Population-Based Assessment of Surgical Treatment Trends for Patients With Melanoma in the Era of Sentinel Lymph Node Biopsy
http://www.100md.com
《临床肿瘤学》
The University of Texas M.D. Anderson Cancer Center, Houston, TX
ABSTRACT
PURPOSE: The surgical staging of melanoma dramatically changed with the introduction of sentinel lymph node (SLN) biopsy. In this study, Surveillance, Epidemiology, and End Results (SEER) data were examined to determine how surgical treatment is being carried out and whether SLN biopsy is being performed in melanoma patients in conformance with National Comprehensive Cancer Network (NCCN) guidelines.
PATIENTS AND METHODS: The SEER database (1998 to 2001) was searched for all patients with invasive melanoma. NCCN guidelines were used to define optimal stage-specific surgical treatment. Treatment trends in patients with stages I to III disease were summarized, and multivariate analyses were performed to identify factors associated with nonadherence with treatment guidelines.
RESULTS: A total of 21,867 melanoma patients were identified; 18,499 of these patients met the inclusion criteria. The number of patients diagnosed with stage III melanoma increased by 55.7% over the study period, and this corresponded to a 53% increase in the number of SLN biopsies performed annually. The odds ratios for nonadherence were 2.32, 2.27, and 1.54 for stages IB, II, and III disease, respectively, compared with stage IA melanoma. Multivariate analyses revealed that age more than 65 years, marital status, minority populations, and primary tumor location were associated with nonadherence with guidelines. Treatment patterns among tumor registries also varied significantly.
CONCLUSION: Stage migration is evident in the SEER registries in consort with increasing use of SLN biopsy. Although treatment trends are improving, SLN biopsy continues to be underused, particularly in the elderly and minority populations, in patients with truncal and head/neck melanomas, and also in some geographic regions of the United States.
INTRODUCTION
The incidence of melanoma has been climbing steadily since the early 1970s.1 Fortunately, most of the newly diagnosed patients have disease clinically confined to the primary tumor site (stages I and II). Rational treatment strategies for stage I and II patients have evolved over the last decade to optimize survival, locoregional disease control, and staging and, at the same time, minimize treatment morbidities. Accepted standards for the extent of excision margins vary according to ranges of tumor thickness based on the results of several prospective randomized trials.2-5
Historically, the approach to the clinically negative regional lymph nodes has been more controversial, with recommendations ranging from observation to elective node dissection. The introduction of sentinel lymph node (SLN) biopsy in 1992,6 followed by worldwide confirmation of the accuracy of this technique,7-10 promoted a selective approach to regional node dissections. For SLN-positive patients (occult stage III), a formal lymphadectomy is performed to accomplish durable regional disease control and possibly to provide a survival advantage compared with patients who undergo a dissection for clinically apparent (macroscopic) nodal disease. SLN-negative patients are spared the cost and morbidity of a formal dissection. Evidence that SLN biopsy provides critical staging information is derived from multivariate analyses demonstrating that SLN status is the most powerful independent predictor of survival in stage I and II patients.8 Although it is not surprising that SLN biopsy has been embraced as an integral component in the management of stage I and II patients across the United States and around the world, particularly at cancer centers, to what extent it has been incorporated into general practice patterns has yet to be determined.
The National Comprehensive Cancer Network (NCCN) is a nonprofit corporation that includes 19 of the world's leading cancer centers. The collective expertise of these institutions is used to develop, update, and disseminate clinical practice guidelines in oncology.11 Current NCCN guidelines for the treatment of patients with melanoma recommend SLN biopsy for all patients with primary tumors greater than 1-mm thick and for particular subsets of patients with high risk, thin ( 1 mm) melanomas.12 Completion lymph node dissection (LND) is recommended for patients in whom nodal metastases are identified.
Despite these recommendations, there is currently no information available on the actual use of SLN biopsy for patients with melanoma. Given the significant prognostic implications and possible survival benefits of this surgical staging technique, it is of great interest to determine the actual practice patterns relative to the currently recommended standards of surgical care. The Surveillance, Epidemiology, and End Results (SEER) tumor registry has been identified as a critical resource for studying population-based outcomes in patients with cancer. Studies are conducted annually to evaluate the quality and completeness of the data reported, which, in some studies, includes reabstraction from the medical records for a sample of patients to evaluate the accuracy of each of the data elements. In addition, several validation studies of SEER have been performed.13-17 In particular, Cooper et al16 have noted that fields associated with resection and radical surgery associated with six different malignancies have excellent correlation when compared with Medicare claims. Tumor registry and claims data have previously been examined to measure the quality of cancer care for patients with lung,18,19 breast,20-27 head and neck,28 ovarian,29 and colorectal cancer,30-34 but not for patients with melanoma. Data from SEER tumor registries were examined in this study to determine the extent to which SLN biopsy has been incorporated into community practice and to identify demographic, pathologic, and geographic characteristics that might be associated with nonadherence with surgical treatment guidelines.
PATIENTS AND METHODS
Data Sources
Data from the SEER Program of the National Cancer Institute Public-Use Data set were extracted from 1998 through 2001 for patients with a primary diagnosis of invasive melanoma. During this time, the SEER program supported population-based prospective tumor registries in the following 11 areas: the metropolitan areas of San Francisco/Oakland, Detroit, Atlanta, and Seattle; Los Angeles county; the San Jose-Monterey area; and the states of Connecticut, Iowa, New Mexico, Utah, and Hawaii. SEER data recorded include demographic characteristics such as age, sex, race, and marital status; histologic type of tumor; primary tumor location, thickness, and presence of ulceration; lymph node and distant organ metastases; and the type of treatment provided in the first 4 months of therapy after diagnosis. Marital status is categorized into four groups: married, single, other (separated, divorced, or widowed), and unknown. Race is classified as white (non-Hispanic), African American, and other (all other minorities and unknown). The data set provides reliable data on the most invasive surgical procedure performed.35 The year 1998 was selected as the earliest year of study for this analysis for the following two reasons: (1) because we needed to allow sufficient time to elapse from the introduction of SLN biopsy to its adoption in community practice; and (2) because the scope of surgical treatment for lymph node surgery was reclassified in SEER in 1998 to include a field for SLN biopsy.
