Key Points
Question
What is the risk of gastrointestinal malignant neoplasms after blood or marrow transplant?
Findings
In this cohort study of 6710 survivors of blood or marrow transplant, exposure to conditioning with cytarabine was associated with increased risk for colorectal cancer, and chronic graft-vs-host disease was associated with increased risk of esophageal cancer. Allogeneic blood or marrow transplant, exposure to anthracyclines prior to blood or marrow transplant, and conditioning with etoposide were associated with risk of liver cancer.
Meaning
High risk of specific gastrointestinal malignant neoplasms after blood or marrow transplant, especially in the context of specific therapeutic exposures, can inform targeted recommendations for evaluation and treatment of long-term survivors.
Abstract
Importance
Survivors of blood or marrow transplant (BMT) are at increased risk of subsequent malignant neoplasms (SMNs). Cancers of the gastrointestinal (GI) system are of special interest because their clinical behavior is often aggressive, necessitating early detection by increasing awareness of high-risk populations.
Objective
To describe the risk of SMNs in the GI tract after BMT.
Design, Setting, and Participants
A cohort study of 6710 individuals who lived at least 2 years after BMT performed between January 1, 1974, and December 31, 2014, at City of Hope, University of Minnesota, or University of Alabama at Birmingham. End of follow-up was March 23, 2020. Data analysis was performed between September 1, 2022, and September 30, 2022.
Exposures
Demographic and clinical factors; therapeutic exposures before or as part of BMT.
Main Outcomes and Measures
Development of SMNs in the GI tract after BMT. Participants self-reported SMNs in the GI tract; these were confirmed with pathology reports, medical records, or both. For deceased patients, death records were used. Standardized incidence ratios determined excess risk of SMNs in the GI tract compared with that of the general population. Fine-Gray proportional subdistribution hazard models assessed the association between risk factors and SMNs in the GI tract.
Results
The cohort of 6710 individuals included 3444 (51.3%) autologous and 3266 (48.7%) allogeneic BMT recipients. A total of 3917 individuals (58.4%) were male, and the median age at BMT was 46 years (range, 0-78 years). After 62 479 person-years of follow-up, 148 patients developed SMNs in the GI tract. The standardized incidence ratios for developing specific SMNs ranged from 2.1 for colorectal cancer (95% CI, 1.6-2.8; P < .001) to 7.8 for esophageal cancer (95% CI, 5.0-11.6; P < .001). Exposure to cytarabine for conditioning (subdistribution hazard ratio [SHR], 3.1; 95% CI, 1.5-6.6) was associated with subsequent colorectal cancer. Compared with autologous BMT recipients, allogeneic BMT recipients with chronic graft-vs-host disease were at increased risk for esophageal cancer (SHR, 9.9; 95% CI, 3.2-30.5). Conditioning with etoposide (SHR, 2.0; 95% CI, 1.1-3.5) and pre-BMT anthracycline exposure (SHR, 5.4; 95% CI, 1.3-23.4) were associated with an increased risk of liver cancer compared with no exposure to the respective agents.
Conclusions and Relevance
The findings of this cohort study are relevant for oncologists and nononcologists who care for the growing number of survivors of transplant. Awareness of subgroups of survivors of BMT at high risk for specific types of SMNs in the GI tract may influence recommendations regarding modifiable risk factors, as well as individualized screening.
This cohort study investigates demographic, clinical, and therapeutic factors associated with the risk of malignant neoplasms of the gastrointestinal tract after blood or marrow transplant.
Introduction
The population of survivors of long-term blood or marrow transplant (BMT) in the US is estimated to exceed 500 000 by 2030.1 The public health significance of long-term outcomes experienced by survivors of BMT is increasing concomitantly. Survivors of BMT are at increased risk for subsequent malignant neoplasms (SMNs); indeed, SMNs are the leading cause of nonrelapse mortality among long-term survivors.2,3,4,5,6 Previous studies have examined SMNs classified as therapy-related leukemia, solid tumors, and lymphoma, with either limited attention or limited statistical power to assess the magnitude of risk and factors associated with the individual types of SMNs.7,8,9,10 Cancers of the gastrointestinal (GI) system are of special interest because their clinical behavior is often aggressive, necessitating early detection by increasing awareness of high-risk populations. Few studies have described the risk of SMNs in the GI tract after BMT, and the number of SMNs in the GI tract in those studies is too small (eg, <20 in a cohort of >28 000 survivors) to allow meaningful evaluation.2 We used the Blood or Marrow Transplant Survivor Study (BMTSS) to conduct a comprehensive evaluation of SMNs in the GI tract after BMT and identified demographic, clinical, and therapeutic factors associated with the risk of SMNs in the GI tract.
