The Utility of Sentinel Lymph Node Biopsy in Elderly Patients with Melanoma
verfasst von:
Hanna Kakish, MD, Carmen A. Jung, BA, Susan J. Doh, MD, Kathleen M. Mulligan, BA, Iris Sheng, MD, John B. Ammori, MD, Ankit Mangla, MD, Richard S. Hoehn, MD, Luke D. Rothermel, MA, MPH
Sentinel lymph node biopsy (SLNB) is performed less often for older patients with melanoma. We investigated the association of SLNB and melanoma-specific survival (MSS) in the elderly.
Methods
We retrospectively reviewed the Surveillance, Epidemiology, and End Results (SEER: 2010–2019) for patients ≥ 70 years with cT2-4N0M0 melanoma. We used multivariable Cox proportional hazard models to evaluate the impact of SLNB performance and SLN status on MSS at increasing age cutoffs. In addition, we evaluated the association of different factors with SLNB performance using multivariable logistic regression.
Results
We identified 11,548 patients. Sentinel lymph node biopsy occurred in 6754 (58.5%) patients, 1050 (15.5%) of whom had a positive SLN. On adjusted SEER analysis, a negative SLN was independently associated with improved MSS (overall hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.63–0.67) for patients up to 87 years old. Positive SLNB was independently associated with inferior MSS (HR 1.71, 95% CI 1.93–1.98). Increasing age groups were significantly associated with decreased SLNB performance.
Conclusions
Sentinel lymph node biopsy is associated with cancer-specific survival and adds prognostic information for elderly patients with melanoma. Sentinel lymph node biopsy performance should not be eliminated in elderly patients based on age alone, unless justified by poor performance status, patient preference, or other surgical contraindications. Decreased SLNB performance with increasing age in our cohort may indicate a missed therapeutic opportunity in the care of elderly patients with melanoma.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The National Comprehensive Cancer Network (NCCN) recommends sentinel lymph node biopsy (SLNB) for patients with melanoma >1.0 mm in Breslow depth.1 Despite having an increased incidence of melanoma, elderly patients are less likely to undergo SLNB.2,3 This may be attributed to patient frailty, medical comorbidities, or provider perceptions that sentinel lymph node (SLN) status bears less importance than in younger populations.4‐7 The prognostic and therapeutic benefits of SLNB in elderly patients with melanoma are debated.8‐10
The results of the Multicenter Selective Lymphadenectomy Trial-I (MSLT-I) trial showed that performing SLNB decreased regional nodal recurrences but did not impact melanoma-specific survival (MSS) for the overall cohort of patients with intermediate and thick melanomas.8,11 However, the authors acknowledged that low nodal positivity rates in this cohort may have blunted the MSS benefit.8 In addition, patients older than 75 years were not enrolled in the MSLT-I trial. Hence, the utility of SLNB remains debatable in elderly patients who more often present with other comorbidities. Murtha et al. studied the Surveillance, Epidemiology, and End Results (SEER) database (2010–2012) and reported an improved association of MSS in patients with intermediate and thick melanomas who underwent SLNB across all age groups.9 Sabel et al. performed an institutional study of 553 melanoma (> 1.0-mm Breslow depth) patients ≥ 75 years between 1996 and 2011 and reported lower MSS for patients who did not undergo SLNB, yet this result did not reach statistical significance (p = 0.172).10 The question remains whether SLNB adds value for elderly patients with melanoma when considering the risks and benefits of the procedure.
Anzeige
The primary objective of this study was to evaluate the association of SLNB and MSS in elderly patients (≥ 70 years) with melanoma using a national dataset (SEER) with the ability to assess cancer-specific survival. We anticipated that if a survival benefit was lost or diminished in the elderly population, this would argue against the prognostic utility of SLNB in elderly patients. Secondarily, we assessed factors associated with SLNB performance and SLN positivity. We hypothesized that SLNB will provide similar benefits in the elderly to those seen in the broader population and that the procedure remains warranted in elderly patients who are fit to undergo surgery.
