The role of surgery following incomplete response to high-dose IL-2 (HD IL-2)

Background: Surgical resection of metastatic cancer is beneficial in select patients with cancer. HD IL-2 is an FDA approved immunotherapy for the treatment of patients with melanoma or renal cell carcinoma. IL-2 induces a complete response (CR) in 4-10% of patients while an additional 10% of patients have a partial response (PR). While not frequently reported, our experience suggests an additional 20% of patients have a stable response (SD) to therapy. The subsequent management of patients with an incomplete response, either partial or stable, has not been well studied and we sought to determine if metastasectomy might have a role in this setting. Methods: 305 patients with metastatic renal cell carcinoma or melanoma treated with IL-2 therapy over a 12-year period were reviewed. Age, response and survival data were available for 215 patients. Response was determined using standard RECIST criteria and patients with partial response (PR) or stable disease (SD) were considered incomplete responders to IL-2. Patients with an incomplete response were evaluated by a surgical oncologist. Surgical complete response (sCR) was defined as complete surgical resection of a single or multiple sites of disease following IL-2 therapy that rendered patients free of disease. Overall survival was estimated analyzed using Kaplan-Meier curves and compared between groups using the log-rank test. Results: The objective response rate (PR + CR) to HD IL-2 in this cohort was 13.6%. An additional 24.4% of patients had SD following their initial course of therapy. Median survival of all treated patients was 16.8 months. Incomplete response to IL-2 does confer an improvement in overall survival compared to patients with progressive disease (median survival 38.2 v. 7.9 months). Eighty-one patients had an incomplete response (PR + SD) to IL-2, fifteen of whom underwent subsequent metastasectomy. Patients undergoing metastasectomy had improved overall survival compared to patients with an incomplete response that did not undergo subsequent surgery (38.2 months v. median not reached in surgical patients, p=0.026). Of patients treated surgically following HD IL-2 12 patients were alive at the end of follow-up with follow-up ranging from 15 months to 96 months. Conclusion: The addition of surgical resection may improve upon the survival benefit in select patients with incomplete response to HD IL-2. These findings are biased by patient selection, but our results support the rationale for a prospective trial to determine the role of metastasectomy following incomplete response to IL-2 therapy. Additionally, we are interested in understanding how surgical resection following immunotherapy may reset immunologic balance in patients with metastatic cancer

Clinical benefit of high dose IL-2 (HD IL-2) therapy: evidence for improved overall survival in patients with stable disease

Background: HD IL-2 is an approved immunotherapy for advanced melanoma and renal cell carcinoma with a reported objective response rate (ORR) up to 20%. Patients with stable disease (SD) following treatment are not considered objective responders and thus are not included in reported response rates. Since the initial reports of IL-2 our understanding of the delayed pharmacokinetics of immunotherapy has improved. The purpose of this study is to report the clinical outcomes for patients with stable response to HD IL-2. Methods: A retrospective chart review of 305 patients diagnosed with metastatic renal cell carcinoma or melanoma and treated with HD IL-2 therapy over a 12-year period was conducted. Age, response to HD IL-2 (based on RECIST criteria) and survival data were available in 215 patients at the time of analysis. Survival analysis was conducted on all patients for whom complete data was available and Kaplan-Meier curves were generated based on overall survival. Results: Among the 215 patients with complete data, 62% had progressive disease (PD), 24% had SD and the objective response rate was 14%. Median overall survival was 16.8 months among all 215 patients. Patients with a PR or CR (median survival not reached in the study period) had significantly prolonged survival than the remaining patients (median survival 13.9 months, log-rank p < 0.01). Patients with SD (median survival of 38.2 months) had improved survival compared to patients with progressive disease (median survival of 7.9 months, log-rank p< 0.01). Discussion: The IL-2 literature has focused on partial or complete responders when reporting objective response rates. In our data, as well as elsewhere in the literature, there are a large number of patients who have a stable response to HD IL-2 that have not been included in the ORR. Our data supports a significant survival benefit associated with stable disease following IL-2, which suggests that HD IL-2 may result in a clinical benefit in a larger number of patients than has previously been reported. Consideration of a disease control rate (DCR) inclusive of objective responders and stable responses may be more appropriate to better define the clinical benefit of IL-2

Surveillance of Sentinel Node-Positive Melanoma Patients with Reasons for Exclusion from MSLT-II:Multi-Institutional Propensity Score Matched Analysis

BACKGROUND: In sentinel lymph node (SLN)-positive melanoma, two randomized trials demonstrated equivalent melanoma-specific survival with nodal surveillance vs completion lymph node dissection (CLND). Patients with microsatellites, extranodal extension (ENE) in the SLN, or >3 positive SLNs constitute a high-risk group largely excluded from the randomized trials, for whom appropriate management remains unknown. STUDY DESIGN: SLN-positive patients with any of the three high-risk features were identified from an international cohort. CLND patients were matched 1:1 with surveillance patients using propensity scores. Risk of any-site recurrence, SLN-basin-only recurrence, and melanoma-specific mortality were compared. RESULTS: Among 1,154 SLN-positive patients, 166 had ENE, microsatellites, and/or >3 positive SLN. At 18.5 months median follow-up, 49% had recurrence (vs 26% in patients without high-risk features, p 3 positive SLN constitute a high-risk group with a 2-fold greater recurrence risk. For those managed with nodal surveillance, SLN-basin recurrences were more frequent, but all-site recurrence and melanoma-specific mortality were comparable to patients treated with CLND. Most recurrences were outside the SLN-basin, supporting use of nodal surveillance for SLN-positive patients with microsatellites, ENE, and/ or >3 positive SLN

Active surveillance of patients who have sentinel node positive melanoma:An international, multi-institution evaluation of adoption and early outcomes after the Multicenter Selective Lymphadenectomy trial II (MSLT-2)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/168248/1/cncr33483.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168248/2/cncr33483_am.pd

Cancer providers and healthcare delivery systems are downstream benefactors of psychosocial support of cancer patients

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/166261/1/pon5501.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/166261/2/pon5501_am.pd

International Center-Level Variation in Utilization of Completion Lymph Node Dissection and Adjuvant Systemic Therapy for Sentinel Lymph Node-Positive Melanoma at Major Referral Centers

Objective: The aim of this study was to determine overall trends and center-level variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy for sentinel lymph node (SLN)-positive melanoma. Summary Background Data: Based on recent clinical trials, management options for SLN-positive melanoma now include effective adjuvant systemic therapy and nodal observation instead of CLND. It is unknown how these findings have shaped practice or how these contemporaneous developments have influenced their respective utilization. Methods: We performed an international cohort study at 21 melanoma referral centers in Australia, Europe, and the United States that treated adults with SLN-positive melanoma and negative distant staging from July 2017 to June 2019. We used generalized linear and multinomial logistic regression models with random intercepts for each center to assess center-level variation in CLND and adjuvant systemic treatment, adjusting for patient and disease-specific characteristics. Results: Among 1109 patients, performance of CLND decreased from 28% to 8% and adjuvant systemic therapy use increased from 29 to 60%. For both CLND and adjuvant systemic treatment, the most influential factors were nodal tumor size, stage, and location of treating center. There was notable variation among treating centers in management of stage IIIA patients and use of CLND with adjuvant systemic therapy versus nodal observation alone for similar risk patients. Conclusions: There has been an overall decline in CLND and simultaneous adoption of adjuvant systemic therapy for patients with SLN-positive melanoma though wide variation in practice remains. Accounting for differences in patient mix, location of care contributed significantly to the observed variation.</p