Poor Response to Checkpoint Immunotherapy in Uveal Melanoma Highlights the Persistent Need for Innovative Regional Therapy Approaches to Manage Liver Metastases

Uveal melanoma is a cancer that develops from melanocytes in the posterior uveal tract. Metastatic uveal melanoma is an extremely rare disease that has a poor long-term prognosis, limited treatment options and a strong predilection for liver metastasis. Median overall survival has been reported to be 6 months and 1 year mortality of 80%. Traditional chemotherapy used in cutaneous melanoma is ineffective in uveal cases. Surgical resection and ablation is the preferred therapy for liver metastasis but is often not feasible due to extent of disease. In this review, we will explore treatment options for liver metastases from uveal melanoma, with a focus on isolated hepatic perfusion (IHP). IHP offers an aggressive regional therapy approach that can be used in bulky unresectable disease and allows high-dose chemotherapy with melphalan to be delivered directly to the liver without systemic effects. Long-term median overall survival has been reported to be as high as 27 months. We will also highlight the poor responses associated with checkpoint inhibitors, including an overview of the biological rationale driving this lack of immunotherapy effect for this disease. The persistent failure of traditional treatments and immunotherapy suggest an ongoing need for regional surgical approaches such as IHP in this disease.

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Examination of The Characteristics of Long-Term Survivors Among Patients With Gallbladder Cancer With Liver Metastasis Who Underwent Surgical Treatment: A Retrospective Multicenter Study (ACRoS1406)

10.21203/rs.3.rs-1187502/v1 ◽

2022 ◽

Author(s):

Ryota Higuchi ◽

Hiroaki Ono ◽

Ryusei Matsuyama ◽

Yusuke Takemura ◽

Shinjiro Kobayashi ◽

...

Keyword(s):

Overall Survival ◽

Liver Metastasis ◽

Liver Metastases ◽

Gallbladder Cancer ◽

Complete Resection ◽

Hazard Ratio ◽

Negative Margin ◽

Long Term Survivors ◽

Retrospective Multicenter Study

Abstract Background: Gallbladder cancer (GBC) with liver metastasis is considered unresectable. However, there have been infrequent reports of long-term survival in patients with GBC and liver metastases. Therefore, we examined the characteristics of long-term survivors of gallbladder cancer with liver metastasis.Methods: A retrospective multicenter study of 503 patients with GBC (mean age, 68.6 years; female, 52%) was performed. Although patients with pre-operatively diagnosed GBC and liver metastasis were generally excluded from resection, some cases identified during surgery were resected.Result: In patients with resected stage III/IV GBC (n = 228), the period 2007–2013 (vs. 2000–2006, hazard ratio 0.55), other type histology (vs. well/moderate histology, hazard ratio 2.34), ≥2 liver metastases (vs. one liver metastasis, hazard ratio 4.30), and positive margin resection (vs. complete resection with a negative margin, hazard ratio 1.57) were independent prognostic factors for overall survival, whereas one liver metastasis (vs. no liver metastasis) was not. The 5-year overall survival and median survival times in those with one liver metastasis with complete resection and a negative margin (40.9%, 28.3 months) were significantly better than those in patients with ≥2 liver metastases with complete resection and a negative margin (0%, 11.0 months, p = 0.025), and comparable to those in patients with liver metastasis with complete resection and a negative margin (37.0%, 33.0 months). According to the univariate analysis of resected patients with GBC and liver metastases (n=24), minor hepatectomy, less blood loss, less surgery time, papillary adenocarcinoma, T2, morbidity of Clavien–Dindo classification ≤ 2, and adjuvant chemotherapy were significantly associated with longer survival. Long-term survivors (n = 5) had a high frequency of T2 tumors (4/5), had small liver metastases near the gallbladder during or after surgery, underwent minor hepatectomy without post-operative complications, and received post-operative adjuvant chemotherapy.Conclusions: Although there is no surgical indication for GBC with liver metastasis diagnosed pre-operatively, minor hepatectomy and post-operative chemotherapy may be an option for selected patients with T2 GBC and liver metastasis identified during or after surgery who do not have other poor prognostic factors.

