Adjuvant Sunitinib in High-Risk Patients with Uveal Melanoma: Comparison with Institutional Controls.

PURPOSE: To compare overall survival in high-risk patients with primary uveal melanoma who received adjuvant sunitinib with institutional controls. DESIGN: Retrospective cohort. PARTICIPANTS: Selection criteria were (1) monosomy 3 and 8q amplification by cytogenetic or DecisionDx-UM Class 2 and (2) monosomy 3 and large tumor size (T3-4 by American Joint Committee on Cancer classification). Exclusion criteria were date of diagnosis before 2007 or after 2013 and age <18 years. METHODS: A cohort of patients who intended to receive adjuvant sunitinib for 6 months was compared with institutional historical controls with the same risk factors. Kaplan-Meier and Cox proportional hazards models were used to analyze the outcome. Propensity score was used to adjust for nonrandom assignment to sunitinib. MAIN OUTCOME MEASURES: Overall survival. RESULTS: From the Wills Eye Hospital Oncology Service Uveal Melanoma Cytogenetic Database (N = 1172), 128 patients fulfilled the selection and exclusion criteria. Median follow-up was 52.7 months (range, 0.26-108 months). A total of 54 patients received sunitinib. Their median age was 56 years (range, 29-81 years), and 48% were men. A total of 74 historical controls in the same risk category were identified. Their median age was 62 years (21-80 years), and 48% were men. Patients in the sunitinib group had worse cytogenetic or molecular features (monosomy 3 and 8q amplification or class 2 87% vs. 57%; P < 0.001), had smaller tumor sizes (T3-4 56% vs. 83%; P = 0.001), and were younger. There were 51 deaths, 14 (26%) in the sunitinib group and 37 (50%) in the control group. In the univariate analysis, the sunitinib group had longer overall survival (hazard ratio, 0.53; 95% confidence interval, 0.29-0.99; P = 0.041). In multivariate Cox regression analysis, interaction between use of sunitinib and age as a dichotomous variable was highly significant (P = 0.003). The following variables were statistically associated with prediction of overall survival: cytogenetic/molecular status (P = 0.015), T-size category (P = 0.022), gender (P = 0.040), and adjuvant sunitinib in patients aged <60 years (P = 0.004). Results were confirmed by propensity score analysis. CONCLUSIONS: In this retrospective study, the use of sunitinib in the adjuvant setting was associated with better overall survival.

What is the Current Role of Immunotherapy for Colon Cancer?

Colon cancer is a leading cause of cancer related mortality. Until very recently the only existing options that medical oncologists had to treat metastatic colon cancer were a combination of chemotherapy, anti-EGFR and anti-angiogenic agents. We currently have the first proof that immune therapies could be an effective approach to battle colorectal cancers that carry a mismatch repair machinery deficient phenotype. It is expected that as our knowledge of the different mechanisms of immune-resistance grows, this therapeutic modality might soon be applicable to all patients. However, due to the continuous increase in the cost of oncological drugs, some treatment overheads may soon become prohibitive for many. In this review we will examine the current evidence related to this topic with the objective to provide the reader with concise but practical information about the potential role of immunotherapy in CRC.

Immunotherapy for Non-Small Cell Lung Cancer - Finally a Hint of Hope.

Lung cancer is a major public health problem worldwide and the leading cause of cancerrelated mortality in developed countries. Significant advances have been made especially with the discovery of targeted agents. However, only a small proportion of patients carry activating mutations; until recently conventional chemotherapy and angiogenesis inhibitors were the preferred treatment for the vast majority of patients. Now, the successful experience of anti-PD-1 agents may have opened the door to a novel and previously unexplored dimension in the treatment of lung cancer: immunotherapy. In this mini-review we will discuss the current applications and future consequences related this topic, paying special attention to the clinical studies that constitute the scientific evidence to supports its use.

Immune Check Point Inhibitors Combination in Melanoma: Worth the Toxicity?

The combination of immune checkpoint inhibitors ipilimumab and nivolumab has been recently been FDA approved for first line treatment of unresectable and metastatic BRAF wild type melanoma. The approval came following the impressive results of the CheckMate 067, where the combination of ipilimumab and nivolumab appeared to outperform each as a single agent in regards to response rate and progression free survival. Though we await final overall survival data, the combination will likely be adapted by many oncologists and integrated into the ever changing melanoma treatment algorithm. In this article we aim to summarize the data leading up to the recent FDA approval and publication by Larkin et al. that presents the results from the CheckMate 067 trial. We will also further explore the feasibility, challenges, and applicability of combination immune checkpoint inhibitor therapy.

