L. Douglas Case

Incidence, Time Course, and Determinants of Menstrual Bleeding After Breast Cancer Treatment: A Prospective Study

PURPOSE To assess ovarian function using the surrogate of monthly bleeding after breast cancer treatment in premenopausal women. PATIENTS AND METHODS Five hundred ninety-five US women age 20 to 45 years were accrued from January 1998 to July 2002 within 8 months of diagnosis with stages I to III breast cancer (median follow-up 45 months). Daily bleeding records were obtained prospectively, as well as extensive clinical, demographic, quality of life, and treatment data. Repeated measures logistic regression was used to assess which variables were predictive of monthly bleeding. RESULTS Significantly different proportions of women had monthly bleeding depending on their age (P < .001), chemotherapy program (P < .001), and time since treatment regimen. In the month after the standard course of doxorubicin and cyclophosphamide (AC), whether or not followed by paclitaxel or docetaxel, approximately 16% had monthly bleeding compared with the cyclophosphamide, methotrexate, fluorouracil (CMF) group, in which 48% bled (P < .001). Following any AC regimen, there was a slow recovery phase of about 9 months followed by a plateau, during which almost half continued monthly bleeding for the remainder of the follow-up period compared with after CMF in which there was no recovery phase and a continual decline in monthly bleeding to approximately 18% of women at study end (P < .001). Tamoxifen use decreased bleeding between months 12 and 24 after chemotherapy with 15% fewer women having bleeding. CONCLUSION Using daily menstrual bleeding records, it is demonstrated that age, the specific chemotherapy regimen received, and tamoxifen use impact ovarian function.

Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer

PURPOSE To determine the maximum-tolerated dose, dose-limiting toxicities, and potential antitumor activity of twice-weekly gemcitabine and concurrent radiation in patients with locally advanced pancreatic cancer. PATIENTS AND METHODS Nineteen patients with histologically confirmed adenocarcinoma of the pancreas were studied at the Wake Forest University Baptist Medical Center and the University of North Carolina at Chapel Hill. The initial dose of gemcitabine was 20 mg/m(2) by 30-minute intravenous infusion each Monday and Thursday for 5 weeks concurrent with 50.4 Gy of radiation to the pancreas. Gemcitabine doses were escalated in 20-mg/m(2) increments in successive cohorts of three to six additional patients until dose-limiting toxicity was observed. RESULTS The dose-limiting toxicities at 60 mg/m(2) given twice-weekly were nausea/vomiting, neutropenia, and thrombocytopenia. Twice-weekly gemcitabine at a 40-mg/m(2) dose was well tolerated. Of the eight patients eligible for a minimum follow-up of 12 months, three remain alive, one of whom has no evidence of disease progression. CONCLUSION A dose of twice-weekly gemcitabine at 40 mg/m(2) produced mild thrombocytopenia, neutropenia, nausea, and vomiting when delivered with concurrent radiation to the upper abdomen in patients with advanced pancreatic cancer. These data suggest this regimen is well tolerated and may possess significant activity. These data and other observations have resulted in a phase II Cancer and Leukemia Group B study to ascertain the efficacy of this treatment regimen in patients with locally advanced pancreatic cancer.

Ethnic Distribution of ECG Predictors of Atrial Fibrillation and Its Impact on Understanding the Ethnic Distribution of Ischemic Stroke in the Atherosclerosis Risk in Communities (ARIC) Study

Background and Purpose— The paradox of the reported low prevalence of atrial fibrillation (AF) in blacks compared with whites despite higher stroke rates in the former could be related to limitations in the current methods used to diagnose AF in population-based studies. Hence, this study aimed to use the ethnic distribution of ECG predictors of AF as measures of AF propensity in different ethnic groups. Methods— The distribution of baseline measures of P-wave terminal force, P-wave duration, P-wave area, and PR duration (referred to as AF predictors) were compared by ethnicity in 15 429 participants (27% black) from the Atherosclerosis Risk in Communities (ARIC) study by unpaired t test, &khgr;2, and logistic-regression analysis, as appropriate. Cox proportional-hazards analysis was used to separately examine the association of AF predictors with incident AF and ischemic stroke. Results— Whereas AF was significantly less common in blacks compared with whites (0.24% vs 0.95%, P<0.0001), similar to what has been reported in previous studies, blacks had significantly higher and more abnormal values of AF predictors (P<0.0001 for all comparisons). Black ethnicity was significantly associated with abnormal AF predictors compared with whites; odds ratios for different AF predictors ranged from 2.1 to 3.1. AF predictors were significantly and independently associated with AF and ischemic stroke with no significant interaction between ethnicity and AF predictors, findings that further justify using AF predictors as an earlier indicator of future risk of AF and stroke. Conclusions— There is a disconnect between the ethnic distribution of AF predictors and the ethnic distribution of AF, probably because the former, unlike the latter, do not suffer from low sensitivity. These results raise the possibility that blacks might actually have a higher prevalence of AF that might have been missed by previous studies owing to limited methodology, a difference that could partially explain the greater stroke risk in blacks.

