How can we mitigate treatment-associated morbidity in patients with germ cell tumors?

KEYWORDS:

• Germ cell tumor
• testicular cancer
• morbidity
• RPLND
• systemic chemotherapy
• miRNA

1. Introduction

Testicular germ cell tumor (GCT) is the most common malignancy in young men [1]. Through a multidisciplinary approach involving surgery, chemotherapy, and radiation, GCTs have cure rates approaching 97% to 100% for localized disease, and greater than 70% for metastatic disease [2]. Given the excellent survival outcomes, any model of GCT treatment and survivorship must carefully weigh the risks and benefits of treatment, with efforts to mitigate morbidity while maintaining excellent oncologic outcomes.

2. Radical orchiectomy

Radical orchiectomy is the first step in diagnosis, treatment, and prognostication in nearly all patients with GCT. There are an array of psychologic and physiologic concerns pre- and post-orchiectomy. Up to a third of men feel a sense of loss and shame after orchiectomy, and 10% may experience hypogonadism [3,4]. All patients should have a discussion of the risks and benefits of a testicular prosthesis, which has generally been associated with improved patient satisfaction, though a percentage of men (10–25%) have concerns about location, size, and interference with sexual function and physical activity [5,6]. While the overall incidence of clinical hypogonadism is low, monitoring for symptoms of hypogonadism with a history and physical exam is simple, cost effective, and allows workup and initiation of testosterone if indicated. In the approximately 2% of patients who develop second testicular primaries, androgen supplementation is requisite and should be coordinated at the time of orchiectomy. Nearly half of men have defects in spermatogenesis at the time of diagnosis, an important quality of life issue in the majority of young men diagnosed with GCT. Patients should be reassured that paternity rates exceed 90% after orchiectomy alone, but abnormalities in semen parameters should warrant discussion regarding further workup and cryopreservation should be discussed with all patients [7].

3. Active surveillance

Active surveillance (AS) is the preferred approach in the majority of patients with clinical stage (CS) I GCT [1,8]. With AS, most modern series show overall cure rates at nearly 100%, with the ability to spare 85% of CSI seminoma and 75% of CSI non-seminoma patients’ additional treatment [8]. For patients with CSI non-seminoma and lymphovascular invasion, AS is the preferred option with appropriate counseling regarding relapse rates of up to 50% that can be salvaged with chemotherapy and/or retroperitoneal lymph node dissection (RPLND) [8]. The majority of relapse in high-risk CSI non-seminoma occurs in the first two years, and some have argued for the use of adjuvant therapy in patients considered prone to lack of follow-up with surveillance imaging [1]. However, we have recently shown that implementation of a standardized multidisciplinary approach to GCT management was associated with similar rates of AS and recurrence regardless of whether a patient was seen at a safety net hospital, where patients are often presumed to be at high risk of poor compliance, or a tertiary care center [9,10].

4. Chemotherapy

In the metastatic setting, platinum-based chemotherapy remains the backbone of systemic therapy in GCT management. The primary regimen used is bleomycin, etoposide, and cisplatin (BEP). Among the most worrisome chemotherapy-related toxicities are bleomycin-induced pneumonitis and pulmonary fibrosis [11]. With regard to monitoring pulmonary toxicity, the role of pulmonary function tests (PFTs) has been controversial. PFTs have historically been used as an indicator of toxicity and aided in the decision to withhold additional doses of bleomycin [12]. However, asymptomatic changes in PFTs with unclear clinical consequences can lead to early discontinuation of bleomycin and result in worse oncologic outcomes [13]. Currently, the highest quality evidence comes from a single randomized controlled trial that showed that abnormal PFTs did not predict toxicity development [14]. However, PFTs are inexpensive, easy to perform, noninvasive, and may identify patients who could benefit from closer monitoring of symptoms. As such, we recommend obtaining baseline PFTs on a case-by-case basis such as in patients with risk factors such as advanced age, smoking history, and extensive pulmonary metastases, and following patients for development of clinical symptoms such as cough or shortness of breath before repeating PFTs. Other long term toxicities of chemotherapy also include infertility and cardiovascular disease [11,15]. All patients should have cryopreservation discussed at the time of initial diagnosis and certainly prior to retroperitoneal surgery and chemotherapy. There are no consensus guidelines on management of cardiovascular disease in testis cancer survivors; it would be prudent to monitor for, counsel, and provide patients early referral to appropriate consultants if there are presence of modifiable risk factors such has obesity, hypertension, diabetes, or smoking. Chemotherapy also carries the risk of development of a secondary malignant neoplasm with a 3–6 fold risk of development of a hematologic malignancy and a 1.4 fold risk of development of a separate solid organ malignancy [16]. While the majority of stage I GCTs can and should be safely surveilled, patients with high-risk features on orchiectomy may be counseled on the use of adjuvant chemotherapy as an alternative treatment option [2,8]. If chemotherapy is pursued in this context, single-cycle of carboplatin has shown efficacy with low morbidity profile and should be the treatment of choice [17]. Again, we would encourage the majority of patients to consider AS in stage I disease. Recurrence rates are low after three cycles of BEP for patients with CS IIB non-seminoma, and is our preferred approach for patients with positive serum tumor markers and most CS IIB or greater non-seminoma [18]. More controversial is the utilization of chemotherapy in CS IIA nonseminoma with negative markers, due to a concern for overtreatment and inability to treat any chemo-resistant teratoma elements. For these patients, surgery may present a better option.