Methods
Study Population
The BMTSS is a retrospective cohort study of patients who received an allogeneic or autologous BMT for a hematologic cancer or other life-threatening condition at City of Hope, University of Minnesota, or University of Alabama at Birmingham between January 1, 1974, and December 31, 2014, and survived at least 2 years after BMT (eMethods in the Supplement). The cohort is linked to the National Death Index Plus periodically to determine the date and cause of death; end of follow-up for the present study was March 23, 2020. Eligible patients were invited to complete the BMTSS survey, which assesses chronic health conditions (including SMNs) and sociodemographic details. The present cohort study excluded patients who underwent multiple BMTs, as well as those with a history of GI cancer before BMT. The institutional review board at the University of Alabama at Birmingham served as the single institutional review board of record. All study participants provided informed written consent. The study followed Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.
Clinical and Treatment Information
Information regarding the primary cancer and its treatment was obtained from medical records and included exposure to pre-BMT radiation and chemotherapy (alkylating agents, anthracyclines, and antimetabolites). Details of BMT conditioning (total body irradiation [TBI] and chemotherapeutic agents), donor type (autologous or allogeneic), and, among allogeneic BMT recipients, history of chronic graft-vs-host disease (cGvHD) were captured from the institutional transplant databases, medical records, or both.
Identification of SMNs in the GI Tract
Subsequent malignant neoplasms were considered to be in the GI tract if they occurred in the alimentary canal (beginning at the esophagus), pancreas, or hepatobiliary system (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes C15-C26). Participants completing the BMTSS survey self-reported a diagnosis of SMN by answering the question “At any time after your BMT, were you diagnosed with another cancer? [yes/no].” A positive response was followed by “What was the name of this illness?” “When was it diagnosed?” and “Where was this diagnosed?” Self-reported SMNs were confirmed by review of definitive pathology reports or documentation in the medical record. Subsequent malignant neoplasms occurring in BMT recipients who were deceased at the BMTSS survey were assessed by review of cause of death information from the National Death Index Plus. A mention of GI cancer on the death certificate was considered a SMN regardless of the proximate cause of death. Because the age at diagnosis of SMNs in the GI tract could not be determined among deceased patients, this was conservatively set as the day of death.
Statistical Analysis
Statistical analyses were performed with SAS, version 9.4 (SAS Institute). Data analysis was performed between September 1, 2022, and September 30, 2022. All P values and 95% CIs were 2-sided, without correction for multiple comparisons. P = .05 was considered significant, and the χ2 test (Table 1) or the Fine-Gray model was used to calculate P values. The main outcome was incident GI cancer after BMT. Death due to causes other than GI cancers was treated as a competing risk. Cumulative incidence rates for SMNs in the GI tract (taken together and by specific type) were calculated with competing risk methods and were computed based on the SAS LIFETEST procedure. Difference in cumulative incidence between groups was assessed with the Gray test. The association of demographic, clinical, and treatment variables with the risk of SMN in the GI tract was assessed with Fine-Gray proportional subdistribution hazard models, with time at risk considered from date of BMT to development of an SMN in the GI tract, last known follow-up, or death. Patients were censored at the BMTSS survey completion or date of death from causes not related to SMNs in the GI tract; patients who developed a SMN in the GI tract were also censored from further analysis. Multivariable subdistributional hazards models were constructed by first including all variables with univariable P < .15 and then performing backward elimination, retaining those variables that were significant at P ≤ .10 in the multivariable model11,12,13; sex and race and ethnicity were retained in all models. Clinical or therapeutic variables included primary cancer diagnosis, exposure to TBI (no TBI, nonmyeloablative TBI [<8 Gy], and myeloablative TBI [≥8 Gy]), chemotherapeutic agents used for conditioning, type of BMT (autologous BMT, allogeneic BMT without cGvHD, and allogeneic BMT with cGvHD), and pre-BMT exposure variables (abdominal, pelvic, or chest radiation; alkylating agents; anthracyclines; or antimetabolites). The magnitude of association was presented as the subdistribution hazard ratio (SHR) with corresponding 95% CI.
Table 1. Demographic and Treatment Characteristics of the Patient Population.
