Assessment of the external validity of the National Comprehensive Cancer Network (NCCN) guidelines for pancreatic ductal adenocarcinoma in a population of older patients aged 70 years and older.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) mainly occurs in older adults. Since randomized clinical trials (RCTs) provide the highest-quality evidence incorporated in NCCN recommendations, the underrepresentation of older patients in RCTs challenges guidelines' external validity and limits the solidity of evidence in this specific population. MATERIALS AND METHODS: The study aimed to investigate external validity of NCCN guidelines for PDCA and the impact of reference studies eligibility on overall survival (OS) in a real-world older population. We retrieved RCTs supporting NCCN recommendations for management of PDAC and identified ten topics. We matched a cohort of 707 PDAC patients aged ≥70 years from the Moffitt Cancer Center database with eligibility criteria of 96 reference RCTs to check the proportion of patients eligible for at least two RCTs. Eligibility >60% was rated full validity, 30%-60% partial validity and < 30% limited validity. We also performed log-rank test to assessed whether "eligibility" status affects OS, stratifying by age (70-74; 75-79; ≥80). RESULTS AND DISCUSSION: We found full validity for neoadjuvant (57/73 patients; 69.86%), locally advanced (28/39; 71.79%) and second line (88/110; 80%) treatment, while lowest validity was found for adjuvant chemotherapy (37/86; 43%). Eligible status was correlated with a significant OS benefit for adjuvant chemoradiation (p = 0.002) in all-comers and for first-line polychemotherapy in patients aged ≥80 (p = 0.01). Our analysis supports the limitation of guidelines' external validity in older patients, and hints at possible correlations with survival, although no definitive conclusions can be drawn at this stage. Renewing RCT design with broader eligibility criteria might help increase inclusion of older and thus strengthen the evidence.

Sarcopenia and low muscle radiodensity associate with impaired FEV1 in allogeneic haematopoietic stem cell transplant recipients.

BACKGROUND: Quantification of skeletal muscle using computed tomography (CT) is accessible using cancer patients' standard oncologic images. Reduced muscle mass may be related to reduced respiratory muscle strength; however, the impact of this on lung functional parameters is not characterized in adult allogeneic haematopoietic stem cell transplant (alloHCT) recipients. METHODS: A consecutive retrospective series (n = 296) of patients who had alloHCT at a comprehensive cancer centre between March 2005 and April 2015 were included. Pre-transplant CT scans were used to quantify skeletal muscle and adipose tissue at the fourth thoracic (T4) and/or third lumbar (L3) level. Tumour and patient characteristics were recorded, including forced expiratory volume in 1 second (FEV1 ) by spirometry. Regression models were created to characterize predictive relationships. RESULTS: A total of 296 patients (♂n = 161; ♀n = 135) were included, all of whom had chest CT as part of standard care; a subset of these (n = 215, 72.6%) also had abdominal CT. Diagnoses were non-Hodgkins lymphoma (n = 165), acute myeloid leukaemia (n = 66), Hodgkin's disease (n = 14), acute lymphocytic leukaemia (n = 14), myelodysplastic syndromes (n = 18), and other (n = 19). In multivariable linear regression adjusted for sex (P < 0.0001), age (P < 0.0001), haematopoietic cell transplantation-specific co-morbidity index (P = 0.010), and parameters of pulmonary function testing (defined by spirometry, P < 0.0001), both T4 muscle index [ß 0.127 (95% confidence interval 0.019; 0.252), P < 0.0001] and T4 muscle radiodensity [ß 0.132 (95% confidence interval 0.087; 0.505), P = 0.006] were independently associated with FEV1 ; disease risk index (P = 0.877) and Karnofsky performance status (P = 0.548) were not associated with FEV1 . Similar conclusions were obtained when L3 muscle index and radiodensity were considered. Unlike T4, L3 muscle index values can be compared with published cut-off values for sarcopenia. Overall rates of sarcopenia were uniformly higher in the HCT population than in age-matched and sex-matched patients with solid tumours [alloHCT ♂64.7% vs. solid tumour ♂56.6% (P < 0.001); alloHCT ♀57.6% vs. solid tumour ♀36.0% (P < 0.001)]. Significant but moderate correlations (P < 0.001) were found for muscle area and radiodensity between L3 and T4, for both men and women; adipose tissue quantity also correlated significantly (P < 0.001) between L3 and T4 for both men and women. CONCLUSIONS: Lumbar or thoracic CT images are useful for body composition assessment in this population and reveal high rates of sarcopenia, similar to those reported in very elderly patients. Reduced muscle mass and radiodensity associate with impaired FEV1 even after adjustment for clinical covariables including co-morbidities, performance status, disease risk, and mild intrinsic pulmonary disease (chronic obstructive pulmonary disease) defined by spirometry.

Assessment of the External Validity of the National Comprehensive Cancer Network and European Society for Medical Oncology Guidelines for Non-Small-Cell Lung Cancer in a Population of Patients Aged 80 Years and Older.

