Caregiver-oncologist prognostic concordance, caregiving esteem, and caregiver outcomes.

INTRODUCTION: Caregiver-oncologist concordance regarding the patient's prognosis is associated with worse caregiver outcomes (e.g., depressive symptoms), but mechanisms underpinning these associations are unclear. We explored whether caregiving esteem mediates these associations. METHODS: At enrollment, caregivers and oncologists used a 5-point ordinal scale to estimate patient survival; identical responses were considered concordant. At 4-6 weeks, caregivers completed an assessment of the extent to which caregiving imparts self-esteem (Caregiver Reaction Assessment self-esteem subscale; range 0-5; higher score indicates greater esteem). They also completed Patient Health Questionnaire-2 (PHQ-2) for depressive symptoms, Distress Thermometer, and 12-Item Short Form Survey for quality of life (QoL). Mediation analysis with bootstrapping (PROCESS macro by Hayes) was used to estimate the extent to which caregiving mediated the effects of prognostic concordance on caregiver outcomes through caregiving esteem. RESULTS: Prognostic concordance occurred in 28% the caregiver-oncologist dyads; 85% of the discordance were due to caregivers estimating a longer patient's survival. At 4-6 weeks, mean caregiving esteem score was 4.4 (range 1.5-5.0). Lower caregiving esteem mediated the associations of concordance with higher PHQ-2 [indirect effect = 0.12; 95% Confidence Interval (CI) 0.03, 0.27], greater distress (indirect effect =0.25; 95% CI 0.08, 0.48), and poorer QoL (indirect effect = -1.50; 95% CI -3.06, -0.41). Caregiving esteem partially mediated 39%, 64%, and 48% of the associations between caregiver-oncologist concordance and PHQ-2, distress, and SF-12, respectively. CONCLUSIONS: Caregiver-oncologist concordance was associated with lower caregiving esteem. Lower caregiving esteem mediated the negative relationship between caregiver-oncologist concordance and caregiver outcomes.

Association Between Pretreatment Sleep Disturbance and Radiation Therapy-Induced Pain in 573 Women With Breast Cancer.

CONTEXT: Pain can be a debilitating side effect of radiation therapy (RT). Data from the general population have shown that sleep disturbance can influence pain incidence and severity; however, less is known about this relationship in patients with breast cancer receiving RT. OBJECTIVES: This secondary analysis examined the association of pretreatment moderate/severe levels of sleep disturbance with subsequent RT-induced pain after adjusting for pre-RT pain. METHODS: We report on 573 female patients with breast cancer undergoing RT from a previously completed Phase II clinical trial for radiation dermatitis. Sleep disturbance, total pain, and pain subdomains-sensory pain, affective pain, and perceived pain intensity were assessed at pre-RT and post-RT. At pre-RT, patients were dichotomized into two groups: those with moderate/severe sleep disturbance (N = 85) vs. those with no/mild sleep disturbance (control; N = 488). RESULTS: At pre-RT, women with moderate/severe sleep disturbance were younger, less likely to be married, more likely to have had mastectomy and chemotherapy, and more likely to have depression/anxiety disorder and fatigue than the control group (all Ps < 0.05). Generalized estimating equations model, after controlling for pre-RT pain and other covariates (e.g., trial treatment condition and covariates that were significantly correlated with post-RT pain), showed that women with moderate/severe sleep disturbance at pre-RT vs. control group had significantly higher mean post-RT total pain as well as sensory, affective, and perceived pain (effect size = 0.62, 0.60, 0.69, and 0.52, respectively; all Ps < 0.05). CONCLUSION: These findings suggest that moderate/severe disturbed sleep before RT is associated with increased pain from pre-to-post-RT in patients with breast cancer.

Oral curcumin for radiation dermatitis: a URCC NCORP study of 686 breast cancer patients.

