Carcinoids and pancreatic neuroendocrine tumors are becoming increasingly common, with the majority of patients presenting with either lymph node involvement or metastatic disease. An improved understanding of the molecular mechanisms involved in these tumors has implicated several pathways that have led to new therapeutic approaches. Phase III studies indicate that pharmacologic inhibition of the vascular endothelial growth factor pathway with sunitinib, and of the mammalian target of rapamycin pathway with everolimus, appears to have altered the natural history of these diseases.
After completing this course, the reader will be able to:
Describe the underlying biology of neuroendocrine tumors including pancreatic neuroendocrine tumors (PNETs) and carcinoids and the importance of these biologic features in the evolution of new drugs for these diseases.Cite the historical data regarding the use of cytotoxic agents in the treatment of pancreatic neuroendocrine tumors and carcinoids.Explain the significance of recent clinical trials utilizing biologic agents, in particular octreotide, the small molecule tyrosine kinase inhibitor, sunitinib and the mammalian target of rapamycin (mTOR) inhibitor, everolimus, and how these medications have altered the natural history of both pancreatic neuroendocrine tumors and carcinoids.
This article is available for continuing medical education credit at CME.TheOncologist.com
Carcinoids and pancreatic neuroendocrine tumors are becoming increasingly common, with the majority of patients presenting with either lymph node involvement or metastatic disease. An improved understanding of the molecular mechanisms involved in these tumors has implicated several pathways that have led to new therapeutic approaches. In this manuscript, we describe the biology of neuroendocrine tumors and approaches to systemic therapy. We review early data regarding the use of cytotoxics and several recent studies employing more targeted approaches that promise to change the standard of care. Specifically, phase III studies indicate that pharmacologic inhibition of the vascular endothelial growth factor pathway with sunitinib, and of the mammalian target of rapamycin pathway with everolimus, appears to have altered the natural history of these diseases. These successes set the stage for further advances in the management of patients with neuroendocrine tumors.
Carcinoid; Neuroendocrine tumor; Gastroenteropancreatic neuroendocrine tumor; Islet cell tumor; Pancreatic neuroendocrine tumor
To determine whether patients' expectations of benefit in early-phase oncology trials depend on how patients are queried and to explore whether expectations are associated with patient characteristics.
Patients and Methods
Participants were 171 patients in phase I or II oncology trials in the United States. After providing informed consent for a trial but before receiving the investigational therapy, participants answered questions about expectations of benefit. We randomly assigned participants to one of three groups corresponding to three queries about expectations: frequency type, belief type, or both. Main outcomes were differences in expectations by question type and the extent to which expectations were associated with demographic characteristics, numeracy, dispositional optimism, religiousness/spirituality, understanding of research, and other measures.
The belief-type group had a higher mean expectation of benefit (64.4 of 100) than the combination group (51.6; P = .01) and the frequency-type group (43.1; P < .001). Mean expectations in the combination and frequency groups were not significantly different (P = .06). Belief-type expectations were associated with a preference for nonquantitative information (r = −0.19; 95% CI, −0.19 to −0.36), knowledge about research (r = −0.21; 95% CI, −0.38 to −0.03), dispositional optimism (r = 0.20; 95% CI, 0.01 to 0.37), and spirituality (r = 0.22; 95% CI, 0.03 to 0.38). Frequency-type expectations were associated with knowledge about clinical research (r = −0.27; 95% CI, −0.27 to −0.51).
In early-phase oncology trials, patients' reported expectations of benefit differed according to how patients were queried and were associated with patient characteristics. These findings have implications for how informed consent is obtained and assessed.
Dual inhibition of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) demonstrated initial promise in clinical trials. This phase II study tested the efficacy and safety of capecitabine, oxaliplatin, and cetuximab with or without bevacizumab as first-line treatment for metastatic colorectal cancer patients.
Patients were randomized to receive capecitabine 850 mg/m2 PO twice daily for 14 days, oxaliplatin 130 mg/m2 IV day 1, and cetuximab 400 mg/m2 IV loading dose followed by 250 mg/m2 IV days 1, 8, and 15 with (Arm A) or without (Arm B) bevacizumab 7.5 mg/kg IV day 1 every 21 days. Tumor samples were collected and retrospectively analyzed for KRAS mutation status. The primary endpoint was response rate, with time to progression (TTP) and overall survival (OS) as secondary objectives.
