A randomized phase II study of adjuvant sunitinib or valproic acid in high-risk patients with uveal melanoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22059-e22059
Author(s):  
Takami Sato ◽  
Marlana M. Orloff ◽  
Matias Emanuel Valsecchi ◽  
Ayako Shimada ◽  
Inna Chervoneva ◽  
...  
Keyword(s):  
Valproic Acid ◽  
High Risk ◽  
Uveal Melanoma ◽  
Adjuvant Treatment ◽  
Survival Rates ◽  
Distant Metastases ◽  
Toxicity Assessment ◽  
Primary Tumors ◽  
Systemic Metastasis ◽  
Melanoma Patients

e22059 Background: Uveal melanoma is the most common primary intraocular cancer in adults. Despite successful treatment of primary tumors, up to 50% of patients later die of distant metastases. Currently, no effective adjuvant treatment is available. Presence of both monosomy 3 and 8q amplification (M3 + 8q amp) or DecisionDx-UM Class 2 in the primary uveal melanoma characterizes a group of patients with high metastatic death rates with reported 2-year survival rates ranging from 50% to 78%. This study aims to decrease or delay the death from metastatic uveal melanoma. Methods: Uveal melanoma patients with high risk for systemic metastasis defined as any of the following were eligible: A) M3 + 8q amp; B) Class 2. Patients must show no evidence of systemic metastasis and they need to be enrolled within 6 months of initial treatment of primary uveal melanoma. Patients were randomized to receive either sunitinib 25 mg daily or valproic acid (VPA) 750 mg daily as adjuvant treatment for 6 consecutive months. Improvement of 2-year overall survival (OS) rate from historical reference (70%) to 85% was the primary endpoint. The secondary endpoints included 1) systemic relapse-free survival (RFS) rate at 18 months, 2) ability to complete adjuvant treatment and, 3) toxicity assessment. The study was not powered to compare the efficacy between each arm. Results: A total of 90 patients were enrolled in this study. Two patients were excluded from the study including one in the sunitinib arm (did not start treatment after randomization) and one in the VPA arm (refused to stop VPA at 6 months). Nine of 45 patients in the sunitinib arm and 4 of 43 patients in the VPA arm could not complete the 6-month treatment due to toxicity (sunitinib n = 6, VPA n = 2) or systemic progression (sunitinib n = 3, VPA n = 2). The rest of patients completed the 6-month course of study treatments and all patients were followed at least for 2 years. With a median follow-up of 40.2 months, the 2-year OS rates of the sunitinib and VPA group were 95.6% (90% CI 86.5-98.6) and 90.7% (90% CI 80.1 - 95.8), respectively. The 18-month RFS rates of the sunitinib and VPA group were 75.6% (90% CI 63.1 - 84.3) and 62.8% (90% CI 49.4 - 73.5), respectively. Conclusions: Although the study is still ongoing, adjuvant sunitinib and VPA were considered to be safe and tolerable treatments for high-risk uveal melanoma. Sunitinib showed a tendency for a better outcome, thus a Cohort 2 was created to investigate the safety and potential improvement of 18-month RFS rate with 12 months of treatment with sunitinib. Clinical trial information: NCT02068586.

Adjuvant sunitinib in high-risk patients with uveal melanoma: A pilot study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8560-8560
Author(s):  
Matias Emanuel Valsecchi ◽  
Nancy Shockley ◽  
Deborah Summers ◽  
Carol L Shields ◽  
Jerry A Shields ◽  
...  
Keyword(s):  
Pilot Study ◽  
High Risk ◽  
Uveal Melanoma ◽  
Death Rate ◽  
Large Tumor ◽  
Primary Tumors ◽  
High Risk Patients ◽  
Monosomy 3 ◽  
Risk Patients ◽  
Melanoma Patients