Materials and methods
Data Source and Institutional Review Board Exemption
This is a retrospective study of patients with invasive cutaneous melanoma using the SEER database. The data used in this project is publicly available and deidentified; therefore, this study is exempt from IRB review and approval as determined by the University Hospitals Cleveland Medical Center IRB (STUDY20231391). The SEER database is a jointly issued (by the ACS, the Centers for Disease Control and Prevention (CDC), the North American Association of Central Cancer Registries (NAACCR), and the NCI) cancer registry,12 which represents approximately 48% of the U.S. population from 19 geographic areas.13 We utilized the Incidence–SEER Research Plus Data, 17 Registries, Nov 2021 Sub (2000–2019) database, which was based on data submitted from November 2021.
Patient Selection
We identified patients with the diagnosis of cutaneous melanoma (2010–2019) by using the International Classification of Disease (ICD) codes (ICD-O-3: C44.0-C44.9) and histology codes (8720-8723, 8730, 8740-8745, 8761, and 8770-8774). We extracted cases for patients ≥ 70 years diagnosed with cutaneous melanoma > 1 mm in Breslow depth. To minimize the chance that thicker melanomas could be a confounding factor in our analysis of intermediate-thickness melanomas, we excluded patients with tumors ≤ 4.0 mm in Breslow depth when the deep margin was transected at biopsy. Furthermore, we excluded patients with distant or regional lymph node metastasis, those who underwent lymph node aspiration or complete lymph node dissection without SLNB, and those with unknown survival data and SLN status. Finally, we excluded patients for whom melanoma was not the primary listed tumor among patients registered with multiple tumors. Figure 1 depicts the inclusion flowchart.
Fig. 1
Inclusion criteria
×
Study Variables
We collected data for baseline demographics (age, sex, and race), tumor characteristics (SLNB performance, nodal positivity, tumor location, tumor subtype, ulceration status, and mitotic rate), and receipt of adjuvant treatment. Patient age at diagnosis was divided into groups 70–79, 80–89, ≥ 90 years. Race/ethnicity categories included non-Hispanic White and others (non-Hispanic Black, Asian, Hispanic, and others/unknown). Tumor locations were designated head and neck, upper extremity, lower extremity, trunk, overlapping lesions, or not specified. Overlapping lesions have overlapping boundaries of two or more categories or subcategories. Histologic subtypes included nodular, lentigo maligna, superficial spreading, acral lentiginous, desmoplastic, and others. Mitotic rate was classified as: nonmitogenic, 1 mitotic figure/mm2, ≥ 2 mitotic figures/mm2, and other/unknown. In addition, we included presence and absence of ulceration. Both variables “RX Summ—Scope Reg LN Sur” and “Regional nodes positive” were used to identify patients who underwent SLNB with or without LN involvement.14 We included patients registered in 2010 or after because certain variables such as mitotic rate were not collected before then.
Anzeige
Statistical Analysis
We stratified our cohort into two groups based on SLNB performance (patients who underwent SLNB vs. those who did not), and those who underwent SLNB based on SLN results (positive: sentinel lymph node involved with the disease vs. negative: sentinel lymph node not involved with the disease). Categorical variables were compared by using Pearson’s chi-square test, and multivariable logistic regression was utilized to assess the association between different factors and SLNB performance or SLN metastasis. We reported the 5-year MSS between patients who underwent SLNB versus those who did not undergo SLNB. Next, because we noticed a survival difference between the previous groups (SLNB vs. no SLNB), we reported the 5-year MSS between patients who underwent SLNB with positive and negative results compared with those who did not undergo SLNB. Next, we studied the association between SLNB and MSS (groups: SLN positive, SLN negative, and no SLNB) in elderly melanoma patients overall (≥ 70 years) and at increasing age cutoffs (≥ 71, ≥ 72, ≥ 73, ≥ 74…, ≥ 90) (age removed from these models) by using multivariable Cox proportional hazard models. We performed our analysis at increasing age cutoffs to identify if the association between performing SLNB and MSS, if present, persisted in more elderly patients. Similarly, we performed a similar analysis for patients with T2–3 and T4 tumors separately. We performed all statistical analyses using Stata 17®, defining statistical significance as p < 0.05.15
Subgroup Analysis
The question of whether SLNB is associated with improved MSS in intermediate and thick melanomas remains controversial across all age groups. Therefore, as a comparison, we studied the association between SLNB and MSS in melanoma patients < 70 years at increasing age cutoffs (≥ 21, ≥ 22, ≥ 23, ≥ 24…, ≥ 69) (age removed from these models) using multivariable Cox proportional hazard models.
