[Show abstract][Hide abstract] ABSTRACT: Background Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront identification of patients
who are more likely or unlikely to benefit from treatment is a major need.
Full-text · Article · Jan 2016 · Annals of Oncology
[Show abstract][Hide abstract] ABSTRACT: Approximately 50% of patients with uveal melanoma (UM) will develop metastatic disease, usually involving the liver. The outcome of metastatic UM (mUM) is generally poor and no standard therapy has been established. Additionally, clinicians lack a validated prognostic tool to evaluate these patients. The aim of this work was to develop a reliable prognostic nomogram for clinicians.
Two cohorts of mUM patients, from Veneto Oncology Institute (IOV) (N=152) and Mayo Clinic (MC) (N=102), were analyzed to develop and externally validate, a prognostic nomogram.
The median survival of mUM was 17.2 months in the IOV cohort and 19.7 in the MC cohort. Percentage of liver involvement (HR 1.6), elevated levels of serum LDH (HR 1.6), and a WHO performance status=1 (HR 1.5) or 2-3 (HR 4.6) were associated with worse prognosis. Longer disease-free interval from diagnosis of UM to that of mUM conferred a survival advantage (HR 0.9). The nomogram had a concordance probability of 0.75 (SE .006) in the development dataset (IOV), and 0.80 (SE .009) in the external validation (MC). Nomogram predictions were well calibrated.
The nomogram, which includes percentage of liver involvement, LDH levels, WHO performance status and disease free-interval accurately predicts the prognosis of mUM and could be useful for decision-making and risk stratification for clinical trials.
[Show abstract][Hide abstract] ABSTRACT: We retrospectively evaluated the benefit of transarterial chemoembolization with CPT-11 charged microbeads (TACE) in 58 of 141 uveal melanoma patients with liver metastases.
This was a retrospective analysis of a prospectively maintained database ranging from September 1990 to April 2014. Statistical analyses adjusting for possible confounding effects of extent of liver metastases were carried out using the Cox regression model under the verified hypothesis of proportional hazards.
Among 141 patients with liver metastases, 58 were treated with TACE as first-line therapy and 36 were dead at the time of the analysis; 83 patients received other first-line treatments (deaths=83). The treatment with TACE conferred a survival advantage (median 16.5 vs. 12.2 months, respectively); when the two cohorts were analyzed comparing the two groups according to the percentage of liver involvement, there was significant evidence that patients with worse hepatic involvement benefited most from the treatment (liver metastases=20-50%: hazard ratio=0.50, P=0.048 and liver metastases ≥50%: hazard ratio=0.17, P=0.009). Liver function tests (transaminases and γ-glutamyl-transpeptidase) and age were higher in the historic group, and LDH tended to show higher values. There were no high-grade toxicities with TACE.
TACE seems to be a tolerable regimen that confers an improvement in the survival of uveal melanoma patients with liver metastases. Confirmation of the clinical efficacy of TACE is recommended in a phase III trial, possibly with the inclusion of a targeted therapy such as a MEK inhibitor.
No preview · Article · Dec 2014 · Melanoma Research
[Show abstract][Hide abstract] ABSTRACT: The impact of BRAF mutations in metastatic melanoma on the incidence of brain metastases and melanoma prognosis and the effect of BRAF inhibitors on the incidence of brain metastases has not been defined. Therefore, a retrospective analysis of patients with metastatic melanoma treated at three institutions was carried out to examine the impact of BRAF mutations and a BRAF inhibitor, vemurafenib, on the incidence of brain metastases. A retrospective review of 436 records revealed no difference in the incidence of brain metastases between patients with BRAF-mutated tumors versus those without (incidence rate ratio=1.11, 95% confidence interval: 0.80-1.53; P=0.53). A lower incidence of brain metastases was observed in patients with BRAF-mutated tumors who took vemurafenib before the development of brain metastases versus those who did not (incidence rate ratio=0.51, 95% confidence interval: 0.30-0.86; P=0.009). Although treatment with vemurafenib led to improvement in extracranial disease control, it did not significantly affect progression of existing intracranial disease and survival in these patients (P=0.7). Although our previous preclinical data have indicated that penetration of vemurafenib into the brain is limited, our retrospective analysis showed that there was a lower incidence of brain metastases in patients with BRAF-mutated tumors who took vemurafenib before the diagnosis of brain metastases.