| Characteristic | Patients, No. (%) | P value | ||
|---|---|---|---|---|
| Overall (N = 6710) | Autologous (n = 3444) | Allogeneic (n = 3266) | ||
| Age at BMT, y | ||||
| Median (range) | 46 (0-78) | 53 (0-78) | 36 (0-75) | <.001 |
| ≤21 | 1190 (17.7) | 271 (7.9) | 919 (28.1) | |
| 22-45 | 2103 (31.3) | 860 (25.0) | 1243 (38.1) | |
| >45 | 3417 (50.9) | 2313 (67.2) | 1104 (33.8) | |
| Sex | ||||
| Female | 2793 (41.6) | 1403 (40.7) | 1390 (42.6) | .10 |
| Male | 3917 (58.4) | 2041 (59.3) | 1876 (57.4) | |
| Race and ethnicity | ||||
| Non-Hispanic White | 4909 (73.2) | 2540 (73.8) | 2369 (72.5) | <.001 |
| Hispanic | 878 (13.1) | 377 (10.9) | 501 (15.3) | |
| Black | 434 (6.5) | 326 (9.5) | 108 (3.3) | |
| Asian | 336 (5.0) | 131 (3.8) | 205 (6.3) | |
| Other or mixeda | 153 (2.3) | 70 (2.0) | 83 (2.5) | |
| Diagnosis | ||||
| SAA | 183 (2.7) | 1 (0.03) | 182 (5.6) | <.001 |
| HL | 486 (7.2) | 457 (13.3) | 29 (0.9) | |
| ALL | 611 (9.1) | 51 (1.5) | 560 (17.1) | |
| CML | 596 (8.9) | 61 (1.8) | 535 (16.4) | |
| PCD | 1319 (19.7) | 1271 (36.9) | 48 (1.5) | |
| AML or MDS | 1442 (21.5) | 215 (6.2) | 1227 (37.6) | |
| NHL | 1551 (23.1) | 1242 (36.1) | 309 (9.5) | |
| Otherb | 522 (7.8) | 146 (4.2) | 376 (11.5) | |
| Donor type | ||||
| Autologous | 3444 (51.3) | 3444 (100) | 0 | NA |
| Allogeneic (related) | 1985 (29.6) | 0 | 1985 (60.8) | |
| Allogeneic (unrelated) | 1281 (19.1) | 0 | 1281 (39.2) | |
| TBI dose categories | ||||
| None | 3639 (54.2) | 2447 (71.1) | 1192 (36.5) | <.001 |
| Nonmyeloablative dose (2-7.5 Gy) | 372 (5.5) | 18 (0.5) | 354 (10.8) | |
| Myeloablative dose (8-16.7 Gy) | 2128 (31.7) | 785 (22.8) | 1343 (41.1) | |
| Dose unknown | 553 (8.2) | 182 (5.3) | 371 (11.4) | |
| Missing | 18 (0.3) | 12 (0.3) | 6 (0.2) | |
| cGvHD | ||||
| Yes | NA | NA | 1820 (55.7) | NA |
| No | NA | NA | 1300 (39.8) | |
| Missing | NA | NA | 146 (4.5) | |
| Conditioning intensity | ||||
| MAC | ||||
| No TBI | 2643 (39.4) | 2377 (69.0) | 266 (8.1) | <.001 |
| TBI | 2603 (38.8) | 964 (28.0) | 1639 (50.2) | |
| Non-MAC | ||||
| No TBI | 996 (14.8) | 70 (2.0) | 926 (28.4) | |
| TBI | 450 (6.7) | 21 (0.6) | 429 (13.1) | |
| Missing | 18 (0.3) | 12 (0.3) | 6 (0.2) | |
| Conditioning chemotherapy | ||||
| Cyclophosphamide | 3733 (55.6) | 1711 (49.7) | 2022 (61.9) | .26 |
| Melphalan | 2242 (33.4) | 1653 (48.0) | 589 (18.0) | .81 |
| Fludarabine | 1106 (16.5) | 20 (0.6) | 1086 (33.3) | .05 |
| Etoposide | 2445 (36.4) | 1748 (50.8) | 697 (21.3) | .15 |
| Cytarabine | 466 (6.9) | 365 (10.6) | 101 (3.1) | <.001 |
| Busulfan | 862 (12.8) | 282 (8.2) | 580 (17.8) | .09 |
| Nitrosoureas | 945 (14.1) | 918 (26.7) | 27 (0.8) | .82 |
| Immune modulators | 889 (13.2) | 165 (4.8) | 724 (22.2) | <.001 |
| Pre-BMT therapeutic exposuresc | ||||
| Anthracycline | 3113 (66.7) | 1741 (69.4) | 1372 (63.6) | <.001 |
| Alkylator | 2218 (47.5) | 1585 (63.2) | 633 (29.3) | <.001 |
| Antimetabolite | 2110 (45.2) | 798 (31.8) | 1312 (60.8) | <.001 |
| Abdominal or pelvic radiation | 197 (4.2) | 155 (6.2) | 42 (1.9) | <.001 |
Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; BMT, blood or marrow transplant; cGvHD, chronic graft-vs-host disease; CML, chronic myeloid leukemia; HL, Hodgkin lymphoma; MAC, myeloablative conditioning; MDS, myelodysplastic syndrome; NA, not applicable; NHL, non-HL; PCD, plasma cell dyscrasias; SAA, severe aplastic anemia; TBI, total body irradiation.
“Other” was a convenience category with no further breakdown available.
Other diagnosis includes autoimmune disorders (n = 6), histiocytic disorders (n = 13), immune disorders (n = 43), inherited skin disorders (n = 15), erythrocyte disorders (n = 77), inherited disorders of metabolism (n = 142), other leukemias (n = 72), solid tumors (n = 149), and missing or unspecified (n = 5).
Pre-BMT chemotherapy was missing for 2045 patients (936 autologous and 1109 allogeneic BMT recipients).
