Potential Impact of Revised NCI Eligibility Criteria Guidance: Prior Malignancy Exclusion in Breast Cancer Clinical Trials

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  • 1 School of Medicine, UT Southwestern Medical Center, Dallas, Texas;
  • | 2 Now with Department of Radiology, University of Washington, Seattle, Washington;
  • | 3 School of Public Health, University of Texas Health Science Center at Houston, Dallas, Texas; and
  • | 4 Department of Population and Data Sciences,
  • | 5 Harold C. Simmons Comprehensive Cancer Center,
  • | 6 Department of Internal Medicine, and
  • | 7 Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas.

Background: Many individuals with cancer have survived a prior cancer and for this reason may have been excluded from clinical trials. Recent NCI guidance recommends including these individuals, especially when the risk of the prior malignancy interfering with either safety or efficacy endpoints is very low. Using breast cancer as an example, we determined the potential effect this policy change may have on clinical trial accrual. Patients and Methods: We reviewed protocols of NCI-sponsored breast cancer clinical trials activated in 1991 through 2016. We quantified prevalence of prior cancer-related exclusion criteria and assessed the association with trial characteristics using Fisher’s exact tests. Using SEER data, we estimated the prevalence and timing of prior primary (nonbreast) cancer diagnoses among patients with breast cancer. Results: Among 87 clinical trials (total target enrollment, 137,253 patients), 77% excluded individuals with prior cancer, most commonly (79%) within the preceding 5 years. Among trials with radiographic response or toxicity endpoints, 69% excluded prior cancer. In SEER data, the prevalence of a prior (nonbreast) cancer diagnosis ranged from 5.7% to 7.7%, depending on breast cancer stage, of which 39% occurred within 5 years of the incident breast cancer. For trials excluding prior cancer, the estimated proportion of patients excluded for this reason ranged from 1.3% to 5.8%, with the estimated number of excluded patients ranging from 1 to 288. Conclusions: More than three-fourths of NCI-sponsored breast cancer clinical trials exclude patients with prior cancer, including almost 70% of trials with response or toxicity endpoints. Given that >5% of patients with breast cancer have a history of prior cancer, in large phase III trials this practice may exclude hundreds of patients. Following recent NCI eligibility guidance, the inclusion of patients with prior cancer on breast cancer trials may have a meaningful impact on accrual.

Background

In December 2021, NCI issued revised guidance on eligibility criteria for cancer clinical trials.1 Based on 2017/2021 recommendations from ASCO and Friends of Cancer Research (Friends),24 the document addresses several aspects of eligibility, including brain metastases, HIV and viral hepatitis infection, organ function, concomitant medications, performance status, and prior or concurrent malignancies. For this last category, NCI specifically recommends including patients with prior or concurrent malignancies, especially when the risk of malignancy interfering with either safety or efficacy endpoints is very low. This approach resembles that put forth in recent FDA guidance, which recommends including patients with prior or concurrent malignancies if the natural history or treatment does not have the potential to interfere with safety or efficacy assessment of the investigational drug. In particular, FDA recommends including such patients in initial dose-finding, preliminary activity-estimating, or proof-of-concept studies.5

In recent years, the number of cancer survivors in the United States has increased dramatically, from <4 million in 1977, to an estimated 18 million in 2022, to a projected 26 million in 2040.6,7 These individuals are living longer. Whereas only half of cancer survivors in the 1970s were beyond 5 years of diagnosis, that proportion now exceeds two-thirds, with almost half beyond 10 years of diagnosis.6 As a result, the number of persons diagnosed with multiple cancers has increased.810 Given these trends, to estimate the impact of prior cancer diagnoses on clinical trial enrollment and the potential effect of recent NCI guidance, we determined (1) the prevalence and nature of prior cancer-related eligibility criteria in NCI-sponsored breast cancer clinical trials, and (2) the estimated proportion and numbers of patients excluded from these trials due to a prior cancer diagnosis.

