[Show abstract][Hide abstract] ABSTRACT: To investigate survival, efficacy, and safety of selective internal yttrium-90 radioembolization therapy (Y-SIRT) in patients with unresectable metastatic melanoma (MM) to liver refractory to systemic therapy.
[Show abstract][Hide abstract] ABSTRACT: Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts-including physicians, nurses, and patient advocates-to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.
[Show abstract][Hide abstract] ABSTRACT: Metastatic melanoma is difficult to treat, and often portends a grim prognosis. For patients with cerebral metastases, the prognosis is even more dire. Systemic immunotherapy and targeted agents are emerging as the mainstay of treatment for metastatic melanoma. Although immunotherapy has been shown to prolong relapse-free survival and long-term control of micrometastatic disease, the response rate is suboptimal, prompting the need to optimize and improve therapy. Accumulating evidence suggests that in addition to effective locoregional control, radiation therapy (RT) may induce immune activation and expansion of T lymphocytes recognizing melanocyte-specific antigens including activated cytotoxic T lymphocytes that can potentially kill melanoma cells. In some cases, RT contributes to the clearance of metastatic disease in distant, nonirradiated regions, a bystander phenomenon called the abscopal effect. Here, we evaluate the potential promise of ablative radiation treatment in the era of modern immunotherapy by presenting a patient with metastatic melanoma who remained disease free for over 3 years after an initial diagnosis of advanced metastatic melanoma with brain, subcutaneous tissue, mesenteric, pelvic, and retroperitoneal involvement. The patient failed initial stereotactic radiosurgery, but responded to whole-brain RT in combination with interleukin-2 immunotherapy. Thus, combination RT with immunotherapy may be synergistic by promoting the release and processing of melanoma antigens that can be presented by dendritic cells. This in turn may augment the response to therapies that center on expansion and/or activation of antitumor T cells.
American journal of clinical oncology 05/2013; · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-2, a T-cell cytokine used to treat malignant melanoma, can induce profound depression. To determine whether pretreatment with the antidepressant escitalopram could reduce IL-2-induced neuroendocrine, immune, and neurobehavioral changes, 20 patients with Stage IV melanoma were randomized to either placebo or the serotonin reuptake inhibitor, escitalopram (ESC) 10-20 mg/day, two weeks prior to, and during IL-2 treatment [720 000 units/kg q8 hrs X 5 days (1 cycle) every 3 weeks X 4 cycles]. Generalized estimation equations were used to examine HPA axis activity (plasma ACTH and cortisol), immune activation (plasma IL-6), and depressive symptoms [Hamilton Depression Rating Scale (HDRS) score]. Tolerance of IL-2 treatment (concomitant medications required) and adherence (number of IL-2 doses received) were also assessed. Both groups [ESC (n=9), placebo (n=11)] exhibited significant IL-2-induced increases in plasma cortisol, IL-6, and depressive symptoms (p<0.05), as well as a temporal trend for increases in plasma ACTH (p=0.054); the effects of age and treatment were not significant. Higher plasma ACTH concentrations were associated with higher depressive symptoms during cycles 1-3 of IL-2 therapy (p<0.01). Though ESC had no significant effects on ACTH, cortisol, IL-6, tolerance of, or adherence to IL-2, ESC treatment was associated with lower depressive symptoms, i.e., a maximal difference of ~3 points on the HDRS, which, though not statistically significant (in part due to small sample size), represents a clinically significant difference according to National Institute for Health and Clinical Excellence guidelines. A larger sample size will establish whether antidepressant pretreatment can prevent IL-2- induced neurobehavioral changes.Neuropsychopharmacology accepted article preview online, 10 April 2013; doi:10.1038/npp.2013.85.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 04/2013; · 8.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES:: Brain metastases (BM) cause significant morbidity and mortality in patients with melanoma. We aimed to identify prognostic factors for overall survival (OS) in patients undergoing stereotactic radiosurgery (SRS) for BM from melanoma. METHODS:: We identified 135 patients treated with SRS at Emory University between 1998 and 2010 for BM from melanoma. We recorded patient age, number and size of all BM, Karnofsky Performance Status (KPS), presence of extracranial metastases, serum lactate dehydrogenase (LDH), use of whole-brain radiation therapy (WBRT), use of temozolomide, and surgical resection of BM. We used the Kaplan-Meier method to calculate OS, and we compared time-to-event data with the log-rank test. We performed Cox multivariate analysis to identify factors independently associated with OS. RESULTS:: Median OS for all patients was 6.9 months. Patients with KPS≥90, 70 to 80, and <70 had median OS of 10.4, 6.1, and 4.5 months, respectively (P=0.02). Patients with LDH<240 had median OS of 7.8 months versus 3.5 months for LDH≥240 (P=0.01). Patients receiving WBRT had median OS of 7.3 months versus 6.5 months for patients not receiving WBRT (P=0.05). KPS and LDH (but not WBRT) were significantly associated with OS on multivariate analysis. CONCLUSIONS:: In addition to previously identified prognostic factors for OS in patients with BM from melanoma, serum LDH is independently associated with OS. If this finding is confirmed in a prospective manner, the serum LDH level should be included in future prognostic algorithms for patients with melanoma and BM who are to receive SRS.