8560 Background: Uveal melanoma is the most common primary intraocular cancer in adults. Despite the successful treatments for primary tumors, up to 50% of the patients later die of distant metastases. Currently no effective adjuvant treatment is available for these patients. Our group previously reported that sunitinib stabilized systemic metastases in 65% of uveal melanoma patients who failed prior treatments. In this pilot study, we tested sunitinib in an adjuvant setting in high-risk patients with primary uveal melanoma. Methods: Patients with estimated metastatic death rate ≥ 50% based on the following criteria were eligible: (1) monosomy 3 and 8q amplification; (2) large tumor (≥ 15 mm in diameter and ≥7 mm in thickness); (3) monosomy 3 and other risk factors (large tumor, epithelioid dominant cell type, local recurrence, or extra-scleral extension). Sunitinib was given at 25 mg PO daily for at least 6 months. Primary endpoint was disease-free survival (DFS) and overall survival (OS), estimated with Kaplan-Meier analysis (SPSS 17.0). Secondary endpoint was safety. Results: A total of 23 Caucasian patients (median, 54 years; range: 25 – 77) were enrolled. All patients received sunitinib for at least 6 months (range: 6 – 12). Eighteen patients had confirmed monosomy 3, from whom 13 (72%) also showed 8q amplification. The median follow-up was 24 months (range 12 – 54 months). Only one patient died of unknown cause (OS: 30.4 months). A total of seven patients (30%) developed systemic metastases, all of which were liver metastases. The DFS and OS rates at 2 years were 70% (95% CI: 47 – 86%) and 100%, respectively. The OS rate at 2 years was better than historical control with monosomy 3 patients (51%, 95% CI: 31 – 71%) (Invest Ophthalmol Vis Sci 2003; 44:1008). In those patients who relapsed, the median time to progression after finishing sunitinib was 2 months (range: 0 – 8). The most common adverse events were: diarrhea (47%), fatigue (39%), dermatitis (30%), stomatitis (13%), leucopenia (8%), and nausea (4%). Most were grade 1 or 2 (88%) and only one was considered grade 4 (diarrhea). Conclusions: In high-risk uveal melanoma patients with estimated metastatic death rate of ≥ 50%, adjuvant sunitinib showed promising results and deserves further investigation.

Deleted in Colon Cancer Protein Expression in Colorectal Cancer Metastases: A Major Predictor of Survival in Patients With Unresectable Metastatic Disease Receiving Palliative Fluorouracil-Based Chemotherapy

2004 ◽  
Vol 22 (18) ◽  
pp. 3758-3765 ◽  
Author(s):  
Carlo Aschele ◽  
Domizia Debernardis ◽  
Sara Lonardi ◽  
Roberto Bandelloni ◽  
Stefania Casazza ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Protein Expression ◽  
Regional Lymph Node ◽  
Survival Rates ◽  
Distant Metastases ◽  
Patient Characteristics ◽  
Rank Test ◽  
Primary Tumors ◽  
Major Predictor

Purpose To determine whether deleted in colon cancer (DCC) protein expression in colorectal cancer (CRC) metastases could predict outcome to palliative fluorouracil (FU)-based chemotherapy and to assess whether it is similar to that observed in the corresponding primary tumors. Patients and Methods DCC protein expression was assessed immunohistochemically on archival specimens of CRC metastases from 42 patients homogeneously treated by methotrexate-modulated bolus FU alternated to 6-S-leucovorin–modulated infused FU and was retrospectively correlated with patient characteristics and clinical outcome. In a subset analysis, DCC immunoreactivity was compared between metastatic CRC and the corresponding primary tumors and regional lymph node metastases. Results Positive immunoreactivity for DCC was found in 45% of patients. Eighteen (78%) of 23 patients for whom multiple samples were available displayed a similar pattern of expression in distant metastases and primary tumors. The median survival time was 14.3 months in patients without DCC expression and 21.4 months in patients with DCC-positive tumors (log-rank test, P = .04); the 2-year survival rates were 8.5% and 42.5%, respectively. Response rates to chemotherapy were not significantly different between the two groups. By multivariate analysis, DCC protein expression maintained its prognostic value and showed to be the single best predictor of survival, with a relative risk of 2.16. Conclusion Our results indicate that expression of the DCC protein in CRC metastases is similar to that observed in the corresponding primary tumors and represents a dominant predictor of survival in patients with unresectable, advanced CRC who are undergoing palliative FU-based chemotherapy.

CDK12 upregulation and adverse correlation with tumor-associated immune cell infiltrates in prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 181-181
Author(s):  
Marie C. Hupe ◽  
Anne Offermann ◽  
Cleopatra Schreiber ◽  
Axel Stuart Merseburger ◽  
Sven Perner
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Immune Cell ◽  
Locally Advanced ◽  
Survival Rates ◽  
Distant Metastases ◽  
Genetic Alterations ◽  
Primary Tumors ◽  
Locally Advanced Tumors ◽  
Advanced Tumors

