Long-Term Sexual Dysfunction and Fertility Outcomes Following Post-Chemotherapy Retroperitoneal Lymph Node Dissection in Testicular Cancer Patients

doi:10.21203/rs.3.rs-8228319/v1

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Long-Term Sexual Dysfunction and Fertility Outcomes Following Post-Chemotherapy Retroperitoneal Lymph Node Dissection in Testicular Cancer Patients

https://doi.org/10.21203/rs.3.rs-8228319/v1

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Background

Since testicular cancer typically affects relatively young patients, retroperitoneal sympathetic nerve injury following post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) may lead to significant sexual dysfunction. This study aims to assess long-term outcomes related to ejaculatory dysfunction, erectile dysfunction (ED), and fertility in patients who have undergone PC-RPLND for advanced-stage testicular tumors.

Methods

Patients who underwent PC-RPLND between 2000 and 2021 were retrospectively contacted via telephone or email. Patients' pre-treatment paternity status, sperm cryopreservation, and post-treatment fertility status were evaluated. The impact of factors such as patient age, tumor laterality, surgical approach, and second-line chemotherapy on ED and ejaculatory dysfunction was analyzed. Erectile function was assessed using the Turkish-validated International Index of Erectile Function-5 (IIEF-5). Statistical analyses were performed using SPSS version 23.0.

Results

The study included patients with a mean surgical age of 28.8 ± 7.7 years and a mean current age of 39.2 ± 9.5 years, with a median follow-up of 116 months (53–290 months). Prior to treatment, 42 patients (38.5%) underwent sperm cryopreservation, while post-treatment, 52 patients (47.7%) expressed a desire for paternity. Paternity status was only predictor for sperm cryopreservation (p = 0.002, OR = 0.186 95%CI 0.062–0.552). Ejaculatory dysfunction (EjD) was reported in 28.4% of patients, with a significantly higher incidence in the fully bilateral template RPLND group compared to the modified template group (67.9% vs. 14.8%, p < 0.001). ED was identified in 37.6% of patients, but no significant associations were found between ED and clinical or surgical variables.

Conclusion

Long-term sexual dysfunction, particularly ejaculatory disorders, remains a significant issue following PC-RPLND, especially in patients undergoing fully bilateral template dissection. Fertility and ejaculation problems associated with this technique may be mitigated through preoperative sperm cryopreservation.

RPLND

PC-RPLND

Sperm cryopreservation

retrograde ejaculation

infertility

sexual dysfunction

Testicular tumors account for approximately 1% of adult cancers, and their incidence has been increasing over the years in industrialized countries (1–3). The introduction of cisplatin-based chemotherapy as a cornerstone of multimodal treatment has advanced testicular tumor management, leading to a significant improvement in survival rates, reaching approximately 60% even in advanced-stage patients with poor prognostic factors (4). Currently, post chemotherapy retroperitoneal lymph node dissection (PC-RPLND) remains a critical component of the multimodal treatment approach for advanced-stage testicular tumors (5).

Retroperitoneal sympathetic nerve injury following PC-RPLND, performed in relatively young patients, highlights the importance of evaluating the risks, incidence, and preventive strategies for potential post-treatment sexual dysfunction, particularly ejaculatory disorders (6). Ejaculatory dysfunction, primarily retrograde ejaculation due to sympathetic nerve disruption (7), along with erectile dysfunction resulting from prior retroperitoneal surgery and chemotherapy-induced infertility, are among the most significant sexual complications associated with testicular cancer treatment (8).

This study aims to investigate long-term ejaculatory dysfunction, erectile dysfunction, and fertility trends in patients who underwent PC-RPLND for advanced-stage testicular tumors.

Between 2000 and 2021, patients who underwent PC-RPLND for advanced testicular tumors were contacted via telephone or email. Exclusion criteria included patients treated for recurrent testicular cancer, those diagnosed with extragonadal germ cell tumors, and individuals who did not provide informed consent for participation. Data were collected on 109 patient age, pre-treatment parity, the use of cryopreservation prior to therapy, post-treatment reproductive intentions, fertility status, and methods employed to achieve fertility. Additionally, patients were asked to complete the Turkish-validated version of the International Index of Erectile Function (IIEF-5).

All patients underwent evaluation with thoracoabdominal computed tomography and tumor marker analysis following orchiectomy. For patients with non-seminomatous germ cell tumors (NSGCT), these assessments were repeated after receiving first-line platinum-based chemotherapy, while Positron Emission Tomography – Computed Tomography (PET-CT) imaging was performed for seminoma cases. Patients in the NSGCT group with persistently elevated tumor markers proceeded to second-line chemotherapy. PC-RPLND was performed in NSGCT patients presenting with a residual retroperitoneal mass larger than 1 cm and in seminoma patients with evidence of viable tumor on PET-CT imaging. Full bilateral template or modified template RPLND was performed at the discretion of the attending surgeon (4, 6).