Study Cohort
All patients with a diagnosis of primary melanoma in a SEER area (identified by the SEER code 25010) during the years 1998 through 2001 were potentially eligible for inclusion in our study. Patients with melanoma-in-situ (corresponding to Summary Stage 2000 SEER code 0) were excluded, thus restricting the study cohort to patients with a histologic diagnosis of invasive melanoma (histologic type International Classification of Diseases for Oncology, third edition, SEER codes 8720, 8721, 8723, 8730, 8741, 8743 to 8746, 8761, 8770 to 8772, and 8780). We further selected those patients with adequate pathologic information so that their disease could be classified according to the American Joint Committee on Cancer staging system.36 Patients with stage IV (distant metastatic) disease (SEER Summary Stage 2000 [1998+] code 7) were excluded.
Surgical Treatment
Surgical treatment was determined on the basis of the most invasive surgical treatment rendered within 4 months of the melanoma diagnosis. Patients were categorized into the following four surgical groups: biopsy (surgery of primary site codes 20, 27, and 30 to 33), wide local excision (WLE; defined as excision with margins of 1 cm or more; surgery of primary site codes 40, 50, 60, and 90), SLN biopsy (scope of regional lymph node surgery code 1), and LND (scope of regional lymph node surgery code 2). Patients excluded from the analysis included those patients in whom a true biopsy was not performed (surgery of primary site codes 21 to 26), which included ablative procedures (eg, fulguration and cryosurgery), and patients for whom no pathologic specimens were available (surgery of primary site codes 10 to 14).
Treatment Guidelines
NCCN guidelines11 for the treatment of patients with melanoma were used to define stage-specific surgical treatment (Table 1) to achieve the primary goals of the study. For example, under the current guidelines, patients with melanomas 1 mm in thickness that are Clark level II or III without ulceration (stage IA disease) should have, at a minimum, a WLE of their primary tumor. Patients with melanoma 1 mm in thickness that are Clark level IV or V or have ulceration (stage IB) and tumors greater than 1-mm thick (stage IIC) should undergo a WLE and SLN biopsy to identify or confirm the absence of micrometastatic nodal disease. For patients with regional nodal disease (stage III) detected by clinical evaluation or SLN biopsy, a completion LND is recommended.
Statistical Analyses
The following clinicopathologic and nonclinical characteristics were included in the analysis to examine the possible factors associated with nonadherence with surgical treatment guidelines: age at diagnosis, sex, marital status, race, American Joint Committee on Cancer tumor stage, primary tumor location, individual SEER registry location, and year of diagnosis. The Mantel-Haenszel trend test was performed to assess the significance of nonadherence over time. Multivariate analyses were performed using logistic regression models for factors associated with nonadherence with surgical treatment guidelines while controlling for potential confounders. To perform binary comparisons, patients receiving optimal surgical treatment and overtreatment according to NCCN guidelines were combined and compared with patients receiving treatment that was nonadherent.
The results are presented as odds ratios (ORs) with 95% CIs calculated on the basis of Wald tests.37 With a cohort of 18,499 patients, we had 100% power (at a 5% significance level) to detect differences in treatment rates of 10% or greater for symmetrically distributed variables, such as sex (10,100 males v 8,399 females). However, for asymmetrically distributed variables such as race (83 African Americans v 17,107 whites), we had only 80% power to detect a 15% difference in treatment rates. For stage-specific differences, with a cohort of 1,094 patients (stage III), we had 90% power to detect differences in treatment rates of 10% or greater for variables such as sex (707 males v 387 females). All P values were two sided, and P = .05 was considered significant. SAS software (version 8.0; SAS Institute, Cary, NC) was used for the statistical analyses.
RESULTS
Patient Characteristics and Stage Distributions
A total of 21,867 patients with newly diagnosed melanoma were identified. Excluded from the cohort were patients with inadequate pathologic (n = 1,801) or treatment (n = 1,275) information and patients presenting with distant metastatic (ie, stage IV) melanoma (n = 292). The resulting cohort consisted of 18,499 patients with newly diagnosed stage IA, IB, II, or III melanoma. The pathologic characteristics of the primary tumors for these patients are listed in Table 2. The Los Angeles registry contributed the largest percentage of patients (18.5%) to the cohort, followed by the Seattle (14.7%), Connecticut (11.9%), San Francisco (10%), and Detroit (9.8%) registries.
Patient characteristics, as stratified by tumor stage, are listed in Table 3. At the time of diagnosis, more than 80% of patients had stage I disease. The median age of the cohort was 55 years; 54.6% of patients were male, 54.5% were married, and 92.5% were white. The annual number of incident melanoma cases increased by 9.6% from 1998 to 2001. During this interval, the number of patients diagnosed with stage IA and stage II disease increased by 11.8% and 12.9%, respectively, whereas the number of patients diagnosed with stage IB disease decreased by 6%. The number of patients diagnosed with stage III disease increased by 55.7% during the same period, which corresponded to a 53% increase in the annual rate of SLN biopsies performed (data not shown).
Stage-Specific Treatment Patterns
Thirty-one percent of patients with stage IA disease were treated with surgical biopsy only (Table 3); in other words, primary tumors were biopsied for diagnostic purposes but not subsequently re-excised with WLE. Similarly, approximately 40% of patients with stage IB and stage II disease underwent surgical treatment with both WLE and SLN biopsy, in accordance with NCCN guidelines. Eleven percent and 13% of patients with stage IB and II disease, respectively, who were determined to have node-negative disease underwent elective LND. Only 69% of patients with node-positive disease (stage III) underwent completion LND.