Twenty-three patients (12 in Arm A, 11 in Arm B) were enrolled onto the study. Median follow-up was 25.9 months. Both treatments were well tolerated, with expected higher rates of grade 1/2 hypertension and bleeding in Arm A. The overall response rate was 54% (36.4% in Arm A and 72.7% in Arm B). Median time to progression was 8.7 months in Arm A and 14.4 months in Arm B. The median survival was 18.0 months in Arm A and 42.5 months in Arm B. The study was prematurely terminated after other studies reported inferior outcomes with dual antibody therapy.
Although terminated early, the study supports the detrimental effect of combining VEGF and EGFR inhibition in metastatic colorectal cancer.
Metastatic colon cancer; Vascular endothelial growth factor (VEGF); Epidermal growth factor receptor (EGFR)
We examined the feasibility of home videoconferencing for providing cancer genetic education and risk information to people at-risk. Adults with possible hereditary colon or breast-ovarian cancer syndromes were offered Internet-based counselling. Participants were sent webcams and software to install on their home PCs. They watched a pre-recorded educational video and then took part in a live counselling session with a genetic counsellor. 31 participants took part in Internet counselling sessions. Satisfaction with counselling was high in all domains studied, including technical (mean 4.3 on scale from 1–5), education (mean 4.7), communication (mean 4.8), psychosocial (mean 4.1), and overall (mean 4.2). Qualitative data identified technical aspects that could be improved. All participants reported that they would recommend Internet-based counselling to others. Internet-based genetic counselling is feasible and associated with a high level of satisfaction among participants.
To determine factors associated with symptomatic cardiac toxicity in patients with esophageal cancer treated with chemoradiotherapy.
Material and Methods
We retrospectively evaluated 102 patients treated with chemoradiotherapy for locally advanced esophageal cancer. Our primary endpoint was symptomatic cardiac toxicity. Radiation dosimetry, patient demographic factors, and myocardial changes seen on 18F-FDG PET were correlated with subsequent cardiac toxicity. Cardiac toxicity measured by RTOG and CTCAE v3.0 criteria was identified by chart review.
During the follow up period, 12 patients were identified with treatment related cardiac toxicity, 6 of which were symptomatic. The mean heart V20 (79.7% vs. 67.2%, p=0.05), V30 (75.8% vs. 61.9%, p=0.04), and V40 (69.2% vs. 53.8%, p=0.03) were significantly higher in patients with symptomatic cardiac toxicity than those without. We found the threshold for symptomatic cardiac toxicity to be a V20, V30 and V40 above 70%, 65% and 60%, respectively. There was no correlation between change myocardial SUV on PET and cardiac toxicity, however, a greater proportion of women suffered symptomatic cardiac toxicity compared to men (p=0.005).
A correlation did not exist between percent change in myocardial SUV and cardiac toxicity. Patients with symptomatic cardiac toxicity received significantly greater mean V20, 30 and 40 values to the heart compared to asymptomatic patients. These data need validation in a larger independent data set.
Chemoradiotherapy; Esophageal cancer; Cardiac Toxicity
To evaluate rate of pathologic complete response (pCR) and toxicity of two neoadjuvant chemoradiation (chemoRT) regimens for T3/T4 rectal cancer in a randomized phase II study.
Methods and Materials
Patients with T3 or T4 rectal cancer < 12 cm from the anal verge were randomized to preoperative RT (50.4 Gy in 1.8 Gy fractions) with (1) concurrent capecitabine (1200 mg/m2/d M-F) and irinotecan (50 mg/m2 weekly × 4 doses) (arm 1), or (2) concurrent capecitabine (1650 mg/m2/d M-F) and oxaliplatin (50 mg/m2 weekly × 5 doses) (arm 2). Surgery was performed 4–8 weeks after chemoRT, and adjuvant chemotherapy 4–6 weeks after surgery. The primary endpoint was pCR rate, requiring 48 evaluable patients per arm.
146 patients were enrolled. Protocol chemotherapy was modified due to excessive GI toxicity after treatment of 35 patients; 96 were assessed for the primary endpoint—final regimen described above. Patient characteristics were similar for both arms. Following chemoRT, tumor downstaging was 52% and 60%, and nodal downstaging (excluding N0 patients) was 46% and 40%, for arms 1 and 2, respectively. The pCR rate for arm 1 was 10% and for arm 2 was 21%. For arms 1 and 2, respectively, preop chemoRT grade 3/4 hematologic toxicity was 9% and 4%, and grade 3/4 non-hematologic toxicity was 26% and 27%.