Patients and Methods

Protocol Identification and Data Abstraction

This study was approved by the UT Southwestern Medical Center Institutional Review Board. We requested protocol documents for breast cancer clinical trials activated in 1991 through 2016 directly from the sponsoring National Clinical Trials Network (NCTN) group (Alliance, ECOG-ACRIN, NRG, SWOG). We developed and pretested a data abstraction form to collect relevant data from trial protocols. The form was implemented in REDCap (Research Electronic Data Capture), a secure web-based application designed to support data capture for research studies.11

Our abstraction form (supplemental eTable 1, available with this article at JNCCN.org) collected data related to trial phase, disease stage, primary endpoint, primary treatment modality, sponsoring NCI Network group, and year of activation. For trials comprising multiple phases (eg, phase I/II), we characterized the trial according to the highest phase. For trials including patients with multiple stages of breast cancer (eg, included patients with stage II or III disease), we characterized the trial according to the most advanced stage as the most conservative approach because rates of prior cancer are higher for earlier-stage breast cancer. For trials with multiple primary endpoints, we categorized by a single endpoint using the following hierarchy: survival > progression > recurrence > other. For trials with multiple treatment modalities, we characterized according to which treatment modality represented the primary research question. We recorded whether protocols excluded patients with prior cancer (including type, time frame, and exceptions), and prior cancer treatment (including type and time frame). We recorded separately whether protocols included “guidance” statements related to prior cancer; in these cases, the enrollment of participants with a history of prior cancer was cautioned but ultimately left to the discretion of the enrolling clinician. For this analysis, prior cancer diagnosis and prior cancer treatment related to earlier breast cancer were not included.

Primary data abstraction was performed by a single investigator (M. Perez). For quality assurance, a senior clinical investigator (D.E. Gerber) reviewed all fields of data abstraction for the first 10 protocols entered and reviewed fields related to exclusion of prior cancer diagnoses and prior cancer treatment for all protocols.

SEER Data

We analyzed data from the SEER 9 program of population-based cancer registries. We included women aged ≥18 years diagnosed with breast cancer (SEER behavior code 3, AJCC 7th edition stages 0–IV) between 2016 and 2017. We excluded male breast cancer from this analysis because of its rarity (<1% of all breast cancers) and because the prevalence and timing of prior cancers may differ according to patient sex.12,13 We defined prior cancer as any primary cancer of a different type (inclusive of women with different type prior cancers only and women with a different type prior cancer and a same type [breast cancer] prior cancer) using the sequence number variable as previously described.13 For women diagnosed with more than one breast cancer during 2016 through 2017, we used sequence number and year of diagnosis to select the most recent breast cancer as the index case.

Statistical Analysis

We reported the time frame and other characteristics of prior cancer-related exclusion criteria using descriptive statistics (number, percent) and qualitatively assessed similarities and differences in the wording of these criteria. We used Fisher’s exact tests to explore associations between trial characteristics and prior cancer-related exclusion criteria. We estimated the proportion and number of patients excluded due to a prior cancer diagnosis from clinical trials through the following steps. First, we determined the proportion of patients with prior nonbreast cancer diagnoses in SEER according to the breast cancer stage under study in the clinical trial. Second, we multiplied this proportion by the proportion of prior cancer cases occurring within the time frame specified in the clinical trial (eg, within 5 years). Third, we used the resulting modified proportion to estimate the number of patients expected to be excluded due to prior cancer as follows:
(% of targeted breast cancer population by stage with prior cancer diagnosis×proportion of prior cancer diagnoses within specified time frame/100)
Lastly, for each trial we estimated the absolute number of patients excluded due to prior cancer by using the trial target sample size and the estimated proportion excluded as follows:
{target enrollment/[1(% excluded/100)]}target enrollment
For trials excluding patients with “current” or “active” cancer, we estimated the proportion of affected patients by using the ≤2 years’ time frame.

Statistical analyses were performed using STATA, version 15.1 (StataCorp LLC).14

Results

In total, 87 trials (representing a combined target enrollment of 137,253 patients) were included in the analysis. All trials were phase II or III, 74 (85%) focused on medical therapies, and 4 (5%) had an overall survival primary endpoint. Additional trial characteristics are listed in Table 1.

Table 1.

Trial Characteristics

Table 1.

