Germ Cell Tumors

Germ Cell Tumors

What every physician needs to know about germ cell tumors:

Germ cell tumors are relatively rare and represent a highly curable epithelial cancer. Optimal management of patients with germ cell tumors requires effective multidisciplinary management with medical oncology, urology, and in some instances, radiation oncology, working as a team.

Over the past several decades through a series of carefully conducted clinical trials, an extensive knowledge base for effective therapy has been developed and validated. Routine cases can be managed effectively by many clinicians; however, subsets of patients benefit from a higher level of experience and expertise, and should be considered for referral to a tertiary care center. Because testis cancer is almost always curable, has relatively complex treatment algorithms and affect younger patients with many decades of life and health at stake, there should be a low threshold for requesting a second opinion from a center of excellence.

For the following patients, referral to a tertiary care center is particularly important: men with poor risk disease, men who relapse following chemotherapy and men who are going to undergo a retroperitoneal lymph node dissection or post-chemotherapy resection of residual tumors.

Because these cancers strike relatively young men and are usually curable, mistakes in management can result in many years of life lost. At the same time, because chemotherapy and radiation therapy can result in future health problems, over-treatment can result in significant morbidity.

Over the last several years, surveillance for stage I testis cancer has replaced radiation therapy (for seminomas) and retroperitoneal lymph node dissection (for non-seminomas) as the preferred management strategy, in an attempt to reduce the incidence of early and late complications of treatment.

Testis cancer is most common between the ages of 20 and 45 years, and is the most common cancer among males aged between 20 and 40 years. However, it is extremely rare in Afro-Caribbean men. The major risk factors are a personal history of testis cancer or cryptorchidism, and a family history of testis cancer in a brother or father.

Testis cancers are typically aggressive and rapidly progressive cancers that require rapid diagnostic work-up and expedited treatment. Testis cancers are almost always first discovered by the patient himself, but they sometimes delay seeking medical care. Testis cancers may be either tender or nontender and must be considered as a possible diagnosis in a man with testicular pain or tenderness.

Although the incidence of testicular cancer in the US has been slowly rising, it remains a rare disease. Complex management decisions regarding the integrated role of systemic therapy and surgery requires significant experience and many patients may benefit from an evaluation by an expert group at a variety of experienced centers around the US.

Are you sure your patient has a germ cell tumor? What should you expect to find?

The vast majority of testis germ cell tumors are detected by men who notice enlargement, induration, pain or tenderness in the involved testicle. Testis cancer can also result in testicular atrophy, gynecomastia, back pain (from retroperitoneal adenopathy), or palpable supraclavicular adenopathy.

On imaging studies, transcrotal ultrasound can almost always confirm the presence of a hypoechoic, often heterogeneous mass. On CT scans, the most common sites of metastatic disease are the retroperitoneal lymph nodes, followed by the lungs, posterior mediastinal lymph nodes, liver, and pelvic lymph nodes. Bone and brain metastases are less common.

Mediastinal germ cell tumors present as an anterior mediastinal mass, often resulting in chest symptoms. Retroperitoneal germ cell tumors may present as a palpable abdominal mass or with back pain. Like primary testis cancers, extragonadal germ cell tumors can present with gynecomastia.

Men presenting with a medianstinal and/or retroperitoneal mass should have assessment of serum hCG and AFP levels. Marked elevation of one or both of these markers can in some clinical settings obviate the need for tissue, allowing for a rapid diagnosis and management in critically ill patients in need of urgent treatment. However, the vast majority of patients should have histopathologic confirmation of the diagnosis because hCG and AFP can be elevated in other types of cancer.

Beware of other conditions that can mimic germ cell tumors:

The differential diagnosis for a testicular mass and/or tenderness include hydrocele, spermatocele, orchitis, epididymitis, germ cell tumors and non-germ cell cancers. Tumors can generally be distinguished from other abnormalities with a transscrotal ultrasound. Although most painful lesions of the testis are not malignant, many testis cancers are painful and/or tender. The presence of pain or tenderness does not exclude the presence of cancer. Lymphomas involving the testis can be mistaken for seminomas histopathologically, but immunohistochemical staining can distinguish them.

Mediastinal germ cell tumors originate in the anterior mediastinum and typically originate in the thymus. Other anterior mediastinal tumors include thymomas and both Hodgkin lymphoma and non-Hodgkin lymphoma.

Men with seminoma are at increased risk of developing sarcoid granulomas, which can mimic metastatic disease. Sarcoid should be considered in men with testis cancer with isolated mediastinal and/or hilar adenopathy.

Several different cancers can result in elevated serum hCG and/or AFP levels. Hepatocellular carcinoma typically produces very highly elevated serum AFP levels. Other cancers that sometimes produce AFP include cancers of the stomach, pancreas, biliary tract and the lung. Elevated serum hCG levels have been reported in cancers of the liver, biliary tract, pancreas, stomach, lung, breast, kidney and bladder.

Which individuals are most at risk for developing germ cell tumors:

The primary risk factors for a testicular germ cell tumor is a personal history of cryptorchidism, testis cancer in the other testicle or a family history of testis cancer, particularly in a man’s brother or father. Testis cancer is not known to be associated with any behaviors (i.e. smoking etc.). Even for men with risk factors, the absolute lifetime risk of being diagnosed with testis cancer is low:

• 2%-3% of men with testis cancer will develop a second tumor in the other testis.

• Less than 2% of men with cryptorchidism will develop testis cancer.

• Less than 2% of men with a first degree male relative with a history of testis cancer will develop testis cancer themselves.

Testis cancer is most commonly diagnosed between the ages of 15 and 50, with non-seminomas predominating in younger men, and seminomas in middle-aged men. Testis cancer is most common in white males and is exceedingly rare in men of African ancestry.

Men with Klinefelter syndrome are at increased risk of developing mediastinal germ cell tumors.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Testis germ cell tumors are divided histopathologically into seminomas and non-seminomas which include embryonal carcinomas, teratomas, yolk-sac tumors and choriocarcinomas. Seminomas must consist only of seminoma where as non-seminomas can, and usually do, consist of two or more different germ cell tumor components and may include components of seminoma. Hence, a tumor that is 99% seminoma and 1% embryonal carcinoma is considered a non-seminoma.