181 Background: Biallelic loss of CDK12 has recently been identified as a novel subtype of prostate cancer (PCa). CDK12 altered PCa associates with elevated neoantigen burden and thus may be suitable for checkpoint inhibition. Up to now, data about CDK12 refer to its genetic alterations in PCa while its characterization on protein level and its association with tumor infiltrating T-cells are lacking. Methods: Immunohistochemistry (IHC) for CDK12 was performed on a PCa cohort including 74 benigns, 391 primary tumors from 222 patients, 63 locally advanced tumors, 92 lymph node (LN) metastases, and 56 distant metastases. CDK12 was categorized into negative, weak, moderate and high expression. Density of tumor associated T-cells per tumor area was assessed by IHC for CD3 and graduated into negative (<1%), slight (1-5%), weak (5-10%), moderate (10-50%) and high (>50%). Results: CDK12 significantly increases during PCa progression showing highest levels in LN and distant metastases while benign samples harbor no or weak CDK12 expression (ANOVA p<0.001). Kaplan-Meier curve reveals 5-year-biochemical recurrence free survival rates of 89.5%, 69.1%, 59.1% and 20.0% for primary tumors expressing no, weak, moderate and high CDK12 (log-rank p=0.05). High CDK12 expression significantly associates with attenuated tumor associated T-cells (p=0.009) revealing CD3 negativity in 64.7% of CDK12 high expressing tumors. Intratumoral CDK12 and density of CD3 positive T-cells correlates adversely in particular in locally advanced tumors (p=0.007). Overall, tumor associated T-cells are significantly reduced in distant metastases compared to local PCa (p<0.001). Conclusions: Our study highlights the prognostic potential of CDK12 for PCa and its overexpression in advanced tumors. Of note, CDK12 overexpressing tumors can be designated as immunologic “cold” tumors which is in line with their more aggressive phenotype. Concordantly, distant metastases show attenuated tumor associated T-cells supporting the poor response to immunotherapy.

Prospective study of surveillance testing for metastasis in 100 high-risk uveal melanoma patients

2015 ◽  
Vol 38 (6) ◽  
pp. 526-534 ◽  
Author(s):  
S. Piperno-Neumann ◽  
V. Servois ◽  
P. Mariani ◽  
C. Plancher ◽  
C. Lévy-Gabriel ◽  
...  
Keyword(s):  
High Risk ◽  
Prospective Study ◽  
Uveal Melanoma ◽  
Melanoma Patients

Lack of GNAQ germline mutations in uveal melanoma patients with high risk for hereditary cancer predisposition

2010 ◽  
Vol 10 (2) ◽  
pp. 319-321 ◽  
Author(s):  
Mohamed H. Abdel-Rahman ◽  
Robert Pilarski ◽  
James B. Massengill ◽  
Benjamin B. Christopher ◽  
Frederick H. Davidorf
Keyword(s):  
High Risk ◽  
Uveal Melanoma ◽  
Hereditary Cancer ◽  
Germline Mutations ◽  
Cancer Predisposition ◽  
Melanoma Patients ◽  
Hereditary Cancer Predisposition

scholarly journals BAP1 methylation: a prognostic marker of uveal melanoma metastasis

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Mathieu F. Bakhoum ◽  
Ellis J. Curtis ◽  
Michael H. Goldbaum ◽  
Paul S. Mischel
Keyword(s):  
High Risk ◽  
Dna Sequencing ◽  
Prognostic Marker ◽  
Uveal Melanoma ◽  
Primary Tumor ◽  
Melanoma Metastasis ◽  
Primary Cancer ◽  
Melanoma Patients

AbstractUveal melanoma, the most common intraocular primary cancer in adults, is characterized by striking variability in metastatic tendencies. BAP1 deletion in the primary tumor is associated with uveal melanoma metastasis, but it cannot always be resolved by bulk DNA sequencing of heterogeneous tumors. Here, we show that assessment of BAP1 methylation is an accurate and readily clinically actionable assay to accurately identify high-risk uveal melanoma patients.

Neoadjuvant ipilimumab + nivolumab (IPI+NIVO) in palpable stage III melanoma: Updated data from the OpACIN trial and first immunological analyses.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9586-9586 ◽  
Author(s):  
Elisa A. Rozeman ◽  
Christian U. Blank ◽  
Alexander Christopher Jonathan Van Akkooi ◽  
Pia Kvistborg ◽  
Lorenzo Fanchi ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Adjuvant Treatment ◽  
Stage Iv ◽  
Study Data ◽  
Stage Iii ◽  
Feasibility Trial ◽  
Melanoma Patients ◽  
Stage Iii Melanoma ◽  
Grade 3

