Article selection

The combined search strategies yielded an initial 1,812 articles. Nine hundred ninety-three duplicates were removed, including articles from the 2021 search identified in the 2024 search. Eight hundred nineteen titles and abstracts were reviewed for relevance. Two hundred ninety-five articles underwent full-text screening, with 194 studies excluded as detailed in the PRISMA flow diagram (Figure 1). A resulting total of 101 articles were included in the review.

Figure 1. PRISMA flow diagram of selected articles.

Study information

Approximately 66% of included studies (n = 67) primarily addressed tumor-directed, therapeutic trials, with 39.6% providing specific information on intervention types studied (n = 40). Only 12.8% of studies (n = 13) explicitly addressed trials with at least one supportive care, psychosocial, or behavioral component, with 5.0% of all studies (n = 5) exclusively focused on such CCTs. Approximately 18.8% of studies provided minimal detail on trial type eligibility criteria (n = 19). This information is summarized in Table 1.

Case-control studies – that is, studies examining differences between participants and non-participants using patient data repositories – constituted 44.6% (n = 45) of articles, with most utilizing population data to compare characteristics between CCT participants and corresponding oncologic populations. Nearly 29% of studies were conceptualized as cohort designs (n = 29, i.e., using patient data to evaluate predictors of CCT enrollment over time), and 7.5% (n = 7) were cross-sectional studies. Twenty-one studies were meta-analyses of aggregate demographic, socioeconomic, or medical characteristics across published trials (20.8%). Where classification according to these descriptions was ambiguous, our authors relied on self-identification of study design by the cited authors. This information is detailed in Table 2.

Approximately 81% (n = 82) of studies included race and/or ethnicity as a primary focus. In comparison, 54.4% (n = 55) addressed age, 35.6% (n = 36) addressed at least one socioeconomic indicator, 30.7% addressed sex or gender (n = 31), and 26.7% (n = 27) addressed at least one indicator of disability as CCT inequity targets. Only one eligible study addressed SGM status (0.99%) even following several modifications of advanced search strategies (Supplementary Table 1). The availability of social, economic, and medical characteristics across studies is detailed in Table 3.

Quality assessment

Across all 101 studies, the quality mean MMAT score calculated was 4.59, with a median of 5. Score distribution was as follows: 5: 65.3% (n = 66), 4: 28.7% (n = 29), 3: 5.9% (n = 6), 2: 0.0% (n = 0), 1: 0.0% (n = 0). Quality ratings are summarized in Table 1.

Synthesis of findings

Race and ethnicity

Extant literature reflects robust evidence of CCT underrepresentation among patients of color, with mixed findings on representativeness across specific racial and ethnic minority groups. Early studies reflect lower enrollment among patients of color across multiple diagnostic sites, including in therapeutic lung, breast, colorectal, lymphoma, leukemia, and reproductive system CCTs [Reference Craig, Gilbert, Herndon, Vogel and Quinn33], with some revealing decreased participation among patients of color across time (e.g., Baquet: 8.9% annual decrease among Black patients) [Reference Baquet, Ellison and Mishra34]. Similar early trends are documented in surgical breast, colorectal, and thoracic CCTs [Reference Stewart, Bertoni, Staten, Levine and Gross35]. Across the 50 largest National Cancer Institute (NCI) CCTs from 1996 to 2002, Black, Hispanic, and Asian American or Pacific Islander (AAPI) patients were all less likely to enroll in lung and colorectal CCTs, with Black and Hispanic women also less likely to enroll in breast trials [Reference Murthy, Krumholz and Gross36]. These data indicated the poorest representation among Hispanic patients overall, and lower prostate CCT enrollment – a disparity not observed among other minority groups. This case-control study also showed a proportional decline in CCT enrollment among patients of color despite increased overall CCT participation from 1998 to 2002 [Reference Murthy, Krumholz and Gross36]. While other evidence supports attenuation of some of these inequities with clinical cooperative group efforts (e.g., Newman: % Black CCT participants vs. cancer population: 10.5% and 9.4%) [Reference N., Hurd and Leitch37], early research consistently reflects national CCT underrepresentation among patients of color across various cancers.

Studies from the following decade demonstrate continued CCT underrepresentation among patients of color, adjusting for other relevant characteristics [Reference Behrendt, Hurria, Tumyan, Niland and Mortimer38,Reference Fayanju, Ren and Thomas39]. Longitudinal data emphasize stagnant therapeutic lung CCT enrollment among Black, Hispanic, and AAPI patients from 1990 to 2012, even with NCI cooperative group support [Reference Pang, Wang and Stinchcombe40]. Similar studies indicate worsening representation of Black women in gynecologic CCTs up to 2013, demonstrating 4.5–15 times lower enrollment than expected [Reference Scalici, F. and Black41]. A meta-analysis from this period suggests still poorer trends, reporting 6.5 and 18.5 times lower enrollment than expected for Black women in cervical and ovarian trials, respectively, with representation worse from 2015 to 2018 compared to the late 1990s [Reference Awad, Paladugu and Jones4]. Other studies corroborate underrepresentation among patients of color in prostate, breast, colorectal, pancreatic gastric, hematologic, myelodysplastic, and varied sample CCTs at the catchment area level [Reference Borno, Small and Zhang42,Reference Brierley, Zabor and Komrokji43], in multi-site and multi-trial pharmacologic studies [Reference Dressler, Deal and Owzar44,Reference Ramamoorthy, Knepper and Merenda45], Food and Drug Administration (FDA) CCTs with pharmaceutical sponsors [Reference Unger, Hershman and Osarogiagbon46], and in NIH CCTs from 1999 to 2019 [Reference Gopishetty, Kota and G.5]. Meta-analytic studies corroborate persistence of these inequities, reflecting poorest representation among Black and Hispanic patients in various therapeutic breast, colorectal, lung, prostate, pancreatic, renal, melanoma, and multiple myeloma CCTs, with such data collectively spanning 1981 to 2017 (e.g., Guerrero et al.: Not Reported, White, Black, and Hispanic CCT enrollment fractions [EF], respectively: 66.95%, 25.94%, 1.08%, 0.16%).[Reference Duma, Vera Aguilera and Paludo47,Reference Guerrero, López-Cortés and Indacochea48]. Other national gynecologic CCT data not only accentuate Black and Hispanic underrepresentation but also larger disproportionate effects on Hispanic women with uterine and cervical cancers [Reference Mishkin, M., K., N. and T.49]. State-level studies reveal similar trends, with women of color less likely to enroll in early-stage breast radiotherapy CCTs overall, with Hispanic, then AAPI, then Black women, respectively, showing the lowest representation [Reference Housri, Khan and Taunk50]. However, other findings during this period indicate the highest relative underrepresentation among AAPI, then Hispanic, then Black patients across breast, prostate, colorectal, and lung CCTs in national databases [Reference Grant, Lin and Miller6].

A few studies prior to 2021 suggest minimal inequities in CCT representation among patients of color with certain diagnoses, locations, and trial types. One national study reports no racial or ethnic differences in opportunities to participate in breast CCTs from 2013 to 2014 [Reference Patel, Shah and Abrahamse51], with similar findings regarding prostate CCTs in earlier years [Reference Craig, Gilbert, Herndon, Vogel and Quinn33,Reference Stewart, Bertoni, Staten, Levine and Gross35]. A case-control analysis of FDA-approved therapies for breast, lung, colorectal, and prostate cancers showed persisting underrepresentation among patients of color relative to non-Hispanic White patients, though with recent improvements (% participants of color, 2008–2013: 20%; 2014–2017: 29%) [Reference Ramamoorthy, Knepper and Merenda45]. Other evidence emphasizes representative accrual to surgical breast, thoracic, and sarcoma CCTs among Black and Hispanic patients [Reference Diehl, Green and Weinberg52], as is observed in NCI Community Cancer Centers Program CCTs overall [Reference Langford, Resnicow and Dimond53]. Some findings during this period suggest equitable representation among patients of color in therapeutic lung CCTs, despite participation inequities in five other diagnostic sites [Reference Gopishetty, Kota and G.5]. Nonetheless, nonsurgical breast CCTs reliably demonstrate worsening representation among patients of color despite progress in other cancers (e.g., Zullig: 1996: < 1% vs. 2009: 3.5% enrollment difference between White and minority women, p < .001) [Reference Zullig, F.B., Rao, T., G. and C.54]. Other studies reporting nonsignificant participation differences in some areas emphasize persisting trends toward underrepresentation among patients of color where typically observed [Reference Craig, Gilbert, Herndon, Vogel and Quinn33].

Studies published within the past three years corroborate the intractability of CCT underrepresentation among patients of color while providing further nuance surrounding these inequities. State and national cohort, case-control, and meta-analytic studies of overall CCT representation evidence participation inequities that disproportionately impact Black [Reference Tharakan, Zhong and Galsky55–Reference Wagar, Mojdehbakhsh, Godecker, Rice and Barroilhet59] and/or Hispanic [Reference Duma, Vera Aguilera and Paludo47,Reference Guerrero, López-Cortés and Indacochea48,Reference Bero, Rein and Banerjee56,Reference Perni, Moy and Nipp57,Reference Wagar, Mojdehbakhsh, Godecker, Rice and Barroilhet59,Reference Choradia, Karzai, Nipp, Naqash, Gulley and Floudas60] patients in phase I [Reference Perni, Moy and Nipp57], II [Reference Fakhry, Pena, Pomputius, Giap and Vega61], and III [Reference Wagar, Mojdehbakhsh, Godecker, Rice and Barroilhet59]; radiation [Reference Bero, Rein and Banerjee56,Reference Fakhry, Pena, Pomputius, Giap and Vega61]; drug [Reference Tharakan, Zhong and Galsky55,Reference Green, Tabatabai and Aghajanian58,Reference Wagar, Mojdehbakhsh, Godecker, Rice and Barroilhet59]; brachytherapy [Reference Ladbury, Liu, Novak, Amini and Glaser62]; and general CCTs [Reference Guerrero, López-Cortés and Indacochea48,Reference Choradia, Karzai, Nipp, Naqash, Gulley and Floudas60] utilizing updated datasets and study repositories (e.g., Bero: Black proton participants vs. population 6.0% vs. 12.7%; Choradia: Hispanic participants vs. population: 7.1% vs. 13%; ). While some studies note mild representative improvement among Black [Reference Choradia, Karzai, Nipp, Naqash, Gulley and Floudas60,Reference Saphner, Marek, Homa, Robinson and Glandt63] and Hispanic patients (e.g., Saphner: no significant inequities in White, Black, and Hispanic accrual: 90.4%, 6.6%, 1.9%; p = .078) [Reference Saphner, Marek, Homa, Robinson and Glandt63], others demonstrate worsened representation in common cancers over time (e.g., 2009 vs. 2011–2015) [Reference Duma, Vera Aguilera and Paludo47]. Other case-control and meta-analyses emphasize underrepresentation among AAPI, Native Hawaiian, and American Indian/Alaska Native patients, in recent, CCTs for various prevalent cancers [Reference Guerrero, López-Cortés and Indacochea48,Reference Bero, Rein and Banerjee56,Reference Acoba, Sumida and Berenberg64]. Still other findings evidence minimal underrepresentation among patients of color [Reference Saphner, Marek, Homa, Robinson and Glandt63] and demonstrate even higher CCT participation among Asian patients, though such results have been primarily limited to singular institutions diagnostic sites, or trial types (e.g., Wagar: polymerase inhibitor CCT EF: White: 1.5%, Black: 0.47%, Hispanic: 0.33%, AAPI: 2.38%) [Reference Duma, Vera Aguilera and Paludo47,Reference Perni, Moy and Nipp57,Reference Wagar, Mojdehbakhsh, Godecker, Rice and Barroilhet59,Reference Saphner, Marek, Homa, Robinson and Glandt63].

Contemporary, cancer-specific studies reveal the importance of tumor site in dictating such inequities. Recent cohort, case-control, and meta-analytic studies of the most prevalent cancers continue to demonstrate underrepresentation among Black [Reference Ladbury, Liu, Novak, Amini and Glaser62,Reference Javier-DesLoges, Nelson and Murphy65–Reference Owens-Walton, Williams, Rompré-Brodeur, Pinto and Ball72], Hispanic [Reference Ladbury, Liu, Novak, Amini and Glaser62,Reference Javier-DesLoges, Nelson and Murphy65–Reference Kwak, Bassiri and Jiang70,Reference Owens-Walton, Williams, Rompré-Brodeur, Pinto and Ball72], Asian [Reference Ladbury, Liu, Novak, Amini and Glaser62,Reference Owens-Walton, Williams, Rompré-Brodeur, Pinto and Ball72,Reference Abbas, Diaz and Obeng-Gyasi73], and American Indian and Alaskan Native [Reference Ladbury, Liu, Novak, Amini and Glaser62,Reference Aldrighetti, Niemierko, Van Allen, Willers and Kamran67,Reference Kilic, Zhao and Okut69] individuals in breast [Reference Ladbury, Liu, Novak, Amini and Glaser62,Reference Moloney and Shiely66–Reference Pittell, Calip and Pierre68,Reference Ajewole, Akindele, Abajue, Ndulue, Marshall and Mossi71,Reference Keegan, Crown, DiMaggio and Joseph74], lung [Reference Javier-DesLoges, Nelson and Murphy65,Reference Aldrighetti, Niemierko, Van Allen, Willers and Kamran67–Reference Ajewole, Akindele, Abajue, Ndulue, Marshall and Mossi71], and prostate CCTs (e.g., Ajewole: FDA oral chemotherapy CCT enrollment composition, 2009–2019: White: 71.5%, Black: 2.5%, Hispanic: 2.3%; Ladbury.: brachytherapy CCTs, enrollment incident disparity: Asian: −2.65%) [Reference Ladbury, Liu, Novak, Amini and Glaser62,Reference Javier-DesLoges, Nelson and Murphy65,Reference Aldrighetti, Niemierko, Van Allen, Willers and Kamran67,Reference Ajewole, Akindele, Abajue, Ndulue, Marshall and Mossi71,Reference Owens-Walton, Williams, Rompré-Brodeur, Pinto and Ball72,Reference Lythgoe, Krell, Savage and Prasad75–Reference Patki, Aquilina and Thorne77]. Similar patterns are observed in understudied cancers, with CCT underrepresentation among Black [Reference Pittell, Calip and Pierre68,Reference Owens-Walton, Williams, Rompré-Brodeur, Pinto and Ball72,Reference Elshami, Hue and Hoehn78–Reference Shinder, Kim and Srivastava87], Hispanic [Reference Pittell, Calip and Pierre68,Reference Owens-Walton, Williams, Rompré-Brodeur, Pinto and Ball72,Reference Elshami, Hue and Hoehn78–Reference Khadraoui, Meade, Backes and Felix80,Reference Hantel, Brunner and Plascak82,Reference Hantel, Kohlschmidt and Eisfeld83,Reference Reihl, Patil and Morshed86], and Asian [Reference Owens-Walton, Williams, Rompré-Brodeur, Pinto and Ball72,Reference Khadraoui, Meade, Backes and Felix80,Reference Reihl, Patil and Morshed86] patients with gastrointestinal [Reference Javier-DesLoges, Nelson and Murphy65,Reference Aldrighetti, Niemierko, Van Allen, Willers and Kamran67,Reference Pittell, Calip and Pierre68,Reference Abbas, Diaz and Obeng-Gyasi73,Reference Sawaf, Gudipudi and Ofshteyn88], hepato-biliary [Reference Elshami, Hue and Hoehn78,Reference Jan, Osho and Murphy79], pancreatic [Reference Pittell, Calip and Pierre68,Reference Elshami, Hue and Hoehn78,Reference Hue, Katayama and Markt89,Reference Eskander, Gil and Beal90], gynecologic [Reference Ladbury, Liu, Novak, Amini and Glaser62,Reference Khadraoui, Meade, Backes and Felix80,Reference Steventon, Nicum, Man, Chaichana, Wei and Chambers91], HPV-associated oropharyngeal [Reference Gordis, Cagle, Nguyen and Newman92], renal and urologic [Reference Owens-Walton, Williams, Rompré-Brodeur, Pinto and Ball72,Reference Shinder, Kim and Srivastava87,Reference Freudenburg, Bagheri and Srinivas93], hematologic [Reference Pittell, Calip and Pierre68,Reference Al Hadidi, Schinke, Thanendrarajan, Zangari and van Rhee81–Reference Kanapuru, Fernandes and Baines85], and neurologic [Reference Reihl, Patil and Morshed86] malignancies. Some evidence suggests potential mitigation of such inequities for certain cancers in recent years [Reference Javier-DesLoges, Nelson and Murphy65,Reference Khadraoui, Meade, Backes and Felix80,Reference Reihl, Patil and Morshed86,Reference Palmer, Borno, Gregorich, Livaudais-Toman and Kaplan94–Reference Dudipala, Burns and Jani97], particularly among Asian individuals (e.g., Javier-DesLoges: breast, colorectal, lung, and prostate participation odds ratios [OR], 2000–2004 vs. 2015–2019: Black: 2.19, 1.15, 1.54, 1.14; Hispanic: 3.32, 2.46, 2.21, 1.70; Asian: 1.94, 2.48, 3.88, 1.64) [Reference Duma, Vera Aguilera and Paludo47,Reference Javier-DesLoges, Nelson and Murphy65,Reference Aldrighetti, Niemierko, Van Allen, Willers and Kamran67,Reference Kanapuru, Fernandes and Baines85]. Nonetheless, such findings are primarily limited to studies with strong infrastructural support or smaller, singular institutional studies, while other contemporary studies reveal stagnation or worsened disparities over time (e.g., Owens-Walton: unchanging representation quotients from 2000 to 2017) [Reference Owens-Walton, Williams, Rompré-Brodeur, Pinto and Ball72,Reference Keegan, Crown, DiMaggio and Joseph74].