Although all germ cell tumors have the potential to grow rapidly, seminomas typically grow less rapidly than non-seminomas. The most aggressive germ cell tumor subtypes are choriocarcinoma, embryonal carcinoma and yolk-sac tumors. While seminomas only very rarely spread distantly without first spreading to retroperitoneal (i.e. regional) lymph nodes, choriocarcinoma typically metastases hematogenously and embryonal carcinoma also does occasionally.

If tumor markers are elevated prior to orchiectomy, they should be measured again after orchiectomy to determine whether they are returning to normal. Standard imaging studies include a CT scan with intravenous contrast and either a PA and lateral chest radiograph, or chest CT. A chest CT is mandatory for any patient with elevated serum tumor markers or an abnormal CT of the abdomen and pelvis.

Seminomas do not produce AFP and, therefore, elevation of serum AFP excludes a diagnosis of pure seminoma even if the diagnosis is pure seminoma by histopathology. Some patients however have a constitutively mildly elevated AFP, typically in the range of 15 to 30 ng/ml (in which case the AFP level should be stable and unaffected by orchiectomy), so minor elevations in AFP should be interpreted with caution.

There is no role for routine PET scans or MRIs when staging testis cancer.

CT or MRI of the brain with and without contrast should be obtained in any patient with very highly elevated serum tumor markers (for example, AFP or HCG greater than 10,000), unexplained neurological signs or symptoms, or a primary tumor consisting primarily of choriocarcinoma.

Most men with testis germ cell tumors are stage I, meaning that there is no evidence of metastatic disease. Men who have normal imaging studies but persistently elevated AFP or HCG are technically stage Is, but are treated as having stage III disease.

Men with metastatic disease confined to the retroperitoneal lymph nodes are stage II. Low volume disease is typically treated with resection (for non-seminomas) or infradiaphragmatic radiation therapy (for pure seminomas), while bulkier disease is treated with systemic chemotherapy typically using the three drugs bleomycin, etoposide and cisplatin or, less often, the two drugs etoposide and cisplatin.

The traditional TNM staging is used in patients with germ cell tumors also takes into account serum tumor marker levels, so it could also be considered TMNS staging. An example of the relevance of this is that T2N3M0S1 is considered stage II while T2N1M0S2 is considered stage III. For men with disseminated germ cell tumors, the most widely used classification system is that developed by the International Germ Cell Cancer Collaborative Group (IGCCCG) which is a prognostic-factor based staging system for metastatic germ cell cancer.

These prognostic factors were established based on analyses of outcomes of patients treated with chemotherapy. It does not apply to patients with early stage disease. It is worth noting that the AJCC staging of germ cell tumors in adolescent and adult males reflects the prognostic factors established by the IGCCCG.

Staging

See Table I. TNM staging of Testicular Cancer.

Seminoma

Patients with disseminated seminomas are divided into good and intermediate prognosis groups, and patients with NSGCT are divided into good, intermediate and poor prognosis groups, as defined below. These classifications are used to determine the specific chemotherapy treatment plan:

Good prognosis:

• Any primary site.

• No metastases to organs other than the lungs.

• Serum tumor markers do not influence staging of seminomas but an elevated AFP is not consistent with a diagnosis of pure seminoma and highly elevated HCG (i.e. > 1000 U/L) is suggestive of nonseminomatous elements.

Intermediate prognosis:

• Any primary site AND

• Metastases to organs other than the lungs.

Long term disease-specific survival is about 85% for men with good risk seminoma and about 70% for men with intermediate-risk seminoma. There are no seminomas that are classified as “poor-risk.”

NSGCT

Good prognosis:

• Testis/retroperitoneal primary.

• no metastases to organs other than the lungs.

• AFP less than 1000, bcCG less than 5000, LDH less than 1.5 X ULN (upper limit of normal).

Intermediate prognosis:

• Testis/retroperitoneal primary.

• No metastases to organs other than the lungs.

• AFP more than 1000 and less than 10,000 or hCG more than 5000 and less than 50,000 or

• LDH more than 1.5 x ULN and less than 10 ULN.

Poor prognosis:

• Mediastinal primary or

• Metastases to organs other than the lungs or

• AFP more than 10000 or hCG more than 50,000 or LDH more than 10 x ULN.

Long term disease-specific survival is about 90% for men with good risk non-seminoma, 80% for men with intermediate risk non-seminoma and 50% for men with poor risk disease.

In other words, men with large volume stage II disease or with stage III disease are divided into prognostic categories based on some or all of the following variables, depending on whether the tumor is a pure seminoma or an NSGCT: site of primary tumor, sites of metastatic disease, and the levels of AFP, LDH and beta-hCG on day one of chemotherapy.

For pure seminomas, favorable risk patients have no metastases outside the lungs and lymph nodes.

Intermediate risk seminomas are those that have metastasized to liver, bones or other non-pulmonary organs. Favorable risk non-seminomas have no metastases outside the lungs or lymph nodes and have tumor marker levels that are below the intermediate range. Intermediate risk non-seminomas have metastases limited to the lungs and/or lymph nodes and have at least one tumor marker in the intermediately elevated range.

Poor risk patients are those with non-seminomas with any of the following risk factors: primary mediastinal tumor, metastases to organs other than the lungs, and/or at least one highly elevated tumor marker.

The therapeutic significance of the risk categories for disseminated germ cell tumors in men is that intermediate and poor risk patients receive more chemotherapy than favorable risk patients.

What therapies should you initiate immediately i.e., emergently?

Germ cell tumors are aggressive and rapidly growing cancers. Prompt referral for transscrotal ultrasound and, if indicated, inguinal orchiectomy should be made with the goal of having the involved testis removed urgently, preferably within seven days. When chemotherapy is indicated for metastatic disease, it too, should be initiated urgently, although delaying treatment to allow time for sperm banking is appropriate in most cases.

