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. Author manuscript; available in PMC: 2023 Dec 1.
Published in final edited form as: Dis Colon Rectum. 2022 Sep 5;65(12):1448–1455. doi: 10.1097/DCR.0000000000002600

Assessment of Patient-Reported Outcomes in Patients with Anal Squamous Cell Cancer Undergoing Combined Modality Therapy

EVALUACIÓN DE LOS RESULTADOS INFORMADOS POR LOS PACIENTES CON CÁNCER ANAL DE CÉLULAS ESCAMOSAS QUE SE SOMETEN A UNA TERAPIA DE MODALIDAD COMBINADA

James P Taylor 1, Iris H Wei 1, J Joshua Smith 1, Amy L Tin 2, Nate Aiken 2, Andrew J Vickers 2, Paul B Romesser 3, Christopher H Crane 3, Maria Widmar 1, Garrett M Nash 1, Martin R Weiser 1, Philip B Paty 1, Julio Garcia-Aguilar 1, Emmanouil Pappou 1
PMCID: PMC9851905  NIHMSID: NIHMS1859716  PMID: 36102865

Abstract

BACKGROUND:

There is limited knowledge on long-term bowel, sexual, and urinary function after combined modality therapy for anal squamous cell cancer.

OBJECTIVE:

To evaluate long-term changes in bowel, sexual, and urinary function in patients treated with combined modality.

DESIGN:

This was a retrospective study of prospectively collected patient reported outcome surveys.

SETTING:

Single institution.

PATIENTS:

There were 143 patients with stage I-III anal cancer who were treated with chemoradiation and had completed the survey.

MAIN OUTCOME MEASURES:

Patient-reported outcomes reflecting bowel, sexual, and urinary function.

RESULTS:

Thirty-nine percent of patients had major low anterior resection syndrome scores at baseline. Major low anterior resection syndrome scores remained stable (38%; 95% CI 31%, 46%) with no change over time (OR 0.95, 95% CI 0.74, 1.21, p = 0.7). Higher rates of major low anterior resection syndrome scores were observed for patients who had major low anterior resection syndrome scores at baseline (OR 20.7; 95% CI 4.70, 91.3, p < 0.001) and for females (OR 2.14; 95% CI 1.01, 4.56; p = 0.047). On 5-point scales, we saw a non-significant increased level of sexual arousal during sexual activity after therapy for women (β for 1 year = 0.15; 95% CI −0.01, 0.32; p = 0.072) and non-significant decreased confidence in getting and keeping an erection after therapy for men (β for 1 year = −0.33; 95% CI −0.66, 0.00; p = 0.053).

LIMITATIONS:

This is a single-institution study. Only patients who answered the questionnaire were included in the study.

CONCLUSIONS:

A significant proportion of patients have major low anterior resection syndrome scores at baseline and after successful treatment for anal cancer. Having major low anterior resection syndrome scores at baseline was the biggest predictor of having major low anterior resection syndrome scores after treatment. Bowel, sexual, and urinary function did not improve over time up to 2 years after end of treatment. Physicians should counsel their patients prior to treatment that baseline poor bowel function is a risk factor for post treatment bowel dysfunction. See Video Abstract at http://links.lww.com/DCR/Bxxx.

Keywords: Anal cancer, Low anterior resection syndrome, Patient reported outcomes, Quality of life

INTRODUCTION

Despite only representing 1–2% of all bowel cancers,1 the incidence of anal squamous cell carcinoma (ASCC) continues to rise, with a projected estimate of 9,090 new cases in the United States in 2021.2 The treatment paradigm for ASCC took a dramatic shift in the 1970s with the introduction of neoadjuvant combined modality therapy (CMT), consisting of 5-flourouracil, mitomycin C and concomitant radiation (the Nigro protocol).3 The efficacy and success of this therapy has been confirmed in several subsequent studies,4,5 and as such, the rates of sphincter preservation have increased and the need for permanent colostomy decreased.