American journal of clinical oncology 02/2013; · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: CTLA4 blocking monoclonal antibodies provide a low frequency but durable tumor responses in patients with metastatic melanoma, which led to the regulatory approval of ipilimumab based on two randomized clinical trials with overall survival advantage. The similarly fully human anti-CTLA4 antibody tremelimumab had been developed in the clinic at a fixed rate infusion, resulting in very prolonged infusion times. A new formulation of tremelimumab allowed testing a shorter infusion time. METHODS: A phase 1 multi-center study to establish the safety and tolerability of administering tremelimumab as a 1-hour infusion to patients with metastatic melanoma. Secondary endpoints included pharmacokinetic and clinical effects of tremelimumab. RESULTS: No grade 3 or greater infusion-related adverse events or other adverse events preventing the administration of the full tremelimumab dose were noted in 44 treated patients. The overall side effect profile was consistent with prior experiences with anti-CTLA4 antibodies. Objective tumor responses were noted in 11% of evaluable patients with metastatic melanoma, which is also consistent with the prior experience with CTLA4 antagonistic antibodies. CONCLUSIONS: This study did not identify any safety concerns when tremelimumab was administered as a 1-hour infusion. These data support further clinical testing of the 1-hour infusion of tremelimumab. (Clinical trial registration number NCT00585000).
Journal of Translational Medicine 11/2012; 10(1):236. · 3.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the prognostic value of (18)F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) in predicting survival in patients with unresectable metastatic melanoma to the liver undergoing yttrium-90 ((90)Y) radioembolization.
A retrospective review of 12 patients with unresectable hepatic melanoma metastases (5 patients with cutaneous metastases, 7 patients with ocular metastases) who underwent (18)F-FDG PET-CT before (90)Y was performed. Metabolically significant tumors, defined as having a long-axis diameter ≥ 1 cm and maximum standardized uptake value (SUV(max)) ≥ 2.5, were identified on (18)F-FDG PET-CT. SUV(max), glycolytic activity, and volume were determined for each tumor. Overall SUV(max), total tumor glycolytic activity (TGA), total metabolic tumor volume (MTV), and metabolic tumor burden (MTB) based on percentage of liver involvement (MTV/total liver volume) were calculated. Kaplan-Meier method, life-table analysis, and Cox proportional hazards model were used for statistical analysis.
Median SUV(max) was 10.9 (range, 4.6-15.3), median TGA was 377.0 SUV/cm(3) (range, 53.6-20,393.4 SUV/cm(3)), median MTV was 85.4 cm(3) (range, 11.5-2,504.1 cm(3)), and median MTB was 5.5% (range, 0.1%-54.0%). MTB was found to be a significant negative prognostic marker of survival on univariate (P = .020) and multivariate (P = .018) analyses accounting for age and duration from metastatic diagnosis to first (90)Y treatment. A 60th percentile MTB of 7.0% (hazard ratio, 5.704; P = .040) was a statistically significant cutoff. Median survivals from first (90)Y treatment in patients with MTB < 7.0% and ≥ 7.0% were 10.8 months (95% confidence interval [CI], 6.8-14.8) and 4.7 months (95% CI, 1.6-7.8), respectively. SUV(max) (P = .422), TGA (P = .064), and MTV (P = .065) were not found to be statistically significant.
