Abstract
Background:
Identifying patient and disease-specific characteristics associated with clinical trial enrollment of adolescents and young adults (AYAs) with cancer may target efforts to improve accrual.
Methods:
We identified Alliance for Clinical Trials in Oncology (Alliance) trials opened from 1/1/2000 and closed before 1/1/2018 for common AYA cancers. Using descriptive statistics, we summarized proportions of AYAs (18–39 years) versus non-AYAs (≥40 years) enrolled by cancer type. Among studies with ≥20 AYAs enrolled, we compared demographic and disease characteristics of AYAs versus non-AYAs using chi-squared and Kruskal-Wallis tests. We also conducted a qualitative review of therapeutic trials included in our analysis in PubMed through 12/31/2021 that reported AYA-specific survival.
Results:
Among 188 trials enrolling 40,396 patients, AYAs represented 11% (4,468/40,396) of accrual. AYA accrual varied by cancer type (leukemia, 23.6%; breast, 9.9%; lymphoma, 14.8%; colorectal, 6.2%; central nervous system, 8.1%; melanoma, 11.8%; sarcoma, 12%). Across ages, the proportion of Black and Hispanic patients enrolled was 1%−10%. Compared to non-AYAs, AYAs on breast and colorectal cancer trials were less likely to be White and more likely Hispanic. Disease characteristics differed by age for selected trials. Two trials reported AYA-specific survival, with no significant differences observed by age.
Conclusion:
AYA accrual to Alliance trials was comparable to or exceeded population-based, age-specific prevalence estimates for most cancer types. Greater proportional representation of Hispanic and non-White patients among AYAs reflects United States demographic trends. The small number of minority patients enrolled across ages underscores the persistent challenge of ensuring equitable access to trials, including for AYAs.
Keywords: Adolescent and young adult (AYA), clinical trials accrual, clinical trial enrollment disparities
Introduction
More than one million adolescents and young adults (AYAs), age 15–39 years, are diagnosed with cancer globally each year.1 While outcomes in AYAs have improved over time, there remain disparities in survival gains compared to both pediatric and adult cancer patient populations.1 Historically, AYAs have been underrepresented in clinical trials and it has been suggested that this may contribute to the lagging improvement in outcomes AYAs have experienced relative to their younger and older counterparts.2–4
Between 2010 and 2015, overall enrollment to National Cancer Institute (NCI) -sponsored treatment trials decreased, with fewer trials open during period.4, 5 Suggested contributors to this decrease include the restructuring of NCI adult patient cooperative groups, resulting in the formation of the National Clinical Trials Network (NCTN) that took place during this time, as well as the shifting of some trials from cooperative group sponsorship to pharmaceutical industry support.5 AYA trial enrollment (with the exception of acute lymphoblastic leukemia enrollment [ALL]) similarly decreased during these years.4 Encouragingly, a recent evaluation of accrual from 2004 to 2019 to Cancer Therapy Evaluation Program phase 2, 2/3, and 3 trials across the NCTN found that AYA enrollment increased from 9.5% pre-formation of the NCTN (2004–2014) to 14% post-formation of the NCTN (2015–2019).6
Yet, barriers to AYA clinical trial enrollment remain. Identifying whether there are certain disease or patient characteristics of AYAs where enrollment is suboptimal relative to older patients may help better target efforts to improve AYA accrual to ongoing trials as well as inform strategies for enhancing accrual to future studies. We therefore sought to systematically evaluate AYA accrual trends across Alliance for Clinical Trials in Oncology (Alliance) trials from 2000–2017 among patients aged 18–39 years diagnosed with the most common AYA cancers.7, 8 In addition to comparing differences in AYA accrual by disease and demographic characteristics to non-AYAs (18–39 vs. ≥40 years), we examined differences in disease characteristics in a subset of trials, which to the best of our knowledge has not been previously explored in clinical trial populations. Because it is also unknown how often trials explore differences in survival in AYAs relative to older patients, we also conducted a qualitative review of results of trials published through December 31, 2021 to evaluate whether AYA-specific survival was reported, and if so, whether a differential impact of age on disease outcomes was found.
Methods
Data source
Alliance was established following the merger of adult cooperative groups Cancer and Leukemia Group B (CALGB), American College of Surgeons Oncology Group (ACOSOG), and North Central Cancer Treatment Group (NCCTG) in 2011. In April 2019, we retrospectively identified all closed-to-accrual CALGB/ACOSOG/NCCTG/Alliance-sponsored trials. Inclusion criteria for the current analysis included trials opened to accrual beginning 1/1/2000 and closed to accrual prior to 1/1/2018 with trial eligibility criteria inclusive of patients 18–39 years of age. While the definition of “AYA” includes patients as young as 15 years old, it is uncommon for Alliance trials to enroll patients younger than age 18. We restricted inclusion to the most common AYA cancer types: breast, non-Hodgkin and Hodgkin lymphoma, leukemia, central nervous system (CNS)-brain, colorectal, melanoma, genitourinary (GU) – germ cell, and sarcomas.7, 8 We excluded correlative/companion studies that did not enroll new patients.
Trials included in the analyses had been approved by either the National Cancer Institute (NCI) Central Institutional Review Board or an individual trial site’s institutional review board (IRB); patients provided informed consent at the time of trial enrollment. Given the current study was a secondary analysis of deidentified data, no additional IRB review or consent was needed. The study concept was approved by the Alliance Health Disparities Committee (Alliance A151945).
Analysis
Counts and the proportions of patients accrued were calculated for AYAs (aged 18–39 years), and non-AYAs (aged ≥40 years) for breast, non-Hodgkin and Hodgkin lymphoma, leukemias, central nervous system (CNS)/brain, colorectal, melanoma, genitourinary (GU)-germ cell, and sarcoma. Changes in accrual from 2000 through 2017 were calculated for all cancer types combined as well as individually for each cancer type. For studies that enrolled at least 20 AYA patients, we compared demographic characteristics, including sex, race, and ethnicity, between AYAs and non-AYAs. For the subset of these studies where clinical information (e.g., stage, tumor location, hormone receptor status) was available, disease-specific information was extracted from the trial case report form for each individual trial, with selected disease characteristics compared by age (AYAs vs. non-AYAs). Chi-squared tests were applied to compare proportional differences, and Kruskal-Wallis tests were used to compare median differences, between groups. Data collection and statistical analyses were conducted by the Alliance Statistics and Data Management Center. Data quality was ensured by review of data by the Alliance Statistics and Data Management Center and by the study chairperson following Alliance policies. All statistical analyses were performed using SAS statistical software (version 9.4M7, SAS Institute, Cary, NC on a database locked on September 8, 2021).
Additionally, we conducted a qualitative review of published results (indexed through PubMed) through December 31, 2021, of therapeutic trials included in our analysis. Publications were reviewed to determine whether disease-free and/or overall survival were reported in younger subsets (e.g., age <40 years or age <50 years) of the study population and results of such analyses.
Results
Of 617 trials opened to accrual during 2000–2017,188 (30%) trials enrolling 40,396 patients aged ≥18 years met inclusion criteria (Supplemental Figure 1); 69% were enrolled to either a breast or colorectal trial (27,808/40,396). Overall, AYAs (18–39 years old) represented 11% (4,468/40,396) of the total patients accrued across these trials. AYA accrual was highest in 2002 (approximately 15% of all patients accrued), with declines observed in 2003–2007 and 2013–2017 (Figure 1). Breast (k=52), lymphoma (k=41), leukemia (k=28), colorectal (k=24), and central nervous system (CNS)/brain (k=20) trials were most common. A single genitourinary (GU) – germ cell trial (CALGB-90106) that enrolled only one participant was excluded from subsequent analyses. AYAs aged 18–24 represented less than 5% of AYA accrual over the evaluation period.
Figure 1.
Overall AYA accrual changes by age 2000–2017 in Alliance trials
Total AYA accrual during 2000–2017 varied by disease (Table 1), with leukemia trials having the largest proportion (23.6%) of AYAs and colorectal cancer trials the smallest proportion (6.2%). Disease-specific accrual trends varied considerably (Supplemental Figure 2a–2g). High AYA accrual in select years was attributable to individual trials that enrolled only AYAs, including CALGB 10403 (open November 2007-September 2012), or ones that had a high AYA accrual, including Alliance A091105 (phase III, double blind, randomized, placebo-controlled trial of sorafenib in desmoid tumors or aggressive fibromatosis, open March 2014-December 2016) in which AYAs represented 57.5% of all patients accrued. AYA accrual was lower in more recent years (2015–2017) across several cancer types, including breast, leukemia, colorectal, melanoma, and sarcoma.
