Abstract
Background:
The prevalence and associated psychosocial morbidity of late-onset anorectal disease after surgery and radiotherapy for treatment of childhood cancer is not known.
Methods:
A total of 25,530 survivors diagnosed between 1970–1999 (median age at cancer diagnosis, 6.1 years; age at survey, 30.2) and 5,036 siblings were evaluated for late-onset anorectal disease, defined as self-reported fistula-in-ano, self-reported anorectal stricture, or pathology- or medical record-confirmed anorectal subsequent malignant neoplasm (SMN) 5 or more years after primary cancer diagnosis. Piecewise exponential models compared the survivors and siblings and examined associations between cancer treatments and late-onset anorectal disease. Multiple logistic regression with generalized estimating equations evaluated associations between late-onset anorectal disease and emotional distress, as defined by the Brief Symptom Inventory-18 (BSI-18), and Health Related Quality of Life, using the 36-item Short Form Health Survey (SF-36).
Results:
By 45 years after diagnosis, 394 survivors (fistula, n=291; stricture, n=116; anorectal SMN, n=26) and 84 siblings (fistula, n=73; stricture, n=23; anorectal neoplasm, n=1) developed late-onset anorectal disease (adjusted rate ratio [RR]=1.2 for survivors vs. siblings, 95% CI=1.0–1.5). Among survivors, pelvic radiotherapy ≥30 Gy within five years of cancer diagnosis was associated with late-onset anorectal disease (30–49.9 Gy vs. none, adjusted RR=1.6, 95% CI=1.1–2.3; ≥50 Gy vs. none, adjusted RR=5.4, 95% CI=3.1–9.2). Late-onset anorectal disease was associated with psychosocial impairment in all BSI-18 and SF-36 domains.
Conclusions:
Late-onset anorectal disease was more common among childhood cancer survivors who received higher doses of pelvic radiotherapy and was associated with substantial psychosocial morbidity.
Keywords: Anal / Rectal fistula, Anal / Rectal stricture, Second primary neoplasms, Survivorship, Psychosocial factors
PRÉCIS / CONDENSED ABSTRACT
Late-onset anorectal disease in survivors of childhood cancer was more common among survivors with a history of higher dose pelvic radiotherapy. Those survivors who developed anorectal disease had significant psychosocial morbidity, in comparison to survivors who did not.
INTRODUCTION
Among children diagnosed with cancer, mortality has decreased in the past decades with advancements in multimodal therapies.1 Five-year mortality exceeded 70% in 1960 and has fallen below 20% in recent years,2,3 such that the population of survivors of childhood cancer in the United States is expected to exceed 500,000 by 2020.3,4 One consequence of this remarkable improvement in survival is that a high proportion of childhood cancer survivors live to develop chronic health conditions, often as long-term complications of early cancer treatments.5 Among childhood cancer survivors, it has been shown that, over the past decades, the modification of treatment regimens to reduce toxicity has led to a reduction in chronic health conditions,4 thereby underlining the importance of identifying patterns in treatment factors and late effects.
One group of medical conditions that is common in the general population and may contribute to substantial economic and psychosocial hardship is anorectal disease.6,7 Due to sequelae of early cancer treatments, it is possible that childhood cancer survivors have higher than average risk of these conditions. For example, one potential mechanism could include pelvic radiotherapy resulting in intestinal damage secondary to chronic ischemia and fibrosis leading to stenosis, fissure, ulceration and fistula formation.8,9 Likewise, the known association between radiotherapy and gastrointestinal malignancy, which may extend to anorectal malignancy.10 Finally, abdominal operations for local control of primary malignancy have the potential to cause stricture and bowel obstruction.11,12 However, it is not known whether anorectal disease, including fistula-in-ano, anorectal stricture, and anorectal subsequent malignant neoplasms (SMN) develop at a higher rate as a result of late effects of multimodal cancer therapies.
Chronic symptoms from conditions such as fistula-in-ano and stricture have the potential to substantially impair quality of life.13 Furthermore, while less frequent compared with benign anorectal conditions, anorectal malignancies necessitate expedited multimodal treatment and can be associated with substantial morbidity and mortality in addition to the above symptoms. For these reasons, the Childhood Cancer Survivor Study (CCSS) provides a unique opportunity to evaluate the incidence of late anorectal disease in childhood cancer survivors, and assess the impact of this outcome on quality of life.
METHODS
Population
We included 25,530 childhood cancer survivors and 5,036 siblings who participated in the CCSS, a retrospective cohort with longitudinal follow-up of survivors who were diagnosed with cancer prior to age 21 between January 1, 1970 and December 31, 1999, survived until five years from diagnosis, and were treated at one of 32 institutions in North America. Primary cancer diagnoses included leukemia, lymphoma, neuroblastoma, nephroblastoma, bone/soft tissue sarcoma, and central nervous system (CNS) tumors. Nearest-age siblings of a randomly-selected subset of survivors were recruited to participate in the CCSS as a comparison group. The calendar date of last follow-up was November 30, 2016. Further details of the CCSS methodology have been previously published.14–16
Outcome measures
The primary outcome was late-onset anorectal disease occurring five or more years after cancer diagnosis, defined as one of the following: 1) self-reported benign anorectal disease, defined as survivors having been told by a physician that they had fistula-in-ano or anorectal stricture or 2) detection of an anorectal SMN, as confirmed by review of pathology reports, medical records, or both. Anorectal SMNs were defined as malignancies arising from the gastrointestinal tract between the rectosigmoid junction and anus, excluding perianal skin lesions, categorized using International Classification of Diseases for Oncology (ICD-O-3) topographical and morphological codes. Subsequent malignancies for survivors and primary malignancies for siblings were ascertained and validated by the same mechanism. Survivors who developed anorectal disease less than 5 years after cancer diagnosis (n=127) or siblings who developed anorectal disease less than 5 years after their counterpart survivor’s diagnosis (n=18), were excluded.
Emotional distress was measured by the Brief Symptom Inventory-18 (BSI-18), which evaluates the following domains, each with six items: depression, anxiety, and somatization.17 Participants completed the BSI-18 at up to four time points (Baseline, 2003, 2007, and 2014 surveys) for survivors diagnosed 1970–1986 and up to two time points (Baseline and 2014 surveys) for survivors diagnosed 1987–1999. Participants <18 years of age and survivors for whom BSI-18 was answered by a proxy were excluded from this analysis. Health Related Quality of Life (HRQOL) was measured by the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), which evaluated the following domains based on participants’ experience in the past 4 weeks: physical functioning, role limitations due to physical health problems, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health.18 Participants diagnosed 1970–1986 completed the SF-36 at up to two time points (2003 and 2014 surveys) and those diagnosed 1987–1999 at one time point (2014 survey).
Treatment exposures
Treatment-related exposures included anthracycline dose (0, <250, or ≥250 mg/m2), cumulative cisplatin-equivalent doses (None, 1–499, 500–749, ≥750 mg; with cumulative dose of carboplatin weighted by 0.25),19 and pelvic radiotherapy (maximum tumor dose [maxTD]; none, indirect stray dose (including low indirect stray and high indirect stray dose), direct 0.1–29.9, 30–49.9, or ≥50 Gy). Cranial radiotherapy (none, indirect stray dose, 0.1–19.9 Gy maxTD, or ≥20 Gy maxTD) was included in the analysis of psychosocial outcomes.20 If an individual received pelvic or cranial directed fields, the maxTD to either the pelvis or brain was taken as the total prescribed dose from all overlapping pelvic or cranial radiotherapy fields, respectively. If there were no direct pelvic (or cranial) fields, but adjacent or distant sites were irradiated, the pelvis (or brain) was classified as having received only indirect stray dose (from scatter and leakage radiation).
Statistical analysis
When a participant reported developing the primary outcome without age at its occurrence (n=114), we utilized a methodology of multiple imputation specifically tailored to such situations21 so that the reporting of the outcome occurrence was properly accounted for. Specifically, 10 imputed datasets were created using a model to predict age of the outcome occurrence with a parameter-vector of values drawn from its posterior distribution. Subsequently all analyses were performed using each of the 10 datasets. The final analysis results were derived by combining the 10 analysis results using Rubin’s rules.22
Descriptive statistics were reported for survivors and siblings with and without the primary outcome. Cumulative incidence of late-onset anorectal disease was calculated and compared between survivors and siblings, taking death and non-anorectal SMN as competing risk events. Follow-up time began with time of entry into the cohort (i.e., 5 years after childhood cancer diagnosis); for the siblings, their corresponding survivors’ cohort entry dates were used. Follow-up ended at the earliest of late anorectal disease, death, or latest questionnaire date. Piecewise exponential models (incorporating duration of follow-up) were used to estimate the cause-specific adjusted rate ratio (RR) of late anorectal disease between survivors and siblings adjusting for attained age as natural cubic splines, sex, race/ethnicity, and body mass index, accounting for potential within-family correlation using generalized estimating equations.23,24
Among survivors, the exposures potentially associated with late anorectal disease (i.e., pelvic radiotherapy and platinum dose) were evaluated using the same model, additionally adjusting for decade of diagnosis, and history of smoking.
Standardized incidence ratios were calculated for anorectal SMNs among childhood cancer survivors, where age-, sex-, and calendar-year-specific U.S. cancer incidence rates of anorectal malignancies were obtained from the most recent installment of the Surveillance, Epidemiology, and End Results (SEER) database25 and used as reference rates.
Using the SF-36 (n=14,747) and the BSI-18 (n=20,405) instruments, psychosocial impairment was compared between survivors who did and did not report late anorectal disease occurring prior to completing the instruments. Psychosocial outcomes were dichotomized into impaired vs. not impaired using thresholds set at the population norm highest 10th percentile (T-score ≥63) values for the BSI-18 and the lowest 16th percentile (T-score <40) for the SF-36. Multivariable logistic regressions were used to estimate the association between time-varying late anorectal disease and time-varying psychosocial impairment longitudinally, with generalized estimating equations to account for repeated measurement, adjusted for age at evaluation as cubic splines, sex, race/ethnicity, highest attained education, household income, BMI, age at cancer diagnosis, pelvic radiotherapy, and cranial radiotherapy. Statistical analyses were conducted with R Statistical Software (version 3.5.1) and SAS Version 9.4 (SAS Institute, Cary, NC).
RESULTS
Among 25,530 survivors the median age at cancer diagnosis was 6.1 years (interquartile range [IQR], 3.0–12.4) years and median follow-up time from diagnosis was 22.5 (IQR 17.4–28.9) years. The median attained age of survivors and siblings was 30.2 (IQR 23.8–37.7) and 35.9 (IQR 27.7–44.3, Table 1), respectively. Female participants comprised 46% of survivors.
Table 1.
Characteristics of survivors of childhood cancer and siblings with and without late-onset anorectal disease
| Survivors | Siblings | |||
|---|---|---|---|---|
| Characteristic | Late-onset Anorectal Disease N=394 | No Late-onset Anorectal Disease N=25,136 | Late-onset Anorectal Disease N=84 | No Late-onset Anorectal Disease N=4,952 |
| Female | 216 (54) | 11654 (46) | 59 (70) | 2576 (52) |
| Race/Ethnicity | ||||
| Non-Hispanic white | 347 (88) | 20359 (80) | 80 (95) | 4387 (89) |
| Non-Hispanic black | 14 (4) | 1607 (6) | 0 (0) | 153 (3) |
| Hispanic | 20 (5) | 2009 (9) | 3 (4) | 231 (5) |
| Other | 13 (3) | 1161 (5) | 1 (1) | 181 (4) |
| Education (highest attained) | ||||
| ≤ High school | 79 (19) | 7609 (31) | 2 (2) | 908 (18) |
| >High school | 313 (81) | 17094 (68) | 82 (98) | 3905 (81) |
| Household income, $ | ||||
| <20,000 | 66 (18) | 3138 (14) | 5 (6) | 318 (7) |
| 20,000–39,999 | 41 (12) | 3639 (16) | 5 (6) | 506 (11) |
| 40,000–59,999 | 52 (14) | 3532 (16) | 11 (13) | 646 (14) |
| ≥60,000 | 225 (57) | 12747 (54) | 63 (75) | 3213 (69) |
| Body mass index, kg/m2 | ||||
| <18.5 | 23 (6) | 1546 (6) | 0 (0) | 162 (3) |
| 18.5–24.9 | 145 (38) | 10340 (42) | 34 (40) | 2024 (41) |
| 25–29.9 | 114 (28) | 6961 (28) | 28 (34) | 1511 (31) |
| ≥30 | 110 (29) | 5491 (23) | 22 (26) | 1200 (25) |
| Lack of health insurance | 28 (8) | 2846 (13) | 2 (2) | 466 (9) |
| Ever smoked | 150 (37) | 7857 (32) | 34 (40) | 2041 (42) |
| Age at last contact or death, years | 38.4 (31.8–46.6) | 30.1 (23.6–37.6) | 46.2 (37.2–52.4) | 35.8 (27.5–44.1) |
| Primary cancer diagnosis | ||||
| Leukemia | 111 (34) | 7728 (40) | ||
| Central nervous system tumor | 53 (12) | 4424 (15) | ||
| Hodgkin lymphoma | 84 (20) | 3002 (10) | ||
| Non-Hodgkin lymphoma | 31 (7) | 2078 (7) | ||
| Wilms tumor | 19 (5) | 2250 (8) | ||
| Neuroblastoma | 18 (4) | 1922 (7) | ||
| Soft tissue sarcoma | 37 (9) | 1687 (6) | ||
| Bone cancer | 41 (10) | 2045 (7) | ||
| Age at cancer diagnosis, years | ||||
| 0–3 | 88 (25) | 8199 (35) | ||
| 4–9 | 110 (29) | 7508 (32) | ||
| 10–14 | 103 (25) | 5312 (19) | ||
| 15–20 | 93 (22) | 4117 (14) | ||
| Year of diagnosis | ||||
| 1970–1979 | 151 (35) | 6413 (22) | ||
| 1980–1989 | 183 (47) | 9806 (37) | ||
| 1990–1999 | 60 (18) | 8917 (41) | ||
| Any chemotherapy | 302 (83) | 18732 (84) | ||
| Platinum dose, mg/m2 | ||||
| None | 346 (94) | 20302 (91) | ||
| 1–499 | 12 (3) | 1381 (5) | ||
| 500–749 | 8 (2) | 576 (2) | ||
| ≥750 | 6 (2) | 479 (2) | ||
| Pelvic radiotherapy | ||||
| None | 129 (38) | 10270 (50) | ||
| Indirect stray dose | 139 (37) | 7839 (32) | ||
| Direct RT | ||||
| 0.1–29.9 Gy | 36 (10) | 2496 (11) | ||
| 30.0–49.9 Gy | 43 (11) | 1591 (6) | ||
| ≥50.0 Gy | 17 (4) | 241 (1) | ||
| Cranial radiotherapy, Gy | ||||
| None | 129 (38) | 10270 (50) | ||
| Indirect stray dose | 141 (36) | 5604 (22) | ||
| Direct RT | ||||
| 0.1 to 19.9 Gy | 28 (10) | 2122 (10) | ||
| ≥20.0 Gy | 64 (16) | 4425 (18) | ||
| Follow-up time since diagnosis, years | 30.1 (24.5–35.0) | 22.4 (17.4–28.8) | ||
Reported as number (%) or median (interquartile range). CED, cyclophosphamide equivalent dose; LAD, late anorectal disease
For time-dependent variables, the frequency and % are based on the time at the last contact. Analyses, including reported percentages, were weighted to account for undersampling of ALL survivors in the latter recruitment era (1987–1999), with a weight of 1.21 for ALL age 0 or 11–20 at diagnosis, and a weight of 3.63 for those age 1–10. Income was adjusted to 2016 dollars with inflation rate 3% annually.
Of 394 survivors who developed late anorectal disease, 74% (n=291) had fistula-in-ano, 19% (n=116) had anorectal stricture, and 7% (n=26) had anorectal SMN (Table 2). The median age at diagnosis of anorectal disease was 27 (range 6–63) years. The 40-year cumulative incidence of late anorectal disease among survivors was 2.7% (95% CI=2.4–3.1). Of 84 siblings with anorectal disease, 87% (n=73) had fistula-in-ano, 27% (n=23) had anorectal stricture, and 1% (n=1) developed anorectal primary cancer. The median age at diagnosis for siblings was 30 (range 9–50) years. The 40-year cumulative incidence of late anorectal disease among siblings was 2.7 (95% CI=1.9–3.5). Compared with siblings, survivors had a 1.2-fold higher rate of late-onset anorectal disease (95% confidence interval [CI]=0.95–1.5).
Table 2.
Cumulative incidence of late-onset anorectal disease at 40 years from diagnosis among survivors of childhood cancer, and by specific treatment exposures
| Numbera | Cumulative incidence (%) at 40 years after diagnosis (95% confidence interval) | Median (range) age at LAD, years | Numbera | Cumulative incidence (%) at 40 years after diagnosis (95% confidence interval) | Median (range) age at LAD, years | Numbera | Cumulative incidence (%) at 40 years after diagnosis (95% confidence interval) | Median (range) age at LAD, years | |
|---|---|---|---|---|---|---|---|---|---|
| All survivors | Survivors treated with 30–49.9 Gy pelvic radiotherapy | Survivors treated with ≥50 Gy pelvic radiotherapy | |||||||
| Any LAD | 394 | 2.7 (2.4 – 3.1) | 27 (6–63) | 42 | 3.9 (2.5 – 5.2) | 30 (13–63) | 17 | 9.7 (4.8 – 14.7) | 26 (12–45) |
| Benign LAD | |||||||||
| Fistula-in-ano | 291 | 2.1 (1.8 – 2.4) | 28 (6–57) | 29 | 2.8 (1.6 – 4.0) | 32 (18–57) | 6 | 3.0 (0.6 – 5.4) | 27 (22–35) |
| Stricture | 116 | 0.8 (0.6 – 1.0) | 26 (7–56) | 11 | 1.0 (0.3 – 1.6) | 28 (13–41) | 13 | 8.8 (3.0 – 14.5) | 26 (12–45) |
| Anorectal SMN | 26 | 0.2 (0.1 – 0.3) | 33 (17–63) | 6 | 0.4 (0.0 – 0.8) | 29 (23–63) | 2 | 1.5 (0.0 – 3.8) | 38 (32–45) |
LAD, late anorectal disease; SMN, subsequent malignant neoplasm
Numbers sum to >100% due to potential for a given individual to have more than one type of event.
Among the 26 survivors who developed anorectal SMN, SMN types included adenocarcinoma (n=19), epithelial carcinoma (n=2), non-Hodgkin lymphoma (n=2), neuroendocrine carcinoma (n=1), and unspecified (n=2), as reported in Supplementary Table 1. Among 22 survivors with available radiotherapy treatment information, nine (41%) survivors who developed anorectal SMN had radiotherapy directed to the pelvis, 8 (36%) had indirect stray dose to the pelvis from adjacent or distant sites, and 5 (23%) did not receive radiotherapy. Among those who received radiotherapy directed to the pelvis, the median dose was 44 Gy and ranged from 21 to 55 Gy. The standardized incidence ratios of anorectal SMN among survivors was 3.0 (95% CI=2.0–4.4; Supplementary Table 2).
For survivors who underwent treatment with no pelvic radiotherapy, no direct pelvic radiotherapy (scatter only), 0.1–29.9 Gy direct pelvic radiotherapy, 30–49.9 Gy direct pelvic radiotherapy, and ≥50 Gy direct pelvic radiotherapy, the 40-year cumulative incidence of late-onset anorectal disease was 2.7% (95% CI=2.0–3.4%), 2.5% (2.0–3.0%), 2.7% (1.5–3.9%), 3.9% (95% CI=2.5–5.2%), and 9.7% (95% CI=4.8–14.7), respectively (Figure 1). Among survivors, treatment with pelvic radiotherapy 30–49.9 Gy (reference none, adjusted RR=1.6, 95% CI=1.1–2.3) or ≥50 Gy (reference none, adjusted RR=5.4, 95% CI=3.1–9.2) were independently associated with late-onset anorectal disease (Table 3). Female sex was associated with a 1.2-fold increased rate (95% CI=1.0–1.6) of late anorectal disease.
Figure 1.
Cumulative incidence of late anorectal disease, based on treatment with RT to the pelvis. For participants with a history of no pelvic RT, no direct pelvic RT (scatter only), 0.1 to 29 Gy of direct pelvic RT, 30 to 49 Gy of direct pelvic RT, and ≥50 Gy of direct pelvic RT, the 40-year cumulative incidence of late-onset anorectal disease was 2.7% (95% CI, 2.0%–3.4%), 2.5% (95% CI, 2.0%–3.0%), 2.7% (95% CI, 1.5%–3.9%), 3.9% (95% CI, 2.5%–5.2%), and 9.7% (95% CI, 4.8%–14.7), respectively. CI indicates confidence interval; RT, radiotherapy.
Table 3.
Risk factors for late-onset anorectal disease among survivors of childhood cancer
| Rate ratioa | 95% confidence interval | |
|---|---|---|
| Female (vs. male) | 1.2 | 1.0 – 1.6 |
| Race/Ethnicity | ||
| Non-Hispanic white | Ref. | - |
| Non-Hispanic black | 0.7 | 0.4 – 1.6 |
| Hispanic | 0.7 | 0.4 – 1.2 |
| Other | 0.8 | 0.4 – 1.5 |
| Body mass index, kg/m2 | ||
| <18.5 | 0.8 | 0.5 – 1.4 |
| 18.5–24.9 | Ref. | - |
| 25–39.9 | 0.9 | 0.7 – 1.2 |
| ≥40 | 1.0 | 0.7 – 1.4 |
| Ever smoked | ||
| No | Ref. | - |
| Yes | 1.0 | 0.8 – 1.3 |
| Year of diagnosis | ||
| 1970–1979 | Ref. | - |
| 1980–1989 | 1.2 | 1.0 – 1.6 |
| 1990–1999 | 0.7 | 0.5 – 1.1 |
| Pelvic radiotherapy, Gy | ||
| None | Ref. | - |
| Indirect stray dose | 1.1 | 0.8 – 1.4 |
| Direct radiotherapy | ||
| 0.1–29.9 | 1.1 | 0.7 – 1.8 |
| 30.0–49.9 | 1.6 | 1.1 – 2.3 |
| ≥50.0 | 5.4 | 3.1 – 9.2 |
| Platinum dose, mg/m2 | ||
| None | Ref | |
| 1–499 | 0.8 | 0.4 – 1.5 |
| 500–749 | 1.0 | 0.5 – 2.2 |
| ≥750 | 1.7 | 0.8 – 3.9 |
Additionally adjusted for attained age as natural cubic splines.
Adjusting for age, sex, race, education, household income, body mass index, and radiotherapy exposure, survivors who developed late-onset anorectal disease were more likely to report impairment in HRQOL (physical health adjusted odds ratio [OR]=2.0, 95% CI=1.5–2.6; physical role OR=2.2, 95% CI=1.7–2.9; bodily pain OR=2.0, 95% CI=1.5–2.5; general health OR=2.1, 95% CI=1.6–2.7; vitality OR=1.7, 95% CI=1.4–2.3; emotional role OR=2.4, 95% CI=1.9–3.2, social function OR=2.1, 95% CI=1.6–2.7; and mental health OR=1.9, 95% CI=1.4–2.5) subscales, compared to those without late anorectal disease (Table 4). Similarly, survivors with late anorectal disease were significantly more likely to report symptoms of depression (OR=2.1, 95% CI=1.6–2.8), anxiety (OR=2.5, 95% CI=1.8–3.4), and somatization (OR=2.5, 95% CI=1.9–3.2) compared with those without late anorectal disease.
Table 4.
Association between late-onset anorectal disease and impaired health-related quality of life and psychological outcomes
| Measure | Odds ratioa | 95% Confidence interval |
|---|---|---|
| SF-36 physical component | ||
| Physical health | 2.0 | 1.5 – 2.6 |
| Physical role | 2.2 | 1.7 – 2.9 |
| Bodily pain | 2.0 | 1.5 – 2.5 |
| General health | 2.1 | 1.6 – 2.7 |
| Physical component (summary) | 2.3 | 1.7 – 3.0 |
| SF-36 mental component | ||
| Vitality | 1.7 | 1.4 – 2.3 |
| Emotional role | 2.4 | 1.9 – 3.2 |
| Social function | 2.1 | 1.6 – 2.7 |
| Mental health | 1.9 | 1.4 – 2.5 |
| Mental component (summary) | 1.9 | 1.5 – 2.6 |
| BSI-18 | ||
| Depression | 2.1 | 1.6 – 2.8 |
| Anxiety | 2.5 | 1.8 – 3.4 |
| Somatization | 2.5 | 1.9 – 3.2 |
| Global Status Index | 2.4 | 1.8 – 3.3 |
Adjusted for gender, race, highest attained education, household income, body mass index, age at cancer diagnosis, age at outcome evaluation as cubic splines, pelvic radiotherapy, cranial radiotherapy.
BSI-18, Brief Symptom Inventory-18; SF-36, Medical Outcomes Study 36-Item Short-Form Health Survey
DISCUSSION
In this study, we leveraged a large cohort of adult survivors of childhood cancer with longitudinal follow-up to address a knowledge gap regarding the late occurrence of anorectal disease. While the unadjusted 40-year cumulative incidence of late anorectal disease was similar among survivors and siblings (2.7% and 2.7%), the rate (accounting for censoring and adjusted for age, sex, race/ethnicity, and BMI) of late anorectal disease was slightly higher among survivors (RR=1.2, 95% CI=1.0–1.5), although not statistically significant. In particular, survivors who received ≥30 Gy pelvic radiotherapy for treatment of their primary cancer were especially at-risk. The most frequent anorectal disease reported by survivors was fistula-in-ano, followed by stricture and anorectal SMN. Survivors more frequently had anorectal strictures compared to siblings. But perhaps most importantly, occurrence of anorectal disease was found to have a detrimental impact on the well-being of survivors, as it was associated with increased emotional distress and impaired HRQOL.
Previous work by Goldsby and colleagues identified that childhood cancer survivors develop gastrointestinal complications at an elevated rate, compared with their siblings. With respect to the lower gastrointestinal tract, survivors were found to have 1.9-times the rate of developing the complication of polyps, diverticular disease, colitis, frequent constipation, chronic diarrhea, fistula or stricture, colostomy, and/or other lower intestinal trouble.26 In the present study, we focused on fistula-in-ano, anorectal stricture, and subsequent malignant neoplasms, with a goal of gaining a deeper understanding specifically of late anorectal disease among childhood cancer survivors to guide prevention, early diagnosis, and treatment.
Benign anorectal stricture has generally been studied in the post-operative setting among patients with inflammatory bowel disease, colorectal cancer, or diverticulitis. Risk factors for stenosis have been inconsistently reported, but have been posited to include radiotherapy, diverticulitis, and pelvic sepsis.27 In the present study, there was no clear association between chemotherapy within five years of cancer diagnosis and the occurrence of late-onset anorectal disease. However, higher dose radiotherapy (≥30 Gy) was significantly associated with late anorectal disease. Careful treatment strategies including sparing the rectum from radiation fields when possible may be critical in preventing late anorectal disease.28
In general, gastrointestinal complications resulting from multimodal cancer treatments are common and often substantially impact quality of life.29 However, the impact of anorectal issues on the quality of life of cancer survivors has not previously been well-defined. In a 2016 study, Owen and colleagues surveyed 146 patients from the general population (non-cancer survivors) with newly diagnosed fistula-in-ano and demonstrated reduced quality of life, compared to population norms.30 Furthermore, the impaired quality of life from benign anorectal conditions, such as fistula-in-ano, appears not to resolve over time. Among 54 patients diagnosed with fistula-in-ano in 2015–2016, Ferrer-Márquez and colleagues noted no improvement in quality of life impairment one month after a baseline survey was initially administered.31 Anorectal disease has been shown to affect quality of life in the non-cancer population through physical as well as biopsychosocial impact,31 including depression and poor self-perception.32 Finally, in a retrospective study from 2012, Polese and colleagues reported that patients who developed benign strictures following colorectal resection and anastomosis endorsed poorer quality of life at six or more months post-operatively, compared to controls.27 Thus, the current report documenting that childhood cancer survivors reported significant emotional distress and impairment in quality of life across multiple areas of physical and mental function associated with anorectal conditions suggests that consideration of treatment options and methods of symptom reduction are crucial in survivors.
Among childhood cancer survivors, anorectal SMNs were rare, with a 45-year cumulative incidence rate of <1%. Despite this, it is important to recognize that subsequent anorectal neoplasms may occur more frequently as survivors continue to age, due to late effects of ionizing radiation which is associated with increased risk for SMNs even beyond age 40.33,34 Likewise, chronic inflammation from non-healing wounds can lead to malignant transformation with the development of epithelial carcinomas or other malignancies such as lymphoma.33,35 While sarcoma and, to a lesser extent, squamous cell carcinoma are most frequently encountered in anatomic locations exposed to radiation, reports also exist of radiation-induced lymphoma and adenocarcinoma, which was the most frequently observed SMN in the present study.36 Physicians caring for cancer survivors should have a low threshold to perform a focused perianal evaluation including digital rectal examination for anorectal complaints.37 Furthermore, routine human papilloma virus vaccination should be recommended in accordance with existing guidelines by the Advisory Committee on Immunization Practices.38
There were important limitations to this study. First, the self-reported nature of the benign anorectal conditions may have led to underreporting. Furthermore, the competing risk of mortality may bias the risk of late anorectal disease as well as of the association between cancer treatment exposures and late anorectal disease. Second, terminology and diagnosis of anorectal conditions are not always straightforward, which may lead to measurement error by misclassification. Finally, although we adjusted for potential confounders in multivariable models, there is likely residual or uncontrolled confounding. However, establishing an association between late-onset anorectal disease and subsequent psychosocial morbidity should raise awareness and education about these issues for both cancer survivors and the clinicians caring for them.
In conclusion, survivors are at increased risk for late anorectal disease after pelvic radiation. For those survivors who experience late anorectal disease, there is substantial psychosocial morbidity. Clinicians who treat cancer survivors must be aware of late anorectal diseases and their impact on quality of life, which warrant conscientious treatment and symptom reduction.
Supplementary Material
Funding support:
The Childhood Cancer Survivor Study is supported by the National Cancer Institute Grant No. CA55727 (G.T. Armstrong, PI) and by Cancer Center Support (CORE) Grant No. CA21765 (C. Roberts, PI) to St. Jude Children’s Research Hospital, as well as the American Lebanese Syrian Associated Charities.
Footnotes
Conflict of interest disclosures: The authors make no disclosures
REFERENCES
- 1.Armstrong GT, Liu Q, Yasui Y, et al. Late mortality among 5-year survivors of childhood cancer: a summary from the Childhood Cancer Survivor Study. J Clin Oncol. 2009;27(14):2328–2338. doi: 10.1200/JCO.2008.21.1425 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Robison LL, Green DM, Hudson M, et al. Long-term outcomes of adult survivors of childhood cancer. Cancer. 2005;104(11 Suppl):2557–2564. doi: 10.1002/cncr.21249 [DOI] [PubMed] [Google Scholar]
- 3.Robison LL, Hudson MM. Survivors of childhood and adolescent cancer: life-long risks and responsibilities. Nat Rev Cancer. 2014;14(1):61–70. doi: 10.1038/nrc3634 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Gibson TM, Mostoufi-Moab S, Stratton KL, et al. Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970–99: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol. 2018;19(12):1590–1601. doi: 10.1016/S1470-2045(18)30537-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355(15):1572–1582. doi: 10.1056/NEJMsa060185 [DOI] [PubMed] [Google Scholar]
- 6.Santoro G, Di Falco G. Benign Anorectal Diseases: Diagnosis with Endoanal and Endorectal Ultrasound and New Treatment Options. Berlin: Springer; 2006. [Google Scholar]
- 7.Nelson RL, Abcarian H, Davis FG, Persky V. Prevalence of benign anorectal disease in a randomly selected population. Dis Colon Rectum. 1995;38(4):341–344. [DOI] [PubMed] [Google Scholar]
- 8.Do NL, Nagle D, Poylin VY. Radiation proctitis: current strategies in management. Gastroenterol Res Pract. 2011;2011:917941. doi: 10.1155/2011/917941 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Bölling T, Willich N, Ernst I. Late effects of abdominal irradiation in children: a review of the literature. Anticancer Res. 2010;30(1):227–231. [PubMed] [Google Scholar]
- 10.Henderson TO, Oeffinger KC, Whitton J, et al. Secondary gastrointestinal cancer in childhood cancer survivors: a cohort study. Ann Intern Med. 2012;156(11):757–766, W-260. doi: 10.7326/0003-4819-156-11-201206050-00002 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Kaselas C, Molinaro F, Lacreuse I, Becmeur F. Postoperative bowel obstruction after laparoscopic and open appendectomy in children: a 15-year experience. J Pediatr Surg. 2009;44(8):1581–1585. doi: 10.1016/j.jpedsurg.2008.11.049 [DOI] [PubMed] [Google Scholar]
- 12.Schlegel RD, Dehni N, Parc R, Caplin S, Tiret E. Results of reoperations in colorectal anastomotic strictures. Dis Colon Rectum. 2001;44(10):1464–1468. [DOI] [PubMed] [Google Scholar]
- 13.Sailer M, Bussen D, Debus ES, Fuchs KH, Thiede A. Quality of life in patients with benign anorectal disorders. Br J Surg. 1998;85(12):1716–1719. [DOI] [PubMed] [Google Scholar]
- 14.Leisenring WM, Mertens AC, Armstrong GT, et al. Pediatric cancer survivorship research: experience of the Childhood Cancer Survivor Study. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(14):2319–2327. doi: 10.1200/JCO.2008.21.1813 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Robison LL, Mertens AC, Boice JD, et al. Study design and cohort characteristics of the Childhood Cancer Survivor Study: a multi-institutional collaborative project. Med Pediatr Oncol. 2002;38(4):229–239. [DOI] [PubMed] [Google Scholar]
- 16.Robison LL, Armstrong GT, Boice JD, et al. The Childhood Cancer Survivor Study: a National Cancer Institute-supported resource for outcome and intervention research. J Clin Oncol. 2009;27(14):2308–2318. doi: 10.1200/JCO.2009.22.3339 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Derogatis LR. BSI 18, Brief Symptom Inventory 18: Administration, Scoring and Procedures Manual. NCS Pearson, Incorporated; 2001. https://books.google.com/books?id=MPNYHQAACAAJ. [Google Scholar]
- 18.McHorney CA, Ware JE, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care. 1993;31(3):247–263. [DOI] [PubMed] [Google Scholar]
