Background In the U.S., lung cancer accounts for 14% of cancer diagnoses and 28% of cancer deaths annually. Since no cure exists for advanced lung cancer, the main treatment goal is to prolong survival. Chemotherapy regimens produce side effects with different profiles. Coupling this with individual patient’s preferred side effects could result in patient-centered choices leading to better treatment outcomes. There are apparently no previous studies of or tools for assessing and utilizing patient chemotherapy preferences in clinical settings. The long-term goal of the study was to facilitate patients’ treatment choices for advanced-stage lung cancer. A primary aim was to determine how preferences for chemotherapy side effects relate to chemotherapy choices. Methods An observational, longitudinal, open cohort study of patients with advanced-stage non-small cell lung cancer (NSCLC) was conducted. Data sources included patient medical records and from one to three interviews per subject. Data were analyzed using Chi-square, Fisher’s Exact and McNamara’s test, and logistic regression. Results Patients identified the top three chemotherapy side effects that they would most like to avoid: shortness of breath, bleeding, and fatigue. These side effects were similar between first and last interviews, although the rank order changed after patients experienced chemotherapy. Conclusions Patients ranked drug side effects that they would most like to avoid. Patient-centered clinical care and patient-centered outcomes research are feasible and may be enhanced by stakeholder commitment. The study results are limited to patients with advanced NSCLC. Most of the subjects were White, since patients were drawn from the U.S. Midwest, a predominantly White population.
Purpose We performed a UGT1A1 genotype-guided study to determine the maximum tolerated dose (MTD) and evaluate the toxicities and pharmacokinetics of the combination of capecitabine (CAP), oxaliplatin (OX), and irinotecan (IRIN). Experimental Design Patients were screened for UGT1A1 *28 genotype prior to treatment. The starting dose (mg/m2) was IRIN (150), OX (85) and CAP (400), days 2-15. Doses were escalated or de-escalated within each genotype group (*28/*28, *1/*28 and *1/*1). IRIN pharmacokinetics was performed at the MTD. Results 50 patients were evaluable for toxicity [11 (*28/*28); 18 (*1/*28); 21 (*1/*1)]. UGT1A1 *28/*28 patients experienced hematologic dose limiting toxicity (DLT), requiring dose-de-escalation. The UGT1A1 *28/*28 recommended phase 2 dose (RP2D) was IRIN (75), OX (85), and CAP (400). In contrast, both UGT1A1 *1/*28 and *1/*1 tolerated higher doses of IRIN and non-hematologic toxicity was dose limiting for UGT1A1 *1/*1. The RP2D was IRIN (150), OX (85), and CAP (400) for UGT1A1*1/*28 and IRIN (150), OX (100), and CAP (1600) for UGT1A1 *1/*1. UGT1A1 *1/*28 and *1/*1 patients treated with IRIN (150) had similar AUCs for the active irinotecan metabolite, SN38 (366 +/− 278 and 350 +/− 159 ng/ml*hr, respectively). UGT1A1 *28/*28 patients (n=3) treated with a lower IRIN dose (100) had non-significantly higher mean SN38 exposures (604 +/− 289 ng/ml*hr, p=0.14). Antitumor activity was observed in all genotype groups. Conclusions UGT1A1 genotype affects the dose and pharmacokinetics of the CAPIRINOX regimen and UGT1A1 genotype-guided dosing of CAPIRINOX is ongoing in a phase II study of small bowel cancer (NCT00433550).
IntroductionDuctal carcinoma in situ (DCIS) of the breast is a heterogeneous group of proliferative cellular lesions that have the potential to become invasive. Very little is known about the molecular alterations involved in the progression from DCIS to invasive ductal carcinoma (IDC). Heparan endosulfatase (HSulf-2) edits sulfate moieties on heparan sulfate proteoglycans (HSPGs) and has been implicated in modulating heparin binding growth factor signaling, angiogenesis and tumorigenesis. However, the role of HSulf-2 in breast cancer progression is poorly understood. MCF10DCIS.com cells (referred as MCF10DCIS) express HSulf-2 and form comedo type DCIS and progress to IDC when transplanted in immune-deficient mice and, therefore, is an ideal model to study breast cancer progression. We evaluated the role of HSulf-2 in progression from DCIS to IDC using mouse fat pad mammary xenografts.MethodsNon-target control (NTC) and HSulf-2 knockdown in MCF10DCIS breast cancer cells were achieved by NTC shRNA and two different lentiviral shRNA against HSulf-2 respectively. Xenografts were established by injecting NTC and HSulf-2 deficient MCF10DCIS cells in mouse mammary fat pads. Xenografts were subjected to H&E staining for morphological analysis, TUNEL and Propidium iodide staining (to determine the extent of apoptosis), Western blot analysis and zymography.ResultsUsing a mouse mammary fat pad derived xenograft model, we observed that compared to control treated xenografts, down-regulation of HSulf-2 was associated with significant delays in growth at Week 7 (P-value < 0.05). Histological examination of the tumors demonstrated substantial differences in comedo necrosis, with marked luminal apoptosis and up-regulation of apoptotic markers Bim, cleaved PARP and cleaved caspase 3 in HSulf-2 depleted xenografts. Furthermore, HSulf-2 depleted xenografts retained the basement membrane integrity with decreased activity and expression of matrix metalloproteinase 9 (MMP-9), an enzyme critical for degradation of extracellular matrix compared to nontargeted control.ConclusionOur data suggest that HSulf-2 expression may be critical for human breast cancer progression. Down-regulation of HSulf-2 leads to retention of comedo type DCIS and delays the progression of DCIS to IDC. Further studies are necessary to determine if therapeutic targeting of HSulf-2 expression might delay the progression of DCIS to IDC.
PURPOSE: In the United States, lung cancer accounts for 14% of cancer diagnoses and 28% of cancer deaths annually. Because no cure exists for advanced lung cancer, the primary treatment goal is to prolong survival. OBJECTIVES: The study aim was to determine whether individual preferences, characteristics, and treatment experiences affect the meaning of treatment success. MATERIALS AND METHODS: A quantitative study using an observational, longitudinal cohort of patients with advanced stage non–small-cell lung cancer was conducted. Data sources included medical records and patient interviews. Data were analyzed using χ2, Fisher’s exact, and McNemar’s tests, as well as logistic regressions. RESULTS: At the first interview of 235 individuals, 12% considered survival alone as their definition of treatment success; others defined treatment success as survival plus other aspects, such as quality of life and reaching an important personal goal. As they moved through chemotherapy, 47% of the patients changed their definition of treatment success. Bivariate analysis showed that patients with lower incomes tended to be more likely to change their definition of treatment success compared with their counterparts with higher income ( P = .0245). CONCLUSION: By taking chemotherapy, patients expect to increase their odds of survival and want to maintain the quality of life and functionality. A patient’s definition of treatment success is often changing as treatment continues, making it appropriate to ensure patient-provider communication throughout their clinical care. The study results are limited to patients with advanced non–small-cell lung cancer and drawn from a predominantly white patient population, mainly from the US Midwest.
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