Over time, there was an overall significant decrease in the percentage of patients receiving nonadherent treatment (P < .001, Mantel-Haenszel trend test). Stage-specific treatment according to the year of melanoma diagnosis is graphically depicted in Figure 1. For patients with stage IA melanoma (Fig 1A), there was little treatment variation, with approximately 60% of patients undergoing WLE in accordance with practice guidelines. For patients with stage IB melanoma (Fig 1B), the proportion of patients treated with SLN biopsy increased by 43% (35% to 50%) from 1998 to 2001, whereas patients treated with WLE alone decreased by 33% (39% to 26%). Similarly, for patients with stage II melanoma (Fig 1C), the proportion of patients undergoing WLE and SLN biopsy increased by 47% (32% to 47%). Overall, the majority of patients (69%) with stage III melanoma were treated with LND, but throughout the study period, LND rate decreased from 76% in 1998 to 66% in 2001 (Fig 1D). At the same time, there was an increasing number of patients (22% to 30%) treated with SLN biopsy alone.
There were significant variations in the proportion of patients receiving nonadherent surgical treatment when individual SEER tumor registries were examined. The highest percentages of patients receiving surgical treatment that was nonadherent with NCCN guidelines were from Connecticut (48.7%), New Mexico (47.3%), Seattle (45.6%), and Atlanta (45.2%), whereas the lowest percentages were seen in San Francisco (22.7%), San Jose-Monterey (26.1%), and Los Angeles (26.3%).
Multivariate Analyses for Factors Associated With Surgical Treatment
Table 4 lists the overall and stage-specific adjusted ORs and 95% CIs for patients receiving surgical treatment that was nonadherent to NCCN guidelines. Compared with patients less than 35 years of age, the OR for nonadherent surgical treatment was 1.37 (95% CI, 1.20 to 1.57) for patients 65 to 74 years of age and 2.38 (95% CI, 2.08 to 2.73) for patients 75 years of age or older. Marital status was also significantly associated with nonadherent surgical treatment; patients who were separated, divorced, or widowed (other category) were more likely to receive nonadherent treatment (OR = 1.16; 95% CI, 1.04 to 1.29) compared with married patients. Minority populations were more likely to receive nonadherent surgical treatment compared with whites. Patients with primary tumors located on the lower extremity, trunk, and head and neck were also more likely to receive nonadherent treatment than patients with upper-extremity melanomas.
The OR for nonadherent surgical treatment varied significantly by individual tumor registry. Patients registered in New Mexico (OR = 3.87; 95% CI, 3.22 to 4.65), Connecticut (OR = 3.30; 95% CI, 2.86 to 3.82), Seattle (OR = 2.68; 95% CI, 2.33 to 3.09), Iowa (OR = 2.53; 95% CI, 2.16 to 2.95), Atlanta (OR = 2.49; 95% CI, 2.11 to 2.93), Hawaii (OR = 2.10; 95% CI, 1.70 to 2.59), Utah (OR = 1.92; 95% CI, 1.60 to 2.29), Los Angeles (OR = 1.31; 95% CI, 1.14 to 1.51), and San Jose-Monterey (OR = 1.23; 95% CI, 1.02 to 1.48) were all more likely to receive nonadherent surgical treatment than patients registered in San Francisco (Table 4). There were also significant stage-specific trends for individual tumor registries. For example, for patients with stage IB and II disease, the ORs associated with receiving surgical treatment nonadherent with NCCN practice guidelines were significantly higher in Connecticut, Detroit, Hawaii, Iowa, New Mexico, Atlanta, and Los Angeles. For stage III patients, the ORs for nonadherent surgical treatment were highest in Utah (OR = 4.34; 95% CI, 2.23 to 8.46), Hawaii (OR = 4.26; 95% CI, 1.58 to 11.46), Connecticut (OR = 3.45; 95% CI, 1.98 to 6.03), Seattle (OR = 2.16; 95% CI, 1.28 to 3.64), and Iowa (OR = 2.13; 95% CI, 1.16 to 3.91).
The stage-specific ORs for nonadherent surgical treatment were 2.32 (95% CI, 2.14 to 2.51), 2.27 (95% CI, 2.05 to 2.51), and 1.54 (95% CI, 1.33 to 1.78) for patients with stages IB, II, and III melanoma, respectively, compared with patients with stage IA disease. Because of the interaction noted between the year of diagnosis and disease stage (decreasing ORs for nonadherent treatment for patients with stage IA, IB, and II disease, with increasing ORs for stage III patients), the overall annual trend is not presented. For patients with stage IB and II disease, the OR of receiving nonadherent surgical treatment decreased over time, indicating improved conformity with the guidelines during 1998 to 2001. Specifically, the OR for nonadherent treatment in patients with stage IB disease decreased annually from 1998 to 2001, with an adjusted OR of 0.48 (95% CI, 0.40 to 0.58) for 2001 (P < .0001). Similarly, for patients with stage II disease, the OR decreased annually to 0.41 (95% CI, 0.32 to 0.53; P < .0001). In contrast, for patients with stage III melanoma, there was an increase in the OR for receiving surgical treatment that was nonadherent with practice guidelines, with an OR of 1.66 (95% CI, 1.10 to 2.53) in 2001 compared with 1998 (P = .09).
