Sam J. Lubner

Report of a Multicenter Phase II Trial Testing a Combination of Biweekly Bevacizumab and Daily Erlotinib in Patients With Unresectable Biliary Cancer: A Phase II Consortium Study

PURPOSE Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras. PATIENTS AND METHODS Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction. RESULTS Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12%; 95% CI, 6% to 27%) had a confirmed partial response. Stable disease was documented in another 25 patients (51%). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes. CONCLUSION Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer.

Multi-Institutional Experience with FOLFIRINOX in Pancreatic Adenocarcinoma

CONTEXT Combination chemotherapy with FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) was shown to be effective in a large phase III trial. OBJECTIVE The purpose of this study was to examine the tolerance and effectiveness of FOLFIRINOX as practiced outside of the confines of a clinical trial and to document any dose modifications used by practicing oncologists. METHODS Data on patients with all stages of pancreatic adenocarcinoma treated with FOLFIRINOX at three institutions was analyzed for efficacy, tolerance, and use of any dose modifications. RESULTS Total of 61 patients was included in this review. Median age was 58 years (range: 37 to 72 years), 33 were male (54.1%) and majority had ECOG performance of 0 or 1 (86.9%, 53 patients). Thirty-eight (62.3%) had metastatic disease, while 23 (37.7%) were treated for locally advanced or borderline resectable disease. Patients were treated with a median number of four cycles of FOLFIRINOX, with dose modifications in 58.3% (176/302) of all cycles. Ten patients had stable disease (16.4%), four had a partial response (6.6%) while eight had progressive disease (13.1%) on best imaging following therapy. Median progression-free survival and overall survival were 7.5 months and 13.5 months, respectively. The most common grade 3-4 adverse event was neutropenia at 19.7% (12 cases), with 4.9% (3 cases) rate of febrile neutropenia. Twenty-one patients (34.4%) were hospitalized as a result of therapy but there were no therapy-related deaths. Twenty-three (37.7%) had therapy eventually discontinued as a result of adverse events. CONCLUSION Despite substantial rates of adverse events and use of dose modifications, FOLFIRINOX was found to be clinically effective in both metastatic and non-metastatic patients. Regimen toxicity did not detract from overall response and survival.

A Pilot Phase II Study of Valproic Acid for Treatment of Low-Grade Neuroendocrine Carcinoma

INTRODUCTION Notch1 has been shown to be a tumor suppressor in neuroendocrine tumors (NETs). Previous in vitro studies in NET cell lines have also suggested that valproic acid (VPA), a histone deacetylase inhibitor, can induce Notch1 and that Notch1 activation correlates with a decrease in tumor markers for NETs. Thus, this study aimed to evaluate the role of VPA in treating NETs and to determine whether VPA induced the Notch signaling pathway signaling in vivo. PATIENTS AND METHODS Eight patients with low-grade NETs (carcinoid and pancreatic) were treated with 500 mg of oral VPA twice a day with dosing adjusted to maintain a goal VPA level between 50 and 100 μg/mL. All patients were followed for 12 months or until disease progression. RESULTS Notch1 signaling was absent in all tumors prior to treatment and was upregulated with VPA. One patient had an unconfirmed partial response and was noted to have a 40-fold increase in Notch1 mRNA levels. Four patients had stable disease as best response. Tumor markers improved in 5 out of 7 patients. Overall, treatment with VPA was well tolerated. CONCLUSION . VPA activates Notch1 signaling in vivo and may have a role in treating low-grade NETs.

Chronic granulomatous disease presenting with disseminated intracranial aspergillosis

We describe an 8‐year‐old boy who presented with multiple unresectable aspergillus brain abscesses as the initial presentation of X‐linked chronic granulomatous disease (CGD). He failed initial therapy with amphotericin B, but was subsequently salvaged with voriconazole. CGD should be considered in the differential diagnosis for all children presenting with invasive fungal infections, particularly, those involving the central nervous system (CNS). Whereas, optimal pharmacologic therapy is still unknown for CNS aspergillosis, voriconazole may have an advantage due to its ability to cross the blood brain barrier and excellent oral absorption and bioavailability.

Precision medicine in colorectal cancer: the molecular profile alters treatment strategies.

When considering treatment options for patients with metastatic colorectal cancer (mCRC), molecular profiling has become a pivotal component in guiding clinical decisions. FOLFOX and FOLFIRI (fluorouracuil, leucovorin plus oxaliplatin or ininotecan, respectively) are the standard base regimens used for the treatment of mCRC. Biologic agents, such as the epidermal growth factor receptor (EGFR) targeted therapies, cetuximab and panitumumab and the vascular endothelial growth factor monoclonal antibody, bevacizumab, are safe and effective in the first-line setting. The most efficacious use of these agents in terms of timing and selection of the right patient population continues to be debated. Here we review multiple investigations into the effectiveness of treatment options as a function of the mutations present in colon cancers. Early studies have reported that KRAS mutations at exon 2 predict resistance to EGFR targeted therapies. More recently the data have expanded to include KRAS mutations at exons 3 and 4 and NRAS mutations at exons 2, 3 and 4 as well as other biomarkers including BRAF and PIK3CA, leading to the evolution of the treatment of mCRC to a more precision-based approach. As our understanding of relevant biomarkers increases, and data from both molecular profiling and treatment response become more readily available, treatment options will become more precise and their outcomes more effective.