Results
Study Cohort
Table 1 shows the characteristics of patients in our SEER cohort. Our analysis identified 11,548 patients who fit our inclusion criteria, 6,754 (58.5%) of whom underwent SLNB. For those who underwent SLNB, 1,050 (15.5%) patients had SLN metastasis and 5,704 (84.5%) patients did not have SLN metastasis. Sentinel lymph node biopsy performance decreased significantly with age (70–79 years = 72.8%, 80–89 years = 48.7%, and ≥ 90 years = 16%, p < 0.001). However, our analysis did not show a significant difference in the rate of SLN positivity among the different age groups (14.5–16.8%, p > 0.05) for those who underwent a SLNB.
Table 1
Summary of patients ≥ 70 years based on SLNB in the Surveillance, Epidemiology, and End Results database (2010 to 2019) diagnosed with clinically nonmetastatic melanomas >1.0 mm in Breslow thickness
On multivariable analysis for predictors of SLNB performance (Table 2), tumors that were mitotic, acral lentiginous (vs. superficial spreading), and present on the extremity (vs. trunk) had significantly higher likelihood of undergoing SLNB. Our analysis reported lower likelihood of SLNB performance with increased age, female sex, races other than non-Hispanic White, head and neck tumors, lentigo maligna subtype, and Breslow depth >4.0 mm (compared with >1–2 mm tumors). Furthermore, SLNB performance was more likely in patients with higher income. On adjusted analysis for nodal positivity (Table 2), increased likelihood of nodal positivity was seen with acral lentiginous melanomas (vs. superficial spreading), increased Breslow thickness, ulceration, and mitotic tumors. In contrast, nodal positivity was less likely in patients 80–89 years (vs. 70–79), tumors on the head and neck and upper extremity (vs. trunk), and lentigo maligna and desmoplastic melanomas (vs. superficial spreading).
Table 2
Predictors of SLNB performance and sentinel lymph node positivity in the Surveillance, Epidemiology, and End Results database (2010–2019) for patients diagnosed with clinically nonmetastatic melanomas >1.0 mm in Breslow thickness
Kaplan–Meier survival analysis identified an increased 5-year MSS for patients who underwent SLNB (81.7%, 95% confidence interval [CI] 80.5–82.9%) compared with those who did not undergo SLNB (75.1%, 95% CI 73.3–76.8%), p < 0.001. The difference in MSS was significant up to 86-year-old patients. Next, we separated patients who underwent SLNB into negative SLN and positive SLN. Our analysis reported increased 5-year MSS for patients with negative SLN (85.7%, 95% CI 84.5–86.9%) compared with those who did not undergo SLNB and those with a positive SLN (58%, 95% CI 53.7–62.2%), p < 0.001. This result were consistent across the entire age continuum (Fig. 2). Multivariable Cox analysis identified an association between negative SLN and improved MSS (compared with patients who did not undergo SLNB, hazard ratio [HR] 0.59; 95% CI 0.63–0.67) (Supplemental Table 1). Inferior MSS was associated with increased age, positive SLN, male sex, acral lentiginous subtype, increased Breslow thickness, ulcerated tumors, and ≥ 2 mitotic figures/mm2. Next, we performed multiple regression models (removing the age variable) to study the effect of SLNB at increasing age cutoffs (Fig. 3). The association between negative SLN and improved MSS (compared with no SLNB) remained significant for patients at increasing age cutoffs until age ≥ 87 years. No significant association between negative SLN and MSS was seen in age ≥ 88 years; however, low event rates in older age cohorts may limit the accuracy of this data. When this data was stratified by intermediate (T2–3) versus thick (T4) melanomas, the impact of negative SLN on MSS was less for the T4 tumors. Multivariable Cox analysis showed positive SLN to be significantly associated with worse MSS (compared with no SLNB) at increasing age cutoffs across all age cutoffs.
