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The modern multimodal approach to testicular cancer treatment represents one of the success stories of modern oncology, with survival rates >90% . While the exact indications may be controversial, it is indisputable that retroperitoneal lymph node dissection (RPLND) is a vital tool in the management of advanced non-seminomatous germ cell tumour (NSGCT) . In the modern era of treatment for advanced NSGCT, post-chemotherapy (PC) RPLND is an important adjunct in attaining cure for these patients. Apart from enlarged masses or rising serum tumour markers, there are no reliable preoperative predictors for the exclusion of PC-RPLND in appropriate patients after induction chemotherapy [3,4].
With improved survival and decreased morbidity from treatment , focus has shifted to improvements in quality of life, which is negatively affected by the long-term toxicity of treatment. One of the most significant factors after treatment for a patient with testis cancer is fertility. Specific challenges are reduced spermatogenesis secondary to chemotherapy as well as anejaculation after treatment. As testicular cancer strikes at an early age, patients often have yet to start a family. Indeed, in a survey of young cancer survivors, 55% of men who already had children wanted more, and 77% of men without children wanted children in the future .
The aim of the present study was to evaluate fertility outcomes and the effect of the use of a structured clinical pathway in patients referred for infertility after PC-RPLND at a major cancer referral centre.
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Currently, RPLND is an essential tool in the management of advanced NSGCT after induction chemotherapy . Bilateral RPLND damages the lumbar splanchnic nerves and hypogastric plexus resulting in the permanent loss of emission and ejaculation ; however, advances in surgical treatment have allowed sympathetic nerve sparing even in the PC setting, where fibrosis and desmoplastic reaction of tumour to chemotherapy makes identification and sparing of nerves exceedingly difficult [8–13]. At our institutions, ≈40% of patients needing PC-RPLND are candidates for nerve-sparing surgery, and modern series of patients who have undergone nerve-sparing PC-RPLND report preservation of some antegrade ejaculation in 74–96% of cases [8,11,14–16].
While ‘dry ejaculate’ is often the outcome measured in oncological studies, in reality a lack of seminal fluid at the time of orgasm may be attributable to either RE or FOE. RE, in which seminal fluid travels into the urinary bladder, is attributable to incompetence of the bladder neck. Thus, with orgasm, little or no seminal fluid is ejaculated. FOE, on the other hand, is the complete absence of seminal fluid deposition into the prostatic urethra. This represents greater damage to the innervations of the seminal vesicles and the prostate.
Conventional treatment for those who are anejaculatory often includes the use of sympathomimetics to enable antegrade ejaculation. For those who fail, a retrograde specimen can be obtained from the urinary bladder by catheterization. This is followed by use of EEJ or surgical sperm retrieval. There are very few data to guide treatment selection after chemotherapy in these patients with testicular cancer. Jacobsen et al. , in their series of PC-RPLND patients had 9 anejaculatory patients, of which 7 utilized cryopreserved sperm while two were successfully treated with sympathomimetics. Rosenlund et al.  found a live birth rate/ongoing pregnancy rate in 11/15 couples where collection was mostly by EEJ. Chan et al.  and Damani et al.  have both reported successful treatment of persistent PC azoospermia with retrieval of testicular sperm coupled with intracytoplasmic sperm injection. Hsiao et al.  later updated the series at Weill Cornell. In these series, representing the outcomes of three major fertility centres, sperm was successfully retrieved in 37–65% of men with pregnancy rates of 30–50%. Overall, a weakness of published studies is their focus on the efficacy of single procedures and resulting fertility outcomes. In our opinion, more research is needed on the use of clinical care pathways for these patients and the resulting outcomes.
We undertook the present study to evaluate our outcomes in men with anejaculation after PC-RPLND in our reproductive medicine practice. Our approach is as follows: an initial trial of medical therapy is followed by the use of EEJ with subsequent TESE (in the same session) if EEJ revealed azoospermia or extremely poor sperm quality. Using this algorithm, we found that no patients with FOE responded to medication, suggesting the futility of medical treatment for those with FOE. In addition, although EEJ was technically successful in 20/22 (90%) of patients, sperm was found in only 15/22 (68%) of men. Finally, of the seven patients with FOE who were either azoospermic or did not have emission during EEJ, three had sperm found on TESE. Overall, we were able to find sperm in 21/26 (81%) of our patients.
Based on our results, we recommend a clinical care pathway (Fig. 3). In this pathway, the initial evaluation for a patient with anejaculation includes a retrograde semen analysis. For those with RE, based on our data, a trial of medical therapy is warranted, followed by EEJ and TESE. Men with FOE should proceed directly to EEJ and then to TESE, if needed.
Figure 3. Proposed clinical care pathway. ART, assisted reproductive technique; AID, artificial insemination with donor sperm.
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The weaknesses of the present study are its retrospective nature and its relatively small number of patients, as well as the lack of pregnancy and reproductive outcomes. In addition, some may question our use of pseudoephredrine for medical therapy. We treated all patients with pseudoephedrine (60 mg four times daily for 2 days), which is a widely used and easily available α-agonist. While other medical treatments, e.g. imipramine, midodrine or ephedrine, can also be used to increase sympathetic tone to the bladder (or decrease parasympathetic tone), there are specific concerns with the use of each. Midodrine and ephedrine can have major effects on systemic blood pressure. And though Kamischke and Nieschlag  point out, in a well written review, that imipramine has the highest effectiveness for converting RE to antegrade ejaculation, comparative controlled trials are needed to establish superiority over other drugs, as most of the published trials were small and not well controlled. Drawbacks of imipramine include its numerous side effects, e.g. dry mouth, drowsiness and nausea, and although doses used for ejaculatory dysfunction are lower than those used for depression, there is a potential risk of fatal tricyclic antidepressant overdose with imipramine. Without level 1 evidence to guide our choice, our clinical judgement led us to use pseudoephredrine, a widely available and commonly administered drug for this indication.
We believe that the present study shows an organized approach to the clinical problem of anejaculation after PC-RPLND.
In summary, the main cause of PC-RPLND-associated anejaculation was FOE in the present series. α-agonist medication was only effective in some of the patients with RE and not in the patients with FOE. EEJ is highly successful in patients with FOE, with sperm found in the majority of such patients on either EEJ or TESE. The use of a clinical pathway optimizes results in patients with anejaculation after PC-RPLND.