Systemic inflammation and changes in physical well-being in patients with breast cancer: a longitudinal study in community oncology settings.

BACKGROUND: Chemotherapy adversely affects physical well-being and inflammation may be related to changes in physical well-being. We evaluated the association of systemic inflammation with changes in physical well-being. METHODS: In a prospective study of 580 patients with stages I-III breast cancer we assessed immune cell counts, neutrophil:lymphocyte ratio (NLR), lymphocyte:monocyte ratio (LMR), and platelet:lymphocyte ratio (PLR) within 7 days before chemotherapy (pre-chemotherapy). Physical well-being was assessed using the Functional Assessment of Cancer Therapy: General-Physical Well-being subscale (FACT-PWB) pre-chemotherapy and 1 month and 6 months post-chemotherapy. Clinically meaningful decline in physical well-being was determined as decreasing FACT-PWB by more than one point from pre-chemotherapy level, and non-resilience defined as having decline post-chemotherapy and not returning to within one-point of pre-chemotherapy FACT-PWB by 6 months post-chemotherapy. Multivariable logistic regressions examined the association between inflammation and changes in physical well-being, adjusting for sociodemographic and clinical characteristics. RESULTS: Fifty-nine percent (310/529) and 36% (178/501) of participants had physical well-being decline post-chemotherapy and 6 months post-chemotherapy, respectively. Fifty percent (147/294) were non-resilient. Low NLR and PLR were associated with 1.78 (P = .01) and 1.66 (P = .02) fold greater odds of having a decline in physical well-being 6 months post-chemotherapy compared to those with high NLR and PLR, respectively. Low NLR and PLR were associated with 1.92 (P = .02) and 2.09 (P = 0.01) fold greater odds of being non-resilient 6 months post-chemotherapy compared to those with high NLR and PLR, respectively. CONCLUSION: Low NLR and PLR were associated with chemotherapy-induced changes in physical well-being independent of sociodemographic and clinical risk factors.

Inflammation, Attention, and Processing Speed in Patients With Breast Cancer Before and After Chemotherapy.

BACKGROUND: Inflammation may contribute to cognitive difficulties in patients with breast cancer. We tested 2 hypotheses: inflammation is elevated in patients with breast cancer vs noncancer control participants and inflammation in patients is associated with worse attention and processing speed over the course of chemotherapy. METHODS: Serum cytokines (interleukin [IL]-4, 6, 8, 10; tumor necrosis factor [TNF]-α) and soluble receptors [sTNFRI, II]) were measured in 519 females with breast cancer before and after chemotherapy and 338 females without cancer serving as control participants. Attention and processing speed were measured by Rapid Visual Processing (RVP), Backward Counting (BCT), and Trail Making-A (TMT-A) tests. Linear regression models examined patient vs control cytokines and receptor levels, adjusting for covariates. Linear regression models also examined relationships between patient cytokines and receptor levels and test performance, adjusting for age, body mass index, anxiety, depression, cognitive reserve, and chemotherapy duration. Statistical tests were 2-sided (α = .05). RESULTS: sTNFRI and sTNFRII increased over time in patients relative to controls, whereas IL-4, IL-6, and IL-10 decreased. Prechemotherapy, higher IL-8 associated with worse BCT (ß = 0.610, SE = 0.241, P = .01); higher IL-4 (ß = -1.098, SE = 0.516, P = .03) and IL-10 (ß = -0.835, SE = 0.414, P = .04) associated with better TMT-A. Postchemotherapy, higher IL-8 (ß = 0.841, SE = 0.260, P = .001), sTNFRI (ß = 6.638, SE = 2.208, P = .003), and sTNFRII (ß = 0.913, SE = 0.455, P = .045) associated with worse BCT; higher sTNFRII also associated with worse RVP (ß = -1.316, SE = 0.587, P = .03). At prechemotherapy, higher IL-4 predicted RVP improvement over time (ß = 0.820, SE = 0.336, P = .02); higher sTNFRI predicted worse BCT over time (ß = 5.566, SE = 2.367, P = .02). Longitudinally, increases in IL-4 associated with BCT improvement (ß = -0.564, SE = 0.253, P = .03). CONCLUSIONS: Generally, worse attention and processing speed were associated with higher inflammatory cytokines and receptors and lower anti-inflammatory cytokines in patients; future confirmatory studies are needed.

Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: a multicenter study.

PURPOSE: We examined the feasibility of using CYP2D6 genotyping to determine optimal tamoxifen dose and investigated whether the key active tamoxifen metabolite, endoxifen, could be increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism. PATIENTS AND METHODS: One hundred nineteen patients on tamoxifen 20 mg daily ≥ 4 months and not on any strong CYP2D6 inhibiting medications were assayed for CYP2D6 genotype and plasma tamoxifen metabolite concentrations. Patients found to be CYP2D6 extensive metabolizers (EM) remained on 20 mg and those found to be intermediate (IM) or poor (PM) metabolizers were increased to 40 mg daily. Eighty-nine evaluable patients had tamoxifen metabolite measurements repeated 4 months later. RESULTS: As expected, the median baseline endoxifen concentration was higher in EM (34.3 ng/mL) compared with either IM (18.5 ng/mL; P = .0045) or PM (4.2 ng/mL; P < .001). When the dose was increased from 20 mg to 40 mg in IM and PM patients, the endoxifen concentration rose significantly; in IM there was a median intrapatient change from baseline of +7.6 ng/mL (-0.6 to 23.9; P < .001), and in PM there was a change of +6.1 ng/mL (2.6 to 12.5; P = .020). After the dose increase, there was no longer a significant difference in endoxifen concentrations between EM and IM patients (P = .84); however, the PM endoxifen concentration was still significantly lower. CONCLUSION: This study demonstrates the feasibility of genotype-driven tamoxifen dosing and demonstrates that doubling the tamoxifen dose can increase endoxifen concentrations in IM and PM patients.

