Chad M. Gundy

Neuropsychological Performance in Survivors of Breast Cancer More Than 20 Years After Adjuvant Chemotherapy

PURPOSE Adjuvant chemotherapy for breast cancer can have adverse effects on cognition shortly after administration. Whether chemotherapy has any long-term effects on cognition is largely unknown, yet it becomes increasingly relevant because of the widespread use of chemotherapy for early-stage breast cancer and the improved survival. We investigated whether cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy for breast cancer is associated with worse cognitive performance more than 20 years after treatment. PATIENTS AND METHODS This case-cohort study compared the cognitive performance of patients with breast cancer who had a history of adjuvant CMF chemotherapy treatment (six cycles; average time since treatment, 21 years; n = 196) to that of a population-based sample of women never diagnosed with cancer (n = 1,509). Participants were between 50 and 80 years of age. Exclusion criteria were ever use of adjuvant endocrine therapy, secondary malignancy, recurrence, and/or metastasis. RESULTS The women exposed to chemotherapy performed significantly worse than the reference group on cognitive tests of immediate (P = .015) and delayed verbal memory (P = .002), processing speed (P < .001), executive functioning (P = .013), and psychomotor speed (P = .001). They experienced fewer symptoms of depression (P < .001), yet had significantly more memory complaints on two of three measures that could not be explained by cognitive test performance. CONCLUSION Survivors of breast cancer treated with adjuvant CMF chemotherapy more than 20 years ago perform worse, on average, than random population controls on neuropsychological tests. The pattern of cognitive problems is largely similar to that observed in patients shortly after cessation of chemotherapy. This study suggests that cognitive deficits following breast cancer diagnosis and subsequent CMF chemotherapy can be long lasting.

Cognitive Rehabilitation in Patients With Gliomas: A Randomized, Controlled Trial

PURPOSE Patients with gliomas often experience cognitive deficits, including problems with attention and memory. This randomized, controlled trial evaluated the effects of a multifaceted cognitive rehabilitation program (CRP) on cognitive functioning and selected quality-of-life domains in patients with gliomas. PATIENTS AND METHODS One hundred forty adult patients with low-grade and anaplastic gliomas, favorable prognostic factors, and both subjective cognitive symptoms and objective cognitive deficits were recruited from 11 hospitals in the Netherlands. Patients were randomly assigned to an intervention group or to a waiting-list control group. The intervention incorporated both computer-based attention retraining and compensatory skills training of attention, memory, and executive functioning. Participants completed a battery of neuropsychological (NP) tests and self-report questionnaires on cognitive functioning, fatigue, mental health-related quality of life, and community integration at baseline, after completion of the CRP, and at 6-month follow-up. RESULTS At the immediate post-treatment evaluation, statistically significant intervention effects were observed for measures of subjective cognitive functioning and its perceived burden but not for the objective NP outcomes or for any of the other self-report measures. At the 6-month follow-up, the CRP group performed significantly better than the control group on NP tests of attention and verbal memory and reported less mental fatigue. Group differences in other subjective outcomes were not significant at 6 months. CONCLUSION The CRP has a salutary effect on short-term cognitive complaints and on longer-term cognitive performance and mental fatigue. Additional research is needed to identify which elements of the intervention are most effective.

Effects of Tamoxifen and Exemestane on Cognitive Functioning of Postmenopausal Patients With Breast Cancer: Results From the Neuropsychological Side Study of the Tamoxifen and Exemestane Adjuvant Multinational Trial

PURPOSE To evaluate the influence of adjuvant tamoxifen and exemestane on cognitive functioning in postmenopausal patients with breast cancer (BC). PATIENTS AND METHODS Neuropsychological assessments were performed before the start (T1) and after 1 year of adjuvant endocrine treatment (T2) in Dutch postmenopausal patients with BC, who did not receive chemotherapy. Patients participated in the international Tamoxifen and Exemestane Adjuvant Multinational trial, a prospective randomized study investigating tamoxifen versus exemestane as adjuvant therapy for hormone-sensitive BC. RESULTS Participants included 80 tamoxifen users (mean age, 68.7 years; range 51 to 84), 99 exemestane users (mean age, 68.3 years; range, 50 to 82), and 120 healthy controls (mean age, 66.2 years; range, 49 to 86). At T2, after adjustment for T1 performance, exemestane users did not perform statistically significantly worse than healthy controls on any cognitive domain. In contrast, tamoxifen users performed statistically significantly worse than healthy controls on verbal memory (P < .01; Cohens d = .43) and executive functioning (P = .01; Cohens d = .40), and statistically significantly worse than exemestane users on information processing speed (P = .02; Cohens d = .36). With respect to visual memory, working memory, verbal fluency, reaction speed, and motor speed, no significant differences between the three groups were found. CONCLUSION After 1 year of adjuvant therapy, tamoxifen use is associated with statistically significant lower functioning in verbal memory and executive functioning, whereas exemestane use is not associated with statistically significant lower cognitive functioning in postmenopausal patients with BC. Our results accentuate the need to include assessments of cognitive effects of adjuvant endocrine treatment in long-term safety studies.