Preoperative chemoRT with capecitabine plus oxaliplatin for distal rectal cancer has significant clinical activity (10/48 pCRs) and acceptable toxicity. This regimen is currently being evaluated in a phase III randomized trial (NSABP R04).
Neoadjuvant; chemotherapy; radiation; rectal; cancer
Response fatigue can cause measurement error and misclassification problems in survey research. Questions asked later in a long survey are often prone to more measurement error or misclassification. The response given is a function of both the true response and participant response fatigue. We investigate the identifiability of survey order effects and their impact on estimators of treatment effects. The focus is on fatigue that affects a given answer to a question rather than fatigue that causes non-response and missing data. We consider linear, Gamma, and logistic models of response that incorporate both the true underlying response and the effect of question order. For continuous data, survey order effects have no impact on study power under a Gamma model. However, under a linear model that allows for convergence of responses to a common mean, the impact of fatigue on power will depend on how fatigue affects both the rate of mean convergence and the variance of responses. For binary data and for less than a 50% chance of a positive response, order effects cause study power to increase under a linear probability (risk difference) model, but decrease under a logistic model. The results suggest that measures designed to reduce survey order effects might have unintended consequences. We present a data example that demonstrates the problem of survey order effects.
Newer systemic therapies have the potential to decrease morbidity and mortality from metastatic colorectal cancer, yet such therapies are costly and have side effects. Little is known about their non-evidence-based use.
We conducted a retrospective cohort study using commercial insurance claims from UnitedHealthcare, and identified incident cases of metastatic colon cancer (mCC) from July 2007 through April 2010. We evaluated the use of three regimens with recommendations against their use in the National Comprehensive Cancer Center Network Guidelines, a commonly used standard of care: 1) bevacizumab beyond progression; 2) single agent capecitabine as a salvage therapy after failure on a fluoropyridimidine-containing regimen; 3) panitumumab or cetuximab after progression on a prior epidermal growth factor receptor antibody. We performed sensitivity analyses of key assumptions regarding cohort selection. Costs from a payer perspective were estimated using the average sales price for the entire duration and based on the number of claims.
A total of 7642 patients with incident colon cancer were identified, of which 1041 (14%) had mCC. Of those, 139 (13%) potentially received at least one of the three unsupported off-label (UOL) therapies; capecitabine was administered to 121 patients and 49 (40%) likely received it outside of clinical guidelines, at an estimated cost of $718,000 for 218 claims. Thirty-eight patients received panitumumab and six patients (16%) received it after being on cetuximab at least two months, at an estimated cost of $69,500 for 19 claims. Bevacizumab was administered to 884 patients. Of those, 90 (10%) patients received it outside of clinical guidelines, at an estimated costs of $1.34 million for 636 claims.
In a large privately insured mCC cohort, a substantial number of patients potentially received UOL treatment. The economic costs and treatment toxicities of these therapies warrant increased efforts to stem their use in settings lacking sufficient scientific evidence.
Colorectal cancer; Off-label; Evidence-based medicine; Physician practice patterns
Whether or not the process of data disclosure regarding KRAS status and treatment of advanced colorectal cancer patients was effective in permitting timely decisions regarding ongoing publicly funded clinical trials and whether or not such decisions were rational and ethical are discussed with the overall goals of highlighting lessons learned regarding early disclosure of clinical trial results, as well as vetting and adoption of new scientific data, and proposing modifications for handling similar situations in the future.