MTB based on (18)F-FDG PET-CT performed before treatment was found to be a negative prognostic factor for patient survival after (90)Y radioembolization for unresectable metastatic melanoma to liver.
Journal of vascular and interventional radiology: JVIR 05/2012; 23(7):943-8. · 1.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. While it is established that the incidence of cutaneous melanoma has risen over time in the United States, the incidence trend for mucosal melanoma of the head and neck (MMHN) is unknown. Methods. We used the Surveillance, Epidemiology, and End Results (SEER) database to determine incidence trends for MMHN from 1987 to 2009 in the United States. We determined annual percent change (APC) by weighted least squares and joinpoint regression analysis. Results. MMHN incidence increased from 1987 to 2009 (APC 2.4%; P < 0.01). Nasal cavity lesions increased in incidence (APC 2.7%; P < 0.01) over this duration, while the incidence of non-nasal cavity lesions remained stable. The highest rate of increase was in white females ages 55 to 84 (APC 5.1%; P = 0.01). Conclusions. The incidence of MMHN in the United States has been rising since 1987. This trend is driven primarily by increased incidence of nasal cavity melanomas.
[Show abstract][Hide abstract] ABSTRACT: α(v) integrins are involved in angiogenesis and melanoma tumourigenesis. Intetumumab (CNTO 95) is a fully human anti-α(v)-integrin monoclonal antibody.
In a multicentre, randomised, phase II study, stage IV melanoma patients were randomised 1:1:1:1 to 1000 mg m(-2) dacarbazine+placebo (n=32), 1000 mg m(-2) dacarbazine+10 mg kg(-1) intetumumab (n=32), 10 mg kg(-1) intetumumab (n=33), or 5 mg kg(-1) intetumumab (n=32) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), adverse events, and pharmacokinetics.
No statistically significant differences in efficacy were observed between groups. In the dacarbazine+placebo, dacarbazine+intetumumab, 10 mg kg(-1) intetumumab, and 5 mg kg(-1) intetumumab groups, median PFS was 1.8, 2.5, 1.4, and 1.4 months; median OS was 8, 11, 15, and 9.8 months; and ORR of complete+partial response was 10, 3, 6, and 0%. Nonlinear intetumumab pharmacokinetics and potential intetumumab-dacarbazine interactions were observed. Transient, asymptomatic, nonrecurring, grade 1-2, uveitic reactions that resolved spontaneously or with topical steroids were seen in 22-30% of intetumumab-treated patients. Low-grade infusion-reaction symptoms (headache, fatigue, nausea, vomiting, fever, chills) were observed, as expected, in 16-73% of dacarbazine-treated patients. No intetumumab-related myelosuppression, laboratory/electrocardiogram abnormalities, or deaths occurred.
With its favourable safety profile and a nonsignificant trend towards improved OS, intetumumab merits further investigation in advanced melanoma.
British Journal of Cancer 07/2011; 105(3):346-52. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone.
We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival.
The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine-interleukin-2 group, as compared with the interleukin-2-only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P=0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P=0.008). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P=0.06).
In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.).
New England Journal of Medicine 06/2011; 364(22):2119-27. · 54.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Atypical spitzoid melanocytic neoplasms (ASMN) are cutaneous lesions of uncertain malignant potential, which can be difficult to distinguish from cutaneous melanoma. Sentinel lymph node (SLN) biopsy is a safe and useful prognostic tool for staging melanoma, but its role in staging ASMNs is not established nor is the significance of positive SLNs in these patients known. This study attempts to characterize the significance of nodal disease in ASMN.
Patients with ASMNs who presented to the melanoma service from 1992 to 2007 were identified from a prospective database. Histological review was performed by two dermatopathologists. Demographic, treatment, and outcome data were reviewed.
