Nonseminomatous Testicular Tumors Treatment & Management

Radical (inguinal) orchiectomy is used to determine the histologic type of the cancer and the local tumor stage in testicular cancer. It also provides initial treatment and is the gold standard of care for suspected testicular neoplasms. It has no contraindications, other than potential anesthetic risks and uncontrolled bleeding diathesis. In such high-risk patients, preoperative clearance and preparation may be required, but radical orchiectomy should still be performed at the earliest opportunity. 

In stage I nonseminomatous germ cell tumors (NSGCTs), surgery may be considered possibly curative; the National Comprehensive Cancer Network (NCCN) recommends selecting treatment of stage I disease following orchiectomy on the basis of the patient's risk of relapse. Risk factors for relapse include lymphovascular invasion, invasion of the spermatic cord, or invasion of the scrotum. ^[17]

Surveillance is the preferred primary treatment in patients without risk factors. Alternatives (eg, when compliance with follow-up examination is in doubt) are nerve-sparing retroperitoneal lymph node dissection (RPLND) or single-cycle primary chemotherapy with bleomycin, etoposide, and cisplatin (BEP). For stage I disease with risk factors, all three treatment options should be considered. ^[17]

A retrospective analysis of 423 patients with stage 1 disease receiving a single-cycle of BEP reported a 5-year relapse-free survival rate of 96.2%. ^[18]

European Association of Urology guidelines support a similar risk-adapted approach to treatment of stage I NSGCT. Surveillance is recommended for patients without vascular invasion. Adjuvant chemotherapy with one cycle of BEP is recommended for patients who are unable or unwilling to undergo surveillance; and in those with invasion of the primary tumor in blood or lymphatic vessels, which is the most important predictor of occult metastatic disease. ^[19]

According to the NCCN, primary treatment options for stage IIA disease with negative post-orchiectomy tumor markers include nerve-sparing RPLND or chemotherapy with three cycles of BEP or four cycles of EP; both BEP and EP are preferred regimens. For patients with stage IIB disease the recommendations generally are for primary chemotherapy, with initial RPLND being a management option in few isolated cases. ^[17]

Chemotherapy is used as primary therapy in advanced disease (stage IIC and III) and in low-stage disease when risk factors persist or tumor markers are persistently elevated after orchiectomy (stage IS). Recommended primary chemotherapy dose and protocols for advanced disease (stage IIC-III) are based on risk stratification. ^[17]

A good prognosis can typically be expected in patients with the following:

• Testicular or retroperitoneal primary tumor
• No nonpulmonary visceral metastases
• Alpha-fetoprotein (AFP) level below 1000 ng/mL
• Human chorionic gonadotropin (hCG) level below 5000 IU/L
• Lactate dehydrogenase (LDH) level less than 1.5 times the upper limit of the reference range

In patients with disseminated disease who have a good prognosis, a three-cycle regimen of BEP has typically been used as first-line chemotherapy. Alternatively, some centers administer etoposide and platinum alone (ie, the EP regimen) for four cycles. These regimens elicit a response rate that ranges from 81%-92%. In patients with a good prognosis, the 5-year progression-free survival rate is 89%, and the 5-year overall survival rate is 92%.

Poor-risk patients and those with an intermediate prognosis are managed with the same initial regimen (four cycles of BEP). The cure rate is approximately 70% for intermediate risk patients. Patients who may not tolerate bleomycin may be treated with four cycles of etoposide, cisplatin, and ifosfamide (VIP). ^[17]

Intermediate prognostic features include (1) a testis or retroperitoneal primary tumor, (2) no nonpulmonary visceral metastases, and (3) one of the following:

• AFP level of 1000-10,000 ng/mL
• hCG level of 5000-50,000 IU/L
• LDH level 1.5-10 times the upper limit of the reference range

High-risk prognostic features include any of the following:

• Mediastinal primary tumor
• Nonpulmonary visceral metastases
• AFP level greater than 10,000 ng/mL
• hCG level greater than 50,000 IU/L
• LDH level greater than 10 times the upper limit of the reference range

