.3) (9.8) (10.2) (10.7) (11.1) (11.1) (11.6) (12.8) (14.4)
875 1047 1127 1204 1204 1311 1249 1346 1604
(8.0) (9.5) (10.3) (11.0) (11.0) (12.0) (11.4) (12.3) (14.6)
219 254 313 288 305 318 302 377 403
(7.9) (9.1) (11.3) (10.4) (11.0) (11.4) (10.9) (13.6) (14.5)
168 186 213 216 208 220 218 266 263
(8.6) (9.5) (10.9) (11.0) (10.6) (11.2) (11.1) (13.6) (13.4)
J AM ACAD DERMATOL
Conic et al 7.e4
VOLUME jj, NUMBER j
Supplemental Table II. Multivariate analysis of overall survival across all stages
Supplemental Table II. Cont’d
Characteristic
Laterality Left Midline Right Unknown Histologic type Superficial spreading Lentigo maligna Acral lentiginous Amelanotic Nodular Desmoplastic Spindle Other Unspecified Breslow depth \1 mm 1.01-2.00 mm 2.01-4.00 mm [4 mm Unknown Ulceration Not present Present Unknown Lymphovascular invasion Not present Present Unknown TNM pathologic stage Stage I Stage II Stage III Time to surgery 1-29 d 30-59 d 60-89 d 90-119 d $120 d
Age at diagnosis \30 30-39 40-49 50-59 60-69 70-79 $80 Sex Female Male Charlson-Deyo comorbidity score 0 1 $2 Insurance type/status Unknown Medicaid Medicare Not insured Other government Private insurance/ managed care Facility type (%) Academic/research program Community cancer program Comprehensive community cancer program Integrated network cancer program Other Facility location (%) East north central East south central Middle Atlantic Mountain New England Pacific South Atlantic West north central West south central Unknown Primary site Head and neck Lower extremities Overlapping Trunk Upper extremities Not specified
Hazard Ratio
95% CI
P value
Reference 1.22 1.34 1.61 2.03 3.24 6.31
1.08-1.38 1.08-1.65 1.31-1.98 1.64-2.49 2.63-4.00 5.11-7.78
Reference 1.37
1.33-1.41 \.001
Reference 1.29 2.08
1.24-1.33 \.001 1.96-2.20 \.001
Reference 1.64 1.13 1.35 1.18 0.83
.001 .007 \.001 \.001 \.001 \.001
1.46-1.83 \.001 1.04-1.24 .03 1.21-1.51 \.001 1.01-1.38 .14 0.76-0.90 \.001
Reference 1.18
1.13-1.24 \.001
1.06
1.03-1.09 \.001
1.11
1.05-1.16 \.001
0.88
0.47-1.63
.62
Reference 1.18 0.94 1.00 0.92 0.92 1.01 0.99 1.10 0.81
1.12-1.24 \.001 0.90-0.99 .02 0.94-1.06 .97 0.87-0.97 .007 0.88-0.97 \.001 0.97-1.05 .77 0.94-1.04 .47 1.04-1.17 \.001 0.67-0.98 .03
Reference 0.71 0.71 0.85 0.77 0.88
0.68-0.74 0.56-1.11 0.82-0.89 0.74-0.80 0.77-1.02
\.001 \.001 \.001 \.001 .03
Continued
Characteristic
CI, Confidence interval.
Hazard Ratio
95% CI
P value
Reference 1.12 1.00 1.1
1.07-1.17 \.001 0.97-1.03 .9 1.05-1.16 \.001
Reference 1.07 1.30 0.82 1.13 0.79 0.91 1.03 1.06
1.01-1.14 1.20-1.42 0.56-1.19 1.09-1.18 0.72-0.86 0.83-0.99 0.90-1.18 1.03-1.09
.04 \.001 .3 \.001 \.001 .01 .69 \.001
Reference 1.12 1.25 1.80 1.24
1.08-1.16 1.19-1.30 1.72-1.88 1.16-1.33
\.001 \.001 \.001 \.001
Reference 5.69 1.28
5.40-5.99 \.001 1.24-1.31 \.001
Reference 1.74 1.11
1.60-1.88 \.001 1.11-1.16 \.001
Reference 1.57 3.28
1.51-1.64 \.001 3.15-3.41 \.001
Reference 1.02 1.03 1.09 1.12
0.99-1.04 0.99-1.08 1.01-1.18 1.02-1.22
.12 .09 .03 .02
J AM ACAD DERMATOL
7.e5 Conic et al
n 2017
Supplemental Table III. Multivariate analysis of melanoma for TNM stage I
Supplemental Table III. Cont’d
Characteristic
Laterality Left Midline Right Unknown Histologic type Superficial spreading Acral lentiginous Amelanotic Desmoplastic Lentigo maligna Nodular Spindle Other Unspecified Breslow depth \1 mm 1.01-2.00 mm Ulceration Not present Present Unknown Lymphovascular invasion Not present Present Unknown Time to treatment 1-29 d 30-59 d 60-89 d 90-119 d $120 d