A total of 58 patients with ASMNs were treated during the time analyzed; 31 (53%) underwent wide local excision and observation (WLE); 27 underwent wide excision and SLN biopsy. Median age was 24 (range, 6-60) years. Mean Breslow thickness was 2.9 (range, 0.5-10) mm. Median follow-up was 56 (range, 1-160) months. Ten of 58 (17%) patients had nodal metastasis. Four (13%) of 31 patients who underwent WLE developed nodal recurrences, and 6 of 27 (22%) patients had a positive SLN biopsy. Of patients with positive SLNs, none have recurred after undergoing completion lymphadenectomy. One patient presented with synchronous brain metastasis and inguinal lymphadenopathy and died of disease.
Nodal status does not seem to convey the same prognosis that it does in standard melanoma. There may be a limited ability for progression within the nodal basin in patients with these lesions. This subset of patients would benefit from genetic data complementing histologic analysis.
Annals of Surgical Oncology 03/2010; 17(9):2471-5. · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Melanoma continues to be a major health problem with no effective therapy. Melanocytes, both benign and malignant, express many anti-apoptotic factors. Survivin is a member of the family of inhibitors of apoptosis proteins (IAP) and is preferentially expressed in tumor cells, including melanoma. YM155 is a small molecule suppressant of survivin that has been shown in preclinical cell lines, xenograft models and phase I studies to have anti-tumor activity.
This was an open-label, multi-center, study of YM155 monotherapy in subjects with unresectable stage III or IV melanoma. Thirty-four chemotherapy naïve subjects were treated with YM155 at a dose of 4.8 mg/m(2)/day administered by continuous infusion for 168-hours (7 days) followed by a 14-day rest period, for up to 6 cycles or until disease progression.
One subject had a partial response to treatment seen at cycle two and lasting through cycle eight. Median progression-free survival was 1.3 months (95% CI; 1.3-2.7). Median overall survival was 9.9 months (95% CI; 7.0-14.5). Overall, YM155 was well tolerated with the most common (>20%) adverse events reported as fatigue, nausea, pyrexia, headache, arthralgia and back pain. Only four subjects required dose reductions.
YM155 was well tolerated in subjects with advanced melanoma; however, the pre-specified primary end-point for efficacy which required two responders in 29 evaluable subjects was not achieved.
Investigational New Drugs 10/2009; 29(1):161-6. · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Elesclomol is a novel, small-molecule, oxidative stress inducer believed to exert selective cytotoxicity by increasing intracellular concentrations of reactive oxygen species, which results in cell death via mitochondrial apoptosis. We evaluated whether the addition of elesclomol to weekly paclitaxel could improve efficacy in patients with stage IV metastatic melanoma.
We randomly assigned patients with metastatic melanoma, measurable disease, and one or fewer prior chemotherapy regimens to elesclomol 213 mg/m(2) plus paclitaxel 80 mg/m(2) (E + P) or to paclitaxel 80 mg/m(2) alone at a 2:1 ratio; regimens were given as a 1-hour intravenous infusion weekly, during 3 of every 4 weeks until disease progression per Response Evaluation Criteria in Solid Tumors or death occurred. Patients who experienced progression were unblended, and patients on paclitaxel alone were permitted to cross over to E + P. The primary efficacy end point was progression-free survival (PFS); secondary end points were response rate (RR), toxicity, and overall survival (OS; analyzed post hoc).
At 21 US sites, 53 patients were randomly assigned to E + P, and 28 patients were randomly assigned to paclitaxel. The addition of elesclomol to paclitaxel yielded a doubling of median PFS (112 v 56 days) and a 41.7% risk reduction for disease progression/death (hazard ratio, 0.583; P = .035). Respective RRs for the E + P and paclitaxel groups were 15% and 3%; median OS was 11.9 v 7.8 months. Of patients on paclitaxel alone, 19 (68%) of 28 crossed over to E + P after they experienced progression. Weekly E + P was well tolerated.
E + P resulted in a statistically significant doubling of median PFS, with an acceptable toxicity profile and encouraging OS. A multinational, phase III trial (SYMMETRY) of E + P compared with paclitaxel alone in metastatic melanoma has closed.
Journal of Clinical Oncology 10/2009; 27(32):5452-8. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interferon-alpha therapy, which is used to treat metastatic malignant melanoma, can cause patients to develop two distinct neurobehavioral symptom complexes: a mood syndrome and a neurovegetative syndrome. Interferon-alpha effects on serotonin metabolism appear to contribute to the mood and anxiety syndrome, while the neurovegetative syndrome appears to be related to interferon-alpha effects on dopamine.
