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
When making treatment decisions, cancer patients must make trade-offs among efficacy, toxicity and cost. However little is known about what patient characteristics may influence these trade-offs.
400 cancer patients reviewed two of three stylized curative and non-curative scenarios that asked them to choose between two treatments of varying levels of efficacy, toxicity and cost. Each scenario which included nine choice sets. Demographics, cost concerns, numeracy and optimism were assessed. Within each scenario, we used latent class methods to distinguish groups with discrete preferences. We then used regressions with group membership probabilities as covariates to identify associations.
Median age was 61 years (range 27-90). 25% were enrolled at a community hospital. and 99% were insured. Three latent classes were identified that demonstrated 1) Preference for survival or aversion to 2) high cost or 3) toxicity. Across all scenarios, patients with higher income were more likely to be in the class that favored survival. Lower income patients were more likely to be in the class that was averse to high cost (p<.05). Similar associations were found between education, employment status, numeracy, cost concerns and latent class.
Even in these stylized scenarios, socioeconomic status (SES) predicted treatment choice. Higher income patients may be more likely to focus on survival while those of lower SES may be more likely to avoid expensive treatment, regardless of survival or toxicity. This raises the possibility that insurance plans with greater cost-sharing may have the unintended consequence of increasing disparities in cancer care.
Cancer patients and their oncologists often report differing perceptions of consultation discussions and discordant expectations regarding treatment outcomes. CONNECT™, a computer-based communication aid, was developed to improve communication between patients and oncologists.
CONNECT includes assessment of patient values, goals, and communication preferences; patient communication skills training; and a pre-consult physician summary report. CONNECT was tested in a three-arm, prospective, randomized clinical trial. Prior to the initial medical oncology consultation, adult patients with advanced cancer were randomized to (a) control; (b) CONNECT with physician summary, or (c) CONNECT without physician summary. Outcomes were assessed with post-consultation surveys.
Of 743 patients randomized, 629 completed post-consultation surveys. Patients in the intervention arms (versus control) felt that the CONNECT program made treatment decisions easier to reach (p=0.003) and helped them to be more satisfied with these decisions (p<0.001). In addition, patients in the intervention arms reported higher levels of satisfaction with physician communication format (p=0.026) and discussion regarding support services (p=0.029) and quality of life concerns (p=0.042). The physician summary did not impact outcomes. Patients with higher levels of education and poorer physical functioning experienced greater benefit from CONNECT.
This prospective randomized clinical trial demonstrates that computer-based communication skills training can positively affect patient satisfaction with communication and decision making. Measureable patient characteristics may be used to identify subgroups most likely to benefit from an intervention such as CONNECT.
Cancer communication; health communication; physician-patient communication; decision making; computer assisted; cancer
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.
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.
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
Cancer is responsible for approximately 7.6 million deaths per year worldwide. A 2012 survey in the United Kingdom found dramatic improvement in survival rates for childhood cancer because of increased participation in clinical trials. Unfortunately, overall patient participation in cancer clinical studies is low. A key logistical barrier to patient and physician participation is the time required for identification of appropriate clinical trials for individual patients. We introduce the Trial Prospector tool that supports end-to-end management of cancer clinical trial recruitment workflow with (a) structured entry of trial eligibility criteria, (b) automated extraction of patient data from multiple sources, (c) a scalable matching algorithm, and (d) interactive user interface (UI) for physicians with both matching results and a detailed explanation of causes for ineligibility of available trials. We report the results from deployment of Trial Prospector at the National Cancer Institute (NCI)-designated Case Comprehensive Cancer Center (Case CCC) with 1,367 clinical trial eligibility evaluations performed with 100% accuracy.
clinical trial; gastrointestinal cancer; clinical oncology; patient recruitment; clinical decision support system
In 2010, the National Cancer Institute and the American Society of Clinical Oncology cosponsored a symposium to examine the state of clinical trial accrual science and identify opportunities to facilitate trial enrollment. The authors provide recommendations for best practices and for future research developed from the symposium.