The 5-year overall survival rate is 80% in the intermediate group and only 48% in the high-risk group. Due to the poor response to standard chemotherapy regimens in those patients with advanced stage disease and high risk prognostic indicators. Recommendations for these patients is to consider consultation at higher volume centers. ^[17]

For second-line chemotherapy in patients with metastatic disease, preferred regimens include standard-dose TIP or VeIP, or high-dose regimens with carboplatin and etoposide followed by autologous stem cell transplantation, or paclitaxel, ifosfamide, carboplatin, and etoposide with stem cell support. In patients who have not previously received high-dose chemotherapy, those high-dose regimens are also preferred for third-line therapy. For patients who did receive high-dose chemotherapy, preferred third-line therapy is with one of the following ^[17] :

• Gemcitabine, paclitaxel, oxaliplatin
• Gemcitabine and oxaliplatin
• Gemcitabine and paclitaxel
• Etoposide (oral).

Alternatively, high-dose therapy in combination with autologous bone marrow transplantation has been used with some success for the most refractory cases. ^[20]

Selected patients who do not achieve a complete medical response and who present with residual masses after treatment may be candidates for adjuvant surgery (RPLND) if certain criteria are met. ^[21] Palliative chemotherapy regimens for metastatic NSGCTs include gemcitabine plus oxaliplatin and/or paclitaxel. ^[17]

For more information, see Nonseminoma Testicular Cancer Treatment Protocols

Toxicities

Chemotherapy for testicular cancer carries perioperative and postoperative implications. Acute and late toxicities are well recognized. Myelosuppression is caused by the commonly used agents.

These agents increase the risk of cardiovascular disease and myocardial infarction. Proposed mechanisms include direct endothelial damage, vasospasm, and increased cardiac risk factors such as hypertension, hyperlipidemia, increased body mass index (BMI), and renal insufficiency.

Cisplatin may cause nephrotoxicity, ototoxicity, hypomagnesemia, neuropathy, and infertility. In some cases, the adverse effects are persistent. Cisplatin has also been associated with myocardial infarction, angina pectoris, and thromboembolic events. 

Bleomycin is known to cause pulmonary toxicity. This adverse effect is dose related and develops in approximately 6.8-8.5% of patients treated with more than 300 U of bleomycin (three cycles of BEP consists of 270 U of bleomycin; four cycles consists of 370 U). ^[22] Interstitial pneumonitis is the most common pulmonary manifestation and leads to fibrosis and death in 1% of patients. The toxic effects of bleomycin are thought to be partly due to induction of free radicals. Raynaud phenomenon has also been attributed to bleomycin and may be exacerbated by cisplatin and vinblastine.

Other potential adverse effects include the following:

• Etoposide - Secondary leukemia
• Ifosfamide - Nephrotoxicity, hemorrhagic cystitis, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), CNS toxicity
• Paclitaxel - Neuropathy, hypersensitivity reaction, diarrhea
• Vinblastine - Constipation, ileus, SIADH

Chemotherapy also carries an increased risk of secondary malignancies. The relative risk of the following cancers is increased by a factor of 1.7-8.8:

• Leukemia
• Lymphoma
• Sarcoma
• Melanoma
• Colon cancer
• Stomach cancer
• Kidney cancer
• Prostate cancer
• Bladder cancer
• Thyroid cancer
• Rectal cancer
• Pancreatic cancer
• Connective soft-tissue cancer 

In a study by the Netherlands Cancer Institute, radiation and chemotherapy were found to increase the risk of secondary malignancies or cardiovascular disease to a degree similar to that of smoking. ^[23]

Radical orchiectomy is performed when there is suspicion for testicular malignancy either upon examination or scrotal ultrasound. This procedure is performed via an inguinal incision in order to prevent tumor spread or alteration of the lymphatic drainage pattern of the testicle by violation of the scrotal wall.

