Management of metastatic renal cell carcinoma - mini review.

The management of metastatic renal cell carcinoma (mRCC) has evolved considerably in the last decade. A number of different systemic molecular targeted agents that have been recently approved have improved the survival of patients with mRCC. This mini-review focuses on the implementation of multi-modality therapy in the management of mRCC and the approved indications of the various available novel agents. These novel agents have expanded our armamentarium and improved clinical outcomes of this challenging disease that has considerable biological heterogeneity and clinical variability.

Breast cancer resistance protein (BCRP) and excision repair cross complement-1 (ERCC1) expression in esophageal cancers and response to cisplatin and irinotecan based chemotherapy.

BACKGROUND: Esophageal cancer patients face a dismal outcome despite tri-modality management and median survival remains 15-18 months. Breast cancer resistance protein (BCRP) is an ATP-dependent efflux protein associated with chemotherapy resistance. The role of BCRP expression in esophageal cancer and normal esophageal cells is not known. Excision repair cross complement-1 (ERCC1) overexpression has been correlated with poorer response to cisplatin based chemotherapy. We examined the expression of BCRP and ERCC1 in patients with esophageal cancer and correlated it with survival in patients receiving irinotecan and cisplatin based chemotherapy. METHODS: With IRB approval, 40 cases of esophageal cancer diagnosed from 2004-2008, were stained for BCRP and ERCC1 expression by immunohistochemistry and scored by a pathologist blinded to clinical data. Baseline demographics, therapy given and survival data were collected and correlated with BCRP and ERCC1 expression. Fisher's exact test was used to determine association between BCRP and ERCC1 expression and demographics. Cox proportional hazards model was used for association of BCRP and ERCC1 with survival. RESULTS: On immunohistochemistry, 30/40 cancers (75%) expressed BCRP. Interestingly, down-regulation of BCRP expression in tumor compared with normal cells was seen in 40% of patients. ERCC1 positivity was seen in 15/30 cases (50%). Median overall survival (OS) was 19 months with no difference in survival between BCRP positive and negative patients (P=0.13) or ERCC1 positive and negative patients (P=0.85). Estimated hazard ratio (HR) of death for BRCP positive patients was 2.29 (95% CI: 0.79-6.64) and for ERCC1 positive patients was 1.09 (95% CI: 0.46-2.56). There was no association of BCRP and ERCC1 expression with disease stage, age, gender or histology. For patients who received cisplatin and irinotecan as first line chemotherapy, there was no difference in survival based on BCRP or ERCC1 status. CONCLUSIONS: BCRP expression is seen in a majority of esophageal cancers and normal esophageal mucosa. ERCC1 expression is seen in about half of the patients with esophageal cancer. Irinotecan based studies with esophageal and gastric cancer suggest response rates of 14-65%. Whether the 40% of tumors in our study found with down regulation of BCRP expression, constitute a majority of these responders needs to be prospectively validated in a larger data set. It should include markers such as ERCC1 predicting response to 5-fluorouracil and platinum based chemotherapy, to enable individualizing therapy for this cancer.

Circulating microparticle tissue factor, thromboembolism and survival in pancreaticobiliary cancers.

BACKGROUND: Tissue factor (TF), the physiologic initiator of coagulation, is over-expressed in pancreatic cancer, and is associated with a pro-coagulant and pro-angiogenic state. We hypothesized that in patients with pancreaticobiliary cancers (PBC), elevated circulating microparticle-associated TF (MP-TF) activity would be associated with thrombosis and worsened survival. PATIENTS AND METHODS: Clinical data and plasma were obtained for consecutive patients with PBC seen at Roswell Park Cancer Institute from 2005-08. MP-TF activity levels were measured using a TF-dependent FXa generation assay. RESULTS: The study population comprised 117 patients, including pancreatic (n=80), biliary (n=34) or unknown primary histologically consistent with PBC (n=3). Of these, 52 patients (44.5%) experienced thromboembolism, including pulmonary embolism (n=15), deep venous thrombosis (n=21) and other arterial or venous events (n=32). Mean TF was 2.15 (range 0.17- 31.01) pg/mL. Median survival was 98.5 days for MP-TF activity ≥ 2.5 pg/mL versus 231 days for MP-TF activity<2.5 pg/mL (p<0.0001). In multivariate analysis, elevated MP-TF activity was associated with both VTE (OR 1.4, 95% CI 1.1-1.6) and mortality (HR 2.5, 95% CI 1.4-4.5). CONCLUSIONS: Elevated circulating MP-TF activity is associated with thrombosis and worsened survival in patients with PBC. MP-TF activity as a prognostic biomarker warrants further prospective evaluation.