Role of Anti-HER-2 Therapies in the Neo-Adjuvant Setting: Is Complete Pathological Response a Solid Surrogate?

Breast cancer continues to be a major health problem. Both patients and clinicians demand faster access to drugs that could result in better outcomes. In part motivated by this necessity, there has been a change in the dominant paradigm regarding how drugs become approved. Complete pathological response (pCR), understood as the absence of remanent and viable tumor after a neoadjuvant treatment, is now considered by a large proportion of the medical community as a valid surrogate. The presumption is that patients achieving pCR are less likely to develop tumor recurrence. Consequently, if a drug can improve the number of patients achieving pCR it could then obtain approval by the regulatory agencies. Pertuzumab, an anti-HER- 2 monoclonal antibody, was granted accelerated approval based on this principle. The unprecedented approval of this drug is now an example that can help us to understand the advantages but also the potential risks associated with this new approach. In this review, we will discuss the results of the two clinical trials leading to the FDA-approval of pertuzumab in the neo-adjuvant setting. We will also analyze the outcomes from long term follow up of two important neoadjuvant clinical trials, the NeoALTTO and the NOAH studies. These last ones had provided further insights regarding the magnitude, the quality as well as some limitations of the relationship between pCR and harder endpoints such as event-free or overall survival. It seems evident that the acknowledgement of pCR as a potential surrogate endpoint represents an important step in the right direction. However, it still remains controversial whether this is applicable to all subtypes of breast cancers. Additional investigations may be necessary to safely generalize this concept.

Anti-Hormonal Therapies for Premenopausal Patients--What did we Learn from the TEXT/SOFT Trials?

Between 20-25% of all breast cancers are diagnosed in patients younger than 50 years of age, most of whom are still premenopausal. Currently, tamoxifen is considered the standard of care for adjuvant treatment in these cases. However, in postmenopausal women, aromatase inhibitors (AIs) are a better choice. Given the superiority of AIs over tamoxifen in postmenopausal women, multiple investigators explored the potential role of AIs in premenopausal patients receiving ovarian suppression. Until very recently, available data derived from the ABCSG-12 clinical trial argued against the combination of AIs and ovarian suppression. This idea, however, may have changed with the release of the combined analysis of two clinical trials: SOFT and TEXT which evaluated the use of ovarian suppression in combination therapy. Clinicians will soon reconsider the possibility of using this strategy for premenopausal patients. Given the availability of this new data this review will analyze the consequences derived from this study, contextualize this new information within the vast available literature of anti-hormonal therapy, and discuss potential arguments in favor of and against the use of this approach.

Role of Carboplatin in the Treatment of Triple Negative Early- Stage Breast Cancer.

Triple negative breast cancer (TNBC) is more prevalent in younger patients and those carrying BRCA mutations. Although the incidence of breast cancer in general has dropped during the last years, TNBC has shown a relative increase. It is recognized as a breast cancer subtype with a high risk of tumor relapse and mortality. However, patients who achieve pathological complete response (pCR) with the use of neoadjuvant treatments have better prognosis and may attain cure. The lack of effective targeted therapies makes the use of conventional chemotherapy the only alternative available to fight this disease. Since many TNBCs share at least some phenotypic characteristics with germline BRCA-mutated tumors (BRCAness) cross-linking agents, such platinum salts, are particularly useful. Recently, two randomized phase 2 clinical trials support this presumption. However, improvement in pCR rates does not come free of toxicity. Given the potential change in practice associated with the generalized use of carboplatin in the neoadjuvant setting for TNBC patients, the aim of this review is to discuss the benefits as well as the potential drawbacks linked with the use of this strategy.

Successes and setbacks of early investigational drugs for melanoma.

Treatment of advanced and metastatic melanoma is a rapidly changing field. Over the past 10 years, there have been six new drugs approved by the FDA for the treatment of metastatic melanoma. These approved drugs include a number of immune checkpoint inhibitors and MAPK-pathway-targeted therapies. The discovery of such agents as ipilimumab, pembrolizumab, nivolumab, vemurafenib, trametininb and dabrafenib have revolutionized the way in which melanoma in managed. While these agents have succeeded in both early and later phase clinical trials, a large number of investigational therapies have not yet been developed or researched past Phase I clinical studies. Furthermore, there are dozens of potential agents in Phase I and Phase II clinical development that appear promising and are currently being explored. The field currently aims to determine the optimal sequence and combination of these therapies to best overcome such setbacks as toxicity and resistance and build upon the successes previously seen.