Limited data reflect mixed findings regarding representation among patients of color in psychosocial CCTs. Some such evidence suggests minimal enrollment inequities between non-Hispanic and Hispanic women; however, even these data reflect higher attrition risk for Hispanic and immigrant women [Reference Osann, Wenzel and Dogan98]. An institutional study of all cancers identified no racial/ethnic participation inequities among patients who were eligible for two pain and symptom-focused CCTs; however, patients of color were more likely to be ineligible [Reference H., E., W. and ResearchTracking99]. Recent analyses suggest that psychosocial CCT representation among patients of color may be particularly contingent on intervention type, target population, and funding. For example, national evidence indicates Black underrepresentation in prostate exercise, advanced disease, and nongovernmental CCTs; adequate representation in dietary and multi-component trials; and disproportionately higher participation in pelvic floor muscle training, localized disease, and government-funded trials relative to their non-Black counterparts [Reference Zuniga, Borno and Chan100]. While observing poor representation among patients of color overall, a meta-analysis of integrated palliative CCTs suggests mitigated underrepresentation among Black patients compared to therapeutic CCTs (EF: 5.7% vs. 3.0%) [Reference Pirl, Saez-Flores, Schlumbrecht, Nipp, Traeger and Kobetz101], with similar, state-level results observed among Black men in behavioral CCTs [Reference Palmer, Borno, Gregorich, Livaudais-Toman and Kaplan94]. Analyses of two psychosocial CCTs among women with gynecologic, gastrointestinal, and thoracic cancers demonstrate parallel trends, with even higher enrollment among Hispanic patients [Reference Hanvey, Padron and Kacel102]. Nonetheless, other evidence investigating breast, lung, prostate, and colorectal CCTs reveals trends toward poorer representation among Black patients in supportive care trials compared to tumor-directed studies [Reference Grant, Lin and Miller6].

Age

Strong evidence demonstrates CCT underrepresentation among older adults across time. Early such inequities are observed in NCI Cooperative Group trials in prevalent cancers, with patients 65 to 74 and patients older than 75 years old, respectively, exhibiting progressively lower accrual to nonsurgical, therapeutic trials compared to younger patients [Reference Murthy, Krumholz and Gross36]. Such findings are replicated in later general CCT samples [Reference Unger, Hershman and Albain13,Reference Baquet, Ellison and Mishra34], surgical CCTs [Reference Stewart, Bertoni, Staten, Levine and Gross35], and NCI, state-specific data further classifying older age subgroups [Reference Craig, Gilbert, Herndon, Vogel and Quinn33,Reference Baquet, Ellison and Mishra34]. Early large studies corroborate these trends across cancer types and within drug-specific trials, with underrepresentation among older adults relative to their incident populations[Reference Ramamoorthy, Knepper and Merenda45,Reference Yonemori, Hirakawa and Komiyama103–Reference Talarico, Chen and Pazdur105] and lower likelihood of CCT enrollment with age [Reference Langford, Resnicow and Dimond53], with progressively greater underrepresentation (e.g., Talarico: participants vs. population, respectively: 65+: 25% vs. 60%; 75+: 4% vs. 31%) [Reference Talarico, Chen and Pazdur105].

Contemporary literature corroborates these findings, reflecting continued CCT underrepresentation among older adults over time. Recent institutional, state, and national cohort, case-control, and meta-analytic studies reveal persisting underrepresentation among older adults in surgical [Reference Fayanju, Ren and Thomas39], drug [Reference Borno, Small and Zhang42,Reference Moloney and Shiely66,Reference Jayakrishnan, Aulakh and Baksh106], brachytherapy [Reference Ladbury, Liu, Novak, Amini and Glaser62], and other trial types [Reference Javier-DesLoges, Nelson and Murphy65,Reference Palmer, Borno, Gregorich, Livaudais-Toman and Kaplan94,Reference Patel, Shah and Abrahamse51]; phase I [Reference Perni, Moy and Nipp57], II [Reference VanderWalde, Dockter and Wakefield107], and III[Reference Zhao, Miao, Wang, Zhao, Yang and Wang108–Reference Borad, Saeed, Toscani, Barone and Weber110] trials; and multimodal [Reference VanderWalde, Dockter and Wakefield107] CCTs in general (e.g., Baldini: CCT referral vs. population 70 +: 17.7% vs. 50%) [Reference Borno, Small and Zhang42,Reference Perni, Moy and Nipp57,Reference Green, Tabatabai and Aghajanian58,Reference Saphner, Marek, Homa, Robinson and Glandt63,Reference Jayakrishnan, Aulakh and Baksh106,Reference VanderWalde, Dockter and Wakefield107,Reference Baldini, Charton and Schultz111,Reference Sedrak, Ji, Tiwari, Mohile, Dale and Le-Rademacher112]. Such findings are replicated in specific cancers, including breast [Reference Borno, Small and Zhang42,Reference Javier-DesLoges, Nelson and Murphy65,Reference Moloney and Shiely66,Reference Fayanju, Ren and Thomas39,Reference Zhao, Miao, Wang, Zhao, Yang and Wang108,Reference Javid, Unger and Gralow113], gynecologic [Reference Mishkin, M., K., N. and T.49,Reference Patel, Shah and Abrahamse51], lung [Reference Javier-DesLoges, Nelson and Murphy65,Reference Bruno, Li and Hess96,Reference Zhao, Miao, Wang, Zhao, Yang and Wang108], prostate [Reference Javier-DesLoges, Nelson and Murphy65,Reference Riaz, Islam and Ikram76,Reference Palmer, Borno, Gregorich, Livaudais-Toman and Kaplan94,Reference Zhao, Miao, Wang, Zhao, Yang and Wang108], pancreatic [Reference Hue, Katayama and Markt89,Reference Eskander, Gil and Beal90], hepatic [Reference Jan, Osho and Murphy79], gastroesophageal [Reference Hennessy, Hamid and Keegan114], gastrointestinal [Reference Borno, Small and Zhang42,Reference Javier-DesLoges, Nelson and Murphy65,Reference Abbas, Diaz and Obeng-Gyasi73,Reference Zhao, Miao, Wang, Zhao, Yang and Wang108,Reference Canouï-Poitrine, Lièvre and Dayde115], renal [Reference Shinder, Kim and Srivastava87], skin [Reference Shah, Patel, Patel, Toscani, Barone and Weber109], head and neck [Reference Kaanders, van den Bosch and Kleijnen116], other solid organ [Reference Gopishetty, Kota and G.5,Reference VanderWalde, Dockter and Wakefield107], and hematologic cancers [Reference Gopishetty, Kota and G.5,Reference Borad, Saeed, Toscani, Barone and Weber110,Reference Costa, Hari and Kumar117], with further evidence of greater inequities among the oldest groups [Reference Canouï-Poitrine, Lièvre and Dayde115].