HEALTH LITERACY AND HEALTH-RELATED QUALITY OF LIFE AMONG A POPULATION-BASED SAMPLE OF CANCER PATIENTS

Health-related quality of life is an important outcome in cancer care. A few studies indicate that health literacy influences cancer patients’ health-related quality of life, but additional investigation is needed. The authors examined the relation between health literacy and health-related quality of life among cancer patients. A cross-sectional survey was conducted with cancer patients in Wisconsin during 2006–2007. Data on sociodemographics, clinical characteristics, health-related quality of life, and health literacy were obtained from the states cancer registry and a mailed questionnaire. Regression analyses were used to characterize the association between health-related quality of life and health literacy. The study sample included 1,841 adults, newly diagnosed with lung, breast, colorectal, or prostate cancer in 2004 (response rate = 68%). Health-related quality of life was measured with the Functional Assessment of Cancer Therapy-General. Adjusting for confounders, higher health literacy was associated with greater health-related quality of life (p < .0001). Controlling for covariates, we found significant differences between those in the highest and lowest health literacy categories (p < .0001) and in the physical (p < .0001), functional (p < .0001), emotional (p < .0001), and social (p = .0007) well-being subscales. These associations exceeded the minimally important difference threshold for overall health-related quality of life and functional well-being. Health literacy is positively and independently associated with health-related quality of life among cancer patients. These findings support adoption of health literacy best practices by cancer care systems.

A phase II study of capecitabine and lapatinib in advanced refractory colorectal adenocarcinoma: A Wisconsin Oncology Network study

BACKGROUND Prognosis remains poor after progression on first-line chemotherapy for colorectal adenocarcinoma, and inactivation of the EGFR pathway with monoclonal antibodies is an effective treatment strategy in selected patients with metastatic disease. Lapatinib is an oral EGFR and HER-2 dual tyrosine kinase inhibitor that has not shown significant activity in metastatic colorectal cancer. However, lapatinib may act synergistically with capecitabine in anticancer effects. METHODS This was an open-label, non-randomized phase II study of lapatinib 1,250 mg orally daily and capecitabine 2,000 mg/m(2) by mouth split into twice-daily dosing for 14 days of a 21 days cycle. Inclusion criteria included metastatic or locally advanced adenocarcinoma of the colon or rectum with progression by RECIST on or within six months of receiving a fluoridopyrimidine-, oxaliplatin- or irinotecan-containing regimen. Prior EGFR monoclonal antibody was permitted. K-ras testing was not routinely performed and was not a part of the study protocol. RESULTS Twenty nine patients (16 M; 13 F) were enrolled in this study. There were no complete or partial responses. 41.4% of patients achieved stable disease as a best response. Median overall survival was 6.8 months, with a 1-year survival rate of 22%, and median progression-free survival was 2.1 months. The combination produced few grade 3 and no grade 4 toxicities. No grade 3 toxicity occurred in more than 10% of patients. CONCLUSIONS Although capecitabine and lapatinib is well tolerated, it is not an effective regimen in patients with refractory colorectal adenocarcinoma.

Cost-effectiveness of adjuvant FOLFOX and 5FU/LV chemotherapy for patients with stage II colon cancer

Purpose. We evaluated the cost-effectiveness of adjuvant chemotherapy using 5-fluorouracil, leucovorin (5FU/LV), and oxaliplatin (FOLFOX) compared with 5FU/LV alone and 5FU/LV compared with observation alone for patients who had resected stage II colon cancer. Methods. We developed 2 Markov models to represent the adjuvant chemotherapy and follow-up periods and a single Markov model to represent the observation group. We used calibration to estimate the transition probabilities among different toxicity levels. The base case considered 60-year-old patients who had undergone an uncomplicated hemicolectomy for stage II colon cancer and were medically fit to receive 6 months of adjuvant chemotherapy. We measured health outcomes in quality-adjusted life-years (QALYs) and estimated costs using 2007 US dollars. Results. In the base case, adjuvant chemotherapy of the FOLFOX regimen had an incremental cost-effectiveness ratio (ICER) of

Phospholipid ether analogs for the detection of colorectal tumors.

54,359/QALY compared with the 5FU/LV regimen, and the 5FU/LV regimen had an ICER of

A Preclinical and Clinical Study of Lithium in Low-Grade Neuroendocrine Tumors

14,584/QALY compared with the observation group from the third-party payer perspective. The ICER values were most sensitive to 5-year relapse probability, cost of adjuvant chemotherapy, and the discount rate for the FOLFOX arm, whereas the ICER value of 5FU/LV was most sensitive to the 5-year relapse probability, 5-year survival probability, and the relapse cost. The probabilistic sensitivity analysis indicates that the ICER of 5FU/LV is less than