Our goal is to propose a design for utilizing a sequential, multiple assignment, randomized trial design for patients with malignant melanoma to test the relative efficacy of drugs that target serotonin versus dopamine metabolism during 4 weeks of intravenous, then 8 weeks of subcutaneous, interferon-alpha therapy.
Patients will be offered participation in a double-blinded, randomized, controlled, 14-week trial involving two treatment phases. During the first month of intravenous interferon-alpha therapy, we will test the hypotheses that escitalopram will be more effective in reducing depressed mood, anxiety, and irritability, whereas methylphenidate will be more effective in diminishing interferon-alpha-induced neurovegetative symptoms, such as fatigue and psychomotor slowing. During the next 8 weeks of subcutaneous interferon therapy, participants whose symptoms do not improve significantly will be randomized to the alternate agent alone versus escitalopram and methylphenidate together.
We present a prototype for a single-center, sequential, multiple assignment, randomized trial, which seeks to determine the efficacy of sequenced and targeted treatment for the two distinct symptom complexes suffered by patients treated with interferon-alpha.
Because we cannot completely control for external factors, a relevant question is whether or not 'short-term' neuropsychiatric interventions can increase the number of interferon-alpha doses tolerated and improve long-term survival.
This sequential, multiple assignment, randomized trial proposes a framework for developing optimal treatment strategies; however, additional studies are needed to determine the best strategy for treating or preventing neurobehavioral symptoms induced by the immunotherapy interferon-alpha.
[Show abstract][Hide abstract] ABSTRACT: A 42-year-old white woman with a diagnosis of metastatic melanoma developed severe neutropenia during treatment with ipilimumab (anticytotoxic T-lymphocyte-associated antigen-4 antibody). Bone marrow aspiration and biopsy specimens revealed marked myeloid hypoplasia, with unremarkable erythropoiesis and megakaryopoiesis. The patient's neutropenia did not respond to therapy with a combination of colony stimulating factors and steroids; however, it rapidly improved after administration of intravenous immunoglobulin. Treatment with ipilimumab has not been reported to be associated with hematologic toxicities, and to our knowledge, no case of neutropenia has previously been reported. This report of acute grade 4 neutropenia associated with ipilimumab and clinically consistent with an autoimmune process emphasizes the importance of monitoring complete blood count during treatment with this new monoclonal antibody.
[Show abstract][Hide abstract] ABSTRACT: Accurate assessment of estrogen receptor (ER), progesterone receptor (PR), and Her2 status of breast carcinomas is critical for predicting response to systemic therapies. Recently, developed rabbit monoclonal antibodies (RMab) are reported to have higher sensitivity than murine monoclonal antibodies (Mab). This study compares RMabs against FDA-approved Mab (FMab) in breast carcinoma cell block sections using visual and image quantification. Cell blocks from 52 breast cancers were studied. Immunohistochemistry using RMab (ER, PR, and Her2) was compared with FMabs (ER, PR, Dako) and HercepTest (HerFDA). Fluorescent in situ hybridization (FISH) was used as a reference standard for Her2. Slides were later scanned and reanalyzed with an automated cellular imaging system (ACIS III, Dako). Frequency of ER (38.5% vs. 36.5% for visual; 55.8% vs. 57.7% for image) and PR (28.8% vs. 36.5% for visual; 50% vs. 51.9% for image), and concordance (overall agreement is 71.2% and 75% for visual and image ER; and 84.6% and 59.6% for visual and image PR) were similar for both FMab and RMab, respectively. Overall agreement (53.8% vs. 77.1% for visual and image detection, respectively, using HerFDA and RMab) is poor to moderate for Her2. Visual Her2 (RMab) has the highest concordance (94.1%), and visual HerFDA has the lowest concordance (35.3%) with FISH. ER and PR analysis (FMab vs. RMab) are almost comparable using both detection methods with good overall agreement. For Her2 overexpression, RMab proved to be superior to HerFDA and showed excellent agreement with FISH results with both quantitative detection methods.