Table 1:
Accrual of patients by age and by disease in Alliance trials (188 trials)
| Disease Site | Number of Studies |
18–39 years | ≥ 40 years | Total Accrued |
|---|---|---|---|---|
| Breast | 52 | 1,758 (9.9%) | 16,024 (90.1%) | 17,782 |
| Lymphoma | 41 | 545 (14.8%) | 3,146 (85.2) | 3,691 |
| Leukemia | 28 | 1,123 (23.6%) | 3,631 (76.4%) | 4,754 |
| Colorectal | 24 | 626 (6.2%) | 9,400 (93.8%) | 10,026 |
| Central nervous system | 20 | 165 (8.1%) | 1,877 (91.9%) | 2,042 |
| Melanoma | 16 | 121 (11.8%) | 905 (88.2%) | 1,026 |
| GU Germ Cell | 1 | 1 | 0 | 1 |
| Sarcoma | 6 | 129 (12.0) | 945 (88.0%) | 1,074 |
Race, ethnicity, and gender by cancer type and age
Of 188 trials, 29 enrolled at least 20 AYAs and were eligible for the analyses comparing additional patient characteristics by age for breast (k=12), leukemia (k=6), lymphoma (k=5), colorectal (k=4), melanoma (k=1), and sarcoma (k=1) disease. Of these, most (18/29, 62%) were phase III trials (Supplemental Table 1). Overall, across all diseases and age groups (Table 2), American Indian or Alaska Native and Native Hawaiian/Other Pacific Islander were least frequently represented (each ≤1%), followed by Asian (<5% for breast, colorectal, lymphoma, leukemia; 0%/not reported for melanoma and sarcoma). The proportion of Black patients enrolled ranged from 1% (melanoma) to 10% (breast, colorectal, lymphoma, sarcoma). With the exception of melanoma (1.6%), the proportion of Hispanic patients ranged from 5% to 7% for other cancer types. Regarding gender, while nearly all breast cancer patients were female, there was heterogeneity in gender distribution across other cancer types. Slightly more than half of colorectal, leukemia and lymphoma patients were male, approximately 57% of patients enrolled on the melanoma trial were male, and 69% of patients enrolled on the sarcoma trial were female.
Table 2.
Race, ethnicity, and gender by age in Alliance trials by disease site (18–39 vs. 40+ years)
| Breast (k=12 trials) | Total N=12,876 |
18–39 years N=1611 |
40+ years N=11265 |
p |
|---|---|---|---|---|
| Race | N (%) | N (%) | N (%) | <0.0001 |
| American Indian or Alaska Native | 76 (0.6) | 8 (0.5) | 68 (0.6) | |
| Asian | 346 (2.7) | 65 (4.0) | 281 (2.5) | |
| Black or African American | 1,290 (10.0) | 171 (10.6) | 1,119 (9.9) | |
| Native Hawaiian or Other Pacific Islander | 41 (0.3) | 7 (0.4) | 34 (0.3) | |
| Unknown: Patient refused or unsure | 365 (2.8) | 76 (4.7) | 289 (2.6) | |
| White | 10,757 (83.5) | 1,284 (79.7) | 9,473 (84.1) | |
| Missing | 1 | 0 | 1 | |
| Ethnicity | <0.0001 | |||
| Hispanic or Latino | 744 (5.8) | 136 (8.4) | 608 (5.4) | |
| Not Hispanic or Latino | 11,506 (89.4) | 1,391 (86.3) | 10,115 (89.8) | |
| Not Reported | 626 (4.9) | 84 (5.2) | 542 (4.8) | |
| Gender | ||||
| Female | 12,856 (99.9) | 1,610 (99.9) | 11,246 (99.8) | 0.3720 |
| Male | 18 (0.1) | 1 (0.1) | 17 (0.2) | |
| Missing | 2 | 0 | 2 | |
| Leukemia (k=6 trials) | Total N=2666 |
18–39 years N=1042 |
40+ years N=1624 |
p |
| Race | N (%) | N (%) | N (%) | --- |
| American Indian or Alaska Native | 21 (0.8) | 16 (1.5) | 5 (0.3) | |
| Asian | 59 (2.2) | 26 (2.5) | 33 (2.0) | |
| Black or African American | 181 (6.8) | 82 (7.9) | 99 (6.1) | |
| Hispanic American | 14 (0.5) | 7 (0.7) | 7 (0.4) | |
| Indian Subcontinent | 1 (0.0) | 0 (0.0) | 1 (0.1) | |
| Native Hawaiian or Other Pacific Islander | 7 (0.3) | 5 (0.5) | 2 (0.1) | |
| Unknown: Patient refused or unsure | 479 (18.0) | 154 (14.8) | 325 (20.0) | |
| White | 1,904 (71.4) | 752 (72.2) | 1,152 (70.9) | |
| Ethnicity | --- | |||
| Hispanic or Latino | 167 (6.3) | 111 (10.7) | 56 (3.4) | |
| Not Hispanic or Latino | 1,828 (68.6) | 725 (69.6) | 1,103 (67.9) | |
| Not Reported | 671 (25.2) | 206 (19.8) | 465 (28.6) | |
| Gender | 0.0011 | |||
| Female | 1,267 (47.5) | 454 (43.6) | 813 (50.1) | |
| Male | 1,399 (52.5) | 588 (56.4) | 811 (49.9) | |
| Lymphoma (k=5 trials) | Total N=968 |
18–39 years N=376 |
40+ years N=592 |
p |
| Race | N (%) | N (%) | N (%) | |
| American Indian or Alaska Native | 4 (0.4) | 1 (0.3) | 3 (0.5) | 0.4383 |
| Asian | 27 (2.8) | 12 (3.2) | 15 (2.5) | |
| Black or African American | 100 (10.3) | 42 (11.2) | 58 (9.8) | |
| Hispanic American | 2 (0.2) | 2 (0.5) | 0 (0.0) | |
| Native Hawaiian or Other Pacific Islander | 2 (0.2) | 0 (0.0) | 2 (0.3) | |
| Unknown: Patient refused or unsure | 38 (3.9) | 16 (4.3) | 22 (3.7) | |
| White | 795 (82.1) | 303 (80.6) | 492 (83.1) | |
| Ethnicity | 0.4652 | |||
| Hispanic or Latino | 49 (5.1) | 17 (4.5) | 32 (5.4) | |
| Not Hispanic or Latino | 866 (89.5) | 342 (91.0) | 524 (88.5) | |
| Not Reported | 53 (5.5) | 17 (4.5) | 36 (6.1%) | |
| Gender | 0.9528 | |||
| Female | 455 (47.1) | 176 (46.9) | 279 (47.1) | |
| Male | 512 (52.9) | 199 (53.1) | 313 (52.9) | |
| Missing | 1 | 1 | 0 | |
| Colorectal (k=4 trials) | Total N=8732 |
18–39 years N=487 |
40+ years N=8245 |
p |
| Race | N (%) | N (%) | N (%) | 0.0002 |
| American Indian or Alaska Native | 47 (0.5) | 1 (0.2) | 46 (0.6) | |
| Asian | 376 (4.3) | 31 (6.4) | 345 (4.2) | |
| Black or African American | 859 (9.8) | 69 (14.2) | 790 (9.6) | |
| More than one race | 7 (0.1) | 0 (0.0) | 7 (0.1) | |
| Native Hawaiian or Other Pacific Islander | 31 (0.4) | 1 (0.2) | 30 (0.4) | |
| Unknown: Patient refused or unsure | 307 (3.5) | 27 (5.5) | 280 (3.4) | |
| White | 7,104 (81.4) | 358 (73.5) | 6,746 (81.8) | |
| Missing | 1 | 0 | 1 | |
| Ethnicity | <0.0001 | |||
| Hispanic or Latino | 534 (6.1) | 63 (12.9) | 471 (5.7) | |
| Not Hispanic or Latino | 7,432 (85.1) | 368 (75.6) | 7,064 (85.7) | |
| Not Reported | 766 (8.8) | 56 (11.5) | 710 (8.6) | |
| Gender | 0.5243 | |||
| Female | 3887 (44.5) | 210 (43.1) | 3677 (44.6) | |
| Male | 4845 (55.5) | 277 (56.9) | 4568 (55.4) | |
| Melanoma (k=1 trial) | Total N=314 |
18–39 years N=67 |
40+ years N=247 |
p |
| Race | N (%) | N (%) | N (%) | 0.6568 |
| Black or African American | 3 (1.0) | 0 (0.0) | 3 (1.2) | |
| Unknown: Patient refused or unsure | 13 (4.1) | 3 (4.5) | 10 (4.0) | |
| White | 298 (94.9) | 64 (95.5) | 234 (94.7) | |
| Ethnicity | 0.2877 | |||
| Hispanic or Latino | 5 (1.6) | 0 (0.0) | 5 (2.0) | |
| Not Hispanic or Latino | 282 (89.8) | 59 (88.1) | 223 (90.3) | |
| Not Reported | 27 (8.6) | 8 (11.9) | 19 (7.7) | |
| Gender | 0.0743 | |||
| Female | 134 (42.7) | 35 (52.2) | 99 (40.1) | |
| Male | 180 (57.3) | 32 (47.8) | 148 (59.9) | |
| Sarcoma (k=1 trial) | Total N=87 |
18–39 years N=50 |
40+ years N=37 |
p |
| Race | N (%) | N (%) | N (%) | 0.3981 |
| American Indian or Alaska Native | 1 (1.1) | 1 (2.0) | 0 (0.0) | |
| Black or African American | 9 (10.3) | 7 (14.0) | 2 (5.4) | |
| Unknown: Patient refused or unsure | 7 (8.0) | 3 (6.0) | 4 (10.8) | |
| White | 70 (80.5) | 39 (78.0) | 31 (83.8) | |
| Ethnicity | 0.9043 | |||
| Hispanic or Latino | 6 (6.9) | 3 (6.0) | 3 (8.1) | |
| Not Hispanic or Latino | 79 (90.8) | 46 (92.0) | 33 (89.2) | |
| Not Reported | 2 (2.3) | 1 (2.0) | 1 (2.7) | |
| Gender | 0.8084 | |||
| Female | 60 (69.0) | 35 (70.0) | 25 (67.6) | |
| Male | 27 (31.0) | 15 (30.0) | 12 (32.4) | |
Among breast cancer patients, there were modest but statistically significant differences by race (p<0.0001) and ethnicity (p<0.0001) between AYAs and patients ≥40 years, with AYA patients less likely to be White than patients ≥40 years (79.7% vs. 84.1%), and more likely to be Hispanic than patients ≥40 years (8.4% vs. 5.4%). Of AYA breast cancer patients, 10.6% (vs. 9.9%, aged ≥40) were Black and 4% (vs. 2.5%, aged ≥40) Asian. Similarly, there were statistically significant differences by race (p=0.0002) and ethnicity (p<0.0001) among patients enrolled in colorectal cancer trials, with more Hispanic AYAs (12.9% vs. 5.7%, aged ≥40) and fewer White patients (73.5% vs. 81.8%, aged ≥40). Of AYA colorectal cancer patients, 14.2% (vs. 9.6%, aged ≥40) were Black and 6.4% (vs. 4.2%, aged ≥40) were Asian.