The Epidemiology of Arm and Hand Swelling in Premenopausal Breast Cancer Survivors

Background: Breast cancer survivors suffer from lymphedema of the arm and/or hand. Accurate estimates of the incidence and prevalence of lymphedema are lacking, as are the effects of this condition on overall quality of life. Methods: Six hundred twenty-two breast cancer survivors (age, ≤45 years at diagnosis) were followed with semiannual questionnaires for 36 months after surgery to determine the incidence of lymphedema, prevalence of persistent swelling, factors associated with each, and quality of life. Results: Of those contacted and eligible for the study, 93% agreed to participate. Fifty-four percent reported arm or hand swelling by 36 months after surgery, with 32% reporting persistent swelling. Swelling was reported to occur in the upper arm (43%), the hand only (34%), and both arm and hand (22%). Factors associated with an increased risk of developing swelling included having a greater number of lymph nodes removed [hazards ratio (HR), 1.02; P < 0.01], receiving chemotherapy (HR, 1.76; P = 0.02), being obese (HR, 1.51 versus normal weight; P = 0.01), and being married (HR, 1.36; P = 0.05). Factors associated with persistent swelling were having more lymph nodes removed (odds ratio, 1.03; P = 0.01) and being obese (odds ratio, 2.24 versus normal weight; P < 0.01). Women reporting swelling had significantly lower quality of life as measured by the functional assessment of cancer therapy-breast total score and the SF-12 physical and mental health subscales (P < 0.01 for each). Conclusions: Lymphedema occurs among a substantial proportion of young breast cancer survivors. Weight management may be a potential intervention for those at greatest risk of lymphedema to maintain optimal health-related quality of life among survivors. (Cancer Epidemiol Biomarkers Prev 2007;16(4):775–82)

A genome-wide genotyping study in patients with ischaemic stroke: initial analysis and data release

BACKGROUND Despite evidence of a genetic role in stroke, the identification of common genetic risk factors for this devastating disorder remains problematic. We aimed to identify any common genetic variability exerting a moderate to large effect on risk of ischaemic stroke, and to generate publicly available genome-wide genotype data to facilitate others doing the same. METHODS We applied a genome-wide high-density single-nucleotide-polymorphism (SNP) genotyping approach to a cohort of samples with and without ischaemic stroke (n=278 and 275, respectively), and did an association analysis adjusted for known confounders in a final cohort of 249 cases and 268 controls. More than 400,000 unique SNPs were assayed. FINDINGS We produced more than 200 million genotypes in 553 unique participants. The raw genotypes of all the controls have been posted publicly in a previous study of Parkinsons disease. From this effort, results of genotype and allele association tests have been publicly posted for 88% of stroke patients who provided proper consent for public release. Preliminary analysis of these data did not reveal any single locus conferring a large effect on risk for ischaemic stroke. INTERPRETATION The data generated here comprise the first phase of a genome-wide association analysis in patients with stroke. Release of phase I results generated in these publicly available samples from each consenting individual makes this dataset a valuable resource for data-mining and augmentation.