PURPOSE: Despite advances in medical technology, radiation dermatitis occurs in 95% of patients receiving radiation therapy (RT) for cancer. Currently, there is no standard and effective treatment for the prevention or control of radiation dermatitis. The goal of the study was to determine the efficacy of oral curcumin, one of the biologically active components in turmeric, at reducing radiation dermatitis severity (RDS) at the end of RT, using the RDS scale, compared to placebo. METHODS: This was a multisite, randomized, double-blinded, placebo-controlled trial of 686 breast cancer patients. Patients took four 500-mg capsules of placebo or curcumin three times daily throughout their prescribed course of RT until 1 week post-RT. RESULTS: A total of 686 patients were included in the final analyses (87.5% white females, mean age = 58). Linear mixed-model analyses demonstrated that curcumin did not reduce radiation dermatitis severity at the end of RT compared to placebo (B (95% CI) = 0.044 (- 0.101, 0.188), p = 0.552). Fewer curcumin patients with RDS > 3.0 suggested a trend toward reduced severity (7.4 vs. 12.9%, p = 0.082). Patient-reported changes in pain, symptoms, and quality of life were not statistically significant between arms. CONCLUSIONS: Oral curcumin did not significantly reduce radiation dermatitis severity compared to placebo. The skin rating variation and broad eligibility criteria could not account for the undetectable therapeutic effect. An objective measure for radiation dermatitis severity and further exploration for an effective treatment for radiation dermatitis is warranted.

Phase II study of paclitaxel plus the protein kinase C inhibitor bryostatin-1 in advanced pancreatic carcinoma.

PURPOSE: To determine the efficacy and toxicity of the protein kinase C inhibitor bryostatin-1 plus paclitaxel in patients with advanced pancreatic carcinoma. METHODS: Each treatment cycle consisted of paclitaxel 90 mg/m by intravenous infusion over 1 hour on days 1, 8, and 16, plus bryostatin 25 mcg/m as a 1-hour intravenous infusion on days 2, 9, and 15, given every 28 days. Patients were evaluated for response after every 2 treatment cycles, and continued therapy until disease progression or prohibitive toxicity. The primary objective was to determine whether the combination produced a response rate of at least 30%. RESULTS: Nineteen patients with locally advanced or metastatic pancreatic adenocarcinoma received a total of 52 cycles of therapy (range: 1-10). Patients received the combination as first-line therapy for advanced disease (N = 5) or after prior chemotherapy used alone or in combination with local therapy. No patients had a confirmed objective response. The median time to treatment failure was 1.9 months (95% confidence intervals: 1.2, 2.6 months). Reasons for discontinuing therapy included progressive disease or death in 14 patients (74%) or because of adverse events or patient choice in 5 patients (26%). The most common grade 3 to 4 toxicities included leukopenia in 26%, anemia in 11%, myalgias in 11%, gastrointestinal bleeding in 11%, infection in 10%, and thrombosis in 10%. CONCLUSION: The combination of weekly paclitaxel and bryostatin-1 is not an effective therapy for patients with advanced pancreatic carcinoma.

A phase I trial of oblimersen sodium in combination with cisplatin and 5-fluorouracil in patients with advanced esophageal, gastroesophageal junction, and gastric carcinoma.

PURPOSE: To determine the maximum tolerated dose of oblimersen, an antisense oligonucleotide directed to the Bcl-2 mRNA, in combination with cisplatin and 5-flourouracil in patients with advanced gastric and esophageal carcinoma. METHODS: Patients were treated with escalating doses of oblimersen administered by continuous intravenous infusion (CIVI) days 1 to 7, CIVI 5-fluorouracil (5-FU) days 4 to 7, and cisplatin on day 4 every 3 weeks. RESULTS: Fifteen patients received a total of 49 courses of oblimersen at doses of 3, 5, or 7 mg/kg/d given as a 7 day CIVI in combination with 4 or 5 day CIVI of 5-FU (1000 or 750 mg/m2/d) plus intravenous cisplatin (100 or 75 mg/m2 over 2 hours). The recommended phase II dose of oblimersen was 5 mg/kg/d in combination with 5-FU (750 mg/m2/d for 4 days) and cisplatin (75 mg/m). The most common grade 3 to 4 adverse events that occurred in at least 10% of patients at all dose levels included neutropenia (33%), hypokalemia (27%), infection (20%), and mucositis, fatigue, dizziness, thrombosis, and dehydration (in 13% for each category). CONCLUSION: The combination of oblimersen with 5-FU and cisplatin chemotherapy is feasible in patients with advanced upper gastrointestinal cancer, with antitumor activity observed in gastric carcinoma.

Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women's Intervention Nutrition Study.

BACKGROUND: Preclinical and observational studies suggest a relationship between dietary fat intake and breast cancer, but the association remains controversial. We carried out a randomized, prospective, multicenter clinical trial to test the effect of a dietary intervention designed to reduce fat intake in women with resected, early-stage breast cancer receiving conventional cancer management. METHODS: A total of 2437 women were randomly assigned between February 1994 and January 2001 in a ratio of 40:60 to dietary intervention (n = 975) or control (n = 1462) groups. An interim analysis was performed after a median follow-up of 60 months when funding for the intervention ceased. Mean differences between dietary intervention and control groups in nutrient intakes and anthropometric variables were compared with t tests. Relapse-free survival was examined using Kaplan-Meier analysis, stratified log-rank tests, and Cox proportional hazards models. Statistical tests were two-sided. RESULTS: Dietary fat intake was lower in the intervention than in the control group (fat grams/day at 12 months, 33.3 [95% confidence interval {CI} = 32.2 to 34.5] versus 51.3 [95% CI = 50.0 to 52.7], respectively; P<.001), corresponding to a statistically significant (P = .005), 6-pound lower mean body weight in the intervention group. A total of 277 relapse events (local, regional, distant, or ipsilateral breast cancer recurrence or new contralateral breast cancer) have been reported in 96 of 975 (9.8%) women in the dietary group and 181 of 1462 (12.4%) women in the control group. The hazard ratio of relapse events in the intervention group compared with the control group was 0.76 (95% CI = 0.60 to 0.98, P = .077 for stratified log rank and P = .034 for adjusted Cox model analysis). Exploratory analyses suggested a differential effect of the dietary intervention based on hormonal receptor status. CONCLUSIONS: A lifestyle intervention reducing dietary fat intake, with modest influence on body weight, may improve relapse-free survival of breast cancer patients receiving conventional cancer management. Longer, ongoing nonintervention follow-up will address original protocol design plans, which called for 3 years of follow-up after completion of recruitment.

Phase I and pharmacokinetic study of LY293111, an orally bioavailable LTB4 receptor antagonist, in patients with advanced solid tumors.

PURPOSE: LY293111, a novel diaryl ether carboxylic acid derivative, is a potent and selective inhibitor of the lipoxygenase pathway either directly through 5'-lipoxygenase or via antagonism of the leukotriene B4 (LTB4) receptor. More recently it has been determined to have peroxisome proliferator activated receptor-gamma agonist (PPARgamma) activity. LY293111 has antineoplastic activity in a variety of preclinical models. The tolerability and pharmacokinetics of LY293111 administered continuously, by mouth, BID for repeat cycles of 21 days was evaluated. PATIENTS AND METHODS: Thirty-eight patients with advanced solid tumors were treated at five dose levels (200 to 800 mg BID) for a total of 102 cycles. RESULTS: The most common toxicity was diarrhea (76%). One patient at 600 mg BID (n = 11) and two at 800 mg BID (n = 8), experienced dose-limiting grade 3 diarrhea. Dose reductions and/or delays were infrequent. Increases in steady-state maximum plasma concentration (Cmax,ss) and area under the steady-state plasma concentration time curve 0 to 12 hours (AUCtau,ss) on day 8 could be considered to be dose-proportional over the four-fold-dose range. Interpatient variability in Cmax,ss and AUCtau,ss was estimated to be 65% and 71% respectively. There was a small increase in AUC (1.37; 90% CI, 0.85 to 2.21) between single and multiple doses. Two patients with progressive chondrosarcoma and melanoma had stable disease lasting approximately 336 and 168 days, respectively. CONCLUSION: LY293111 can be administered safely by continuous oral therapy with mild toxicities. Diarrhea is dose-limiting. The recommended phase II dose will be 600 mg BID. The steady-state concentrations in humans exceed relevant levels observed in preclinical models.