There were no statistically significant differences in the racial/ethnic distribution by age among lymphoma patients, or for the patients enrolled in the single melanoma and single sarcoma trials included in the analysis. Because race (18%) and ethnicity (25%) were unknown for a high proportion of leukemia patients, these data are presented descriptively (Table 2). Regarding gender, a greater proportion of AYA leukemia patients were male compared to patients aged ≥40 (56.4% vs. 49.9%, p=0.0011). There were no other statistically significant differences by gender for other cancer types between the two age groups.
Disease characteristics by cancer type and age
Table 3 presents disease characteristic of patients in individual trials (k=18) for solid tumors. Table 4 presents disease characteristic of patients in individual trials (k=11) for hematologic malignancies. Clinical characteristics were available from trial case report forms.
Table 3.
Disease characteristics by age (18–39 vs. ≥40): Alliance solid tumor trials
| Study Number (Cancer Type) |
Total | 18–39 years | 40+ years | P-value | |
|---|---|---|---|---|---|
|
CALGB 40101 (Breast) Cyclophosphamide and doxorubicin (CA x 4 cycles) versus paclitaxel (4 cycles) as adjuvant therapy for breast cancer in women with 0–3 positive axillary lymph nodes: a phase III randomized study |
N=3,871 | N=285 | N=3,586 | ||
| ER Status, n (%) | 0.00091 | ||||
| Unknown | 9 (0.2%) | 3 (1.1%) | 6 (0.2%) | ||
| Negative | 1,298 (33.5%) | 112 (39.3%) | 1,186 (33.1%) | ||
| Positive | 2,564 (66.2%) | 170 (59.6%) | 2,394 (66.8%) | ||
| PR Status, n (%) | 0.09091 | ||||
| Unknown | 15 (0.4%) | 3 (1.1%) | 12 (0.3%) | ||
| Negative | 1,681 (43.4%) | 132 (46.3%) | 1,549 (43.2%) | ||
| Positive | 2,175 (56.2%) | 150 (52.6%) | 2,025 (56.5%) | ||
| HER2 Status, n (%) | 0.00111 | ||||
| Unknown | 2,010 (51.9%) | 178 (62.5%) | 1,832 (51.1%) | ||
| Negative | 1,571 (40.6%) | 90 (31.6%) | 1,481 (41.3%) | ||
| Positive | 290 (7.5%) | 17 (6.0%) | 273 (7.6%) | ||
| Tumor Size, n (%) | 0.48541 | ||||
| Greater than or equal to 2cm | 1,712 (44.3%) | 131 (46.3%) | 1,581 (44.1%) | ||
| Less than 2cm | 2,152 (55.7%) | 152 (53.7%) | 2,000 (55.9%) | ||
| Missing | 7 | 2 | 5 | ||
| Positive Nodal Involvement | 0.12322 | ||||
| Mean (SD) | 0.2 (0.63) | 0.1 (0.42) | 0.2 (0.65) | ||
| Median (range) | 0.0 (0, 17.0) | 0.0 (0, 3.0) | 0.0 (0, 17.0) | ||
|
CALGB 40502 (Breast) A randomized phase III trial of weekly paclitaxel compared to weekly nanoparticle albumin bound NAB - paclitaxel or ixabepilone with or without bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer |
N=799 | N=55 | N=744 | ||
| ER Status, n (%) | 0.03421 | ||||
| Unknown | 2 (0.3%) | 1 (1.8%) | 1 (0.1%) | ||
| Negative | 234 (29.3%) | 19 (34.5%) | 215 (28.9%) | ||
| Positive | 563 (70.5%) | 35 (63.6%) | 528 (71.0%) | ||
| PR Status, n (%) | 0.04141 | ||||
| Unknown | 2 (0.3%) | 1 (1.8%) | 1 (0.1%) | ||
| Negative | 374 (46.8%) | 28 (50.9%) | 346 (46.5%) | ||
| Positive | 423 (52.9%) | 26 (47.3%) | 397 (53.4%) | ||
| HER2 Status, n (%) | 0.75581 | ||||
| Unknown | 232 (29.0%) | 15 (27.3%) | 217 (29.2%) | ||
| Negative | 561 (70.2%) | 40 (72.7%) | 521 (70.0%) | ||
| Positive | 6 (0.8%) | 0 (0.0%) | 6 (0.8%) | ||
|
CALGB 40503(Breast) A randomized, Phase III trial of endocrine therapy alone or endocrine therapy plus bevacizumab for women with hormone receptor-positive advanced breast cancer |
N=392 | N=39 | N=353 | ||
| ER Status, n (%) | 0.73931 | ||||
| Unknown | 0 (0.0%) | ||||
| Negative | 1 (0.3%) | 0 (0.0%) | 1 (0.3%) | ||
| Positive | 391 (99.7%) | 39 (100.0%) | 352 (99.7%) | ||
| PR Status, n (%) | 0.09181 | ||||
| Unknown | 4 (1.0%) | 0 (0.0%) | 4 (1.1%) | ||
| Negative | 79 (20.2%) | 3 (7.7%) | 76 (21.5%) | ||
| Positive | 309 (78.8%) | 36 (92.3%) | 273 (77.3%) | ||
| HER2 Status, n (%) | 0.35301 | ||||
| Unknown | 14 (3.6%) | 0 (0.0%) | 14 (4.0%) | ||
| Negative | 360 (91.8%) | 38 (97.4%) | 322 (91.2%) | ||
| Positive | 18 (4.6%) | 1 (2.6%) | 17 (4.8%) | ||
|
CALGB 40601 (Breast) Randomized phase III trial of paclitaxel plus trastuzumab plus lapatinib versus paclitaxel plus trastuzumab or as neoadjuvant treatment of HER2-positive primary breast cancer |
N=305 | N=58 | N=247 | ||
| ER Status, n (%) | 0.81391 | ||||
| Unknown | 8 (2.6%) | 2 (3.4%) | 6 (2.4%) | ||
| Negative | 125 (41.0%) | 22 (37.9%) | 103 (41.7%) | ||
| Positive | 172 (56.4%) | 34 (58.6%) | 138 (55.9%) | ||
| PR Status, n (%) | 0.54051 | ||||
| Unknown | 6 (2.0%) | 2 (3.4%) | 4 (1.6%) | ||
| Negative | 177 (58.0%) | 31 (53.4%) | 146 (59.1%) | ||
| Positive | 122 (40.0%) | 25 (43.1%) | 97 (39.3%) | ||
| HER2 Status, n (%) | --- | ||||
| Unknown | 0 (0.0%) | ||||
| Negative | 0 (0.0%) | ||||
| Positive | 303 (100.0%) | 58 (100.0%) | 245 (100.0%) | ||
| Missing | 2 | 0 | 2 | ||
| Tumor Size, n (%) | 0.93711 | ||||
| Greater than or equal to 2cm | 274 (98.2%) | 51 (98.1%) | 223 (98.2%) | ||
| Less than 2cm | 5 (1.8%) | 1 (1.9%) | 4 (1.8%) | ||
| Missing | 26 | 6 | 20 | ||
|
CALGB 40603 (Breast) Randomized phase II 2×2 factorial trial of the addition of carboplatin and/or bevacizumab to neoadjuvant weekly paclitaxel followed by dose-dense AC in hormone receptor-poor HER2-negative resectable breast cancer |
N=443 | N=102 | N=341 | ||
| ER Status, n (%) | 0.05981 | ||||
| Unknown | 2 (0.5%) | 0 (0.0%) | 2 (0.6%) | ||
| Negative | 414 (93.5%) | 91 (89.2%) | 323 (94.7%) | ||
| Positive | 27 (6.1%) | 11 (10.8%) | 16 (4.7%) | ||
| PR Status, n (%) | 0.08731 | ||||
| Unknown | 4 (0.9%) | 1 (1.0%) | 3 (0.9%) | ||
| Negative | 421 (95.0%) | 93 (91.2%) | 328 (96.2%) | ||
| Positive | 18 (4.1%) | 8 (7.8%) | 10 (2.9%) | ||
| HER2 Status, n (%) | --- | ||||
| Unknown | 0 (0.0%) | ||||
| Negative | 443 (100.0%) | 102 (100.0%) | 341 (100.0%) | ||
| Positive | 0 (0.0%) | ||||
| Tumor Size, n (%) | 0.40871 | ||||