Radical orchiectomy also allows ligation of the spermatic cord at the level of the internal inguinal ring. This eliminates the need to explore the inguinal canal again if subsequent surgical removal of the spermatic cord is performed, and allows for easy identification of the cord if retroperitoneal lymph node dissection is required (ie, for therapy or staging).

Of note, partial orchiectomy is an option in a select few patients. Patients in whom this may be offered should have an absent or abnormal contralateral testicle with ipsilateral tumor that is less than 2 cm in size and in a polar location. ^[2] The approach for partial orchiectomy is the same as for radical orchiectomy, with care taken not to violate the scrotum.

After radical orchiectomy is performed and the tumor is identified as a nonseminomatous germ cell tumor (NSGCT), clinical and/or surgical staging is mandatory. In those patients for whom surveillance or primary chemotherapy is not an initial management option, primary RPLND is used to determine pathological staging and, in some patients, provides curative therapy.

The long-term adverse effects of RPLND and chemotherapy must be considered and discussed with the patient, especially when either modality can be considered primary therapy. In the hands of an experienced surgeon, RPLND should carry a mortality rate of approximately 0%. However, significant recovery time is required before patients can return to work, primarily because of the length of the incision. The most commonly described long-term complication is the loss of antegrade ejaculation.

In contrast, primary chemotherapy results in azoospermia in most patients for up to 24-36 months, and approximately 25% of patients have persistent absence of sperm in the semen at 2-5 years of follow-up.

As mentioned previously, chemotherapy carries multiple acute and late toxicities that should be considered and discussed with the patient prior to treatment. 

In patients with advanced NSGCT in whom RPLND is indicated, a nerve-sparing procedure can be performed, even in the post-chemotherapy setting, with hopes of preserving ejaculatory function. A 2009 study found that ejaculatory function was maintained in the majority of patients without compromising oncologic outcomes. ^[24]  

The long-term adverse effects of RPLND can be diminished by limiting the dissection in appropriate patients. The short-term adverse effects associated with an extensive dissection include a long postoperative hospital stay, significant pain, and a protracted period before the patient can resume normal work and leisure activities.

Some of these disadvantages can be mitigated with a minimally invasive approach as opposed to the open surgical technique. The advantages of minimally invasive surgery are observed primarily in the postoperative setting, with a shorter hospital stay, decreased pain, and faster convalescence.

Several series on the application of laparoscopic RPLND in patients with clinical stage I NSGCTs have been reported in the literature, with promising results. One such series reported on 73 laparoscopic RPLNDs for clinical stage I NSGCT. Twenty-six percent of the patients had pathological stage II disease, and they all received 2 cycles of adjuvant chemotherapy. All patients with stage I disease (mean follow-up of 43.3 months) and stage II disease (mean follow-up of 42.7 months) were free of disease. Ejaculation was preserved in all 70 patients after an adequate follow-up period. The conversion rate from laparoscopic to open RPLND was only 2.7% (2 of 73 cases). The mean operative time was prolonged (297 minutes); however, the time improved dramatically with experience. ^[25]

The laparoscopic approach to RPLND has been further refined in recent years, and longer-term follow-up studies have suggested that this approach may be an acceptable alternative to traditional RPLND in select patients. Neyer et al reported on 136 patients who underwent laparoscopic RPLND, with 94% of patients remaining relapse-free after a mean follow-up of 68 months. ^[26]  Minimally invasive approaches should be offered only if they will not compromise oncologic control of disease.

Postchemotherapy RPLND is a much more complicated procedure and may be critical to achieving cure. Shayegan et al reported that, even in high-risk patients, long-term freedom from disease progression is best achieved with a combination of chemotherapy and resection of residual masses, with an 81% disease-specific survival rate and a 70% likelihood of no progression. ^{[27, 28]}  In this study, multivariate analyses suggest that residual tumor mass, incomplete surgical resection, and the presence of teratoma and viable tumor all independently predicted disease progression after RPLND.