Standardized incidence ratios (SIRs) and absolute excess risks quantified the excess risk of SMNs in the GI tract among BMT recipients compared with the general population. The person-years at risk were calculated for the BMT cohort. Age-, sex-, and race- and ethnicity-specific incidence rates of GI cancers were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program using SEER*Stat. The expected number of cases was calculated by multiplying the person-years at risk in the BMT cohort by the incidence rates for the general population. The SIR was calculated as the ratio of observed to expected cases. The 95% CI was estimated by assuming Poisson distribution for SIR, where the offset was the number of total person-years and the outcome was the number of SMNs in the GI tract. Absolute excess risks were calculated by subtracting the expected from the observed cases, dividing by the person-years of observation, and multiplying by 100 000.
Results
Study Participants
The median age of the 6710 study participants at BMT was 46 years (range, 0-78 years), 3917 were male (58.4%), and 2793 were female (41.6%). Of the 6710 participants, 336 were Asian (5.0%), 434 were Black (6.5%), 878 were Hispanic (13.1%), 4909 were non-Hispanic White (73.2%), and 153 were other (a convenience category with no further breakdown available) or mixed race and ethnicity (2.3%). Overall, 8970 patients had undergone a BMT between 1974 and 2014 and survived at least 2 years from BMT. Of these individuals, 2806 (31.3%) died; 3 deceased patients were excluded because the date of death was unavailable, yielding 2803 deceased patients in the analysis. Of the 6164 patients alive at the time of the study, 862 (14.0%) were lost to follow-up. Of the 5302 patients approached, 1395 (26.3%) refused participation, and 3907 (73.7%) completed the survey. The final cohort consisted of 6710 BMT recipients (3907 alive; 2803 deceased) (eFigure in the Supplement). As shown in eTable 1 in the Supplement, compared with nonparticipants, study participants were older at BMT, more likely to be non-Hispanic White, less likely to have received TBI, and more likely to have cGvHD.
Table 1 summarizes the demographic, disease, and exposure characteristics of the study cohort. The most common diagnoses for the 6710 patients were non-Hodgkin lymphoma (1551 [23.1%]), acute myeloid leukemia or myelodysplastic syndrome (1442 [21.5%]), and plasma cell dyscrasias (1319 [19.7%]). The cohort included 3444 (51.3%) autologous and 3266 (48.7%) allogeneic BMT recipients. Total body irradiation was used as part of conditioning for 3071 participants (45.8%). Of participants with available pre-BMT therapeutic exposures (n = 4665 [69.5%]), 3113 (66.7%) had received anthracyclines, 2218 (47.5%) had received alkylating agents, and 197 (4.2%) had received abdominal or pelvic irradiation or both. The median length of follow-up from BMT to survey completion or death was 8.9 years and 5.2 years, respectively. Follow-up was longer than 10 years for 2230 patients (33.2%) and longer than 20 years for 644 patients (9.6%). The cohort contributed 62 479 person-years of follow-up; 39 108 person-years (62.6%) occurred more than 10 years after BMT.
Risk of SMNs in the GI Tract After BMT
One hundred forty-eight patients developed SMNs in the GI tract at a median of 8.9 years (range, 0.3-36.6 years) from BMT. Of the 3907 study participants who were alive, 93 (2.4%) developed SMNs in the GI tract. Of the 2803 deceased patients, 55 (2.0%) had SMNs in the GI tract. The median age at diagnosis of an SMN in the GI tract was 59.0 years (range, 20.5-82.6 years). eTable 2 in the Supplement describes the cohort characteristics by the presence or absence of SMNs in the GI tract and other competing events (death due to non-GI SMNs). The mean (SD) 30-year cumulative incidence for an SMN in the GI tract was 4.8% (0.5%) after BMT (Figure 1). The mean (SD) 30-year cumulative incidence was 5.7% (0.8%) after allogeneic BMT (Figure 2A) and 3.6% (0.6%) after autologous BMT (Figure 2B).
Figure 1. Observed and Expected Cumulative Incidence of Subsequent Malignant Neoplasm of the Gastrointestinal Tract as a Function of Follow-up Time After Blood or Marrow Transplant (BMT).
Shaded areas indicate 95% CIs.
Figure 2. Observed and Expected Cumulative Incidence of Subsequent Malignant Neoplasm of the Gastrointestinal Tract as a Function of Follow-up Time After Allogeneic Blood or Marrow Transplant (BMT) (A) and After Autologous BMT (B).
Shaded areas indicate 95% CIs.
The BMT cohort was at a 3.6-fold (95% CI, 3.0-4.2) higher risk of developing an SMN in the GI tract compared with the general population, yielding an absolute excess risk of 170.4 (95% CI, 127.3-213.5) per 100 000 person-years (eTable 3 in the Supplement). Significantly elevated risks were observed among allogeneic and autologous BMT recipients, among male and female participants, and among those exposed and unexposed to TBI.