Systemic therapy has led to a median survival time for patients with advanced colorectal cancer (CRC) almost fourfold longer than that expected with best supportive care, an outcome achieved through combining chemotherapeutic and targeted biologic agents. Although the latter can include anti–epidermal growth factor receptor antibodies, such as cetuximab and panitumumab, we now have strong evidence that patients whose tumors harbor mutated KRAS will not benefit from this class of agent. Acceptance of the reliability and importance of the KRAS data took several years to evolve, however, for a variety of reasons. The timeline from the presentation and publication of small, retrospective phase II studies to widespread acceptance of the KRAS predictive value and changes in behavior—specifically, modifications of ongoing national trials in advanced/metastatic CRC, changes in national guidelines and practice patterns, and adjustments to the labeled indications for the monoclonal antibodies—was lengthy. In this commentary, we discuss whether or not the process of data disclosure regarding KRAS status and treatment of advanced CRC patients was effective in permitting timely decisions regarding ongoing publicly funded clinical trials and whether or not such decisions were rational and ethical. The overall goals are to highlight lessons learned regarding early disclosure of clinical trial results, as well as vetting and adoption of new scientific data, and to propose modifications for handling similar situations in the future.
Ethics; KRAS; Clinical trials; Colorectal neoplasms
Fox Chase Cancer Center Partners (FCCCP) performs an annual quality review of affiliate practices based on National Comprehensive Cancer Network (NCCN) guidelines. Given recent treatment advances, we initiated this medical record review in elderly patients with stage III colon cancer to measure compliance with these guidelines.
Medical records of 124 patients age ≥ 65 diagnosed with stage III colon cancer between 2003 and 2006 were reviewed. Metrics were developed and based on NCCN guidelines for workup and staging, treatment, and gerontology. Documentation was reviewed via paper (13 sites) and electronic record (2 sites).
High compliance with staging and workup guidelines was noted with chest imaging (100%), stage (98%), computed tomography (CT) of the abdomen/pelvis (93%), pathology (91%), and carcinoembryonic antigen (CEA; 91%). Activities of daily living were documented commonly (83%) but colonoscopy less (75%). Age and life expectancy were discussed with the patient in only 49%. Nearly all patients (123 of 124 patients) received adjuvant chemotherapy, with 76 patients (61%) receiving oxaliplatin. Common regimens were FOLFOX (oxaliplatin plus infusional/bolus 5-fluorou-racil and folinic acid) 54%, 5-fluorouracil/leucovorin (5-FU/LV; 19%), and capecitabine (12%). Reasons for excluding oxaliplatin were comorbidity (68%), age (19%), and not specified (13%). Three-quarters of the patients had ≥ 12 lymph nodes sampled and 56% identified the radial margin. Nearly all patients (115 = 93%) received surveillance with history and physical and CEA. Surveillance CT was performed in 78% of the patients.
A quality review of community oncology practices can assess implementation of treatment advances. Guideline compliance for elderly patients with stage III colon cancer is generally high. Forty percent did not receive oxaliplatin and documentation of life expectancy was infrequent. Further study of oncologist decision making for elderly colon cancer patients is warranted.
Colon cancer; Community oncology; Gerontologic oncology; Performance improvement; Quality
Inherited variability in genes that influence androgen metabolism has been associated with risk of prostate cancer. The objective of this analysis was to evaluate interactions for prostate cancer risk using classification and regression tree (CART) models (i.e. decision trees), and to evaluate whether these interactive effects add information about prostate cancer risk prediction beyond that of “traditional” risk factors.
We compared CART models to traditional logistic regression models for associations of factors with prostate cancer risk using 1084 prostate cancer cases and 941 controls. All analyses were stratified by race. We used unconditional logistic regression (LR) to complement and compare to the race-stratified CART results using the area under curve (AUC) for the receiver operating characteristic (ROC) curves.
The CART modeling of prostate cancer risk showed different interaction profiles by race. For European Americans, interactions among CYP3A43 genotype, history of benign prostate hypertrophy, family history of prostate cancer and age at consent revealed a distinct hierarchy of gene-environment and gene-gene interactions. While for African Americans, interactions among family history of prostate cancer, individual proportion of European ancestry, number of GGC AR repeats and CYP3A4/CYP3A5 haplotype revealed distinct interaction effects from those found in European Americans. For European Americans the CART model had the highest AUC while for African Americans, the LR model with the CART discovered factors had the largest AUC.
Conclusion & Impact
These results provide new insight into underlying prostate cancer biology for European Americans and African Americans.
Decision tree; classification and regression tree (CART); androgen pathway; prostate cancer risk; ancestry
Treatment options are limited for advanced pancreatic cancer progressive after gemcitabine therapy. The vascular endothelial growth factor (VEGF) pathway is biologically important in pancreatic cancer, and docetaxel has modest anti-tumor activity. We evaluated the role of the anti-VEGF antibody bevacizumab as second-line treatment for patients with metastatic pancreatic cancer.