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Prognostic Factors Affecting Long-Term Survival after Resection for Noncolorectal, Nonneuroendocrine, and Nonsarcoma Liver Metastases

Gastroenterology Research and Practice ◽

10.1155/2017/5184146 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Fabio Uggeri ◽

Enrico Pinotti ◽

Marta Sandini ◽

Luca Nespoli ◽

Luca Gianotti ◽

...

Keyword(s):

Overall Survival ◽

Liver Metastases ◽

Treatment Options ◽

Postoperative Outcome ◽

Term Outcome ◽

Term Survival ◽

Long Term Outcome ◽

Factors Affecting ◽

Pringle’S Maneuver

Aim. To evaluate feasibility and long-term outcome after hepatic resection for noncolorectal, nonneuroendocrine, and nonsarcoma (NCNNNS) liver metastases in a single center.Methods. We retrospectively reviewed our experience on patients who underwent surgery for NCNNNS liver metastases from 1995 to 2015. Patient baseline characteristics, tumor features, treatment options, and postoperative outcome were retrieved.Results. We included 47 patients. The overall 5-year survival (OS) rate after hepatectomy was 27.6%, with a median survival of 21 months. Overall survival was significantly longer for patients operated for nongastrointestinal liver metastases when compared with gastrointestinal (41 versus 10 months;p=0.027). OS was significantly worse in patients with synchronous metastases than in those with metachronous disease (10 versus 22 months;p=0.021). The occurrence of major postoperative complication negatively affected long-term prognosis (OS 23.5 versus 9.0 months;p=0.028). Preoperative tumor characteristics (number and size of the lesions), intraoperative features (extension of resection, need for transfusions, and Pringle’s maneuver), and R0 at pathology were not associated with differences in overall survival.Conclusion. Liver resection represents a possible curative option for patients with NCNNNS metastases. The origin of the primary tumor and the timing of metastases presentation may help clinicians to better select which patients could take advantages from surgical intervention.

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Unresectable Hepatic Metastasis of Uveal Melanoma: Hepatic Chemosaturation with High-Dose Melphalan—Long-Term Overall Survival Negatively Correlates with Tumor Burden

Radiology Research and Practice ◽

10.1155/2020/5672048 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

R. Brüning ◽

M. Tiede ◽

M. Schneider ◽

P. Wohlmuth ◽

H. Weilert ◽

...

Keyword(s):

Overall Survival ◽

Adverse Events ◽

Confidence Interval ◽

Uveal Melanoma ◽

Hepatic Metastasis ◽

Cox Regression ◽

Tumor Burden ◽

Hepatic Tumor ◽

High Dose

Introduction. Percutaneous hepatic perfusion with melphalan (PHP-M) for hepatic metastasis of uveal melanoma (LMUM) achieves high local response rates, but the individual clinical benefit is poorly defined. We aimed to determine cofactors of response and clinical outcomes including the probability of long-term (5-years) overall survival (OS) in PHP-M-treated patients with LMUM. Patients and Methods. We retrospectively reviewed clinicopathological, radiological, and outcome data of 19 patients with unresectable LMUM treated with 43 PHP-M (median 2 PHP-M) between 2014 and 2019. Tumor response and adverse events were evaluated using RECIST 1.1 and the Clavien–Dindo classification. Kaplan–Meier methods and Cox regression hazard proportional models were used. Results. Of 19 patients, 10 (53%) achieved a partial response (PR) and 9 (47%) had stable disease (SD). There was no progressive disease (PD) and no adverse events exceeding Clavien–Dindo grade IV. Median OS was 16.7 months after the first PHP-M treatment and 26.4 months after initial diagnosis. Low hepatic tumor volume (median of 10 mL vs. 150 mL) was an independent predictor of favorable OS (hazard ratio (95% confidence interval): 0.190 (0.041, 0.893); p<0.05), and female patients were at a lower risk compared with males (0.146 (0.017, 1.240)). Estimates of the overall survival were 0.213 (0.0449, 1) from first imaging (95% confidence interval) to 5 years and 0.793 (0.609, 1) and 0.604 (0.380, 0.960) for 1 and 2 years after chemosaturation, respectively. Discussion. PHP-M for nonresectable LMUV provides a safe and locally efficient liver-directed procedure that offers patients a chance for long-term OS, especially for patients with a low hepatic tumor burden.