DISCUSSION
The diagnostic benefits of SLN biopsy compared with elective LND (removal of clinically negative nodes) have been well documented.38,39 Not only is it a less morbid surgical procedure and less costly to perform, but also its ability to identify the SLN, which is the first lymph node to receive drainage from a primary tumor site,6 allows for a more detailed pathologic analysis than can be performed on numerous nodes.40,41 In addition, this process, which includes immunohistochemical analysis, can detect occult metastases. Thus, SLN biopsy provides important prognostic information and identifies patients who may benefit from completion lymphadenectomy. As a result, SLN biopsy has become an essential component in the staging of patients with melanoma, as evidenced by the fact that NCCN treatment guidelines11 recommend that all patients with melanomas more than 1 mm in thickness and subsets of patients with melanomas 1 mm in thickness (stage IB) undergo SLN biopsy for accurate staging.
However, there has been no direct evidence that SLN biopsy results in a survival benefit for patients with melanoma. The Multicenter Selective Lymphadenectomy Trial, a multi-institutional randomized trial, has been implemented to answer this question. Accrual to this trial was completed in 2002, and survival data are expected to be available in 2007.7 However, there is indirect evidence from other sources of the potential therapeutic benefits of SLN biopsy. In a matched case-control analysis performed by Morton et al,42 patients who underwent immediate completion dissection for metastases identified by SLN biopsy survived for longer than patients who underwent delayed dissections. In particular, the 5-, 10-, and 15-year survival rates were 73%, 69%, and 69%, respectively, in the patients who underwent immediate completion dissection compared with 51%, 37%, and 32%, respectively, in patients who underwent delayed dissections (P .001). Additionally, two retrospective analyses43,44 have suggested that SLN biopsy provides a survival benefit. Nonetheless, it has been postulated that the patients most likely to benefit from SLN biopsy are patients with thinner primary tumors and smaller volume of metastatic nodal disease.42 Indirect evidence of this postulation is derived from studies demonstrating that primary tumor ulceration may be a more important indicator of overall survival than the SLN status in patients with melanomas more than 4 mm in thickness.45-49
We conclude that stage migration is evident in the SEER registries. The examination of data from the SEER data set demonstrated that, on average, one third of melanoma patients in the United States may be receiving surgical care that is nonadherent with current practice guidelines. Although treatment trends are improving, SLN biopsy continues to be underused, particularly in the elderly and minority populations, in patients with truncal and head and neck melanomas, in patients with unknown marital status, and in some geographic regions of the United States. Of particular interest is the finding that the percentage of patients with node-positive (stage III) melanoma undergoing completion LND decreased over time, from 76% in 1999 to 66% in 2001.
However, there are particular drawbacks to using registry data, such as the data in the SEER datasets, for the assessment of quality medical care. First, there are limitations associated with the information in particular fields. For example, in SEER, information in some fields, such as those for race or less represented groups, use nonconsensus definitions. Additionally, there is a paucity of data about comorbid conditions, insurance coverage, and the technical abilities of providers. Second, although SEER registries are used because of the quality of data and because they adequately represent minority populations, they may still not be entirely representative of the entire US population. Indeed, studies performed to determine how well the SEER areas represents the US population have revealed that SEER distributions are comparable with respect to age and sex distribution, but there is a higher concentration of minority populations.49A In addition, the geographic areas where the SEER data are obtained are from more affluent and more urban areas than non-SEER areas.50
Despite these limitations, SEER registries can provide a practical tool for identifying potentially important, medical care, population-based problems.51 Quality control is an integral part of the SEER registry, with studies performed annually to evaluate the quality and completeness of the data being reported.52 These data have been used extensively to study variations in medical treatments, particularly cancer-related surgery.15,30,53-56 With respect to this study, evidence from comparison studies that have made use of Medicare claims has demonstrated good concordance with SEER data in terms of capturing reliable and accurate information on the most invasive surgical procedures performed.16
The explanations for the findings of the current study are not clear. The objective of the analysis was to examine the extent to which SLN biopsy has been incorporated into community practice using population-based data. In addition, we examined potential factors that may be associated with nonadherence with surgical treatment guidelines. Future analyses will use additional data from linked Medicare claims and public access physician and hospital practice datasets to explore potential explanations for disparities in treatment. However, disparities related to preferences (physician or patient related) cannot be measured. For example, for patients with node-positive melanoma, we can only postulate, given our own clinical experience, that the reasons for declining adherence to NCCN guidelines may be related to the increasing belief that SLN biopsy is adequate surgical treatment in patients with micrometastatic nodal disease. However, to date, there are no clinical trial data to support this practice.
Quality medical care has been summarized51 to consist of the "delivery of optimal health services"57 with "technical proficiency"58; "avoiding overuse, underuse, or misuse of technologies"59; and "incorporating patient centered preferences in shared decision making."60 The objective of this study was to examine the adoption of surgical treatment guidelines as a marker for the quality of melanoma surgical care in the community. Nonadherent surgical treatment in this study refers primarily to the underuse of surgical treatment as recommended in the NCCN practice guidelines for patients with melanoma. Underuse has more generally been defined as the "lack of provision of services and whose expected benefits outweigh their expected risks to patients."57 Underuse is often the result of limited access to services viewed in financial terms or it may also be a result of geographical, physical, or psychological reasons.51 Underuse of medical care may also result from the fact that patients are not offered (or do not accept) available services.57 Therefore, as a single indicator, underuse cannot be used to indicate that poor care was delivered but can only be used to "identify outlier areas where the quality of care delivered by certain health-care systems or to certain patient groups differ from the norm and needs to be further investigated."51,61
Our study demonstrated that there is substantial variation in the patterns of surgical care delivered to patients with melanoma in the United States. Subsequent analyses will seek to identify potential explanations for the disparities in treatment identified by this analysis and whether nonadherent surgical care is associated with differences in survival outcomes. The results of these future analyses will be relevant regardless of the findings from ongoing clinical trials. Although randomized clinical trials with strict enrollment criteria, frequent monitoring, and follow-up of participants may define the efficacy of SLN biopsy, they may not truly represent the effectiveness of SLN biopsy in the community at large.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank Beth Notzon for her editorial assistance and Kristine Ash for manuscript preparation.