Overall, 67 trials (77%) excluded individuals with a history of prior cancer. Among these trials, the most common time frame for exclusion was within 5 years of enrollment (79%). Notably, 4 trials (6%) excluded patients regardless of when prior cancers were diagnosed. Additionally, 5 trials included “guidance” statements, of which only 1 also had criteria explicitly excluding prior cancer diagnoses. These statements, which addressed only eligibility related to prior cancer diagnoses, cautioned against enrollment of patients with prior cancer unless the investigator believed the likelihood of recurrence of the prior cancer was below a specified threshold (most commonly 30%). All trials excluding prior cancer mentioned certain exceptions to the exclusion; nearly all (93%) applied ≥2 exceptions. Exceptions included nonmelanoma skin cancer (75%), in situ cervical cancer (68%), other in situ cancers (15%), and other (8%). Sample wording for prior cancer-related exclusion and guidance are presented in Table 2.

Table 2.

Prior Cancer-Related Exclusion Criteria

Table 2.

Breast cancer stage, endpoint, treatment modality, year of activation, and trial phase were not associated with exclusion of prior cancer (Table 3). NCI network group was statistically significantly associated with prior cancer exclusion; for example, all 18 NRG trials excluded patients with prior cancer; fewer Alliance trials applied this exclusion (65%). Furthermore, 16 of the 18 NRG trials (88%) used the same prior cancer exclusion time frame (5 years). Forty-six trials (53%) excluded prior cancer treatment. There was a nearly statistically significant correlation between exclusion of prior cancer treatment and prior cancer diagnosis (P=.08). Of note, 8% of trials that excluded prior cancer treatment did not exclude prior cancer diagnoses, whereas 32% of trials that excluded prior cancer diagnoses did not exclude prior cancer treatment (Figure 1). Among the 46 trials that excluded prior cancer treatment, 44 (96%) excluded prior treatment at any time-point. Categorizing prior cancer treatment as either surgery, radiation therapy, chemotherapy, or other medical therapy (eg, targeted therapy, hormonal therapy), 33 (72%) excluded 1 treatment category, 9 (20%) excluded 2 treatment categories, and 4 (9%) excluded 3 treatment categories. The most commonly excluded treatment category was chemotherapy (65%), followed by other medical therapy (43%), radiation therapy (24%), and surgery (4%).

Table 3.

Association of Selected Trial Characteristics With Prior Cancer Exclusion

Table 3.
Figure 1.
Figure 1.

Number and percent of trials excluding patients with prior cancer and/or prior cancer treatment.

Citation: Journal of the National Comprehensive Cancer Network 20, 7; 10.6004/jnccn.2022.7017

We identified 46,824 women with breast cancers in SEER. We determined the prevalence of prior nonbreast cancer diagnoses overall and according to breast cancer stage among the 45,294 women with available stage (Table 4). We also determined the timing of prior cancer among the 3,008 women with available year of diagnosis of the prior nonbreast cancer (Table 5). In general, we observed numerically higher rates of prior cancer among patients with earlier-stage breast cancer. Among prior nonbreast cancers, 39% occurred within the 5 years preceding a lung cancer diagnosis, representing the most common time frame of prior cancer exclusion in the protocols we examined.

Table 4.

Prevalence of Cancer Diagnoses Prior to Breast Cancer Overall and by Stage of Breast Cancer in SEER 9 Registry

Table 4.
Table 5.

Timing of Nonbreast Cancer Diagnoses Prior to Breast Cancer in SEER 13 Registry (N=3,008)

Table 5.

Using the stage of breast cancer under study, the time frame of prior breast cancer exclusion, and the prevalence and timing of prior nonbreast cancers in the SEER registry, we estimated the proportion and absolute number of patients excluded from the 87 protocols included in our analysis (Table 6 and supplemental eTable 2). Among all trials, which had a total target enrollment of 137,253 patients, we estimated that 3,018 (2.2%) would be excluded due to a prior cancer diagnosis. For 10 trials, we estimated that >100 patients would be excluded due to prior cancer. All 10 trials were phase III and had a primary endpoint of recurrence. For trials excluding prior cancer, the estimated proportion of patients excluded for this reason ranged from 1.3% to 5.8%, with estimated number of excluded patients ranging from 1 to 288. For the 20 trials that did not exclude prior cancer, total target enrollment was 19,633 and estimated number of patients with prior cancer was 1,127 (5.7%).