Nonetheless, other recent studies report no age differences in CCT enrollment, especially controlling for relevant covariates (e.g., Dudipala: OR: 1.023) [Reference Dressler, Deal and Owzar44,Reference Housri, Khan and Taunk50,Reference Gordis, Cagle, Nguyen and Newman92,Reference Dudipala, Burns and Jani97,Reference Unger, Gralow, Albain, Ramsey and Hershman118,Reference Mohd Noor, Sarker and Vizor119]. However, these findings have primarily been exclusive to one institution, diagnosis, or state. Further, evidence of more equitable age representation overall is qualified in persistent inequities relative to the incident population for that specific cancer[Reference Pang, Wang and Stinchcombe40], or among patients initially referred to [Reference Pang, Wang and Stinchcombe40], eligible for [Reference Hanvey, Padron and Kacel102,Reference Javid, Unger and Gralow113], or discussed for such trials [Reference Dudipala, Burns and Jani97,Reference Sedrak, Ji, Tiwari, Mohile, Dale and Le-Rademacher112]. Furthermore, other longitudinal and population-based studies demonstrate stagnated or worsened age inequities in CCT participation over time, particularly among the oldest patients (e.g., Zhao et al. median age difference [DMA] between participant and incident disease median age: −8.15; US DMA before 2017 vs. after 2017: −5.90, −8.00) [Reference Mishkin, M., K., N. and T.49,Reference Zhao, Miao, Wang, Zhao, Yang and Wang108,Reference Baldini, Charton and Schultz111].

Socioeconomic status (SES)

Early national case-control analyses reflect breast CCT underrepresentation among low-SES patients by multiple indicators, including area poverty, unemployment, income, education, and individual government insurance [Reference Gross, Filardo, Mayne and Krumholz120]. Other site-specific studies document similar findings in various cancers, with lower CCT participation associated with higher material deprivation and lower social class (e.g., Mohd Noor.: Index of Multiple Deprivation [IMD] = 5 enrollment OR: 0.53, relative to least deprived IMD = 1) [Reference Baquet, Ellison and Mishra34,Reference Mohd Noor, Sarker and Vizor119]. Another national, cross-sectional study revealed strongly prohibitive effects of low income on breast, colorectal, prostate, and lung CCT participation, controlling for other variables (< $50,000 income vs. $50,000+: OR: 0.73) [Reference Unger, Hershman and Albain13], with progressively larger disparities among patients with the lowest incomes [Reference Unger, Hershman and Albain13,Reference Unger, Gralow, Albain, Ramsey and Hershman118]. State analyses extend similar findings to area income in breast, genitourinary, gastrointestinal, and myelodysplastic CCT enrollment (e.g., Brierley et al.: average median income, participants vs. non-participants: $68,896 vs. $61,241) [Reference Brierley, Zabor and Komrokji43,Reference Borno, Zhang, Siegel, Chang and Ryan121]. Other earlier studies reveal how unemployment, lower educational attainment [Reference Unger, Hershman and Albain13,Reference Ko, Fu and Lane122], and governmental insurance [Reference Borno, Small and Zhang42,Reference Mishkin, M., K., N. and T.49] predict CCT underrepresentation in breast and other common cancers.

Contemporary studies within the past three years have increasingly focused on and further substantiated CCT underrepresentation among lower SES patients. Multilevel cohort, case-control, and meta-analytic studies evidence the effects of lower area income (e.g., Hue: stage IV participants vs. non-participants < $40,227: 11.4% vs. 19.1%) [Reference Saphner, Marek, Homa, Robinson and Glandt63,Reference Shinder, Kim and Srivastava87,Reference Hue, Katayama and Markt89,Reference Sedrak, Ji, Tiwari, Mohile, Dale and Le-Rademacher112,Reference Earl, Colman, Mendez, Jensen and Karsy123], education (e.g., Eskander: CCT participation, higher vs. lower high school attainment OR: 2.0) [Reference Abbas, Diaz and Obeng-Gyasi73,Reference Elshami, Hue and Hoehn78,Reference Khadraoui, Meade, Backes and Felix80,Reference Shinder, Kim and Srivastava87,Reference Hue, Katayama and Markt89,Reference Eskander, Gil and Beal90,Reference Palmer, Borno, Gregorich, Livaudais-Toman and Kaplan94,Reference Sedrak, Ji, Tiwari, Mohile, Dale and Le-Rademacher112], insurance (e.g., Shinder: CCT participation, uninsured, Medicaid, or Medicare vs. private insurance ORs, respectively: 0.57, 0.43, 0.59) [Reference Kwak, Bassiri and Jiang70,Reference Abbas, Diaz and Obeng-Gyasi73,Reference Elshami, Hue and Hoehn78,Reference Shinder, Kim and Srivastava87,Reference Eskander, Gil and Beal90,Reference Bruno, Li and Hess96], or overall SES (e.g., Kwak: CCT participation, lowest [Reference Unger, Cook, Tai and Bleyer1] vs. median [Reference Awad, Paladugu and Jones4] SES group OR: 0.60) [Reference Saphner, Marek, Homa, Robinson and Glandt63,Reference Kwak, Bassiri and Jiang70,Reference Hantel, Brunner and Plascak82,Reference Bruno, Li and Hess96] on breast [Reference Moloney and Shiely66], prostate [Reference Patki, Aquilina and Thorne77,Reference Palmer, Borno, Gregorich, Livaudais-Toman and Kaplan94], lung,[Reference Kwak, Bassiri and Jiang70,Reference Bruno, Li and Hess96] gastrointestinal [Reference Abbas, Diaz and Obeng-Gyasi73], pancreatic [Reference Elshami, Hue and Hoehn78,Reference Hue, Katayama and Markt89,Reference Eskander, Gil and Beal90], hepatic [Reference Abbas, Diaz and Obeng-Gyasi73,Reference Elshami, Hue and Hoehn78], gynecologic [Reference Khadraoui, Meade, Backes and Felix80], renal [Reference Shinder, Kim and Srivastava87], brain [Reference Earl, Colman, Mendez, Jensen and Karsy123], hematologic [Reference Hantel, Kohlschmidt and Eisfeld83], and mixed CCT underrepresentation [Reference Perni, Moy and Nipp57]. Other meta-analyses emphasize how limited SES reporting in CCTs significantly compromises research regarding its effects on representation [Reference Patki, Aquilina and Thorne77,Reference Sawaf, Gudipudi and Ofshteyn88].

