Purpose Older adults are vulnerable to chemotherapy toxicity; however, there are limited data to identify those at risk. The goals of this study are to identify risk factors for chemotherapy toxicity in older adults and develop a risk stratification schema for chemotherapy toxicity. Patients and Methods Patients age ≥ 65 years with cancer from seven institutions completed a prechemotherapy assessment that captured sociodemographics, tumor/treatment variables, laboratory test results, and geriatric assessment variables (function, comorbidity, cognition, psychological state, social activity/support, and nutritional status). Patients were followed through the chemotherapy course to capture grade 3 (severe), grade 4 (life-threatening or disabling), and grade 5 (death) as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events. Results In total, 500 patients with a mean age of 73 years (range, 65 to 91 years) with stage I to IV lung (29%), GI (27%), gynecologic (17%), breast (11%), genitourinary (10%), or other (6%) cancer joined this prospective study. Grade 3 to 5 toxicity occurred in 53% of the patients (39% grade 3, 12% grade 4, 2% grade 5). A predictive model for grade 3 to 5 toxicity was developed that consisted of geriatric assessment variables, laboratory test values, and patient, tumor, and treatment characteristics. A scoring system in which the median risk score was 7 (range, 0 to 19) and risk stratification schema (risk score: percent incidence of grade 3 to 5 toxicity) identified older adults at low (0 to 5 points; 30%), intermediate (6 to 9 points; 52%), or high risk (10 to 19 points; 83%) of chemotherapy toxicity (P < .001). Conclusion A risk stratification schema can establish the risk of chemotherapy toxicity in older adults. Geriatric assessment variables independently predicted the risk of toxicity.

Purpose To provide guidance regarding the practical assessment and management of vulnerabilities in older patients undergoing chemotherapy. Methods An Expert Panel was convened to develop clinical practice guideline recommendations based on a systematic review of the medical literature. Results A total of 68 studies met eligibility criteria and form the evidentiary basis for the recommendations. Recommendations In patients ≥ 65 years receiving chemotherapy, geriatric assessment (GA) should be used to identify vulnerabilities that are not routinely captured in oncology assessments. Evidence supports, at a minimum, assessment of function, comorbidity, falls, depression, cognition, and nutrition. The Panel recommends instrumental activities of daily living to assess for function, a thorough history or validated tool to assess comorbidity, a single question for falls, the Geriatric Depression Scale to screen for depression, the Mini-Cog or the Blessed Orientation-Memory-Concentration test to screen for cognitive impairment, and an assessment of unintentional weight loss to evaluate nutrition. Either the CARG (Cancer and Aging Research Group) or CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) tools are recommended to obtain estimates of chemotherapy toxicity risk; the Geriatric-8 or Vulnerable Elders Survey-13 can help to predict mortality. Clinicians should use a validated tool listed at ePrognosis to estimate noncancer-based life expectancy ≥ 4 years. GA results should be applied to develop an integrated and individualized plan that informs cancer management and to identify nononcologic problems amenable to intervention. Collaborating with caregivers is essential to implementing GA-guided interventions. The Panel suggests that clinicians take into account GA results when recommending chemotherapy and that the information be provided to patients and caregivers to guide treatment decision making. Clinicians should implement targeted, GA-guided interventions to manage nononcologic problems. Additional information is available at www.asco.org/supportive-care-guidelines .

Cellular immunophenotypic studies were performed on a cohort of randomly selected IgM+ B-chronic lymphocytic leukemia (B-CLL) cases for which Ig VH and VL gene sequences were available. The cases were categorized based on V gene mutation status and CD38 expression and analyzed for treatment history and survival. The B-CLL cases could be divided into 2 groups. Those patients with unmutated V genes displayed higher percentages of CD38+ B-CLL cells (≥30%) than those with mutated V genes that had lower percentages of CD38+ cells (<30%). Patients in both the unmutated and the ≥30% CD38+ groups responded poorly to continuous multiregimen chemotherapy (including fludarabine) and had shorter survival. In contrast, the mutated and the <30% CD38+ groups required minimal or no chemotherapy and had prolonged survival. These observations were true also for those patients who stratified to the Rai intermediate risk category. In the mutated and the <30% CD38+ groups, males and females were virtually equally distributed, whereas in the unmutated and the ≥30% CD38+ groups, a marked male predominance was found. Thus, Ig V gene mutation status and the percentages of CD38+B-CLL cells appear to be accurate predictors of clinical outcome in B-CLL patients. These parameters, especially CD38 expression that can be analyzed conveniently in most clinical laboratories, should be valuable adjuncts to the present staging systems for predicting the clinical course in individual B-CLL cases. Future evaluations of new therapeutic strategies and drugs should take into account the different natural histories of patients categorized in these manners.