Non-small-cell lung cancer (NSCLC) is a disease of the elderly, who are under-represented in clinical trials. This challenges the external validity of the evidence base for its management and of current guidelines, that we evaluated in a population of older patients. We retrieved randomized clinical trials (RCTs) supporting the guidelines and identified 18 relevant topics. We matched a cohort of NSCLC patients aged older than 80 years from the Moffitt Cancer Center database with the studies' eligibility criteria to check their qualification for at least 2 studies. Eligibility > 60% was rated full validity, 30% to 60% partial validity, and < 30% limited validity. We obtained data from 760 elderly patients in stage-adjusted groups and collected 244 RCTs from the National Comprehensive Cancer Network (NCCN) and 148 from the European Society for Medical Oncology (ESMO) guidelines. External validity was deemed insufficient for neoadjuvant chemotherapy in stage III disease (27.37% and 25.26% of patients eligible for NCCN and ESMO guidelines, respectively) and use of bevacizumab (13.86% and 16.27% of patients eligible). For ESMO guidelines, it was inadequate regarding double-agent chemotherapy (25.90% of patients eligible), its duration (24.10%) and therapy for Eastern Cooperative Oncology Group performance status 2 patients (17.74%). For NCCN guidelines external validity was lacking for neoadjuvant chemoradiotherapy in stage IIIA disease (25.86% of patients eligible). Our analysis highlighted the effect of RCT eligibility criteria on guidelines' external validity in elderly patients. Eligibility criteria should be carefully considered in trial design and more studies that do not exclude elderly patients should be included in guidelines.

Impact of chemotherapy on medium-term physical function and activity of older breast cancer survivors, and associated biomarkers.

OBJECTIVE: Chemotherapy is less often prescribed in older individuals due to concerns about post-treatment morbidity and quality of life. We evaluated the physical performance of breast cancer survivors treated with and without adjuvant chemotherapy. MATERIALS AND METHODS: We conducted a case-control study in 56 estrogen receptor positive breast cancer survivors (BCS) on adjuvant aromatase inhibitors 1-2years after definitive surgery. Cases had received adjuvant chemotherapy (n=27; age 70.5±3.6years) versus age-matched controls who had not (n=29; age 70.0±4.3years). Measures of grip strength, physical activity and performance, walking speed, fatigue, and self-reported physical function were collected. Biological correlates of inflammation, frailty and markers of DNA and RNA oxidation were compared. RESULTS: Grip strength (controls: 21±7.4 vs. CASES: 29.7±5.0kg, p=0.20), physical activity (5403±3204 vs. 6801±9320steps/day, p=0.45), physical performance (short physical performance battery score: 10.1±1.8 vs. 10.4±1.1, p=0.52) and long-distance walking speed (1.2±0.21 vs. 1.3±0.41m/s, p=0.17) were similar between the two groups. Self-reported physical function was marginally lower in cases than controls (controls: 72±24 vs. CASES: 57±34AU, p=0.07). Fatigue disruptiveness was not different between groups (controls: 11.1±13.0 vs. CASES: 15.7±16.2AU, p=0.24). Similarly, the inflammation, oxidation, and frailty markers did not present a significant difference between groups, except for vitamin D levels (p=0.04). CONCLUSION: Older women who received chemotherapy reported having slightly lower physical function, but a similar physical performance compared to women who did not. These data suggest that older BCS treated with chemotherapy recover to an extent similar to survivors who only received hormonal therapy.

Potential drug interactions and chemotoxicity in older patients with cancer receiving chemotherapy.

PURPOSE: Increased risk of drug interactions due to polypharmacy and aging-related changes in physiology among older patients with cancer is further augmented during chemotherapy. No previous studies examined potential drug interactions (PDIs) from polypharmacy and their association with chemotherapy tolerance in older patients with cancer. METHODS: This study is a retrospective medical chart review of 244 patients aged 70+ years who received chemotherapy for solid or hematological malignancies. PDI among all drugs, supplements, and herbals taken with the first chemotherapy cycle were screened for using the Drug Interaction Facts software, which classifies PDIs into five levels of clinical significance with level 1 being the highest. Descriptive and correlative statistics were used to describe rates of PDI. The association between PDI and severe chemotoxicity was tested with logistic regressions adjusted for baseline covariates. RESULTS: A total of 769 PDIs were identified in 75.4% patients. Of the 82 level 1 PDIs identified among these, 32 PDIs involved chemotherapeutics. A large proportion of the identified PDIs were of minor clinical significance. The risk of severe non-hematological toxicity almost doubled with each level 1 PDI (OR=1.94, 95% CI: 1.22-3.09), and tripled with each level 1 PDI involving chemotherapeutics (OR=3.08, 95% CI: 1.33-7.12). No association between PDI and hematological toxicity was found. CONCLUSIONS: In this convenience sample of older patients with cancer receiving chemotherapy we found notable rates of PDI and a substantial adjusted impact of PDI on risk of non-hematological toxicity. These findings warrant further research to optimize chemotherapy outcomes.

