Patient-reported bowel and urinary function in long-term survivors of squamous cell carcinoma of the anus treated with definitive intensity-modulated radiotherapy and concurrent chemotherapy

Abstract

Background:

Definitive radiotherapy with concurrent chemotherapy is curative for non-metastatic squamous cell carcinoma of the anus (SCCA). However, the true impact of chemoradiation on long-term functional outcomes is poorly understood due to limited follow up and patient-reported outcomes (PROs).

Methods:

We conducted a cross-sectional survey of 248 patients with SCCA treated with definitive intensity-modulated radiation (IMRT) and concurrent chemotherapy from 2010–2018 who were alive and without recurrence. PRO measures were collected, including Functional Assessment of Cancer Therapy - General (FACT-G7), Fecal Incontinence Quality of Life (FIQoL), Low Anterior Resection Syndrome (LARS), and International Consultation on Incontinence Questionnaires (ICIQ). Models were used to determine the association between demographic, tumor, treatment, and dosimetric data with PROs.

Results:

One-hundred twelve (45%) patients completed PROs. Median [IQR] time from radiation completion to survey was 51 [37–85] months. The median scores [IQR] for FACT-G7, FIQoL, and LARS were 21 [15–24], 14 [11–16], and 32 [25–37], respectively. For men, median subscores [IQR] for ICIQ voiding and incontinence subscores were 5 [2–6] and 1 [1–3]. For women, median subscores [IQR] for ICIQ voiding, incontinence, and filling were 1 [1–3], 5 [3–8], and 4 [2–5], respectively. Higher (better) FIQoL scores were associated with higher (better) FACT G7 scores (β=0.83, 95% CI 0.58, 1.09; P<0.001), and higher (worse) LARS scores were associated with lower (worse) FACT G7 scores (β=−0.22, 95% CI −0.31, −0.13; P<0.001).

A separate multivariable analysis revealed higher bowel bag D1% was associated with lower (worse) FIQoL (P=0.001) and higher (worse) LARS (P=0.003) scores. Higher bladder V40Gy was associated with increased (worse) ICIQ voiding subscore (P=0.001).

Conclusions:

Patients treated with modern chemoradiation for SCCA experience significant long-term bowel toxicities with considerable impact on quality of life. Minimizing bowel hotspots and bladder V40Gy may improve bowel and urinary function. Other interventions to reduce long-term toxicities and improve quality of life are needed.

Introduction

Definitive chemoradiation (CRT) is considered the standard of care for non-metastatic squamous cell carcinoma of the anus (SCCA). Cure rates are high, with overall survival (OS) rates approaching 80% in randomized controlled studies such as UK ACT II and RTOG 98–11 (1, 2). In order to achieve cure with definitive CRT, doses of 50–59.4 Gray (Gy) are delivered to the anal tumor plus margin, with 42–47 Gy delivered electively to the pelvic lymph nodes (3). However, these doses can cause considerable toxicity to the pelvic normal tissues, particularly with older radiation techniques. Patients treated with 3-dimensional conformal techniques on RTOG 98–11 had significant acute physician-graded toxicity: 61% G3–4 hematologic toxicities and 74% G3–4 non-hematologic toxicities (2). The standard of care has since shifted to intensity-modulated radiation therapy (IMRT) as the preferred modality in order to reduce unnecessary dose to skin, genitalia, bladder and bowel. Although physician-reported acute toxicity improved significantly on RTOG 0529 using IMRT, 21% of patients still experienced G3+ acute gastrointestinal toxicity, 2% developed G3+ acute genitourinary toxicity, and 23% experienced G3+ acute skin toxicity (4).

Comparatively fewer data exist for late toxicity after definitive treatment of SCCA. A recent systematic review of late gastrointestinal toxicity after CRT for SCCA examined 130 studies and found Grade 3 or greater (G3+) toxicity rates up to 33%, with fecal incontinence in up to 44% and diarrhea in up to 27%. The authors found that most studies reporting higher rates of late toxicities included patients largely treated with 3D conformal techniques and/or with doses of 60 Gy or higher. While G3+ late toxicities were rarely reported for patients treated with IMRT, these patients had much shorter follow up, suggesting that the true long-term rates in these studies were higher. Nevertheless, a significant correlation between late gastrointestinal toxicity and poorer quality of life (QoL) was noted, as was a correlation between use of IMRT and a decrease in late toxicities vs. 3D conformal methods (5). Long-term outcomes of patients treated with IMRT on RTOG 0529 were recently published and showed 55% of patients experienced G2 late toxicity, 16% of patients experienced G3 late toxicity and no patients experienced G4 late toxicity (6).