Table 6.

Estimated Proportion and Number of Patients Excluded From Breast Clinical Trials Due to Prior Cancer Diagnosis

Table 6.

Discussion

With the goal of achieving diverse and representative populations in future clinical trials, recent NCI guidance recommends broadening cancer clinical trial eligibility criteria across numerous categories, including prior or concurrent malignancies. In the present study, we analyzed NCI-sponsored breast cancer clinical trial protocols to determine how this policy change might affect trial enrollment. We found that more than three-quarters of clinical trials excluded patients with prior nonbreast cancer, most commonly if the prior cancer was diagnosed within 5 years of the incident breast cancer. When we applied the prevalence and timing of prior cancer in the SEER dataset, we estimated that in some trials this practice results in excluding almost 6% of potential patients; in almost 11% of trials, it excludes >100 potential patients. Based on these findings, it seems likely that the recent NCI guidance could have a meaningful impact on trial accrual.

Excluding patients with a prior cancer diagnosis from cancer clinical trials appears to be a common practice. For instance, >80% of NCI-sponsored lung cancer clinical trials exclude patients with prior cancer.15 To reconsider this longstanding practice, one must consider and critically appraise the motivations that underlie it. One possible concern is that treatment of prior cancer will interfere with assessment of the intervention under study for the current breast cancer. Prior treatment could hypothetically render patients at greater risk for toxicity. Alternatively, exposure to prior treatment could alter the breast cancer’s sensitivity to the experimental therapy. To address these possibilities, trials could instead exclude prior cancer treatment. Approximately half of the trials in the present analysis took this approach, usually excluding specific cytotoxic or targeted agents evaluated in the clinical trial. Other trials excluded prior treatment only if it exceeded a specific threshold of cumulative dose of number of administered cycles. Importantly, in women with breast cancer, almost two-thirds of nonbreast prior cancers are in situ or localized stage, and <10% of prior cancers are metastatic.16 Thus it seems likely that only a minority of prior cancers would require any systemic therapy.

Another potential concern is the effect of a prior cancer on survival of women with breast cancer. In the SEER-Medicare population, almost 10% of patients with breast cancer with a prior cancer diagnosis die of the previous cancer, and a prior cancer diagnosis is associated with increased risk of death in stage I–III breast cancer.16 However, overall survival is rarely used as a primary endpoint in breast cancer clinical trials, representing only 5% of protocols in the present analysis. Presumably, these factors would be less relevant to trials with nonsurvival endpoints (particularly response or toxicity endpoints). Nonetheless, more than three-quarters of such trials in the present study excluded patients with a prior cancer diagnosis.

Even in the most recent years, the majority of trial protocols exclude patients with previous cancer. Efforts to mitigate the detrimental impact on enrollment are apparent through the multiple exceptions (most commonly nonmelanoma skin cancer and in situ cancers) and “guidance” statements. These clauses request that clinicians estimate an individual patient’s likelihood of prior cancer recurrence to determine eligibility, a challenging directive fraught with uncertainty. As further evidence of the general confusion surrounding the potential concerns related to prior cancer impact on trial conduct or outcomes, our analysis demonstrates widely varying interpretations. Time frames for excluded prior cancer diagnoses range from as short as only concurrently active cancers to a prior cancer diagnosis at any point in the patient’s life. The most common interval—used by more than three-quarters of trials with prior cancer exclusion—was 5 years, a recommendation that was previously made, but is no longer endorsed, by the NCI.15,17 Indeed, despite representing diverse breast cancer stages, endpoints, and treatment modalities, all but 2 of the NRG protocols in the present study used the 5-year interval, suggesting that exclusion criteria may be copied from prior trials without clear reasoning.