In selected patients with non-seminomas who present with high volume disease with significant marker elevation (serum bhcg/AFP) or in whom a tissue diagnosis has been established by biopsy of a metastatic site, initial orchiectomy can be deferred until post chemotherapy retroperitoneal lymph node dissection (or other surgical resection).

Urgent or emergency treatment is also indicated for the rare patient who presents with large volume metastatic disease and who appears medically unstable and/or highly symptomatic. In such circumstances, a highly elevated AFP and/or beta-hCG plus an anatomic distribution of disease consistent with a germ cell tumor (i.e. a testicular mass or a large retroperitoneal or anterior mediastinal mass) may serve as adequate evidence to establish a diagnosis and to start chemotherapy as treatment of a disseminated germ cell tumor.

What should the initial definitive therapy for the cancer be?

The initial procedure for testis germ cell tumors is inguinal orchiectomy, which is both diagnostic and therapeutic. Because of the testis-blood barrier and the consequent potential for the testis to serve as a sanctuary site, all testis germ cell tumor patients should undergo inguinal orchiectomy, regardless of how advanced the stage of the disease is. In rare and select circumstances where the urgency to start chemotherapy precludes orchiectomy, the testis should be removed after chemotherapy has been completed.

Following orchiectomy, persistent elevation of serum tumor markers beta-hCG and AFP almost always represents metastatic disease, even if staging studies show no evidence of regional or distant metastases. The expected serum half life for beta-hCG is less than 36 hours and for AFP is 7 days; in the absence of disseminated disease, serum tumor marker levels should decline following orchiectomy in accordance with these predicted half-lives.

In contrast, LDH is a highly non-specific marker of disease and a persistently elevated LDH is not strong enough evidence of cancer to start treatment without corroborating imaging studies confirming metastatic disease.

Stage I seminomas

Long-term disease-specific survival for men with stage I testis seminoma is over 99% regardless of which treatment strategy is used. Following orchiectomy, treatment strategies include surveillance, carboplatin chemotherapy and radiation therapy.

Surveillance

For stage I seminomas and nonseminomas alike in which the post-orchiectomy serum tumor markers are normal, most men are cured by orchiectomy alone and need no additional treatment. The risk of relapse is less than 20% for seminomas and about 30% for non-seminomas. Therefore, close surveillance is mandatory for men who do not undergo post-orchiectomy treatment so that relapses can be promptly treated.

The standard surveillance schedules are listed below in the section on follow-up surveillance but it is worth noting that the surveillance schedule for seminomas requires no more than three visits per year. Surveillance rather than active treatment is attractive because a large majority of men can thus be spared the acute and chronic side effects and complications associated with additional treatment without jeopardizing their long-term survival.

Men with clinical stage I seminoma who relapse during surveillance almost always relapse in the retroperitoneum (i.e. with stage II disease) and can usually be salvaged with radiation therapy. The number of men requiring systemic chemotherapy for relapse does not differ significantly between those managed with surveillance and those treated immediately with radiation therapy. Some centers prefer to manage all relapsing patients with chemotherapy even if they have early stage II disease, so treatment at relapse depends not only on extent of disease but also on where the man is receiving treatment.

Risk factors for relapse

The best established risk factor for relapse in stage I seminoma is the size of the primary tumor. There is no single best size threshold to distinguish high risk versus low risk, but 4cm is commonly used. Invasion of the rete testis was also found to be an independent risk factor for relapse in one large international study, but this finding has not been validated. The analysis reported that using the risk factors of rete testis invasion and size greater than 4cm, relapse rates were 12%, 16% and 32% for men with 0, 1 or 2 risk factors, respectively.

However, a Spanish study reported that only 6% of patients with neither risk factor relapsed. A risk of relapse higher than 32% has not been identified so the utility of risk stratification is unclear and surveillance is a viable option for essentially all patients who can comply with the surveillance schedule.

Carboplatin chemotherapy

For stage I seminomas, there are two alternatives to surveillance: single agent chemotherapy with carboplatin or subdiaphagmatic radiation. Chemotherapy consists of either one or two doses of carboplatin. Dosing of carboplatin in this setting is AUC = 7 and it must be based on a measured glomerular filtration rate using an isotope technique (such as iothalamate or EDTA) rather than on a calculated creatinine clearance. If a GFR measurement cannot be performed, then creatinine clearance should be measured using a 24-hour urine collection.

Dosing using a creatinine clearance calculation based on a serum creatinine value (such as with the Cockroft-Gault formula) that has not been validated may result in significant under-dosing, and should not be used in this setting. Relapse rates after carboplatin are about 5% after a single dose and 2% after two doses given 21-days apart. Disease specific survival in all studies of single agent carboplatin has been 100%, including the randomized controlled trial comparing a single dose of carboplatin to radiotherapy.

No febrile neutropenia or other major complications have been reported in patients receiving this treatment, but a few patients have been reported to have received platelet transfusions for severe thrombocytopenia. Carboplatin may increase the risk of infertility, thus sperm-banking prior to treatment is recommended.

It is important to remember that a large majority of men treated with chemotherapy for stage one disease are receiving treatment that they do not need. The late effects of carboplatin are not known due to limited long-term follow-up but may include an increased risk of secondary malignancies and cardiovascular disease.

Compared to men undergoing radiation therapy, carboplatin has been reported to result in a lower rate of second primary germ cell tumors in the contralateral testis, but long-term data on this issue is lacking.

Radiation therapy

Radiotherapy for clinical stage I seminoma uses either a subdiaphragmatic para-aortic field alone to treat retroperitoneal lymph nodes or a “dog-leg” field that includes a subdiaphragmatic para-arotic field, plus the ipsilateral iliac nodes (i.e. the iliac nodes on the same side as the primary testis tumor). The para-aortic field is typically defined as running from the disks between T10 and T11 superiorly, and L5-S1 inferiorly. Lateral margins are typically the ipsilateral renal hilum and the lateral margin of the contralateral processus transversus.

The dog-leg field continues the lower ipsilateral margin diagonally to the lateral edge of the acetabulum and then runs vertically downward to the middle of the obturator foramen. The contralateral margin follows parallel to the ipsilateral margin (see Fossa et al, JCO 1999;1147-1148 for additional detail). Alternatively, the dog-leg field may only extend inferiorly as far as the lateral edge of the acetabulum, because the lower internal and external iliac nodes are not typical landing sites for metastases from a testis tumor.