Unfortunately, there is poor agreement between physician-graded toxicity and patient-reported outcomes (PROs) regarding QoL in patients with SCCA (7). Additionally, few trials have long-term follow up for late toxicities and even fewer include validated PRO instruments (8). This is important since the relatively high cure rates for patients with SCCA mean that many survivors live for decades with the permanent toxicities from pelvic CRT. Increasingly, there is interest in collecting and reporting PROs to better inform patients on what they can expect in survivorship, both through retrospective analyses (9) and publications using data derived from prospective studies within the National Clinical Trials Network (10). Therefore, in this cross-sectional survey study and retrospective analysis with linked dosimetric data, we aim to: 1) characterize patient-reported bowel and urinary functional outcomes and quality of life after pelvic CRT using validated quality of life instruments, and 2) evaluate clinical and dosimetric predictors of sexual dysfunction by analyzing clinical data from a retrospective chart review as well as doses of radiation to the small bowel, bowel bag and bladder.

Methods

Following Institutional Review Board approval for this project (protocol 2020–0513), we contacted eligible patients by telephone and presented them with the option to participate in the study; interested patients provided informed consent to participate. Eligible patients completed definitive intensity-modulated radiation and concurrent chemotherapy for SCCA at a single, large tertiary cancer center between 1/1/2010 and 9/1/2018. We excluded patients who died or developed a local, regional or distant recurrence of their disease.

Survey administration.

The survey was sent to eligible patients who gave their consent to participate. A two-week reminder was sent after the date of initial contact to patients who failed to respond to the initial survey request. Patients who did not respond to the request within eight weeks of the initial request were deemed to be non-responders. REDCap, (©2013 Vanderbilt University (11)), a secure web application that allows users to administer and organize data from online surveys, was used to administer the surveys and collect survey responses. The survey was designed to be completed in 15–30 minutes, which was validated by internal pilot testing. Survey completion required patients to respond to all questions that applied to them (e.g., ICIQ-FLUTS for females, ICIQ-MLUTS for males), with the exception of free-response items, which were optional. Study participants who returned the completed surveys received a $10 Amazon gift card to acknowledge their time and effort.

Survey instruments.

All participants received the Functional Assessment of Cancer Therapy - General (7 item version; FACT-G7) survey (12), the Fecal Incontinence Quality of Life (FIQoL) instrument (13) and the Low Anterior Resection Symptoms (LARS) instrument (14–16). Male patients received the International Consultation on Incontinence Questionnaire (ICIQ) and male lower urinary tract symptoms (MLUTS) questionnaire (17), and female patients received the ICIQ female lower urinary tract symptoms (FLUTS) questionnaire (18). The FACT-G7 has been validated in an adult population of patients with cancer with a mean (standard deviation [SD]) score of 19.1 (5.5); scores range from 0 to 28, with higher scores indicating better overall health-related QoL (19). The FIQoL has been validated in an adult population of patients with rectal cancer with a median [interquartile range (IQR)] score of 13.4 [11.4–15.7]; total scores range from 4–20 with higher scores indicating better functional status or QoL. The total score is a composite of four subscale scores: lifestyle, coping/behavior, depression/self-perception and embarrassment (20). The LARS score was initially developed for patients who underwent low anterior resection but has been validated in a group of adult patients treated with definitive pelvic radiation for rectal cancer; the mean (SD) score in that population was 23.4 (11.3) (16). LARS scores range from 0–42, with higher scores indicating worse function. Scores 0–20 are defined as “no LARS”, scores 21–29 are defined as “minor LARS” and scores 30–42 are defined as “major LARS” (14, 21). The ICIQ was developed for patients with urinary dysfunction from any cause but has been validated in a cohort of adult men with prostate cancer with a mean (SD) score of 27.2 (11.5) in this population (22). For men (MLUTS), the total score ranges from 1–44 and is the sum of the voiding symptoms subscale (0–20) and the incontinence symptoms subscale (0–24) (17). For women (FLUTS) the total score ranges from 0–48 and is the sum of the voiding symptoms subscale (0–12), the incontinence symptoms subscale (0–20) and the filling symptoms subscale (0–16) (18).

