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.

Development of a health data derived frailty index as a predictor of adverse outcomes in older patients with pancreatic cancer.

Pancreatic cancer is a prevalent disease among older adults. Well-selected patients, based on a geriatric assessment for risk stratification, could be good candidates for chemotherapy and/or curative resection. Deficits accumulation frailty indices (FI) utilize readily available clinical data and easily obtained patient-reported information to predict hospitalization and mortality of older individuals. Retrospective data from 440 older adults (median age 76 years) with pancreatic cancer, obtained from electronic health records, was used to develop a FI and its ability to predict mortality and other geriatric and cancer related outcomes was tested. Fatigue (n = 45), infection (n = 40) and neutropenia (n = 36) were the most common registered adverse events of treatment; 153 subjects had no adverse events. The mean FI score was 0.26, 112 subjects were fit (0.0 < 0.2), 255 pre-frail (0.2 < 0.35), and 73 frail (≥ 0.35). Median survival was twelve months for the whole sample; at one year 62.5% of fit patients, 46.3% of pre-frail, and 26% of frail patients were alive. The FI categories correlated with institutionalization (p < 0.001) and non-planned hospitalization (p < 0.001). The FI categories did not correlate with the presence of Common Terminology Criteria for Adverse Events (CTCAE) grade 3-4 adverse events (p = 0.377). We conclude that patients with pancreatic cancer classified as frail with our FI had worse survival than those fit and pre-frail. Non-fit patients were also more prone to be institutionalized and have non-planned hospitalizations. The items used for this FI can be usually acquired from electronic health records and could be automated in the future, which could simplify its use as a helping tool for decisions in older patients with pancreatic cancer.

A simple test-based frailty index to predict survival among cancer patients with an unplanned hospitalization: An observational cohort study.

BACKGROUND: Frailty is a state of increased vulnerability to stressors, and predicts risk of adverse outcomes, such as mortality. Frailty can be defined by a frailty index (FI) using an accumulation of deficits approach. An FI comprised of 20 items derived from our previously studied test-based frailty index (TBFI) and an additional 33 survey-based elements sourced from the standard CGA was developed to evaluate if predictive validity of survival was improved. METHODS: One hundred eighty-nine cancer patients during acute hospitalization were consented between September 2018 and May 2019. Frailty scores were calculated, and patients were categorized into four groups: non-frail (0-0.2), mildly frail (0.2-0.3), moderately frail (0.3-0.4), and severely frail (>0.4). Patients were followed for 1-year to assess FI and TBFI prediction of survival. Area under the curve (AUC) statistics from ROC analyses were compared for the FI versus TBFI. RESULTS: Increasing frailty was similarly associated with increased risk of mortality (HR, 4.5 [95% CI, 2.519-8.075] and HR, 4.1 [95%CI, 1.692-9.942]) and the likelihood of death at 6 months was about 11-fold (odds ratio, 10.9 [95% CI, 3.97-33.24]) and 9.73-fold (95% CI, 2.85-38.50) higher for severely frail patients compared to non-frail patients for FI and TBFI, respectively. This association was independent of age and type of cancer. The FI and TBFI were predictive of survival for older and younger cancer patients with no significant differences between models in discriminating survival (FI AUC, 0.747 [95% CI, 0.6772-0.8157] and TBFI AUC, 0.724 [95% CI, 0.6513-0.7957]). CONCLUSIONS: The TBFI was predictive of survival, and the addition of an in-person assessment (FI) did not greatly improve predictive validity. Increasing frailty, as measured by a TBFI, resulted in a meaningfully increased risk of mortality and may be well-suited for screening of hospitalized cancer patients.

Impact of age, comorbidity, and treatment characteristics on survival in older women with advanced high grade epithelial ovarian cancer.

