eMedicine Specialties > Urology > Cancer, Testicle

Nonseminomatous Testicular Tumors: Treatment

Author: David M Hoenig, MD, Associate Professor, Department of Urology, Albert Einstein College of Medicine; Chief of Weiler Division, Director of Laparoscopy and Endourology, Co-Director of Fellowship in Laparoscopy and Endourology, Residency Program Director, Department of Urology, Montefiore Medical Center
Coauthor(s): Janice Angela Santos-Cortes, MD, Chief Resident, Department of Urology, Albert Einstein Program, Montefiore Medical Center; Thomas H Rechtschaffen, MD, Consulting Staff, Department of Urology, A Family Urology Practice, PC
Contributor Information and Disclosures

Updated: Sep 28, 2009

Treatment

Medical Therapy

Testicular cancer is treated primarily with surgery, in the form of radical (inguinal) orchiectomy, to determine the histologic type of the cancer and the local tumor stage. Chemotherapy is used as primary therapy in advanced disease (stage IIC and III) or as adjuvant therapy in low-stage disease. In some cases, chemotherapy is used as primary therapy in low-stage disease when risk factors persist or tumor markers are persistently elevated (stage IS) after orchiectomy. The increase in survival and cure rate in the last decades has been due mainly to effective chemotherapy.

For stage-specific treatment recommendations, also see Staging.

Recommended primary chemotherapy dose and protocols for advanced disease (stage IIc-III) are based on risk stratification.

  • A good prognosis can typically be expected in patients with a testicular or retroperitoneal primary tumor, no nonpulmonary visceral metastases, and an AFP level below 1000 ng/mL, an hCG level below 5000 IU/L, and an 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 3-cycle regimen of bleomycin, etoposide, and cisplatin (BEP) has typically been used as first-line chemotherapy. Alternatively, some centers administer etoposide and platinum alone (ie, the EP regimen) in a 4-course cycle. These regimens elicit a response rate that ranges from 81%-92%. Among patients with a good prognosis, the 5-year progression-free survival rate is 89%, and the 5-year overall survival rate is 92%.
  • High-risk patients and those with an intermediate prognosis are managed with the same initial regimen (4 cycles of BEP. This approach yields a cure rate and a durable response of less than 60% in most series. Intermediate prognostic features include (1) testis or retroperitoneal primary tumor; (2) no nonpulmonary visceral metastases; and (3) one of the following: an AFP level of 1000-10,000 ng/mL, an hCG level of 5000-50,000 IU/L, or an 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, an AFP level greater than 10,000 ng/mL, an hCG level greater than 50,000 IU/L, or an 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.
  • Standard 3-dose regimens using vinblastine/etoposide/paclitaxel, ifosfamide, and cisplatin have been described as salvage therapy for primary treatment failures. Alternatively, high-dose therapy in combination with autologous bone marrow transplantation has been used with success for the most refractory cases.
  • Preliminary results of a phase II trial of paclitaxel plus gemcitabine salvage chemotherapy after progression following high-dose chemotherapy with tandem transplantation show promise, even in these extremely high-risk patients. An objective response was achieved in 31% of patients, with 6 complete responses (19%).10

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.

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 (3 cycles of BEP consists of 270 U of bleomycin; 4 cycles consists of 370 U).
    • 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.
    • Perioperative pulmonary complications were once attributed to high inspired oxygen fractions during surgery, although this theory has been abandoned.
    • A study by Donat and Levy (1998) found that the amount of blood transfused, preoperative forced vital capacity, and length of surgery were the only predictors of postoperative problems with oxygen saturation.11 Therefore, management with intravenous fluids is the mainstay of perioperative therapy.
    • Raynaud phenomenon has also been attributed to bleomycin and may be exacerbated by cisplatin and vinblastine.
  • Other potential adverse effects include the following:
  • Chemotherapy also carries an increased risk of secondary malignancies. The relative risk of leukemia, lymphoma, sarcoma, melanoma, colon cancer, stomach cancer, kidney cancer, prostate cancer, bladder cancer, thyroid cancer, rectal cancer, pancreatic cancer, and connective soft-tissue cancer is increased by a factor of 1.7-8.8. 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.
  • Infertility is a well-known, commonly recognized adverse effect (see Complications).

Surgical Therapy

Radical orchiectomy is performed when a testis tumor is appreciated upon examination or preoperative imaging studies. This is performed via an inguinal incision in order to prevent alteration of the lymphatic drainage pattern of the testicle (ie, drainage to the retroperitoneal lymph nodes) by violating the scrotal wall (ie, drainage to the superficial inguinal lymph nodes). Radical orchiectomy also allows ligation of the vas deferens and testicular vessels at the internal inguinal ring, which eliminates the need to explore the inguinal canal again if subsequent surgical removal of the spermatic cord and retroperitoneal lymph nodes is required (ie, for therapy or staging).

After radical orchiectomy is performed and the tumor is identified as a nonseminomatous germ cell tumor (NSGCT), clinical and/or surgical staging is mandatory. Primary RPLND is used to determine pathological staging and, in most of these patients, to provide curative therapy.

A thorough review of RPLND can be found in the eMedicine article Lymph Node Dissection, Retroperitoneal.

For stage-specific treatment recommendations, also see Staging.

Preoperative Details

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.

Intraoperative Details

For radical orchiectomy, an inguinal incision is made and the cord isolated and compressed with a vessel loop 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.

Typically, the cord is dissected proximally to the level of the internal ring and divided between clamps. The proximal vessels and vas deferens are secured with nonabsorbable sutures in the event subsequent RPLND is to be performed.

A prosthesis may be placed in the scrotum at the time of orchiectomy.

Postoperative Details

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. The results of these studies aid in determining further staging and therapy.

Follow-up

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 but should include, at a minimum, serum marker evaluations, chest radiography, and contralateral testis examination every 1 month for the first year, every 2 months for the second year, every 3 months for the third year, and every 4-6 months for the fourth and fifth years. Abdominal and pelvic CT scanning should be performed every 3 months for the first year, every 3-4 months for the second year, and every 6 months for the third through fifth years.

Physicians who treat patients through the surveillance period have a responsibility to ensure 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. This 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 scanning is warranted periodically, at least 6 months postoperatively and annually for the next few years, particularly if the patient was considered high risk.

A recent randomized study suggests that a more liberal surveillance protocol can be considered for low-risk patients with clinical stage I disease.6 Such surveillance would consist of follow-up imaging with CT scanning at 3 and 12 months (rather than with 5 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 2 y),12 so individualized long-term follow-up is likely prudent.

For excellent patient education resources, visit eMedicine's Men's Health Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Cancer of the Testicle and Testicular Self-Exam.

Complications

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%. 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.

When the patient has low-volume disease and a nerve-sparing procedure can be performed, ejaculation can be maintained in virtually all patients. However, in a patient with stage IIB cancer, a nerve-sparing procedure may compromise surgical cure, and a patient who wishes to preserve ejaculatory function may elect for primary chemotherapy.

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

With respect to concerns regarding postoperative sexual function (ie, libido), erectile function, and the potential for orgasm, sacrifice of the sympathetic nerves in the non–nerve-sparing RPLND does not appear to be contributory.

Chemotherapy also carries an increased risk of secondary malignancies. The relative risk of leukemia, lymphoma, sarcoma, melanoma, and gastrointestinal tumors is increased by a factor of 1.7-8.8.

A study on quality of life by Stava et al (2005) among individuals who survived cancer (including testicular cancer) revealed a 6.8% rate of hearing loss (although this was not specific to patients with testicular cancer).13

In a study from Norway, Mykletun et al (2005) reported that, at a mean of 11 years of follow-up, men who survived testicular cancer had no clinically significant difference in quality of life compared with age-matched controls.14 Overall, only minimal differences were seen in quality of life between different testicular cancer treatment modalities. The apparently excellent quality-of-life results of this study may offer some reassurance regarding the potential for complications and challenges to patients who must face the diagnosis and treatment of testicular cancer.

