Disclosing the Uncertainty Associated with Prognostic Estimates in Breast Cancer.

BACKGROUND: Treatment decision making is often guided by evidence-based probabilities, which may be presented to patients during consultations. These probabilities are intrinsically imperfect and embody 2 types of uncertainties: aleatory uncertainty arising from the unpredictability of future events and epistemic uncertainty arising from limitations in the reliability and accuracy of probability estimates. Risk communication experts have recommended disclosing uncertainty. We examined whether uncertainty was discussed during cancer consultations and whether and how patients perceived uncertainty. METHODS: Consecutive patient consultations with medical oncologists discussing adjuvant treatment in early-stage breast cancer were audiotaped, transcribed, and coded. Patients were interviewed after the consultation to gain insight into their perceptions of uncertainty. RESULTS: In total, 198 patients were included by 27 oncologists. Uncertainty was disclosed in 49% (97/197) of consultations. In those 97 consultations, 23 allusions to epistemic uncertainty were made and 84 allusions to aleatory uncertainty. Overall, the allusions to the precision of the probabilities were somewhat ambiguous. Interviewed patients mainly referred to aleatory uncertainty if not prompted about epistemic uncertainty. Even when specifically asked about epistemic uncertainty, 1 in 4 utterances referred to aleatory uncertainty. When talking about epistemic uncertainty, many patients contradicted themselves. In addition, 1 in 10 patients seemed not to realize that the probabilities communicated during the consultation are imperfect. CONCLUSIONS: Uncertainty is conveyed in only half of patient consultations. When uncertainty is communicated, oncologists mainly refer to aleatory uncertainty. This is also the type of uncertainty that most patients perceive and seem comfortable discussing. Given that it is increasingly common for clinicians to discuss outcome probabilities with their patients, guidance on whether and how to best communicate uncertainty is urgently needed.

Prognostic factors for the feasibility of chemotherapy and the Geriatric Prognostic Index (GPI) as risk profile for mortality before chemotherapy in the elderly.

BACKGROUND: Comprehensive geriatric assessment (CGA) is a multidimensional method to detect frailty in elderly patients. Time saving could be accomplished by identifying those individual items that classify elderly cancer patients at risk for feasibility of chemotherapy and for mortality. MATERIAL AND METHODS: Patients older than 70 years of age were assessed before the first chemotherapy administration. GA consisted of the Mini Nutritional Assessment (MNA), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Groningen Frailty Indicator (GFI) and Mini Mental State Examination (MMSE). Predictive individual items for feasibility of chemotherapy and mortality were entered in the multivariable logistic regression and Cox-regression models, and a three-item sum scale was constructed: the Geriatric Prognostic Index (GPI). RESULTS: The 494 patients had a median age of 75 years (range 70-92 years). The majority of the patients had malignancies of the digestive tract (41.7%) followed by hematological tumors (22.3%). Three items of the MNA ('psychological distress or acute disease in the past three months', 'neuropsychological problems' and 'using > 3 prescript drugs') independently predicted for feasibility of chemotherapy. Two items of the MNA and one of the GFI ('declining food intake in past 3 months', 'using > 3 prescript drugs', and 'dependence in shopping') independently predicted for mortality. In comparison with patients without any positive item on the three-item GPI, patients with one, two or three positive items had hazard ratios (HRs) of 1.58, 2.32, and 5.58, respectively (all p < 0.001). CONCLUSIONS: With only three items of the MNA, feasibility of chemotherapy can be predicted. The three-item GPI may help to identify elderly cancer patients at elevated risk for mortality.

Prognostic factors for the feasibility of chemotherapy and the Geriatric Prognostic Index (GPI) as risk profile for mortality before chemotherapy in the elderly.

BACKGROUND: Comprehensive geriatric assessment (CGA) is a multidimensional method to detect frailty in elderly patients. Time saving could be accomplished by identifying those individual items that classify elderly cancer patients at risk for feasibility of chemotherapy and for mortality. MATERIAL AND METHODS: Patients older than 70 years of age were assessed before the first chemotherapy administration. GA consisted of the Mini Nutritional Assessment (MNA), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Groningen Frailty Indicator (GFI) and Mini Mental State Examination (MMSE). Predictive individual items for feasibility of chemotherapy and mortality were entered in the multivariable logistic regression and Cox-regression models, and a three-item sum scale was constructed: the Geriatric Prognostic Index (GPI). RESULTS: The 494 patients had a median age of 75 years (range 70-92 years). The majority of the patients had malignancies of the digestive tract (41.7%) followed by hematological tumors (22.3%). Three items of the MNA ('psychological distress or acute disease in the past three months', 'neuropsychological problems' and 'using > 3 prescript drugs') independently predicted for feasibility of chemotherapy. Two items of the MNA and one of the GFI ('declining food intake in past 3 months', 'using > 3 prescript drugs', and 'dependence in shopping') independently predicted for mortality. In comparison with patients without any positive item on the three-item GPI, patients with one, two or three positive items had hazard ratios (HRs) of 1.58, 2.32, and 5.58, respectively (all p < 0.001). CONCLUSIONS: With only three items of the MNA, feasibility of chemotherapy can be predicted. The three-item GPI may help to identify elderly cancer patients at elevated risk for mortality.

Prognostic significance of geriatric assessment in combination with laboratory parameters in elderly patients with aggressive non-Hodgkin lymphoma.

The age-adjusted International Prognostic Index (IPI) is an important prognostic factor for patients with non-Hodgkin lymphoma (NHL). We investigated whether a geriatric assessment (GA) is of additional prognostic value in NHL. In this prospective cohort study of 44 patients aged 70 years or older with NHL receiving rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), a GA was administered before the start of chemotherapy. GA was composed of the Mini Nutritional Assessment (MNA), Groningen Frailty Indicator (GFI), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Mini Mental State Examination (MMSE) and levels of albumin, creatinine, lactate dehydrogenase (LDH) and hemoglobin. Multivariate analyses were performed using logistic regression and the Cox regression model. After adjustment for sex, age, comorbidity and univariate laboratory values with p ≤ 0.1, abnormal MNA and GFI scores and low hemoglobin level were associated with not being able to complete the intended chemotherapy: odds ratio (OR) 8.29 (95% confidence interval [CI]: 1.24-55.6; p = 0.03), 9.17 (95% CI: 1.51-55.8; p = 0.02) and 5.41 (95% CI: 0.99-29.8; p = 0.05), respectively. Adjusted for sex, age, comorbidity, age-adjusted IPI and univariate laboratory values with p ≤ 0.1, frailty by GFI and low hemoglobin were associated with worse survival, with a hazard ratio (HR) of mortality of 2.55 (95% CI: 1.07-6.10; p = 0.04) and 4.90 (95% CI: 1.76-13.7; p = 0.002), respectively. We conclude that (risk of) malnutrition, measured with the MNA, frailty, measured with the GFI, and low hemoglobin level had additional predictive value for early treatment withdrawal, and GFI and hemoglobin were, independent of the age-adjusted IPI, predictive for an increased mortality risk.

Frailty and malnutrition predictive of mortality risk in older patients with advanced colorectal cancer receiving chemotherapy.

