Nonseminomatous Testicular Tumors Treatment & Management
- Author: David M Hoenig, MD; Chief Editor: Bradley Fields Schwartz, DO, FACS more...
Surgery, in the form of radical (inguinal) orchiectomy, is used to determine the histologic type of the cancer and the local tumor stage in testicular cancer, and provides initial treatment. In stage IA NSGCTs, surgery may be considered possibly curative; the National Comprehensive Cancer Network (NCCN) recommends surveillance as the preferred primary treatment in those patients, with nerve-sparing retroperitoneal lymph node dissection (RPLND) as an alternative (eg, when compliance with follow-up is in doubt).
European Association of Urology guidelines support a risk-adapted approach to treatment of stage I NSGCT. Adjuvant chemotherapy with one cycle of BEP is recommended for patients with vascular invasion of the primary tumor in blood or lymphatic vessels, which is the most important predictor of occult metastatic disease. Surveillance is recommended for patients without vascular invasion.
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.
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) in a four-course cycle. 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%.
High-risk patients and those with an intermediate prognosis are managed with the same initial regimen (four cycles of BEP). This approach yields a cure rate and a durable response of less than 60% in most series. Patients who may not tolerate bleomycin may be treated with four cycles of etoposide, cisplatin, and ifosfamide (VIP).
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.
Standard three-dose regimens using vinblastine/etoposide/paclitaxel, ifosfamide, and cisplatin are used 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.
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. Palliative chemotherapy regimens for metastatic NSGCTS include gemcitabine plus oxaliplatin and/or paclitaxel.
For more information, see Nonseminoma Testicular Cancer Treatment Protocols
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). 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.
A study by Donat and Levy 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. Therefore, management with intravenous fluids is the mainstay of perioperative therapy.
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 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).
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 Medscape Reference article 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, 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.
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.
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 randomized study suggests that a more liberal surveillance protocol can be considered for low-risk patients with clinical stage I disease. Such surveillance would consist of follow-up imaging with CT scanning 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 2 y), so individualized long-term follow-up is likely prudent.
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 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 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).
In a study from Norway, Mykletun et al 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. 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 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 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 among men seeking an evaluation or treatment from an infertility clinic. Raman et al 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.
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. Spermon et al 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. 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 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.
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 suggested that the patient abstain from ejaculation for 24-48 hours prior to semen collection, when possible. 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.[31, 32]
Outcome and Prognosis
Disease-free survival varies by stage and risk, as follows:
Patients with stage I disease typically achieve a 98% disease-free survival rate at 5 years
Patients with stage IIA and IIB disease typically achieve a 92% disease-free survival rate at 5.5 years
Patients with stage IIC disease can expect an approximately 92% overall survival rate at 5 years
Patients with stage III disease classified as low-risk have a 92% overall survival rate at 5 years Intermediate-risk patients have an 80% overall survival rate at 5 years
High-risk patients have a 48% overall survival rate at 5 years
Future and Controversies
Laparoscopic retroperitoneal lymph node dissection
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 relatively new surgical approach that involves making several small incisions to admit an operative telescope and miniature surgical instruments to accomplish the same surgery as in the traditional, large, single-incision procedure. The advantages of laparoscopic 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 nonseminomatous germ cell tumors (NSGCTs) have already 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 mo) and stage II disease (mean follow-up of 42.7 mo) 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 min); however, the time improved dramatically with experience.
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 (2007) reported on 136 patients who underwent laparoscopic RPLND, with 94% of patients remaining relapse-free after a mean follow-up of 68 months.
The role of RPLND following chemotherapy is controversial. In general, all patients with a residual retroperitoneal mass require RPLND. However, virtually all patients in whom the mass resolves completely or reduces in volume by more than 90% will develop necrosis and fibrosis only, conceivably eliminating the need for RPLND.
Postchemotherapy RPLND is a much more complicated procedure and may be critical to achieving cure. Shayegan et al (2007) 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.[35, 36] 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 laparoscopic RPLND, while initially fraught with significant intraoperative and postoperative morbidities, continues to be explored, with improving results. In a single-surgeon experience, a recent retrospective study of 16 patients showed successful performance of the laparoscopic RPLND in 14 of 16 patients and a dramatic decrease in complications as experience was gained. However, further experience is needed before this procedure can be considered routine.
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