Polymorphisms of XRCC1 and XRCC3 genes and susceptibility to breast cancer

Mammalian cells are constantly exposed to a wide variety of genotoxic agents from both endogenous and exogenous sources. Genetic variability in DNA repair may contribute to human cancer risk. We used a case-control study design (162 cases and 302 controls) to test the association between three amino acid substitution variants of DNA repair genes (XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XRCC3 Thr241Met) and breast cancer susceptibility. We found a weak association between the XRCC1 194Trp allele and breast cancer risk (adjusted odds ratio (OR)=1.98; 95% confidence interval (CI)=0.85-4.63). We also found a potential gene-gene interaction between the XRCC1 194Trp allele and XRCC3 241Met allele and breast cancer risk (adjusted OR=8.74; 95% CI=1.13-67.53). Although larger studies are needed to validate the study results, our data suggest that amino acid substitution variants of XRCC1 and XRCC3 genes may contribute to breast cancer susceptibility.

Interrupted versus Continuous Chemotherapy in Patients with Metastatic Breast Cancer

BACKGROUND Chemotherapy for metastatic breast cancer is palliative, and the optimal duration of therapy is unknown. We designed a trial to determine whether continuous treatment is superior to stopping treatment after a brief induction period and resuming treatment when the disease progresses. METHODS We treated 250 women with metastatic breast cancer with six courses of cyclophosphamide, doxorubicin, and fluorouracil given every three weeks. At the completion of this induction period, women whose disease either regressed or remained stable were randomly assigned to receive either continued treatment with cyclophosphamide, methotrexate, and fluorouracil (maintenance therapy) or no further treatment (observation) followed by treatment with cyclophosphamide, methotrexate, and fluorouracil when disease progression became evident (reinduction). RESULTS The combined rate of complete and partial responses after initial therapy was 30 percent (71 of 233 patients who could be evaluated; 95 percent confidence interval, 25 percent to 37 percent). In another 42 percent (98 patients), the disease remained stable. A total of 145 patients were randomized. Seventy-one were randomly assigned to the maintenance-therapy group, and 74 to the observation group. The median time to progression was 9.4 months for patients in the maintenance-therapy group and 3.2 months for patients in the observation group (P less than 0.001). After reinduction therapy, the median time to progression was 3.5 months. The median length of survival from the time of initial therapy was 14.8 months for all 250 patients; it was 21.1 months for the 71 patients in the maintenance-therapy group and 19.6 months for the 74 patients in the observation group (P = 0.67). Maintenance therapy was the most important determinant of the time before progression (P less than 0.001), but it was not associated with prolonged survival. The changes in performance status were similar in the patients in both groups, but nausea, vomiting, and mucositis were significantly more frequent in the maintenance-therapy group. CONCLUSIONS In patients with breast cancer who received induction chemotherapy for 18 weeks, subsequent continuous chemotherapy was associated with a significant prolongation of the time before progression as compared with those receiving no further therapy; overall survival, however, was not significantly different in the two groups.

Sexual Problems in Younger Women After Breast Cancer Surgery

PURPOSE To examine sexual problems in younger women diagnosed with breast cancer during the first year after surgery and to identify sociodemographic, medical, and psychosocial predictors of sexual problems. PATIENTS AND METHODS Women diagnosed with breast cancer age < or = 50 years completed surveys at three time points: within 24 weeks after initial surgery (baseline), 6 weeks after baseline, and 6 months later. Survey items included the Medical Outcomes Study Sexual Functioning Scale, satisfaction with sex life, feeling sexually attractive, body image, marital satisfaction, quality of life, medical history, symptoms, and sociodemographics. Prediagnosis sexual problems were retrospectively ascertained at the initial survey. RESULTS Analyses included 209 women sexually active at baseline (78.6% of total sample). Sexual problems were significantly greater immediately postsurgery compared with retrospective reports before diagnosis (P < .0001). Although problems gradually decreased over time, they were still greater at 1 year postsurgery than before diagnosis. In multivariate analyses controlling for sexual problems at prediagnosis, vaginal dryness, and lower perceived sexual attractiveness were consistently related to greater overall sexual problems. Chemotherapy was related to sexual problems only at baseline except for women who became menopausal as a result of chemotherapy, who continued to have problems. CONCLUSION Findings substantiate the need to address potential sexual problems related to chemotherapy treatment and menopause among younger breast cancer survivors and to counsel women about possible remedies, particularly for vaginal dryness. Increasing feelings of sexual attractiveness may also help sexual problems, especially among women for whom these feelings were altered by surgery or treatment.