Double-blinded, randomized phase II study using embolization with or without granulocyte-macrophage colony-stimulating factor in uveal melanoma with hepatic metastases.

PURPOSE: To investigate the effects of immunoembolization with granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with uveal melanoma (UM) with liver-only metastasis. MATERIALS AND METHODS: In this double-blind phase II clinical trial, patients were randomized to undergo immunoembolization or bland embolization (BE). Lobar treatment was performed with GM-CSF or normal saline solution mixed with ethiodized oil followed by embolization with gelatin sponge emulsified with iodinated contrast medium. Fifty-two patients (immunoembolization, n = 25; BE, n = 27) were enrolled. Response was assessed after every two treatments. The primary endpoint was overall response rate (ORR) of liver metastases. Progression-free survival (PFS), overall survival (OS), and immunologic responses were secondary endpoints. RESULTS: There were five partial responses in the immunoembolization group (ORR, 21.2%; 90% confidence interval [CI], 10.3%-30.5%) and three in the BE group (ORR, 16.7%; 90% CI, 6.3%-26.9%). Stable disease was seen in 12 patients in the immunoembolization group and 19 in the BE group. OS times were 21.5 months (95% CI, 18.5-24.8 mo) with immunoembolization and 17.2 months (95% CI, 11.9-22.4 mo) with BE. The degree of proinflammatory cytokine production was more robust after immunoembolization and correlated with time to "systemic" extrahepatic progression. In the immunoembolization group, interleukin (IL)-6 levels at 1 hour (P = .001) and IL-8 levels at 18 hours after the procedure (P < .001) were significant predictors of longer systemic PFS. Moreover, a dose-response pattern was evident between posttreatment serum cytokine concentrations and systemic PFS. CONCLUSIONS: Immunoembolization induced more robust inflammatory responses, which correlated with the delayed progression of extrahepatic systemic metastases.

Therapeutic options for HER-2 positive breast cancer: Perspectives and future directions.

During the last 15 years we have witnessed an unprecedented expansion in the drugs developed to target human epidermal growth factor receptor-2 (HER-2) positive breast cancer. Trastuzumab, pertuzumab, ado-trastuzumab emtansine and lapatinib are currently food and drug administration (FDA)-approved for the treatment of breast cancer patients with HER-2 over-expressed. However, given the amount of information gathered from years of uninterrupted clinical research, it is essential to have periodic updates that succinctly recapitulate what we have learnt over these last years and help us to apply that information in our daily practice. This review will pursue that objective. We will summarize the most relevant and updated information related to the state of the art management of HER-2 positive breast cancer in all the clinical scenarios including the adjuvant, neoadjuvant and metastatic settings. But we will also critically appraise that literature in order to highlight some key clinical concepts that should not be overlooked. Lastly, this review will also point out some of the most promising strategies that are currently being tested and may soon become available.

Advances and new perspectives in the treatment of metastatic colon cancer.

During the last decade we have witnessed an unprecedented outburst of new treatment approaches for the management of metastatic colon cancer. Anti-angiogenic drugs, epidermal growth factor receptor blockers and multi-kinase inhibitors have all resulted in small but consistent improvement in clinical outcomes. However, this progress has paradoxically leaded us into new challenges. In many cases the clinical development was done in parallel and the lack of head-to-head comparison evolved into circumstances where several valid new "standards of care" are available. Even though desirable in essence, the availability of many options as well as different possible combinations frequently leaves the busy clinician in the difficult situation of having to choose between one or the other, sometimes without solid evidence to support each decision. In addition, progress never stops and new agents are continuously tested. For these reason this review will try to summarize all the clinical trials that constitute the theoretical framework that support our daily practice but will also procure the reader with rational answers to common clinical dilemmas by critically appraising the current literature. Lastly, we will provide with a compilation of promising new agents that may soon become our next line of defense against this deadly disease.

Recent treatment advances and novel therapies in pancreas cancer: a review.