Neuropsychological functioning in postmenopausal breast cancer patients treated with tamoxifen or exemestane after AC-chemotherapy: Cross-sectional findings from the neuropsychological TEAM-side study

Background. Previous studies have indicated that a subset of cancer patients treated with chemotherapy show cognitive deficits and/or experience cognitive complaints, whereas literature about the influence of hormonal therapies on cognition is sparse. Because of the accumulating knowledge about the importance of estrogen for cognitive functioning, there is growing concern about adjuvant hormonal therapy for breast cancer (BC) affecting cognition. We examined the cognitive functioning of postmenopausal BC patients who were, following doxorubicin/cyclophosphamide (AC) chemotherapy, randomized to tamoxifen or exemestane, and compared their performance with that of non-cancer controls. Materials and methods. Thirty BC patients using tamoxifen and 50 patients using exemestane underwent interviews, questionnaires and cognitive tests, on average two years after completion of AC chemotherapy. Forty eight healthy controls were tested with similar measures. Results. Memory complaints were reported by 28% of AC/tamoxifen users, 24% of AC/exemestane users and 6% of healthy controls (p=0.02). Cognitive testing revealed no statistically significant differences between tamoxifen and exemestane users, but suggested that tamoxifen use is possibly related to worse verbal functioning, while exemestane use is possibly related to slower manual motor speed. Both patient groups performed significantly worse than healthy controls on verbal fluency and information processing speed. Discussion. Our findings show that sequential treatment of AC-chemotherapy and hormonal therapy in postmenopausal, primary BC is associated with lower test scores for certain cognitive functions, and provide indications for possibly distinctive associations for different types of hormonal treatment. Future research with larger groups is recommended to obtain a more definite picture.

Compromised Health-Related Quality of Life in Patients With Low-Grade Glioma

PURPOSE To investigate the generic and condition-specific health-related quality of life (HRQL) of patients with low-grade glioma (LGG). PATIENTS AND METHODS A total of 195 patients with LGG, which was diagnosed, on average, 5.6 years before the study, were compared with 100 patients with hematologic (non-Hodgkins) lymphoma and chronic lymphatic leukemia cancer (NHL/CLL) and 205 general population controls who were comparable with patients with LGG at the group level for age, sex, and education (healthy controls). Generic HRQL was assessed with the Short Form-36 (SF-36) Health Survey, and condition-specific HRQL was assessed with the Medical Outcomes Study cognitive function questionnaire and the European Organisation for Research and Treatment of Cancer brain cancer module. Objective neurocognitive functioning was assessed with a standardized battery of neuropsychological tests. RESULTS No statistically significant differences were observed between patients with LGG and patients with NHL/CLL in SF-36 scores. Patients with LGG scored significantly lower than healthy controls on six of eight scales and on the mental health component score of the SF-36. Approximately one quarter of patients with LGG reported serious neurocognitive symptoms. Female sex, epilepsy burden, and number of objectively assessed neurocognitive deficits were associated significantly with both generic and condition-specific HRQL. Clinical variables, including the time since diagnosis, tumor lateralization, extent of surgery, and radiotherapy, did not show a consistent relationship with HRQL. CONCLUSION Patients with LGG experienced significant problems across a broad range of HRQL domains, many of which were not condition-specific. However, the neurocognitive deficits and epilepsy that were relatively prevalent among patients with LGG were associated with negative HRQL outcomes and, thus, contributed additionally to the vulnerability of this population of patients with cancer.

The frequency, magnitude and timing of post-diagnosis body weight gain in Dutch breast cancer survivors.

To evaluate the association between systemic treatments and post-diagnosis weight gain in breast cancer patients during longer follow-up periods, we conducted a retrospective cohort study (n=271). Information on adjuvant systemic treatments and repeated body weight measurements was obtained from medical records, and analysed using multi-level regressions. During the first year, a mean weight change of +2.0kg (SD 4.9) was observed. Overall, 29% of all breast cancer patients had gained 5kg or more in body weight during total follow-up (median: 3 years). In multi-level analyses, women who received combined systemic treatment gained significantly more weight as compared with women who received no systemic treatment (4.5kg versus 2.0kg at 5 years post-diagnosis, p<0.05). Significant weight gain occurs in breast cancer patients in the Netherlands during the first year post-diagnosis. After the first year, further weight gain mainly occurs in women who receive chemotherapy in combination with endocrine therapy.