NOTES
Supported by National Cancer Institute Clinical Oncology Research Development Program grant No. 5-K12-CA088084.
Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
PURPOSE: The surgical staging of melanoma dramatically changed with the introduction of sentinel lymph node (SLN) biopsy. In this study, Surveillance, Epidemiology, and End Results (SEER) data were examined to determine how surgical treatment is being carried out and whether SLN biopsy is being performed in melanoma patients in conformance with National Comprehensive Cancer Network (NCCN) guidelines.
PATIENTS AND METHODS: The SEER database (1998 to 2001) was searched for all patients with invasive melanoma. NCCN guidelines were used to define optimal stage-specific surgical treatment. Treatment trends in patients with stages I to III disease were summarized, and multivariate analyses were performed to identify factors associated with nonadherence with treatment guidelines.
RESULTS: A total of 21,867 melanoma patients were identified; 18,499 of these patients met the inclusion criteria. The number of patients diagnosed with stage III melanoma increased by 55.7% over the study period, and this corresponded to a 53% increase in the number of SLN biopsies performed annually. The odds ratios for nonadherence were 2.32, 2.27, and 1.54 for stages IB, II, and III disease, respectively, compared with stage IA melanoma. Multivariate analyses revealed that age more than 65 years, marital status, minority populations, and primary tumor location were associated with nonadherence with guidelines. Treatment patterns among tumor registries also varied significantly.
CONCLUSION: Stage migration is evident in the SEER registries in consort with increasing use of SLN biopsy. Although treatment trends are improving, SLN biopsy continues to be underused, particularly in the elderly and minority populations, in patients with truncal and head/neck melanomas, and also in some geographic regions of the United States.
INTRODUCTION
The incidence of melanoma has been climbing steadily since the early 1970s.1 Fortunately, most of the newly diagnosed patients have disease clinically confined to the primary tumor site (stages I and II). Rational treatment strategies for stage I and II patients have evolved over the last decade to optimize survival, locoregional disease control, and staging and, at the same time, minimize treatment morbidities. Accepted standards for the extent of excision margins vary according to ranges of tumor thickness based on the results of several prospective randomized trials.2-5
Historically, the approach to the clinically negative regional lymph nodes has been more controversial, with recommendations ranging from observation to elective node dissection. The introduction of sentinel lymph node (SLN) biopsy in 1992,6 followed by worldwide confirmation of the accuracy of this technique,7-10 promoted a selective approach to regional node dissections. For SLN-positive patients (occult stage III), a formal lymphadectomy is performed to accomplish durable regional disease control and possibly to provide a survival advantage compared with patients who undergo a dissection for clinically apparent (macroscopic) nodal disease. SLN-negative patients are spared the cost and morbidity of a formal dissection. Evidence that SLN biopsy provides critical staging information is derived from multivariate analyses demonstrating that SLN status is the most powerful independent predictor of survival in stage I and II patients.8 Although it is not surprising that SLN biopsy has been embraced as an integral component in the management of stage I and II patients across the United States and around the world, particularly at cancer centers, to what extent it has been incorporated into general practice patterns has yet to be determined.
The National Comprehensive Cancer Network (NCCN) is a nonprofit corporation that includes 19 of the world's leading cancer centers. The collective expertise of these institutions is used to develop, update, and disseminate clinical practice guidelines in oncology.11 Current NCCN guidelines for the treatment of patients with melanoma recommend SLN biopsy for all patients with primary tumors greater than 1-mm thick and for particular subsets of patients with high risk, thin ( 1 mm) melanomas.12 Completion lymph node dissection (LND) is recommended for patients in whom nodal metastases are identified.
Despite these recommendations, there is currently no information available on the actual use of SLN biopsy for patients with melanoma. Given the significant prognostic implications and possible survival benefits of this surgical staging technique, it is of great interest to determine the actual practice patterns relative to the currently recommended standards of surgical care. The Surveillance, Epidemiology, and End Results (SEER) tumor registry has been identified as a critical resource for studying population-based outcomes in patients with cancer. Studies are conducted annually to evaluate the quality and completeness of the data reported, which, in some studies, includes reabstraction from the medical records for a sample of patients to evaluate the accuracy of each of the data elements. In addition, several validation studies of SEER have been performed.13-17 In particular, Cooper et al16 have noted that fields associated with resection and radical surgery associated with six different malignancies have excellent correlation when compared with Medicare claims. Tumor registry and claims data have previously been examined to measure the quality of cancer care for patients with lung,18,19 breast,20-27 head and neck,28 ovarian,29 and colorectal cancer,30-34 but not for patients with melanoma. Data from SEER tumor registries were examined in this study to determine the extent to which SLN biopsy has been incorporated into community practice and to identify demographic, pathologic, and geographic characteristics that might be associated with nonadherence with surgical treatment guidelines.
PATIENTS AND METHODS
Data Sources
Data from the SEER Program of the National Cancer Institute Public-Use Data set were extracted from 1998 through 2001 for patients with a primary diagnosis of invasive melanoma. During this time, the SEER program supported population-based prospective tumor registries in the following 11 areas: the metropolitan areas of San Francisco/Oakland, Detroit, Atlanta, and Seattle; Los Angeles county; the San Jose-Monterey area; and the states of Connecticut, Iowa, New Mexico, Utah, and Hawaii. SEER data recorded include demographic characteristics such as age, sex, race, and marital status; histologic type of tumor; primary tumor location, thickness, and presence of ulceration; lymph node and distant organ metastases; and the type of treatment provided in the first 4 months of therapy after diagnosis. Marital status is categorized into four groups: married, single, other (separated, divorced, or widowed), and unknown. Race is classified as white (non-Hispanic), African American, and other (all other minorities and unknown). The data set provides reliable data on the most invasive surgical procedure performed.35 The year 1998 was selected as the earliest year of study for this analysis for the following two reasons: (1) because we needed to allow sufficient time to elapse from the introduction of SLN biopsy to its adoption in community practice; and (2) because the scope of surgical treatment for lymph node surgery was reclassified in SEER in 1998 to include a field for SLN biopsy.