Cellular immunophenotypic studies were performed on a cohort of randomly selected IgM+ B-chronic lymphocytic leukemia (B-CLL) cases for which Ig VH and VL gene sequences were available. The cases were categorized based on V gene mutation status and CD38 expression and analyzed for treatment history and survival. The B-CLL cases could be divided into 2 groups. Those patients with unmutated V genes displayed higher percentages of CD38+ B-CLL cells (≥30%) than those with mutated V genes that had lower percentages of CD38+ cells (&lt;30%). Patients in both the unmutated and the ≥30% CD38+ groups responded poorly to continuous multiregimen chemotherapy (including fludarabine) and had shorter survival. In contrast, the mutated and the &lt;30% CD38+ groups required minimal or no chemotherapy and had prolonged survival. These observations were true also for those patients who stratified to the Rai intermediate risk category. In the mutated and the &lt;30% CD38+ groups, males and females were virtually equally distributed, whereas in the unmutated and the ≥30% CD38+ groups, a marked male predominance was found. Thus, Ig V gene mutation status and the percentages of CD38+B-CLL cells appear to be accurate predictors of clinical outcome in B-CLL patients. These parameters, especially CD38 expression that can be analyzed conveniently in most clinical laboratories, should be valuable adjuncts to the present staging systems for predicting the clinical course in individual B-CLL cases. Future evaluations of new therapeutic strategies and drugs should take into account the different natural histories of patients categorized in these manners.

Purpose The primary purposes of eligibility criteria are to protect the safety of trial participants and define the trial population. Excessive or overly restrictive eligibility criteria can slow trial accrual, jeopardize the generalizability of results, and limit understanding of the intervention’s benefit-risk profile. Methods ASCO, Friends of Cancer Research, and the US Food and Drug Administration examined specific eligibility criteria (ie, brain metastases, minimum age, HIV infection, and organ dysfunction and prior and concurrent malignancies) to determine whether to modify definitions to extend trials to a broader population. Working groups developed consensus recommendations based on review of evidence, consideration of the patient population, and consultation with the research community. Results Patients with treated or clinically stable brain metastases should be routinely included in trials and only excluded if there is compelling rationale. In initial dose-finding trials, pediatric-specific cohorts should be included based on strong scientific rationale for benefit. Later phase trials in diseases that span adult and pediatric populations should include patients older than age 12 years. HIV-infected patients who are healthy and have low risk of AIDS-related outcomes should be included absent specific rationale for exclusion. Renal function criteria should enable liberal creatinine clearance, unless the investigational agent involves renal excretion. Patients with prior or concurrent malignancies should be included, especially when the risk of the malignancy interfering with either safety or efficacy endpoints is very low. Conclusion To maximize generalizability of results, trial enrollment criteria should strive for inclusiveness. Rationale for excluding patients should be clearly articulated and reflect expected toxicities associated with the therapy under investigation.

The American Society of Clinical Oncology (ASCO) convened a subcommittee to develop recommendations on improving the evidence base for treating older adults with cancer in response to a critical need identified by the Institute of Medicine. Older adults experience the majority of cancer diagnoses and deaths and make up the majority of cancer survivors. Older adults are also the fastest growing segment of the US population. However, the evidence base for treating this population is sparse, because older adults are underrepresented in clinical trials, and trials designed specifically for older adults are rare. The result is that clinicians have less evidence on how to treat older adults, who represent the majority of patients with cancer. Clinicians and patients are forced to extrapolate from trials conducted in younger, healthier populations when developing treatment plans. This has created a dearth of knowledge regarding the risk of toxicity in the average older patient and about key end points of importance to older adults. ASCO makes five recommendations to improve evidence generation in this population: (1) Use clinical trials to improve the evidence base for treating older adults with cancer, (2) leverage research designs and infrastructure for generating evidence on older adults with cancer, (3) increase US Food and Drug Administration authority to incentivize and require research involving older adults with cancer, (4) increase clinicians' recruitment of older adults with cancer to clinical trials, and (5) use journal policies to improve researchers' reporting on the age distribution and health risk profiles of research participants.

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Selecting the most appropriate end points for clinical trials is important to assess the value of new treatment strategies. Well-established end points for clinical research exist in oncology but may not be as relevant to the older cancer population because of competing risks of death and potentially increased impact of therapy on global functioning and quality of life. This article discusses specific clinical end points and their advantages and disadvantages for older individuals. Randomized or single-arm phase II trials can provide insight into the range of efficacy and toxicity in older populations but ideally need to be confirmed in phase III trials, which are unfortunately often hindered by the severe heterogeneity of the older cancer population, difficulties with selection bias depending on inclusion criteria, physician perception, and barriers in willingness to participate. All clinical trials in oncology should be without an upper age limit to allow entry of eligible older adults. In settings where so-called standard therapy is not feasible, specific trials for older patients with cancer might be required, integrating meaningful measures of outcome. Not all questions can be answered in randomized clinical trials, and large observational cohort studies or registries within the community setting should be established (preferably in parallel to randomized trials) so that treatment patterns across different settings can be compared with impact on outcome. Obligatory integration of a comparable form of geriatric assessment is recommended in future studies, and regulatory organizations such as the European Medicines Agency and US Food and Drug Administration should require adequate collection of data on efficacy and toxicity of new drugs in fit and frail elderly subpopulations.