OBJECTIVES: Older women have a worse prognosis with advanced epithelial ovarian cancer (EOC) and comorbidities likely contribute to poor outcomes. We sought to identify comorbid conditions and treatment-related factors in older women. METHODS: A retrospective chart review identified 351 patients who underwent cytoreductive surgery (CRS). 100/351 (28.5%) were ≥ 70 years old. Demographic and clinicopathologic information was collected. Crude progression-free (PFS) and overall survival (OS) estimates were calculated using Kaplan-Meier method. Cox proportional hazards regression model was used to estimate hazard ratios and adjustments for confounders. RESULTS: Study subjects ≥70 years old had significantly: higher Cumulative Illness Rating Scale-Geriatric (CIRS-G) score (5.9 vs 4.3; p = 0.0001), less completion of adjuvant chemotherapy (24% vs 15.1%; p = 0.049), less intraperitoneal (IP) therapy (18.2% vs 35.5%; p = 0.002), less clinical trial participation (16% vs 26.3%; p = 0.040), decreased platinum sensitivity (60% vs 73.7%; p = 0.012) and lacked BRCA mutations (0% vs 12%; p = 0.0006). They were less likely to have optimal CRS (75% vs 86.9%; p = 0.007) with same surgical complexity (p = 0.89). Patients ≥70 had significantly worse PFS and OS. In a multivariate analysis, better OS was associated with younger age (<70 years old), any IP therapy, completion of adjuvant chemotherapy, and platinum sensitivity. CONCLUSION: The older cohort had worse CIRS-G scores (5.9 vs 4.3; p = 0.0001), but no strong associations between comorbidities and treatment characteristics, but less optimal CRS rates (75% vs 86.9%; p = 0.007) with similar surgical complexity and less platinum sensitivity. Our results show comorbid conditions in older patients with advanced EOC may have less impact than tumor biology.

Benchmarking treatment effects for patients over 70 with acute myeloid leukemia: A systematic review and meta-analysis.

OBJECTIVES: The majority of patients with acute myeloid leukemia (AML) are aged 70 and over. However, there is uncertainty about how and whether older patients with AML should receive cytotoxic treatment. MATERIALS AND METHODS: Medline and Cochrane library search was performed for studies in newly diagnosed AML which enrolled at least 20 patients per arm (for randomized controlled trials), or 50 patients (for non-randomized studies) over the age of 70. References were hand searched for additional eligible studies. Study investigators were contacted to maximize relevant data. Dual independent data extraction was done using standardized data collection forms. Data was collected on study and treatment characteristics, baseline patient information, and outcomes. Study methodological quality was assessed. The primary outcome was 1 year overall survival (OS). Impact of treatment [intensive chemotherapy (INT), low-dose chemotherapy (LOW), hypomethylating agents (HMA), or best supportive care (BSC)], cytogenetics, performance status, and comorbidity were assessed. RESULTS: The search produced 11,846 references of which 38 randomized controlled trials and 30 non-randomized studies met inclusion criteria, representing 13,381 patients, with a worldwide distribution. One-year OS with INT was 37% (31-42%), with LOW 11% (6-18%), with HMA 35% (18-54%) and with BSC 17%(13-21%). Two-year OS was 22% (18-26%), 11% (7-15%), 22% (16-28%), 6% (2-12%), respectively. We present subgroup data based on the studies including cytogenetics, performance status, and comorbidity. Formal direct comparisons with adjustment for all prognostic factors were not possible. CONCLUSIONS: In this largest to date series of AML patients aged 70 and older, we provide benchmarks for treatment efficacy and effectiveness that may be used for decision analysis models and for the future development of clinical trials focusing on these patients.

Comparisons of commonly used front-line regimens on survival outcomes in patients aged 70 years and older with acute myeloid leukemia.

In older patients with acute myeloid leukemia, the more frequent presence of biologically inherent therapy-resistant disease and increased comorbidities translate to poor overall survival and therapeutic challenges. Optimal front-line therapies for older patients with acute myeloid leukemia remain controversial. We retrospectively evaluated survival outcomes in 980 elderly (≥70 years) acute myeloid leukemia patients from a single institution between 1995 and 2016. Four treatment categories were compared: high-intensity (daunorubicin/cytarabine or equivalent), hypomethylating agent, low-intensity (low-dose cytarabine or similar without hypomethylating agents), and supportive care therapy (including hydroxyurea). At a median follow up of 20.5 months, the median overall survival for the entire cohort was 7.1 months. Multivariate analysis identified secondary acute myeloid leukemia, poor-risk cytogenetics, performance status, front-line therapy, age, white blood cell count, platelet count, and hemoglobin level at diagnosis as having an impact on survival. High-intensity therapy was used in 360 patients (36.7%), hypomethylating agent in 255 (26.0%), low-intensity therapy in 91 (9.3%), and supportive care in 274 (28.0%). Pairwise comparisons between hypomethylating agent therapy and the three other treatment groups demonstrated statistically significant superior median overall survival with hypomethylating agent [14.4 months) vs high-intensity therapy 10.8 months, hazard ratio 1.35, 95% confidence interval (CI): 1.10-1.65; P =0.004], low-intensity therapy (5.9 months, hazard ratio 2.01, 95%CI: 1.53-2.62; P<0.0001), and supportive care (2.1 months, hazard ratio 2.94, 95%CI: 2.39-3.61; P<0.0001). Our results indicate a significant survival benefit with hypomethylating agents compared to high-intensity, low-intensity, or supportive care. Additionally, high-intensity chemotherapy resulted in superior overall outcomes compared to low-intensity therapy and supportive care. Results from this study highlight the need for novel therapeutic approaches besides utilization of intensive chemotherapy in this specific aged population.