Typical doses are 20 Gy or 26 Gy, typically given in 10 to 13 daily fractions of 2 Gy each, but randomized controlled trials showed no difference in relapse rate when comparing either 20 GY to 30 Gy or a para-aortic field to a dog-leg field.

The risk of relapse after radiation therapy is about 4%. Disease specific survival exceeds 99%. Side effects include nausea, fatigue, peptic ulcers and infertility. Sperm-banking prior to treatment is recommended, as is shielding of the contralateral testis with a clam-shell device. It is important to remember that a large majority of men undergoing radiation therapy for stage I seminoma are receiving treatment that they do not need.

Radiation therapy for seminomas has been associated with an increased risk of secondary malignancies and an increased death rate from gastrointestinal diseases (e.g., bleeding from peptic ulcer disease) and cardiovascular disease. Contraindications to radiation therapy include horseshoe or pelvic kidney and inflammatory bowel disease.

Stage II non-seminomas

Long-term disease-free survival for clinical stage I non-seminomas with normal post-orchiectomy serum AFP and beta-hCG is about 99% regardless of which of the three standard treatment strategies is used: surveillance, retroperitoneal lymph node dissection or primary chemotherapy with bleomycin, etoposide and cisplatin (BEP).

Surveillance

As with seminomas, clinical stage I non-seminomas with serum tumor markers that are normal or that normalize after orchiectomy can be managed with post-orchiectomy surveillance but the follow-up schedule is more intensive with non-seminomas, as detailed below in the section on follow-up surveillance. The risk of relapse for the average patient is 30% but low and high risk groups have been identified.

Risk factors for relapse

Risk factors for relapse include the presence of embryonal carcinoma, a preponderance of embryonal carcinoma, lymphovascular invasion by the tumor, and the absence of yolk-sac tumor elements. However, the most commonly used risk factors today are lymphovascular invasion and a predominance of embryonal carcinoma.

Men with neither risk factor have a relapse risk of less than 20%, those with one risk factor have a relapse risk between 30% and 50% and those with both risk factors have a risk of relapse of 50% to 88%.

Studies have documented that men can be effectively managed with surveillance, even when they have high risk disease, without compromising long-term survival because chemotherapy at relapse is highly reliable at achieving a cure.

All clinical stage I patients with normal serum tumor markers are thus eligible for surveillance, a management strategy that spares most of them from undergoing any additional treatment. When clinical stage I non-semiomas relapse after orchiectomy, they generally relapse with favorable risk disseminated disease, often with elevated serum tumor markers as the earliest sign of relapse. The most common treatment is thus three cycles of BEP chemotherapy, or alternatively, four cycles of etoposide plus cisplatin (see stage III germ cell tumors below).

Retroperitoneal lymph node dissection

Retroperitoneal lymph node dissection (RPLND) is an alternative to surveillance for stage I non-seminomas with normal serum tumor markers but the operation should only be performed by a surgeon with extensive experience. In non-expert hands, there is a higher risk of an incomplete dissection, on the one hand, and nerve injury causing ejaculatory dysfunction on the other.

RPLND offers both staging and therapeutic benefits: only about 10% to 20% of men found to have low volume lymph node metastases (pathological stage IIA) relapse after RPLND in the absence of additional therapy.

For men found to have more extensive lymph node metastases, two 3-week courses of BEP chemotherapy prevents relapse in about 99%. Men should be advised to bank sperm prior to RPLND, due to the risk of an ejaculation or retrograde ejaculation after the operation.

Primary Chemotherapy with BEP

Post-orchiectomy chemotherapy is also an effective treatment strategy for stage I non-seminomas with normal serum tumor markers and the standard treatment regimen is two 21-day cycles of BEP chemotherapy. The dose and treatment schedule is as follows:

• Bleomycin 30 units fixed dose IV on days 2, 9, and 16.

• Etoposide 100mg/m² IV on days 1, 2, 3, 4, and 5.

• Cisplatin 20mg/m² IV on days 1, 2, 3, 4, and 5.

After two cycles of BEP chemotherapy, only about 2% of men relapse and disease-specific survival exceeds 99%. Similar results have been reported with a single cycle of BEP, although in one study of high risk patients a 3.2% relapse rate was reported with a single cycle of BEP compared to 0% in those receiving two cycles. Side effects and complications from BEP include peripheral neuropathy, high-pitch hearing loss, diminished renal and pulmonary function, and an increased risk of cardiovascular disease and secondary cancers. The extent to which these effects are seen after just two cycles of treatment has not been well defined. Men should be advised to bank sperm prior to chemotherapy due to the risk of infertility.

Primary chemotherapy after orchiectomy for clinical stage I non-seminomas can thus be given to prevent relapse and it is highly effective. However, 70% of men require no treatment beyond orchiectomy and chemotherapy in fact represents overtreatment for most men, and may result in significant acute and chronic side effects as well as late complications.

It is worth keeping in mind that most men with stage I disease who relapse while undergoing surveillance after orchiectomy require only three cycles of BEP chemotherapy. So even those stage I patients who are destined to relapse after orchiectomy are only spared a single cycle of chemotherapy by receiving the chemotherapy instead of undergoing surveillance, while those not destined to relapse receive two cycles of chemotherapy that they do not need.

Stage II seminoma

Stage II seminomas are uncommon and have not been studied as extensively as either stage I or stage III. Treatment recommendations are thus mainly derived from observational outcome data. There are two standard treatments: either radiation therapy or chemotherapy. Radiation therapy is generally used for smaller volume disease while chemotherapy is used for bulkier disease.

Radiation therapy for stage II disease uses a dog-leg field as defined above (see stage I seminoma treatment options) but to a dose of 25 Gy divided into 20 daily fractions, plus a 10 Gy boost to the enlarged retroperitoneal lymph nodes. The boost can be administered on the same days as the dog-leg fractions, or subsequently over 5 to 8 fractions.