Excluding patients with prior cancer from breast cancer clinical trials may have a disproportionate effect on older individuals. Similar to other cancers,18 in breast cancer populations the prevalence of prior cancer increases with patient age. For patients aged <65 years, 5% have prior cancer, compared with 6% for those aged 66 to 70 years and 10% for those aged >85 years.13,16 Indeed, this phenomenon may contribute to age disparities in cancer clinical trials, where subjects are >6 years younger than general oncology populations. Notably, this imbalance is greater for industry-sponsored trials (which were not included in the present study) and is increasing over time.19 Failure to meet protocol eligibility or not receiving information about potential trials appears to drive this disparity, and most elderly individuals demonstrate interest in trial participation when provided the opportunity.2024

Can observations from this study be generalized to other breast cancer trials, such as those sponsored by pharmaceutical companies? Among a sample of lung cancer trials, those with pharmaceutical industry sponsors have similar rates of prior cancer exclusion than do NCI-sponsored studies.15 Regardless of sponsor type, the practice of excluding prior cancer likely persists due to historical precedent and inertia. Over time, clinical trial protocols tend to accumulate new eligibility criteria while rarely discarding those no longer relevant. For example, many immunotherapy clinical trials have added new eligibility criteria related to history of autoimmune disease, organ transplantation, and immunosuppressant use, but have not removed or relaxed eligibility criteria less relevant to these new therapies (such as strict minimum blood counts required for safe administration of conventional chemotherapy).25

Complex, poorly justified, inconsistent, and overly restrictive trial eligibility criteria may restrict access to novel therapies, hinder trial recruitment and completion, and limit generalizability of trial results. To simplify eligibility, facilitate searches for appropriate trials, and harmonize trial populations to support comparisons of treatment effects, clinicians, representatives from the pharmaceutical industry, and international regulators have drafted a recommended eligibility criteria framework to guide investigators and sponsors in the design of cancer clinical trials.26 The forthcoming FDA Draft Guidance for Industry, “Eligibility for Non–Small Cell Lung Cancer Trials,” serves as a prototype, with guidance for other cancer types under development.26 By connecting diverse stakeholders and incorporating public input, these efforts may provide opportunities to revise longstanding approaches to trial eligibility, including those related to prior cancer diagnoses.

There are caveats to the interpretation of our findings. The definition of “active” cancer as a cancer diagnosed within 2 years of the incident breast cancer fails to account for the possibility that cancers within this time frame are no longer clinically active, or that prior cancers diagnosed earlier might remain clinically active. We recognize that prior cancer diagnoses may accompany other comorbidities or frailty.16 Accordingly, some patients with prior cancer diagnoses may still not meet protocol eligibility even if the prior cancer no longer excludes them. The age discrepancy between general oncology and clinical trial populations is unlikely to have a major effect on our findings because (1) by using SEER data, we include all patient ages; and (2) based on earlier epidemiologic studies,13,16 the difference in prior cancer prevalence between these populations is likely to be minimal.

Conclusions

More than three-quarters of NCI-sponsored breast cancer clinical trials exclude individuals with prior cancer, a proportion that has not declined over time. This restriction is applied variably, with different time frames and exceptions across trials, suggesting that the rationale and justification for the practice remains unclear. Given the large number of trials and population burden of breast cancer, this restriction alone could potentially exclude tens of thousands of women over time. Overly stringent eligibility criteria may limit trial enrollment, leading to prolonged study accrual and/or premature study closure.2729 Despite repeated calls to simplify these criteria, they have continued to increase in number and complexity over time.25,30 If incorporated into future trial protocols, recent NCI guidance recommending broader eligibility criteria may reverse these trends, enhancing trial accrual, completion, and generalizability.

Acknowledgements

The authors thank Helen Mayo, MLS (UT Southwestern Medical Library) for assistance with literature searches, Ms. Dru Gray for assistance with manuscript preparation, Dr. Aniruddha B. Rathod for assistance with SEER analysis, and Ms. Jessica Philips for assistance obtaining the trial protocols. Study data were collected and managed using REDCap electronic data capture tools hosted at UT Southwestern and supported by UT Southwestern Academic Information Systems; and CTSA Grant UL1TR001105 provided by the National Center for Advancing Translational Sciences of the National Institutes of Health at the NIH.

References

  • 1.