| Greater than or equal to 2cm | 280 (63.2%) | 68 (66.7%) | 212 (62.2%) | ||
| Less than 2cm | 163 (36.8%) | 34 (33.3%) | 129 (37.8%) | ||
|
CALGB 70305 (Breast) Randomized study to prevent lymphedema in women treated for breast cancer |
N=876 | N=58 | N=818 | ||
| ER Status, n (%) | 0.00021 | ||||
| Unknown | 84 (9.6%) | 4 (6.9%) | 80 (9.8%) | ||
| Negative | 189 (21.6%) | 25 (43.1%) | 164 (20.0%) | ||
| Positive | 603 (68.8%) | 29 (50.0%) | 574 (70.2%) | ||
| PR Status, n (%) | 0.00201 | ||||
| Unknown | 84 (9.6%) | 4 (6.9%) | 80 (9.8%) | ||
| Negative | 272 (31.1%) | 30 (51.7%) | 242 (29.6%) | ||
| Positive | 520 (59.4%) | 24 (41.4%) | 496 (60.6%) | ||
| HER2 Status, n (%) | 0.15481 | ||||
| Unknown | 109 (12.4%) | 4 (6.9%) | 105 (12.8%) | ||
| Negative | 622 (71.0%) | 40 (69.0%) | 582 (71.1%) | ||
| Positive | 145 (16.6%) | 14 (24.1%) | 131 (16.0%) | ||
| Tumor Size, n (%) | 0.57101 | ||||
| Greater than or equal to 2cm | 317 (40.0%) | 24 (43.6%) | 293 (39.8%) | ||
| Less than 2cm | 475 (60.0%) | 31 (56.4%) | 444 (60.2%) | ||
| Missing | 84 | 3 | 81 | ||
| Positive Nodal Involvement | 0.01872 | ||||
| N | 731 | 49 | 682 | ||
| Mean (SD) | 1.9 (4.28) | 1.9 (2.56) | 1.9 (4.37) | ||
| Median (range) | 0.0 (0.0, 41.0) | 1.0 (0.0, 11.0) | 0.0 (0.0, 41.0) | ||
|
CALGB 70806 (Breast)* Vitamin D and breast cancer markers |
N=300 | N=72 | N=228 | ||
| ER Status, n (%) | NA | NA | NA | --- | |
| Unknown | |||||
| Negative | |||||
| Positive | |||||
| PR Status, n (%) | NA | NA | NA | --- | |
| Unknown | |||||
| Negative | |||||
| Positive | |||||
|
NCCTG N02C1 (Breast) A phase III randomized, placebo-controlled, double-blind trial of risedronate (actonel) for prevention of bone loss in premenopausal women undergoing chemotherapy for primary breast carcinoma |
N=216 | N=48 | N=168 | ||
| ER Status, n (%) | --- | ||||
| Unknown | 216 (100.0%) | 48 (100.0%) | 168 (100.0%) | ||
| Negative | 0 (0.0%) | ||||
| Positive | 0 (0.0%) | ||||
| PR Status, n (%) | |||||
| Unknown | 216 (100.0%) | 48 (100.0%) | 168 (100.0%) | ||
| Negative | 0 (0.0%) | ||||
| Positive | 0 (0.0%) | ||||
|
NCCTG N063D (Breast) Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation Trial - A randomized, multi-centre, open label, phase III study of adjuvant lapatinib, trastuzumab, their sequence and their combination in patients with HER2/ErbB2 positive primary breast cancer |
N=1,187 | N=140 | N=1,047 | ||
| ER Status, n (%) | 0.68181 | ||||
| Unknown | 125 (10.5%) | 15 (10.7%) | 110 (10.5%) | ||
| Negative | 379 (31.9%) | 49 (35.0%) | 330 (31.5%) | ||
| Positive | 683 (57.5%) | 76 (54.3%) | 607 (58.0%) | ||
| PR Status, n (%) | 0.54211 | ||||
| Unknown | 127 (10.7%) | 15 (10.7%) | 112 (10.7%) | ||
| Negative | 558 (47.0%) | 60 (42.9%) | 498 (47.6%) | ||
| Positive | 502 (42.3%) | 65 (46.4%) | 437 (41.7%) | ||
| HER2 Status, n (%) | 0.39371 | ||||
| Unknown | 487 (41.0%) | 52 (37.1%) | 435 (41.5%) | ||
| Negative | 18 (1.5%) | 1 (0.7%) | 17 (1.6%) | ||
| Positive | 682 (57.5%) | 87 (62.1%) | 595 (56.8%) | ||
| Tumor Size, n (%) | 0.78661 | ||||
| Greater than or equal to 2cm | 259 (22.0%) | 32 (22.9%) | 227 (21.8%) | ||
| Less than 2cm | 920 (78.0%) | 108 (77.1%) | 812 (78.2%) | ||
| Missing | 8 | 0 | 8 | ||
|
NCCTG N9831 (Breast) Phase III trial of doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel with or without trastuzumab as adjuvant treatment for women with HER-2 over-expressing or amplified node positive or high-risk node negative breast cancer |
N=3,505 | N=587 | N=2,918 | ||
| ER Status, n (%) | 0.37741 | ||||
| Unknown | 1 (0.0%) | 0 (0.0%) | 1 (0.0%) | ||
| Negative | 1,663 (47.4%) | 264 (45.0%) | 1,399 (47.9%) | ||
| Positive | 1,841 (52.5%) | 323 (55.0%) | 1,518 (52.0%) | ||
| PR Status, n (%) | 0.02921 | ||||
| Unknown | 9 (0.3%) | 1 (0.2%) | 8 (0.3%) | ||
| Negative | 2,096 (59.8%) | 323 (55.0%) | 1,773 (60.8%) | ||
| Positive | 1,400 (39.9%) | 263 (44.8%) | 1,137 (39.0%) | ||
| HER2 Status, n (%) | --- | ||||
| Unknown | 0 (0.0%) | ||||
| Negative | 0 (0.0%) | ||||
| Positive | 0 (0.0%) | ||||
| Missing | 3505 | 587 | 2918 | ||
| Tumor Size, n (%) | 0.26401 | ||||
| Greater than or equal to 2cm | 2,362 (67.4%) | 384 (65.4%) | 1,978 (67.8%) | ||
| Less than 2cm | 1,143 (32.6%) | 203 (34.6%) | 940 (32.2%) | ||
| Positive Nodal Involvement | 0.10722 | ||||
| N | 3,505 | 587 | 2,918 | ||
| Mean (SD) | 4.3 (5.16) | 4.4 (5.00) | 4.3 (5.19) | ||
| Median (range) | 2.0 (0.0, 41.0) | 3.0 (0.0, 36.0) | 2.0 (0.0, 41.0) | ||
|
ACOSOG Z1041 (Breast) A randomized phase III trial comparing a neoadjuvant regimen of FEC-75 followed by paclitaxel plus trastuzumab with a neoadjuvant regimen of paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab in patients with HER-2 positive operable breast cancer |
N=282 | N=44 | N=238 | ||
| ER Status, n (%) | 0.23591 | ||||
| Unknown | 0 (0.0%) | ||||
| Negative | 119 (42.2%) | 15 (34.1%) | 104 (43.7%) | ||
| Positive | 163 (57.8%) | 29 (65.9%) | 134 (56.3%) | ||
| PR Status, n (%) | 0.09131 | ||||
| Unknown | 0 (0.0%) | ||||
| Negative | 167 (59.2%) | 21 (47.7%) | 146 (61.3%) | ||
| Positive | 115 (40.8%) | 23 (52.3%) | 92 (38.7%) | ||
| HER2 Status, n (%) | |||||
| Unknown | 0 (0.0%) | ||||
| Negative | 0 (0.0%) | ||||
| Positive | 282 (100.0%) | 44 (100.0%) | 238 (100.0%) | ||
| Tumor Size, n (%) | 0.23891 | ||||
| Greater than or equal to 2cm | 43 (38.4%) | 10 (50.0%) | 33 (35.9%) | ||
| Less than 2cm | 69 (61.6%) | 10 (50.0%) | 59 (64.1%) | ||
| Missing | 170 | 24 | 146 | ||
|
ACOSOG Z1071 (Breast) A Phase II Study Evaluating the Role of Sentinel Lymph Node Surgery and Axillary Lymph Node Dissection Following Preoperative Chemotherapy in Women with Node Positive Breast Cancer (T1–4, N1–2, M0) at Initial Diagnosis |
N=700 | N=123 | N=577 | ||
| ER Status, n (%) | 0.00211 | ||||
| Unknown | 0 (0%) | ||||
