Abstract
This cohort study examines quality-of-life and functional outcomes among participants in a clinical trial of total neoadjuvant therapy for advanced rectal cancer.
Introduction
Locally advanced rectal cancer has traditionally been treated with preoperative chemoradiotherapy and total mesorectal excision. Despite effective local control, distant metastasis rates exceed 25%.1 Total neoadjuvant therapy (TNT) facilitates organ preservation and reduces metastases through up-front systemic chemotherapy, and is replacing traditional treatment in quaternary centers.2 However, patient quality of life following this novel approach has not been extensively measured. We therefore assessed longitudinal patient-reported quality of life in a phase II clinical trial of TNT.
Methods
We analyzed patient-reported quality of life outcomes from a single-group trial of FOLFOXIRI following short-course radiotherapy among adults with rectal adenocarcinoma. In this previously published trial, 23 participants (62.2%) demonstrated clinical complete response at the primary post-TNT outcome assessment and 18 (48.6%) pursued organ preservation.3 Patients completed the Memorial Sloan Kettering Bowel Function Instrument (MSKCC-BFI), Low Anterior Resection Syndrome (LARS) questionnaire, International Index of Erectile Function (IIEF), 6-item Female Sexual Functioning Index (FSFI), International Prostate Symptom Score (IPSS), and EuroQoL Group 5-Dimensions Health Questionnaire (EQ-5D) at pretreatment baseline, 8-week posttreatment primary outcome assessment, and 6-, 12-, 18-, and 24-month follow-up, for a data collection period from 2021 through 2025.
Descriptive means were reported; primary analyses used mixed-effect linear models for each outcome with random patient intercepts to account for within-patient correlation. Analysis was conducted using Stata SE version 15.1 (StataCorp LLC). This study was approved by the Stanford University School of Medicine institutional review board. Written informed consent was obtained from all participants. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines for cohort studies.
Results
A total 37 patients enrolled and completed treatment between 2020 and 2023. The median (IQR) age was 52 (44-61) years, 13 patients (35.1%) were female and 10 (27.0%) self-identified as non-White. Most patients (26 [70.3%]) presented with stage clinical T3, and 15 (40.5%) had clinical N1 and N2 disease.
Mean (SD) overall self-rated health among respondents improved from 69.49 (18.47) of 100 at baseline to 80.17 (14.46) of 100 at 24 months, while sexual function worsened (women: baseline, 14.15 [9.20] of 30; 24 months, 13.22 [8.01] of 30; men: baseline, 19.63 [6.08] of 25; 24 months, 13.75 [7.42] of 25). Scores for bowel function (baseline, 64.61 [8.25] of 90; 24 months, 62.47 [10.18] of 90) and urinary function (baseline, 7.24 [5.86] of 35; 24 months, 7.67 [5.74] of 35) indicated mild-to-moderate dysfunction (Figure).
Figure. Line Graph of Longitudinal Health-Related Quality of Life With Health, Bowel, Sexual Function, and Urinary Scores.
Scores included the EuroQoL Group 5-Dimensions Health Questionnaire (EQ-5D) for overall health, Memorial Sloan Kettering Bowel Function Instrument (MSKCC-BFI) for bowel function, International Index of Erectile Function (IIEF) for male sexual function, 6-item Female Sexual Functioning Index (FSFI) for female sexual function, and International Prostate Symptom Score (IPSS) for urinary function.
In mixed-effects models, overall self-rated health improved significantly at later follow-up compared with baseline (mean change: 18 months, 6.49 [95% CI, 0.48 to 12.51]; 24 months, 7.48 [95% CI, 0.72 to 14.24]). Sexual function decreased significantly in men (mean change at 24 months, −4.58 [95% CI, −7.33 to −1.82]) but not in women (−3.93 [95% CI, −8.38 to 0.52]). Bladder function (mean change, 1.39 [95% CI, −0.83 to 3.62]) and bowel function (−2.56 [95% CI, −6.35 to 1.23]) did not differ significantly from baseline at 24 months (Table). Among patients without a stoma, LARS scores improved significantly posttreatment (mean change, −6.55; 95% CI, −11.70 to −1.40) but did not differ significantly from baseline at later time points.