    Broadening/Modernizing Eligibility Criteria for National Cancer Institute (NCI) Sponsored Clinical Trials. Accessed January 13, 2022. Available at: https://ctep.cancer.gov/protocolDevelopment/docs/CTEP_Broadened_Eligibility_Criteria_Guidance.pdf

  • 2.

    Lin NU, Prowell T, Tan AR, et al. Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology-Friends of Cancer Research Brain Metastases Working Group. J Clin Oncol 2017;35:37603773.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Uldrick TS, Ison G, Rudek MA, et al. Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology-Friends of Cancer Research HIV Working Group. J Clin Oncol 2017;35:37743780.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Lichtman SM, Harvey RD, Damiette Smit MA, et al. Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology–Friends of Cancer Research Organ Dysfunction, Prior or Concurrent Malignancy, and Comorbidities Working Group. J Clin Oncol 2017;35:37533759.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    U.S. Food and Drug Administration. Cancer clinical trial eligibility criteria: patients with organ dysfunction or prior or concurrent malignancies. Accessed March 30, 2022. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cancer-clinical-trial-eligibility-criteria-patients-organ-dysfunction-or-prior-or-concurrent

    • Search Google Scholar
    • Export Citation
  • 6.

    de Moor JS, Mariotto AB, Parry C, et al. Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care. Cancer Epidemiol Biomarkers Prev 2013;22:561570.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Bluethmann SM, Mariotto AB, Rowland JH. Anticipating the “Silver Tsunami”: prevalence trajectories and comorbidity burden among older cancer survivors in the united states. Cancer Epidemiol Biomarkers Prev 2016;25:10291036.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Glicksman AS, Fulton JP. Metachronous cancer. R I Med J (2013) 2013;96:4144.

  • 9.

    Ye Y, Neil AL, Wills KE, et al. Temporal trends in the risk of developing multiple primary cancers: a systematic review. BMC Cancer 2016;16:849.

  • 10.

    Weir HK, Johnson CJ, Thompson TD. The effect of multiple primary rules on population-based cancer survival. Cancer Causes Control 2013;24:12311242.

  • 11.

    Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377381.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Anderson WF, Jatoi I, Tse J, et al. Male breast cancer: a population-based comparison with female breast cancer. J Clin Oncol 2010;28:232239.

  • 13.

    Murphy CC, Gerber DE, Pruitt SL. Prevalence of prior cancer among persons newly diagnosed with cancer: an initial report from the Surveillance, Epidemiology, and End Results program. JAMA Oncol 2018;4:832836.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Milas L, Mason KA, Ang KK. Epidermal growth factor receptor and its inhibition in radiotherapy: in vivo findings. Int J Radiat Biol 2003;79: 539545.

  • 15.

    Gerber DE, Laccetti AL, Xuan L, et al. Impact of prior cancer on eligibility for lung cancer clinical trials. J Natl Cancer Inst 2014;106.

  • 16.

    Pruitt SL, Zhu H, Heitjan DF, et al. Survival of women diagnosed with breast cancer and who have survived a previous cancer. Breast Cancer Res Treat 2021;187:853865.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    National Cancer Institute, Cancer Therapy Evaluation Program. Guidelines regarding the inclusion of cancer survivors and HIV-positive individuals on clinical trials. Accessed January 13, 2022. Available at: http://ctep.cancer.gov/protocolDevelopment/policies_hiv.htm

    • Search Google Scholar
    • Export Citation
  • 18.

    Laccetti AL, Pruitt SL, Xuan L, et al. Effect of prior cancer on outcomes in advanced lung cancer: implications for clinical trial eligibility and accrual. J Natl Cancer Inst 2015;107.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Ludmir EB, Mainwaring W, Lin TA, et al. Factors associated with age disparities among cancer clinical trial participants. JAMA Oncol 2019;5:17691773.

  • 20.

    Shenoy P, Harugeri A. Elderly patients’ participation in clinical trials. Perspect Clin Res 2015;6:184189.

  • 21.

    Hutchins LF, Unger JM, Crowley JJ, et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999;341:20612067.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Lee PY, Alexander KP, Hammill BG, et al. Representation of elderly persons and women in published randomized trials of acute coronary syndromes. JAMA 2001;286:708713.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Comis RL, Miller JD, Aldigé CR, et al. Public attitudes toward participation in cancer clinical trials. J Clin Oncol 2003;21:830835.