There is no role for radiation therapy above the diaphragm. Retrocrural nodal metastases represent stage III disease and should be treated with chemotherapy for disseminated disease. The side effects and risks of radiation therapy for stage II seminoma are the same as for stage I, only potentially more severe due to the higher dose to the involved field. Chemotherapy in this setting consists of three cycles of BEP (bleomycin, etoposide and cisplatin) or four cycles of EP (etoposide plus cisplatin). Many centers prefer BEP X 3 over EP X 4 unless there is a medical contraindication to bleomycin such as patients with significant underlying lung disease.

Like BEP, EP chemotherapy is given as repeated 21-day cycles as follows:

• Etoposide 100mg/m² on days 1, 2, 3, 4, and 5.

• Cisplatin 20mg/m² on days 1, 2, 3, 4, and 5.

In general, these chemotherapy regimens are considered more toxic than radiation therapy due to quality of life issues and the risk of potentially fatal side effects (febrile neutropenia, bleomycin pneumonitis).

In stage II seminoma, as the retroperitoneal metastases become bulkier, the likelihood of cure with radiation diminishes. Thus, the general practice is that early stage II disease is treated with radiation therapy while more advanced stage II disease is treated with chemotherapy.

It has not been possible to define an exact cut-off but stage IIA is generally treated with radiation therapy while stage IIC should be treated with chemotherapy. Decisions about which modality to use for stage II depend on the treating physician, the size of the involved nodes, and the distribution of the enlarged retroperitoneal lymph nodes (i.e. the larger the size of the field that would be required to cover all the enlarged nodes, the less attractive radiation therapy is as a treatment option).

Radiation therapy is generally the preferred treatment for stage IIB disease unless there are numerous involved nodes extending craniocaudally or the distribution of nodal mets would require including a significant portion of a kidney or the liver in the boost field. Contraindications to radiation therapy include horseshoe or pelvic kidney, and inflammatory bowel disease.

Theoretically, retroperitoneal lymph node dissection should be a good treatment option for stage I or stage IIA seminoma except that lymph node metastases in seminoma are more likely to invade through the lymph node capsule compared to metastases from non-seminoma. There is no adequate published experience with RPLND for seminomas and therefore, the effectiveness of such an approach is unknown.

Given the lack of data on RPLND for seminoma and the very high effectiveness of surveillance, chemotherapy and radiation therapy for stage I disease and radiation therapy and chemotherapy for stage II disease, a RPLND cannot be recommended for either stage I or II seminoma.

Stage II non-seminoma

The standard treatment for stage II non-seminoma is chemotherapy for disseminated disease, but clinical stage IIA disease with normal serum AFP and beta-hCG is an exception to this practice. As many as 30% of clinical stage IIA patients with normal markers will turn out to have pathological stage I disease (i.e. benign lymphadenopathy and no lymph node metastases) if they undergo retroperitoneal lymph node dissection. Therefore, such patients should either undergo RPLND or be observed with serial cross-sectional imaging to monitor for progression.

If a RPLND is performed on a patient with clinical stage IIA disease, a complete bilateral dissection with nerve sparing should be performed. Patients who are pathological stage IIA have only about a 10% risk of relapse after RPLND and do not require chemotherapy. A randomized controlled trial compared surveillance to immediate post-operative chemotherapy in men found to have pathological stage II disease at RPLND and no difference in survival was observed.

Nonetheless, two cycles of post-RPLND chemotherapy (either BEP or EP) reduces the relapse rate to about 1% and patients thus often prefer to undergo this additional treatment. Men who have pathological stage IIB disease or higher are generally advised to undergo post-RPLND chemotherapy because their risk of relapse is about 50%.

Men with clinical stage IIA non-seminoma and elevated serum AFP or beta-hCG and men with clinical stage IIB or IIC non-seminoma should undergo the same chemotherapy used for stage III disease. These patients are considered good-risk disseminated disease unless one or more of their serum tumor markers (AFP, beta-hCG or LDH) are in the intermediate or high-risk range (i.e. AFP > 1000 ng/ml, beta-hCG >5000 U/L or LDH > 1.5 x ULN). If there are any residual masses at the conclusion of chemotherapy, a full bilateral RPLND should be performed to remove them and any micrometastatic nodal disease.

Stage III germ cell tumors

Extragonadal germ cell tumors and disseminated testicular germ cell tumors are treated with multiagent cisplatin-based chemotherapy. The most commonly used regimen is BEP, which consists of:

• Bleomycin 30 units IV on days 2, 9 and 16.

• Etoposide 100mg/m² on days 1, 2, 3, 4 and 5.

• Cisplatin 20mg/m² on days 1, 2, 3, 4, and 5.

• Cycle length: 21 days.

Men with good-risk disseminated germ cell tumors are treated with three cycles of BEP while men with intermediate or poor-risk disease are treated with four cycles of BEP. The optimal treatment of men with intermediate-risk disease has not been well defined and their prognosis is distinctly better than men with poor-risk disease.

For men with intermediate risk disease whose tumor marker levels are very close to the “good risk” threshold (AFP of 1000ng/ml, beta-hCG of 5000 U/L and LDH 1.5 X ULN), the bleomycin is sometimes withheld from the fourth cycle of chemotherapy.

Other standard regimens include EP, four cycles of which is considered an acceptable alternative to three cycles of BEP for good-risk disease. There is no role for EP in men with intermediate or poor risk disease. EP is:

• Etoposide 100mg/m² on days 1, 2, 3, 4 and 5.

• Cisplatin 20mg/m² on days 1, 2, 3, 4, and 5.

• Cycle length 21-days.

An alternative to four cycles of BEP for intermediate or poor-risk disease is four cycles of VIP chemotherapy:

• Etoposide 75mg/m² on days 1, 2, 3, 4, 5.

• Mesna 400mg/m² every four hours X three doses on days 1, 2, 3, 4, 5(total daily dose of mesna = 1200mg/m²).

• Ifosfamide 1200mg/m² on days 1, 2, 3, 4, 5.

• Cisplatin 20mg/m² on days 1, 2, 3, 4, 5.