Demographic and clinical factors associated with SMNs in the GI tract included older age at BMT (22-25 years: SHR, 3.4; 95% CI, 1.8-6.6; >45 years: SHR, 4.5; 95% CI, 2.3-8.7; reference group, ≤21 years), non-Hispanic White race (SHR, 1.6; 95% CI, 1.1-2.5; reference group, non-White race and ethnicity), allogeneic BMT (without cGvHD: SHR, 1.7; 95% CI, 1.1-2.9; with cGvHD: SHR, 2.0; 95% CI, 1.3-3.0; reference, autologous BMT), and conditioning with cytarabine (SHR, 2.1; 95% CI, 1.3-3.5) (eTable 4 in the Supplement).
Risk of Specific Types of SMNs in the GI Tract
Individual types of SMNs in the GI tract included colorectal (n = 45), liver (n = 36), pancreatic (n = 27), esophageal (n = 22), gastric (n = 11), and other (n = 7) cancers. As shown in eTable 3 in the Supplement, the risk of developing liver (SIR, 8.1; 95% CI, 5.7-11.0), esophageal (SIR, 7.8; 95% CI, 5.0-11.6), pancreatic (SIR, 4.9; 95% CI, 3.3-7.0), gastric (SIR, 3.1; 95% CI, 1.6-5.3), and colorectal (SIR, 2.1; 95% CI, 1.6-2.8) cancer was increased compared with that of the general population. Allogeneic BMT recipients experienced a significantly elevated risk of specific SMNs in the GI tract, ranging from a 22.4-fold (95% CI, 13.6-34.4) increased risk of esophageal cancer to a 3.1-fold (95% CI, 1.9-4.6) increased risk of colorectal cancer compared with the general population. Among patients exposed to myeloablative doses of TBI, the risk of specific types of SMNs in the GI tract was elevated compared with that of the general population, with SIRs ranging from 21.3 (95% CI, 13.5-31.8) for liver cancer to 5.9 (95% CI, 2.1-12.8) for gastric cancer. Among patients exposed to nonmyeloablative doses of TBI, significantly elevated SIRs were observed only for esophageal cancer (SIR, 14.1; 95% CI, 3.5-36.7) and liver cancer (SIR, 10.1; 95% CI, 2.5-26.2).
The results of multivariable models for each type of SMN in the GI tract are shown in Table 2. Conditioning with cytarabine (SHR, 3.1; 95% CI, 1.5-6.6) was associated with increased risk of colorectal cancer. Allogeneic BMT recipients with cGvHD were at a 9.9-fold (95% CI, 3.2-30.5) higher risk of esophageal cancer compared with autologous BMT recipients. Allogeneic BMT recipients were at a higher risk of liver cancer compared with autologous BMT recipients (without cGvHD: SHR, 4.6; 95% CI, 2.0-10.7; with cGvHD: SHR, 3.0; 95% CI, 1.3-6.9). In addition, exposure to etoposide for conditioning (SHR, 2.0; 95% CI, 1.1-3.5) and pre-BMT anthracyclines were associated with a higher risk of liver cancer (SHR, 5.4; 95% CI, 1.3-23.4) compared with exposure to neither of these agents.
Table 2. Multivariable Fine-Gray Subdistribution Hazard Models for Specific Types of SMNs in BMT Recipientsa.
| Type of SMN | Recipient with recent event, No. (%) | SHR (95% CI)b | P value |
|---|---|---|---|
| Colorectal cancer (n = 45) | |||
| Sex (reference: female) | |||
| Male | 29 (64.4) | 1.2 (0.6-2.2) | .57 |
| Race and ethnicity (reference: non-White) | |||
| Non-Hispanic White | 38 (84.4) | 1.9 (0.8-4.3) | .12 |
| Conditioning with cytarabine (reference: no) | |||
| Cytarabine: yes | 8 (17.8) | 3.1 (1.5-6.6) | .003 |
| Age at BMT, y (reference: ≤21) | |||
| 22-45 | 15 (33.3) | 1.8 (0.7-5.0) | .24 |
| >45 | 25 (55.6) | 2.3 (0.9-5.8) | .08 |
| Esophageal cancer (n = 22) | |||
| Sex (reference: female) | |||
| Male | 16 (72.7) | 1.7 (0.7-4.4) | .27 |
| Race and ethnicity (reference: non-White) | |||
| Non-Hispanic White | 19 (86.4) | 2.5 (0.8-8.4) | .13 |
| cGvHD (reference: autologous BMT) | |||
| Allogeneic BMT without cGvHD | 2 (9.1) | 2.3 (0.4-14.1) | .39 |
| Allogeneic BMT with cGvHD | 16 (72.7) | 9.9 (3.2-30.5) | <.001 |