Sperm cryopreservation was recommended to all patients prior to undergoing orchiectomy and before the initiation of chemotherapy. Patients were stratified into two groups—favorable and non-favorable (comprising intermediate and poor prognosis)—based on the International Germ Cell Cancer Collaborative Group (IGCCCG). The patients were divided into two groups based on primary testicular pathology: seminoma and NSGCT. According to the PC-RPLND pathology, they were categorized into three groups: necrosis, viable tumor, and teratoma. Patients requiring additional procedures during surgery to achieve complete resection, including nephrectomy, bowel repair, aortic or vena caval repair (primary or graft-based), and ureteral repair, were classified as the additional procedure group.

This study was approved by the Ethics Committee of Hacettepe University (Approval No: 2024/21 − 02, Date: 30.07.2024).Statistical analysis was performed using SPSS software (version 23.0, Chicago, IL). Parametric data were presented as mean ± standard deviation (SD), while non-parametric data were expressed as median (min–max). Nominal variables were analyzed using the chi-square test. Group comparisons for parametric data were conducted using the t-test. Variables found to be significant in univariate analysis were further evaluated with multivariate analysis using binary logistic regression.

The mean age at the time of surgery was calculated as 28.8 ± 7.7 years, while the current mean age was determined to be 39.2 ± 9.5 years. The median follow-up period was determined to be 116 months (53–290 months).

Prior to treatment, 42 patients (38.5%) underwent sperm cryopreservation. In univariate analysis, treatment age and paternity status were found to be significantly associated with sperm cryopreservation (p = 0.001, p < 0.0001, respectively). However, in multivariate analysis, paternity status was only predictor for sperm cryopreservation (p = 0.002, OR = 0.186 95%CI 0.062–0.552).

After PC-RPLND, 52 patients (47.7%) expressed a desire for paternity. No significant association was found between post-treatment paternity desire and prior sperm cryopreservation (p = 0.988). Among these 52 patients, 36 (33%) successfully achieved fatherhood. Fourteen of them had cryopreserved sperm, whereas the remainder had not opted for sperm cryopreservation. Assisted reproductive techniques were required in 7 patients from the cryopreservation group and in 3 patients from the non-cryopreservation group (p = 0.018).

Among the study population, a total of 31 patients (28.4%) reported experiencing ejaculation disorders (EjD), while 78 patients (71.6%) reported no issues with ejaculation. The incidence of EjD differed significantly between groups, with a rate of 14.8% in the modified template group and 67.9% in the fully bilateral template group (p < 0.001). No statistically significant associations were identified between EjD and factors such as age, tumor side, pathology (seminoma vs. NSGCT), IGCCCG risk group (favorable vs. non-favorable), additional procedures, second-line chemotherapy, or PC-RPLND pathology (necrosis, teratoma, or viable tumor) (p = 0.681, p = 0.975, p = 0.991, p = 0.400, p = 0.683, p = 0.535, and p = 0.354, respectively) (Table 1).

Table 1

Association of surgical and clinical parameters with postoperative ejaculatory and erectile dysfunction.
Parameters		Ejaculator Dysfunction			Erectile Dysfunction
		absent	present	p	absent	present	p
Operation, n(%)	Bil. full template	9 (32.1)	19 (67.9)	< 0.001	18 (64.3)	10 (35.7)	0.810
Operation, n(%)	Modified Uni. template	69 (85.2)	12 (14.8)	< 0.001	50 (61.7)	31 (38.3)	0.810
Tumor side, n(%)	Right	40 (71.4)	16 (28.6)	0.975	39 (69.6)	17 (30.4)	0.108
Tumor side, n(%)	Left	38 (71.7)	15 (28.3)	0.975	29 (54.7)	24 (45.3)	0.108
Pathology, n(%)	Seminoma	10 (71.4)	4 (28.6)	0.991	8 (57.1)	6 (42.9)	0.664
Pathology, n(%)	NSGHTs	68 (71.6)	27 (28.4)	0.991	60 (63.2)	35 (36.8)	0.664
IGCCC risk group, n(%)	Favorable	59 (73.8)	21 (26.8)	0.400	53 (66.3)	27 (33.8)	0.167
IGCCC risk group, n(%)	Non-favorable	19 (65.5)	10 (34.5)	0.400	15 (51.7)	14 (48.3)	0.167
Additional procedures, n(%)	Present	17 (73.9)	6 (26.1)	0.683	14 (60.9)	9 (39.1)	0.908
Additional procedures, n(%)	Absent	57 (69.5)	25 (30.5)	0.683	51 (62.2)	31 (37.8)	0.908
Second-line chemotherapy, n(%)	Present	9 (64.3)	5 (35.7)	0.535	6 (42.9)	8 (57.1)	0.106
Second-line chemotherapy, n(%)	Absent	69 (72.6)	26 (27.4)	0.535	62 (65.3)	33 (34.7)	0.106
PC-RPLND pathology, n(%)	Necrosis	31 (79.5)	8 (20.5)	0.354	24 (61.5)	15 (38.5)	0.989
	Teratoma	39 (66.1)	20 (33.9)		37 (62.7)	22 (37.3)
	Viable tumor	8 (72.7)	3 (27.3)		7 (63.6)	4 (37.6)
IGCCC: The International Germ Cell Cancer Collaborative Group, PC-RPLND: post chemotherapy retroperitoneal lymph node dissection

Analysis of the International Index of Erectile Function-5 (IIEF-5) results revealed that 68 patients (62.4%) had no evidence of ED, while 24 patients (22.0%) experienced mild ED, 14 patients (12.8%) had mild-to-moderate ED, 1 patient (0.9%) exhibited moderate ED, and 2 patients (1.8%) had severe ED. No significant associations were observed between ED and variables such as age, tumor side, surgical approach (modified vs. full template), pathology (seminoma vs. NSGCT), IGCCC risk group, additional procedures, second-line chemotherapy, or PC-RPLND pathology (p = 0.054, p = 0.108, p = 0.664, p = 0.167, p = 0.908, p = 0.106, and p = 0.989, respectively) (Table 1).