Study Cohort
All patients with a diagnosis of primary melanoma in a SEER area (identified by the SEER code 25010) during the years 1998 through 2001 were potentially eligible for inclusion in our study. Patients with melanoma-in-situ (corresponding to Summary Stage 2000 SEER code 0) were excluded, thus restricting the study cohort to patients with a histologic diagnosis of invasive melanoma (histologic type International Classification of Diseases for Oncology, third edition, SEER codes 8720, 8721, 8723, 8730, 8741, 8743 to 8746, 8761, 8770 to 8772, and 8780). We further selected those patients with adequate pathologic information so that their disease could be classified according to the American Joint Committee on Cancer staging system.36 Patients with stage IV (distant metastatic) disease (SEER Summary Stage 2000 [1998+] code 7) were excluded.
Surgical Treatment
Surgical treatment was determined on the basis of the most invasive surgical treatment rendered within 4 months of the melanoma diagnosis. Patients were categorized into the following four surgical groups: biopsy (surgery of primary site codes 20, 27, and 30 to 33), wide local excision (WLE; defined as excision with margins of 1 cm or more; surgery of primary site codes 40, 50, 60, and 90), SLN biopsy (scope of regional lymph node surgery code 1), and LND (scope of regional lymph node surgery code 2). Patients excluded from the analysis included those patients in whom a true biopsy was not performed (surgery of primary site codes 21 to 26), which included ablative procedures (eg, fulguration and cryosurgery), and patients for whom no pathologic specimens were available (surgery of primary site codes 10 to 14).
Treatment Guidelines
NCCN guidelines11 for the treatment of patients with melanoma were used to define stage-specific surgical treatment (Table 1) to achieve the primary goals of the study. For example, under the current guidelines, patients with melanomas 1 mm in thickness that are Clark level II or III without ulceration (stage IA disease) should have, at a minimum, a WLE of their primary tumor. Patients with melanoma 1 mm in thickness that are Clark level IV or V or have ulceration (stage IB) and tumors greater than 1-mm thick (stage IIC) should undergo a WLE and SLN biopsy to identify or confirm the absence of micrometastatic nodal disease. For patients with regional nodal disease (stage III) detected by clinical evaluation or SLN biopsy, a completion LND is recommended.
Statistical Analyses
The following clinicopathologic and nonclinical characteristics were included in the analysis to examine the possible factors associated with nonadherence with surgical treatment guidelines: age at diagnosis, sex, marital status, race, American Joint Committee on Cancer tumor stage, primary tumor location, individual SEER registry location, and year of diagnosis. The Mantel-Haenszel trend test was performed to assess the significance of nonadherence over time. Multivariate analyses were performed using logistic regression models for factors associated with nonadherence with surgical treatment guidelines while controlling for potential confounders. To perform binary comparisons, patients receiving optimal surgical treatment and overtreatment according to NCCN guidelines were combined and compared with patients receiving treatment that was nonadherent.
The results are presented as odds ratios (ORs) with 95% CIs calculated on the basis of Wald tests.37 With a cohort of 18,499 patients, we had 100% power (at a 5% significance level) to detect differences in treatment rates of 10% or greater for symmetrically distributed variables, such as sex (10,100 males v 8,399 females). However, for asymmetrically distributed variables such as race (83 African Americans v 17,107 whites), we had only 80% power to detect a 15% difference in treatment rates. For stage-specific differences, with a cohort of 1,094 patients (stage III), we had 90% power to detect differences in treatment rates of 10% or greater for variables such as sex (707 males v 387 females). All P values were two sided, and P = .05 was considered significant. SAS software (version 8.0; SAS Institute, Cary, NC) was used for the statistical analyses.
RESULTS
Patient Characteristics and Stage Distributions
A total of 21,867 patients with newly diagnosed melanoma were identified. Excluded from the cohort were patients with inadequate pathologic (n = 1,801) or treatment (n = 1,275) information and patients presenting with distant metastatic (ie, stage IV) melanoma (n = 292). The resulting cohort consisted of 18,499 patients with newly diagnosed stage IA, IB, II, or III melanoma. The pathologic characteristics of the primary tumors for these patients are listed in Table 2. The Los Angeles registry contributed the largest percentage of patients (18.5%) to the cohort, followed by the Seattle (14.7%), Connecticut (11.9%), San Francisco (10%), and Detroit (9.8%) registries.
Patient characteristics, as stratified by tumor stage, are listed in Table 3. At the time of diagnosis, more than 80% of patients had stage I disease. The median age of the cohort was 55 years; 54.6% of patients were male, 54.5% were married, and 92.5% were white. The annual number of incident melanoma cases increased by 9.6% from 1998 to 2001. During this interval, the number of patients diagnosed with stage IA and stage II disease increased by 11.8% and 12.9%, respectively, whereas the number of patients diagnosed with stage IB disease decreased by 6%. The number of patients diagnosed with stage III disease increased by 55.7% during the same period, which corresponded to a 53% increase in the annual rate of SLN biopsies performed (data not shown).
Stage-Specific Treatment Patterns
Thirty-one percent of patients with stage IA disease were treated with surgical biopsy only (Table 3); in other words, primary tumors were biopsied for diagnostic purposes but not subsequently re-excised with WLE. Similarly, approximately 40% of patients with stage IB and stage II disease underwent surgical treatment with both WLE and SLN biopsy, in accordance with NCCN guidelines. Eleven percent and 13% of patients with stage IB and II disease, respectively, who were determined to have node-negative disease underwent elective LND. Only 69% of patients with node-positive disease (stage III) underwent completion LND.