| Age at BMT, y (reference: ≤21) | |||
| 22-45 | 7 (31.8) | 3.4 (0.4-31.3) | .28 |
| >45 | 14 (63.6) | 7.0 (0.8-59.7) | .07 |
| Liver cancer (n = 36) | |||
| Sex (reference: female) | |||
| Male | 22 (61.1) | 1.1 (0.6-2.2) | .74 |
| Race and ethnicity (reference: non-White) | |||
| Non-Hispanic White | 27 (75.0) | 1.3 (0.6-2.7) | .51 |
| Chronic GvHD (reference: autologous BMT) | |||
| Allogeneic BMT without cGvHD | 11 (30.6) | 4.6 (2.0-10.7) | <.001 |
| Allogeneic BMT with cGvHD | 13 (36.1) | 3.0 (1.3-6.9) | .01 |
| Etoposide: yes | 18 (50.0) | 2.0 (1.1-3.5) | .03 |
| Pre-BMT anthracyclines (reference: no) | |||
| Anthracyclines: yes | 21 (58.3) | 5.4 (1.3-23.4) | .02 |
| Age at BMT, y (reference: ≤21) | |||
| 22-45 | 20 (55.6) | 8.6 (2.1-34.7) | .003 |
| >45 | 13 (36.1) | 7.0 (1.7-29.6) | .01 |
| Pancreatic cancer (n = 27) | |||
| Sex (reference: female) | |||
| Male | 19 (70.4) | 1.6 (0.7-3.8) | .24 |
| Race and ethnicity (reference: non-White) | |||
| Non-Hispanic White | 22 (81.5) | 1.4 (0.5-3.7) | .49 |
| Conditioning with nitrosoureas (reference: no) | |||
| Nitrosoureas: yes | 6 (22.2) | 2.4 (1.0-5.9) | .06 |
| Pre-BMT anthracyclines (reference: no) | |||
| Anthracyclines: yes | 12 (44.4) | 0.4 (0.2-0.9) | .02 |
| Pre-BMT abdominal radiation (reference: no) | |||
| Abdominal: yes | 2 (7.4) | 3.3 (0.8-13.7) | .10 |
Abbreviations: BMT, blood or marrow transplant; cGvHD, chronic graft-vs-host disease; SHR, subdistributional hazard ratio; SMN, subsequent malignant neoplasm; TBI, total body irradiation.
Only variables that were retained in the multivariable analysis are shown.
Multivariable subdistributional hazards models were constructed by first including all variables with univariable P < .15 and then performing backward elimination, retaining those variables that were significant at P ≤ .01 in the multivariable model. In addition, sex and race and ethnicity were included in all multivariable analyses.
Sensitivity Analyses
Overall, 73.6% of the SMNs in the GI tract were confirmed with pathology reports, medical records, or National Death Index Plus linkage (eTable 5 in the Supplement). We performed sensitivity analyses including only the confirmed SMNs and found that the associations between demographic, clinical, and therapeutic variables and SMNs in the GI tract remained largely unchanged (Table 3; eTables 6 and 7 in the Supplement).
Table 3. Summary of Risk Factors Associated With SMNs in the GI Tract After BMT.
| Risk factor | Any SMN in GI tract (95% CI) | Colorectal cancer (95% CI) | Esophageal cancer (95% CI) | Liver cancer (95% CI) | Pancreatic cancer (95% CI) | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Alla | Confirmedb | Alla | Confirmedb | Alla | Confirmedb | Alla | Confirmedb | Alla | Confirmedb | |
| Race and ethnicity (reference: non-White) | ||||||||||
| Non-Hispanic White | 1.6 (1.1-2.5) | 1.5 (0.9-2.5) | 1.9 (0.8-4.3) | 1.6 (0.6-4.2) | 2.5 (0.8-8.4) | 2.3 (0.7-7.7) | 1.3 (0.6-2.7) | 1.2 (0.5-2.8) | 1.4 (0.5-3.7) | 1.7 (0.7-4.5) |
| Sex (reference: female) | ||||||||||
| Male | 1.3 (0.9-1.8) | 1.5 (1.0-2.2) | 1.2 (0.6-2.2) | 1.1 (0.5-2.3) | 1.7 (0.7-4.4) | 1.5 (0.6-3.9) | 1.1 (0.6-2.2) | 1.6 (0.7-3.7) | 1.6 (0.7-3.8) | 1.7 (0.7-4.5) |
| Age at BMT, y (reference: ≤21) | ||||||||||
| 22-45 | 3.4 (1.8-6.6) | 3.3 (1.5-7.1) | 1.8 (0.7-5.0) | NA | 3.4 (0.4-31.3) | 0.4 (0.0-3.5) | 8.6 (2.1-34.7) | 10.8 (1.5-76.2) | NA | NA |
| >45 | 4.5 (2.3-8.7) | 3.8 (1.7-8.5) | 2.3 (0.9-5.8) | NA | 7.0 (0.8-59.7) | 2.2 (0.9-5.7) | 7.0 (1.7-29.6) | 5.6 (0.7-44.0) | NA | NA |
| BMT type (reference: autologous BMT) | ||||||||||