Fig. 2
Five-year melanoma-specific survival based on SLNB for patients with clinically nonmetastatic melanomas >1.0 mm in Breslow thickness in the Surveillance, Epidemiology, and End Results database (2010–2019) (A: SLNB vs. no SLNB, B: no SLNB vs. negative SLN vs. positive SLN)
Fig. 3
Multivariable Cox proportional hazard model reporting hazard ratios for the effect of SLNB on melanoma-specific survival using SEER (2010–2019) at increasing age cutoffs (starting at ≥ 70) for patients diagnosed with clinically nonmetastatic melanomas >1.0 mm in Breslow thickness (overall cohort [A: T2–4] and separated by T-stage [B: T2–3 and C: T4])
×
×
Subgroup Analysis
Multivariable Cox analysis of patients ≤69 years old identified similar association between negative SLN and improved MSS in the overall cohort and when separated by T-stage compared with patients not undergoing SLNB (Supplemental Fig. 1).
Discussion
The incidence of melanoma in the geriatric population is increasing at a faster rate than in younger patients.2,16 Increasing age also is associated with primary melanomas exhibiting worse features (such as increased Breslow thickness, ulceration, etc.) and a higher incidence of melanoma-related deaths.17‐19 However, the existing literature is inconsistent about the importance of SLNB in the elderly. Sentinel lymph node biopsy is used in the general population as an important prognostic tool that informs treatment decisions and imaging surveillance for qualified melanoma patients. Importantly, systemic treatments, such as immune and targeted therapies, used for patients with melanoma are tolerable and beneficial even in elderly populations.20 Therefore, while acknowledging that prospective studies are needed to confirm the association between SLNB performance and MSS, our data identified an association between SLNB and MSS, persisting for most elderly patients.
In this analysis, SLNB utilization decreased from >70% in patients aged 70–79 years to <50% for patients 80 years or older. Lower SLNB utilization in elderly patients is likely driven by multiple factors involving patient, tumor, and procedural considerations. The surgical complication rate of 5–11%, the vast majority of which are temporary and not lifestyle-limiting, may dissuade providers from performing the procedure in frail patients.21,22 In addition, elderly patients are at higher risk of perioperative morbidity and mortality, including anesthesia-related complications, such as cognitive dysfunction.23 Furthermore, elderly patients exhibit altered lymphatic drainage, as evidenced by poorer uptake of radiotracer dye during lymphoscintigraphy,24,25 and their tumors may have higher rates of hematogenous spread.17,26 These anatomic and biologic differences may influence a provider’s perception of value regarding SLNB. Nonetheless, our data describe a reasonably high and consistent rate of nodal positivity (15–18%) across elderly age groups. Whereas it is sensible to consider the perioperative risks of SLNB in this population, differences in anatomic and biologic factors in the elderly do not preclude the prognostic value of the procedure.
Anzeige
There may be other benefits to identifying occult nodal disease for elderly patients. A latent-subgroup analysis of the MSLT-I reported significantly improved MSS (HR = 0.68; p = 0.05) and distant metastasis-free survival (HR = 0.73; p = 0.04) for patients with intermediate-thickness tumors in whom node-positive disease was discovered on SLNB rather than after a clinical recurrence.8 Moreover, nodal recurrences are associated with worse quality of life and an increased risk of long-term morbidity after complete lymph node dissection.27 MSLT-I data indicate that essentially all metastases detected by SLNB would have eventually become clinically evident if not removed, as there were no differences in the rate of nodal metastasis identified between the SLNB and the observation group with long-term follow-up. While the national dataset used in this study cannot determine rates of melanoma recurrence, performing a SLNB has been shown to consistently decrease rates of regional recurrence in large randomized controlled trials regardless of tumor thickness in nonelderly patients (≤75 years).8,28 Whether elderly patients with occult positive nodes identified by SLNB fare better than those with nodal recurrences after observation requires further study with more granular longitudinal data.
The finding of improved MSS for patients undergoing SLNB, which also was seen in the younger cohort, was surprising. There are rationales that could explain the improved MSS for patients undergoing a SLNB. For instance, the incubator theory for cancer progression suggests that metastasis to a lymph node is essential for the priming of melanoma cells to survive as distant metastases.29 Preclinical studies have suggested a mechanism for this priming through the process of ferroptosis within lymph nodes.30 If this theory is correct, removal of draining lymph nodes before melanoma cells are primed for distant metastasis could improve MSS and may explain the findings in this large retrospective study. However, as mentioned previously, no prospective data has definitively shown an association between SLNB and improved MSS. It may be more likely that our results are influenced by a selection bias wherein more high-risk patients are foregoing SLNB in the elderly group, which may worsen the prognosis of the cohort not undergoing SLNB. While we cannot conclude that there is a definitive association between SLNB performance and MSS based on this retrospective study, there appears to be a potential benefit in younger age groups that persists in elderly patients, using the SEER database.