Patients with metastatic adenocarcinoma of the pancreas who had progressive disease on a gemcitabine-containing regimen were randomized to receive bevacizumab alone or bevacizumab in combination with docetaxel.
Thirty-two patients were enrolled; 16 to bevacizumab alone (Arm A) and 16 to bevacizumab plus docetaxel (Arm B). Toxicities were greater in Arm B with the most common grade 3/4 nonhematologic toxicities including fatigue, diarrhea, dehydration and anorexia. No confirmed objective responses were observed. At 4 months, 2/16 patients in Arm A and 3/16 in Arm B were free from progression. The study was stopped according to the early stopping rule for futility. Median PFS and OS were 43 days and 165 days in Arm A and 48 days and 125 days in Arm B. Elevated D-dimer levels and thrombin-antithrombin complexes were associated with decreased survival and increased toxicity.
Bevacizumab with or without docetaxel does not have antitumor activity in gemcitabine-refractory metastatic pancreatic cancer. Baseline and on-treatment D-dimer and thrombin-antithrombin complex levels are associated with increased toxicity and decreased survival.
Decision support to facilitate informed consent is increasingly important for complicated medical tests. Here, we test a theoretical model of factors influencing decisional conflict in a study examining the effects of a decision support aid that was assigned to assist patients at high risk for hereditary nonpolyposis colorectal cancer deciding whether to pursue the microsatellite instability test.
Participants were 239 colorectal cancer patients at high familial risk for a genetic mutation who completed surveys before and after exposure to the intervention. Half of the sample was assigned to the CD-ROM aid and half received a brief description of the test. Structural equation modeling was employed to examine associations among the intervention, knowledge, pros and cons to having MSI testing, self- efficacy, preparedness and decisional conflict.
The Goodness of Fit for the model was acceptable [FIML Chi-Square (df=280) =392.24;p=0.00]. As expected, the paths to decisional conflict were significant for post-intervention pros of MSI testing (t=−2.43; p<0.05), cons of MSI testing (t=2.78; p<0.05), and preparedness (t=−7.27; p<0.01). The intervention impacted decisional conflict by increasing knowledge about the MSI test and knowledge exerted its effects on decisional conflict by increasing preparedness to make a decision about the test and by increases in perceived benefits of having the test.
Increasing knowledge, preparedness, and perceived benefits of undergoing the MSI test facilitate informed decision making for this test.
Understanding mechanisms underlying health decisions is critical for improving decisional support.
Immunotherapy of colorectal carcinoma (CRC) has great promise as the presence of T lymphocytes in CRC tissues in situ is correlated with reduced recurrence and increased survival. Thus, identification of the antigens recognized by T cells of CRC patients may permit development of vaccines with potential benefit for these patients. Using expression cloning, we identified the antigen, nucleophosmin (Npm), recognized by an HLA-A1 restricted cytotoxic T lymphocyte (CTL) line derived from the peripheral blood mononuclear cells (PBMC) of a rectal cancer patient. A decamer peptide derived from the Npm sequence sensitized peptide-pulsed HLA-A1 positive cells to lysis by the CTL line. The peptide also induced proliferative and cytotoxic T lymphocytes in the PBMC of 4 of 6 CRC patients which lysed HLA-A1 positive peptide-pulsed target cells and CRC cells endogenously expressing Npm. Overexpression of Npm by tumors of various histological types, recognition of the antigen by T cells derived from different CRC patients, and association of the antigen with poor prognostic outcome make it a promising target for immunotherapeutic intervention in cancer patients.
Colorectal carcinoma patients; Cytotoxic T cells; antigens; tumor immunity
Cancer prevention clinical trials seek to enroll individuals at increased risk for cancer. Little is known about attitudes among physicians and at-risk individuals towards cancer prevention clinical trials. We sought to characterize barriers to prevention trial participation among medical oncologists and first-degree relatives of their patients.
Physician participants were practicing oncologists in Pennsylvania. Eligible first-degree participants were adult relatives of a cancer patient being treated by one of the study physicians. The influence of perceived psychosocial and practical barriers on level of willingness to participate in cancer prevention clinical trials was investigated.