Chemoradiation Details.

All patients were discussed in a multidisciplinary team comprised of surgeons, medical oncologists, radiologists, pathologists, and radiation oncologists before initiation of treatment. All patients received a flexible sigmoidoscopy and computed tomography (CT) scan of the chest abdomen and pelvis +/− positron emission tomography (PET) scans for staging. A computed tomography scan was performed in the supine, frog-legged position for treatment planning. A vaginal dilator was recommended during the simulation and daily treatment for female patients and a scrotal shelf was recommended for male patients. Among 90 women, 88 (98%) used a vaginal dilator and among 22 men, all used a scrotal shelf during the simulation and treatment. A 5 mm bolus was used at the discretion of the treating clinician, typically in thin patients with grossly visible inguinal nodal involvement; in these cases, a thermoluminescent dosimeter was used with the first 1–2 fractions to confirm if the delivered dose differed from the planned dose. Patients were instructed to come to simulation and treatment with a comfortably full bladder. Treatment was delivered using IMRT with a simultaneous integrated boost technique. Radiation dose to the primary tumor was delivered at 2 Gy per day; a total of 50 Gy for T0/T1 tumors, 54 Gy for T2 tumors, and 58 Gy for T3/T4 tumors was given. Involved lymph nodes received 50 Gy if <2cm, 54 Gy if 2–5cm and 58 Gy if >5cm. The elective pelvic dose was prescribed based on the number of fractions planned: 43 Gy in 25 fractions, 45 Gy in 27 fractions and 47 Gy in 29 fractions. The clinical target volume used a 10 mm expansion on the primary GTV, a 5mm expansion on involved nodes, and a 7 mm expansion on external and internal iliac vessels, carved out of uninvolved muscle, bone, and bowel for elective nodal treatment. A 5 mm expansion was added to each CTV to create planning target volumes (PTV). Most patients received weekly cisplatin (20mg/m² intravenously once weekly) and daily 5-fluorouracil (300mg/m²/day infused continuously on days of radiation) (23). A minority of patients were treated with mitomycin-C (10mg/m² on day 1 and day 29) in lieu of cisplatin at the discretion of the treating medical oncologist. Radiation dose constraints utilized are as follows: small bowel/duodenum maximum dose<54 Gy, V50Gy <10cc, V35Gy<150cc; bowel bag V45Gy<195cc; bladder V50Gy<30%; femoral heads V45Gy<20%; and genitalia V30Gy<20%.

Clinical and dosimetric data.

Clinical data collected from the patients’ charts included patient age, sex, smoking status, cancer stage, and treatment details. Toxicities were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 (24). Dose metrics from the original radiation treatment plans were collected, including the volume (in cubic centimeters [cc]) of the GTV and PTV as well as the dose to 1% (D1%) of the PTV, and the mean dose to the PTV. Next, the bladder, the small bowel, and the bowel bag structures were contoured by a team of four radiation oncologists (D, KLC, MKR, EBH) according to the Radiation Therapy Oncology Group Consensus Panel Atlas (25). Per consensus definitions, small bowel included the bowel loops contoured tightly. The contoured bowel bag extended to the most inferior loop of small or large bowel, or just above the anal canal, whichever was most inferior. Bowel bag contours were not allowed to overlap with GTV or CTV; however, they were not modified to exclude PTV. Sigmoid colon was included in the bowel bag, however the mesorectum and rectum were excluded. The volumes (in cc) of the small bowel and bowel bag receiving 30 Gy, 35 Gy, 40 Gy, and 45 Gy were recorded, as was the D1% of both the small bowel and bowel bag structures. The volumes of the bladder (in % of total volume) receiving 40 Gy, 45 Gy, and 50 Gy were also recorded.

Statistical Analysis.

Descriptive statistics and frequency tables were used to summarize the FACT-G7, FiQoL, LARS, ICIQ MLUTS, and ICIQ FLUTS scores. To determine if there was selection bias during the study, we compared the baseline characteristics of responders versus non-responders. Baseline characteristics were compared using t-tests for continuous variables and χ2 tests for categorical variables. Univariate linear regression models were used to determine the relationship between each numeric PRO score and potential risk factors such as age, sex, tumor stage, latency from the date of radiation treatment completion to the date of survey completion, and dosimetric parameters. Variables with intuitive potential causal relationships and factors with a P<0.05 were included in the multivariable model. Statistical analysis was performed using Stata version 16.1 statistical software (StataCorp, College Station, TX).

Systematic Review.

To put our results into context, we performed a systematic literature search using the Ovid MEDLINE^® and Pubmed.gov databases according to the guidelines published by the PRISMA-S group (26). Keyword search terms used included: “anal cancer” AND intensity modulated radiation AND (“patient reported outcomes” OR toxicity). Limits included “English language AND humans AND 1980-current”.

Results

Baseline characteristics.

Of 248 patients invited to participate, 112 (45%) completed the survey. A greater proportion of patients who responded to the survey were white vs. non-responders (95% vs. 87%; P=0.04). There were no other significant differences between responders and non-responders with regard to baseline characteristics (Table 1). Of 112 respondents, 90 (80%) were female and 107 (95%) were white. No patients were noted to have inflammatory bowel disease. The median [interquartile range (IQR)] age at survey completion was 61 [54–66] years, and the median [IQR] time from the conclusion of chemoradiation to survey completion was 51 [37–85] months. T stage was 1–2 for 87 (78%) patients and 3–4 for 25 (22%). Forty-eight (43%) had N1 disease. Radiation doses delivered to the gross tumor volume (GTV) were 50 Gy for 27 (24%) patients, 54 Gy for 59 (53%), and 58 Gy for 26 (23%). Target and organ-at-risk dosimetric information is given in Table 2. Notably, the median [IQR] anal PTV D1 was 59.3 [23.3–58.6] Gy; bowel bag V30Gy was 647 [466–852] cc, bowel bag D1 was 49.7 [47.6–52.1] Gy, small bowel V30Gy was 140 [66–223] cc, small bowel D1 was 48.1 [46.7–50.3] Gy; and bladder V45Gy was 28.5% [15.0–39.8%]. A treatment break was reported for 12 (11%) patients; two patients prematurely discontinued RT and each missed their last two fractions, and ten patients had a median [IQR] treatment break of 2.5 [2–3.75] days. While patients who experienced local recurrences were excluded, two (2%) patients had colostomies in place at last follow up. One patient developed a suspected anorectal fistula approximately 2 weeks after completing RT to a prescription dose of 58 Gy in 29 fractions and elected for an APR to maximize her QoL. Similarly, the other patient was treated with a dose of 58 Gy in 29 fractions and developed stool seepage in the three months following completion and elected to have an APR with permanent colostomy for symptom management. Both were alive with no evidence of disease at last follow up.

Table 1.

Baseline characteristics for survey responders and nonresponders

Attribute	Responders (n = 112)	Nonresponders (n = 136)	P value
Age, y			.97
Median (IQR)	61 (53–66)	61(53–67)
Sex			.26
Female	90(80%)	101 (74%)
Male	22 (20%)	35 (26%)
Race			.04*
White	106 (95%)	118(87%)
Non-White	6(5%)	18 (13%)
Ethnicity			.12
Non-Hispanic	108 (96%)	124 (91%)
Hispanic	4(4%)	12(9%)
Smoking status			.22
Never	67 (60%)	77(57%)
Former	37 (33%)	40 (29%)
Current	8(7%)	19(14%)
Median tumor size, cm (IQR)	2.8 (1.9–4.8)	3.0 (2.0–5.0)	.14
T stage			.12
T1/T2	85 (76%)	91 (67%)
T3/T4	27 (24%)	45 (33%)
N stage			.45
N0	63 (56%)	70 (52%)
N1	49 (44%)	66 (48%)
GTV dose (Gy)			.12
Median (IQR)	54 (54–54)	54 (54–58)
CTV dose (Gy)			.09
Median (IQR)	45 (44–47)	45 (45–47)
GI toxicity grade during RT			.85
1	49 (47%)	50 (43%)
2	39 (38%)	50 (43%)
3	13(13%)	13(11%)
4	2(2%)	3(3%)
GU toxicity grade during RT			.43
1	21 (19%)	31 (23%)
2	89 (80%)	104 (77%)
3	1 (1%)	0(0%)
Follow-up time after RT (y)			.06
Median (IQR)	3.0 (2.0–4.8)	3.9 (2.3–5.3)

Abbreviations: CTV = clinical target volume; GI = gastrointestinal; GTV = gross tumor volume; GU = genitourinary; QR = interquartile range; RT = radiation therapy.

Table 2.

Radiation volume and dose to targets and normal tissues for responders (n = 112)

Structure	Median	Interquartile range	Range
Anal PTV volume, cm3	285	214–401	52–990
Anal PTV D1%, Gy	57.3	53.3–58.6	46.7–64.9
Anal PTV D0.5cm3, Gy	57.7	55.0–59.6	52.0–66.4
Anal PTV D0.3cm3, Gy	58.1	55.5–60.2	52.2–68.5
Bowel bag V30Gy, cm3	647	466–852	106–1592
Bowel bag V35Gy, cm3	567	408–756	61–1400
Bowel bag V40Gy, cm3	505	358–634	20–1210
Bowel bag V45Gy, cm3	342	166–515	0.4–942
Bowel bag D1, Gy	49.7	47.6–52.1	40.1–57.5
Small bowel V30Gy, cm3	140	66–223	2–704
Small bowel V35Gy, cm3	109	50–188	0.2–650
Small bowel V40Gy, cm3	93	37–1501	0–589
Small bowel V45Gy, cm3	46	13–95	0–452
Small bowel D1, Gy	48.1	46.7–50.3	21.0–56.2
Bladder V40 (%)	48.3	33.5–61.9	2.5–99.6
Bladder V45 (%)	28.5	15.0–39.8	0.1–77.0
Bladder V50 (%)	0.5	0.0–5.6	0–40.5

Abbreviations: bladder Vx (%) = percentage of bladder volume receiving x Gy or more; D1 = top dose to 1% of the volume; PTV = planning target volume; Vx = volume of the structure receiving x Gy or more.

Survey results.

PRO responses were available for all 112 patients across all instruments for which patients were eligible, as answers to these questions was required for survey completion. The median [IQR] FACT G7 score was 21 [15–24] on a scale from 0–28 with higher scores indicating better overall health-related QoL. The median [IQR] FIQoL score (Table 3) was 14 [11–16]. Of the FIQoL subscale scores, the lowest (worst QoL) median score was reported for coping/behavior and the highest (best QoL) for depression/self-perception. Responses to the LARS questionnaire (Figure 1) showed that most patients experienced minor (25%) or major (61%) LARS, reflective of poor QoL with regard to bowel habits. Most patients reported difficulty with controlling flatus and frequency and urgency of bowel movements. Assessment of urinary function (Table 4) in males (MLUTS) showed generally low (better) scores in the domains of voiding and incontinence and similarly low (better) scores for females (FLUTS) in the domains of voiding, incontinence, and filling. No clear temporal relationship was observed between total score for each instrument and latency from the end of RT to survey response.

Table 3.

Fecal incontinence quality of life subscale items and total scores after definitive chemoradiation for SCCA

Subscale item	Median	Interquartile range	Range of scores
Lifestyle	3.7	2.8–4.0	1.0–5.0
Coping/behavior	2.9	2.1–3.7	1.0–5.0
Depression/self-perception	3.9	3.2–4.3	1.0–5.0
Embarrassment	3.7	2.7–4.0	1.0–5.0
Total	14.1	11.1–16.0	4.0–20.0

Abbreviation: SCCA=squamous cell carcinoma of the anus.

Data were available for all 112 patients.

Fig. 1.

Distribution of patient responses to Low Anterior Resection Syndrome (LARS) questionnaire items. Data were available for all 112 patients.

Table 4.

Lower urinary tract symptoms scores for male and female patients

Subscale item	Median	Interquartile range	Range of scores
Male Lower Urinary Tract Symptoms (n = 22)
Voiding	5.0	2.0–6.0	0.0–20.0
Incontinence	1.0	1.0–3.0	0.0–25.0
Female Lower Urinary Tract Symptoms (n = 89)
Voiding	1.0	1.0–3.0	0.0–12.0
Incontinence	5.0	3.0–8.0	0.0–20.0
Filling	4.0	2.0–5.0	0.0–16.0

Higher scores indicate worse quality of life. Data were available for all 22 men and 89 of 90 women.

Correlates of PROs.

In separate multivariate analysis, higher bowel bag D1% was significantly associated with lower FIQoL score (β=−0.34, 95% CI −0.54, −0.15; P=0.001), and higher LARS score (β=0.84, 95% CI 0.21, 1.47; P=0.01), both signifying worse bowel function. Higher small bowel V30 was significantly associated with higher FIQoL score (β=0.007, 95% CI 0.002–0.012; P=0.005), signifying worse bowel function. On univariate analysis, no significant associations were found between T-stage or the maximum dose within the anal canal target volume, D1% (median [IQR] 57.3 Gy [53.3–58.6 Gy]), D(0.5cc) (median [IQR] 57.7 Gy [55.0–59.6 Gy]) or D(0.03cc) (median [IQR] 58.1 Gy [55.5–60.2 Gy], and either FIQoL or LARS (Supplemental Tables 1 and 2). Higher bladder V40Gy was associated with increased ICIQ voiding subscore (P=0.001), indicating worse urinary function. Bladder volume (median [IQR] 164.4cc [IQR 91.7–286.3cc]) was not associated with FiQOL, LARS, or ICIQ voiding subscore. Male sex (P<0.001), active smoking compared to non-smokers (P=0.040), and higher T-stage (P=0.002) were also associated with higher ICIQ voiding subscore on multivariable analysis (Supplemental Table 3).

Associations between quality-of-life scales.

On univariate analyses, a higher (better) FIQoL score and was associated with a higher (better) FACT G7 score (β=0.83, 95% CI 0.58, 1.09; P<0.001; Figure 2A), and a higher (worse) LARS score was associated with a lower (worse) FACT G7 score (β=−0.22, 95% CI −0.31, −0.13; P<0.001); Figure 2B). On univariate analysis, the proportion of the variance in FACT-G7 score explained by LARS score was moderate (r²=0.28) and the proportion of variance in FACT-G7 score explained by FIQoL score was modest (r²=0.17). On multivariable analysis, only FIQoL score was significantly associated with FACT-G7 score for female patients (β=0.94, 95% CI 0.45–1.42; P<0.001) (Supplemental Table 4).

Fig. 2.

Scatterplots between Functional Assessment of Cancer Therapy-General (FACT-G7) score versus (A) Low Anterior Resection Syndrome (LARS) score and (B) Fecal Incontinence Quality of Life (FIQoL) score.

Systematic Literature Review.

The Ovid MEDLINE^® search yielded 58 results, and the PubMed.gov search yielded 84 results. After removal of duplicates, 97 studies remained. Reference lists of included articles were manually screened to identify additional studies. Three additional pertinent papers were added (Supplemental Figure 1: PRISMA Flowchart). Seven papers included PROs results from patients treated with IMRT for SCCA (Supplemental Table 5). Seven papers included bowel and/or bladder constraints supported by analyses of toxicity data (Supplemental Table 6).

Discussion

In this cross-sectional survey study and retrospective analysis with linked dosimetric data, we report patient-reported outcomes regarding bowel function, bladder function and health-related QoL with at least two years of follow up after definitive CRT for SCCA. Rates of urinary dysfunction as measured by ICIQ MLUTS and FLUTS scores were relatively low but were consistent with population based studies of older adults (27). However, urinary subscores for women in our cohort were higher (worse) than a those of a cohort of women with colon cancer treated mostly with surgery alone (28). Interestingly, for men in our cohort, MLUTS voiding and incontinence subscores were actually lower (better) than a similar cohort of men treated mostly with surgery alone for colorectal cancer (29), potentially driven by the 40% of patients in this study with rectal cancer, who received abdominoperineal resection, pelvic dissection and/or RT.