Postchemotherapy minimally invasive RPLND, while initially fraught with significant intraoperative and postoperative morbidities, continues to be explored, with improving results with continued surgeon experience. A retrospective study of single-surgeon experience demonstrated successful performance of laparoscopic RPLND in 14 of 16 patients and a dramatic decrease in complications as experience was gained. ^[29]  

For a thorough review of RPLND, see Retroperitoneal Lymph Node Dissection.

For stage-specific treatment recommendations, also see Staging.

Prior to radical orchiectomy, routine preoperative preparations should be performed and laboratory studies obtained, as described above.

Prior to planned RPLND, some surgeons advocate that patients should start a low-fat diet 2 weeks before the operation to reduce the risk of chylous ascites, and they should continue this in the immediate postoperative period.

On the day before RPLND, the patient should start a clear liquid diet and take a mechanical bowel preparation at home.

For radical orchiectomy, a roughly 3-5 cm inguinal incision is made. The external oblique is opened sharply. The ilioinguinal nerve should be identified anterior to the cord with attempts made to identify and preserve it. The cord is then isolated and compressed with a vessel loop or penrose drain for vessel control prior to manipulation of the testis. The testicle is maneuvered from the scrotum up into the inguinal canal to expose it in the inguinal incision. The gubernaculum is divided to free the testicle from the inner wall of the scrotum, again with care taken not to violate the scrotal wall.

The cord is then dissected proximally to the level of the internal ring and divided between clamps. The proximal vessels and vas deferens are secured with long nonabsorbable suture in the event subsequent RPLND is to be performed, to permit the proximal end of the cord to be more easily identified.

A prosthesis may be placed in the scrotum at the time of orchiectomy, based on patient preference.

Limitations on physical activity are typically instituted to decrease the risks of pain, bleeding, and/or wound complications.

If serum tumor marker values were elevated prior to orchiectomy, repeat measurements of serum marker levels should be obtained to assess if an appropriate postoperative decrease occurred. Staging is done using the post-orchiectomy tumor marker nadir; appropriate time should be allotted for marker levels to fall, according to their respective half-life. 

Complications of radical orchiectomy, as with any surgical procedure, include risks of bleeding and infection. Additionally, injury to the ilioinguinal nerve may occur, which can cause hypoesthesia of the ipsilateral groin and lateral aspect of the ipsilateral hemiscrotum. 

For patients with more advanced disease that requires retroperitoneal lymph node dissection, complications of that procedure can include the following:

• Bleeding, which may result in retroperitoneal hematoma
• Wound infection
• Anejaculation from damage to nearby sympathetic nerves
• Chylous leak secondary to lymphatic system injury

Finally, patients requiring chemotherapy may be susceptible to both the acute and delayed toxicity associated with the chemotherapeutic agents; those effects depend on the agents used. Acute complications seen with cisplatin-based therapy include but are not limited to myelosuppression, fatigue, peripheral neuropathy, diminished renal function, and—in a small percentage—death. Later sequelae can include the following ^[2] :

• Hearing loss
• Peripheral neuropathy
• Cardiovascular disease
• Hypogonadism

Infertility

Infertility can result from multiple factors in patients with cancer and is an important consideration in patients with testicular cancer. A systematic review by Djaladat et al found that even before orchiectomy, many men with testicular GCTs have reduced sperm count and sperm motility, as well as increased abnormal sperm morphology ^[30] This is attributed to deficiencies or defects in spermatogenesis and has been reported in 10-35% of patients.

Philips and Jequier reported an incidence of 0.7% of testicular malignancy in men seeking an evaluation or treatment from an infertility clinic. ^[31] Raman et al reported the risk of malignancy in men with infertility and abnormal semen analysis findings to be as much as 20-fold higher than in controls. ^[32]

Abnormalities in spermatogenesis have been described, but the mechanism is not well understood. Causes are likely multifactorial and include cryptorchidism, local effect of the tumor, and disruption of the blood-testis barrier, causing the development of antibodies. In addition, the production of hCG by the testicular tumor can disrupt the normal endocrine axis. Other mechanisms, such as stress and certain inflammatory products, can exert negative effects on the semen quality. In some cases, spermatogenesis normalizes after successful cancer treatment.