| Allogeneic BMT without cGvHD | 1.7 (1.1-2.9) | 1.5 (0.8-2.7) | NA | NA | 2.3 (0.4-14.1) | 1.1 (0.1-12.0) | 4.6 (2.0-10.7) | 3.0 (1.1-8.3) | NA | NA |
| Allogeneic BMT with cGvHD | 2.0 (1.3-3.0) | 2.1 (1.3-3.3) | NA | NA | 9.9 (3.2-30.5) | 9.3 (3.0-29.0) | 3.0 (1.3-6.9) | 2.0 (0.7-5.1) | NA | NA |
| Pre-BMT therapeutic exposure | ||||||||||
| Anthracyclines | NA | 1.7 (1.0-2.9) | NA | NA | NA | NA | 5.4 (1.3-23.4) | NA | 0.4 (0.2-0.9) | NA |
| Abdominal radiation | NA | NA | NA | NA | NA | NA | NA | NA | NA | 5.2 (1.2-22.2) |
| Conditioning agents | ||||||||||
| Cytarabine | 2.1 (1.3-3.5) | 2.1 (1.2-3.8) | 3.1 (1.5-6.6) | 3.8 (1.5-9.2) | NA | NA | NA | NA | NA | NA |
| Etoposide | NA | NA | NA | NA | NA | NA | 2.0 (1.1-3.5) | 2.6 (1.3-5.4) | NA | NA |
| Nitrosoureas | NA | NA | NA | NA | NA | NA | NA | NA | 2.4 (1.0-5.9) | NA |
Abbreviations: BMT, blood or marrow transplant; cGvHD, chronic graft-vs-host disease; GI, gastrointestinal; NA, not applicable; SMN, subsequent malignant neoplasm.
All cases: confirmed with source validation plus unconfirmed.
Confirmed: only cases that were confirmed by source validation.
Discussion
In this study, we described the risk of SMNs in the GI tract after BMT and identified therapeutic exposures that are associated with increased risk. Blood or marrow transplant recipients were at a 3.6-fold higher risk for developing an SMN in the GI tract compared with the general population. The cumulative incidence for an SMN in the GI tract was 5.7% at 30 years after allogeneic BMT and 3.6% after autologous BMT. Older age at BMT, non-Hispanic White race and ethnicity, allogeneic BMT, and conditioning with cytarabine were associated with an increased risk of SMNs in the GI tract. Compared with the general population, BMT recipients were at a higher risk for developing esophageal, gastric, colorectal, liver, and pancreatic cancer. Chronic graft-vs-host disease was associated with an increased risk for esophageal cancer, and conditioning with cytarabine was associated with an increased risk of colorectal cancer.
A previous study reported 18 SMNs in the GI tract in an allogeneic BMT cohort followed for 85 583 person-years.2 In comparison, we observed 148 patients with SMNs in the GI tract after 62 479 person-years of follow-up. This difference is likely explained by the fact that the risk for solid tumors increases with time after therapeutic exposure, and one-third of our cohort had been followed up for more than 10 years compared with 7% in the previous study. Another study reported 57 SMNs in an autologous BMT cohort followed up for 28 945 person-years; this study did not examine risk factors associated with increased risk.14 Overall, our study found that BMT recipients experience a 3.6-fold excess risk of subsequent malignant neoplasms in the GI tract, which translates into 170.4 excess SMNs per 100 000 person-years compared with that of the general population.
The higher number of SMNs observed in our study allowed for a detailed analysis of individual types of SMN in the GI tract. Consistent with previous observations,2,4,15 the risk of esophageal and liver SMNs was higher than that observed in the general population; the larger number of observed cases in our cohort allowed for more precise estimates. Unlike the prior studies, ours found a higher risk of pancreatic, gastric, and colorectal cancer among BMT recipients compared with the general population.2,14,15 Similar to the previously reported association between cGvHD and post-BMT squamous cell carcinoma at multiple sites,14,16 a high risk of esophageal cancer among patients with cGvHD was observed in our study.