Evaluation of phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) and epidermal growth factor receptor (EGFR) gene mutations in pancreaticobiliary adenocarcinoma.

BACKGROUND: Phosphatidylinositol-3-kinase (PI3K) activation involves the epidermal growth factor receptor (EGFR) and plays an important role in cell survival signaling in pancreaticobiliary cancer. EGFR gene mutations have been correlated with clinical response to EGFR inhibitors in patients with advanced non-small cell lung cancer. This study examined the prevalence of PIK3CA and EGFR mutations in pancreaticobiliary cancer where erlotinib, an EGFR inhibitor, is approved for therapy. METHODS: Thirty patients who underwent pancreatectomy for pancreaticobiliary carcinoma were identified. Genomic DNA was extracted from formalin fixed paraffin embedded tumor and adjacent normal tissue, and exons 9 and 20 (for the PIK3CA gene) and exons 18-21 (for the EGFR gene) were amplified by PCR and sequenced. Literature review on EGFR and/or PIK3CA mutations in pancreaticobiliary adenocarcinomas was conducted. RESULTS: No mutations in either PIK3CA or EGFR genes were identified. The study identified one synonymous single nucleotide polymorphism (SNP) (rs1050171) in the coding region of EGFR. A previously unreported change, suspected to be a SNP, was observed in intron 18 of EGFR (IVS18+15, C>T). Review of the literature showed EGFR mutation rate of 2% and 10.5% in pancreatic and biliary tract carcinomas, respectively. PIK3CA mutations were found in 3.6% and 11.7% of pancreatic and biliary tract carcinomas, respectively. CONCLUSIONS: A low prevalence of EGFR or PIK3CA mutations exists in pancreatic cancer (<5%), indicating that mutation screening may not be as useful in determining prognosis or response to targeted inhibition.

Metastatic renal cell carcinoma: Current scenario and future trends.

An improved understanding of the biology of renal cell carcinoma (RCC) has led to the development of a number of targeted agents, which has resulted in a paradigm shift in the management of metastatic RCC. We review the current therapeutic strategies for metastatic RCC and present a synopsis of the novel agents in use today with a discussion of the phase III trials that demonstrated their clinical benefit. The management of RCC continues to evolve. The introduction of VEGF and mTOR inhibitors has markedly expanded our drug armamentarium and improved the outcome of a disease that has always been challenging to treat. Knowledge from upcoming trials will help us utilize these drugs for maximum clinical efficacy with optimal dosing and sequencing, either individually or in combination therapy.

A review of erlotinib--an oral, selective epidermal growth factor receptor tyrosine kinase inhibitor.