Full-text · Article · Nov 2014 · Melanoma Research
[Show abstract][Hide abstract] ABSTRACT: Background. Small molecules that inhibit V600 mutated BRAF protein, such as vemurafenib and dabrafenib, are effective in treatment of metastatic melanoma.
Case report. We here describe the clinical course of a V600E BRAF mutated metastatic melanoma patient with systemic disease, who developed tumor progression on superficial soft-tissue metastases during treatment with dabrafenib. Bleomycin electrochemotherapy during dabrafenib treatment was administered to control the soft-tissue progressing metastases and ensured sustained local control without significant toxicity.
Conclusions. The new combined approach maintained the patient quality of life and allowed for the prosecution of the target therapy, which proved to be still effective on systemic disease, up to 17 months.
Full-text · Article · Jul 2014 · Radiology and Oncology
[Show abstract][Hide abstract] ABSTRACT: This article reviews the epidemiology, pathogenesis, diagnosis, prognostic factors and treatment of metastatic melanoma, including the most recent developments in the specific field. It examines the sequential and non-linear models of development and progression of melanoma and the main molecular disorder involved in these processes. Clinical and diagnostic aspects have been divided according to clinical staging. Surgical resectability, the site and number of metastases, the number of involved organs, the duration of remission, serum lactate dehydrogenase levels and tumor doubling-time have the greatest prognostic value. Surgical treatment has been analyzed considering its rational function and examining all sites involved in metastasis. We also discuss the palliative role of radiotherapy in relation to various metastatic sites, chemotherapy and recently introduced targeted-therapy. The association of newer drugs and new biological therapies such as ipilimumab and verumafenib have improved the treatment landscape of stage IV melanoma.
No preview · Article · May 2014 · In vivo (Athens, Greece)
[Show abstract][Hide abstract] ABSTRACT: Background
Ipilimumab improves survival in patients with advanced melanoma. The activity and safety of ipilimumab outside of a clinical trial was assessed in an expanded access programme (EAP).
Ipilimumab was available upon physician request for patients aged 16 or over with pretreated stage III (unresectable)/IV melanoma, for whom no other therapeutic option was available. Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. Patients with stable disease or an objective response to ipilimumab were eligible for retreatment upon disease progression. Tumour assessments were conducted at baseline and week 12. Patients were monitored for adverse events (AEs) within 3 to 4 days of each scheduled visit.
Of 855 patients participating in the EAP in Italy, 833 were evaluable for response. Of these, 13% had an objective immune response, and the immune-related disease control rate was 34%. Median progression-free survival and overall survival were 3.7 and 7.2 months, respectively. Efficacy was independent of BRAF and NRAS mutational status. Overall, 33% of patients reported an immune-related AE (irAE). The frequency of irAEs was not associated with response to ipilimumab.
Outside of a clinical trial setting, ipilimumab is a feasible treatment option in patients with pretreated metastatic melanoma, regardless of BRAF and NRAS mutational status. Data from this large cohort of patients support clinical trial evidence that ipilimumab can induce durable disease control and long-term survival in patients who have failed to respond to prior treatment.
Full-text · Article · May 2014 · Journal of Translational Medicine
[Show abstract][Hide abstract] ABSTRACT: Elderly patients with metastatic melanoma have different disease characteristics and a poorer prognosis than younger patients. Data from clinical trials and expanded access programmes (EAPs) suggest ipilimumab confers a consistent survival benefit and has a similar safety profile across different age groups of patients with metastatic melanoma. Here we report the efficacy and safety of ipilimumab 3 mg/kg in elderly patients enrolled in an EAP in Italy.
Patients aged > 70 years with pretreated melanoma received ipilimumab 3 mg/kg every 3 weeks for four doses through an EAP. Tumour response was evaluated at baseline and after completion of induction therapy using immune-related response criteria and patients were monitored throughout the treatment period for adverse events (AEs), including immune-related AEs.