• Cycle length 21 days.

Side effects and complications from VIP are very similar to those following BEP chemotherapy except that high-grade hematologic toxicity in the form of leukopenia and thrombocytopenia are more common with VIP. The risk of fatal complications with the two regimens was indistinguishable in two randomized controlled trials.

Common side effects include neutropenia, thrombocytopenia, fatigue, nausea, vomiting, peripheral neuropathy, tinnitus, high-frequency hearing loss, and alopecia. Diminished renal function is common after cisplatin chemotherapy but is usually mild and of no clear clinical significance, but renal failure can occur and it is necessary to reduce the risk of this with abundant intravenous hydration. There is a small risk of hemorrhagic cystitis with ifosfamide, but the use of mesna minimizes the likelihood of this complication.

Management of residual masses

For non-seminomas, all residual masses at the end of chemotherapy should be resected if this is surgically feasible and if any elevated serum tumor markers have returned to normal. Men with rising serum tumor markers at the end of chemotherapy generally have refractory disease and the usual treatment is salvage chemotherapy. Men with persistently elevated serum tumor markers (i.e. elevated and either stable or slowly declining) should generally be observed until markers normalize. In these patients, when the markers normalize or if they remain stable without rising for a prolonged period, resection of residual masses should then be performed.

If one or more masses can be resected but others cannot, then resection is not generally performed. If histopathology shows only teratoma and/or benign tissue, then no further treatment is indicated.

If histopathology shows viable germ cell tumor other than teratoma (i.e. embryonal carcinoma, seminoma, yolk-sac tumor, choriocarcinoma or germ cell tumor not otherwise specified), then two cycles of additional chemotherapy using either TIP (paclitaxel, ifosfamide and cisplatin) or VeIP (vinblastine, ifosfamide and cisplatin). See doses and schedule below.

For seminomas, residual masses can be observed with treatment reserved for masses that grow over time. Alternatively, some recommend obtaining a PET scan for patients with residual masses greater than 3cm. When PET scans are performed, they should be delayed until at least six weeks after the end of the last cycle of chemotherapy in order to reduce the risk of false positives.

Men with increased FDG uptake in a residual mass should undergo surgery either to have the mass(es) resected (if surgically possible) or else to have extensive biopsies of the mass(es). Men proven histopathologically to have residual viable seminoma and men whose residual masses grow over time should undergo salvage chemotherapy as discussed below under post-chemotherapy relapse.

Post-chemotherapy relapse: salvage chemotherapy

For men who relapse after having previously received etoposide and cisplatin-based combination chemotherapy as any part of their treatment, the standard treatment is four cycles of additional chemotherapy using either TIP or VeIP. For men who relapse after receiving carboplatin chemotherapy for stage I seminoma, treatment should consist of the appropriate first-line chemotherapy based on their risk categorization (i.e. they should receive either three or four cycles of BEP or an equivalent regimen based on their risk factors):

TIP:

• Paclitaxel 250mg/m² as a continuous 24-hour infusion on day 1.

• Mesna 500mg/m² every four hours X three doses on days 2, 3, 4, 5(daily dose of mesna = 1500mg/m²).

• Ifosfamide 1500mg/m²/day on days 2, 3, 4, 5.

• Cisplatin 25mg/m²/day on days 2, 3, 4, 5.

• Cycle length 21-days.

VeIP:

• Vinblastine 0.11mg/kg/day on days 1 and 2.

• Mesna 400mg/m² every four hours X three doses on days 1, 2, 3, 4, 5(daily dose of mesna = 1200mg/m²).

• Ifosfamide 1200mg/m²/day on days 1, 2, 3, 4, 5.

• Cisplatin 20mg/m²/day on days 1, 2, 3, 4, 5.

• Cycle length 21-days.

An alternative is to give two cycles of high-dose chemotherapy with etoposide (750mg/m²/day on days 1, 2 and 3) and carboplatin (700mg/m²/day on days 1, 2 and 3) followed by autologous hematopoietic stem cell rescue, but this approach has never been shown in a randomized controlled trial to result in superior outcomes.

The largest published randomized controlled trial reported that overall survival was exactly the same when comparing four cycles of standard-dose chemotherapy to three cycles of standard-dose chemotherapy, followed by a single cycle of high-dose salvage chemotherapy.

Standard dose salvage chemotherapy has never been compared to two cycles of high-dose chemotherapy in a clinical trial. Nonetheless, high-dose salvage chemotherapy is offered as standard salvage therapy at many leading cancer centers because outcomes using this approach have been better than historical controls treated with standard-dose chemotherapy.

Third-line chemotherapy

Optimal third-line chemotherapy is not well defined. Active agents include gemcitabine, paclitaxel (in patients who do not receive paclitaxel in the second-line setting), and oxaliplatin have all been shown to have activity and response rates to various combinations of these and other drugs have been reported in the literature.

A small number of durable remissions have been reported but the absence of randomized controlled trials has made it impossible to accurately measure the benefit of any of the studied regimens. Referral to a center that treats a high volume of testis cancer patients is recommended for patients who relapse after salvage chemotherapy.

What other therapies are helpful for reducing complications?

Hydration

Aggressive pre and post-chemotherapy hydration using normal saline is mandatory for patients receiving cisplatin chemotherapy (typically 2 liters of normal saline total/day).

Antiemetics

Aggressive antiemetics are mandatory for all the cisplatin-based regimens discussed in this section on germ cell tumors (including BEP, EP, VIP, VeIP and TIP). This should include a 5HT3 receptor antagonist (such as ondansetron) combined with dexamethasone (20mg daily) and either prochlorperazine or metoclopramide on the first five to seven days of each treatment cycle.

Whether all patients should receive a neurokinin-1 receptor antagonist is controversial due to the very high cost. Aprepitant should be considered for patients whose nausea is not adequately controlled with the three drug regimen described above.

Erythropoiesis stimulating agents

Erythropoiesis stimulating agents (such as Procrit and Aranesp) have a markedly limited role in the treatment of patients with germ cell tumors.

