Adverse effects of treatment for rectal cancer : sexual function, hormones, and bone health

Abstract

Thanks to improved outcomes from multimodal rectal cancer (RC) treatment, long-term survival is increasing; thus, focus on the long-term adverse effects of treatment is required. This thesis aimed to increase knowledge regarding adverse effects to enable well-informed treatment decisions and accurate management of the side effects. Studies I–IV were part of a multicentre, prospective cohort study including 142 females with RC stage I–III from 2008 to 2013. Clinical data and blood samples for hormone and bone biomarker analysis were collected at baseline, after (chemo)radiotherapy (C)RT, and at one year. Questionnaires on sexual function (Female Sexual Function Index; FSFI) and psychological well-being were completed at baseline and one- and two-year follow-up, and on bowel function at two years.

Female androgens are produced in the ovaries, adrenals and by peripheral conversion. Study I explored the impact of preoperative RT on ovarian androgen production and the association between androgens and sexual desire. Testosterone (T), free T, androstenedione (A-4), and dehydroepiandrosterone sulfate (DHEAS) were assessed and compared between non-oophorectomized females treated with RT and surgery (RT+) vs surgery alone (RT-) (N=125). Radiotherapy was associated with a decrease in the androgens predominantly produced in the ovaries (T and free T). Changes in serum levels of all measured androgens were associated with sexual desire.

Rectal cancer treatment negatively affects sexual function, with data being more robust for males than females. Study II aimed to assess sexual function and its association with RT in females. The FSFI scores were assessed in all women who completed the questionnaire at least once during the two years follow-up (N=139). Total and domain scores were compared within and between the treatment groups (RT+ vs RT-), and the associations between RT and change in FSFI scores were explored in multivariable models. Radiotherapy was associated with a decline in FSFI total score and the domain scores of arousal, lubrication, orgasm, and pain. A secondary aim was to assess ovarian reserve. Anti-Müllerian hormone was measured in premenopausal females (N=9) and became undetectable after RT.

Data indicate that androgens are important for female sexual function. The role of endogenous androgen levels in sexual function was not previously investigated in females with RC. Study III explored the association between endogenous levels of the four androgens specified above and FSFI scores among sexually active females (N=99). Increasing levels of T and A-4 were associated with increased FSFI total score, and at least any of T, free T, and A-4 were associated with the FSFI domains of sexual arousal, lubrication, orgasm, or pain.

Pelvic insufficiency fractures are a complication of RT for RC. Serum bone biomarkers reflecting the bone remodelling process have been suggested as useful in assessing bone health. Study IV assessed four bone biomarkers in 134 participants, explored their changes after RC treatment, and if the changes were associated with RT. The prevalence of bone damage was evaluated in a subgroup with magnetic resonance imaging (N=41). Two bone formation markers increased significantly in the RT group between baseline and one year. In the multivariable analysis, RT was associated with an increased level of one of these markers. Bone damage was present in 16 of 38 females who had RT in the subgroup.

Study V investigated if patients were given information regarding sexual side effects. Two surveys were directed at physicians and RC patients, respectively; the numbers participating were 186 and 253. Among physicians, approximately half reported that they addressed sexual side effects before treatment, with more than half of the patients and more males than females. Almost half of the patients recalled getting information before treatment. High age, poor physical status among patients, and short clinical experience among physicians decreased the odds of information being provided.

In conclusion, the results indicate that RT negatively affects sexual function, androgens, and bone health and show room for improvement in the pre-treatment information about and follow-up of sexual side effects with patients.