Testicular cancer treatment represents the most deleterious effect upon spermatogenesis, including a dose-dependent effect of both chemotherapy and radiation. Spermon et al reported that, in men with testicular germ cell tumors, the rate of successfully achieving pregnancy decreased from 66% to 43% after treatment for the tumors. ^[33]

Radiation and chemotherapy can also affect fertility, by different mechanisms. Radiation induces irreparable fragmentation of double-stranded DNA. Sertoli cells are extremely radiosensitive, as are the spermatogonia, while Leydig cells are generally somewhat more resistant to radiation. In addition, in patients who receive radiation to the skull, damage to the pituitary gland can manifest as low follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels post-therapy, which can contribute to infertility concerns.

Chemotherapy can cause azoospermia. This is drug and dose related. Alkylating agents (ie, cisplatin) are the most damaging. Sertoli cells are generally susceptible to chemotherapy, while Leydig cells are more resistant to chemotherapy-induced damage. In addition, chemotherapy may cause mutations, causing more abnormalities in spermatogenesis. ^[34]

Overall, post-treatment fertility issues can be significant following any cancer treatment. Huyghe et al reported that fertility among patients with testicular cancer decreased by 30% after treatment and that radiotherapy appeared to have the most deleterious effect on fertility. ^[35]

Psychosocial consultation may be beneficial in patients who have distress about infertility, as emotional stress can also affect the potential to father a child.

Sperm cryopreservation is a well-established technique for fertility preservation. Using various techniques, the pregnancy success rate following cryopreservation ranges from 18-50%. Men with post-treatment azoospermia or ejaculatory failure who did not preserve semen prior to treatment may benefit from testicular sperm aspiration (TESA) followed by intracytoplasmic sperm injection (ICSI). This technique resulted in pregnancy success rates of 23% and 31% in two studies. ^{[36, 37]}

The median time to recurrence is 7 months, and 90% of patients who experience recurrence do so within 2 years. Hence, an intensive schedule of follow-up and imaging is required for the first 2 years.

Surveillance schedules vary depending on initial tumor staging but should include, at a minimum, serum marker evaluations, chest radiography, and contralateral testis examination. Physical exam should be performed and tumor markers measured at least every 2 months for all NSGCT patients, except those with stage IB disease and those with stage IIA/B disease managed with adjuvant chemotherapy and primary RPLND; these patients should have physical exam and tumor markers drawn at 3 and 6 months respectively for the first 2 years of follow up. Abdominal and pelvic CT scans should be performed as well, with the timing and frequency of imaging varying depending on initial staging and management. Full surveillance recommendations can be found in the NCCN Guideline for Testicular Cancer. ^[17]

Physicians who treat patients through the surveillance period have a responsibility to ensure that patients are not lost to follow-up and that they comply with the regimen.

If findings are negative after RPLND, follow-up may be less stringent. It should include serum marker evaluations, chest radiography, and physical examinations every 3-4 months for the first 2 years and every 6 months for the third through fifth years. Recurrence in the retroperitoneum is rare in these patients. CT scans are warranted periodically, at least 6 months postoperatively and annually for the next few years, particularly if the patient was considered at high risk.

A randomized study suggests that a more liberal surveillance protocol can be considered for low-risk patients with clinical stage I disease. ^[13]  Such surveillance would consist of follow-up imaging with CT scans at 3 and 12 months (rather than with five follow-up sessions required by traditional surveillance protocols). This protocol offers an excellent ability to rule out disease progression. However, confirmatory studies will likely be required before such a protocol will be widely accepted.

Finally, 2-4% of patients with NSGCT experience a late relapse (after more than 2 years). The retroperitoneum is the primary site of relapse. ^[38]