5. Retroperitoneal lymph node dissection

Surgical management of regionally advanced testicular cancer is performed with retroperitoneal lymph node dissection (RPLND) in either a primary (P-RPLND) or post-chemotherapy (PC-RPLND) fashion. While well tolerated in the majority of patients, RPLND carries risk of vascular injury, bowel injury or obstruction, chronic edema, chylous ascites, and retrograde ejaculation [19]. In the hands of experienced surgeons, nerve sparing approaches even in those patients with larger tumors are the standard of care with a strong chance of maintaining antegrade ejaculation [20]. This treatment should occur at a high volume center of excellence, where a multi-disciplinary team is available both for surgical treatment and for long-term surveillance and multimodal therapy [1,9].

Patients with stage I disease with high-risk features who are uncomfortable with the uncertainty of AS may elect to undergo P-RPLND in order to avoid the toxicity of adjuvant chemotherapy. Despite demonstrated excellent oncologic control with relatively low morbidity, P-RPLND will overtreat ~50% of these patients and may be associated with a higher risk of recurrence than chemotherapy [8]. In CS IIA nonseminoma with negative markers, both three cycles of BEP and P-RPLND result in similar oncologic outcomes. However, usage of P-RPLND at expert high-volume centers results in long-term relapse-free rates of greater than 85% and minimal long-term morbidity compared to primary chemotherapy [13]. Furthermore, P-RPLND allows for removal of any chemo-resistant teratoma elements, accurate pathologic staging, and decreases the adjuvant treatment burden, if required, and is our preferred approach for this disease state [2]. In patients with stage IIA/IIB seminoma, P-RPLND presents the possibility to reduce systemic therapy burden, but trials are currently undergoing [21]. Patients with more advanced disease (CSIIB) or persistent serum tumor markers after orchiectomy are typically treated with chemotherapy rather than P-RPLND. This strategy helps to select against those patients most at risk for relapse after P-RPLND, avoiding potentially non-curative surgery. Following this, patients with NSGCT and residual tumors >1 cm undergo PC-RPLND.

6. Radiation

The role of radiation in the treatment of germ cell tumor has narrowed. Radiation is now mostly limited to use for regional control of seminoma (CS IIA/B). No randomized controlled trial exists comparing chemotherapy in this setting to radiation, but chemotherapy is the more common practice. The effectiveness of radiation is likely on par with chemotherapy for low volume (IIA) disease and near equivalent for higher volume (IIB) disease with relapse rates between 9% and 24% [22]. As such, the decision between the two modalities is mostly driven by provider experience and patient preference between risk profiles. Short-term tolerance would seem to favor radiation as chemotherapy is accompanied by known immediate side effects including nausea, hair loss, and immunosuppression, while radiotherapy is associated with diarrhea and dermatitis. The late effects of radiation therapy include nephrotoxicity, secondary malignancy, and cardiotoxicity.

7. Future directions and role of miRNA

Looking forward, utilization of GCT-specific micro-RNAs (miRNA) has the potential to radically change the diagnosis, management, and surveillance of GCTs. Identification of the miR-371-373 cluster in germ cell tissues and cell lines, and subsequent work describing overexpression of 8 GCT-associated miRNA represent the first common molecular abnormality in this heterogenous disease [23–25]. Perhaps most intriguing is the use of miRNAs for risk stratification in the utilization of adjuvant therapy. In patients with CS I non-seminoma with normal post-orchiectomy serum tumor markers, up to 10–50% of patients will have occult disease and relapse. Use of miRNAs to identify patients at risk of occult metastatic disease may lead to earlier less intensive treatment [1,8]. For example, Nappi and colleagues reported on 25 patients with low-risk CS1 seminoma or non-seminoma and demonstrated that miR-371a-3p test correctly identified all patients that ultimately recurred (1/25) and those that did not (24/25) [26]. Relatedly, Lafin et al. showed that miR-371a-3p was able to predict viable germ cell tumor elements in 24 patients with stage I/II GCT who were undergoing chemotherapy naive RPLND with sensitivity and specificity of 100% and 92%, respectively [27]. If validated, these data have far reaching implications with respect to avoiding over and undertreatment in CSI disease and overtreatment in CSIIA marker negative disease, where up to a third of patients are pN0 on final histology.

8. Conclusions and Expert Commentary

GCTs represent a highly curable, but often heterogenous, disease of young men. Care must be taken to minimize treatment-related morbidity by utilizing a multi-disciplinary, patient-focused approach, often at high volume centers. Active surveillance is preferred in the majority of men with CSI marker negative disease where cure can be obtained with orchiectomy alone, and generally systemic therapy for management of patients with persistent serum tumor marker elevation post-orchiectomy. However, questions remain as to the correct choice of treatment in patients with high-risk CS1 disease at risk of occult disease, and those patients with CSIIA marker negative disease, where both risk of under- and over-treatment remain high. Emerging technologies and specifically miRNAs may represent the future of personalized care of GCTs.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded