Sequelae after multimodal treatment of rectal cancer

<p dir="ltr">In recent decades, rectal cancer treatment has shifted from traditional surgical resection to include additional modalities such as radiotherapy and chemotherapy, leading to improved oncological outcomes and long-term survival. As a result, functional outcomes after treatment have become increasingly important, especially as the incidence of rectal cancer among young adults is rising. Because the rectum is close to other pelvic organs, including the bowel, bladder, female and male genitals, as well as essential pelvic nerves and blood vessels, these structures may be affected by rectal cancer treatment. This thesis aimed to assess the impact of multimodal treatment for rectal cancer on bowel function, testicular function, and sexual function.</p><p dir="ltr">Ileostomies are often performed in patients undergoing low anterior resection for rectal cancer to reduce the clinical impact of anastomotic leakage; however, they are associated with an increased risk of postoperative dehydration and acute renal failure. Identifying patients at risk is essential to prevent postoperative morbidity and reduce hospital resource use. In <b><i>Study I</i></b>, the effect of preoperative use of antihypertensive drugs on the risk of readmission within 90 days following ileostomy formation for rectal cancer was examined in a national register-based study including 3252 patients. Use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and diuretics was associated with a two- to threefold increased risk of readmission within 90 days due to dehydration, mainly occurring during the first 2 to 3 weeks after discharge.</p><p dir="ltr">Radiotherapy is known to have gonadotoxic effects, however, knowledge about its impact on testicular function in rectal cancer is limited. <b><i>Studies II and III</i></b> are based on data from an original cohort study designed to assess the effect of preoperative radiotherapy for rectal cancer on testicular function. From the original cohort, 104 men with stage I - III rectal cancer treated with abdominal resection with or without radiotherapy, and 59 men with stage I - III prostate cancer treated with prostatectomy alone were included. Blood samples, semen samples, and patient-reported outcome measures were collected at baseline before oncological treatment, and at one and two years after surgery. For those receiving radiotherapy, an additional blood sample was taken the day before surgery. In <b><i>Study II</i></b>, a decline in sperm count and semen volume was observed in 21 men with rectal cancer who had available semen samples, along with a transient decline in inhibin and a consecutive increase in follicle-stimulating hormone in all 104 men with rectal cancer, suggesting Sertoli cell dysfunction following radiotherapy for rectal cancer. The changes in sperm count and hormone levels were associated with testicular dose. In <b><i>Study III</i></b>, a transient decline in serum testosterone and a consecutive increase in luteinizing hormone were observed in 91 men with rectal cancer who received preoperative RT, suggesting Leydig cell dysfunction following RT for rectal cancer. The changes in hormone levels were associated with testicular dose as well as patient-reported outcome measures for sexual function and testosterone deficiency, assessed by the IIEF-15 and AMS questionnaires, respectively.</p><p dir="ltr">Treatment for rectal cancer impairs sexual function, and genital fibrosis resulting from radiotherapy, surgery, and sexual inactivity limits the potential for postoperative recovery. <b><i>Study IV</i></b> is based on data from a multicenter, open label, randomized controlled trial aimed at evaluating the effect of early and continuous PDE5 inhibition on the recovery of sexual function in women and men treated for rectal cancer. The trial was open to both women and men and consisted of two phases: the intervention phase (baseline to six months after surgery) and the observational phase (six to 24 months after surgery). Adult sexually active patients undergoing surgical resection for stage I – III rectal cancer were eligible. All patients received oncological treatment according to national guidelines and were offered a standardized rehabilitation program for sexual function. The intervention, tadalafil 5 mg daily, was started before cancer treatment and discontinued six months after rectal cancer surgery. Randomization was performed in a 1:1 ratio stratified by neoadjuvant radiotherapy and sphinctersaving surgery. The primary outcome, longitudinal change in sexual function, was assessed monthly during rectal cancer treatment and for 24 months postoperatively using the FSFI-6 (women) and IIEF-5 (men) in a web-based questionnaire. In <b><i>Study IV</i></b>, the external validity was assessed by comparing recruitment data with population-based data from the SCRCR, and safety data were presented based on adverse event reporting. Recruitment ended early due to a low inclusion rate and limited resources, resulting in 30 women and 63 men being included. Compared to population-based data, estimated enrollment rates were 7.9% for women and 9.5% for men. Included participants were generally younger, healthier, and a high proportion had partners. Adverse events potentially related to the study medication were mild to moderate and consistent with the published side-effects of tadalafil. Data collection is ongoing, with the end of follow-up planned for October and September 2026.</p><h3 dir="ltr">List of scientific papers</h3><p dir="ltr">I. <b>de la Motte L,</b> Nordenvall C, Martling A, Buchli C. Preoperative use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and diuretics increases the risk of dehydration after ileostomy formation: population-based cohort study. BJS Open. 2024 May 8;8(3). <a href="https://doi.org/10.1093/bjsopen/zrae051" rel="noreferrer" target="_blank">https://doi.org/10.1093/bjsopen/zrae051</a></p><p dir="ltr">II. <b>de la Motte L,</b> Custovic S, Tapper J, Arver S, Martling A, Buchli C. Effect of preoperative radiotherapy for rectal cancer on spermatogenesis. BJS. 2021 Jul 23;108(7):750-753. <a href="https://doi.org/10.1093/bjs/znab019" rel="noreferrer" target="_blank">https://doi.org/10.1093/bjs/znab019</a></p><p dir="ltr">III. <b>de la Motte L,</b> Tapper J, Arver S, Holm T, Segelman J, Jasuja R, Martling A, Buchli C. Long-term impact of preoperative radiotherapy for rectal cancer on testicular function. Eur J Surg Oncol. 2025 Sep 19;51(11). <a href="https://doi.org/10.1016/j.ejso.2025.110458" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.ejso.2025.110458</a></p><p dir="ltr">IV. <b>de la Motte L</b>, Rosen H, Sjövall A, Ahlberg M, Segelman J, Deborah S, Mijaljevic L, Lydrup M-L, Flöter Rådstad A, Arver S, Martling A, Buchli C. Early intervention and recovery of sexual function in women and men after rectal cancer treatment – external validity and safety of a randomized controlled trial with tadalafil compared to standard care. [Submitted]</p>