Management of primary metastatic breast cancer in elderly patients--an international comparison of oncogeriatric versus standard care.

BACKGROUND: An oncogeriatric approach may affect management of elderly patients with breast cancer. However, little is known about oncogeriatric care in the metastatic setting. Therefore, we performed an international comparison of management of elderly patients with primary metastatic disease who were treated in two different care settings. MATERIALS AND METHODS: Patients who were ≥70years at diagnosis of primary metastatic disease were eligible. The first cohort comprised a population-based cohort of 104 patients (Comprehensive Cancer Center West, The Netherlands), who all received standard care. The second cohort comprised a hospital-based cohort of 42 patients (H. Lee Moffitt Cancer Center, Florida, United States), who all received oncogeriatric care. RESULTS: No large differences in patient and tumor characteristics were observed between both cohorts. Most patients in the standard care cohort received systemic therapy as primary therapy, whereas most patients in the oncogeriatric cohort received a combination of systemic and local therapy. Patients in the standard care cohort received fewer lines of treatment (mean number of treatments 2.1 vs. 3.6, p<0.001), and particularly received less breast surgery, chemotherapy, and trastuzumab. Three-year overall mortality was 71% (95% CI: 61-83%) as compared to 58% (95% CI: 42-75%) among patients in the oncogeriatric care cohort (multivariable HR: 1.59 [95% CI: 0.88-2.87], p=0.125). CONCLUSIONS: In primary metastatic breast cancer, oncogeriatric care intensifies treatment and might improve survival in elderly patients. Future studies on a larger scale should investigate the potential for improved survival, and whether this is accompanied by a better (preservation of) quality of life and functional status.

Comprehensive geriatric assessment basics for the cancer professional.

A comprehensive geriatric assessment (CGA) has been a cornerstone of geriatric practice for many years. However, oncology practitioners are still unfamiliar with it. Yet, recent research has shown an important potential to improve the daily care of older cancer patients. The purpose of this article is to review the basic nature of a CGA, its effectiveness, its applicability to cancer patients, and its cost-effectiveness. Cancer is one of the major health problems in our society. Furthermore, the incidence of cancer increases with age. Nowadays, half of the cancers occur beyond the age of 70. Given the aging of the US population, this proportion is expected to increase in the next decades. A challenge for the oncologists is that older people can have a highly variable health status. Yet little is known yet about how to best assess and integrate into decision making the various health problems patients may have. Taking their clues from the experience of geriatricians, geriatric oncologists advocate the use of a comprehensive geriatric assessment (CGA) as one of the tools to deal with this problem. It is, for example, part of the National Comprehensive Cancer Network (NCCN) guidelines for the elderly'. This article offers a primer on CGA for the reader unfamiliar with the approach in an oncologic setting.

Can older cancer patients tolerate chemotherapy? A prospective pilot study.

BACKGROUND: To the authors' knowledge, few data currently are available regarding the tolerance to chemotherapy in older cancer patients. This prospective pilot study evaluated the changes in functional, mental, nutritional, and comorbid status, as well as the quality of life (QOL), in geriatric oncology patients receiving chemotherapy. METHODS: Sixty patients age > or = 70 years who were undergoing cancer chemotherapy were recruited in a university-based comprehensive cancer center. Changes in physical function were measured by the Eastern Cooperative Oncology Group performance status (ECOG PS) and Instrumental Activities of Daily Living (IADLs), mental health changes were measured by the Mini-Mental State Examination and the Geriatric Depression Scale (GDS), comorbidity was measured by Charlson's index and the Cumulative Illness Rating Scale-Geriatric, nutrition was measured by the Mini-Nutritional Assessment, and QOL was measured by the Functional Assessment of Cancer Therapy-General (FACT-G). Changes were assessed at baseline and at the end of treatment (EOT). Grade 4 hematologic and Grade 3-4 nonhematologic toxicities were recorded. RESULTS: Thirty-seven patients (63%) completed both assessments. Older cancer patients demonstrated a significant decline in measurements of physical function after receiving chemotherapy, as indicated by changes in scores on the IADL (P = 0.04) and on the physical (P = 0.01) and functional (P = 0.03) subscales of the FACT-G. They also displayed worse scores on the GDS administered postchemotherapy (P < 0.01). Patients who experienced severe chemotoxicity had more significant declines in ECOG PS (P = 0.03), IADL (P = 0.03), and GDS (P = 0.04), and more gain in the social well-being subscale (P = 0.02) of the FACT-G, than those who did not experience severe chemotoxicity. However, changes in most scores were small in magnitude clinically. No significant change was found between baseline and EOT in nutrition, comorbidity, and other aspects of the FACT-G. CONCLUSIONS: Older cancer patients undergoing chemotherapy may experience toxicity but generally can tolerate it with limited impact on independence, comorbidity, and QOL levels. It is important to recognize and monitor these changes during geriatric oncology treatment.