This study revealed that sperm cryopreservation did not correspond with actual paternity desires after a ten-year follow-up. Use of a modified template RPLND substantially improved ejaculatory outcomes following surgery. No additional factors were found to significantly affect postoperative ejaculatory function. Moreover, although ED may occur after RPLND, neither surgical technique nor patient-related factors such as age or tumor characteristics demonstrated a significant impact on postoperative erectile function.

The postganglionic sympathetic fibers responsible for facilitating antegrade ejaculation traverse dorsally to the inferior vena cava and ventrally to the aorta, ultimately converging to form the hypogastric plexus on the ventral aspect of the aorta, caudal to the origin of the inferior mesenteric artery. This sympathetic nerve plexus is situated within the surgical field during RPLND, and intraoperative injury to these fibers may impede the physiological mechanism of antegrade ejaculation. Despite the potential for recurrence beyond standard template boundaries, advances in the understanding of testicular lymphatic drainage have led to the development of template-based dissection models in RPLND (7, 9–11). These models, characterized by a more restricted contralateral dissection approach, aimed to reduce surgical complications and preserve ejaculatory function. Subsequently, nerve-sparing techniques were adopted to preserve antegrade ejaculation during RPLND (12). Consistent with these findings, patients in this cohort treated with modified unilateral template PC-RPNL showed positive results on ejaculation.

ED occurs at a moderate rate among testicular cancer survivors. In line with our findings, its reported incidence ranges from 12% to 40% (8, 13–15). Identifying the precise etiology remains challenging, as survivors often undergo different treatment modalities. Proposed contributing factors include both organic and psychological components. Emerging evidence also points to non-vasculogenic mechanisms, potentially influenced by adrenergic activity and anxiety-related pathways (8). Furthermore, irrespective of the RPLND approach, the procedure itself may impair erectile function. Because recovery of normal erectile function is significantly compromised following both primary and post-chemotherapy RPLND (16), appropriate andrological evaluation and management are warranted in patients undergoing PC-RPLND.

Sperm cryopreservation for fertility preservation is a crucial part of pretreatment management of testicular cancer as the treatment of testicular cancer, especially chemotherapy has a detrimental effect on sperm quality. Even before treatment, semen quality may be low in patients diagnosed with testicular cancer (17). In a study of 173 semen samples from 67 patients with testicular cancer who cryopreserved sperm prior to treatment, Hotaling et al. reported that men with seminoma exhibited poorer total motility counts after thawing. The authors concluded that patients with seminoma histology or a lower fresh total motility count (< 25–30 million) should consider preserving additional vials before initiating oncologic therapy (18).

This study has several limitations. Its retrospective, single-center design introduces potential recall and selection bias, limiting generalizability. The long study period spanning two decades adds variability due to evolving surgical techniques, chemotherapy protocols, and fertility preservation strategies. Outcomes relied on self-reported data—paternity rather than semen analysis and the brief IIEF-5 tool—which may not fully capture fertility or sexual health. Finally, surgical approach (full bilateral vs. modified template RPLND) was based on surgeon discretion, introducing additional variability.

Despite its limitations, this study has several important strengths. It represents one of the largest cohorts reported in the literature, with long-term follow-up offering rare insights into late treatment effects. Clinically relevant outcomes—ejaculatory function, ED, and fertility—were comprehensively evaluated in conjunction with demographic and treatment variables. Notably, comparison of surgical approaches underscores the benefits of modified template RPLND, and the study contributes valuable long-term, real-world evidence to a limited body of literature.

The feasibility of nerve-sparing techniques and modified template dissection may be limited in patients with advanced tumor burden. Given the young age and favorable long-term survival of this cohort, comprehensive preoperative counseling is essential, emphasizing sperm cryopreservation, the risk of retrograde ejaculation, and potential postoperative management. Such measures support informed decision-making and help optimize long-term quality-of-life outcomes.

Competing interests

All authors declare no competing interests.

Ethics approval and consent to participate:

Ethics approval was obtained from the Ethics Committee of Hacettepe University with the study number of SBA 24/787, on 10.12.2024 with 2024/21-02 approval number.

Funding: None

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No competing interests reported.

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Long-Term Sexual Dysfunction and Fertility Outcomes Following Post-Chemotherapy Retroperitoneal Lymph Node Dissection in Testicular Cancer Patients

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Abstract

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INTRODUCTION

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RESULTS

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