Impact of Treatment Technique on Testicular Dose and Sexual Activity in Rectal Cancer Patients

Irradiation of the pelvis is an essential component of the contemporary multidisciplinary approach to treat locally-advanced rectal cancer. Neoadjuvant therapy consisting of concurrent radiation and 5-fluorouracil (5-FU) chemotherapy prior to surgery has been shown to improve both recurrence-free and overall survival rates in patients with locally-advanced rectal cancer. Patients who are of reproductive age run a significant risk due to the presence of seminiferous tubules adjacent to the radiation treatment field. Even a single dose as low as 0.78 Gy is sufficient to cause azoospermia in almost all cases.1 2 3 4 5 6

More focus has been placed on the adverse effects of the multimodal treatment in recent years as a result of an increase in the percentage of patients with advanced rectal cancer who are still alive.7

In terms of the effects of radiation on the testicles, there are two distinct compartments. First, the highly radiosensitive seminiferous tubules, which is the site of spermatogenesis in the male reproductive system. Second, the Leydig cells, which are those that produce testosterone, are thought to be less radiosensitive than spermatogonia.8 Recovery depends on the dose that was administered; a treatment of more than 2 Gy will, in most patients, result in azoospermia that is irreversible.8 It has been shown9 that exposure to fractionated radiation, which is the most prevalent kind of therapeutic radiation exposure, is more harmful to the germline cells than exposure to a single dose of radiation.

If the therapy causes hypogonadism, this may have a profound impact on quality of life (QoL). This is frequently demonstrated by subtle changes, such as a reduction in lean body and muscle mass, as well as the development of psychological problems, such as a loss of libido, energy, and drive, or even depression and anxiety.1 10 11

Hence in the present study, we determined the radiation doses that were administered to the testicles of male patients undergoing radiotherapy (RT) for the treatment of rectal cancer. We paid particular attention to the dose contribution of different radiation-delivery techniques to the testicles. In addition, we analyzed the effect of the treatment on sexual life using a QoL questionnaire. This research was submitted to and approved by the Ethics Committee under submission number KMIO/MEC/011/03.2018.

In the present study, the median age of the sample was of 38 years, and most patients presented moderately-differentiated adenocarcinomas, most commonly of 1b nodal status, T2 tumor stage, and Tumor, Node, Metastasis (TNM) stage IIIC; moreover 26/40 participants had a PTV ranging from of 1,000 to 1,500 cc.

The overview of the factors assessed in the study (Table 1) shows that 31 (77.5%) patients completed the minimum follow-up period. The comparison of three techniques regarding the length and thickness of the tumor, as well as the distance from anal verge, showed no statistically significant difference (Table 2).

The dose of radiation delivered by IMRT to both right and left testis and the external genitalia was higher in patients in stage IIA than in those in stage IIIC (Fig. 1). However, this difference was not statistically significant. Whereas PTV coverage with IMRT and its dose contribution to external genitalia, was found to be statistically significant (p = 0.007).

The dose delivered to the right testis by 3DCRT was higher in patients in stage IIIC, but was higher in the left testis and external genitalia in subjects in stage IIA (Fig. 2). However, this difference was not statistically significant. The dose delivered to the right and left testis and the external genitalia correlated with PTV > 1,500 cc. But when the testicular volume was compared to the PTV, no statistically significant difference was observed.

When VMAT protocol was delivered, the radiation dose to the right and left testis and the external genitalia was compared with the staging. There was a statistically significant difference regarding the stages of rectal cancer and the dose delivered to the left testis. However, when we compared the dose delivered to the PTV, there was no statistically significant difference regarding the right and left testis and the external genitalia (Table 3).

The 31 patients who were alive were submitted to a QoL analysis in terms of sexual activity: 4 patients did not respond, but the 27 patients who responded said they had resumed sexual activity without difficulty (score of 4). Most subjects had resumed their normal sexual life three months after the treatment. All patients reported that the main reason for delay in resuming sexual activity was nervousness about disease recurrence.

The present study results shows that treatment technique and PTV bear an influence on the incidental testicular dose, and it also highlights whether or not the tumor length and thickness, as well as the distance from the anal verge contribute enough to have an impact. One of the most interesting aspects of the study is the assessment of sexual life, which is also an integral QoL domain.

