# Radiation Oncology/Toxicity/Testis

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Testicular RT Tolerance
* Spermatogenesis
** Radiation sensitivity to single fraction diminishes rapidly with progression along maturation pathway
*** Spermatogonia: 0.1-0.2 Gy; spermatocytes 10x less sensitive: 2-3 Gy; spermatids 40x less sensitivie: 4-6 Gy
*** Azoospermia after low doses (<2 Gy) takes 60-70 days due to damage to spermatogonia. After higher doses (>4 Gy), azoospermia develops much faster due to concurrent damage to spermatids
*** Recovery of spermatogenesis is driven by recovery of spermatogonia and is dose-dependent. Sperm recovery after <1 Gy takes 1-1.5 years. After 4-6 Gy, it may take 2-5 years. After 6-8 Gy, permanent azoospermia likely although University of Washington data from TBI show spermatogenesis can recover after 10 Gy single fraction in 20% patients
** Spermatogenesis more sensitive to fractionated damage than single fraction damage due to long (~16 day) cell cycle of stem cells
*** Fractionated doses 0.7-0.9 Gy lead to oligospermia/azoospermia but with frequent recovery at 1-1.5 years. Permanent azoospermia may occur after fractionated doses as low as 1.2 Gy, and is likely >2 Gy. However, University of Washington data from TBI show spermatogenesis can recover after 12-14 Gy fractionated in ~17% patients
* Endocrine function
** Subtle Leydig cell dysfunction can be seen after cumulative 2 Gy in fractionated therapy, although testosterone serum levels are clinically not impaired
** Testosterone production impaired at 14 Gy in 2 Gy/fx

## Effect on Spermatogenesis

Review
* Manchester, 2005 (UK) PMID 15784814 -- "Spermatogenesis after cancer treatment: damage and recovery." (Howell SJ, J Natl Cancer Inst Monogr. 2005;(34):12-7.)
** Review. Spermatogonia: 0.2 Gy
** FSH levels: 0.2 - 0.7 Gy cause transient dose-dependent increase in FSH and decrease in sperm concentration. Normalized in 12-24 months
** Azoospermia: no threshold dose identified; doses >1.2 Gy reduced likelihood of spermatogenesis recovery

## Effect on Testosterone

* Review: Princess Margaret, 1995 PMID 7792393 -- "Leydig cell function and radiation: a review of the literature." (Izard MA, Radiother Oncol. 1995 Jan;34(1):1-8.)
* Copenhagen, 2002 (Denmark) PMID 11896102 -- "Effect of graded testicular doses of radiotherapy in patients treated for carcinoma-in-situ in the testis." (Petersen PM, J Clin Oncol. 2002 Mar 15;20(6):1537-43.)
** Prospective. Dose reduction starting at 20/10 in 2 Gy steps. Results verified by biopsies
** Remission in all patients at 20, 18, and 16 Gy. One relapse at 14 Gy after 20 months
** Toxicity: Leydig cell function - stable testosterone decrease for >5 years after RT, at rate ~4%/year. Median time-to-decrease 3 months. No obvious dose-reponse between 14-20 Gy. No impact on serum estradiol or DHT. Need for androgen substitution similar at all RT dose levels; 43% of available patients required androgen substitution for clinical symptoms of androgen insufficiency
** Conclusion: Androgen production impaired even at 14 Gy

## Both

* National Cancer Institute; 1985 (1977-1981) PMID 3928830 -- "Effects of fractionated irradiation of endocrine aspects of testicular function." (Shapiro E, J Clin Oncol. 1985 Sep;3(9):1232-9.)
** Retrospective. 27 males with soft tissue sarcoma, treated with surgery + adjuvant RT. Dose 45/25 + 9-18 Gy boost. No adjuvant chemo. Direct TLD measurement in 17 patients, extrapolations in rest. Testicular dose from scatter RT ranged from 0.01 - 25 Gy. Dose groups <0.5 Gy, 0.5-2 Gy, and >2 Gy
** Serum FSH: peak at 6 months, then rapid decline 6-12 months, then slow decline thereafter. If dose <0.5 Gy, return to baseline, if dose 0.5-2 Gy or >2 Gy, not complete recovery and dose dependent
** Serum LH: peak at 6 months, then decline 6-18 months, then further gradual decline. Statistically significant elevation from baseline only if dose >2 Gy
** Serum testosterone: No significant change
** Conclusion: Subtle Lyedig cell dysfunction may occur at fractionated doses >2 Gy
* University of Washington
** 1983 (1970-1980) PMID 6412404 -- "Late effects on gonadal function of cyclophosphamide, total-body irradiation, and marrow transplantation." (Sanders JE, Transplantation. 1983 Sep;36(3):252-5.)
*** Retrospective. 137 patients, bone marrow transplant, survival >1 year after transplant, after puberty. 72 men conditioned either with chemotherapy (n=31) or chemo+TBI (n=41). TBI 9.2-17.5 Gy
*** Outcome:
**** Chemo conditioning: normal LH 97%, normal FSH 65%, spermatogenesis 67%
**** Chemo + TBI conditioning: normal LH 88%, normal FSH 24%, spermatogenesis 6%. All men had gonadal failure for 5 years after TBI, 2/7 patients followed >5 years recovered spermatogenesis. 1 patient fathered 4 normal children
*** Conclusion: Cyclophosphamide doesn't prevent normal gonadal function in most men; TBI does in majority of patients
** 1996 (1971-1992) PMID 8639928 -- "Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation." (Sanders JE, Blood. 1996 Apr 1;87(7):3045-52.)
*** Retrospective. 618 postpubertal men, treated with BMT. TBI in 75%. TBI 10/1, 12/6, 14/7, or 15.75/7 fractions
*** Outcome: recovery of testicular function for TBI men 17% (CY 61%, BUCY 17%, TBI-10 20%, TBI-12 16%, TBI-14 18%). Partners of 35 male patients (CY 80%, BUCY 6%, TBI 14%) became pregnant, resulting in 82% live births (4 spontaneous and 7 elective abortions). Pregnancy rate for male TBI patients 5/618 (0.8%). Abortion rate comparable to general population. Partners of TBI patients didn't seem to have high risk pregnancies
*** Conclusion: Testicular recovery after TBI ~17%, pregnancy rate for partners ~1%
* Swedish Hospital Seattle, 1974 (1963-1973) PMID 4428015 -- "Effect of graded doses of ionizing radiation on the human testis." (Rowley MJ, Radiat Res. 1974 Sep;59(3):665-78.)
** Prospective. 67 volunteers, health 25 - 52 year old. Single dose escalation to human subject testis 0.8 Gy to 6 Gy, contralateral testis served as control
** Gonadotropins: plasma FSH slightly elevated at 0.2 Gy, highly elevated at 0.75 Gy; plasma LH elevated at 0.75 Gy. Plasma testosterone no significant change
** Spermatogenesis: At 0.5 Gy, marked oligospermia; At 0.8 Gy total azoospermia; at 2-3 Gy, recovery took ~30 months; at 4-6 Gy, recoverey took >5 years; at 6-8 Gy irreversible azoospermia. At 6 Gy, histologic recovery of germinal cells took place ~1.5 years before sperm were produced

## References

* Textbook: Radiation Oncology - Radiobiological and Physiological Perspectives: The Boundary-Zone Between Clinical Radiotherapy and Fundamental Radiobiology and Physiology, Awwad HK, 1990