Patient-Reported Quality of Life After Stereotactic Ablative Radiotherapy for Early-Stage Lung Cancer

Background: Deterioration in health-related quality of life (HRQOL) is frequently observed after surgery for stage I non–small-cell lung cancer. As stereotactic ablative radiotherapy (SABR) can result in local control percentages exceeding 90%, we studied baseline and post-treatment HRQOL in SABR patients. Methods: HRQOL data were collected prospectively using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire in 382 consecutive patients treated with SABR. Patients were referred from 68 Dutch centers, with 86% judged unfit for surgery, and 14% declining surgery. An SABR dose of 60 Gy was delivered in three-, five-, or eight treatment fractions, depending on tumor diameter and location. HRQOL data were available for 382 patients at baseline (pre-SABR), and for 282, 212, 144, 56, and 43 patients at 3, 6, 12, 18, and 24 months post-SABR, respectively. Results: Median survival was 40 months, with a 2-year survival of 66%. Local, regional, and distant failure percentages at 2 years were 6%, 13%, and 22%, respectively. Mean baseline global HRQOL and physical functioning scores were 62.9 ± 1.1 and 61.7 ± 1.1, respectively. Baseline symptom scores were highest for dyspnea (47.1 ± 1.7) and fatigue (37.4 ± 1.3). Except for a nonsignificant decrease in 2 to 3 points per year in physical functioning, no statistically or clinically significant worsening of any of the HRQOL functioning or symptom scores at any follow-up time point was observed. Conclusions: Patients referred for SABR have substantially worse baseline HRQOL scores than those reported in the surgical literature. Clinically relevant deteriorations in HRQOL subscale scores were not observed after SABR.

A simulation study provided sample size guidance for differential item functioning (DIF) studies using short scales

OBJECTIVE Differential item functioning (DIF) analyses are increasingly used to evaluate health-related quality of life (HRQoL) instruments, which often include relatively short subscales. Computer simulations were used to explore how various factors including scale length affect analysis of DIF by ordinal logistic regression. STUDY DESIGN AND SETTING Simulated data, representative of HRQoL scales with four-category items, were generated. The power and type I error rates of the DIF method were then investigated when, respectively, DIF was deliberately introduced and when no DIF was added. The sample size, scale length, floor effects (FEs) and significance level were varied. RESULTS When there was no DIF, type I error rates were close to 5%. Detecting moderate uniform DIF in a two-item scale required a sample size of 300 per group for adequate (>80%) power. For longer scales, a sample size of 200 was adequate. Considerably larger sample sizes were required to detect nonuniform DIF, when there were extreme FEs or when a reduced type I error rate was required. CONCLUSION The impact of the number of items in the scale was relatively small. Ordinal logistic regression successfully detects DIF for HRQoL instruments with short scales. Sample size guidelines are provided.

Differential item functioning (DIF) analyses of health-related quality of life instruments using logistic regression

BackgroundDifferential item functioning (DIF) methods can be used to determine whether different subgroups respond differently to particular items within a health-related quality of life (HRQoL) subscale, after allowing for overall subgroup differences in that scale. This article reviews issues that arise when testing for DIF in HRQoL instruments. We focus on logistic regression methods, which are often used because of their efficiency, simplicity and ease of application.MethodsA review of logistic regression DIF analyses in HRQoL was undertaken. Methodological articles from other fields and using other DIF methods were also included if considered relevant.ResultsThere are many competing approaches for the conduct of DIF analyses and many criteria for determining what constitutes significant DIF. DIF in short scales, as commonly found in HRQL instruments, may be more difficult to interpret. Qualitative methods may aid interpretation of such DIF analyses.ConclusionsA number of methodological choices must be made when applying logistic regression for DIF analyses, and many of these affect the results. We provide recommendations based on reviewing the current evidence. Although the focus is on logistic regression, many of our results should be applicable to DIF analyses in general. There is a need for more empirical and theoretical work in this area.

Treatment of vulvar intraepithelial neoplasia with topical imiquimod: Seven years median follow-up of a randomized clinical trial

OBJECTIVE Recently we reported on the efficacy of imiquimod for treating vulvar intraepithelial neoplasia (VIN) in a placebo-controlled, double-blinded randomized clinical trial (RCT). Four weeks after treatment, a complete response was observed in 35% of patients and a partial response in 46%. All complete responders remained disease-free at 12 months follow-up. In the current investigations, we assessed long-term follow-up at least 5 years after the initial RCT. METHODS Twenty-four of 26 imiquimod-treated patients who had participated in the initial RCT were seen for follow-up. Primary endpoint was durability of clinical response to imiquimod assessed by naked eye vulvar examination and histology. Long-term clinical response was correlated to lesion size before start of the initial RCT. Secondary endpoints were mental health, global quality of life, body image and sexual function in relation with long-term clinical response. RESULTS Median follow-up period was 7.2 years (range 5.6-8.3 years). VIN recurred in one of nine complete responders. Of the initial partial responders, two became disease-free after additional imiquimod treatment. In the other partial responders, VIN recurred at least once after the initial RCT. In long-term complete responders, lesion size at study entry was smaller and these patients had a significantly better global quality of life at follow-up than patients with residual disease and/or recurrence after imiquimod treatment. CONCLUSIONS In case of a complete response, imiquimod is effective in the long-term. Furthermore, patients with a long-term complete response had a significantly better global quality of life than patients who recurred after imiquimod treatment.