Infertility

Infertility can result from multiple factors in patients with cancer and is an important consideration in patients with testicular cancer. As reported by Bahadur et al (2005), cancer in general can affect semen parameters (especially sperm count), even before any form of systemic treatment has been initiated.15 This is attributed to deficiencies or defects in spermatogenesis and has been reported in 10%-35% of patients. Philips and Jequier (2007) reported an incidence of 0.7% of testicular malignancy among men seeking an evaluation or treatment from an infertility clinic.16 Raman et al (2005) reported the risk of malignancy among men with infertility and abnormal semen analysis findings to be as much as 20-fold higher than in controls.17

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 (see Treatment) represents the most deleterious effect upon spermatogenesis. Spermon et al (2003) reported that, among men with testicular germ cell tumors, the rate of successfully achieving pregnancy decreased from 66% before diagnosis and orchiectomy to 43% after treatment. Radiation and chemotherapy can also affect fertility, by different mechanisms.18 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 the setting of 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, and Leydig cells are more resistant to chemotherapy-induced damage. In addition, chemotherapy may cause mutations, causing more abnormalities in spermatogenesis.

RPLND can injure the sympathetic nerves within the retroperitoneum in the region of the vena cava and aorta, leading to retrograde ejaculation. This can prevent proper delivery of sperm.

Overall, post-treatment fertility issues can be significant following any cancer treatment. Huyghe et al (2004) 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.19

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. In order to be successful, Agarwal et al (1995) suggested that the patient abstain from ejaculation for 24-48 hours prior to semen collection, when possible.20 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 between 23% and 31% in two studies.

More on Nonseminomatous Testicular Tumors

Overview: Nonseminomatous Testicular Tumors
Workup: Nonseminomatous Testicular Tumors
Treatment: Nonseminomatous Testicular Tumors
Follow-up: Nonseminomatous Testicular Tumors
References
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Further Reading

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Keywords

testicular tumor, nonseminomatous testicular tumor, testis cancer, testicular cancer, testis mass, testicular mass, nonseminomatous germ cell tumor, non-seminomatous germ cell tumor, non-seminoma germ cell tumor, nonseminoma germ cell tumor, NSGCT, nonseminomatous germ cell testicular tumor, nonseminomatous testicular germ cell tumor, NSGCTT, NSTGCT, seminoma, nonseminoma, embryonal carcinoma, teratoma, choriocarcinoma, yolk sac tumor, cryptorchidism, testicular trauma, mumps orchitis, gynecomastia, orchiectomy

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Contributor Information and Disclosures

Author

David M Hoenig, MD, Associate Professor, Department of Urology, Albert Einstein College of Medicine; Chief of Weiler Division, Director of Laparoscopy and Endourology, Co-Director of Fellowship in Laparoscopy and Endourology, Residency Program Director, Department of Urology, Montefiore Medical Center
David M Hoenig, MD is a member of the following medical societies: American Urological Association and Endourological Society
Disclosure: Boston Scientific Grant/research funds Consulting; Endocare Consulting fee Speaking and teaching; Applied Medical Consulting fee Speaking and teaching

Coauthor(s)

Janice Angela Santos-Cortes, MD, Chief Resident, Department of Urology, Albert Einstein Program, Montefiore Medical Center
Janice Angela Santos-Cortes, MD is a member of the following medical societies: Alpha Omega Alpha
Disclosure: Nothing to disclose.

Thomas H Rechtschaffen, MD, Consulting Staff, Department of Urology, A Family Urology Practice, PC
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

CME Editor

J Stuart Wolf Jr, MD, FACS, David A Bloom Professor of Urology, Director of Division of Minimally Invasive Urology, Department of Urology, University of Michigan
J Stuart Wolf Jr, MD, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Catholic Medical Association, Endourological Society, Society for Urology and Engineering, Society of Laparoendoscopic Surgeons, Society of University Urologists, and Society of Urologic Oncology
Disclosure: Terumo Corporation Consulting fee Consulting; Gyrus-ACMI Honoraria Speaking and teaching

Chief Editor

Bradley Fields Schwartz, DO, FACS, Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine
Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Association of Military Osteopathic Physicians and Surgeons, Endourological Society, Society of Laparoendoscopic Surgeons, and Society of University Urologists
Disclosure: Nothing to disclose.

 
 
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