The immune-related disease control rate among 188 evaluable patients was 38%, including four patients with an immune-related complete response, 24 with an immune-related partial response and 44 with immune-related stable disease. Median progression-free survival (PFS) was 4.0 months and the 1- and 2-year PFS rates were 21% and 12%, respectively. Median overall survival (OS) was 8.9 months; 1- and 2-year OS rates were 38% and 22%, respectively. The safety profile of ipilimumab was consistent with that observed in the general population of the Italian EAP and treatment-related AEs generally resolved within a median of 2 weeks with treatment as per protocol-specific guidelines.
These results suggest ipilimumab is a feasible treatment option in elderly patients with metastatic melanoma. Ipilimumab treatment was generally well tolerated and resulted in clinical benefit and extended survival in elderly patients treated at centres in Italy.
Full-text · Article · Apr 2014 · Journal of Experimental & Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: Background:
Retreatment with ipilimumab has been shown to re-establish disease control in some patients with disease progression. Here, we report the efficacy and safety of retreatment with ipilimumab 3 mg kg−1 among patients participating in an expanded access programme in Italy.
Patients who achieved disease control during induction therapy were retreated with ipilimumab upon progression (3 mg kg−1 every 3 weeks for up to four doses), providing they had not experienced toxicity that precluded further dosing. Tumour assessments were conducted after retreatment, and patients were monitored throughout for adverse events.
Of 855 patients treated with ipilimumab, 51 were retreated upon disease progression. Of these, 28 (55%) regained disease control upon retreatment and 42% were alive 2 years after the first induction dose of ipilimumab; median overall survival was 21 months. Eleven patients (22%) had a treatment-related adverse event of any grade during retreatment. These were generally mild-to-moderate and resolved within a median of 4 days. No new types of toxicity were reported.
For patients who meet predefined criteria, retreatment with ipilimumab is generally well tolerated and can translate into clinical benefit. This strategy should be compared with other therapeutic options in randomised controlled trials.
Full-text · Article · Mar 2014 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: Patients with melanoma brain metastases have a poor prognosis and historically have been excluded from clinical trials. The Expanded Access Program (EAP) provided an opportunity to evaluate the feasibility of ipilimumab (3 mg/kg every 3 weeks for four doses) in patients with stage 3 (unresectable) or 4 melanoma and asymptomatic brain metastases, who had failed or did not tolerate previous treatments and had no other therapeutic option available. Tumor assessments were conducted at baseline and week 12 using immune-related response criteria and patients were monitored for adverse events (AEs). Of 855 patients participating in the EAP in Italy, 146 had asymptomatic brain metastases. With a median follow-up of 4 months, the global disease control rate was 27 %, including 4 patients with a complete response and 13 with a partial response. Median progression-free survival and overall survival were 2.8 and 4.3 months, respectively and approximately one-fifth of patients were alive 1 year after starting ipilimumab. In total, 29 % of patients reported a treatment-related AE of any grade, which were grade 3/4 in 6 % of patients. AEs were generally reversible with treatment as per protocol-specific guidelines. Ipilimumab shows durable benefits in some patients with advanced melanoma metastatic to the brain, with safety results consistent with those previously reported in clinical trials.
Full-text · Article · Feb 2014 · Journal of Neuro-Oncology
[Show abstract][Hide abstract] ABSTRACT: Mucosal melanoma is an extremely rare and aggressive malignancy that often remains undetected until it reaches an advanced stage, when effective treatment options are limited. The activity and safety of ipilimumab were assessed in an Expanded Access Programme (EAP) that included patients with metastatic, mucosal melanoma.
Ipilimumab was available upon physician request for patients aged ⩾16years with stage III (unresectable) or IV skin, ocular or mucosal melanoma, who had failed or did not tolerate previous treatments and had no other therapeutic option available. Patients received ipilimumab 3mg/kg every 3weeks for four doses. Patients with stable disease or an objective response to ipilimumab were eligible for retreatment upon disease progression. Tumour assessments were conducted at baseline and week 12 using immune-related response criteria. Patients were monitored for adverse events (AEs), including immune-related AEs, within 3 to 4days of each scheduled visit.