Biologic Mechanisms Linked to Prognosis in Ovarian Cancer that May Be Affected by Aging.

The increase of both life expectancy of the Western industrialized population and cancer incidence with aging is expected to result in a rapid expansion of the elderly cancer population, including patients with epithelial ovarian cancer (EOC). Although the survival of patients with EOC has generally improved over the past three decades, this progress has yet to provide benefits for elderly patients. Compared with young age, advanced age has been reported as an adverse prognostic factor influencing EOC. However, contradicting results have been obtained, and the mechanisms underlying this observation are poorly defined. Few papers have been published on the underlying biological mechanisms that might explain this prognosis trend. We provide an extensive review of mechanisms that have been linked to EOC prognosis and/or aging in the published literature and might underlie this relationship in humans.

Association of multidimensional comorbidities with survival, toxicity, and unplanned hospitalizations in older adults with metastatic colorectal cancer treated with chemotherapy.

BACKGROUND: Studies of older patients with colorectal cancer(CRC) have found inconsistent results about the correlation of various comorbidities with overall survival(OS) and treatment tolerance. To refine our understanding, we evaluated this correlation using the Cumulative Illness Rating Scale-Geriatric(CIRS-G) and heat maps to identify subgroups with the highest impact. METHODS: We retrospectively reviewed 153 patients aged 65 years and older with stage IV CRC undergoing chemotherapy. We calculated CIRS-G scores, and a Total Risk Score(TRS) derived from a previous heat map study. The association between CIRS-G scores/TRS and OS, unplanned hospitalizations, and chemotoxicity was examined by the Cox proportional hazards model. RESULTS: Median age was 71 years. Median MAX2 score of chemotherapies was 0.134(0.025-0.231). The most common comorbidities were vascular(79.8%), eye/ear/nose/throat(68%), and respiratory disease(52.4%). Median OS was 25.1 months(95% confidence interval: 21.2-27.6). In univariate analysis, ECOG PS ≥ 2(HR 1.86(1.1-3.17), p = 0.019), poorly differentiated histology(HR 2.03(1.27-3.25), p = 0.003), primary site(rectum vs colon)(HR 0.58 (0.34-0.98), p = 0.04), age at diagnosis(HR per 5y 1.20 (1.04-1.39), p = 0.012), and number of CIRS-G grade 4 comorbidities(HR 1.86 (1.1-3.17), p = 0.019) were associated with OS. In multivariate analysis, the number of CIRS-G grade 4 comorbidities lost significance, although it retained it in the subgroup of patients with colon cancer. Conversely, the TRS was associated with OS in patients with rectal cancer. No association of comorbidity with unplanned hospitalization or chemotoxicity was observed. CONCLUSIONS: In older adults with metastatic CRC, the number of CIRS-G grade 4 comorbidities was associated with worse OS but no specific CIRS-G category was independently associated with OS, unplanned hospitalization, or toxicities.

Using Big Data in oncology to prospectively impact clinical patient care: A proof of concept study.

OBJECTIVE: Big Data is widely seen as a major opportunity for progress in the practice of personalized medicine, attracting the attention from medical societies and presidential teams alike as it offers a unique opportunity to enlarge the base of evidence, especially for older patients underrepresented in clinical trials. This study prospectively assessed the real-time availability of clinical cases in the Health & Research Informatics Total Cancer Care™ (TCC) database matching community patients with cancer, and the impact of such a consultation on treatment. MATERIALS AND METHODS: Patients aged 70 and older seen at the Lynn Cancer Institute (LCI) with a documented malignancy were eligible. Geriatric screening information and the oncologist's pre-consultation treatment plan were sent to Moffitt. A search for similar patients was done in TCC and additional information retrieved from Electronic Medical Records. A report summarizing the data was sent and the utility of such a consultation was assessed per email after the treatment decision. RESULTS: Thirty one patients were included. The geriatric screening was positive in 87.1% (27) of them. The oncogeriatric consultation took on average 2.2 working days. It influenced treatment in 38.7% (12), and modified it in 19.4% (6). The consultation was perceived as "somewhat" to "very useful" in 83.9% (26). CONCLUSION: This study establishes a proof of concept of the feasibility of real time use of Big Data for clinical practice. The geriatric screening and the consultation report influenced treatment in 38.7% of cases and modified it in 19.4%, which compares very well with oncogeriatric literature. Additional steps are needed to render it financially and clinically viable.

