Testicular Cancer Treatment & Management

Updated: Jul 05, 2017
  • Author: Kush Sachdeva, MD; Chief Editor: E Jason Abel, MD  more...
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Treatment

Medical Care

Testicular cancers are curable even in the presence of metastatic disease. If the cancer progresses or recurs despite initial chemotherapy, these patients are candidates for salvage therapy.

Nonseminoma is more aggressive than seminoma. When the elements of both seminoma and nonseminoma are present or the alpha-fetoprotein (AFP) concentration is elevated, the tumor should be treated as a nonseminoma.

Initial therapy is selected according to American Joint Committee on Cancer (AJCC) stage group; risk stratification (good, intermediate, or poor risk), as per the guidelines of the International Germ Cell Cancer Collaborative Group [17] ; and histology (seminoma versus nonseminoma). [18]

Current guidelines from the National Comprehensive Cancer Network (NCCN) [14] and the National Cancer Institute [1] recommend a treatment approach keyed to AJCC staging. These treatment groups are as follows:

  • Seminoma stage IA, IB
  • Seminoma stage IS
  • Seminoma stage IIA, IIB
  • Seminoma stage IIC, III
  • Nonseminoma stage IA, IB, IS
  • Nonseminoma stage IIA, IIB
  • Nonseminoma stage IIC, IIIA, IIIB, IIIC and brain metastases
  • Recurrent disease and salvage treatment

Seminoma stage IA, IB

Clinical stage I seminomas have a very high cure rate. Cure can sometimes be achieved by radical inguinal orchiectomy alone. Options after orchiectomy include active surveillance, adjuvant chemotherapy, and adjuvant radiation therapy. Median time to relapse in patients who do not receive adjuvant treatment is 12 months, but relapse can occur even beyond 5 years.

Active surveillance is recommended for patients with horseshoe or pelvic kidney or inflammatory bowel disease and for those who have received prior radiotherapy. Surveillance can also be offered to selected patients with T1 or T2 or T3 disease. Surveillance consists of a history and physical exam and measurement of  aAFP and hCG every 3 to 4 months for the first 3 years, every 6 months for years 4 to 7, then annually up to year 10. A CT scan of the abdomen and pelvis is recommended at each visit and a chest x-ray at alternate visits. It is essential that patients maintain strict adherence to the surveillance program for at least 10 years.

Adjuvant radiation therapy consists of delivery of 20-30 Gy to the infradiaphragmatic area, including the para-aortic lymph nodes and in some cases the ipsilateral ileoinguinal nodes. According to surveillance data, the overall incidence of disease failure without radiation therapy is 15% to 27%, with median of 20%. With radiation therapy, failure rates were 2% to 5%, with a median of 3%.

Adjuvant chemotherapy with a single dose of carboplatin (see Medication) is currently recommended as an alternative to radiation therapy. [19] In a randomized study in 1,477 patients, median followup of 6.5 years confirmed that single-dose carboplatin is noninferior to radiation therapy in terms of relapse-free rate (RFR), producing a statistically significant reduction in the medium-term risk of a contralateral germ cell tumor. RFRs at 5 years were 94.7% for carboplatin and 96.0% for radiation therapy. [21] Acute toxicity such as lethargy and days missed from work was less with carboplatin than with radiation therapy.

A prospective, population-based, risk-adapted treatment protocol study by the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) concluded that stromal invasion in the rete testis and tumor diameter >4 cm are risk factors for relapse in clinical stage I seminoma. Relapse rates in patients without those risk factors were 4.0% in patients managed with surveillance and 2.2% in those who received adjuvant carboplatin. The SWENOTECA researchers concluded that adjuvant therapy is not justified in those patients. [22]

In patients with one or two risk factors, the relapse rate was 15.5% with surveillance versus 9.3% in patients receiving adjuvant carboplatin. However, the relapse rate was not higher in patients whose carboplatin dose was less than 7 × area under the curve (AUC) than in those who received a higher dose. [22]

Seminoma stage IS

Stage IS seminoma is defined by persistent elevation of serum tumor markers (LDH, AFP, and beta-hCG). Current NCCN guidelines recommend repeating serum tumor marker assays in these patients and assessing with abdominal/pelvic CT for evaluable disease. However, the NCCN advises that stage IS pure seminoma is very uncommon and that other causes may be responsible for minimally elevated LDH or beta-hCG levels, so caution is warranted before intervening in those cases. [14]

Seminoma stage IIA

Active surveillance is not an option. These patients receive adjuvant chemotherapy or radiation therapy.

For radiation therapy, 30 Gy is administered to the para-aortic and ipsilateral iliac lymph nodes. Mediastinal radiation is not recommended.

For adjuvant chemotherapy, four cycles of chemotherapy with etoposide and cisplatin (EP) or three courses of bleomycin, etoposide and cisplatin (BEP) is recommended.

