Rectal cancer : aspects on radiotherapy, androgens and body composition

Abstract

Rectal cancer is diagnosed among 1200 men in Sweden every year. Current treatment for local and regional disease implies surgical resection of the rectum often in combination with preoperative radiotherapy (RT). This treatment results in a cancer-specific survival of approximately 90% after three years and a cumulative incidence of local recurrence of 5% after five years. The oncological benefits frequently come at the price of impaired bowel and sexual function with consequences for quality of life. To design a research project with the aim to investigate the effects of preoperative RT on testicular function and sexual health in men treated for rectal cancer a review of the available literature was performed.

The findings of this review (Paper I) showed that the testicular dose (TD) was on average 3% to 17% of the pre- scribed dose for RT. No reports on semen analysis in men treated for rectal cancer were identified. The androgen levels decreased in men treated with RT and the relative risk to have low serum testosterone (T < 8 nmol/l) was 2.7 (95% CI 1.6 to 4.7; p<0.001) after four years. Low serum T was also related to post-treatment erectile dysfunction.

Based on the results of Paper I, a cohort study with preoperative RT as exposure was initiated. One hundred and five men with rectal cancer stage I to III were included between April 2010 and May 2014. To increase the sample size of the unexposed group 63 men with prostate cancer planned to robot-assisted prostatectomy were included additionaly. All participants had a baseline and two follow-up visits 12 and 24 months after surgery to collect blood samples, patient-reported outcome measures and semen samples. Men receiving preoperative RT had an additional blood sample the week prior to surgery.

The planned TD was calculated with the treatment planning system based on the planning computed tomography (CT) in 101 men (Paper II). The median planned TD for short course RT was 0.57 Gy (range 0.06 to 14.37 Gy) and 0.81 Gy (range 0.36 to 10.80 Gy) for long course RT. In 32 men the delivered TD was assessed for each RT frac- tion with repeated cone beam CT. The comparison between planned and delivered TD show that the planned TD is an accurate estimate of the delivered dose. The within-person variability of the delivered TD is related to the posi- tion of the testes in men with moderate to high TD.

The androgen levels at baseline of the entire cohort were similar and independent of the type of preoperative RT or the type of cancer (Paper III). Preoperative RT resulted in a significant decrease of T and increase of luteinising hormone (LH) and LH-T ratio. The risk of low serum T (T < 8 nmol/l) increased from 14.6% at baseline to 35.5% at the time of surgery in men treated with RT corresponding to a relative risk of 2.41 (95% CI 1.57 to 3.71, p<0.001). These findings confirm that preoperative RT leads to primary testicular failure. The preliminary analy- sis indicates a dose-response relationship between the TD and the negative impact on testicular function.

The biochemical signs of testicular failure persisted in 40 men analysed 12 months after surgery (Paper IV). The cross-sectional area of the psoas and erector spinae muscle, assessed on routinely acquired planning and follow-up CT, was related to the level of bioavailable T. The area of subcutaneous tissue was not related to androgen levels. The decrease in these muscle groups is an androgen-dependent sign and identified men with testicular failure that had T levels in the grey zone of hypogonadism one year after surgery.