| Negative | 274 (39.1%) | 33 (26.8%) | 241 (41.8%) | ||
| Positive | 426 (60.9%) | 90 (73.2%) | 336 (58.2%) | ||
| PR Status, n (%) | 0.00401 | ||||
| Unknown | 1 (0.1%) | 1 (0.8%) | 0 (0.0%) | ||
| Negative | 336 (48.0%) | 46 (37.4%) | 290 (50.3%) | ||
| Positive | 363 (51.9%) | 76 (61.8%) | 287 (49.7%) | ||
| HER2 Status, n (%) | 0.22711 | ||||
| Unknown | 230 (33.6%) | 48 (40.3%) | 182 (32.2%) | ||
| Negative | 324 (47.3%) | 51 (42.9%) | 273 (48.2%) | ||
| Positive | 131 (19.1%) | 20 (16.8%) | 111 (19.6%) | ||
| Missing | 15 | 4 | 11 | ||
| Tumor Size, n (%) | 0.16031 | ||||
| Greater than or equal to 2cm | 541 (90.8%) | 96 (87.3%) | 445 (91.6%) | ||
| Less than 2cm | 55 (9.2%) | 14 (12.7%) | 41 (8.4%) | ||
| Missing | 104 | 13 | 91 | ||
| Positive Nodal Involvement | 0.50862 | ||||
| N | 694 | 123 | 571 | ||
| Mean (SD) | 1.1 (0.42) | 1.1 (0.27) | 1.1 (0.44) | ||
| Median (range) | 1.0 (0.0, 6.0) | 1.0 (1.0, 3.0) | 1.0 (0.0, 6.0) | ||
|
CALGB 80405 (Colorectal) Phase III trial of irinotecan/5-FU/leucovorin or oxaliplatin/5-FU/leucovorin with bevacizumab, or cetuximab (C225), or with the combination of bevacizumab and cetuximab for patients with untreated metastatic adenocarcinoma of the colon or rectum |
N=2,326 | N=143 | N=2,183 | ||
| Tumor Location, n (%) | 0.17431 | ||||
| Left-sided | 616 (28.9%) | 28 (21.4%) | 588 (29.4%) | ||
| Multiple | 11 (0.5%) | 0 (0.0%) | 11 (0.5%) | ||
| Right-sided | 1,336 (62.7%) | 90 (68.7%) | 1,246 (62.3%) | ||
| Transverse | 169 (7.9%) | 13 (9.9%) | 156 (7.8%) | ||
| Missing | 194 | 12 | 182 | ||
|
CALGB 80702 (Colorectal) A phase III trial of 6 versus 12 treatments of adjuvant FOLFOX plus celecoxib or placebo for patients with resected stage III colon cancer |
N=2,524 | N=87 | N=2,437 | ||
| T Stage, n (%) | 0.39141 | ||||
| 4 | 375 (15.0%) | 10 (11.8%) | 365 (15.1%) | ||
| 1–3 | 2,120 (85.0%) | 75 (88.2%) | 2,045 (84.9%) | ||
| Missing | 29 | 2 | 27 | ||
| Positive Nodal Involvement | 0.79822 | ||||
| N | 2,494 | 85 | 2,409 | ||
| Mean (SD) | 2.9 (3.07) | 3.1 (3.16) | 2.9 (3.07) | ||
| Median | 2.0 | 2.0 | 2.0 | ||
| Range | 0.0, 46.0 | 0.0, 17.0 | 0.0, 46.0 | ||
| Tumor Location, n (%) | 0.27751 | ||||
| Left-sided | 1,172 (47.2%) | 45 (52.9%) | 1,127 (47.0%) | ||
| Multiple | 0 (0.0%) | ||||
| Right-sided | 1,313 (52.8%) | 40 (47.1%) | 1,273 (53.0%) | ||
| Transverse | 0 (0.0%) | ||||
| Missing | 39 | 2 | 37 | ||
|
NCCTG N0147 (Colorectal) A randomized phase III trial of oxaliplatin (OXAL) plus 5-Fluorouracil (5-FU)/leucovorin (CF) with or without cetuximab (C225) after curative resection for patients with stage III colon cancer |
N=3,397 | N=219 | N=3,178 | ||
| T Stage, n (%) | 0.17261 | ||||
| 0 | 6 (0.2%) | 1 (0.6%) | 5 (0.2%) | ||
| 1 | 87 (3.4%) | 1 (0.6%) | 86 (3.6%) | ||
| 2 | 222 (8.7%) | 10 (6.4%) | 212 (8.9%) | ||
| 3 | 1,817 (71.6%) | 114 (72.6%) | 1,703 (71.5%) | ||
| 4 | 404 (15.9%) | 31 (19.7%) | 373 (15.7%) | ||
| I | 2 (0.1%) | 0 (0.0%) | 2 (0.1%) | ||
| Missing | 859 | 62 | 797 | ||
| Positive Nodal Involvement | 0.01722 | ||||
| N | 2,548 | 160 | 2,388 | ||
| Mean (SD) | 4.1 (3.96) | 4.6 (3.64) | 4.1 (3.98) | ||
| Median | 3.0 | 4.0 | 3.0 | ||
| Range | 0.0, 36.0 | 1.0, 16.0 | 0.0, 36.0 | ||
| Tumor Location, n (%) | 0.02991 | ||||
| Left-sided | 1,143 (46.5%) | 87 (56.9%) | 1,056 (45.8%) | ||
| Multiple | 0 (0.0%) | ||||
| Right-sided | 1,158 (47.1%) | 58 (37.9%) | 1,100 (47.7%) | ||
| Transverse | 156 (6.3%) | 8 (5.2%) | 148 (6.4%) | ||
| Missing | 940 | 66 | 874 | ||
|
ACOSOG Z6051 (Colorectal) A phase III prospective randomized trial comparing laparoscopic-assisted resection versus open resection for rectal cancer |
N=485 | N=38 | N=447 | ||
| T Stage, n (%) | 0.30621 | ||||
| 0 | 0 (0.0%) | ||||
| 1 | 94 (20.8%) | 10 (27.8%) | 84 (20.2%) | ||
| 2 | 40 (8.8%) | 1 (2.8%) | 39 (9.4%) | ||
| 3 | 133 (29.4%) | 8 (22.2%) | 125 (30.0%) | ||
| 4 | 185 (40.9%) | 17 (47.2%) | 168 (40.4%) | ||
| Missing | 33 | 2 | 31 | ||
| Positive Nodal Involvement | 0.06762 | ||||
| N | 464 | 36 | 428 | ||
| Mean (SD) | 1.0 (2.63) | 1.3 (2.68) | 0.9 (2.62) | ||
| Median | 0.0 | 0.0 | 0.0 | ||
| Range | 0.0, 27.0 | 0.0, 13.0 | 0.0, 27.0 | ||
|
CALGB 500105 (Melanoma) A prospective study of melastatin expression in predicting the risk for developing local regional metastases of primary melanoma |
N=314 | N=67 | N=247 | ||
| Stage, n (%) | 0.02061 | ||||
| 1A | 44 (14.7%) | 18 (27.3%) | 26 (11.1%) | ||
| 1B | 111 (37.0%) | 28 (42.4%) | 83 (35.5%) | ||
| 2A | 67 (22.3%) | 7 (10.6%) | 60 (25.6%) | ||
| 2B | 36 (12.0%) | 6 (9.1%) | 30 (12.8%) | ||
| 2C | 11 (3.7%) | 1 (1.5%) | 10 (4.3%) | ||
| 3A | 15 (5.0%) | 4 (6.1%) | 11 (4.7%) | ||
| 3B | 13 (4.3%) | 2 (3.0%) | 11 (4.7%) | ||
| 3C | 2 (0.7%) | 0 (0.0%) | 2 (0.9%) | ||
| 4 | 1 (0.3%) | 0 (0.0%) | 1 (0.4%) | ||
| Missing | 14 | 1 | 13 | ||
| Nodes Involved, n (%) | 0.75471 | ||||
| 0 | 231 (78.3%) | 50 (83.3%) | 181 (77.0%) | ||
| 1–3 with Macrometastasis | 10 (3.4%) | 1 (1.7%) | 9 (3.8%) | ||
| 1–3 with Micrometastasis | 51 (17.3%) | 9 (15.0%) | 42 (17.9%) | ||
| 4 or More | 2 (0.7%) | 0 (0.0%) | 2 (0.9%) | ||
| In Transit | 1 (0.3%) | 0 (0.0%) | 1 (0.4%) | ||
| Missing | 19 | 7 | 12 | ||
|
Alliance A091105 (Sarcoma) A phase III, double blind, randomized, placebo-controlled trial of sorafenib in desmoid tumors or aggressive fibromatosis (DT/DF) |
N=87 | N=50 | N=37 | ||
| Intrabdominal Disease, n (%) | 0.86051 | ||||
| No | 55 (63.2%) | 32 (64.0%) | 23 (62.2%) | ||
| Yes | 32 (36.8%) | 18 (36.0%) | 14 (37.8%) | ||
| Primary Tumor Site, n (%) | 0.64721 | ||||
| Abdominal | 29 (33.3%) | 18 (36.0%) | 11 (29.7%) | ||
| Both | 7 (8.0%) | 3 (6.0%) | 4 (10.8%) | ||
| Extraabdominal | 51 (58.6%) | 29 (58.0%) | 22 (59.5%) |
Chi-Square p-value;
Kruskal-Wallis p-value
prevention trial that enrolled pre-menopausal women without cancer
Table 4.