Seminoma stage IIB

Primary chemotherapy with three cycles of bleomycin, etoposide and cisplatin (BEP) or four cycles of chemotherapy with etoposide and cisplatin (EP) is recommended. In select cases of non-bulky (≤3 cm) disease, radiation therapy that includes the para-aortic and ipsilateral iliac lymph nodes can be given, in a dose of 36 Gy.

Seminoma stage IIC and III

Stage IIC and III seminomas are categorized as good risk or intermediate risk. Intermediate-risk seminomas include nonpulmonary visceral metastatic disease. Chemotherapy is the option for both groups, with different regimens for the two categories, as follows:

  • Good-risk seminoma stage IIC and III: Either three cycles of BEP or four cycles of EP 
  • Intermediate-risk seminoma stage IIC and III: Four cycles of BEP is preferred, other option is VIP (VP 16/etoposide + ifosfamide + platinol/cisplatin) is another option for four cycles. 

Seminoma stage IIB, IIC, III after primary treatment with chemotherapy

For stage II and III seminoma after primary treatment with chemotherapy, recommended surveillance includes CT scans of the chest, abdomen, and pelvis along with serum tumor marker assays. For patients with a residual mass but normal markers, PET scanning should also be considered. In some cases of seminoma, a PET scan may detect nodal and extranodal disease that is not evident on CT scans. [23]

PET scans for evaluating the response to chemotherapy in seminoma should be performed 3-4 weeks after the last course of chemotherapy. If the PET scan is negative, surveillance is recommended. Options for patients with a positive PET scan include the following:

  • Surgery with biopsy
  • Biopsy and salvage chemotherapy or radiation therapy

If a PET scan cannot be done and the residual mass is 3 cm or less in size, surveillance is recommended. When the mass is larger than 3 cm in size, surveillance could be considered but surgery and radiation therapy are options and should be discussed with the patient.

Patients who experience progressive disease with a growing mass or rising marker levels should receive salvage chemotherapy.

Nonseminoma stage IA, IB, IS

After radical inguinal orchiectomy, treatment options are active surveillance or chemotherapy. Retroperitoneal lymph node dissection (RPLND) is used to guide chemotherapy; the number of positive nodes present in the sample determines the number of chemotherapy cycles given. Open nerve-sparing RPLND is preferred over laparoscopic RPLND. RPLND has multiple complications, including retrograde ejaculation.

A long-term surveillance study by Daugaard et al in 1226 patients with stage I nonseminoma germ cell cancer who had been treated with orchiectomy only found that relapse occurred more often in patients with vascular invasion together with embryonal carcinoma and rete testis invasion in the testicular primary. Relapse risk at 5 years in patients with those features was 50%, versus 12% in patients without them. Relapses were diagnosed within the first year after orchiectomy in 80% of cases. [24]

These findings suggest that the majority of stage I nonseminoma germ cell tumors can be safely managed without subjecting the patient to chemotherapy or RPLND; orchiectomy and followup surveillance will suffice. The small subset of patients at high risk for systemic recurrence may considered for adjuvant chemotherapy.

Nonseminoma stage IA

Active surveillance can be used in compliant patients and is preferred; see Follow-up for surveillance guidelines. The cure rate is 95%. Adherence to the surveillance program is the key to success. Noncompliant patients should be offered RPLND within 4 weeks of the CT scan and 7-10 days of tumor marker assays. If RPLND results are negative, primary chemotherapy BEP for one cycle is another option

Nonseminoma stage IB

Options are open nerve-sparing RPLND; chemotherapy with BEP for 1-2 cycles. Active surveillance, although not a preferred option, could be considered for compliant patients who have T2 or T3 disease. 

Nonseminoma stage IS

If persistent tumor marker elevation is present but no abnormality is visible on imaging studies, chemotherapy with EP for 4 cycles or BEP for 3 cycles is recommended.

Nonseminoma stage IIA, IIB

Treatment varies according to the stage and the results of tumor marker assays and CT scan. Chemotherapy in these cases consists of either EP for four cycles or BEP for three cycles. Treatment recommendations are as follows:

  • Nonseminoma stage IIA with normal tumor markers: open nerve-sparing RPLND or chemotherapy BEP three cycles or EP for four cycles.
  • Nonseminoma stage IIA with persistent elevation of tumor markers: chemotherapy
  • Nonseminoma stage IIB with normal tumor markers and lymph node metastasis within lymphatic drainage site by CT scan: open nerve-sparing RPLND or chemotherapy BEP three cycles or EP for four cycles
  • Nonseminoma stage IIB normal tumor markers and multifocal symptomatic lymph node metastases with aberrant lymphatic drainage by CT scan: Primary chemotherapy BEP three cycles or EP for four cycles
  • Nonseminoma stage IIB with persistent elevation of tumor markers: chemotherapy

Nonseminoma stage IIC, IIIA, IIIB, IIIC and brain metastases

Patients with stage IIC and III are treated with chemotherapy, with the regimen choice based on risk status. Approximately 20-30% of patients with metastatic testicular cancer cannot be cured.