PURPOSE: Over the last couple of years, we have witnessed the availability of a wide variety of different therapeutic agents and the identification of effective combinations of existing ones that have transformed the way we approach and treat pancreatic cancer. Proof of this are the recent validations that combinations of conventional chemotherapy drugs, the FOLFIRINOX regimen and gemcitabine plus nab-paclitaxel, significantly improves clinical outcomes in patients with metastatic disease. However, deeper and more sophisticated understanding of the biology of this cancer as well as the ability to develop better and perhaps more precise drugs predict that the landscape may be changing even more. METHODOLOGY AND RESULTS: In this review, we will summarize the most recent treatment advances including FOLFIRINOX, gemcitabine plus nab-paclitaxel and discuss novel approaches such as immune-mediated therapies, drugs that disrupt the tumor-stromal compartment, PARP inhibitors for BRCA pathway-deficient pancreatic cancer and new generations of conventional chemotherapeutics, which are in early phases of clinical development and have shown promising early results. We will also discuss some examples of drugs that failed, despite very good preliminary data, in order to appraise the lessons learned from these negative clinical trials. Lastly, we will comment on ongoing adjuvant and neoadjuvant trials. CONCLUSION: We hope that at least some of these will result in positive trials and add to our armamentarium for treating this challenging malignancy.

The potential role of sunitinib targeting melanomas.

INTRODUCTION: Metastatic melanoma - independently of its cutaneous, uveal or mucosal origin - represents an exceptionally aggressive tumor with poor prognosis. Molecular and genetics investigations permitted to identify several important driver mutations: BRAF, NRAS, c-Kit, GNA11 and GNAQ. Additionally, hypervascular and immunlogenic characteristics of metastatic melanoma make in this tumor a unique therapeutic target. In this regard, the antiangiogenic, antiproliferative and immunomodulator properties of sunitinib make it an attractive drug to explore in melanoma. AREAS COVERED: In this article, the currently available data on sunitinib in terms of its pharmacokinetics and mechanisms of action is summarized. The reader will also be updated on current clinical experience using this drug in the treatment of cutaneous, mucosal and uveal melanomas. Special attention is placed on the scientific rationales behind its development in melanoma including the potentiality to broadly attack receptor-tyrosine kinases as well as its remarkable but certainly still unexplored immunomodulatory qualities. EXPERT OPINION: Given its wide spectrum of actions and the encouraging results obtained from the limited clinical experience, sunitinib remains as a promising drug, especially for mucosal and uveal melanoma, that deserves further exploration in properly designed clinical trials.

Somatostatin receptor scintigraphy in patients with metastatic uveal melanoma.

As uveal melanoma originates in the neural crest, we aimed to explore whether somatostatin receptor (SSTR) expression is present and plays any role in these patients. Heavily pretreated metastatic uveal melanoma patients were tested with somatostatin receptor scintigraphy (SRS). Planar images of the whole body complemented by single-photon emission computed tomography on suspected sites were acquired between 4 and 24 h after an intravenous administration of 185-222 MBq (5-6 mCi) of indium-octeotride. SSTR expression in metastatic tissues was confirmed by immunohistochemistry. In seven patients, sandostatin LAR was used with therapeutic intention. Thirty white patients were tested. All had extensive metastatic disease and the median number of previous treatments was three. SRS was found to be positive in 14 (46%) of the patients, but was not related to sex, type of previous treatments, tumor site, or histological type. In 10 patients, sufficient tumor specimens were available to perform immunohistochemical staining for SSTR. All cases with positive SSTR-2A staining were also positive by SRS. Two of the seven patients who received sandostatin LAR died within a month after receiving the first dose, whereas another two (28.5%) had stable disease for more than 5 months. The median time to progression after starting sandostatin was 2.1 months (range: 0.2-5.5 months). Approximately 50% of the uveal melanoma patients with extensive metastatic disease were positive for SSR, which was consistent with immunohistochemical staining for SSTR-2A. Therapeutic approaches targeting SSTR might be beneficial in patients with metastatic uveal melanoma.

Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline.