Nonetheless, other studies present contrasting findings. data have shown higher breast CCT enrollment among Medicaid-eligible and lower-education patients [Reference Behrendt, Hurria, Tumyan, Niland and Mortimer38]. Other studies have reflected higher surgical breast CCT participation with higher area education, but lower income [Reference Fayanju, Ren and Thomas39], with similar income findings in gynecologic trials [Reference Khadraoui, Meade, Backes and Felix80]. Some contemporary studies have observed no SES impact on CCT enrollment (e.g., Perni et al. participation OR, $100,000 median income vs. < $50,000: 1.28) [Reference Perni, Moy and Nipp57] or attenuated effects in multivariate models [Reference Saphner, Marek, Homa, Robinson and Glandt63,Reference Shinder, Kim and Srivastava87,Reference Hue, Katayama and Markt89], though these studies only examined socioeconomic factors as covariates. While the most equivocal evidence appears in the relationship between income and CCT participation, recent authors conceptualize such findings in reliance on area, rather than patient, indicators due to systemic data deficiencies [Reference Khadraoui, Meade, Backes and Felix80]. Despite the nuances observed in these mixed findings, the literature provides growing evidence of socioeconomic CCT inequities by various indicators.

Sex

Mixed literature on sex-related CCT inequities suggests contingency of representation on cancer and trial type. For example, early national data suggest higher therapeutic CCT enrollment among men with colorectal and lung cancers (participation, men vs. women OR: colorectal, lung, respectively: 1.30, 1.23) [Reference Murthy, Krumholz and Gross36] with similar results replicated in center-specific analyses [Reference Du, Gadgeel and Simon124]. However, other early evidence regarding surgical CCTs reflects the reversal of this trend, with women five times more likely than men to enroll overall in a combined, national breast, colorectal, lung, and prostate sample [Reference Stewart, Bertoni, Staten, Levine and Gross35]. Other data provide further insight into contrasting results, suggesting greater overall CCT participation among men, though lower enrollment compared to women when examining sex-specific cancers [Reference Baquet, Ellison and Mishra34].

More recent studies have observed more equitable CCT representativeness across sexes. National cohort and meta-analytic studies addressing various cancers, including sex-specific [Reference Dressler, Deal and Owzar44] and rare diagnoses [Reference Costa, Hari and Kumar117], reflect minimal sex differences in representation (e.g., Costa: observed-expected ratio, % male participants: 1.03). Similar evidence has emerged in psychosocial CCTs, revealing no sex differences in participation (e.g., Huang: % eligible enrolled in symptom CCT, within each sex: women: 75%, men: 78%) [Reference H., E., W. and ResearchTracking99]. Longitudinal analyses reveal improvement in lung CCT representation over time among women younger than 65 years old (overall enrollment disparity difference between sexes reduced 0.07 to 0.03, 1994–2012) [Reference Pang, Wang and Stinchcombe40], as is consistent with equitable sex representation among younger patients in earlier lung and other CCTs [Reference Murthy, Krumholz and Gross36]. Some state-specific evidence reflects even higher therapeutic lung, colorectal, and sex-specific CCT enrollment among women relative to men [Reference Zullig, F.B., Rao, T., G. and C.54], as with the aforementioned surgical CCT findings [Reference Stewart, Bertoni, Staten, Levine and Gross35]. Nonetheless, women’s underrepresentation persists in certain rarer cancers, such as myelodysplastic syndrome [Reference Brierley, Zabor and Komrokji43] or HPV-associated oropharyngeal CCTs (e.g., Gordis: % total female enrollees: 11.8%) [Reference Gordis, Cagle, Nguyen and Newman92]. Conversely, other data reflect disadvantages for men for certain CCT types across cancers, such as eligibility for chemoradiation trials [Reference Hosoya, Fujimoto and Kawachi125] and participation in sex-related CCTs [Reference Baquet, Ellison and Mishra34]. FDA approvals between 2008 and 2017 similarly demonstrate attenuated inequities when including sex-related CCTs, while simultaneously revealing worsened women’s representation over time when exclusively examining trials for cancers affecting all sexes (% women: 2008 to 2013: 47%, 2014 to 2017: 37%) [Reference Ramamoorthy, Knepper and Merenda45].

Studies within the past three years continue to reveal minimal sex-related CCT inequities. Multiple institutional, state, and national cohort and case-control studies suggest equitable CCT participation across sexes in colorectal [Reference Pittell, Calip and Pierre68], lung [Reference Pittell, Calip and Pierre68–Reference Kwak, Bassiri and Jiang70], pancreatic [Reference Pittell, Calip and Pierre68,Reference Hue, Katayama and Markt89], neurologic [Reference Earl, Colman, Mendez, Jensen and Karsy123], hematologic [Reference Pittell, Calip and Pierre68,Reference Hantel, Kohlschmidt and Eisfeld83,Reference Kanapuru, Fernandes and Baines85], and mixed samples [Reference Saphner, Marek, Homa, Robinson and Glandt63], with some analyses suggesting higher representation among women (e.g., Saphner: participation OR, men vs. women: 0.70) [Reference Saphner, Marek, Homa, Robinson and Glandt63,Reference Kwak, Bassiri and Jiang70]. However, some of these findings are restricted to specific institutions, with their results challenged by more nationally representative analyses suggesting persistent underrepresentation among women in colorectal [Reference Javier-DesLoges, Nelson and Murphy65,Reference Sawaf, Gudipudi and Ofshteyn88], lung [Reference Javier-DesLoges, Nelson and Murphy65], neurologic [Reference Reihl, Patil and Morshed86], and hematologic CCTs [Reference Casey, Odhiambo, Aggarwal, Shoukier, Islam and Cortes84]. Additional studies document lower participation among women in hepatic [Reference Jan, Osho and Murphy79], head and neck [Reference Patel, Shah, Brinley, Abrahamse, Veenstra and Schott95], and renal CCTs [Reference Shinder, Kim and Srivastava87], in addition to women’s underrepresentation in overall therapeutic [Reference Choradia, Karzai, Nipp, Naqash, Gulley and Floudas60], radiation [Reference Bero, Rein and Banerjee56], phase II and III [Reference Perni, Moy and Nipp57], non-sex- [Reference Saphner, Marek, Homa, Robinson and Glandt63], and sex-specific diagnostic CCTs [Reference Choradia, Karzai, Nipp, Naqash, Gulley and Floudas60]. Though recent evidence of improved representation among women is qualified by these contrasting findings, contemporary results suggest partial mitigation of such inequities over time for certain diagnostic sites (e.g., Javier-DesLoges: women’s participation OR, 2015–2019 vs. 2000–2014: 1.38, with remaining inequities relative to men [OR: 0.89]) [Reference Javier-DesLoges, Nelson and Murphy65,Reference Reihl, Patil and Morshed86].