  • 24.

    Townsley CA, Chan KK, Pond GR, et al. Understanding the attitudes of the elderly towards enrolment into cancer clinical trials. BMC Cancer 2006;6:34.

  • 25.

    Garcia S, Bisen A, Yan J, et al. Thoracic oncology clinical trial eligibility criteria and requirements continue to increase in number and complexity. J Thorac Oncol 2017;12:14891495.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Gerber DE, Singh H, Larkins E, et al. Standardizing eligibility criteria: a new approach to simplifying and harmonizing cancer clinical trials. JAMA Oncol, in press.

    • Search Google Scholar
    • Export Citation
  • 27.

    Kotwall CA, Mahoney LJ, Myers RE, et al. Reasons for non-entry in randomized clinical trials for breast cancer: a single institutional study. J Surg Oncol 1992;50:125129.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Lee JY, Breaux SR. Accrual of radiotherapy patients to clinical trials. Cancer 1983;52:10141016.

  • 29.

    Simon MS, Du W, Flaherty L, et al. Factors associated with breast cancer clinical trials participation and enrollment at a large academic medical center. J Clin Oncol 2004;22:20462052.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Fuks A, Weijer C, Freedman B, et al. A study in contrasts: eligibility criteria in a twenty-year sample of NSABP and POG clinical trials. J Clin Epidemiol 1998;51:6979.

    • Crossref
    • Search Google Scholar
    • Export Citation

Submitted March 1, 2022; final revision received March 31, 2022; accepted for publication March 31, 2022.

Author contributions: Study concept and design: Pruitt, Gerber. Data collection: Perez. Statistical analysis: Murphy, Pruitt. Data interpretation: Murphy, Pruitt, Rashdan, Rahimi, Gerber. Manuscript preparation: Perez, Murphy, Pruitt, Gerber.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: This work was supported by NCI Midcareer Investigator Award in Patient-Oriented Research (K24 CA201543-01; D.E. Gerber) and R01CA229834-02 (S.L. Pruitt).

Correspondence: David E. Gerber, MD, Division of Hematology-Oncology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Mail Code 8852, Dallas, TX 75230-8852. Email: david.gerber@utsouthwestern.edu

Supplementary Materials

  • View in gallery

    Number and percent of trials excluding patients with prior cancer and/or prior cancer treatment.

  • 1.

    Broadening/Modernizing Eligibility Criteria for National Cancer Institute (NCI) Sponsored Clinical Trials. Accessed January 13, 2022. Available at: https://ctep.cancer.gov/protocolDevelopment/docs/CTEP_Broadened_Eligibility_Criteria_Guidance.pdf

  • 2.

    Lin NU, Prowell T, Tan AR, et al. Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology-Friends of Cancer Research Brain Metastases Working Group. J Clin Oncol 2017;35:37603773.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Uldrick TS, Ison G, Rudek MA, et al. Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology-Friends of Cancer Research HIV Working Group. J Clin Oncol 2017;35:37743780.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Lichtman SM, Harvey RD, Damiette Smit MA, et al. Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology–Friends of Cancer Research Organ Dysfunction, Prior or Concurrent Malignancy, and Comorbidities Working Group. J Clin Oncol 2017;35:37533759.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    U.S. Food and Drug Administration. Cancer clinical trial eligibility criteria: patients with organ dysfunction or prior or concurrent malignancies. Accessed March 30, 2022. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cancer-clinical-trial-eligibility-criteria-patients-organ-dysfunction-or-prior-or-concurrent

    • Search Google Scholar
    • Export Citation
  • 6.

    de Moor JS, Mariotto AB, Parry C, et al. Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care. Cancer Epidemiol Biomarkers Prev 2013;22:561570.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Bluethmann SM, Mariotto AB, Rowland JH. Anticipating the “Silver Tsunami”: prevalence trajectories and comorbidity burden among older cancer survivors in the united states. Cancer Epidemiol Biomarkers Prev 2016;25:10291036.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Glicksman AS, Fulton JP. Metachronous cancer. R I Med J (2013) 2013;96:4144.