Many challenges to clinical trial accrual exist, resulting in studies with inadequate enrollment and potentially delaying answers to important scientific and clinical questions.
The National Cancer Institute (NCI) and the American Society of Clinical Oncology (ASCO) cosponsored the Cancer Trial Accrual Symposium: Science and Solutions on April 29-30, 2010 to examine the state of accrual science related to patient/community, physician/provider, and site/organizational influences, and identify new interventions to facilitate clinical trial enrollment. The symposium featured breakout sessions, plenary sessions, and a poster session including 100 abstracts. Among the 358 attendees were clinical investigators, researchers of accrual strategies, research administrators, nurses, research coordinators, patient advocates, and educators. A bibliography of the accrual literature in these three major areas was provided to participants in advance of the meeting. After the symposium, the literature in these areas was revisited to determine if the symposium recommendations remained relevant within the context of the current literature.
Few rigorously conducted studies have tested interventions to address challenges to clinical trials accrual. Attendees developed recommendations for improving accrual and identified priority areas for future accrual research at the patient/community, physician/provider, and site/organizational levels. Current literature continues to support the symposium recommendations.
A combination of approaches addressing both the multifactorial nature of accrual challenges and the characteristics of the target population may be needed to improve accrual to cancer clinical trials. Recommendations for best practices and for future research developed from the symposium are provided.
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
Combining cytotoxic agents with bevacizumab has yielded significant benefits in a number of solid tumors. Combining small-molecule kinase inhibitors of VEGFR with chemotherapy has yet to demonstrate clinical benefit. The dose, schedule and agents used may be critical to the development of this combinatorial therapy.
We performed a phase I trial of sunitinib and gemcitabine in patients with advanced solid tumor malignancies based on strong preclinical rationale.
Two different MTDs were determined. The schedule of gemcitabine 800 mg/m2 on days 1, 8, 15 and sunitinib 25 mg daily was considered to be a MTD. However, omission of day 15 gemcitabine was common, and thus, a second MTD of gemcitabine of 675 mg/m2 on days 1 and 8 with sunitinib 25 mg daily was determined to be the recommended phase II dose. Grade 4 neutropenia and thrombocytopenia occurred in 33 and 6 %, respectively. Grade 3/4 non-hematological toxicities were uncommon. Four of 33 patients had a partial response. Another 11 patients had stable disease ranging from 3 to 36 months. Thus, the recommended phase II dose of this combination is gemcitabine 675 mg/m2 on days 1 and 8 on an every 21-day schedule along with sunitinib 25 mg continuous daily.
This combination is well-tolerated and has significant clinical activity.
Phase I; Sunitinib; Gemcitabine; Pancreatic cancer
This article describes the rigorous development process and initial feedback of the PRE-ACT (Preparatory Education About Clinical Trials) web-based- intervention designed to improve preparation for decision making in cancer clinical trials.
The multi-step process included stakeholder input, formative research, user testing and feedback. Diverse teams (researchers, advocates and developers) participated including content refinement, identification of actors, and development of video scripts. Patient feedback was provided in the final production period and through a vanguard group (N = 100) from the randomized trial.
Patients/advocates confirmed barriers to cancer clinical trial participation, including lack of awareness and knowledge, fear of side effects, logistical concerns, and mistrust. Patients indicated they liked the tool’s user-friendly nature, the organized and comprehensive presentation of the subject matter, and the clarity of the videos.
The development process serves as an example of operationalizing best practice approaches and highlights the value of a multi-disciplinary team to develop a theory-based, sophisticated tool that patients found useful in their decision making process.
Practice implications Best practice approaches can be addressed and are important to ensure evidence-based tools that are of value to patients and supports the usefulness of a process map in the development of e-health tools.
Decision support tools; Decision aids; Clinical trials; Cancer
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.
Cost concerns are common among patients with cancer who have health insurance. Health care providers may alleviate concerns by discussing cost-related concerns with all patients, not only those of lower socioeconomic status or those without insurance.