Ability, staging, and functional status

Until the past three years, few studies had examined indicators of ability status as direct contributors to CCT participation, typically focusing on staging (i.e., measured by tumor size, lymph node presence, and/or metastases) [126], comorbidity, and more rarely, performance status ratings. Earlier findings evidence higher participation in breast [Reference Housri, Khan and Taunk50,Reference Patel, Shah and Abrahamse51,Reference Javid, Unger and Gralow113,Reference Zafar, Heilbrun and Vishnu127], colorectal, lung, prostate [Reference Unger, Hershman and Albain13], and multiple myeloma CCTs [Reference Costa, Hari and Kumar117] among patients with lower staging or fewer comorbidities (e.g., Unger: participation OR, comorbidity score: 0.81), though primarily examine such indicators as covariates. Some institutional analyses characterize exclusionary comorbidities as restrictive to CCT participation across multiple cancers [Reference Ko, Fu and Lane122], while other data document positive relationships between symptom risk and therapeutic CCT enrollment in rarer cancers (e.g., Brierley: participation OR, high vs. very low risk: 1.88) [Reference Brierley, Zabor and Komrokji43]. Still, other investigators report no association between disease characteristics, comorbidities, and CCT participation [Reference Craig, Gilbert, Herndon, Vogel and Quinn33], though these early studies still conceptualize such ability proxies as covariates, rather than key predictors.

While evidence remains scarce compared to other marginalizing indicators, contemporary studies have increasingly documented relationships among comorbidity, functional impairment, and CCT participation. National cohort, case-control, and meta-analytic studies reveal the potentially restrictive impact of comorbidity burden or associated lower performance status on pancreatic,[Reference Elshami, Hue and Hoehn78,Reference Hue, Katayama and Markt89,Reference Eskander, Gil and Beal90], breast [Reference Moloney and Shiely66], lung [Reference Abi Jaoude, Kouzy and Mainwaring128], hepatic [Reference Elshami, Hue and Hoehn78], gynecologic [Reference Khadraoui, Meade, Backes and Felix80], other gastrointestinal and genitourinary [Reference Abi Jaoude, Kouzy and Mainwaring128], renal [Reference Shinder, Kim and Srivastava87], head and neck [Reference Kaanders, van den Bosch and Kleijnen116], solid organ [Reference Yekedüz, Trapani and Xu129], and overall CCT representativeness (e.g., Green: % comorbidity score = 0, participants vs. non-participants: 69.2% vs. 51.6%) [Reference Green, Tabatabai and Aghajanian58,Reference Sedrak, Ji, Tiwari, Mohile, Dale and Le-Rademacher112]. Other analyses, while not directly centering ability proxies as enrollment predictors, evidence the covarying impact of performance status on CCT participation (e.g., Bruno: lung participation OR, Eastern Cooperative Oncology Group [ECOG] score, 2 vs. 0: 0.27) [Reference Bruno, Hess, Li, Su and Patel130]. Still other recent results evidence positive relationships between comorbidity burden and CCT participation, though these findings are exclusive to one state and disease site [Reference Patel, Shah, Brinley, Abrahamse, Veenstra and Schott95].

Intersectionality in CCT participation inequities

The above-summarized data provide robust evidence of persistent CCT underrepresentation among patients of color and older adults, with mixed evidence of changing representativeness over time across diagnostic sites and trial types. Recent evidence reveals similar relationships between SES and CCT participation, demonstrating how lower education, inadequate insurance, and to a smaller extent, lower income, may further stifle CCT representativeness. While sex disparities have negatively impacted CCT participation depending upon cancer type, some contemporary studies evidence more equitable CCT representation in common cancers. While the singular impacts of such factors quantitatively vary, the interactivity among these social, economic, and medical marginalizing indicators further complexifies CCT representativeness.

This review characterizes the nexus among race, ethnicity, and SES as one of the most intricate intersections in determining CCT representation. Early breast CCTs have revealed diminishing underrepresentation among Black patients after considering area poverty, unemployment, and Medicaid coverage (participation OR, Black vs. White: 0.99) [Reference Gross, Filardo, Mayne and Krumholz120]. Later population data corroborate such findings, illustrating partial attenuation of Black and Hispanic underrepresentation in surgical breast CCTs when accounting for income and education [Reference Fayanju, Ren and Thomas39], as well as insurance [Reference Penberthy, Brown, Wilson-Genderson, Dahman, Ginder and Siminoff131]. Institutional analyses of multiple cancers have demonstrated resolution in CCT underrepresentation among patients of color after accounting for age, sex, and deprivation index [Reference Mohd Noor, Sarker and Vizor119]. However, other evidence reveals underrepresentation among higher income and privately insured Black and Hispanic women compared to their less affluent counterparts in gynecologic [Reference Mishkin, M., K., N. and T.49,Reference Osann, Wenzel and Dogan98] and breast CCTs (e.g., Fayanju: participation OR, Black and Hispanic, respectively, median income $63,000+ vs. < $38,000: 0.45, 0.19) [Reference Fayanju, Ren and Thomas39]. These findings constitute a reversal of typically observed relationships, wherein racial, ethnic, and socioeconomic marginalization multiplicatively serve to restrict CCT participation with concurrent marginalization, rather than poorer participation among higher SES women of color. A meta-analysis of FDA approvals, regardless of SES, emphasizes the intersection among sex and minoritized identity, with the greatest underrepresentation observed among women of color in prevalent cancers (i.e., % Black participants breast sample: 2%) [Reference Ramamoorthy, Knepper and Merenda45].

Studies within the last three years have increased explicit efforts to explore the interactive influences of racial, ethnic, and socioeconomic marginalizing indicators on CCT participation, while similarly indicating nuanced results across diagnostic sites. Multilevel cohort, case-control, and meta-analytic studies demonstrate the simultaneous impact of minoritized race/ethnicity, lower area SES, and inadequate insurance coverage in limiting breast [Reference Moloney and Shiely66], gynecologic [Reference Khadraoui, Meade, Backes and Felix80], pancreatic [Reference Eskander, Gil and Beal90], and renal [Reference Shinder, Kim and Srivastava87] CCT participation (e.g., Khadraoui: participation ORs, racial/ethnic minority vs. White: Black: 0.70, Hispanic: 0.53, Asian: 0.44, Other: 0.48; education, 15.3%+ vs. < 5.0% without high school education: 0.41). Similar studies demonstrate partial contingency of hematologic CCT underrepresentation among people of color on lower area income or insurance coverage [Reference Hantel, Brunner and Plascak82]. Still, other recent studies corroborate persistent CCT inequities that disproportionately affect among women of color regardless of income, in gastrointestinal trials [Reference Abbas, Diaz and Obeng-Gyasi73], as is consistent with earlier breast and gynecologic CCTs [Reference Mishkin, M., K., N. and T.49,Reference Fayanju, Ren and Thomas39].

Studies investigating relationships among race, ethnicity, and SES in determining CCT representation have increasingly revealed potential contributions of disease characteristics, comorbidity burden, and performance status. For instance, early analyses demonstrate how controlling for advanced disease diminishes otherwise observed racial CCT inequities [Reference N., Hurd and Leitch37,Reference Housri, Khan and Taunk50]. Similar interactive relationships have been observed in early case-control studies regarding lung CCTs, interpreting underrepresentation among Black and other patients of color within the intersections among race, SES, insurance, comorbidity, and performance status [Reference Du, Gadgeel and Simon124]. Other national data corroborate higher comorbidity among Black patients considered for CCTs (medical comorbidity presence, OR: 1.53) [Reference Langford, Resnicow and Dimond53]. More recent analyses directly explore how ability indicators color the intersectional effects of race, ethnicity, and SES on CCT representation [Reference Moloney and Shiely66,Reference Khadraoui, Meade, Backes and Felix80,Reference Shinder, Kim and Srivastava87,Reference Palmer, Borno, Gregorich, Livaudais-Toman and Kaplan94,Reference Yekedüz, Trapani and Xu129]. While some such studies reveal how higher staging and comorbidity may further limit CCT participation among minoritized or lower SES patients (e.g., Yekeduz: % Black participants vs. population: 2.1% vs. 9.8%, with 82% total sample with ECOG 0–1) [Reference Moloney and Shiely66,Reference Owens-Walton, Williams, Rompré-Brodeur, Pinto and Ball72,Reference Khadraoui, Meade, Backes and Felix80,Reference Shinder, Kim and Srivastava87,Reference Yekedüz, Trapani and Xu129], others offer opposing evidence among certain underserved populations. Specifically, some studies indicate increased CCT participation among patients of color with higher comorbidity burden and staging, such as Hispanic men with prostate cancer [Reference Palmer, Borno, Gregorich, Livaudais-Toman and Kaplan94]. Still others indirectly examine complex, intersectional influences of comorbidity, illness characteristics, and ability on CCT representativeness, suggesting poorer overall CCT participation due to the COVID-19 pandemic, though with unexpected impacts on participation inequities (e.g., Choradia et al.: participation ORs, 2005–2020, each vs. White patients: Hispanic: 0.52, American Indian: 0.41, AAPI: 0.81; peak participation among these underserved in 2020, despite lowest year of enrollment across population) [Reference Choradia, Karzai, Nipp, Naqash, Gulley and Floudas60,Reference Pittell, Calip and Pierre68].

Such patterns are further influenced by age and sex, especially among older adults of color with an increased comorbidity burden. Early analyses demonstrate how older age compromises breast, colorectal, thoracic, and prostate CCT participation across racial and ethnic groups, though drives underrepresentation otherwise unobserved in younger patients among women of color [Reference Murthy, Krumholz and Gross36]. Other investigators demonstrate how older age heightens gynecologic CCT attrition risk for Hispanic, but not for non-Hispanic, women [Reference Osann, Wenzel and Dogan98]. Recent national cohort, case-control, and meta-analytic studies strengthen evidence of simultaneous underrepresentation regarding older age, comorbidity, performance status, and other marginalizing factors underpinning CCT underrepresentation (e.g., Kaanders: % participants with World Health Organization [WHO] 0–1 or Karnofsky performance score 90–100: 70%; median age, participant vs. population: 57, 64 [Reference Green, Tabatabai and Aghajanian58,Reference VanderWalde, Dockter and Wakefield107,Reference Shah, Patel, Patel, Toscani, Barone and Weber109,Reference Sedrak, Ji, Tiwari, Mohile, Dale and Le-Rademacher112,Reference Kaanders, van den Bosch and Kleijnen116], with some evidence emphasizing how trial characteristics themselves may limit participation among older adults with higher disease burden [Reference VanderWalde, Dockter and Wakefield107].

Regarding intersecting sex influences, some early state studies indicate elevated racial disparities among men relative to women in therapeutic trials for common cancers [Reference Baquet, Ellison and Mishra34,Reference Zullig, F.B., Rao, T., G. and C.54], with recent studies similarly accentuating how cancer sex-specificity may underpin racial and ethnic representativeness in radiation CCTs (i.e., Black underrepresentation observed in all CCT types except sex-specific female [13.1% sample] and male [18.4% sample] US trials) [Reference Bero, Rein and Banerjee56]. While quantitatively unexamined to date, contemporary studies have begun to comment on how relationships among these marginalizing factors may be furthermore impacted by sexual minoritization, through its influence on preexisting health and CCT eligibility [Reference Moloney and Shiely66]. Overall, relationships among social, economic, and medical marginalizing indicators in underpinning CCT inequities have gained increasing attention in recent years, with more investigators explicitly exploring the structural, intersectional context of such factors when interpreting their findings regarding CCT representativeness [Reference Owens-Walton, Williams, Rompré-Brodeur, Pinto and Ball72,Reference Fayanju, Ren and Thomas39].