  • 9.

    Ye Y, Neil AL, Wills KE, et al. Temporal trends in the risk of developing multiple primary cancers: a systematic review. BMC Cancer 2016;16:849.

  • 10.

    Weir HK, Johnson CJ, Thompson TD. The effect of multiple primary rules on population-based cancer survival. Cancer Causes Control 2013;24:12311242.

  • 11.

    Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377381.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Anderson WF, Jatoi I, Tse J, et al. Male breast cancer: a population-based comparison with female breast cancer. J Clin Oncol 2010;28:232239.

  • 13.

    Murphy CC, Gerber DE, Pruitt SL. Prevalence of prior cancer among persons newly diagnosed with cancer: an initial report from the Surveillance, Epidemiology, and End Results program. JAMA Oncol 2018;4:832836.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Milas L, Mason KA, Ang KK. Epidermal growth factor receptor and its inhibition in radiotherapy: in vivo findings. Int J Radiat Biol 2003;79: 539545.

  • 15.

    Gerber DE, Laccetti AL, Xuan L, et al. Impact of prior cancer on eligibility for lung cancer clinical trials. J Natl Cancer Inst 2014;106.

  • 16.

    Pruitt SL, Zhu H, Heitjan DF, et al. Survival of women diagnosed with breast cancer and who have survived a previous cancer. Breast Cancer Res Treat 2021;187:853865.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    National Cancer Institute, Cancer Therapy Evaluation Program. Guidelines regarding the inclusion of cancer survivors and HIV-positive individuals on clinical trials. Accessed January 13, 2022. Available at: http://ctep.cancer.gov/protocolDevelopment/policies_hiv.htm

    • Search Google Scholar
    • Export Citation
  • 18.

    Laccetti AL, Pruitt SL, Xuan L, et al. Effect of prior cancer on outcomes in advanced lung cancer: implications for clinical trial eligibility and accrual. J Natl Cancer Inst 2015;107.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Ludmir EB, Mainwaring W, Lin TA, et al. Factors associated with age disparities among cancer clinical trial participants. JAMA Oncol 2019;5:17691773.

  • 20.

    Shenoy P, Harugeri A. Elderly patients’ participation in clinical trials. Perspect Clin Res 2015;6:184189.

  • 21.

    Hutchins LF, Unger JM, Crowley JJ, et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999;341:20612067.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Lee PY, Alexander KP, Hammill BG, et al. Representation of elderly persons and women in published randomized trials of acute coronary syndromes. JAMA 2001;286:708713.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Comis RL, Miller JD, Aldigé CR, et al. Public attitudes toward participation in cancer clinical trials. J Clin Oncol 2003;21:830835.

  • 24.

    Townsley CA, Chan KK, Pond GR, et al. Understanding the attitudes of the elderly towards enrolment into cancer clinical trials. BMC Cancer 2006;6:34.

  • 25.

    Garcia S, Bisen A, Yan J, et al. Thoracic oncology clinical trial eligibility criteria and requirements continue to increase in number and complexity. J Thorac Oncol 2017;12:14891495.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Gerber DE, Singh H, Larkins E, et al. Standardizing eligibility criteria: a new approach to simplifying and harmonizing cancer clinical trials. JAMA Oncol, in press.

    • Search Google Scholar
    • Export Citation
  • 27.

    Kotwall CA, Mahoney LJ, Myers RE, et al. Reasons for non-entry in randomized clinical trials for breast cancer: a single institutional study. J Surg Oncol 1992;50:125129.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Lee JY, Breaux SR. Accrual of radiotherapy patients to clinical trials. Cancer 1983;52:10141016.

  • 29.

    Simon MS, Du W, Flaherty L, et al. Factors associated with breast cancer clinical trials participation and enrollment at a large academic medical center. J Clin Oncol 2004;22:20462052.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Fuks A, Weijer C, Freedman B, et al. A study in contrasts: eligibility criteria in a twenty-year sample of NSABP and POG clinical trials. J Clin Epidemiol 1998;51:6979.

    • Crossref
    • Search Google Scholar
    • Export Citation
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