Hormones, muscles and oncological outcome in men with rectal cancer

Abstract

Paper I. The aim was to elucidate if testosterone (T) dose-dependently increase muscle size in abdomen and pelvis, analogous to the known anabolic influence on appendicular muscles. Participants were young (age 18-50) healthy men participating in the 5a-reductase trail, a double blinded RCT. Endogenous T production was supressed and replaced with four dosages (50, 125, 300, or 600 mg) of T enanthate. Magnetic Resonance Imaging scans from baseline and end of study was used to analyse change in muscle areas of the lower trunk and pelvis. The estimated change (95% CI) of muscle area increase per 100 mg of T enanthate dosage increase was 0.622 cm2 (0.394, 0.850) for psoas; 1.789 cm2 (1.317, 2.261) for paraspinal muscles; 2.530 cm2 (1.627, 3.434) for total abdominal muscles; 0.455 cm2 (0.233, 0.678) for obturator internus; 0.082 cm2 (0.003, 0.045) for ischiocavernosus. Areas were also associated on-treatment T and free T levels. In conclusion, the abdominal and pelvic muscle are responsive to T administration, opening up for future studies regarding T treatment in frail men with risk for falls and men with pelvic dysfunction.

Paper II. Preoperative radiotherapy (RT) is used in treatment of rectal cancer (RC) to enhance local control. Acute testicular failure with risk for permanent damage to T production is a less known adverse effect of RT. The aim was to elucidate long-term effects on T production, and the association of elevated luteinizing hormone (LH) and cancer recurrence. This was a longitudinal prospective cohort study including men with rectal- or prostate cancer stage I-III. Exposure was RT, quantified by mean cumulative testicular dose (TD). Testicular function was assessed by sampling of T, LH and follicle stimulating hormone (FSH) at baseline and at follow-ups after one and two years. Exposed men were additionally sampled preoperatively. Within two years after surgery, T levels recovered, but LH and FSH levels were significantly higher in exposed. Changes in LH and FSH were related to TD. Elevated LH one year after surgery inferred an incidence rate ratio for cancer recurrence in five years of 3·19 (95% C.I.: 0·97-11.2, mid-p=0·036).

Paper III. The aim was to analyse the impact of RT induced primary testicular failure on severe postoperative adverse events (AE, Clavien-Dindo grade 3+) in men treated for RC. 104 men were included from the previous cohort study. T and LH were sampled at baseline and after RT. The association between of primary testicular failure and severe postoperative AE was analysed using longitudinal regression. 25% had severe postoperative AE (AE+). Baseline data did not differ significantly between groups. The AE+ group had comparably higher LH/T-ratio after RT. 0.603 (0.2-2.5) vs 0.452 (0.127-5.926, p=0.035). The longitudinal regression analysis found that preoperative change in T (OR 0.844, 95% CI 0.720-0.990, p=0.034), LH/T-ratio (OR 2.020, 95% CI 1.010-4.039, p=0.047) and low T (<8 nmol/L, OR 2.605, 95 CI 0.951-7.139, p=0.063) were associated to severe postoperative AE. Preoperative RT induced decline in T seems to be a risk factor for severe postoperative AE in men with RC.

Paper IV. Sarcopenic signs have been related to worse cancer specific survival and the skeletal muscles in men are sensitive to T. The effect of RT induced testicular failure may therefore be of importance in men treated for RC. Based on the cohort study in Paper II, 102 men with RC were included. Using CT or MRI scans from routine examinations at baseline and one year after surgery, skeletal muscle (SM) area at 3rd lumbar vertebra was measured. Testicular function was evaluated by measurement of serum T and LH. The association between change in T (and calculated free T) and SM as well as systemic cancer recurrence and SM were analyzed. Change in free T level is associated with change in psoas major area (p=0.005) and abdominal muscle area (p<0.001). Systemic cancer recurrence was associated with changes in total SM area (-5.96 (-10.7 - -1.24) cm2, p=0.013).

In conclusion, Abdominal and pelvic muscles are as androgen sensitive as appendicular muscles, and impaired testicular endocrine function due to RT impacts muscle area. Preoperative decrease in T increase risk of severe postoperative AE. Elevated LH and decreased muscle area are associated with systemic cancer disease.