Occurence, etiology, and clinical significance of extreme thrombocytosis: A study of 280 cases

PURPOSE To determine the etiology and to evaluate the clinical consequences of an extremely elevated platelet count. PATIENTS AND METHODS A review of the medical records was performed on all patients encountered during a 5 1/2-year period who had at least one platelet count of 1,000 x 10(9)/L or greater. RESULTS Of the total of 280 patients with extreme thrombocytosis (EXT), 231 (82%) had reactive thrombocytosis (RT), 38 (14%) had a myeloproliferative disorder (MPD), and 11 (4%) had cases of uncertain etiology. RT was more common than MPD in all age groups except those in the eighth decade and older. Symptoms of bleeding and/or vaso-occlusive phenomena were noted in association with EXT in 21 (56%) of the MPD patients but in only 10 (4%) of the RT patients. Treatment to lower the platelet count and/or inhibit platelet function was employed in 36 MPD patients and 23 RT patients. Eight patients with MPD and 34 with RT are known to have died, but no patient in either group is known to have died of a thrombotic or bleeding event when the platelet count was greater than or equal to 1,000 x 10(9)/L. CONCLUSIONS Platelet counts greater than or equal to 1,000 x 10(9)/L should not be considered rare events in the general, acute-care hospital population, and usually represent a reactive phenomenon.

A prospective quality-of-life study in men with clinically localized prostate carcinoma treated with radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy.

PURPOSE To prospectively assess the health-related quality of life (HRQOL) and changes in HRQOL during the first year after 3 different treatments for clinically localized prostate cancer. METHODS AND MATERIALS Ninety men with T1-T2 adenocarcinoma of the prostate were treated with curative intent between May 1998 and June 1999 and completed a quality-of-life Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire before treatment (T0) and 1 month (T1), 3 months (T3), and 12 months (T12) after treatment. Forty-four men were treated with permanent source interstitial brachytherapy (IB), 23 received external beam radiotherapy (EBRT), and 23 men were treated with radical prostatectomy (RP). The mean age of the entire study population was 65.9 years (median 67, range 42-79). The mean pretreatment prostate-specific antigen level of the entire study population was 6.81 ng/mL (median 6.25, range 1.33-19.6). The Gleason score was <or=6 in 65 (72%) of 90. The repeated measures analysis of variance and analysis of covariance were conducted on all quality-of-life and urinary outcome measures. RESULTS A comparison of the demographic characteristics of the 3 treatment groups demonstrated significant differences. The men treated with RP were significantly younger than the men in either the IB or EBRT group (median age 61.0 RP, 67.1 IB, 68.8 EBRT; p = 0.0006). The men in the IB group were more likely to have a Gleason score of <or=6 than the EBRT group (Gleason score <or=6, 86% IB and 48% EBRT; p = 0.015). The mean score (standard deviation) at T0, T1, T3, and T12 for the FACT-P questionnaire for each group was as follows: IB 138.4 (17.0), 120.5 (21.7), 130.0 (18.4), and 138.5 (14.2); EBRT 137.1 (12.1), 129.5 (21.0), 134.4 (19.2), and 136.9 (15.6); and RP 138.3 (14.7), 117.7 (18.3), 134.4 (17.8), and 140.4 (14.9), respectively. Statistically significant differences over time were observed for the FACT-P in the IB and RP groups (p <0.0001), but not for the EBRT group (p = 0.08). The examination of the subscales within the FACT-P instrument demonstrated statistically significant changes over time in the IB and RP groups for the following: physical well-being, functional well-being, and prostate cancer symptoms. After adjusting for age, race, T stage, Gleason score, use of hormonal therapy, and baseline FACT-P scores, statistically significant differences in the FACT-P score at T1 according to treatment group were observed. At T12, the FACT-P scores were not significantly different than the baseline FACT-P scores for any group. CONCLUSIONS The results of this analysis suggest that significant decreases in HRQOL, as measured by the FACT-P instrument, are evident in the first month after IB or RP, but not after EBRT. One year after treatment, however, the FACT-P scores were not statistically different from the baseline measures for any group. For all treatment groups, most of the HRQOL decreases were observed in the physical, functional, and prostate cancer-specific domains. These results suggest that the HRQOL changes are likely to be treatment-specific, further emphasizing the importance of a randomized trial comparing the different treatment options in this population of men.