Response rate was low among physicians, 137/478(29%), and modest among eligible first-degree relatives, 82/129(64%). Lack of access to an eligible population for prevention clinical trials was the most commonly cited barrier to prevention clinical trials among oncologists. Nearly half (45%) of first-degree relatives had not heard of cancer prevention clinical trials, but 68% expressed interest in learning more, and 55% expressed willingness to participate. In the proportional odds model, greater information source seeking/responsiveness (i.e. interest in learning more about clinical prevention trials from more information sources)(p=0.04), and having fewer psychosocial barriers (p=0.02) were associated with a greater willingness to participate.
Many individuals who may be at greater risk for developing cancer because of having a first-degree relative with cancer are unaware of the availability of clinical cancer prevention trials. Nonetheless, many perceive low personal risk associated with these studies, and are interested in learning more.
Cancer; prevention; clinical trials; barriers
The study used a convenience sample of patients undergoing surveillance following curative treatment for localized cancer who completed a paper survey to estimate the maximum copayment patients are willing to pay for better treatment outcomes. Results suggest that patients may be less willing to pay high copayments for treatments with modest benefit. In addition, sociodemographic factors such as education and employment status were associated with willingness to pay.
Cost sharing, intended to control the “overuse” of health care resources, may also reduce use of necessary services. The influence of cost on the treatment choices of patients with life-threatening illness, such as cancer, is unknown.
A convenience sample of patients undergoing surveillance following curative treatment for localized cancer completed a paper survey that included three scenarios to elicit the maximum copayment they would be willing to pay for better treatment outcomes. Scenario A described a treatment for a curable cancer in terms of recurrence risk. Scenarios B and C described treatments for noncurable cancer in terms of the 2-year survival probability and median life expectancy.
The sample (n = 60) was 78% female, 83% aged <65 years, and 58% college graduates. Thirteen percent reported making financial sacrifices to pay for treatment. Patients were willing to pay higher copayments for more effective treatments (p < .05 for all three scenarios). In scenario B, patients who were employed demonstrated a greater willingness to pay (WTP) (odds ratio [OR], 12.6; 95% confidence interval [CI], 2.0–80.4), when controlling for efficacy. In scenario C, college graduates showed greater WTP (OR, 5.0; 95% CI, 1.2–20.9) and patients who reported previous financial sacrifices showed lower WTP (OR, 0.2; 95% CI, 0.04–0.6).
This pilot study suggests that patients may be less willing to pay high copayments for treatments with modest benefit. Even among this relatively young, affluent, and educated population, demographic variables were related to WTP. Larger studies in more diverse populations should be conducted to better understand how cost may influence treatment decisions and cancer treatment outcomes.
The relationship between local, regional, or distant disease control (LC, RC, DC) and maximal posttreatment standardized uptake value (SUVmax) in patients with esophageal cancer has not been elucidated. This study was initiated to explore whether a decrease in SUV on positron emission tomography-computed tomography (PET-CT) scan is associated with LC, RC, or DC in patients with esophageal carcinoma treated with definitive chemoradiotherapy.
Medical records of 40 patients with inoperable esophageal cancer treated with definitive intent and who underwent pre- and posttreatment PET-CT scans were reviewed. The histology, nodal status, tumor location, and radiotherapy (RT) dose were investigated as variables to determine a relationship between SUVmax and LC, RC, and DC as well as disease-free survival (DFS).
Decreased posttreatment SUVmax on PET scan (P = .02) and increased RT dose (P = .009) were the only significant predictors of improved LC on univariate analysis. Mean RT doses in patients with no evidence of disease or with local, regional, or distant recurrences were 5,244, 4,580, 5,094, and 4,968, respectively. Decreased posttreatment SUV (P = .03) and increased RT dose (P = .008) were also associated with an improvement in DFS. Furthermore, decreased posttreatment SUVmax correlated with an improvement in LC (hazard ratio [HR] = 1.3, 95% confidence interval [CI] = 1.03–1.6, P = .03) as well as DFS (HR = 1.3, 95% CI = 1.03–1.6, P = .03). These findings were maintained on multivariate analysis.
Posttreatment decrease in SUV is associated with LC and DFS in esophageal cancer patients receiving definitive chemoradiotherapy. RT dose was also associated with both LC and DFS. The prognostic significance of these findings warrants prospective confirmation.