Rates of bowel dysfunction as measured by the LARS and FIQoL scales were high in our cohort. Sixty-one percent of patients in our cohort had major LARS, which is higher than most surgical series after sphincter-sparing surgery for rectal cancer (30). A study of patients with rectal cancer who received pelvic CRT followed by a watch-and-wait protocol reported the mean [SD] LARS score was 23.4 [11.3] and 33% of the patients had major LARS (16). However, it should be noted that many patients on this study likely did not have tumor involving the anal canal, and that some of the dysfunction noted may be related to tumor rather than treatment sequelae. Another study of patients with rectal cancer on a watch-and-wait protocol after pelvic CRT reported a median [range] FIQoL score of 2.8 [1.9–4.0], which was calculated as the average of the four FIQoL subscores (31), which is lower (worse) than the median [IQR] FIQoL score in our cohort of 3.5 [2.8–4.0]. Both bowel dysfunction PRO scores were associated with worse health-related QoL as measured by the FACT-G7, which agrees with studies in the surgical literature (32).

The present study is the largest analysis utilizing validated PRO instruments to specifically assess long-term bowel and bladder function in patients with SCCA treated with IMRT-based CRT. Our systematic review of the literature identified seven prior studies reporting PRO results from patients with SCCA treated with IMRT (Supplemental Table 5). One study only included on-treatment PROs (33). Two studies included baseline, on-treatment, and 2–12 week post-treatment PROs and showed peak bother from GI symptoms during treatment with gradual improvement during the subacute post-treatment period (7, 34). Three studies also included medium term follow up with PROs collected at 12–18 months post-treatment. Han et al. and Gilbert et al. found PROs were the worst at the conclusion of treatment but returned to baseline at 3 months following treatment and remained stable at one year (35, 36). Shaw et al. retrospectively analyzed patient-reported bowel questionnaires administered at baseline and at follow up, at a median of 16 months. The total bowel function score was the same from baseline to post-treatment (23/100 vs 20/100), stool-related domain subscore improved (41/100 to 23/100), and other subscores (need for medication, frequency, social impact and incontinence) did not change (37). Only one study included outcomes more than two years following treatment. Axelsson et al. collected outcomes using a non-validated custom bowel and urinary function questionnaire at three and six years following treatment. They did not have baseline scores but compared patient outcomes results with a healthy reference population who completed the same questionnaire. In the patient population, 51% and 33% reported major bother regarding bowel and urinary function compared with 13% and 13% in the reference population. Bother regarding pain and bowel function decreased slightly from 3 to 6 years (38). Our study likewise lacked baseline data, but had the benefit of utilizing validated PRO instruments.

While PROs are powerful tools, it is essential to more broadly consider their strengths and limitations. PROs may serve as independent predictors of oncologic outcomes, and their use in trials has been associated with fewer emergency department visits, improved quality of life, and increased survival in some instances (39). PROs have many advantages to physician-assessed toxicity, which shows only modest correlation with patient-reported QoL (40). Despite these strengths, a key shortcoming is that they may not be uniformly accepted by or accessible to patients. PROs are often lengthy, time-consuming and may not be available in all languages. Much remains to done to streamline accurate capture of PRO and to ensure equitable access to them (41). Lack of agreement on the optimal battery of PROs for a given patient population also limits the ability to compare data between studies. One validated PRO not incorporated into the current study is the PRO-CTCAE, which has demonstrated high validity (42). Factors such as minimum clinically important differences (MCID) are also needed to more precisely interpret PROs. Data exist regarding MCID for the FACT G7 (43) and ICIQ-FLUTS (44), but to our knowledge, analogous validated thresholds for MCID do not yet exist for LARS or FIQoL.