Granulocyte colony stimulating factors

The usual patient who is receiving first-line BEP or EP chemotherapy and has good-risk disease is at low risk of febrile neutropenia, and hematopoetic growth factors are not routinely used in this setting. However, filgrastim and pegfilgrastim do have a role in specific circumstances. Men receiving chemotherapy for intermediate or poor-risk disseminated germ cell tumors are at increased risk of febrile neutropenia and using hematopoetic growth factors (filgrastim or pegfilgrastim) is appropriate in such patients as routine prophylaxis.

Similarly, patients receiving salvage chemotherapy with TIP, VeIP or VIP are at high risk of severe myelosuppression and should receive either filgrastim or pegfilgrastim starting on day 7 of the treatment cycle. Moreover, any patient who has suffered an episode of febrile neutropenia should receive filgrastim or pegfilgrastim on subsequent cycles regardless of the stage of their disease.

Avoid overuse of imaging studies with contrast

In the vast majority of cases, re-imaging (CT scans with intravenous contrast) are only needed following completion of chemotherapy i.e. following 3 or 4 cycles of chemotherapy BEP or EP. Patients with stage I disease treated with surveillance or primary chemotherapy almost always relapse in the retroperitoneum. IV contrast is not needed to detect retroperitoneal adenopathy and a noncontrast CT scan is adequate for surveillance.

Stage I patients treated with radiation therapy or retroperitoneal lymph node dissection almost always relapse above the diaphragm and/or with elevated serum tumor markers. Chest x-ray is adequate for surveillance. If a chest CT is ordered, IV contrast is not required. However, patients treated with paraaortic radiation without inclusion of the ipsilateral hemipelvis are at risk of pelvic relapse and non-contrast pelvic CT scan is required for surveillance of such patients.

Clinical stage IIA-IIB seminoma patients treated with radiation should undergo surveillance with chest radiographs and CT scans of the abdomen and pelvis but IV contrast is not required as relapses typically occur in the lymph nodes and bones. In contrast, stage IIC and stage III seminoma patients should undergo surveillance with a chest radiograph and abdominopelvic CT scans using IV contrast.

What should you tell the patient and the family about prognosis?

The goal of treatment for testis cancer is cure, regardless of stage. Essentially, all patients have a reasonable chance of cure and for most patients the chances are very high. Overall, 5-year relative survival is 96%.

Stage I seminomas and non-seminomas:

• Five-year survival is 99% or higher.

• Relapse later than 5 years is rare.

Stage II seminoma and non-seminoma:

• Five-year survival is over 95%.

Stage III:

• Favorable risk disease – 5-year survival exceeds 90%.

• Intermediate risk disease – 5-year survival is 70-80%.

• Poor risk disease – 5-year survival is about 50%.

Salvage therapy response rates/survival:

Long-term survival after salvage chemotherapy ranges from 25-50%. Although some single institution reports have reported higher figures.

What if scenarios.

What if the patient develops signs or symptoms of pulmonary toxicity (pneumonitis) while receiving BEP chemotherapy?

Bleomycin should be discontinued if credible evidence of pulmonary toxicity develops. Class signs and symptoms include a persistent dry cough, shortness of breath, bibasilar rales and/or an inspiratory lag. There is no medical test for bleomycin pneumonitis that is highly sensitive and specific for the condition in its early stages. Because bleomycin pneumonitis can progress to fatal ARDS or pulmonary fibrosis, there should be a low threshold for discontinuing bleomycin when pneumonitis is suspected.

Patients with good risk disease whose planned treatment is three cycles of BEP should have the bleomycin discontinue and they should receive a total of four cycles of chemotherapy using EP (etoposide plus cisplatin) for any remaining cycles. The final treatment plan would thus be four cycles of chemotherapy with some cycles including bleomycin and the others consisting of EP.

Patients with intermediate or poor risk disease who were scheduled to receive four cycles of BEP should have the bleomycin discontinued and any remaining cycles of chemotherapy should consist of VIP (etoposide, ifosfamide and cisplatin).

What if the patient presents for chemotherapy but is neutropenic and/or thrombocytopenic?

For patients receiving first-line chemotherapy for an extragonadal or disseminated testicular germ cell tumor, chemotherapy should be continued regardless of neutrophil count. Treatment should not be delayed nor should the dose of chemotherapy be reduced.

For patients receiving salvage chemotherapy with TIP (paclitaxel, ifosfamide and cisplatin), cycles 2, 3,and 4 should not be started until the absolute neutrophil count is at least 450/ microliter and a platelet count of 75,000/microliter.

What if the patient presents for cycles 2,3 or 4 (in the case of intermediate or poor-risk disease) of BEP and has developed moderate renal insufficiency?

For patients in whom therapy is administered with curative intent, the cisplatin dose/schedule is not altered. Increased attention to adequate hydration during days 1-5, aggressive use of hydration during weeks 2 and 3 for those patients with problems maintaining adequate hydration and avoidance of any renal toxic agents i.e. aminoglycosides etc) is mandatory. Carboplatin is less effective at curing testis cancer than cisplatin and switching from cisplatin to carboplatin would thus be expected to lower the likelihood of cure.

What if the serum AFP and/or beta-hCG do not decline as fast as predicted by their biological half-lives?

The half lives of AFP and beta-hCG are 7 days and 1-3 days respectively. If markers decline more slowly than these figures would predict, then the likelihood of cure is lower but treatment should not be changed or aborted. In contrast, if either of these markers shows a consistent pattern of rising during chemotherapy, that is evidence that the treatment regimen is not effectively killing the cancer and should be discontinued in favor of an alternative regimen.

What if a patient who was in complete remission developing a persistently rising serum AFP and/or beta-hCG but no disease is seen in imaging studies?

Rising serum tumor markers AFP and/or beta-hCG are diagnostic of relapsed testis cancer unless a convincing alternative explanation can be confirmed. Radiologically detectable disease is not necessary to start chemotherapy for treatment of metastatic disease. However, several values should be obtained to confirm that a persistent rise is occurring.

In addition, for a mildly elevated and slowly rising beta-hCG, hypogonadism should be excluded as a cause (because leutenizing hormone [LH] can cross-react with the beta-hCG assay) by administering an injection of testosterone (300 mg IM) and assessing suppression.