Infiltration of colorectal carcinomas (CRC) with T-cells has been associated with good prognosis. There are some indications that chemokines could be involved in T-cell infiltration of tumors. Selective modulation of chemokine activity at the tumor site could attract immune cells resulting in tumor growth inhibition. In mouse tumor model systems, gene therapy with chemokines or administration of antibody (Ab)-chemokine fusion proteins have provided potent immune mediated tumor rejection which was mediated by infiltrating T cells at the tumor site. To develop such immunotherapeutic strategies for cancer patients, one must identify chemokines and their receptors involved in T-cell migration toward tumor cells.
To identify chemokine and chemokine receptors involved in T-cell migration toward CRC cells, we have used our previously published three-dimensional organotypic CRC culture system. Organotypic culture was initiated with a layer of fetal fibroblast cells mixed with collagen matrix in a 24 well tissue culture plate. A layer of CRC cells was placed on top of the fibroblast-collagen layer which was followed by a separating layer of fibroblasts in collagen matrix. Anti-CRC specific cytotoxic T lymphocytes (CTLs) mixed with fibroblasts in collagen matrix were placed on top of the separating layer. Excess chemokine ligand (CCL) or Abs to chemokine or chemokine receptor (CCR) were used in migration inhibition assays to identify the chemokine and the receptor involved in CTL migration.
Inclusion of excess CCL2 in T-cell layer or Ab to CCL2 in separating layer of collagen fibroblasts blocked the migration of CTLs toward tumor cells and in turn significantly inhibited tumor cell apoptosis. Also, Ab to CCR2 in the separating layer of collagen and fibroblasts blocked the migration of CTLs toward tumor cells and subsequently inhibited tumor cell apoptosis. Expression of CCR2 in four additional CRC patients' lymphocytes isolated from infiltrating tumor tissues suggests their role in migration in other CRC patients.
Our data suggest that CCL2 secreted by tumor cells and CCR2 receptors on CTLs are involved in migration of CTLs towards tumor. Gene therapy of tumor cells with CCL2 or CCL2/anti-tumor Ab fusion proteins may attract CTLs that potentially could inhibit tumor growth.
To evaluate the impact of a CD-ROM intervention in the education of patients with suspected Lynch syndrome (LS) about microsatellite instability (MSI) and immunohisochemistry (IHC) testing.
Patients and Methods
Two hundred thirteen patients meeting Bethesda criteria were randomly assigned to receive either a brief educational session with a health educator (n = 105) or a brief educational session plus a CD-ROM (n = 108). Assessments were administered at baseline and 2 weeks post-treatment. Primary outcomes included MSI and IHC knowledge and level of satisfaction with and completeness of the preparation to make the decision for MSI testing. Secondary outcomes included decisional conflict, difficulty making the decision, cancer-specific and global anxiety, and level of discussion about MSI testing with family and friends.
Participants in the education plus CD-ROM condition reported significant increases in knowledge about the MSI and IHC tests, greater satisfaction with the preparation to make a decision for testing, lower decisional conflict, and greater decisional self-efficacy. The effects of the education plus CD-ROM on most outcomes were not moderated by preintervention levels of exposure to MSI testing, family support for MSI testing, or the family history of cancer.
Incorporation of new media education strategies for individuals at risk for LS may be a valuable component of the informed consent process. As clinical criteria for MSI and IHC testing continue to expand, the need for alternative educational approaches to meet this increased demand could be met by the self-administered computer-based strategy that we described.
To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics, and preliminary anticancer activity of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor (VEGFR)-2.
Patients and Methods
Patients with advanced solid malignancies were treated once weekly with escalating doses of ramucirumab. Blood was sampled for PK studies throughout treatment. The effects of ramucirumab on circulating vascular endothelial growth factor-A (VEGF-A), soluble VEGFR-1 and VEGFR-2, tumor perfusion, and vascularity using dynamic contrast-enhanced magnetic resonance imaging were assessed.
Thirty-seven patients were treated with 2 to 16 mg/kg of ramucirumab. After one patient each developed dose-limiting hypertension and deep venous thrombosis at 16 mg/kg, the next lower dose (13 mg/kg) was considered the MTD. Nausea, vomiting, headache, fatigue, and proteinuria were also noted. Four (15%) of 27 patients with measurable disease had a partial response (PR), and 11 (30%) of 37 patients had either a PR or stable disease lasting at least 6 months. PKs were characterized by dose-dependent elimination and nonlinear exposure consistent with saturable clearance. Mean trough concentrations exceeded biologically relevant target levels throughout treatment at all dose levels. Serum VEGF-A increased 1.5 to 3.5 times above pretreatment values and remained in this range throughout treatment at all dose levels. Tumor perfusion and vascularity decreased in 69% of evaluable patients.