The present study is the first to evaluate dosimetric predictors of bowel and bladder function PROs in patients treated with IMRT-based CRT for SCCA. Our analyses of pelvic organ dosimetry and PROs showed that: (1) higher bladder V40Gy was associated with higher (worse) ICIQ scores, (2) higher D1% to the bowel bag as well as the V30Gy of the small bowel loops were associated with lower (worse) FIQoL scores, and (3) higher D1% to the bowel bag and the small bowel loops were also associated with higher (worse) LARS scores. Our systematic review of the literature identified seven prior studies reporting bowel or bladder dose constraints for patients with SCCA treated with IMRT were largely based on physician-assessed toxicity. Two resulting studies examined the relationship between dose to the tightly contoured loops of small bowel with G2+ GI toxicity (46, 47). Olsen et al. performed a secondary analysis of RTOG 0529 which showed that small bowel volumes of 186ccs, 155ccs, 41ccs and 30.4ccs receiving doses greater than 25, 30, 35, and 40 Gy, respectively, correlated with increased risk of acute grade ≥2 GI toxicity (46). Five studies showed a dose-volume relationship between the bowel cavity, or “bowel bag” and toxicity (45, 48–51). Suggested constraints for the bowel cavity V30Gy included <300ccs (48), <310ccs (49), <450ccs (50), and <660ccs (51) to decrease the risk of acute G2+ or G3+ GI toxicity. Suggested constraints for V40Gy included <70cc to decrease the risk of acute G3+ GI toxicity (49). Two studies examined the relationship between dose constraints and late toxicity. Koerber et al. suggested bowel cavity V20Gy <25% decreased the risk for chronic increased fecal frequency (45). Nilsson et al. suggested dose to the large bowel loops V20Gy <118ccs decreased the risk for late G2+ GI toxicity (51). Only one study suggested a bladder constraint; Koerber et al recommended bladder V40Gy <25% to decrease the risk of acute urinary urgency (45).

This study has several limitations not yet discussed. The overall response rate of 45% is low. We were unable to contact 39% of patients by telephone to discuss participation, which was the major driver of the low response rate. Among patients whom we reached, 76% returned completed surveys. The overall response rate is in line with other published anal cancer quality of life studies, which have had response rates ranging from 40–89% (53). Nevertheless, non-response bias may potentially affect interpretation of these data. Among patients who responded, cognitive biases such as social desirability bias—the tendency to answer questions in a way that is likely to be perceived favorably—are potential confounders as well. Such bias would falsely attenuate the patient-reported functional changes and obscure true relationships between covariates. In addition to having a lack of baseline information, this study captures PROs at a single time point for each patient, with heterogeneous latencies following RT, which precludes robust longitudinal assessment of toxicities. While comparison outcomes to other disease sites are provided for reference, the study lacks a proper control population. Our analysis of bladder volume and late patient-reported urinary dysfunction is limited by potential inconsistencies in bladder filling throughout radiation treatment. Patients were instructed to drink the same amount of water 1 hour prior to simulation and each day’s radiation treatment, but bladder filling was not uniformly verified daily prior to treatment with either ultrasound or CT. Our study population had low proportions of non-White and male patients, thereby limiting generalizability to vulnerable populations including African Americans (54) and men who have sex with men (55).

Based on the results of this study, we recommend several best practices for minimizing long-term morbidity in the treatment of anal cancer: (1) routine use of IMRT with a simultaneous integrated boost technique and (2) treatment with a full bladder with use of daily cone beam CT or other quantitative methods to ensure reproducible bladder filling in order to reduce dose to the bowels. Following treatment, we recommend referral to an experienced pelvic floor physical therapist may also improve long-term bowel and bladder function. There is growing interest in radiation dose and volume de-escalation (56) to reduce toxicity, as endorsed by the American Radium Society Appropriate Use Criteria (ARS AUC) (57). Results from the ongoing DECREASE study will provide valuable information regarding the impact of dose on validated PROs assessing bowel and urinary function (58).

In conclusion, we found patients treated with IMRT-based CRT for SCCA experience poor LARS and FiQOL scores more than two years following treatment. ICIQ MLUTS and FLUTS scores were poor, but similar to healthy populations of a similar age. To reduce long-term urinary dysfunction, efforts to reduce the volume of bladder receiving at least 40Gy by ensuring more precise and reproducible bladder filling may be helpful; bladder ultrasound or daily cone beam CT may allow the treating team to achieve a patient-specific bladder volume. To reduce long-term bowel dysfunction, efforts to minimize hotspots within the bowel and to limit the low dose bath to the small bowel loops may also be helpful. However, prospective studies utilizing serial validated PRO instruments are warranted and will be essential in better characterizing late toxicities of chemoradiation treatment. Until such data are available, our results may help patients clarify expectations at the time of initial consultation regarding longer-term sequelae of treatment.