Telomere length and telomerase activity delineate distinctive replicative features of the B-CLL subgroups defined by immunoglobulin V gene mutations.

Patients with B-cell chronic lymphocytic leukemia (B-CLL) segregate into subgroups with very different survival times. Because clinical observations suggest that leukemic cells accumulate at different rates, we measured telomere length and telomerase activity in B-CLL cells to distinguish differences in cellular replication. Our data indicate that the telomeres of B-CLL cells are shorter than telomeres of B cells from healthy subjects, indicating that the leukemic cells have a prolonged proliferative history. Leukemic cells of the immunoglobulin V gene mutation subgroups differ in telomere length and telomerase activity. B lymphocytes from the subgroup with poor outcome and with limited IgV gene mutations have uniformly shorter telomeres and more telomerase activity than those from the subgroup with better outcome and with considerable mutations. Differences in telomere length appear to largely reflect the proliferative histories of precursors of the leukemic cells, although differences in cell division, masked by the action of telomerase, cannot be excluded. These results may provide insight into the stages of maturation and the activation pathways of the cells that give rise to B-CLL. In addition, they reinforce the concept that B-CLL is not simply an accumulative disease of slowly dividing B lymphocytes but possibly one of B cells with extensive proliferative histories.

Chronic lymphocytic leukemia B cells can undergo somatic hypermutation and intraclonal immunoglobulin V(H)DJ(H) gene diversification.

Chronic lymphocytic leukemia (CLL) arises from the clonal expansion of a CD5(+) B lymphocyte that is thought not to undergo intraclonal diversification. Using V(H)DJ(H) cDNA single strand conformation polymorphism analyses, we detected intraclonal mobility variants in 11 of 18 CLL cases. cDNA sequence analyses indicated that these variants represented unique point-mutations (1-35/patient). In nine cases, these mutations were unique to individual submembers of the CLL clone, although in two cases they occurred in a large percentage of the clonal submembers and genealogical trees could be identified. The diversification process responsible for these changes led to single nucleotide changes that favored transitions over transversions, but did not target A nucleotides and did not have the replacement/silent nucleotide change characteristics of antigen-selected B cells. Intraclonal diversification did not correlate with the original mutational load of an individual CLL case in that diversification was as frequent in CLL cells with little or no somatic mutations as in those with considerable mutations. Finally, CLL B cells that did not exhibit intraclonal diversification in vivo could be induced to mutate their V(H)DJ(H) genes in vitro after stimulation. These data indicate that a somatic mutation mechanism remains functional in CLL cells and could play a role in the evolution of the clone.

B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes.

B-cell chronic lymphocytic leukemia (B-CLL) is considered an accumulative disease of antigen-naive CD5(+) B lymphocytes that circulate in the resting state. However, to evaluate the possibility that B-CLL cells resemble antigen-experienced and activated B cells, we analyzed the expression of markers of cellular activation and differentiation on CD5(+)CD19(+) cells from B-CLL patients and from age-matched healthy donors. The leukemic cells from all B-CLL patients, including those that lack significant numbers of V gene mutations, bear the phenotype of activated B cells based on the overexpression of the activation markers CD23, CD25, CD69, and CD71 and the underexpression of CD22, Fcgamma receptor IIb, CD79b, and immunoglobulin D that are down-regulated by cell triggering and activation. Furthermore, these leukemic cells resemble antigen-experienced lymphocytes in the underexpression of molecules that are down-regulated by cell triggering and in the uniform expression of CD27, an identifier of memory B cells. A comparison of the phenotypes of B-CLL patients with and without immunoglobulin V gene mutations suggests that the 2 subgroups differ both in specific marker expression (CD69, CD71, CD62 L, CD40, CD39, and HLA-DR) and in the time since antigenic stimulation, based on the reciprocal relationship of CD69 and CD71 expression. These findings imply that the leukemic cells from all B-CLL cases (irrespective of V gene mutations) exhibit features of activated and of antigen-experienced B lymphocytes and that the B-CLL cells that differ in immunoglobulin V genotype may have different antigen-encounter histories.