INTRODUCTION: In general, geriatric assessment (GA) provides the combined information on comorbidity and functional, nutritional and psychosocial status and may be predictive for mortality outcome of cancer patients. The impact of geriatric assessment on the outcome of older patients with colorectal cancer treated with chemotherapy is largely unknown. METHODS: In a prospective study, 143 patients with colorectal cancer who were 70years and older were assessed before chemotherapy by Mini Nutritional Assessment (MNA), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Groningen Frailty Indicator (GFI) and Mini Mental State Examination (MMSE). RESULTS: Fifty-four (38%) patients received adjuvant chemotherapy and 89 (62%) patients received palliative chemotherapy. Malnutrition and frailty were prevalent in 39 (27%, assessed by MNA) and 34 (24%, by GFI) patients, respectively; whereas cognitive impairment was prevalent in 19 (13%, by IQCODE) and 11 (8%, by MMSE) patients, respectively. In patients with palliative chemotherapy, poor MNA scores were associated with receiving less than 4cycles of chemotherapy (p=0.008). Poor MNA and GFI scores were associated with increased hazard ratios (HR) for mortality for patients with palliative chemotherapy: HR=2.76 (95% confidence interval [CI]: 1.60-4.77; p<0.001) and HR=2.72 (95% CI: 1.58-4.69; p<0.001), respectively, after adjustment for several clinical parameters. CONCLUSIONS: Malnutrition and frailty were strongly associated with an increased mortality risk in patients who underwent palliative chemotherapy. Furthermore, a poor score on MNA was predictive for less tolerance of chemotherapy. Our findings may help the oncologist in future decision making and advice for elderly patients with colorectal cancer.

Omission of surgery in elderly patients with early stage breast cancer.

AIM: To assess national trends over time in surgery for elderly patients with resectable breast cancer (BC) and to evaluate clinical outcome and cause of death after the omission of surgery in a regional cohort of elderly patients. METHODS: National trends in 1995-2005 were calculated using cancer registry data. In addition, a chart review was performed in a cohort of patients aged ≥ 75 years, with early stage BC but no primary surgery, diagnosed at five Dutch hospitals in 1990-2005. Patient characteristics, comorbidity and reason for the omission of surgery were collected from the chart. Cause of death was retrieved from death certificate data registered at Statistics Netherlands. RESULTS: Omission of surgery increased significantly over time for patients aged 80 years and older (p<0.05). Of the 187 patients in the regional cohort (median age 85.9 years (range 75.0-97.7), 174 (92%) received hormonal therapy. Omission of surgery was at the patient's request in 59 patients (32%). Of the 178 patients that died during follow-up, 60 patients (34%) died of BC. For 81 patients (45%), BC was not clinically relevant at the time of death. Median overall survival was 2.3 years (range 0.2-10.7) and did not differ between BC and other causes of death (p=0.9). CONCLUSION: Omission of surgery for elderly patients with resectable BC has increased significantly over the past decade; instead patients often received primary endocrine treatment. Although this may appear an effective alternative to surgery, the potential for a longer term negative impact on disease control and quality of life deserves further investigation.

Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity.

Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme acting in the catabolism of the widely used antineoplastic agent 5-fluorouracil (5FU). DPD deficiency is known to cause a potentially lethal toxicity following administration of 5FU. Here, we report novel genetic mechanisms underlying DPD deficiency in patients presenting with grade III/IV 5FU-associated toxicity. In one patient a genomic DPYD deletion of exons 21-23 was observed. In five patients a deep intronic mutation c.1129-5923C>G was identified creating a cryptic splice donor site. As a consequence, a 44 bp fragment corresponding to nucleotides c.1129-5967 to c.1129-5924 of intron 10 was inserted in the mature DPD mRNA. The deleterious c.1129-5923C>G mutation proved to be in cis with three intronic polymorphisms (c.483 + 18G>A, c.959-51T>G, c.680 + 139G>A) and the synonymous mutation c.1236G>A of a previously identified haplotype. Retrospective analysis of 203 cancer patients showed that the c.1129-5923C>G mutation was significantly enriched in patients with severe 5FU-associated toxicity (9.1%) compared to patients without toxicity (2.2%). In addition, a high prevalence was observed for the c.1129-5923C>G mutation in the normal Dutch (2.6%) and German (3.3%) population. Our study demonstrates that a genomic deletion affecting DPYD and a deep intronic mutation affecting pre-mRNA splicing can cause severe 5FU-associated toxicity. We conclude that screening for DPD deficiency should include a search for genomic rearrangements and aberrant splicing.