Health care providers are accustomed to identifying populations for whom cost-related concerns may be a significant barrier, such as the poor, but few empiric data have been collected to substantiate such assumptions, particularly among insured patients.
Patients with cancer from academic and community hospitals completed a questionnaire that included closed-ended items concerning demographic variables, optimism, numeracy, and concerns about present and future medical costs. In addition, they answered open-ended questions regarding cost concerns and medical expenses.
Nearly all (99%) participants were insured. In response to the closed-ended questions, 30.3% of patients reported concern about paying for their cancer treatment, 22.3% reported that their family had made sacrifices to pay for their care, and 8.3% stated that their insurance adequately covered their current health care costs, and 17.3% reported concerns about coverage for their costs in the future. On open-ended questions, 35.3% reported additional expenses, and 47.5% reported concerns about health care costs. None of the assessed patient characteristics proved to be a robust predictor across all cost-related concerns. There was a strong association between the identification of concerns or expenses on the open-ended questions and concerns on closed-ended questions.
Cost concerns are common among patients with cancer who have health insurance. Health care providers may alleviate concerns by discussing cost-related concerns with all patients, not only those of lower socioeconomic status or those without insurance. A closed-ended screening question may help to initiate these conversations. This may identify potential resources, lower distress, and enable patients to make optimal treatment decisions.
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.
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.
Optimal patient decision making requires integration of patient values, goals, and preferences with information received from the physician. In the case of life-threatening illness such as cancer, the weights placed on quality of life (QOL) and length of life (LOL) represent critical values. The objective of this study is to describe cancer patient values regarding QOL and LOL, and explore associations with communication preferences.
Patients with advanced cancer completed a computer-based survey prior to the initial consultation with a medical oncologist. Assessments included sociodemographics, physical and mental health state, values regarding quality and length of life, communication preferences and cancer-related distress.
Seven hundred forty three advanced cancer patients were enrolled. Among 459 advanced cancer patients, fifty-five percent of patients equally valued QOL and LOL, 27% preferred QOL, and 18% preferred LOL. Patients with a QOL preference had lower levels of cancer-related distress (p < 0.001). QOL preference was associated with older age (p = 0.001), male gender (p = 0.003), and higher education (p = 0.062). Patients who preferred LOL over QOL desired a more supportive and less pessimistic communication style from their oncologists.
These data indicate that a values preference for length vs. quality of life may be simply measured, and is associated with wishes regarding the nature of oncologist communication. Awareness of these values during the clinical encounter could improve decision making by influencing the style and content of the communication between oncologists and their patients.
Quality of Life; Cancer Communication; Doctor-Patient Communication; Patient Preferences; Communication Preferences; Cancer-Related Distress; Length of Life Preferences; Patient Decision Making; Cancer Communication Aid; Patient Values
Approximately one-third of those treated curatively for colorectal cancer (CRC) will experience recurrence. No evidence-based consensus exists on how best to follow patients after initial treatment to detect asymptomatic recurrence. Here, a new approach for simulating surveillance and recurrence among CRC survivors is outlined, and development and calibration of a simple model applying this approach is described. The model’s ability to predict outcomes for a group of patients under a specified surveillance strategy is validated.
We developed an individual-based simulation model consisting of two interacting submodels: a continuous-time disease-progression submodel overlain by a discrete-time Markov submodel of surveillance and re-treatment. In the former, some patients develops recurrent disease which probabilistically progresses from detectability to unresectability, and which may produce early symptoms leading to detection independent of surveillance testing. In the latter submodel, patients undergo user-specified surveillance testing regimens. Parameters describing disease progression were preliminarily estimated through calibration to match five-year disease-free survival, overall survival at years 1–5, and proportion of recurring patients undergoing curative salvage surgery from one arm of a published randomized trial. The calibrated model was validated by examining its ability to predict these same outcomes for patients in a different arm of the same trial undergoing less aggressive surveillance.