With nonseminoma stage IIC, IIIA good risk, 95% of patients are cured with chemotherapy, either EP for four cycles or BEP for three cycles. In nonseminoma stage IIIB intermediate risk, BEP for four cycles is given; the cure rate is 70%.

With nonseminoma stage IIIB poor risk, enrollment in clinical trials is preferred. Chemotherapy with four cycles with BEP can be considered, but fewer than 50% of patients will experience a durable complete response. In patients who cannot tolerate BEP because of pneumonitis from the bleomycin component, VIP (etoposide [VePesid], ifosfamide, mesna, cisplatin [Platinol-AQ]) is recommended.

Patients with brain metastases should receive primary chemotherapy plus radiation. Surgery should be performed if clinically indicated.

In nonseminoma stage IIC, IIIA, IIIB, or IIIC, a CT scan of the abdomen and pelvis and tumor marker assays are indicated after the completion of chemotherapy. With patients in whom these tests indicate a complete response, options are surveillance or open nerve-sparing RPLND. If residual disease is present but tumor marker levels are normal, all the residual disease should be resected. If the resection specimen shows only necrotic tissue or teratoma, no further therapy is recommended and active surveillance should be done. If residual embryonal, yolk sac, choriocarcinoma, or seminoma elements are present, the patient should receive two cycles of chemotherapy with EP, TIP (paclitaxel, ifosfamide and cisplatin), VIP, or VeIP (vinblastine, ifosfamide, mesna, cisplatin).

Patients who do not have a complete response to chemotherapy and/or whose disease cannot be resected should receive salvage chemotherapy.

Recurrent disease and salvage treatment

Patients who do not have a complete response to first-line therapy, or whose disease recurs after complete response, are categorized into favorable and unfavorable prognostic groups.

Salvage treatment for patients with a favorable prognosis

This group includes patients with low tumor marker levels, low-volume disease, complete response to first-line chemotherapy, and testis primary. These patients are treated with chemotherapy—VeIP or TIP. If they have an incomplete response or relapse, they should be considered for high-dose chemotherapy with autologous stem cell transplantation or enrollment in a clinical trial. In patients with a solitary metastatic site, salvage surgery should be considered. Patients who have a complete response should be followed closely and if they experience relapse, should be considered for clinical trials or high-dose chemotherapy.

Salvage treatment for patients with an unfavorable prognosis

This group includes patients with an incomplete response to first-line chemotherapy, high tumor marker levels, high-volume disease, extratesticular primary, and late relapse. In these patients, enrollment in a clinical trial is preferred. Other options include high-dose chemotherapy plus autologous stem cell support, conventional chemotherapy with either VeIP or TIP, or best supportive care. Third-line chemotherapy with or without cyclophosphamide/ifosfamide can produce a durable complete response in 15%-20% of patients and should be considered for patients with good performance scores.

High-dose chemotherapy and stem cell rescue

High-dose chemotherapy with tandem courses of carboplatin and etoposide followed by hematopoietic stem cell rescue can produce complete remission in 5%-10% of cisplatin-refractory testicular cancers. [25] Non–cisplatin-refractory testicular cancers have much better responses; more than 60% of these patients can be cured with high-dose chemotherapy.

Palliative chemotherapy and radiation

Most patients who do not respond to high-dose chemotherapy probably have incurable disease; an exception is those with solitary metastatic disease that is surgically resectable. If surgery cannot be done, these patients can be considered for palliative chemotherapy or palliative radiation therapy. Gemcitabine and oxaliplatin (GEMOX) has shown efficacy in relapsed cisplatin-refractory disease and may offer a chance for long-term survival. [26]

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Surgical Care

Surgical resection is recommended for patients with residual disease after chemotherapy. Retroperitoneal lymph node dissection (RPLND) should clear the region of residual disease. Open nerve-sparing RPLND is preferred over laparoscopic RPLND, although open nerve-sparing RPLND has multiple complications, including retrograde ejaculation and other infertility issues.

Patients in whom RPLND reveals viable cancer (in approximately 60% of patients, postchemotherapy residual masses are either viable cancer or teratoma) are treated with subsequent chemotherapy.

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Fertility and Sperm Banking

Because 45% to 55% of testicular cancer patients have azoospermia or oligospermia at or beyond 2 years after therapy, those patients who wish to preserve fertility should be offered semen cryopreservation before the start of therapy. [27] Some experts recommend performing a baseline sperm count and sperm banking prior to the radiographic diagnostic evaluation, to avoid radiation exposure of the sperm. An increased rate of fetal malformations has not been reported in the subsequent offspring of men who have retained fertility after treatment for testicular cancer.

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