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A case of repeat hepatectomy for liver metastasis from solid pseudopapillary neoplasm of the pancreas: a case report

Surgical Case Reports ◽

10.1186/s40792-021-01134-6 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Atsushi Morito ◽

Kojiro Eto ◽

Kozue Matsuishi ◽

Hirokazu Hamasaki ◽

Keisuke Morita ◽

...

Keyword(s):

Liver Metastasis ◽

Liver Metastases ◽

Distal Pancreatectomy ◽

Treatment Guidelines ◽

Histopathological Examination ◽

Repeat Hepatectomy ◽

R0 Resection ◽

Solid Pseudopapillary Neoplasm ◽

Long Term Prognosis

Abstract Background Solid pseudopapillary neoplasm of the pancreas is a rare tumor in young women, metastasizing in only 5–15% of cases, and most commonly to the liver. Although treatment guidelines have not been established, surgical resection is usually performed. We report a rare case of repeat hepatectomy for liver metastases after distal pancreatectomy with solid pseudopapillary neoplasm. Case presentation The patient was a 71-year-old woman who underwent distal pancreatectomy for solid pseudopapillary neoplasm, and liver metastasis occurred 4 years after the first surgery. Partial liver resection was performed for four liver metastases, and histopathological examination revealed a diagnosis of liver metastasis from solid pseudopapillary neoplasm. However, 18 months later, liver metastases were detected again; three tumors were identified, and partial resection was performed, which has provided 18 months’ recurrence-free survival. Conclusions Long-term prognosis can be expected following R0 resection for resectable liver metastasis from solid pseudopapillary neoplasm.

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Long-Term Survival and Value of 18F-FDG PET/CT in Patients with Gastroenteropancreatic Neuroendocrine Tumors Treated with Second Peptide Receptor Radionuclide Therapy Course with 177Lu-DOTATATE

Life ◽

10.3390/life11030198 ◽

2021 ◽

Vol 11 (3) ◽

pp. 198

Author(s):

Margarida Rodrigues ◽

Kevin-Klaus Winkler ◽

Hanna Svirydenka ◽

Bernhard Nilica ◽

Christian Uprimny ◽

...

Keyword(s):

Overall Survival ◽

Fdg Pet ◽

Median Overall Survival ◽

Peptide Receptor Radionuclide Therapy ◽

Term Survival ◽

Peptide Receptor ◽

Pet Ct ◽

18F Fdg ◽

Fdg Pet Ct

Peptide receptor radionuclide therapy (PRRT) has been recognized as a promising therapy against neuroendocrine tumors (NETs). The use of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in NETs has been a matter of controversy. The purpose of this study was to evaluate the long-term survival and efficacy of a second PRRT course with 177Lu-DOTATE in patients with advanced gastroenteropancreatic (GEP) NETs. Furthermore, the value of 18F-FDG PET/CT in these patients was evaluated. 40 patients with GEP NETs who underwent two PRRT courses with 177Lu-DOTATATE and combined examinations with 68Ga-DOTA-TOC and 18F-FDG PET/CT were evaluated. After the second PRRT course, two patients (5.0%) were in partial remission, 21 patients (52.5%) in stable disease and 17 patients (42.5%) had progressive disease. The median overall survival was 122.10 months. After the second PRRT course, the median overall survival was significantly higher (p = 0.033) in the 18F-FDG-negative group compared to the 18F-FDG-positive group (145.50 versus 95.06 months, respectively). The median time to progression was 19.37 months. In conclusion, a second PRRT course with 177Lu-DOTATE is an effective treatment approach for GEP NET patients with disease progression. A change in 18F-FDG status after PRRT may predict the disease course and survival. Patients who are 18F-FDG-negative have a significantly longer overall survival than those who are 18F-FDG-positive.

