Table 1.

Opportunities in Geriatric Oncology Clinical Trial Designs

Design	Description and Characteristics	Potential Objectives and Outcomes	Advantages	Limitations and Vital Considerations	Clinical Trial Examples
RCT	RCTs are gold standard of clinical trial design; study participants are randomly assigned among different treatment arms	Determination of gold standard of treatment by comparing efficacy and tolerability of different outcomes	Excellent for direct comparison of different treatment regimens	Requires large sample size because of randomized design	CALGB 4990737
	Eligibility criteria considerations:     Method 1: accrue only older patients     Method 2: accrue patients of all ages, then stratify into age groups representative of general population with disease Trial design consideration:     Adaptive (Bayesian) design; trial design is modified as study proceeds based on interim data analysis; randomization ratio can be altered by shifting patients to more effective treatment arm and eliminating underperforming arms	Development of novel end points (including composite measures of tolerability and toxicity)	Method 1:     Particularly important if there is age-related change in cancer biology     Important for identifying treatment options among patients who are traditionally excluded from clinical trials because of chronic health conditions or concerns regarding toxicity and who would otherwise not enroll onto clinical trials for all age groups     End points can be specifically tailored for geriatric oncology population Method 2:     Allows for greater generalizability of results     Would rectify current situation of older adults being under-represented on clinical trials	Can be costly and time intensive Method 2:     Could result in slower accrual due to the enrollment of specific age strata     Lack of end points tailored specifically for geriatric oncology population	PI, Hyman Muss; ClinicalTrials.gov ID, NCT00024102 Comparison of different adjuvant chemotherapy (standard treatment [AC or CMF] v new therapy [capecitabine]) treatments for older women with early-stage breast cancer
Prospective cohort study	Assessment of treatments currently on market to evaluate outcomes of interest in older patients	Identification of patterns of care	Enrollment of patients receiving standard-of-care treatment increases generalizability of findings	Treatment is not randomized; therefore, investigators unable to determine which treatment is most efficacious and least toxic for older patients	CALGB 36990138
	Cohort can be defined by host, tumor, or treatment factors	Understanding decision making	Can be used to understand patterns of care and decision making	Significant data management resources required to accurately capture drug dosing and toxicity data	PI, Jeanne Mandelblatt; ClinicalTrials.gov ID: NCT00068328
	Observational No randomization Hypothesis driven	Determination of toxicity and feasibility of delivering specific therapies			Patient preference as determinant of breast cancer adjuvant chemotherapy use in older women
Embedded study	Also known as correlative or ancillary study	Use of GA to describe cohort	Better baseline characterization of the geriatric oncology population that enters the study	The parent study may not be specifically targeted to older adults, thus limiting the sample size of older patients	CALGB 361006
	Additional measurements of interest to geriatric oncology research (such as GA measures) are placed within infrastructure of parent study	Use of GA in longitudinal follow-up to understand impact of therapy on function and other GA measures Identification of characteristics of specific group of patients who are at high risk for toxicity	Ability to identify baseline predictors of treatment tolerance and/or longitudinal declines in function	If participation in embedded study is optional, then characteristics of patients who choose to enroll may not be representative of entire cohort and/or adequate sample size of older patients may not be accrued	PI, Heidi Klepin GA embedded in CALGB 1100139 PI, Geoffrey Uy; ClinicalTrials.gov ID for CALGB 11001, NCT01253070 Sorafenib tosylate and chemotherapy in treating older patients with AML
Single-arm trial	Current gold-standard design for phase II clinical trials	Evaluation of efficacy of drug for which there are limited data for older adults	Quantification of novel end points such as impact of therapy on functional status and QOL	No comparison of treatment under study with gold standard	CALGB 976240
	No randomization	Identification of predictors of toxicity based on GA variables or biomarkers	Fills gap in knowledge regarding efficacy, feasibility, and toxicity of drugs that have been understudied in older adults		PI, Stuart Lichtman; ClinicalTrials.gov ID, NCT00003092
	All patients receive treatment under study	Understanding of age-related changes in pharmacokinetics and pharmacodynamics of cancer therapeutics			Prospective evaluation of relationship of patient age and paclitaxel clinical pharmacology
Extended trial	Addition of cohort of older patients to treatment arm from RCT that was shown to be superior	Determination of tolerability of treatment in older adults	Trial infrastructure is already in place	Currently no precedent exists for reopening study several years after closure	No precedent
			Accrual of older patients might be easier because efficacy of treatment has been previously demonstrated Additional data regarding tolerability in older patients will be obtained	Accrual is only to superior arm to bolster data about tolerability in older adults; however, data regarding efficacy of treatment (compared with inferior arm) in older population will not be obtained

Abbreviations: AC, doxorubicin and cyclophosphamide; AML, acute myeloid leukemia; CALGB, Cancer and Leukemia Group B; CMF, cyclophosphamide, methotrexate, and fluorouracil; GA, geriatric assessment; PI, principal investigators; QOL, quality of life; RCT, randomized controlled trial.