PURPOSE: The American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) sought to provide an evidence-based guideline on the use of lymphatic mapping and sentinel lymph node (SLN) biopsy in staging patients with newly diagnosed melanoma. METHODS: A comprehensive systematic review of the literature published from January 1990 through August 2011 was completed using MEDLINE and EMBASE. Abstracts from ASCO and SSO annual meetings were included in the evidence review. An Expert Panel was convened to review the evidence and develop guideline recommendations. RESULTS: Seventy-three studies met full eligibility criteria. The evidence review demonstrated that SLN biopsy is an acceptable method for lymph node staging of most patients with newly diagnosed melanoma. RECOMMENDATIONS: SLN biopsy is recommended for patients with intermediate-thickness melanomas (Breslow thickness, 1 to 4 mm) of any anatomic site; use of SLN biopsy in this population provides accurate staging. Although there are few studies focusing on patients with thick melanomas (T4; Breslow thickness, > 4 mm), SLN biopsy may be recommended for staging purposes and to facilitate regional disease control. There is insufficient evidence to support routine SLN biopsy for patients with thin melanomas (T1; Breslow thickness, < 1 mm), although it may be considered in selected patients with high-risk features when staging benefits outweigh risks of the procedure. Completion lymph node dissection (CLND) is recommended for all patients with a positive SLN biopsy and achieves good regional disease control. Whether CLND after a positive SLN biopsy improves survival is the subject of the ongoing Multicenter Selective Lymphadenectomy Trial II.

RB-pathway disruption is associated with improved response to neoadjuvant chemotherapy in breast cancer.

PURPOSE: We sought to determine whether dysregulation of the retinoblastoma (RB) tumor suppressor pathway was associated with improved response to neoadjuvant chemotherapy in breast cancer. EXPERIMENTAL DESIGN: An RB-loss signature was used to analyze the association between pathway status and pathologic complete response in gene expression datasets encompassing three different neoadjuvant regimens. Parallel immunohistochemical analysis of the RB pathway was conducted on pretreatment biopsies to determine the association with pathologic response to neoadjuvant chemotherapy. RESULTS: An RB-loss gene expression signature was associated with increased pathologic complete response in datasets from breast cancer patients treated with 5-fluorouracil/adriamycin/cytoxan (FAC; P < 0.001), T/FAC (P < 0.001), and Taxane/Adriaymcin (P < 0.001) neoadjuvant therapy encompassing approximately 1,000 patients. The association with improved response to neoadjuvant chemotherapy was true in both estrogen receptor (ER)-positive and ER-negative breast cancer. Elevated expression of p16ink4a is associated with the RB-loss signature (R = 0.493-0.5982), and correspondingly p16ink4a mRNA levels were strongly associated with pathologic complete response in the same datasets analyzed. In an independent cohort, immunohistochemical analyses of RB and p16ink4a revealed an association of RB loss (P = 0.0018) or elevated p16ink4a (P = 0.0253) with pathologic complete response. In addition, by Miller-Payne and clinicopathologic scoring analyses, RB-deficient tumors experienced an overall improved response to neoadjuvant chemotherapy. CONCLUSION: Disruption of the RB pathway as measured by several independent methods was associated with improved response to neoadjuvant chemotherapy. The RB-pathway status was relevant for pathologic response in both ER-positive and ER-negative breast cancer with similar results observed with multiple chemotherapy regimens. Combined, these data indicate that RB status is associated with the response to neoadjuvant chemotherapy in breast cancer and could be used to inform treatment.

Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline.

PURPOSE: The American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) sought to provide an evidence-based guideline on the use of lymphatic mapping and sentinel lymph node (SLN) biopsy in staging patients with newly diagnosed melanoma. METHODS: A comprehensive systematic review of the literature published from January 1990 through August 2011 was completed using MEDLINE and EMBASE. Abstracts from ASCO and SSO annual meetings were included in the evidence review. An Expert Panel was convened to review the evidence and develop guideline recommendations. RESULTS: Seventy-three studies met full eligibility criteria. The evidence review demonstrated that SLN biopsy is an acceptable method for lymph node staging of most patients with newly diagnosed melanoma. RECOMMENDATIONS: SLN biopsy is recommended for patients with intermediate-thickness melanomas (Breslow thickness, 1-4 mm) of any anatomic site; use of SLN biopsy in this population provides accurate staging. Although there are few studies focusing on patients with thick melanomas (T4; Breslow thickness, >4 mm), SLN biopsy may be recommended for staging purposes and to facilitate regional disease control. There is insufficient evidence to support routine SLN biopsy for patients with thin melanomas (T1; Breslow thickness, <1 mm), although it may be considered in selected patients with high-risk features when staging benefits outweigh risks of the procedure. Completion lymph node dissection (CLND) is recommended for all patients with a positive SLN biopsy and achieves good regional disease control. Whether CLND after a positive SLN biopsy improves survival is the subject of the ongoing Multicenter Selective Lymphadenectomy Trial II.