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Final overall survival in the phase 3 NETTER-1 study of lutetium-177-DOTATATE in patients with midgut neuroendocrine tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4112 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4112-4112

Author(s):

Jonathan R. Strosberg ◽

Martyn E Caplin ◽

Pamela L. Kunz ◽

Philippe B Ruszniewski ◽

Lisa Bodei ◽

...

Keyword(s):

Overall Survival ◽

Neuroendocrine Tumors ◽

High Dose ◽

Radioligand Therapy ◽

Phase 3 ◽

Long Term Follow Up ◽

Long Acting ◽

Safety Signals

4112 Background: As demonstrated in the primary analysis of the phase 3 NETTER-1 trial, 177Lu-DOTATATE significantly prolonged progression-free survival (PFS) versus high-dose long-acting octreotide, with a HR of 0.18 (95% CI: 0.11, 0.29; p < 0.0001), in patients with advanced, progressive, well-differentiated, somatostatin receptor-positive midgut neuroendocrine tumors (NETs). Here we report final overall survival (OS) for NETTER-1. Methods: In this international open-label trial, eligible patients were randomized to receive either four cycles of 177Lu-DOTATATE 7.4 GBq (200 mCi) every 8 ± 1 weeks plus long-acting octreotide 30 mg or high-dose long-acting octreotide 60 mg every 4 weeks (control arm), both on top of best supportive care. After disease progression on randomized treatment or completion of an 18-month treatment period, patients in both arms entered long-term follow-up and could receive further anti-cancer treatment as recommended by their physicians. The primary endpoint was PFS per RECIST 1.1 and OS was a key secondary endpoint. Primary intention-to-treat analysis of OS was prespecified to take place after 158 deaths or 5 years after the last patient was randomized, whichever occurred first. Results: Of 231 randomized patients, 101/117 (86.3%) in the 177Lu-DOTATATE arm and 99/114 (86.8%) in the control arm entered long-term follow-up. Final analysis occurred 5 years after the last patient was randomized, following 142 deaths, with a median follow-up of more than 76 months. During long-term follow-up, 41/114 (36%) of patients in the control arm received subsequent radioligand therapy (“cross-over”), the majority (22.8%) within 24 months. Median OS was 48.0 months (95% CI: 37.4, 55.2) in the 177Lu-DOTATATE arm and 36.3 months (95% CI: 25.9, 51.7) in the control arm. HR was 0.84 (95% CI: 0.60, 1.17) with p = 0.30 (unstratified 2-sided log-rank test). A total of 2/112 (1.8%) 177Lu-DOTATATE treated patients in the study developed myelodysplastic syndrome (MDS). No new cases of MDS or acute leukemia were reported in the long-term follow-up. Overall, no new safety signals emerged during long-term follow-up. Conclusions: Median OS was 48.0 months in the 177Lu-DOTATATE arm of the NETTER-1 trial and 36.3 months in the control arm. This difference was not statistically significant, potentially impacted by a high rate (36%) of cross-over of patients in the control arm to radioligand therapy after progression. In overall conclusion, the NETTER-1 study demonstrated that 177Lu-DOTATATE yielded a clinically and statistically significant improvement in PFS as a primary endpoint (HR: 0.18, p < 0.0001) as well as a clinically meaningful trend towards improvement in median OS of 11.7 months. No new safety signals emerged during the 5-year long-term follow-up. Clinical trial information: NCT01578239.