One factor that has often been overlooked in studies focusing on oncological outcomes, is the impact that CMT has upon bowel function, sexual function, and quality of life as reported by patients. A handful of studies have evaluated this area, suggesting that bowel and sexual function are negatively impacted by CMT;6–8 however, these changes are often reported as subsections of large and burdensome quality of life questionnaires. As such, the true and long-term impact of CMT upon bowel and sexual function remains unknown. In addition to disease activity, survival, and toxicity, life impact was identified as 1 of 4 key domains for future clinical trials in anal cancer using the Core Outcome Measure in Effectiveness Trials method in 2018.9 This further emphasizes the importance of gaining a greater understanding of the impact of CMT upon bowel and sexual function.

The aim of this study was to examine the long-term impact on bowel, sexual and urinary function for patients with ASCC treated with CMT. We used a patient-reported outcome measure (PROM) survey at Memorial Sloan Kettering Cancer Center, which incorporated questions from the low anterior resection syndrome score (LARS), in addition to questions related to urinary function and sexual function. The LARS score has been previously validated in patients undergoing colorectal surgery;10 however, to the authors’ knowledge, it has not been previously utilized to assess bowel function in patients undergoing CMT for ASCC

PATIENTS AND METHODS

The study was approved by the institutional review board, and a waiver of informed consent was obtained. Patients undergoing CMT treatment for ASCC were asked to answer the PROM – a survey asking 5 questions measuring bowel dysfunction and low anterior resection syndrome (LARS), 2 questions regarding their urinary function, 4 questions about sexual function, a question about overall health and overall quality of life. The sexual function questions differed based on gender, with male patients being asked about their confidence in getting and keeping an erection, and about ejaculation; female patients were asked to rate their level of sexual arousal during sexual activity, and lubrication during sexual activity.

We identified 178 unique patients who underwent successful CMT for their stage I-III cancer between January 2016 and April 2021 and were free of disease. Enrollment for the study began in 2019, and as such baseline data was not available for patients who had already undergone treatment. All patients with anal cancer were treated at our center using a standard protocol with Intensity-Modulated Radiation Therapy and use of vaginal dilators for women in order to prevent vaginal stenosis. They completed a total of 316 PROM surveys. Surveys were administered every 6-months to coincide with clinic visits and were filled out in person in clinic, or via a patient portal prior to clinic visit. Survey was assessed in real time in clinic by the treating clinician. We binned surveys based on when they were completed in relation to the end of their radiation treatment: baseline, 3-months, 6-months, 12-months, 18-months, 24-months, 3-year, 4-year, and 5-year. Among patients who responded to multiple surveys within the same binned time frame, we retained the survey closest to the time frame of interest. For example, if a patient completed a survey 10-months and 11-months after the end of radiation treatment, the 11-month survey was used to reflect 12-month follow-up and the 10-month survey was excluded from analysis. We excluded three surveys completed during CMT, and additionally excluded one survey which was taken more than a year prior to the start of radiation treatment and would therefore not be a reasonable estimation of baseline function. Since our analyses were related to surveys completed by patients after the end of their CMT, we retained 203 surveys completed by 143 patients after their treatment for analysis.

The questions used in this concise PROM were validated questions from validated PROMs already in use, including the International Index of Erectile Function erectile function domain (IIEF-6), Female Sexual Function Index (FSFI6), the Overactive Bladder Questionnaire (OAB-q), the American Urological Association Symptom Index, and EurQol Visual Analogue Scale (EQ VAS) questionnaires.11–15 Within internal analyses, not yet currently published, the sum of the two questions used in our PROM and the overall FSFI-6 score have been shown to have a strong correlation (Spearman’s correlation 0.96).Similarly the sexual question for men related to confidence to achieve erections has been shown to be highly correlated with the overall IIEF-6 score (spearman’s correlation 0.88). The overall health and overall quality of life scales used in our PROM are the validated scales used in EQ VAS (EQ-5D-5L version). Specific question and answer text for the survey are shown in Supplementary Table 1 at http://links.lww.com/DCR/Bxxx.

As a preliminary aim, we were interested in describing the rates of major LARS or any LARS after CMT treatment. We used two separate longitudinal models using generalized estimating equations (GEE) with an autoregressive correlation structure, for each of the outcomes, then reported the predicted rates over time and their corresponding asymptomatic confidence intervals.

For our primary analysis, we were interested in assessing the association between major LARS after CMT and age, gender, and baseline LARS. We used longitudinal models GEE with an autoregressive correlation structure, for each of the predictors, separately.

As a secondary aim, we were interested in exploring the change in sexual function and urinary function over time. We first used five separate longitudinal models using GEE with an autoregressive correlation structure. Next, we visualized this association by plotting the trend in response to the corresponding question over time and fitting a linear model with robust standard errors to account for patients answering multiple surveys. For female patients, the outcome was the response to the questions asking about “level of sexual arousal during sexual activity.” For male patients, the outcome was the response to the question asking about “confidence in getting and keeping an erection” and “how often did you ejaculate.” Surveys where patients reported not engaging in any sexual activity were excluded from this analysis. Responses to the urinary questions “how often have you leaked urine” and “how often have you felt like you didn’t empty your bladder completely after you finished urinating” were analyzed without distinguishing between patient sex.

All analyses were conducted using R version 4.1.016 with the tidyverse v1.3.117 and gtsummary v1.4.218 packages.

RESULTS

Patient characteristics for the unique 143 patients completed surveys after CMT are shown in Table 1. The majority of patients were female (73%), white (92%), and had AJCC stage 3 disease (50%). Among patients who completed the PROM prior to initiation of CMT (a total of 44 patients), 39% answered in such a way that they were be considered as having major LARS at baseline.

Table 1.

Patient characteristics. Results are presented as median (quartiles) and frequency (%).

Characteristic N = 143
Age at RT Start 62 (57, 69)
Female 104 (73%)
Race
 White 127 (92%)
 Black 7 (5.1%)
 Asian 1 (0.7%)
 Other 3 (2.2%)
 Unknown 5
Major LARS at Baseline 17 (39%)
 Unknown 99
RT Fraction 27 (25, 50)
RT Dose 4,500 (4,300, 7,650)
AJCC Stage
 1 35 (24%)
 2 37 (26%)
 3 71 (50%)
Follow-up Survey Completed
 3-Months 19 (13%)
 6-Months 36 (25%)
 12-Months 42 (29%)
 18-Months 18 (13%)
 24-Months 37 (26%)
 3-years 29 (20%)
 4-years 18 (13%)
 5-years 4 (2.8%)
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Among 180 surveys for 129 unique patients with available LARs status, we did not find evidence of a change in major or any LARs after CMT (OR 0.95, 95% CI 0.74, 1.21, p = 0.7; and OR 1.05, 95% CI 0.83, 1.4, p = 0.7; respectively), and therefore report the average level of major vs. any LARS over the follow-up period: 38% (95% CI 31%, 46%) and 64% (95% CI 57%, 71%) (Fig. 1).

Figure 1.

Figure 1.

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Change in rates of major (red) and any (blue) LARS over time.

Our analyses assessing the association between characteristics and major LARS after CMT yielded non-significant higher rates of major LARS for older patients (OR per 10 years: 1.13; 95% CI 0.84, 1.52; p = 0.4) and evidence of higher rates of major LARS for female patients (OR 2.14; 95% CI 1.01, 4.56; p = 0.047). Patients who reported having major LARS at baseline had much higher rates of LARS post-CMT (OR 20.7; 95% CI 4.70, 91.3, p < 0.001). Analyses related to major LARs and age and sex utilized the same 180 surveys for 129 unique patients, whereas the analysis looking into baseline LARS was only among 57 surveys, corresponding to 43 patients, where baseline LARS was available.

Figure 2 depicts sexual function over time in women, where formal hypothesis testing yielded non-significant increased level of sexual arousal (1–5 scales) during sexual activity as time passes since the end of CMT for women (β for one-year = 0.15; 95% CI −0.01, 0.32; p = 0.072; analysis among 68 surveys corresponding to 55 unique patients). Figure 3 and 4 depict sexual function in men (1–5 scales) after CMT over time, where we see non-significant decreased confidence in getting and keeping an erection (β for one year = −0.33; 95% CI −0.66, 0.00; p = 0.053; analysis among 47 surveys corresponding to 33 unique patients), and non-significant decreased ejaculation (β for one year = −0.30; 95% CI −0.65, 0.05; p = 0.088; analysis among 45 surveys for 31 unique patients). The upper bound of the 95% CI in all cases exclude any large change.

Figure 2.

Figure 2.

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Responses to “level of sexual arousal during sexual activity” among women over time.

Figure 3.

Figure 3.

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Responses to “confidence in getting and keeping an erection” among men over time.

Figure 4.

Figure 4.

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Responses to “how often did you ejaculate” among men over time.

We did not see evidence of a change in urinary function related to incontinence (β for one year = −0.03; 95% CI −0.14, 0.09; p = 0.6; 4-point scale, Fig. 5) or sensation of incomplete emptying (β for one year = 0.04; 95% CI −0.10, 0.19; p = 0.6; 6-point scale, Fig. 6), with the confidence interval excluding any important temporal effects. Both analyses related to urinary function were among 203 surveys corresponding to 143 unique patients.

Figure 5.

Figure 5.

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Responses to “how often have you leaked urine” over time.

Figure 6.

Figure 6.

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Responses to “how often have you had a sensation of not emptying your bladder completely after you finished urinating” over time.

DISCUSSION

We found that a significant proportion of patients with anal cancer have major LARS at baseline and following successful treatment with CMT. The greatest predictor of major LARS after CMT was major LARS at baseline. Bowel, sexual, and urinary function did not improve over time after end of CMT to follow up at 2 years after end of treatment. We found no evidence of change in major or any LARS at any time point after CMT. Lack of improvement of bowel, urinary, and sexual function over time suggests that CMT does not significantly affect long-term function. To our knowledge, this is the first study to utilize LARS scoring questions to assess PRO’s following CMT for ASCC.

When counselling patients on the treatment effects of CMT, it is imperative to be able to offer guidance on the effects that the therapy may have on their function. Obtaining baseline functional data can assist physicians in setting expectations on the impact of CMT upon both bowel and sexual function. Our study suggested that over a third of patients had major LARS symptoms prior to the initiation of CMT, and that while the treatment did not result in a deterioration in their symptoms in the long term, it did not result in a significant improvement. The baseline rates of LARS in a healthy population is often quoted at approximately 20% in females and 10% in males, which is lower than the baseline level in our cohort.19 This may be secondary to the presence of anal cancer, or reflect worse baseline function, and requires further research. Similar findings related to the effect of CMT on bowel function have been reported by other studies. Joseph et al. reported that 10% of patients had severe fecal incontinence and 26% had minimal incontinence prior to starting treatment, with no increase in severe fecal incontinence (11%) by the conclusion of treatment.6 Our results additionally suggest that females have a higher likelihood of having major LARS following CMT. However, despite the result meeting conventional levels of significance, it should be interpreted in the context on multiple testing. Nonetheless, the central estimate and the upper bound of the confidence interval does not exclude clinical significance, with female patients having much higher likelihood of developing major LARS after CMT compared to male patients, This finding was mirrored in the ACCORD 03 trial, where female were found to have more diarrhea two months after treatment compared to males.20 This could be secondary to weaker baseline pelvic floor musculature, or the differences between male and female pelvic anatomy. However, other studies have failed to show a significant difference in bowel function related to gender.

With regards to sexual side effects, our results suggest that there is no significant impact of CMT on sexual function in males or females (Figs. 2–4). The results of prior studies are mixed, with some suggestion that women may be more profoundly affected than males. Joseph et al found that sexual interest was impaired significantly at the end of treatment but improved to baseline by 12 weeks in both men and women. The authors showed a non-significant improvement in sexual function in males at 12 months, which matches our non-significant improvement in “confidence in keeping an erection” score (Fig. 3).6 For women, however, dyspareunia increased by 10% at the end of follow-up, which the authors postulate may have a negative impact on sexual function. Other studies have not supported these findings, with suggestions that male impotence ratings may be higher following CMT,21 and that female libido scores may improve following treatment.22

Urinary function has been shown to be affected by pelvic radiation in previous studies. Barraclough and colleagues studied the impact of radiation therapy upon 226 female patients with gynecological malignancy, and found that urinary urgency frequency increased from 39% pre-treatment to 75% at 3 years, while incontinence increased from 18% pre-treatment to 27% at 3 years.23 While the radiation fields may not be the same for ASCC therapy, there is much overlap given the close proximity of the bladder and urethra to the anal canal. Gilbert and colleagues from the UK showed that urinary symptoms (frequency/dysuria) improved non-significantly at one-year follow up after radiotherapy for anal cancer,22 while other groups have suggested that urinary frequency persisted at long-term follow-up.24,25 Interestingly, Joseph et al. found that while urinary frequency rates returned to baseline by 12 weeks, 8% of patients had “quite a bit” of urinary incontinence at 12 months.6 We observed no significant changes in urinary incontinence or urinary retention in our study (Figs. 5 and 6).

Due to the effectiveness of CMT on the management of ASCC,3–5 quality of life measures have become an important prognostic factor to consider when advising patients on the impact of both the disease and the therapy. Many different tools have been utilized to assess quality of life for patients with anal cancer, including the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30),26 EORTC QLQ-CR 3827 and QLQ-CR29,28 and the Functional Assessment of Cancer Therapy-Colorectal (FACT-C).29 These quality of life questionnaires were first developed to examine PRO in patients with rectal cancer, and as such an anal cancer-specific quality of life questionnaire has been developed by EORTC, termed QLQ-ANL27, which is currently being utilized as an endpoint in the PLATO trial.30,31 Many other validated tools that assess quality of life are employed in studies related to PRO in anal cancer, which makes analysis of results difficult to compare across studies. Several studies have compared the effectiveness of some of these questionnaires, attempting to assess their responsiveness, which is defined as a tool’s ability to detect a clinically significant change. Uwer et al. looked at the responsiveness of EORTC QLQ-C30, QLQ-C38 and FACT-C in rectal cancer survivors, discovering that QLQ-C30 was significantly more responsive than the other two, despite not being designed particularly for colorectal cancer patients.32 A further systematic review showed that FACT-C was the most extensively evaluated questionnaire, however the EORTC QLQ-CR38 was recommended to assess quality of life due to the highest number of positive ratings in the overall level of evidence.33 The downside to the majority of the existing questionnaires is the burdensome length of the questionnaire, which can result in lower response rates, reduced completion and reduced data quality.34,35 As such, the PROM used in our study appears to be an acceptable alternative and low burden tool to adequately monitor PRO following CMT for ASCC.

This current study has several limitations, the most notable being its retrospective nature. The data arises from a single, tertiary referral academic center, which may result in referral bias.36 It is also important to consider the impact of missing data and how this might affect baseline scores, as healthier patients who are less impacted by CMT may be less likely to fill out the questionnaires. An additional limitation is that the study is most likely underpowered to detect differences between responses, particularly with reference to the Likert scales utilized to assess sexual and urinary function, and that fact that only a third of baseline data was available for analysis. Another limitation of the study is its single-center nature. While all patients at our center are treated with a standard protocol using intensity-modulated radiation therapy and the use of vaginal dilators for women in order to prevent vaginal stenosis, distribution of radiation and normal tissue avoidance may be variable among different centers. It is also important to note that the LARS score used in our study was originally developed and validated for assessment of bowel dysfunction following a low anterior resection and may not be generalizable to patients with anal cancer. However, LARS score is a concise PROM, it has proven to have good psychometric properties with robust internal consistency, repeatability, and discriminant validity comparted to other bowel function tools and appears to be a valid instrument for measuring bowel dysfunction long term.37,38

CONCLUSION

In conclusion, a significant proportion of patients with anal cancer have major LARS at baseline and following successful treatment of anal cancer with CMT. Patients with major LARS at baseline appear to be at the greatest risk of having major LARS following treatment, and as such physicians should counsel their patients prior to the initiation of treatment. Bowel, sexual, and urinary function did not improve over two years after the end of CMT.

Further research is needed to elucidate long term bowel, urinary and sexual function up to 5 years after end of treatment and compared to baseline. The use of a short, concise PROM, which incorporates validated questions related to LARS in addition to questions on urinary and sexual function, appears to be a useful tool to assess PROs in ASCC patients treated with CMT given the fact that our findings mirror those of other published data that utilize more complex quality of life questionnaires.

Supplementary Material

Supplementary Table 1
Video Abstract (Max Length 2 Minutes)
Download video file (83.3MB, mov)

Funding/Support:

This work was supported by the NIH/NCI Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748).

Footnotes

Financial Disclosures: None reported.

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