- 19.Travis LB, Holowaty EJ, Bergfeldt K, et al. Risk of leukemia after platinum-based chemotherapy for ovarian cancer. N Engl J Med. 1999;340(5):351–357. doi: 10.1056/NEJM199902043400504 [DOI] [PubMed] [Google Scholar]
- 20.Zeltzer LK, Lu Q, Leisenring W, et al. Psychosocial outcomes and health-related quality of life in adult childhood cancer survivors: a report from the childhood cancer survivor study. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2008;17(2):435–446. doi: 10.1158/1055-9965.EPI-07-2541 [DOI] [PubMed] [Google Scholar]
- 21.Taylor JM, Muñoz A, Bass SM, Saah AJ, Chmiel JS, Kingsley LA. Estimating the distribution of times from HIV seroconversion to AIDS using multiple imputation. Multicentre AIDS Cohort Study. Stat Med. 1990;9(5):505–514. [DOI] [PubMed] [Google Scholar]
- 22.Rubin DB. Multiple Imputation for Nonresponse in Surveys. Hoboken NJ: Wiley-Interscience; 2004. [Google Scholar]
- 23.Zhou B, Fine J, Latouche A, Labopin M. Competing risks regression for clustered data. Biostat Oxf Engl. 2012;13(3):371–383. doi: 10.1093/biostatistics/kxr032 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Austin PC, Lee DS, Fine JP. Introduction to the Analysis of Survival Data in the Presence of Competing Risks. Circulation. 2016;133(6):601–609. doi: 10.1161/CIRCULATIONAHA.115.017719 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.SEER*Stat Database: Incidence - SEER 9 Regs Research Data, Nov 2017 Sub (1973–2015) <Katrina/Rita Population Adjustment> - Linked To County Attributes - Total U.S., 1969–2016 Counties. National Cancer Institute, DCCPS, Surveillance Research Program; 2018. www.seer.cancer.gov. [Google Scholar]
- 26.Goldsby R, Chen Y, Raber S, et al. Survivors of childhood cancer have increased risk of gastrointestinal complications later in life. Gastroenterology. 2011;140(5):1464–1471.e1. doi: 10.1053/j.gastro.2011.01.049 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Polese L, Vecchiato M, Frigo AC, et al. Risk factors for colorectal anastomotic stenoses and their impact on quality of life: what are the lessons to learn? Colorectal Dis Off J Assoc Coloproctology G B Irel. 2012;14(3):e124–128. doi: 10.1111/j.1463-1318.2011.02819.x [DOI] [PubMed] [Google Scholar]
- 28.Andreyev HJN. Gastrointestinal problems after pelvic radiotherapy: the past, the present and the future. Clin Oncol R Coll Radiol G B. 2007;19(10):790–799. doi: 10.1016/j.clon.2007.08.011 [DOI] [PubMed] [Google Scholar]
- 29.Gami B, Harrington K, Blake P, et al. How patients manage gastrointestinal symptoms after pelvic radiotherapy. Aliment Pharmacol Ther. 2003;18(10):987–994. [DOI] [PubMed] [Google Scholar]
- 30.Owen HA, Buchanan GN, Schizas A, Cohen R, Williams AB. Quality of life with anal fistula. Ann R Coll Surg Engl. 2016;98(5):334–338. doi: 10.1308/rcsann.2016.0136 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Ferrer-Márquez M, Espínola-Cortés N, Reina-Duarte A, Granero-Molina J, Fernández-Sola C, Hernández-Padilla JM. Design and Psychometric Evaluation of the Quality of Life in Patients With Anal Fistula Questionnaire. Dis Colon Rectum. 2017;60(10):1083–1091. doi: 10.1097/DCR.0000000000000877 [DOI] [PubMed] [Google Scholar]
- 32.Jayarajah U, Wickramasinghe DP, Samarasekera DN. Anal incontinence and quality of life following operative treatment of simple cryptoglandular fistula-in-ano: a prospective study. BMC Res Notes. 2017;10(1):572. doi: 10.1186/s13104-017-2895-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Alam M, Ratner D. Cutaneous Squamous-Cell Carcinoma. N Engl J Med. 2001;344(13):975–983. doi: 10.1056/NEJM200103293441306 [DOI] [PubMed] [Google Scholar]
- 34.Turcotte LM, Whitton JA, Friedman DL, et al. Risk of Subsequent Neoplasms During the Fifth and Sixth Decades of Life in the Childhood Cancer Survivor Study Cohort. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(31):3568–3575. doi: 10.1200/JCO.2015.60.9487 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Meaume S, Fromantin I, Teot L. Neoplastic wounds and degenerescence. J Tissue Viability. 2013;22(4):122–130. doi: 10.1016/j.jtv.2013.07.001 [DOI] [PubMed] [Google Scholar]
- 36.Malone JP, Levin RJ. Second Malignant Tumors After Treatment of Nasopharyngeal Carcinoma. Skull Base. 2002;12(2):87–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Bussières A, Bouchard A, Simonyan D, Drolet S. Family medicine residents’ training in, knowledge about, and perceptions of digital rectal examination. Can Fam Physician Med Fam Can. 2017;63(4):e232–e237. [PMC free article] [PubMed] [Google Scholar]
- 38.Kim DK, Riley LE, Hunter P. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older - United States, 2018. MMWR Morb Mortal Wkly Rep. 2018;67(5):158–160. doi: 10.15585/mmwr.mm6705e3 [DOI] [PMC free article] [PubMed] [Google Scholar]
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