Phase III trial of gabapentin alone or in conjunction with an antidepressant in the management of hot flashes in women who have inadequate control with an antidepressant alone: NCCTG N03C5.

PURPOSE: Despite the utility of newer antidepressants for alleviating hot flashes, antidepressants do not work adequately enough in many patients. Gabapentin is a nonhormonal agent that also can reduce hot flashes. No data have been available to address whether the combination of both agents would more effectively alleviate hot flashes, compared with gabapentin alone, in patients with inadequate hot flash control with an antidepressant alone. PATIENTS AND METHODS: This was a randomized trial in which 118 patients with inadequate hot flash control on an antidepressant were randomly assigned to receive both an antidepressant and gabapentin versus being weaned off the antidepressant and receiving gabapentin alone. Patients were observed for 5 weeks (including a baseline week in which patients continued on their current antidepressant without gabapentin) during which time they completed validated daily hot flash diaries. RESULTS: Ninety-one patients provided complete data at the 5-week assessment. Regardless of whether or not the antidepressant was continued when gabapentin was started, there was an approximately 50% median reduction in hot flash frequencies (54%; 95% CI, 34% to 70% for combined treatment v 49%; 95% CI, 26% to 58% for gabapentin alone) and scores (56%; 95% CI, 26% to 71% for combined treatment v 60%; 95% CI, 33% to 73% for gabapentin alone). CONCLUSION: Gabapentin seems to decrease hot flashes by approximately 50% in women with inadequate hot flash control who were using an antidepressant. This study saw no significant additional hot flash reduction from continuation of the antidepressant.

Paclitaxel/carboplatin/etoposide versus paclitaxel/topotecan for extensive-stage small cell lung cancer: a Minnie Pearl Cancer Research Network randomized, prospective phase II trial.

PURPOSE: To compare the combination of paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and topotecan (Hycamtin; Glaxo SmithKline, Philadelphia, http://www.gsk.com) with paclitaxel, carboplatin (Paraplatin; Bristol-Myers Squibb), and etoposide (Etopophos, VePesid; Bristol-Myers Squibb) in patients with previously untreated extensive-stage small cell lung cancer. PATIENTS AND METHODS: In this phase II trial, 120 patients were randomly allocated to receive either topotecan (1.5 mg/m(2) i.v. days 1, 2, and 3) and paclitaxel (175 mg/m(2) i.v. day 1) every 21 days orpaclitaxe l (200 mg/m(2) i.v. day 1), carboplatin (area under the concentration-time curve 6 i.v. day 1), and etoposide (50 mg/100 mg alternating daily by mouth days 1-10) every 21 days, each regimen for a maximum of eight cycles. The primary end points were objective response rate and time to progression. RESULTS: The paclitaxel-carboplatin-etoposide combination produced a significantly higher overall response rate (78% versus 48%), longer median time to progression (7.6 months versus 5.5 months), and greater number of patients free from progression at 1 year (14% versus 8%) compared with paclitaxel plus topotecan. There was no difference in overall survival. Toxicities were similar in the two treatment arms. CONCLUSIONS: The paclitaxel-carboplatin-etoposide combination produced a superior overall response rate and time to progression in patients with extensive-stage small cell lung cancer compared with paclitaxel plus topotecan. The platinum compounds continue to be a necessary component of the initial therapy for these patients.

Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma.

PURPOSE: To evaluate response to single-agent rituximab in patients with indolent non-Hodgkin's lymphoma (NHL) and no previous systemic therapy, and the feasibility, toxicity, and efficacy of maintenance rituximab, administered at 6-month intervals, in patients with objective response or stable disease after first-line rituximab therapy. PATIENTS AND METHODS: Patients with indolent NHL (follicular or small lymphocytic subtypes) previously untreated with systemic therapy received rituximab 375 mg/m(2) intravenously weekly for 4 weeks. Patients were restaged at week 6 for response; those with objective response or stable disease received maintenance rituximab courses (identical dose and schedule) at 6-month intervals. Maintenance was continued for a maximum of four rituximab courses or until progression. Between March 1998 and May 1999, 62 patients were entered onto this trial; minimum follow-up was 24 months. RESULTS: Sixty patients (97%) completed the first 4-week course of rituximab and were assessable for response. All have now completed rituximab therapy; 36 (58%) received four courses at 6-month intervals. The objective response rate at 6 weeks was 47%; 45% of patients had stable disease. With continued maintenance, final response rate increased to 73%, with 37% complete responses. Response was similar in patients with follicular versus small lymphocytic subtypes (76% v 70%, respectively). Median actuarial progression-free survival was 34 months. Two patients experienced grade 3/4 toxicity with the first dose; one patient was removed from treatment. No cumulative or additional toxicities were seen with maintenance courses. CONCLUSION: Rituximab is highly active and extremely well tolerated as first-line single-agent therapy for indolent NHL. First-line treatment with scheduled maintenance at 6-month intervals produces high overall and complete response rates and a longer progression-free survival (34 months) than has been reported with a standard 4-week treatment.