Disease characteristics by age (18–39 vs. ≥40): Alliance hematologic trials
| Study Number (Cancer Type) | Total | 18–39 years | 40+ years | P-value | |
|---|---|---|---|---|---|
|
CALGB 10001 (Leukemia) A phase II trial of sequential chemotherapy, imatinib mesylate (Gleevec, STI 571)(NSC #716051, IND #61135), and transplantation for adults with newly diagnosed Ph+ acute lymphoblastic leukemia by the CALGB and SWOG |
N=58 | N=23 | N=35 | ||
| Karyotype, n (%) | 0.62111 | ||||
| No | 4 (20.0%) | 2 (28.6%) | 2 (15.4%) | ||
| Unknown | 1 (5.0%) | 0 (0.0%) | 1 (7.7%) | ||
| Yes | 15 (75.0%) | 5 (71.4%) | 10 (76.9%) | ||
| Missing | 38 | 16 | 22 | ||
|
CALGB 10102 (Leukemia) A phase I/II dose escalation study of subcutaneous Campath-1H (NSC # 715969, IND # 10864) during intensification therapy in adults with untreated acute lymphoblastic leukemia (ALL) |
N=300 | N=120 | N=180 | ||
| Ph-like Genetic Profile, n (%) | 0.49211 | ||||
| No | 59 (50.9%) | 23 (47.9%) | 36 (52.9%) | ||
| Unknown | 32 (27.6%) | 16 (33.3%) | 16 (23.5%) | ||
| Yes | 25 (21.6%) | 9 (18.8%) | 16 (23.5%) | ||
| Missing | 184 | 72 | 112 | ||
| Immunophenotype, n (%) | 0.00021 | ||||
| B cell | 242 (81.8%) | 86 (72.3%) | 156 (88.1%) | ||
| Other | 8 (2.7%) | 2 (1.7%) | 6 (3.4%) | ||
| T cell | 46 (15.5%) | 31 (26.1%) | 15 (8.5%) | ||
| Missing | 4 | 1 | 3 | ||
| CNS Extramedullary Disease, n (%) | 0.89731 | ||||
| Involved | 7 (2.5%) | 3 (2.6%) | 4 (2.4%) | ||
| Not Involved | 277 (97.5%) | 112 (97.4%) | 165 (97.6%) | ||
| Unknown | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||
| Missing | 16 | 5 | 11 | ||
|
CALGB 10403 (Leukemia) An intergroup phase II clinical trial for adolescents and young adults with untreated acute lymphoblastic leukemia (ALL) |
N=314 | N=314 | N=0 | ||
| Ph-like Genetic Profile, n (%) | --- | ||||
| No | 90 (68.7%) | 90 (68.7%) | 0 (%) | ||
| Unknown | 0 (0.0%) | 0 (0.0%) | 0 (%) | ||
| Yes | 41 (31.3%) | 41 (31.3%) | 0 (%) | ||
| Missing | 183 | 183 | 0 | ||
| Immunophenotype, n (%) | --- | ||||
| B cell | 241 (77.0%) | 241 (77.0%) | 0 (%) | ||
| Other | 0 (0.0%) | 0 (0.0%) | 0 (%) | ||
| T cell | 72 (23.0%) | 72 (23.0%) | 0 (%) | ||
| Missing | 1 | 1 | 0 | ||
| CNS Extramedullary Disease, n (%) | --- | ||||
| Involved | 34 (10.9%) | 34 (10.9%) | 0 (%) | ||
| Not Involved | 270 (86.3%) | 270 (86.3%) | 0 (%) | ||
| Unknown | 9 (2.9%) | 9 (2.9%) | 0 (%) | ||
| Missing | 1 | 1 | 0 | ||
|
Aberrant CRLF2 expression, n (%) |
--- | ||||
| No | 103 (78.6%) | 103 (78.6%) | 0 (%) | ||
| Yes | 28 (21.4%) | 28 (21.4%) | 0 (%) | ||
| Missing | 183 | 183 | 0 | ||
|
CALGB 10503 (Leukemia) Phase II study of maintenance therapy with decitabine (NSC #127716, IND #50733) following standard induction and cytogenetic risk-adapted intensification in previously untreated patients with AML < 60 years |
N=548 | N=167 | N=381 | ||
| FAB Histological Sub-Type, n (%) | 0.47651 | ||||
| M0 | 34 (6.2%) | 13 (7.8%) | 21 (5.5%) | ||
| M1 | 95 (17.3%) | 25 (15.0%) | 70 (18.4%) | ||
| M2 | 124 (22.6%) | 41 (24.6%) | 83 (21.8%) | ||
| M4 | 133 (24.3%) | 45 (26.9%) | 88 (23.1%) | ||
| M5 | 82 (15.0%) | 23 (13.8%) | 59 (15.5%) | ||
| M6 | 21 (3.8%) | 3 (1.8%) | 18 (4.7%) | ||
| M7 | 2 (0.4%) | 0 (0.0%) | 2 (0.5%) | ||
| Other | 57 (10.4%) | 17 (10.2%) | 40 (10.5%) | ||
|
CALGB 10603 (Leukemia) A phase III randomized, double-blind study of induction (daunorubicin/cytarabine) and consolidation (high dose cytarabine) chemotherapy + midostaurin (PKC412) (IND #101261) or placebo in newly diagnosed patients < 60 years of age with FLT3 |
N=715 | N=191 | N=524 | ||
| FAB Histological Sub-Type, n (%) | 0.78761 | ||||
| M0 | 26 (3.9%) | 9 (5.0%) | 17 (3.5%) | ||
| M1 | 165 (24.7%) | 45 (25.1%) | 120 (24.6%) | ||
| M2 | 138 (20.7%) | 42 (23.5%) | 96 (19.7%) | ||
| M4 | 187 (28.0%) | 48 (26.8%) | 139 (28.5%) | ||
| M5 | 146 (21.9%) | 34 (19.0%) | 112 (23.0%) | ||
| M6 | 4 (0.6%) | 1 (0.6%) | 3 (0.6%) | ||
| M7 | 1 (0.1%) | 0 (0.0%) | 1 (0.2%) | ||
| Other | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||
| Missing | 48 | 12 | 36 | ||
| FLT3 Mutation Subtype, n (%) | 0.80061 | ||||
| FLT3 TKD (No ITD) | 162 (22.7%) | 40 (20.9%) | 122 (23.3%) | ||
| ITD Allelic ratio <0.7 (+/− FLT3 TKD) | 339 (47.4%) | 93 (48.7%) | 246 (46.9%) | ||
| ITD Allelic ratio =>0.7 (+/− FLT3 TKD) | 214 (29.9%) | 58 (30.4%) | 156 (29.8%) | ||
|
CALGB 19808 (Leukemia) Phase III randomized study of induction chemotherapy with or without MDR-modulation with PSC-833 (NSC # 648265, IND # 41121) followed by cytogenetic risk-adapted intensification therapy followed by immunotherapy with rIL-2 (NSC# 373364, IND # 1969) vs. observation in previously untreated patients with AML < 60 years |
N=731 | N=227 | N=504 | ||
| FAB Histological Sub-Type, n (%) | 0.59391 | ||||
| M0 | 41 (5.6%) | 14 (6.2%) | 27 (5.4%) | ||
| M1 | 136 (18.6%) | 36 (15.9%) | 100 (19.8%) | ||
| M2 | 217 (29.7%) | 74 (32.6%) | 143 (28.4%) | ||
| M4 | 122 (16.7%) | 40 (17.6%) | 82 (16.3%) | ||
| M5 | 47 (6.4%) | 14 (6.2%) | 33 (6.5%) | ||
| M6 | 26 (3.6%) | 6 (2.6%) | 20 (4.0%) | ||
| M7 | 10 (1.4%) | 1 (0.4%) | 9 (1.8%) | ||
| Other | 132 (18.1%) | 42 (18.5%) | 90 (17.9%) | ||
|
CALGB 50203 (Lymphoma) A phase II trial of doxorubicin, vinblastine, and gemcitabine (AVG) chemotherapy for non-bulky stage I and II Hodgkin lymphoma |
N=99 | N=55 | N=44 | ||
| Stage, n (%) | 0.27381 | ||||
| I | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||
| IA | 10 (10.4%) | 4 (7.4%) | 6 (14.3%) | ||
| IB | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||
| II | 86 (89.6%) | 50 (92.6%) | 36 (85.7%) | ||
| IV | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||
| Missing | 3 | 1 | 2 | ||
|