Age at diagnosis \30 30-39 40-49 50-59 60-69 70-79 $80 Sex Female Male Charlson-Deyo comorbidity score 0 1 $2 Insurance type/status Medicare Medicaid Private insurance/ managed care Other government Not insured Insurance status unknown Facility type Academic/research program Community cancer program Comprehensive community cancer program Integrated network cancer program Other Facility location East north central East south central Middle Atlantic Mountain New England Pacific South Atlantic West north central West south central Primary site Head and neck Trunk Upper extremities Lower extremities Not specified
Hazard ratio
95% CI
P value
Reference 1.52 2.23 3.35 4.75 8.68 21.66
1.13-2.04 1.7-2.93 2.57-4.36 3.65-6.18 6.66-11.32 16.6-28.26
.005 \.001 \.001 \.001 \.001 \.001
Reference 1.48
1.41-1.55
\.001
Reference 1.45 2.51
1.37-1.54 2.27-2.77
\.001 \.001
Reference 1.6 0.65
1.34-1.91 0.61-0.69
\.001 \.001
0.94 1.11 0.74
0.74-1.21 0.93-1.33 0.63-0.87
.648 .264 \.001
Reference 1.19
1.1-1.29
\.001
1.06
1.01-1.11
.017
1.13
1.04-1.23
.004
0.78
0.25-2.43
.671
Reference 1.16 0.92 1 0.92 0.87 0.96 0.96 1.08
1.06-1.26 0.86-1 0.9-1.12 0.84-1.01 0.81-0.95 0.9-1.03 0.88-1.05 0.97-1.2
.001 .042 .942 .091 .001 .292 .42 .165
Reference 0.77 0.76 0.63 1
0.73-0.82 0.71-0.8 0.58-0.68 0.77-1.3
\.001 \.001 \.001 .982
Characteristic
CI, Confidence interval.
Continued
Hazard ratio
95% CI
P value
Reference 1.11 0.99 1.15
1.03-1.19 0.95-1.04 1.06-1.24
.007 .74 .001
Reference 1.25 1.26 0.83 1 1.27 1 0.65 1.04
1.03-1.51 0.57-2.82 0.67-1.04 0.93-1.08 1.15-1.4 0.82-1.21 0.47-0.88 0.99-1.09
.022 .568 .104 .931 \.001 .973 .005 .107
Reference 1.35
1.29-1.41
\.001
Reference 7.11 1.22
5.9-8.58 1.14-1.31
\.001 \.001
Reference 1.41 1.02
0.94-2.09 0.94-1.11
.093 .597
Reference 1.05 1.16 1.29 1.41
1.01-1.1 1.07-1.25 1.12-1.48 1.21-1.65
.029 \.001 \.001 \.001
J AM ACAD DERMATOL
Conic et al 7.e6
VOLUME jj, NUMBER j
Supplemental Table IV. Multivariate analysis of melanoma by TNM stage II
Supplemental Table IV. Cont’d
Characteristic
Laterality Left Midline Right Unknown Histologic type Superficial spreading Acral lentiginous Amelanotic Desmoplastic Lentigo maligna Nodular Spindle Other Unspecified Breslow depth 1.01-2.00 2.01-4 [4 Ulceration Not present Present Unknown Lymphovascular invasion Not present Present Unknown Time to treatment 1-29 d 30-59 d 60-89 d 90-119 d $120 d
Age at diagnosis \30 30-39 40-49 50-59 60-69 70-79 $80 Sex Female Male Charlson-Deyo comorbidity score 0 1 $2 Insurance type/status Medicare Medicaid Private insurance/ managed care Other government Not insured Insurance status unknown Facility type Academic/research program Community cancer program Comprehensive community cancer program Integrated network cancer program Other Facility location East north central East south central Middle Atlantic Mountain New England Pacific South Atlantic West north central West south central Primary site Head and neck Trunk Upper extremities Lower extremities Not specified
Hazard ratio
95% CI
P value
Reference 1.26 1.39 1.6 1.88 2.87 5.26
0.94-1.68 1.07-1.82 1.24-2.07 1.45-2.43 2.21-3.73 4.05-6.82
.115 .015 \.001 \.001 \.001 \.001
Reference 1.26
1.2-1.33
\.001
Reference 1.25 1.95
1.17-1.33 \.001 1.75-2.16 \.001
Reference 1.24 0.79
1.04-1.48 .015 0.73-0.84 \.001
1.05 1.13 0.93
0.81-1.36 0.96-1.34 0.76-1.14
.726 .136 .488
Reference 1.23
1.12-1.34 \.001
1.06
1.01-1.11
.028
1.17
1.07-1.28
.001
1.41
0.53-3.76
.495
Reference 1.13 0.96 1.01 0.92 0.95 1.03 0.95 1.18
1.02-1.24 0.88-1.04 0.9-1.13 0.82-1.02 0.87-1.04 0.96-1.11 0.86-1.05 1.04-1.32
.017 .33 .879 .113 .248 .44 .328 .008
Reference 0.95 0.85 0.79 0.86
0.89-1.03 .203 0.79-0.91 \.001 0.72-0.86 \.001 0.65-1.15 .316 Continued
Characteristic
CI, Confidence interval.