9586 Background: The combination of IPI+NIVO induces high response rates and improved overall survival in late stage melanoma. T cell checkpoint inhibition is of greatest value at the moment of TCR triggering and therefore dependent on the amount of antigen present, indicating that adjuvant immunotherapy may work most efficiently, when initiated prior to surgery. Methods: Two-arm Phase 1b feasibility trial of 20 high risk AJCC stage IIIB and IIIC melanoma patients with palpable nodal disease receiving the combination of IPI 3mg/kg and NIVO 1mg/kg, either adjuvant four courses after surgery, or split two courses neo-adjuvant and two courses adjuvant. Results: In this update all 20 patients are evaluable. Neo-adjuvant application of IPI+NIVO was feasible and no surgery-associated adverse events were attributed to (neo-)adjuvant therapy. 18/20 patients had to stop early due to grade 3/4 toxicities. Neo-adjuvant IPI+NIVO reduced tumor load in 8/10 patients (3 pCR, 4 near-pCRs [minimal remaining micrometastases], 1 pPR [75% reduction], 1 SD and 1 PD). To date, after a median follow-up of 45 weeks (range 13-74), none of the responders in the neoadjuvant arm has relapsed. Relapse was observed for both non-responders within the neo-adjuvant arm and for 3 patients within the adjuvant arm. TCR sequencing and MHC tetramer-based analysis to compare the induction and expansion of tumor (neo-)antigen-specific T cell responses between both treatment arms are underway and will be presented. Conclusions: The combination of IPI+NIVO in the (neo-)adjuvant treatment setting for high risk stage III melanoma patients is feasible and induces very frequent responses. At the same time, severe grade 3/4 toxicity is more frequent than expected from stage IV melanoma patient study data. These results indicate that IPI+NIVO is a promising combination for neo-adjuvant treatment in stage III melanoma. Adjusted combination schemes are currently tested in the phase 2 OpACIN-neo trial, with the aim of reducing toxicity while preserving efficacy. Clinical trial information: NCT02437279.

The value of lymph node ultrasound and whole body PET/CT in stage IIB/C patients prior to SLNB.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22079-e22079
Author(s):  
Emma H.A. Stahlie ◽  
Bernies Van Der Hiel ◽  
Annemarie Bruining ◽  
Michel W.J.M. Wouters ◽  
Yvonne Schrage ◽  
...  
Keyword(s):  
Lymph Node ◽  
High Risk ◽  
Whole Body ◽  
Preoperative Imaging ◽  
Cross Sectional ◽  
Primary Tumors ◽  
Pet Ct ◽  
Cross Sectional Imaging ◽  
Melanoma Patients ◽  
Sectional Imaging

e22079 Background: Stage IIB/IIC (pT3b-T4N0) patients are known to have high-risk primary tumors, even higher risk than some stage IIIA/B melanomas (AJCC Staging System 8th edition), however they follow the same routine to sentinel lymph node biopsy (SLNB) as more low-risk tumors. A priori the risk of finding SLNB or other metastases is much higher for these thick and/or ulcerated primary melanomas compared to the thinner ones. Guidelines are not conclusive regarding the use of preoperative imaging in these cases. Recently, a trend to more frequently use cross-sectional imaging has been noticed. However, others have previously shown that preoperative ultrasound was the most sensitive. The aim of this pilot study was to assess the value of ultrasound (US) and Positron Emission Tomography/Computerized Tomography (PET/CT) prior to SLNB for stage IIB/C (pT3b-T4N0) melanoma patients. Methods: Starting 2019-04, all patients with a pT3b melanoma or higher (8th AJCC) were included. All patients underwent US and PET/CT before their planned lymphoscintigraphy and routine SLNB. Suspected metastases were confirmed with cytologic puncture. Results: A total of 20 patients were screened. Seven patients (35%) had metastases detected by imaging: one by PET/CT, three by US and three by both imaging modalities. Three of these metastases were detected by US as well as PET/CT. All metastases were nodal. For all seven patients treatment was altered to lymph node dissection with adjuvant therapy. Of the 13 patients in whom no metastases were identified by imaging, six (46%) still had a positive sentinel node (SN). Conclusions: This study showed that this select group of patients had a high risk of metastases prior to SLNB and that all recurrences except one, were detected by ultrasound. This suggests that nodal staging with US is sufficient and can replace the need for SLNB when metastases is proven with cytology. Despite negative imaging, SLNB cannot be foregone for pT3b-pT4N0 melanoma patients, as many still have an involved SN. Cross-sectional imaging can be reserved for patients after positive cytology or SN to confirm the absence of distant visceral metastases.

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