Of 855 patients participating in the EAP in Italy, 71 (8%) had metastatic, mucosal melanoma. With a median follow-up of 21.8months, the response rate was 12% and the immune-related disease control rate was 36%. Median progression-free survival and overall survival were 4.3 and 6.4months, respectively. In total, 34% of patients reported treatment-related AEs of any grade, which were grade 3 or 4 in 9% of patients. AEs were generally manageable as per protocol-specific guidelines.
Ipilimumab may be a feasible treatment option in pretreated patients with metastatic mucosal melanoma, and warrants further investigation in prospective clinical trials.
No preview · Article · Oct 2013 · European journal of cancer (Oxford, England: 1990)
[Show abstract][Hide abstract] ABSTRACT: Patients with advanced uveal melanoma have a poor prognosis and limited treatment options. Ipilimumab is approved for pre-treated adult patients with advanced melanoma. However, because previous clinical trials with ipilimumab have excluded patients with uveal melanoma, data in this patient population are limited.
Pre-treated patients with advanced uveal melanoma received ipilimumab 3 mg/kg through an expanded access programme, every 3 weeks for four doses. Tumour assessments were conducted at baseline and after completion of treatment and patients were monitored throughout for adverse events.
Among 82 assessable patients, 4 (5%) had an immune-related objective response and 24 (29%) had immune-related stable disease lasting ≥3 months for an immune-related disease control rate of 34%. With a median follow-up of 5.6 months, median overall survival (OS) was 6.0 months and median progression-free survival (PFS) was 3.6 months. The 1-year rates of OS and PFS were 31% and 11%, respectively. The safety profile of ipilimumab was similar to that in patients with cutaneous melanoma.
These data suggest ipilimumab 3 mg/kg is a feasible option in pre-treated patients with metastatic uveal melanoma. Evidence of disease control and a 1-year survival rate of 31% indicate the need for further investigation in randomised, controlled trials to determine the optimal timing and use of ipilimumab in this patient population.
No preview · Article · Sep 2013 · Annals of Oncology
[Show abstract][Hide abstract] ABSTRACT: Paraneoplastic cerebellar degeneration (PCD) is characterized by subacute development of pancerebellar dysfunction as a remote effect of a systemic cancer and usually develops in patients affected by gynecological tumors. Uveal melanoma is a very rare disease with a severe prognosis. A 58-year-old man affected by uveal melanoma developed anti-Yo positive paraneoplastic cerebellar degeneration (PCD) 42months after the initial diagnosis. The onset and worsening of the neurological symptoms were parallel to the course of liver metastasis. To our knowledge this is the first case of PCD in a patient with uveal melanoma. We speculate that the cerebellar degeneration-related protein 2 (CDR2), to which the anti-Yo antibodies are directed, may have been expressed in melanoma cells and conferred proliferative advantage to the disease.
Full-text · Article · Aug 2013 · Journal of the neurological sciences
[Show abstract][Hide abstract] ABSTRACT: Background
In recent decades, melanoma incidence has been increasing in European countries; in 2006, there were approximately 60,000 cases leading to 13,000 deaths. Within Europe there is some geographical variation in the incidence of melanoma, with the highest rates reported in Scandinavia (15 cases per 100,000 inhabitants per year) and the lowest in the Mediterranean countries (5 to 7 cases per 100,000 inhabitants per year).
The present article is based on the information collected in the MELODY study (MELanoma treatment patterns and Outcomes among patients with unresectable stage III or stage IV Disease: a retrospective longitudinal survey).
In that study, the medical charts of patients were reviewed to document current treatment patterns and to analyse information on patients, disease characteristics and healthcare resource utilization related to the treatment of advanced melanoma regarding patients who presented with a diagnosis of malignant melanoma (stage I to IV) at participating sites between 01 July, 2005 and 30 June, 2006.
Summarizing, though the length of the follow-up period varies among sample patients, an amount of the yearly cost per patient can be estimated, dividing the average per patient total cost (€ 5.040) by the average follow-up duration (17.5 months) and reporting to one year; on these grounds, unresectable stage III or stage IV melanoma in Italy would cost € 3,456 per patient per year.
Full-text · Article · Nov 2012 · Journal of Experimental & Clinical Cancer Research