Various studies in literature have evaluated changes in the testicular dose among patients receiving external-beam RT for pelvic malignancy. Piroth et al.14 evaluated the dose to the testicles from scattered irradiation following RT for rectal cancer. A total cumulative dose of 50.4 Gy was administered to 18 patient susing a 3-field method during their treatment. The cumulative dose to the testicles was of 1.6 (0.98–3.19) Gy, which is almost half of the dose that was measured in a study conducted by Hermann et al.,1 whose findings o were comparable to those of the present study. This could be the result of discrepancies between the studies in the distribution of the site of the tumor, and in the treatment and immobilization procedures used (four-field versus three-field method), as well as the treatment volumes. External beam radiation administered to the pelvis using a four-field approach for the treatment of prostate and rectal cancers has been demonstrated to result in a radiation dose to the testicles that falls somewhere in the range of 200 to 400 cGy.1 3

Martin et al.2 assessed a cohort of 16 patients with prostate cancer and found that the mean dose to the testicles was minimal regardless of the modality used: the value ranged from 21.1 to 93.4cGy, with a maximum value lower than 400 cGy. Accidental irradiation of the testicles due to the use of IMRT to treat prostate cancer was reported by King et al.5 Within the scope of their research, they considered the additional contribution of the dose brought about by factors such as field size, beam energy, and the use of daily imaging guiding.5 A prostate-alone field treated with 6-megavolt (MV) photons resulted in a mean testicular dose of 68cGy, while a pelvic nodal field treated with 15-MV photons resulted in a mean testicular dose of 220cGy.5

We would like to point out that most of the trials in the literature evaluate incidental testicular RT dose in prostate malignancy, whereas there is very limited data on dose contribution in carcinoma of the rectum. And even in those studies, a major limiting factor is the assessment restricted to the 3 and 4-field RT delivery techniques. Hence, the analysis of the contribution of the radiation dose performed in the present study, with currently-employed conformal techniques (3DCRT, IMRT, and VMAT) in the treatment of rectal cancer around the world, is helpful in providing the much needed data.

In our institutional Scientific Review Board, it was pointed out to us the non-inclusion/non-utilization of testicular shielding, prone position, dose beyond 25 fr as a boost, and short-course RT. In the routine clinical practice, testicular shielding is not included in the treatment of carcinoma of the rectum, and since we perform long-course RT, with 45Gy/25fr as per the institutional protocol based on ACCORD 12/0405 PRODIGE 2 randomized trial,15 an additional RT dose was not delivered beyond planned 25 fr. However, we do agree that a comparison of the variations in position could have added further weight to the present study.

One of the major limitations to the present study was the lack of assessment of testosterone levels prior to, during, and after the treatment. Since the planned treatment for rectal cancer was neoadjuvant therapy followed by mesorectal excision, the goal of the study was to assess whether there is any toxicity in the routine treatment practice; hence, we did not assess the testosterone levels in the present study.

In a review, Cherven et al.16 stated that one of the most prevalent and upsetting side effects of cancer treatment is sexual dysfunction. It has been demonstrated16 that severe sexual dysfunction has a detrimental impact on QoL. Many survivors do not feel prepared for potential sexual changes and frequently do not receive adequate support to manage this issue, even though there are many intervention strategies that can help patients cope with treatment-related sexual problems.

In the current study, we found that many patients were reluctant to resume their sexual life out of concern about recurrence, fear of transferring an illness to the spouse/partner, and a feeling of embarrassment to discuss their sexual life with the clinicians or even with their spouse/partner. Most patients started showing improvements in QoL at the third month of follow-up, once they had gained enough confidence. According to a review by Bober and Varela,17 various factors, including emotional trauma and treatment outcomes, have an impact on QoL and sexual activity.

The main idea behind the present study was to assess if the conformal techniques used to treat carcinoma of the rectum can lead to sexual dysfunction due to incidental testicular dose or not. The study findings shed light on the need to address the physical aspect of treating the disease, as well as the psychosocial, sexual and emotional aspects associated with the treatment; the findings also highlight the need for comprehensive patient counseling to clear any doubts which may hinder cancer survivals to resume their normal lives,. thereby mitigating any apprehensions faced by the patients and their spouse/partner while making treatment decisions based on the suggestions made by the clinicians.

In the current study, IMRT showed a significant reduction in the testicular dose when compared to 3DCRT and VMAT, the PTV had a statistically significant impact on the testicular dose, and, after the third month of follow-up, most patients resumed their sexual life.