Follow-up surveillance and therapy/management of recurrences.

Follow-up schedules for both seminoma and non-seminomas have not been prospectively validated. The following are reasonable schemas that may be adapted based upon patient specific risk factors.

Non-seminomas

Clinical stage I : surveillance protocol

Year 1: monthly with PE, AFP, bhcg. CXR every two months. CT abd/pelvis at 3 and 9 months.

Year 2: every two months with PE, AFP, bhcg, CXR. CT abd/pelvis at 6 months (i.e. 18 months after diagnosis).

Year 3: every three months with PE, AFP, bhcg, CXR. CT abd/pelvis yearly.

Year 4: every four months with PE, AFP, bhcg, CT abd/pelvis yearly.

Year 6 and beyond: yearly with PE, AFP, bhcg, CXR.

Stage II-III good/intermediate risk post-completion of chemotherapy/surgery

Year 1: monthly with PE, AFP, bhcg. CXR every 2 months. CT abdomen pelvis every three to 4 months.

Year 2: every two months with with PE, AFP, bhcg, CXR. CT abdomen/pelvis every four months.

Years: 3: every two months with PE, AFP, bhcg, CXR. CT abdomen/pelvis every six months.

Years 4:-5: every three months with PE, AFP, bhcg. CXR every six months. CT abd/pelvis yearly if RPLND not performed.

Year 6 and beyond: yearly with PE, AFP, bhcg, CXR.

Seminomas

Clinical stage I: surveillance

Years 1 and 2: every four months with PE, CXR, CT abd/pelvis.

Years 3-5: every six months with PE, CXR, CT abd/pelvis.

Year 6-10: yearly with PE, CXR, CT abd/pelvis.

Clinical stage II/III: post chemotherapy (CR or residual disease less than 3cm or greater than 3cm but PET negative)

Year 1: every three months with PE, AFP, bhcg, LDH, CXR CT chest/abd/pelvis every 6 months (chest CT vs cxr clinical judgment).

Year 2: every three months with PE, AFP, bhcg, LDH, CXR CT chest/abd/pelvis at 12 months (chest CT vs cxr clinical judgment).

Years 3-5: every six months with PE, AFP, bhcg, LDH, CXR.

Year 6 and beyond: yearly with PE, AFP, bhcg, LDH, CXR.

Pathophysiology

The pathophysiology of germ cell tumors is not well understood. It appears that they derive from a precursor lesion referred to as intratubular germ cell neoplasia (ITGCN), which is analogous to carcinoma in situ.

The precursor for ITGCN appears to be an arrested primordial germ cell or gonocyte. In a normally developing boy, these primitive germ cells no longer exist at the time of birth and therefore it has been concluded that key events in germ cell tumor carcinogenesis must occur in utero. These arrested, pre-malignant cells presumably then lay quiescent until stimulated by testosterone after puberty.

Because the incidence of testis cancer has increased substantially over the past 60 or more years, and because there are strong variations in incidence based on geography and year of birth, it is thought that environmental exposures (possible through diet) probably contribute significantly to germ cell tumor carcinogenesis.

However, there are no specific exposures or behaviors that have been clearly linked to an increased risk of germ cell tumors. The only modifiable risk factor for testis cancer is cryptorchidism, as discussed above.

What other clinical manifestations may help me to diagnose germ cell tumors?

It is essential to remember that testis cancer is the most common cancer in men in their 20s and 30s, and that it typically spreads first to the retroperitoneum. Testis cancer can result in gynecomastia, back pain (from retroperitoneal adenopathy), infertility, thromboembolisms, hemoptysis, and testicular pain.

Testis cancer should thus be considered and a testis exam performed for any adolescent, young-adult or middle-aged male who complains of any of the following signs or symptoms:

• back pain.

• enlarged or tender breasts (gynecomastia).

• lower extremity edema.

• unexplained shortness of breath.

• hemoptysis.

• infertility.

• testicular or pelvic pain.

• abdominal mass.

• deep venous thrombosis or pulmonary embolism.

• evidence of cancer on an imaging test of physical examination.

On physical examination key elements are:

• careful palpation of the testes.

• palpation of the breasts.

• nodal examination, with particular attention to the supraclavicular nodes.

• abdominal exam to evaluate for bulky retroperitoneal adenopathy.

• examination of the extremities to evaluate for swelling.

What other additional laboratory studies may be ordered?

The key studies for testis cancer include:

• Testis ultrasound if a mass is suspected or palpated.

• Serum beta-hCG and AFP prior to orchiectomy and regularly thereafter (tumor markers do not need to be followed repeatedly in stage I seminoma).

• Men with metastatic germ cell tumors who are starting chemotherapy should have serum beta-hCG, AFP and LDH measured on day 1 of chemotherapy for risk stratification and to determine the correct chemotherapy treatment plan.

• CT scan of the abdomen and pelvis for initial staging.

• Chest x-ray or CT for initial staging.

• Imaging studies and serum tumor markers are then repeated for restaging and surveillance depending on the patient’s specific diagnosis, staging and treatment.

Pulmonary function tests have not been shown to be helpful in detecting or in ruling in or ruling out bleomycin lung toxicity and PFTs are not generally indicated for testis cancer patients receiving bleomycin.

Hearing tests are not generally indicated for patients with germ cell tumors whose treatment plan includes chemotherapy. Cisplatin causes loss of high-pitch hearing but is also an essential part of all chemotherapy regimens for disseminated germ cell tumors, except for high-dose salvage chemotherapy.

In patients with carcinoma of unknown primary, cytogenetic analysis of tumor material (typically of retroperitoneal or mediastinal masses) for extra copies of the short arm of chromosome 12 (12p may be helpful in establishing a diagnosis of a germ cell tumor. Finding an isochromosome 12p or finding extra copies of 12p incorporated into other chromosome is generally adequate to establish a diagnosis of a germ cell tumor.

Sperm banking is recommended for any man whose treatment will include chemotherapy, radiation therapy or retroperitoneal lymph node dissection.

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