Exposure to TBI was of particular interest, given previous studies showing an association between TBI and post-BMT solid tumors.2,5,17,18 In the present study, the absolute excess risk of SMNs in the GI tract ranged from 199 per 100 000 person-years for patients exposed to myeloablative doses of TBI to 141.3 among those not exposed to TBI. Multivariable analyses did not find exposure to TBI to be associated with an increased risk of SMNs in the GI tract. Conversely, conditioning with cytarabine was associated with an increased risk of colorectal cancer. Cytarabine acts through inhibition of DNA polymerase, and this DNA-damaging effect could result in carcinogenesis, although, to our knowledge, there are no previous reports of this association. Our observation of the association of etoposide and anthracyclines with liver cancer is consistent with emerging evidence that these exposures are also associated with solid SMNs.19 Both etoposide and anthracyclines are known to be associated with hepatotoxicity and could explain the association between these agents and liver SMNs. Our observation of the association between abdominal radiation and pancreatic cancer, albeit based on small numbers, is consistent with previous reports of SMNs in the GI tract associated with abdominal radiation in survivors of childhood cancer treated without BMT, with the risk exceeding 5-fold for those with the exposure.20
Long-term follow-up of the large BMTSS cohort has allowed for refined estimates of the excess risk of SMNs in the GI tract after BMT and for further understanding about individual risk. These findings are relevant for not only the transplant physicians but also oncologists and nononcologists (primary care and specialists) who care for the growing number of survivors of transplant by providing evidence for intensified screening of those at high risk. Recommendations to screen for other SMNs in the GI tract are not well developed. Awareness of subgroups of survivors of BMT at high risk for specific types of SMNs in the GI tract sensitizes the health care professionals to perform appropriate tests to make correct diagnoses, thus preventing delays, and may influence recommendations regarding modifiable risk factors (eg, smoking, alcohol consumption, and obesity), as well as individualized screening. Current screening recommendations for colorectal cancer in survivors of BMT follow the US Preventive Services Task Force guidelines for the general population.21 Our study provides evidence for modifying recommendations for individuals exposed to cytarabine for conditioning. Screening for esophageal cancer is not typically recommended in the United States, but screening programs need to be examined, particularly for populations at high risk, such as those who developed cGvHD. Endoscopy every 5 years may be a reasonable preventive strategy among survivors of allogeneic BMT, particularly those with a history of cGvHD.22 Health care professionals should be aware of the increased incidence of liver cancer after allogeneic BMT, particularly among patients with prior anthracycline and etoposide exposure.23,24 The association between pre-BMT abdominal radiation and pancreatic cancer indicates the need for a high index of suspicion for this cancer with a high case fatality rate.
Strengths and Limitations
This study needs to be placed in the context of its limitations. The BMTSS relies on self-report of SMNs. Although the self-reported SMNs were largely confirmed by review of pathology reports or medical record review, the primary vulnerability stems from the fact that some SMNs may not be captured (if not reported by study participants), and the results of this study may underestimate the true incidence. For patients who were deceased at the time of BMTSS, the assessment for SMNs was performed with death records. The date of SMN was conservatively set as the date of death, which could also lead to an underestimation of the true incidence of SMNs in the GI tract after BMT. Including all deceased patients and 63% of eligible patients who were alive has the potential for overestimating factors that may lead to death; however, the prevalence of SMNs in the GI tract in the alive and deceased cohorts was comparable. We captured pretreatment exposures, but some information, such as cumulative chemotherapy doses or lines of therapy, was not available. Exposure to radiation and anthracyclines is associated with SMNs in a non-BMT setting.19,20,25,26 Comparing the association of these exposures with the incidence of SMNs in the BMT population vs non-BMT populations is challenging because of differences in the clinical characteristics of the populations receiving or not receiving transplant, but it is an important future direction. Characterizing the clinical course of SMNs in the GI tract among survivors of BMT also requires further study. Finally, certain factors that could be associated with risk of an SMN in the GI tract (eg, genetic predisposition, diet, and viral infections) were not captured. Further work is needed to better understand the interaction between baseline predisposition to GI cancer and exposures before and during BMT.
Conclusions
This cohort study provides evidence that survivors of BMT are at increased risk for developing SMNs in the GI tract in the setting of specific pre-BMT and BMT-related therapeutic exposures and cGvHD, providing a framework for personalizing the follow-up and treatment of those at highest risk.
eMethods. BMT Survivor Study (BMTSS)
eTable 1. Characteristics of Participants and Nonparticipants
eTable 2. Prevalence of Cohort Characteristics by the Presence or Absence of Gastrointestinal Subsequent Malignant Neoplasms
eTable 3. Standardized Incidence Ratios for Subsequent Malignant Neoplasm of the GI Tract After BMT
eTable 4. Multivariable Fine-Gray Subdistribution Hazard Models for GI SMNs After BMT
eTable 5. Prevalence of Confirmed Cases of GI SMNs After BMT
eTable 6. Multivariable Fine-Gray Subdistribution Hazard Models for Confirmed GI SMNs in BMT Recipients
eTable 7. Multivariable Fine-Gray Subdistribution Hazard Models for Confirmed Specific GI SMNs in BMT Recipients
eFigure. CONSORT Diagram of Inclusion in Study Cohort
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods. BMT Survivor Study (BMTSS)
eTable 1. Characteristics of Participants and Nonparticipants
eTable 2. Prevalence of Cohort Characteristics by the Presence or Absence of Gastrointestinal Subsequent Malignant Neoplasms
eTable 3. Standardized Incidence Ratios for Subsequent Malignant Neoplasm of the GI Tract After BMT
eTable 4. Multivariable Fine-Gray Subdistribution Hazard Models for GI SMNs After BMT
eTable 5. Prevalence of Confirmed Cases of GI SMNs After BMT
eTable 6. Multivariable Fine-Gray Subdistribution Hazard Models for Confirmed GI SMNs in BMT Recipients
eTable 7. Multivariable Fine-Gray Subdistribution Hazard Models for Confirmed Specific GI SMNs in BMT Recipients
eFigure. CONSORT Diagram of Inclusion in Study Cohort