Over time, there was an overall significant decrease in the percentage of patients receiving nonadherent treatment (P < .001, Mantel-Haenszel trend test). Stage-specific treatment according to the year of melanoma diagnosis is graphically depicted in Figure 1. For patients with stage IA melanoma (Fig 1A), there was little treatment variation, with approximately 60% of patients undergoing WLE in accordance with practice guidelines. For patients with stage IB melanoma (Fig 1B), the proportion of patients treated with SLN biopsy increased by 43% (35% to 50%) from 1998 to 2001, whereas patients treated with WLE alone decreased by 33% (39% to 26%). Similarly, for patients with stage II melanoma (Fig 1C), the proportion of patients undergoing WLE and SLN biopsy increased by 47% (32% to 47%). Overall, the majority of patients (69%) with stage III melanoma were treated with LND, but throughout the study period, LND rate decreased from 76% in 1998 to 66% in 2001 (Fig 1D). At the same time, there was an increasing number of patients (22% to 30%) treated with SLN biopsy alone.
There were significant variations in the proportion of patients receiving nonadherent surgical treatment when individual SEER tumor registries were examined. The highest percentages of patients receiving surgical treatment that was nonadherent with NCCN guidelines were from Connecticut (48.7%), New Mexico (47.3%), Seattle (45.6%), and Atlanta (45.2%), whereas the lowest percentages were seen in San Francisco (22.7%), San Jose-Monterey (26.1%), and Los Angeles (26.3%).
Multivariate Analyses for Factors Associated With Surgical Treatment
Table 4 lists the overall and stage-specific adjusted ORs and 95% CIs for patients receiving surgical treatment that was nonadherent to NCCN guidelines. Compared with patients less than 35 years of age, the OR for nonadherent surgical treatment was 1.37 (95% CI, 1.20 to 1.57) for patients 65 to 74 years of age and 2.38 (95% CI, 2.08 to 2.73) for patients 75 years of age or older. Marital status was also significantly associated with nonadherent surgical treatment; patients who were separated, divorced, or widowed (other category) were more likely to receive nonadherent treatment (OR = 1.16; 95% CI, 1.04 to 1.29) compared with married patients. Minority populations were more likely to receive nonadherent surgical treatment compared with whites. Patients with primary tumors located on the lower extremity, trunk, and head and neck were also more likely to receive nonadherent treatment than patients with upper-extremity melanomas.
The OR for nonadherent surgical treatment varied significantly by individual tumor registry. Patients registered in New Mexico (OR = 3.87; 95% CI, 3.22 to 4.65), Connecticut (OR = 3.30; 95% CI, 2.86 to 3.82), Seattle (OR = 2.68; 95% CI, 2.33 to 3.09), Iowa (OR = 2.53; 95% CI, 2.16 to 2.95), Atlanta (OR = 2.49; 95% CI, 2.11 to 2.93), Hawaii (OR = 2.10; 95% CI, 1.70 to 2.59), Utah (OR = 1.92; 95% CI, 1.60 to 2.29), Los Angeles (OR = 1.31; 95% CI, 1.14 to 1.51), and San Jose-Monterey (OR = 1.23; 95% CI, 1.02 to 1.48) were all more likely to receive nonadherent surgical treatment than patients registered in San Francisco (Table 4). There were also significant stage-specific trends for individual tumor registries. For example, for patients with stage IB and II disease, the ORs associated with receiving surgical treatment nonadherent with NCCN practice guidelines were significantly higher in Connecticut, Detroit, Hawaii, Iowa, New Mexico, Atlanta, and Los Angeles. For stage III patients, the ORs for nonadherent surgical treatment were highest in Utah (OR = 4.34; 95% CI, 2.23 to 8.46), Hawaii (OR = 4.26; 95% CI, 1.58 to 11.46), Connecticut (OR = 3.45; 95% CI, 1.98 to 6.03), Seattle (OR = 2.16; 95% CI, 1.28 to 3.64), and Iowa (OR = 2.13; 95% CI, 1.16 to 3.91).
The stage-specific ORs for nonadherent surgical treatment were 2.32 (95% CI, 2.14 to 2.51), 2.27 (95% CI, 2.05 to 2.51), and 1.54 (95% CI, 1.33 to 1.78) for patients with stages IB, II, and III melanoma, respectively, compared with patients with stage IA disease. Because of the interaction noted between the year of diagnosis and disease stage (decreasing ORs for nonadherent treatment for patients with stage IA, IB, and II disease, with increasing ORs for stage III patients), the overall annual trend is not presented. For patients with stage IB and II disease, the OR of receiving nonadherent surgical treatment decreased over time, indicating improved conformity with the guidelines during 1998 to 2001. Specifically, the OR for nonadherent treatment in patients with stage IB disease decreased annually from 1998 to 2001, with an adjusted OR of 0.48 (95% CI, 0.40 to 0.58) for 2001 (P < .0001). Similarly, for patients with stage II disease, the OR decreased annually to 0.41 (95% CI, 0.32 to 0.53; P < .0001). In contrast, for patients with stage III melanoma, there was an increase in the OR for receiving surgical treatment that was nonadherent with practice guidelines, with an OR of 1.66 (95% CI, 1.10 to 2.53) in 2001 compared with 1998 (P = .09).
DISCUSSION
The diagnostic benefits of SLN biopsy compared with elective LND (removal of clinically negative nodes) have been well documented.38,39 Not only is it a less morbid surgical procedure and less costly to perform, but also its ability to identify the SLN, which is the first lymph node to receive drainage from a primary tumor site,6 allows for a more detailed pathologic analysis than can be performed on numerous nodes.40,41 In addition, this process, which includes immunohistochemical analysis, can detect occult metastases. Thus, SLN biopsy provides important prognostic information and identifies patients who may benefit from completion lymphadenectomy. As a result, SLN biopsy has become an essential component in the staging of patients with melanoma, as evidenced by the fact that NCCN treatment guidelines11 recommend that all patients with melanomas more than 1 mm in thickness and subsets of patients with melanomas 1 mm in thickness (stage IB) undergo SLN biopsy for accurate staging.