There are several limitations when interpreting data from this study. The retrospective nature of the study introduces selection biases. The lack of detailed information in a deidentified national dataset could obscure confounding factors. For instance, we were unable to account for the false-negative rate for patients who underwent SLNB, weigh the risks and benefits of SLNB, or include other outcomes such as recurrence-free survival. Also, not all factors that influence the decision for or against SLNB are captured in this dataset. Examples of this include frailty, inability to undergo general anesthesia, patients’ preference (with concern about prolonging recovery), physician recommendations, other comorbidities, proximity to treatment providers, and the limited life expectancy in the extremely elderly patients who are vulnerable to poorer outcomes even if fewer comorbidities are listed.3 The SEER program does not recommend comparing outcomes conditioned on systemic treatment using the SEER data without careful considerations of possible biases and appropriate adjustments. In addition, during the time period studied, adjuvant therapies for melanoma were variable, and utilization of contemporary treatments affects care substantially. Therefore, our study lacks sufficient information to suggest whether these therapies impact MSS, and the relevance of this data remains in question. Finally, although we used SEER to determine melanoma-specific survival, the accuracy of the “cause-specific survival” variable in the SEER database is debated. Cancer registries use algorithms to capture the cause of death from death certificates and identifying a single cause may be difficult, leading to a possible over- or under-attribution of cancer as a cause of death.31 For example, a death may be attributed to a site of metastasis or to a side effect of treatment. Although these deaths are not cancer deaths in a biological sense, they reflect the consequences of cancer. In addition, the cancer-specific survival becomes less reliable in elderly patients, raising inaccuracies as well.32 Although we interpret our results with caution, several authors have used a similar methodology and determined that using the SEER database’s cause-specific survival in calculating cancer-specific survival has acceptable validity.33
Conclusions
This analysis of the SEER database shows a prognostic benefit to SLNB in elderly patients and suggests a persistent association between SLNB performance and SLN status and melanoma-specific survival in all age groups. The survival benefit was neither eliminated nor decreased in the elderly population. Whereas some elderly patients may not undergo SLNB because of poor performance status, patient preference, or contraindications to surgery, our analysis highlights that SLNB should not be omitted based on age alone if patients can otherwise tolerate surgery.
Anzeige
DISCLOSURE
The authors have no relevant financial or non-financial interests to disclose.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Mit der Zeitschrift Die Chirurgie erhalten Sie zusätzlich Online-Zugriff auf weitere 43 chirurgische Fachzeitschriften, CME-Fortbildungen, Webinare, Vorbereitungskursen zur Facharztprüfung und die digitale Enzyklopädie e.Medpedia.
The Utility of Sentinel Lymph Node Biopsy in Elderly Patients with Melanoma
verfasst von
Hanna Kakish, MD Carmen A. Jung, BA Susan J. Doh, MD Kathleen M. Mulligan, BA Iris Sheng, MD John B. Ammori, MD Ankit Mangla, MD Richard S. Hoehn, MD Luke D. Rothermel, MA, MPH
Bisher wird für den interventionellen Mitralklappenersatz standardmäßig der transapikale Zugangsweg gewählt. In einer Registeranalyse hat dieser in puncto Sicherheit allerdings den Kürzeren gezogen.
Die medikamentöse Therapie für Menschen mit Karotisstenosen hat sich in den vergangenen Dekaden verbessert. Braucht es also noch einen invasiven Eingriff zur Revaskularisation der Halsschlagader bei geringem bis moderatem Risiko für einen ipsilateralen Schlaganfall?
Personen mit Hirnmetastasen, die perioperativ höhere kumulative Dosen von Dexamethason erhalten, haben eine schlechtere Prognose. Um die Ergebnisse zu verbessern, bedarf es strengerer Dosierungsschemata.
Wird der Wurmfortsatz bei Personen mit Colitis ulcerosa entfernt, ist die Rückfallrate um ein Drittel geringer als unter konservativer Behandlung. Auch die Lebensqualität verbessert sich und der Bedarf an Medikamenten nimmt ab.