Hazard ratio
95% CI
P value
Reference 1.21 1.04 1.11
1.12-1.31 \.001 0.98-1.09 .19 1-1.22 .048
Reference 1.14 0.43 0.71 0.85 0.99 0.74 1.1 0.94
0.97-1.33 .109 0.19-0.96 .039 0.63-0.8 \.001 0.72-1 .048 0.92-1.06 .716 0.65-0.84 \.001 0.87-1.4 .434 0.88-1 .068
Reference 1.35 2
1.26-1.45 \.001 1.85-2.15 \.001
Reference 6.2 1.2
5.71-6.74 \.001 1.14-1.26 \.001
Reference 1.73 1.1
1.46-2.05 \.001 1.02-1.2 .02
Reference 0.99 0.96 1.03 1.06
0.94-1.04 0.88-1.04 0.89-1.2 0.89-1.26
.771 .296 .647 .548
J AM ACAD DERMATOL
7.e7 Conic et al
n 2017
Supplemental Table V. Multivariate analysis of melanoma by TNM stage III
Supplemental Table V. Cont’d
Characteristic
Histologic type Superficial spreading Acral lentiginous Amelanotic Desmoplastic Lentigo maligna Nodular Spindle Other Unspecified Breslow depth \1 mm 1.01-2.00 mm 2.01-4.00 mm [4 mm Not specified Ulceration Not present Present Unknown Lymphovascular invasion Not present Present Unknown Time to treatment 1-29 d 30-59 d 60-89 d 90-119 d $120 d
Age at diagnosis \30 30-39 40-49 50-59 60-69 70-79 $80 Sex Female Male Charlson-Deyo comorbidity score 0 1 $2 Insurance type/status Medicaid Medicare Not insured Other government Private insurance/ managed care Facility type Academic/research program Community cancer program Comprehensive community cancer program Integrated network cancer program Facility location East north central East south central Middle Atlantic Mountain New England Pacific South Atlantic West north central West south central Primary site Head and neck Trunk Upper extremities Lower extremities Not specified Laterality Left Midline Right Unknown
Hazard ratio
95% CI
Characteristic
P value
Reference 1.32 1.65 1.79 2.03 2.47 3.74
1.12-1.56 1.41-1.94 1.53-2.1 1.73-2.38 2.09-2.92 3.15-4.44
Reference 1.28
1.21-1.34 \.001
Reference 1.16 1.7
1.09-1.24 \.001 1.51-1.9 \.001
Reference 1.32 1.09 1.13 1.18 0.86
1.09-1.6 0.92-1.28 0.94-1.37 0.92-1.52 0.73-1.01
.001 \.001 \.001 \.001 \.001 \.001
.004 .313 .187 .2 .069
Reference 1.08
0.98-1.18
.13
0.99
0.94-1.05
.781 CI, Confidence interval.
1.02
0.92-1.13
.661
Reference 1.16 0.96 0.96 0.91 0.97 1.01 1.02 1
1.04-1.28 0.89-1.05 0.86-1.08 0.81-1.02 0.88-1.06 0.93-1.08 0.92-1.12 0.9-1.12
.007 .377 .521 .101 .455 .888 .732 .979
Reference 0.89 0.77 0.79 0.74
0.82-0.97 .007 0.71-0.84 \.001 0.72-0.86 \.001 0.6-0.92 .006
Reference 1.12 0.99 1.04
1.02-1.22 0.94-1.04 0.95-1.15
.021 .619 .381
Continued
Hazard ratio
95% CI
P value
Reference 1.25 0.81 0.65 0.92 1.05 0.85 0.98 1.05
1.09-1.43 0.42-1.57 0.51-0.83 0.74-1.16 0.98-1.13 0.69-1.04 0.77-1.24 0.98-1.12
Reference 0.82 1.09 1.62 1.18
0.76-0.89 \.001 1.01-1.17 .024 1.51-1.73 \.001 1.05-1.32 .005
Reference 1.65 1.51
1.48-1.84 \.001 1.44-1.59 \.001
Reference 1.57 1.2
1.4-1.76 \.001 1.11-1.31 \.001
Reference 1.03 1.03 0.97 0.98
0.98-1.09 0.95-1.12 0.85-1.12 0.85-1.14
.001 .534 .001 .484 .142 .114 .85 .152
.201 .436 .703 .836