CALGB 50303 (Lymphoma) Phase III randomized study of R-CHOP vs dose-adjusted EPOCH-R with molecular profiling in untreated de novo diffuse large B-cell lymphomas |
N=523 | N=74 | N=449 | ||
| Stage, n (%) | 0.00691 | ||||
| I | 14 (2.7%) | 6 (8.3%) | 8 (1.8%) | ||
| IA | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||
| IB | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||
| II | 244 (47.6%) | 33 (45.8%) | 211 (47.8%) | ||
| IV | 255 (49.7%) | 33 (45.8%) | 222 (50.3%) | ||
| Missing | 10 | 2 | 8 | ||
| Extranodal Disease Sites, n (%) | 0.18321 | ||||
| 0 | 374 (73.2%) | 47 (64.4%) | 327 (74.7%) | ||
| 1 | 17 (3.3%) | 3 (4.1%) | 14 (3.2%) | ||
| >=2 | 120 (23.5%) | 23 (31.5%) | 97 (22.1%) | ||
| Missing | 12 | 1 | 11 | ||
|
CALGB 50604 (Lymphoma) Phase II trial of response-adapted chemotherapy based on positron emission tomography for non-bulky stage I and II Hodgkin lymphoma |
N=158 | N=117 | N=41 | ||
| Stage, n (%) | 0.11911 | ||||
| I | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||
| IA | 19 (12.2%) | 11 (9.5%) | 8 (20.0%) | ||
| IB | 4 (2.6%) | 4 (3.4%) | 0 (0.0%) | ||
| II | 133 (85.3%) | 101 (87.1%) | 32 (80.0%) | ||
| IV | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||
| Missing | 2 | 1 | 1 | ||
|
CALGB 50801 (Lymphoma) Phase II trial of response-adapted therapy based on positron emission tomography (PET) for bulky stage I and stage II classical Hodgkin lymphoma (HL) |
N=95 | N=68 | N=27 | ||
| Stage, n (%) | 0.07841 | ||||
| I | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||
| IA | 8 (8.5%) | 6 (9.0%) | 2 (7.4%) | ||
| IB | 2 (2.1%) | 0 (0.0%) | 2 (7.4%) | ||
| II | 84 (89.4%) | 61 (91.0%) | 23 (85.2%) | ||
| IV | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||
| Missing | 1 | 1 | 0 | ||
|
CALGB 59804 (Lymphoma) A phase I/II study of gemcitabine(Gemzar)/vinorelbine (Navelbine)/liposomal doxorubicin (Doxil) in relapsed/refractory Hodgkin’s disease |
N=93 | N=62 | N=31 | ||
| Stage, n (%) | --- | ||||
| I | 0 (0.0%) | 0 (%) | 0 (%) | ||
| IA | 0 (0.0%) | 0 (%) | 0 (%) | ||
| IB | 0 (0.0%) | 0 (%) | 0 (%) | ||
| II | 0 (0.0%) | 0 (%) | 0 (%) | ||
| IV | 0 (0.0%) | 0 (%) | 0 (%) | ||
| Missing | 93 | 62 | 31 |
Chi-Square p-value;
Breast
Nine of 12 breast trials enrolled patients with estrogen receptor (ER) positive (+) or negative (−) disease, with ER+ status known for the majority of patients enrolled. The proportion with ER+ breast cancer was greater in the aged ≥40 group vs AYAs in three studies: CALGB 40101 (66.8% vs. 59.6, aged 18–39, p=0.0009), CALGB 40502 (71.0%, vs. 63.6%, aged 18–39, p=0.03), and CALGB 70305 (70.2% vs. 50.0%, aged 18–39, p=0.0002). In contrast, the proportion of ER+ tumors were greater in AYA patients in ACOSOG Z1071 (73.2% vs. 58.2%, p=0.002). In other trials, there were no significant differences in ER status by age group. Similarly, no differences by age group were observed for tumor size (≥2 vs. <2 centimeters) and minimal differences for nodal involvement across trials. Differences by age group in Her2 positivity could not be conclusively evaluated given the large proportion of patients with unknown Her2 status across several trials.
Colorectal
Among colorectal trials (k=4), disease characteristics differed by age only for NCCTG N0147 where median nodal involvement was higher among AYAs vs. patients aged ≥40 (4.0 vs. 3.0, p=0.02) and AYAs were also more likely to have left-sided tumors compared to older patients (56.9% vs. 45.8%, p=0.03).
Melanoma
Stage and nodal involvement data were available for the single melanoma trial (CALGB 500105) that enrolled ≥ 20 AYA patients. Patients 18–39 enrolled in this this trial were more likely (p=0.02) to be diagnosed with Stage 1A (27.3%) or Stage 1B (42.4%) disease and less likely with Stage 2A (10.6%), Stage 2B (9.1%) and Stage 2C (1.5%) compared to patients 40 and older (Stage 1A: 11.1%; Stage 1B: 35.5%; Stage 2A: 25.6%, Stage 2B: 12.8%; Stage 2C: 4.3%). Nodal involvement did not differ by age (p=0.75) with the majority in both groups (18–39, 83.3%; ≥40, 77%) presenting with node negative disease.
Sarcoma
Among 87 sarcoma patients enrolled in Alliance A091105, similar proportions in each age group had intrabdominal disease (18–39, 36.0%; ≥40, 37.8%, p=0.86). There were no differences by age in primary tumor site (p=0.64), with 36% and 58% presenting with abdominal and extra-abdominal disease, respectively, in the 18–39 group and 29.7% and 59.5% presenting with abdominal and extra-abdominal disease, respectively, in the ≥40 group. Six percent of AYAs and 10.8% of patients aged ≥40 presented with disease at both sites.
Leukemia
Among three acute myeloid leukemia (AML) trials, there were no statistically significant differences in characteristics, including the French-American-British (FAB) histological subtype classification. Of the three ALL trials, only CALGB 10102 had evaluable age comparison data (CALGB 10403 only enrolled AYA patients and CALGB 10001 had minimal disease information available). In this study, immunophenotype differed by age (p=0.0002) with B-Cell (B-ALL) less frequent (72.3%) and T-cell (T-ALL) more frequent (26.1%) in patients aged 18–39 compared to patients ≥40 (B-ALL: 88.1%; T-ALL: 8.5%). There were no differences by age group in the proportions with extramedullary CNS disease involvement (18–39: 2.6% vs. ≥40: 2.4%, p=0.90).
Lymphoma
Staging information was available for 4 of 5 lymphoma trials that enrolled at least 20 patients. Stage distribution differed by age only for one trial CALGB 50303, which enrolled patients with diffuse large B-cell lymphoma, where AYAs were more likely to be diagnosed with Stage I disease (8.3%) and less likely to be diagnosed with Stage IV disease (45.8%) compared to patients aged ≥40 (Stage I: 1.8%; Stage IV: 50.3%, p=0.007).