Using heat maps to assess the multidimensional association of comorbidities with survival in older cancer patients treated with chemotherapy.

OBJECTIVE: To date, most comorbidity studies have analyzed either a subgroup of frequent diseases, or used summary instruments such as the Charlson score or the Cumulative Illness Rating Scale-Geriatric (CIRS-G). Yet, comorbidity is a multidimensional construct and impacts function, treatment tolerance, and survival. We assessed how heat maps can unveil specific patterns of comorbidities associated with overall survival (OS) in older cancer patients treated with chemotherapy. MATERIAL AND METHODS: We reviewed four trials that prospectively evaluated comorbidities using CIRS-G. Eligible patients were 65years or older and had solid tumors with 30 or more patients per tumor site. Heat maps were constructed based on CIRS-G scores and correlated with OS. RESULTS: Among 818 patients accrued, 399 were eligible: Median follow-up was 53.4months and median OS was 19.6months (95% CI: 16.5-24.2). In the univariate model for OS, patients with a severe CIRS-G score in 6 organ categories (3-4 in heart, hematopoietic, respiratory, and musculoskeletal-integument and 2-4 in upper GI and liver) had statistically worse OS than those with lower scores. According to a total risk score (TRS) based on hazard ratios for OS, OS of the low risk group (N=309, TRS<2) was significantly higher (24.3m vs. 10.8m, HR=2.05, 95% CI: 1.58-2.66). TRS was a predictor for OS independently from stage, primary site, prior chemotherapy, ECOG performance status, and IADL (HR=1.94, 95% CI: 1.47-2.57). CONCLUSIONS: High TRS was a predictor of poor survival. Comorbidity heat maps appear promising to identify diseases most affecting the OS of older cancer patients.

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.

Chemotoxicity recurrence in older patients: Risk factors and effectiveness of preventive strategies-a prospective study.

BACKGROUND: The National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) and adjustment rules after severe toxicity are derived by consensus, but to the authors' knowledge little is known regarding the determinants of toxicity recurrence, especially in the elderly. METHODS: The authors prospectively accrued 200 patients (aged ≥65 years) before chemotherapy. For those with CTCAE grade 3 to 4 nonhematologic or CTCAE grade 4 hematologic toxicities (severe toxicity), the duration and functional impact, treatment modifications, and severe toxicity recurrence were recorded. The regimen's toxicity was adjusted with the MAX2 index, the average of the most frequent grade 4 hematologic toxicities and the most frequent grade 3 to 4 nonhematologic toxicities reported in publications of a regimen. RESULTS: The median patient age was 73 years (range, 65-90 years). Among 163 patients who were evaluable for toxicity after ≥1 treatment cycle (receiving on average 4.73 cycles), 82 had severe toxicity, 10 were discontinued for toxicity, 6 were discontinued for other reasons, and 5 patients had died. Sixty-one patients received further chemotherapy: 41 without dose modification (16 with secondary prevention measures) and 20 with dose modifications. Without modification, 19 patients (46%) experienced toxicity recurrence (0 deaths). With modification, 7 patients (35%) experienced a toxicity recurrence (1 death). On univariate analysis, treatment intent, hospitalization, duration-adjusted activities of daily living (ADL), quality of life impact, and fatigue were associated with dose modification. ADL remained associated on multivariate analysis (P = .02). On univariate analysis for toxicity recurrence, Eastern Cooperative Oncology Group performance status and MAX2 score demonstrated an association, with only the latter found to remain statistically significant on multivariate analysis (P = .04). CONCLUSIONS: If a severe toxicity does not have a long duration of impact on ADL, oncologists are less inclined to modify treatment. With proper supportive measures, this leads to recurrence risks similar to those shown in patients with modified treatment, with low risks of toxic deaths overall.