IMPORTANCE OF THE FIELD: The epidermal growth factor receptor (EGFR) is a cell surface receptor for EGF and transforming growth factor-alpha which is overexpressed by a number of human tumors. Erlotinib, developed by OSI Pharmaceuticals, is an oral selective EGFR tyrosine kinase inhibitor, the only drug of its class approved for the treatment of locally advanced non-small cell lung cancer (NSCLC) after failure of at least one previous chemotherapy regimen and for first-line treatment of advanced pancreatic cancer with gemcitabine. AREAS COVERED IN THIS REVIEW: Findings from major Phase III studies that led to the approval of erlotinib are summarized in this review. Key aspects of erlotinib clinical pharmacology, dosing in special populations (e.g., smokers), and toxicity are also reviewed. The article also outlines the results of all correlative studies that have been done in clinical trials of patients receiving erlotinib to identify biomarkers that predict response, such as rash, EGFR status of the tumor by immunohistochemistry and activating EGFR mutations. WHAT WILL THE READER GAIN: The reader will have an outline of the landmark trials leading to the approval of this drug and know which ongoing Phase III trials are expected to enhance the knowledge of this drug's activity. The reader will also understand the pharmacologic bases for the recent change in dosing guidelines of erlotinib, and the current knowledge of clinical and laboratory correlates that can serve as surrogates of response. TAKE HOME MESSAGE: This is a well-tolerated oral biologic agent with two approved clinical indications. More studies to individualize therapy and optimize dosing are needed.

Breast cancer-related preferences among women with and without BRCA mutations.

Preference ratings are used to quantify quality of life in analyses used for health care policy making. Subjects indicated how many years of their life expectancy they would trade to avoid BRCA mutations, breast/ovarian cancer, and five preventive measures including prophylactic surgery, annual mammograms, and annual magnetic resonance imaging (MRI). Among 243 respondents, both the 83 women with mutations and the 160 controls rated mammography highest (most favorably), MRI next highest, having a child with a mutation lowest, and ovarian cancer next lowest. Controls rated prophylactic surgery higher than cancer (P < 0.01), but women with mutations did not. In logistic regression, controls were twice as willing as women with mutations to trade time except for screening modalities; younger, lower-income, and non-white women were more willing to trade time than older, higher-income, and white women. Our findings support the use of average-risk individuals' time trade-off preference ratings for health care policy development.

Metastatic pancreatic adenocarcinoma and renal cell carcinoma treated with gemcitabine and sunitinib malate. A case report.

CONTEXT: Pancreatic adenocarcinoma and renal cell carcinoma are relatively frequent cancers that have been rarely reported as synchronous primary malignancies. When present simultaneously, they pose a therapeutic challenge given the many available targeted agents with reported efficacy in renal cell cancer and limited options for metastatic pancreatic cancer. CASE REPORT: We report the case of a 43-year-old Caucasian gentleman diagnosed simultaneously with metastatic pancreatic adenocarcinoma and localized renal cell carcinoma treated with combination chemotherapy, consisting of gemcitabine and sunitinib. Patient had a radiographic response and prolonged progression free survival of twenty six weeks; side effects were manageable and included grade 3 neutropenia and grade 2 hypertension. CONCLUSION: This encouraging response, safety profile and progression free survival response suggest that we should further examine this and other such regimens to improve clinical outcomes for maximum efficacy with minimal side-effects.

Rituximab-based therapy for gemcitabine-induced hemolytic uremic syndrome in a patient with metastatic pancreatic adenocarcinoma: a case report.

PURPOSE: The purpose of this report is to describe the management and outcome of an unusual complication of a commonly used chemotherapeutic agent. Gemcitabine is a known risk factor for hemolytic uremic syndrome (HUS), which can often have a rapidly fatal clinical course despite intervention with steroids, plasmapheresis and hemodialysis. METHODS: A retrospective report of the first case of gemcitabine-related HUS, in a patient with metastatic pancreatic adenocarcinoma, treated with a variety of standard therapies in addition to rituximab is presented. The hematologic response parameters and clinical outcomes to each of the therapies given are described. RESULTS: Chemotherapy-induced HUS was aggressively treated with plasmapheresis, high-dose steroids, vincristine and rituximab. Platelet recovery and clinical improvement coincided with administration of rituximab. In addition, aggressive supportive measures to manage renal failure (hemodialysis) and labile hypertension, allowed this patient to have an extended survival as a result of successful therapy for this complication despite an underlying rapidly fatal malignancy. CONCLUSION: This case highlights the importance of timely application of aggressive measures even in patients with known diagnosis of a fatal malignancy as these interventions can prolong life and be of palliative benefit.