Objective antitumor activity and antiangiogenic effects were observed over a wide range of dose levels, suggesting that ramucirumab may have a favorable therapeutic index in treating malignancies amenable to VEGFR-2 inhibition.
Cost-sharing, intended to control the “over-use” of healthcare resources, may also reduce utilization of necessary services. The influence of cost on the treatment choices of patients with life-threatening illness such as cancer is unknown.
A convenience sample of patients undergoing surveillance following curative treatment for localized cancer completed a paper survey that included three scenarios to elicit the maximum co-payment they would be willing to pay for improved treatment outcomes. Scenario A described a treatment for a curable cancer in terms of recurrence risk. Scenarios B and C described treatments for non-curable cancer in terms of 2-year survival and median life expectancy. .
The sample (n=60) was 78% female, 83% age <65, and 58% college graduates. 13% reported making financial sacrifices to pay for treatment. Patients were willing to pay higher co-payments for more effective treatments (p<0.05 for all three scenarios). In Scenario B, patients who were employed demonstrated a greater willingness to pay (WTP) (OR 12.6, 95% CI 2.0–80.4), when controlling for efficacy. In Scenario C, college graduates showed greater WTP (OR 5.0, 95% CI 1.2–20.9) and patients who reported previous financial sacrifices showed lower WTP (OR 0.2, 95% CI 0.04–0.6).
This pilot study suggests patients may be less willing to pay high co-payments for treatments with modest benefit. Even among this relatively young, affluent and educated population, demographic variables were related to WTP. Larger studies in more diverse populations should be conducted to better understand how cost may influence treatment decisions and cancer treatment outcomes.
Cost of Illness; Chemotherapy; Cost Sharing; Cancer; Health Care Costs
To evaluate the effect of bevacizumab on the pharmacokinetics (PK) of irinotecan and its active metabolite. Exploratory analyses of the impact of variability in uridine diphosphate glucuronosyltransferase 1A (UGT1A) genes on irinotecan metabolism and toxicity were conducted.
This was an open-labeled, fixed-sequence study of bevacizumab with FOLFIRI (irinotecan, leucovorin, and infusional 5-fluorouracil). Pharmacokinetic assessments were conducted in cycles 1 and 3.
Forty-five subjects were enrolled. No difference in dose-normalized AUC0-last for irinotecan and SN-38 between irinotecan administered alone or in combination with bevacizumab was identified. Leukopenia was associated with higher exposure to both irinotecan and SN-38. UGT1A1 polymorphisms were associated with variability in irinotecan PK. Gastrointestinal toxicity was associated with UGT1A6 genotype. No other associations between UGT1A genotypes and toxicity were detected.
Bevacizumab does not affect irinotecan PK when administered concurrently. A variety of pharmacogenetic relationships may influence the pharmacokinetics of irinotecan and its toxicity.
Purpose: This study was undertaken to describe cancer risk assessment practices among primary care providers (PCPs). Methods: An electronic survey was sent to PCPs affiliated with a single insurance carrier. Demographic and practice characteristics associated with cancer genetic risk assessment and testing activities were described. Latent class analysis supported by likelihood ratio tests was used to define PCP profiles with respect to the level of engagement in genetic risk assessment and referral activity based on demographic and practice characteristics. Results: 860 physicians responded to the survey (39% family practice, 29% internal medicine, 22% obstetrics/gynecology (OB/GYN), 10% other). Most respondents (83%) reported that they routinely assess hereditary cancer risk; however, only 33% reported that they take a full, three-generation pedigree for risk assessment. OB/GYN specialty, female gender, and physician access to a genetic counselor were independent predictors of referral to cancer genetics specialists. Three profiles of PCPs, based upon referral practice and extent of involvement in genetics evaluation, were defined. Conclusion: Profiles of physician characteristics associated with varying levels of engagement with cancer genetic risk assessment and testing can be identified. These profiles may ultimately be useful in targeting decision support tools and services.