Review of Trials for Age-specific Differences in Survival Outcomes
In our review of published trial results, we identified two therapeutic trials that compared disease-free and/or overall survival between AYA and older patients: NCCTG N9831 (combined analysis with NSABP B-31), which randomized women with early-stage HER2-positive breast cancer to chemotherapy with or without trastuzumab; and CALGB/SWOG 80405, which randomized patients with metastatic colorectal cancer to chemotherapy combined with cetuximab and/or bevacizumab. In N9831/NSABP B-31, the addition of trastuzumab improved disease-free survival among all ages: age ≤39 years: HR: 0.53, 95% CI 0.33–0.86; age 40–49 years: HR: 0.52, 95% CI: 0.36–0.76; age 50–59 years: HR: 0.46, 95% CI: 0.32–0.67; age ≥60 years: HR: 0.41, 95% CI: 0.24–0.68.9 In CALGB/SWOG 80405, when compared to patients age 50 years and older, there were no differences in either progression-free survival or overall survival for patients younger than 35 years (multivariable adjusted HR for progression-free survival: 1.22, 95% CI: 0.93–1.59; multivariable adjusted HR for overall survival: 1.08, 95% CI, 0.81–1.44) or patients age 35–39 (multivariable adjusted HR for progression-free survival: 0.94, 95% CI: 0.74–1.19; multivariable adjusted HR for overall survival: 0.91, 95% CI, 0.70–1.18).10
An additional seven trials reported subgroup analyses in younger patients (Supplemental Table 2), using older age cutoffs (e.g., age 50 years or 45 years) and included a breast trial (CALGB 4050311) a colorectal trial (CALGB 8070212), three CNS trials (NCCTG N017713, N027214, N087415), a leukemia trial (CALGB 1980816), and a lymphoma trial (CALGB 5030317); most did not observe any differences by age. Alliance A091105, which randomized 87 patients with desmoid tumors to sorafenib or placebo, did not evaluate survival in the subgroup of AYAs enrolled in the trial, however the median age of the study population was 37 years.18 CALGB 10403 tested a pediatric ALL treatment protocol in patients age ≤39 years and did not enroll any older patients, precluding any cross-age comparisons.19
Discussion
Our analysis revealed that from 2000–2017, patients aged 18–39 years represented 11% of patients accrued across 188 Alliance trials that enrolled over 40,000 total patients, spanning the most common AYA solid tumor and hematologic malignancies; the vast majority of AYAs (86%) enrolled in these trials were between the ages of 25 and 39 years. We observed that that the proportion of Hispanic patients enrolled was higher and White patients lower among AYAs compared to non-AYAs in breast and colorectal trials, which collectively represented over half (55%, 16/29) of trials included in our sub-cohort that compared demographic characteristics in patients 18–39 vs. ≥40 years. While many NCTN adult trials are open to patients aged 18 and older, AYA clinical trial accrual has only been comprehensively explored more recently. In an analysis of AYA clinical trial enrollment in the SWOG Cancer Research Network Group between 1996–2020, AYAs represented 8.4% of patients enrolled.20 Of note, the SWOG analysis was inclusive of all cancer types, including those uncommon in AYAs (e.g., pancreatic, myeloma, gastric, lung, bladder, prostate), included only therapeutic trials that enrolled at least 100 patients, included patients younger than 18 years, and spanned a longer enrollment period (1996–2020).20 These differences may explain the modestly lower proportion of AYAs enrolled when compared to our results. In a separate analysis of SWOG AYA (15–39 years), enrollment to therapeutic studies restricted to 2004–2013 and which excluded cancer types not commonly diagnosed in AYAs, approximately 10% of patients were AYAs which was aligned with our estimate.21
Similar to our findings, compared to patients aged 40 years and older, AYAs enrolled in SWOG trials were more likely to be Black, Asian/Pacific Islander, Native American or Hispanic (25% vs. 17.2%).20 Greater proportional representation of both Hispanic and non-White patients in AYAs compared to older patients in clinical trials is largely reflective of recent demographic trends in the United States general population, where a greater percentage of racial and ethnic minorities are younger vs. older than 45 years.22
To the best of our knowledge, differences in disease characteristics among AYA vs. older patients in clinical trial populations has not been widely explored; thus, we sought to compare select disease characteristics, including stage, tumor location and size, nodal involvement, and hormone receptor status, where this information was applicable and available. Breast cancer is the second most common AYA cancer in the United States, with only thyroid cancer more frequently diagnosed in this age demographic.23 While approximately 4–5% of new cases of invasive breast cancer are in women younger than 40 years,24, 25 AYAs represented 10% of overall accrual to breast trials in our analysis, indicating that younger women were well represented in these trials. Importantly, there are well documented differences in the breast cancers diagnosed in younger vs. older women, with younger women more likely to be diagnosed with larger size, node positive, high grade tumors and less likely to be diagnosed with luminal A tumors, the breast cancer subtype associated with the best prognosis.26 Consistent with this, the proportion of ER+ tumors were lower in AYAs compared to those aged 40 years and older in three studies that collectively enrolled over 5,500 breast cancer patients.
AYAs represented 6.2% of 10,000 patients enrolled in colorectal cancer trials. New cases in AYAs represented approximately 4% of all new colorectal cancers diagnosed in the United States in 2017, with the incidence increasing in recent years in young adults.25, 27, 28 In our analysis, disease characteristics differed by age for a single trial, NCCTG N0147, where median nodal involvement was higher among AYAs vs. patients aged ≥40 (4.0 vs. 3.0, p=0.02) and AYAs were also more likely to have left-sided tumors compared to older patients (56.9% vs. 45.8%, p=0.03), which is consistent with studies that have similarly found that younger patients (age <50 years) are less likely to present with right-sided tumors.28, 29
It is encouraging that AYA accrual to Alliance trials was comparable to or exceeded population-based, age-specific cancer prevalence estimates for most cancer types, including breast and colorectal cancer.25 Given the increasing incidence of both of these malignancies in young adults, efforts to ensure that young adults, especially those from diverse racial and ethnic backgrounds, continue to be appropriately represented should be prioritized. This should begin in the study design phase and continue through enrollment and study follow-up, with targeted efforts to offer participation to eligible patients coupled with robust retention strategies.
We found that investigators infrequently conduct AYA-specific subgroup survival analyses. While the majority of therapeutic trials included in our analysis were phase I or II, of the phase III trials identified, only two reported results that compared disease-free and/or overall survival between AYA and older patients: NCCTG N9831 and CALGB/SWOG 80405.9, 10 Recognizing that analyses may be underpowered due to the small number of AYAs that enroll even in large phase III trials, when possible, studies should be designed to allow for the evaluation of the potential for a differential effect in AYAs, further informing expected clinical outcomes in this population. Additionally, the small number of non-therapeutic trials included in this analysis highlights the need to develop more supportive care trials, particularly given the psychosocial and survivorship concerns that are often priorities for AYAs (e.g., fertility, genetics, long-term surveillance for late effects of treatment). This is a recognized gap and efforts are underway across the NCTN and the NCI Community Oncology Research Program (NCORP) to promote development of supportive care trials for AYAs.30
Our analysis has several limitations. As noted above, we chose to restrict the current analysis to closed CALGB/ACOSOG/NCCTG/Alliance sponsored trials, excluding ongoing trials, resulting in an underestimate of actual annual accrual in more recent years. Additionally, small numbers precluded meaningful evaluation of clinical and demographic characteristics in the vast majority studies since subgroups would be too small. It is also important to note that some trials, due to disease biology and/or the design of the trial, will have selected for older vs. younger patients. For example, CALGB 10001 and 10701 enrolled individuals with Ph+ acute lymphoblastic leukemia (ALL), which is much more common in older adults. Additionally, racial and ethnic minority accrual for certain trials may reflect the underlying disease biology in select populations.
While the focus of the current analysis was on patient-level characteristics among the most common AYA cancer types, it is important to consider other factors may impact trial accrual, most notably where AYA patients receive their care. Recent data indicate lower AYA accrual at community oncology practices, which is concerning given that most AYAs are treated in non-academic/non-urban settings.21, 31 Identifying systems-level barriers to enrollment is critical to implementing strategies to improve AYA accrual at the site level. Ongoing initiatives to address some of these barriers include the Children’s Oncology Group’s (COG) AYA Responsible Investigator Network, an effort to promote AYA trial enrollment that includes designating champions at study sites,30 and the revitalization of the NCTN-NCORP AYA Working Group, which was formed to bring key stakeholders from the NCI and the cooperative groups to foster an AYA-focused research agenda.
Results from our study, in combination with the recent SWOG analyses, indicate AYA representation in NCTN clinical trials is aligned with or exceeds population prevalence estimates for most cancer types. Continued collaboration across the NCTN, including coordinated efforts involving the COG and the adult cooperative groups to support the development of intergroup trials may help enhance accrual to and preplanned age-specific subgroup analyses of both therapeutic and supportive care clinical trials,32 ultimately optimizing both disease and psychosocial outcomes in this vulnerable population.
Supplementary Material
Precis:
Adolescent and Young Adult (AYA) patients represented 11% of overall accrual to Alliance for Clinical Trials in Oncology trials from 2000–2017 and was comparable to or exceeded population-based, age-specific prevalence estimates for most cancer types. The small number of minority patients enrolled across ages underscores the persistent challenge of ensuring equitable access to trials, including for AYAs.
Acknowledgements:
The authors would like to acknowledge Mr. Hugh Wallace Meadows and Ms. Taylor Stein for their contributions to the study.
Funding Statement:
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under the Award Number UG1CA189823 (Alliance for Clinical Trials in Oncology NCORP Grant), U10CA180821, U10CA180882; UG1CA232760, UG1CA233180, UG1CA233327, UG1CA233331, and UG1CA233373. Dr. Rosenberg received funding from the Agency for Healthcare Research and Quality (K01HS023680). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Agency for Healthcare Research and Quality. https://acknowledgments.alliancefound.org
Footnotes
Conflicts of Interest: Dr. Galanis reports serving on the advisory board for Kaypopharm Therapeutics, Inc and Kiyatec, Inc and research funding (institutional) from Celgene, Denovo Biopharma, Medimmune, Inc. and Servier Pharmaceuticals LLC. Dr. Leonard has served as an advisor/consultant to Abbvie, Astellas, AstraZeneca, Bayer, Beigene, BMS, Calithera, Constellation, Caribou Biosciences, Eisai, Lilly, Epizyme, Genmab, Grail, Incyte, Jansssen, MEI Pharma, Merck, Mustang Bio, Novartis, Pfizer, Roche/Genentech, Seagen, Second Genome, Sutro. Dr. Meyerhardt has served as an advisor/consultant to Merck Pharmaceutical and COTA Healthcare. Dr. Ng reports institutional research funding from Pharmavite, Evergrande Group, Revolution Medicines, and Janssen; and has served on advisory boards and/or as a consultant for Bayer, GlaxoSmithKline, and Pfizer. Dr. Paskett reports research funding from Pfizer, Merck Foundation, Genentech and Guardant Health not related to this work and is an Advisory Board member for GSK. Dr. Partridge receives royalties from Elsevier for UpToDate authorship. Dr. George research funding from Tracon, Springworks, Blueprint Medicines, Theseus Pharmaceuticals, IDRX, BioAtla, Equity Abbot Laboratories, royalties from Elsevier for UpToDate authorship.
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