Table. Longitudinal Health-Related Quality of Life Outcomes Among Patients With Rectal Cancer Treated With Total Neoadjuvant Therapy.
| Outcome | Mean change (95% CI) | ||||
|---|---|---|---|---|---|
| Posttreatment | 6 mo | 12 mo | 18 mo | 24 mo | |
| EQ-5 | |||||
| Overall self-rated healtha | 1.64 (−3.93 to 7.22) | −0.19 (−5.84 to 5.46) | −0.09 (−6.10 to 5.92) | 6.50 (0.48 to 12.51) | 7.48 (0.72 to 14.24) |
| Mobilityb | 0.23 (−0.01 to 0.46) | 0.36 (0.13 to 0.60) | 0.18 (−0.07 to 0.42) | 0.17 (−0.08 to 0.42) | 0.34 (0.06 to 0.62) |
| Anxiety or depressionb | −0.22 (−0.46 to 0.03) | −0.19 (−0.44 to 0.06) | −0.04 (−0.30 to 0.22) | −0.31 (−0.58 to −0.05) | −0.20 (−0.50 to 0.10) |
| Self-careb | 0.03 (−0.19 to 0.25) | 0.15 (−0.07 to 0.37) | 0.08 (−0.15 to 0.32) | 0.12 (−0.12 to 0.35) | 0.28 (0.01 to 0.54) |
| Pain or discomfortb | −0.18 (−0.48 to 0.11) | −0.03 (−0.33 to 0.27) | 0.00 (−0.31 to 0.32) | −0.01 (−0.33 to 0.31) | −0.21 (−0.57 to 0.15) |
| Usual activitiesb | −0.00 (−0.34 to 0.33) | 0.19 (−0.15 to 0.53) | 0.16 (−0.20 to 0.51) | −0.17 (−0.53 to 0.19) | 0.08 (−0.32 to 0.49) |
| IPSS Bladder functionb | 0.00 (−1.85 to 1.85) | 1.52 (−0.34 to 3.37) | 2.64 (0.66 to 4.61) | 0.84 (−1.19 to 2.88) | 1.39 (−0.83 to 3.62) |
| MSKCC-BI bowel functiona | 2.59 (−0.51 to 5.69) | −1.53 (−4.80 to 1.74) | −2.23 (−5.62 to 1.16) | −1.81 (−5.21 to 1.58) | −2.56 (−6.35 to 1.23) |
| FSFI female sexual functiona | −0.88 (−5.15 to 3.39) | −4.15 (−8.19 to −0.10) | −2.57 (−6.86 to 1.72) | −3.38 (−8.02 to 1.26) | −3.93 (−8.38 to 0.52) |
| IIEF male sexual functiona | −2.16 (−4.09 to −0.24) | −1.49 (−3.56 to 0.58) | −3.26 (−5.38 to −1.14) | −3.85 (−5.97 to −1.73) | −4.58 (−7.33 to −1.82) |
| LARSb | −6.55 (−11.70 to −1.40) | 1.16 (−4.67 to 6.98) | 0.22 (−5.82 to 6.27) | 2.74 (−3.42 to 8.91) | 0.68 (−6.09 to 7.45) |
Abbreviations: EQ-5, EuroQoL Group 5-Dimensions Health Questionnaire; FSFI, 6-item Female Sexual Functioning Index; IIEF, International Index of Erectile Function; IPSS, International Prostate Symptom Score; LARS, Low Anterior Resection Syndrome; MSKCC-BI, Memorial Sloan Kettering Bowel Function Instrument.
Higher scores indicate better functioning: EQ-5 overall self-rated health (score range, 0-100), MSKCC-BFI (18-90), FSFI (2-30), and IIEF (5-25).
Higher scores indicate worse functioning: EQ-5 individual dimensions (score range, 1-5), IPSS (0-35), and LARS (0-42).
Discussion
In this longitudinal analysis of patient-reported quality of life and functional outcomes in a phase II rectal cancer trial, overall self-reported health improved despite persistent functional deficits. While bowel and bladder function remained largely stable through 24 months, sexual function decreased during follow-up, reaching statistical significance in men. These findings are consistent with prior reports among patients treated with earlier multimodal approaches including surgery, in which clinically significant sexual dysfunction was reported by 85% of women and 67% of men by end of treatment in one study.4
Our findings highlight the importance of evaluating multiple quality of life domains over extended follow-up. The burden of sexual dysfunction warrants further investigation, although estimates were imprecise due to limited sample size, particularly at later time points. Study limitations include small cohort size, particularly in women, and possible bias from attrition. In future research, we plan to compare surgical and nonsurgical patients, although the need for surgery is not yet known prior to deployment of TNT. Despite these limitations, our study provides novel long-term longitudinal quality of life data from patients undergoing TNT. These data can be used to counsel patients as they engage in shared decision making for the new paradigm in rectal cancer treatment.
Data sharing statement
References
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Supplementary Materials
Data sharing statement
