The blessing and curse of testicular cancer is near-uniform curability juxtaposed with the long-term adverse effects of any intervention that these young cancer survivors must contend with for the rest of their lives. While it is “straightforward” to perform an orchiectomy, obtain staging, and then offer observation, adjuvant therapy, locoregional therapy (retroperitoneal lymph node dissection [RPLND] or radiotherapy), or systemic platinum-based therapy, there are many potential opportunities to optimize patient care and reduce treatment-related morbidity. We highlight moments across the testicular cancer treatment journey and disease spectrum that may be underappreciated. These nuanced considerations ensure that we address the concerns of our patients and also minimize overtreatment and undertreatment.

The socioeconomic and psychological impact of a cancer diagnosis and orchiectomy in a young man cannot be overstated.¹ These young men experience significant rates of anxiety, depression, and financial toxicity that come with a cancer diagnosis and cancer care. It is incumbent upon us to perform a comprehensive psychosocial intake and provide relevant support services. Additionally, history and physical should screen for symptoms and signs of hypogonadism, anxiety, and depression.² Prior to orchiectomy, sperm banking and testicular prosthesis should be discussed, which may mitigate downstream fertility concerns and body image changes.²

In patients with stage I disease, it is critical to follow serum tumor markers to the nadir for accurate staging. Failure to do so can misclassify a patient as having occult systemic disease and lead to unnecessary chemotherapy. Further, low/stable levels of alpha-fetoprotein and human chorionic gonadotropin can be seen from noncancer causes and should be confirmed to be rising prior to initiation of systemic therapy. While all options should be discussed as part of the shared decision-making process, the overwhelmingly preferred management option for stage I disease is observation for both seminoma and nonseminoma. Since 1981, the Princess Margaret Hospital recommended active surveillance for all stage I tumors.³ Based on this experience, the relapse rate is 28% with median time to relapse of 7 months.³ The estimated 5-year cancer-specific survival is 98%-99%.³ An important exception is for patients with stage I secondary somatic malignancy, who should be directed toward primary RPLND. In seminoma patients, surveillance with MRI should be considered to minimize ionizing radiation exposure. The recent phase III TRISST (TE24 Trial of Imaging and Schedule in Seminomas Testis) trial randomized patients with stage I seminoma to surveillance with CT or MRI. MRI was noninferior to CT at detecting relapse at 72-month median follow-up.⁴ Ostensibly these same principles are applicable to patients with nonseminoma histology.

In stage II disease, there are multiple opportunities to optimize treatment. Patients presenting with de novo stage II disease may behave differently from patients who develop metastases confined to the retroperitoneum during surveillance for stage I disease. Patients who develop metastases during surveillance may be ideal candidates for RPLND since their natural history indicates they are less likely to have systemic relapse.

Providers should also recognize that the rate of pN0 in patients with clinical stage II disease approaches 20%-30%. First and foremost, the unequivocal presence of metastases should be confirmed in small-volume (stage IIA) retroperitoneal metastases to avoid overtreating patients who do not harbor metastases. Our practice is to perform short-interval (6-8 weeks) restaging with axial imaging of the chest, abdomen, and pelvis along with serum tumor markers; if the node involutes, surveillance is preferred; if metastases develop, systemic therapy is pursued. For persistent/slightly enlarging nodes, high-quality nerve-sparing RPLND is our preferred option to avoid the long-term side effects of systemic chemotherapy.

Historically, patients with pathological pN1 disease were observed, while those with pN2/N3 disease received adjuvant or full-dose chemotherapy. More recently, there is evidence to support surveillance in lieu of adjuvant therapy in pathological node-positive stage II disease. Based on a recent series from Indiana University, pathological stage II patients who underwent surveillance experienced 5-year recurrence-free survival of 79%, with no significant differences in relapse rates between pN1, pN2, and pN3 patients.⁵ All patients who recurred were successfully treated with chemotherapy at median follow-up of 52 months.⁵ These data suggest that most pathological stage II patients may be safely observed.

There is renewed interest in RPLND for patients with low-volume stage II seminoma. Emerging evidence from the phase II SEMS (Surgery in Early Metastatic Seminoma) trial suggests that RPLND for stage II seminoma could achieve oncologic outcomes similar to those of nonseminomas.⁶ In this multi-institutional single-arm trial, patients with seminoma and lymphadenopathy 1-3 cm underwent RPLND.⁶ Recurrence rate was 18% with median follow-up of 24 months.⁶ As these data and others mature, RPLND may very well become a standard option for appropriately selected patients with low-volume stage II seminoma.

Fortunately, we are in the midst of a revolution in testicular cancer diagnosis and management as novel sensitive and specific biomarkers enter our armamentarium. Circulating microRNA miR-371a-3p has emerged as such a biomarker, which holds the promise of informing treatment decisions across the testicular cancer spectrum.⁷ The reported sensitivity, specificity, and area under the curve for seminoma and nonseminoma are consistently >90%.⁷ Notably, miR-371a-3p is unable to detect residual teratoma.^6,8 The diagnostic potential of microRNA is currently being validated in several clinical trials prior to clinical use.

In summary, we draw attention to nuanced considerations that can impact the way we manage testicular cancer patients in an effort to limit treatment-related morbidity. Volume, expertise, and treatment at high-volume centers are important to confirm optimal outcomes.⁹