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A grading system for predicting the prognosis of gastric cancer with liver metastasis

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyab140 ◽

2021 ◽

Author(s):

Soshi Hori ◽

Michitaka Honda ◽

Hiroshi Kobayashi ◽

Hidetaka Kawamura ◽

Koichi Takiguchi ◽

...

Keyword(s):

Colorectal Cancer ◽

Gastric Cancer ◽

Overall Survival ◽

Liver Metastasis ◽

Confidence Interval ◽

Liver Metastases ◽

Hazard Ratio ◽

Maximum Diameter ◽

Grading System ◽

Computed Tomography Images

Abstract Objective The prognosis of patients with liver metastases from gastric cancer is determined using tumor size and number of metastases; this is similar to the factors used for the prediction of liver metastases from colorectal cancer. The relationship between the degree of liver metastasis from gastric cancer and prognosis with reference to the classification of liver metastasis from colorectal cancer was investigated. Methods This was a multi-institutional historical cohort study. Among patients with stage IV gastric cancer, who visited the cancer hospitals in Fukushima Prefecture, Japan, between 2008 and 2015, those with simultaneous liver metastasis were included. Abdominal pretreatment computed tomography images were reviewed and classified into H1 (four or less liver metastases with a maximum diameter of ≤5 cm); H2 (other than H1 and H3) or H3 (five or more liver metastases with a maximum diameter of ≥5 cm). The hazard ratio for overall survival according to the H grade (H1, H2 and H3) was calculated using the Cox proportional hazards model. Results A total of 412 patients were analyzed. Patients with H1, H2 and H3 grades were 118, 162 and 141, respectively, and their median survival time was 10.2, 5.7 and 3.1 months, respectively (log-rank P < 0.001). The adjusted hazard ratio for overall survival was H1: H2: H3 = reference: 1.39 (95% confidence interval: 1.04–1.85): 1.69 (95% confidence interval: 1.27–2.27). Conclusions The grading system proposed in this study was a simple and easy-to-use prognosis prediction index for patients with liver metastasis from gastric cancer.

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Sorafenib for the Treatment of Unresectable Hepatocellular Carcinoma: Preliminary Toxicity and Activity Data in Dogs

Cancers ◽

10.3390/cancers12051272 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1272 ◽

Cited By ~ 1

Author(s):

Laura Marconato ◽

Silvia Sabattini ◽

Giorgia Marisi ◽

Federica Rossi ◽

Vito Ferdinando Leone ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Safety Profile ◽

Median Overall Survival ◽

Response Rate ◽

Treatment Options ◽

Objective Response ◽

Metronomic Chemotherapy ◽

Time To Progression ◽

Activity Data

Unresectable nodular and diffuse hepatocellular carcinoma (HCC) have a poor prognosis with limited treatment options. Systemic traditional chemotherapy has been only rarely reported, with unsatisfactory results. The aim of this prospective, non-randomized, non-blinded, single center clinical trial was to investigate safety profile, objective response rate, time to progression and overall survival of sorafenib in comparison with metronomic chemotherapy (MC) consisting of thalidomide, piroxicam and cyclophosphamide in dogs with advanced, unresectable HCC. Between December 2011 and June 2017, 13 dogs were enrolled: seven received sorafenib, and six were treated with MC. Median time to progression was 363 days (95% CI, 191–535) in dogs treated with sorafenib versus 27 days (95% CI, 0–68) in dogs treated with MC (p = 0.044). Median overall survival was 361 days (95% CI, 0–909) in dogs receiving sorafenib, while 32 days (95% CI, 0–235) in those receiving MC (p = 0.079). Sorafenib seems to be a good candidate for the treatment of dogs with advanced HCC, due to a benefit in disease control and an acceptable safety profile, offering a good basis on which new randomized prospective clinical trials should be undertaken to compare the efficacy and drawback of sorafenib versus MC or traditional chemotherapy.