Calibrated parameter values were consistent with generally observed recurrence patterns. Sensitivity analysis suggested probability of curative salvage surgery was most influenced by sensitivity of carcinoembryonic antigen assay and of clinical interview/examination (i.e. scheduled provider visits). In validation, the model accurately predicted overall survival (59% predicted, 58% observed) and five-year disease-free survival (55% predicted, 53% observed), but was less accurate in predicting curative salvage surgery (10% predicted; 6% observed).
Initial validation suggests the feasibility of this approach to modeling alternative surveillance regimens among CRC survivors. Further calibration to individual-level patient data could yield a model useful for predicting outcomes of specific surveillance strategies for risk-based subgroups or for individuals. This approach could be applied toward developing novel, tailored strategies for further clinical study. It has the potential to produce insights which will promote more effective surveillance—leading to higher cure rates for recurrent CRC.
Colorectal cancer; Recurrence; Surveillance; Follow-up; Model
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)
Src, EphA2, and platelet-derived growth factor receptors α and β are dysregulated in pancreatic ductal adenocarcinoma (PDAC). Dasatinib is an oral multitarget tyrosine kinase inhibitor that targets BCR-ABL, c-Src, c-KIT, platelet-derived growth factor receptor β, and EphA2. We conducted a phase II, single-arm study of dasatinib as first-line therapy in patients with metastatic PDAC.
Dasatinib (100 mg twice a day, later reduced to 70 mg twice a day because of toxicities) was orally administered continuously on a 28-day cycle. The primary endpoint was overall survival (OS). Response was measured using the Response Evaluation Criteria in Solid Tumors. Circulating tumor cells (CTCs) were also collected.
Fifty-one patients enrolled in this study. The median OS was 4.7 months (95% confidence interval [CI]: 2.8–6.9 months). Median progression-free survival was 2.1 months (95% CI: 1.6–3.2 months). In 34 evaluable patients, the best response achieved was stable disease in 10 patients (29.4%). One patient had stable disease while on treatment for 20 months. The most common nonhematologic toxicities were fatigue and nausea. Edema and pleural effusions occurred in 29% and 6% of patients, respectively. The number of CTCs did not correlate with survival.
Single-agent dasatinib does not have clinical activity in metastatic PDAC.
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
Bevacizumab improves survival for metastatic colorectal cancer patients with chemotherapy, but no proven predictive markers exist. The VEGF-A splice form, VEGF165b, anti-angiogenic in animal models, binds bevacizumab. We tested the hypothesis that prolonged progression-free survival (PFS) would occur only in patients with low relative VEGF165b levels treated with bevacizumab.
Blinded tumor samples from the phase-III trial of FOLFOX4±bevacizumab were assessed for VEGF165b and VEGFtotal by immunohistochemistry and scored relative to normal tissue. A predictive index (PI) was derived from the ratio of VEGF165b:VEGFtotal for 44 samples from patients treated with FOLFOX+bevacizumab (Arm A) and 53 samples from patients treated with FOLFOX4 (Arm B), and PFS, and overall survival (OS) analysed based on PI relative to median ratio.
Unadjusted analysis of PFS showed significantly better outcome for individuals with VEGF165b:VEGFtotal ratio scores below median treated with FOLFOX4+bevacizumab compared to FOLFOX4 alone (median 8.0 months vs 5.2 months, p<0.02), but no effect of bevacizumab on PFS in patients with VEGF165b:VEGFtotal ratio >median (5.9 months vs 6.3 months). These findings held after adjustment for other clinical and demographic features. Overall survival (OS) was increased in Arm A (median 13.6 months) compared with Arm B (10.6 months) in the low VEGF165b group, but this did not reach statistical significance. There was no difference in the high VEGF165b:VEGFtotal group between FOLFOX+bevacizumab (10.8 months) and FOLFOX alone (11.3months).
Low VEGF165b:VEGFtotal ratio may be a predictive marker for bevacizumab in metastatic colorectal cancer, and individuals with high relative levels may not benefit.
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.