However, there has been no direct evidence that SLN biopsy results in a survival benefit for patients with melanoma. The Multicenter Selective Lymphadenectomy Trial, a multi-institutional randomized trial, has been implemented to answer this question. Accrual to this trial was completed in 2002, and survival data are expected to be available in 2007.7 However, there is indirect evidence from other sources of the potential therapeutic benefits of SLN biopsy. In a matched case-control analysis performed by Morton et al,42 patients who underwent immediate completion dissection for metastases identified by SLN biopsy survived for longer than patients who underwent delayed dissections. In particular, the 5-, 10-, and 15-year survival rates were 73%, 69%, and 69%, respectively, in the patients who underwent immediate completion dissection compared with 51%, 37%, and 32%, respectively, in patients who underwent delayed dissections (P .001). Additionally, two retrospective analyses43,44 have suggested that SLN biopsy provides a survival benefit. Nonetheless, it has been postulated that the patients most likely to benefit from SLN biopsy are patients with thinner primary tumors and smaller volume of metastatic nodal disease.42 Indirect evidence of this postulation is derived from studies demonstrating that primary tumor ulceration may be a more important indicator of overall survival than the SLN status in patients with melanomas more than 4 mm in thickness.45-49
We conclude that stage migration is evident in the SEER registries. The examination of data from the SEER data set demonstrated that, on average, one third of melanoma patients in the United States may be receiving surgical care that is nonadherent with current practice guidelines. Although treatment trends are improving, SLN biopsy continues to be underused, particularly in the elderly and minority populations, in patients with truncal and head and neck melanomas, in patients with unknown marital status, and in some geographic regions of the United States. Of particular interest is the finding that the percentage of patients with node-positive (stage III) melanoma undergoing completion LND decreased over time, from 76% in 1999 to 66% in 2001.
However, there are particular drawbacks to using registry data, such as the data in the SEER datasets, for the assessment of quality medical care. First, there are limitations associated with the information in particular fields. For example, in SEER, information in some fields, such as those for race or less represented groups, use nonconsensus definitions. Additionally, there is a paucity of data about comorbid conditions, insurance coverage, and the technical abilities of providers. Second, although SEER registries are used because of the quality of data and because they adequately represent minority populations, they may still not be entirely representative of the entire US population. Indeed, studies performed to determine how well the SEER areas represents the US population have revealed that SEER distributions are comparable with respect to age and sex distribution, but there is a higher concentration of minority populations.49A In addition, the geographic areas where the SEER data are obtained are from more affluent and more urban areas than non-SEER areas.50
Despite these limitations, SEER registries can provide a practical tool for identifying potentially important, medical care, population-based problems.51 Quality control is an integral part of the SEER registry, with studies performed annually to evaluate the quality and completeness of the data being reported.52 These data have been used extensively to study variations in medical treatments, particularly cancer-related surgery.15,30,53-56 With respect to this study, evidence from comparison studies that have made use of Medicare claims has demonstrated good concordance with SEER data in terms of capturing reliable and accurate information on the most invasive surgical procedures performed.16
The explanations for the findings of the current study are not clear. The objective of the analysis was to examine the extent to which SLN biopsy has been incorporated into community practice using population-based data. In addition, we examined potential factors that may be associated with nonadherence with surgical treatment guidelines. Future analyses will use additional data from linked Medicare claims and public access physician and hospital practice datasets to explore potential explanations for disparities in treatment. However, disparities related to preferences (physician or patient related) cannot be measured. For example, for patients with node-positive melanoma, we can only postulate, given our own clinical experience, that the reasons for declining adherence to NCCN guidelines may be related to the increasing belief that SLN biopsy is adequate surgical treatment in patients with micrometastatic nodal disease. However, to date, there are no clinical trial data to support this practice.
Quality medical care has been summarized51 to consist of the "delivery of optimal health services"57 with "technical proficiency"58; "avoiding overuse, underuse, or misuse of technologies"59; and "incorporating patient centered preferences in shared decision making."60 The objective of this study was to examine the adoption of surgical treatment guidelines as a marker for the quality of melanoma surgical care in the community. Nonadherent surgical treatment in this study refers primarily to the underuse of surgical treatment as recommended in the NCCN practice guidelines for patients with melanoma. Underuse has more generally been defined as the "lack of provision of services and whose expected benefits outweigh their expected risks to patients."57 Underuse is often the result of limited access to services viewed in financial terms or it may also be a result of geographical, physical, or psychological reasons.51 Underuse of medical care may also result from the fact that patients are not offered (or do not accept) available services.57 Therefore, as a single indicator, underuse cannot be used to indicate that poor care was delivered but can only be used to "identify outlier areas where the quality of care delivered by certain health-care systems or to certain patient groups differ from the norm and needs to be further investigated."51,61
Our study demonstrated that there is substantial variation in the patterns of surgical care delivered to patients with melanoma in the United States. Subsequent analyses will seek to identify potential explanations for the disparities in treatment identified by this analysis and whether nonadherent surgical care is associated with differences in survival outcomes. The results of these future analyses will be relevant regardless of the findings from ongoing clinical trials. Although randomized clinical trials with strict enrollment criteria, frequent monitoring, and follow-up of participants may define the efficacy of SLN biopsy, they may not truly represent the effectiveness of SLN biopsy in the community at large.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank Beth Notzon for her editorial assistance and Kristine Ash for manuscript preparation.
NOTES
Supported by National Cancer Institute Clinical Oncology Research Development Program grant No. 5-K12-CA088084.
Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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