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Radiofrequency ablation versus traditional liver resection and chemotherapy for liver metastases from gastric cancer

Journal of International Medical Research ◽

10.1177/0300060520940509 ◽

2020 ◽

Vol 48 (7) ◽

pp. 030006052094050

Author(s):

Kezhong Tang ◽

Bo Zhang ◽

Linping Dong ◽

Lantian Wang ◽

Zhe Tang

Keyword(s):

Gastric Cancer ◽

Radiofrequency Ablation ◽

Liver Resection ◽

Liver Metastasis ◽

Liver Metastases ◽

Statistical Significance ◽

Local Treatment ◽

Long Term Outcomes ◽

Short And Long Term

Objective To compare the short- and long-term outcomes of radiofrequency ablation (RFA) versus liver resection and chemotherapy for liver metastases from gastric cancer. Methods We retrospectively evaluated 50 patients who underwent curative gastrectomy and local treatments for liver metastases (RFA, n = 20; liver resection, n = 20; and chemotherapy, n = 10) from 2008 to 2018. Results The short- and long-term outcomes of each local treatment were evaluated. The median overall survival (OS) after RFA was similar to that after liver resection (20 vs. 20 months, respectively) and longer than that after chemotherapy (20 vs. 10 months, respectively). The 3-year OS and progression-free survival (PFS) rates after RFA were 20% and 10%, respectively, while those in the liver resection group were 23.5% and 23.5%, respectively. The 3-year OS rate after chemotherapy was 10%. The size and number of metastases were prognostic factors for patients with gastric cancer with liver metastasis without statistical significance. Conclusions Among patients with liver metastasis from gastric cancer, OS and PFS were satisfactory and comparable between RFA and liver resection but better than those of chemotherapy. RFA is an appropriate option for patients with gastric cancer who have a solitary liver metastasis measuring ≤3.0 cm.

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Major Hepatectomy for Colorectal Metastases in the Elderly: A Tertiary Center Experience

International Surgery ◽

10.9738/intsurg-d-14-00155.1 ◽

2015 ◽

Vol 100 (9-10) ◽

pp. 1276-1280

Author(s):

Osama Damrah ◽

Panagis M. Lykoudis ◽

Rafael Orti-Rodriguez ◽

Theodora Pissanou ◽

Dinesh Sharma ◽

...

Keyword(s):

Overall Survival ◽

Liver Resection ◽

Elderly Patients ◽

Liver Metastases ◽

Colorectal Liver Metastases ◽

Major Hepatectomy ◽

Major Liver Resection ◽

Primary Tumor Site ◽

Group A

The purpose of this retrospective study was to investigate whether patients over 70 years old are at significantly higher risk for worse outcomes following major liver resection. Hepatic resection is the only treatment offering long-term survival for patients with colorectal liver metastases. As the population considered for metastasectomy is aging, there are still controversial published results regarding the safety of major hepatectomy in elderly patients. Between December 2002 and April 2010, 327 patients underwent major liver resection for colorectal liver metastasis. Patients were stratified into 2 groups: group A, <70 years old; and group B, ≥70 years old. Recorded, analyzed, and compared data across groups included the following: (1) patient characteristics including age, sex, American Society of Anesthesiologists performance status, primary tumor site and stage, adjuvant chemotherapy, number and size of metastatic lesions; (2) perioperative data including extent of resection, in-hospital mortality, postoperative morbidity, length of hospital stay, length of intensive treatment unit stay and blood loss; and (3) overall survival. The patients' characteristics were similar as were the characteristics of their tumors. There was no difference in overall morbidity (25% versus 22%) or postoperative mortality (2.6% versus 2.9%) (P = 0.44 and 0.57, respectively). The overall survival was 67% versus 62% in group A and B, respectively (P = 0.09). Elderly patients can safely undergo major liver resection for colorectal liver metastases with short- and long-term outcomes comparable with younger patients.

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