Testicular Cancer Recurrence: What to Ask

Testicular cancer is unusual among solid tumors. It has blood tests that work. Three markers do the monitoring. They are alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (beta-hCG), and lactate dehydrogenase (LDH).

NCI's health-professional summary is direct about what these markers do. Raised levels are often the earliest sign of relapse. That makes them useful for monitoring all stages of nonseminoma, and metastatic seminoma. All three should be measured before the affected testicle is removed. Those baseline values anchor everything afterward.

One sentence in the PDQ is worth reading twice. Clearly rising levels of AFP or beta-hCG signal relapsed germ cell tumor in most cases. They are an indication for treatment even when scans show nothing.

That is not how most cancers work. A relapse conversation can start from a lab slip. It need not start from a symptom or a scan.

The two markers carry different information, and knowing which applies matters.

AFP is raised in 40% to 60% of men with nonseminoma. Seminomas do not produce AFP at all. That fact does real diagnostic work. A man with a raised serum AFP has a mixed germ cell tumor, meaning a nonseminomatous germ cell tumor. That holds even if the pathology report says pure seminoma. The one exception is a more persuasive explanation, such as liver disease.

Beta-hCG is broader. It is raised in about 14% of patients with stage I pure seminoma before orchiectomy. It is raised in roughly half of patients with metastatic seminoma. In nonseminoma, 40% to 60% have a raised beta-hCG.

For nonseminoma, one of the strongest predictors of prognosis is how far the markers stay raised after the cancerous testicle has been removed.

The PDQ says tumor marker elevations need to be interpreted with caution, and it names the traps.

• Assay cross-reactivity. A false-positive beta-hCG can come from the test cross-reacting with luteinizing hormone. There is a specific way to sort that out: PDQ describes an intramuscular testosterone injection suppressing luteinizing hormone, after which a truly false-positive beta-hCG returns to normal. That is a test your germ cell team arranges and interprets, not something to ask for off a page, and a rising marker still needs urgent specialist review rather than waiting.
• Marijuana. Clinical reports describe marijuana use raising serum beta-hCG. Some experts advise asking about drug use, then retesting after a break from it.
• A personal baseline. AFP runs mildly high in some people all the time, for reasons that are not clear.
• Liver disease. Liver problems can push AFP up a long way.

Each of those has a fix that does not involve chemotherapy. So "the marker is up" begins a conversation rather than ending one.

Seminomas and nonseminomas alike can raise LDH. The PDQ says its meaning during surveillance is unclear. LDH rises in many conditions unrelated to cancer. Two studies make the case concretely.

The first followed 499 patients on surveillance after orchiectomy, or after treatment of stage II or III disease. In that group, 7.7% had a raised LDH unrelated to cancer. Only 1.4% had a cancer-related increase. More than 9% had a lasting false-positive rise. Among the 15 patients who did relapse, LDH was raised in 6. It was the first sign of relapse in exactly 1. The positive predictive value of a raised LDH was 12.8%.

A second study covered 494 patients with stage I germ cell tumors who later relapsed. Of those, 125 had a raised LDH at the time of relapse. Every one of the 125 had other evidence of relapse as well. In 112, the AFP or beta-hCG rose at the same time. One had CT evidence before the LDH moved. One had disease that could be felt on examination. One reported back pain, which led to imaging that showed retroperitoneal relapse.

So LDH appears to have little value for predicting relapse during surveillance. In metastatic nonseminoma, the picture flips. Large prognostic-model studies have found LDH to be a significant independent predictor of survival. The same test does two different jobs, depending on the setting.

The PDQ names the standard first salvage regimen. It is ifosfamide, cisplatin, and either etoposide or vinblastine. It can produce long-term complete responses in about 25% of patients whose disease persisted, or came back, after another cisplatin-based regimen.

Two features predict who does best with it. An initial complete response to first-line chemotherapy, and disease that is not extensive.

There is an important exception. Some nonseminomatous germ cell tumors are extragonadal, meaning they start outside the testis. When those recur after a regimen containing etoposide and cisplatin, few if any patients reach long-term disease-free survival with vinblastine, ifosfamide, and cisplatin.

High-dose chemotherapy with autologous marrow transplant has been used in uncontrolled case series. But one randomized trial tested it directly against conventional-dose salvage chemotherapy. The high-dose arm produced more toxic effects and more treatment-related deaths. It did not improve response rate or overall survival. The summary grades that as its highest level of evidence.

Surgery has a role in carefully selected cases. Chemotherapy-resistant disease confined to a single site may yield long-term disease-free survival after resection. One case series also suggested a maintenance option. Oral etoposide, taken 21 days out of every 28, may benefit patients who reach complete remission after salvage therapy.

A relapse more than 2 years after complete remission is a distinct situation. It affects fewer than 5% of patients who are in complete remission at the 2-year mark.

Here, chemotherapy results are poor. Surgical treatment appears to be better, when it is technically possible. Histology drives that. Teratoma may be treatable with surgery at relapse. Teratoma also carries a better prognosis than carcinoma after late relapse. And teratoma resists chemotherapy fairly well, so chemotherapy may not be the right tool.

Clinical trials, including phase I and phase II studies, are described as appropriate in three situations. When induction therapy does not produce complete remission. When etoposide and cisplatin for a first relapse do not. And after a second relapse.

Cured testicular cancer carries roughly a 2% cumulative risk of cancer in the opposite testicle. That figure covers the 15 years after initial diagnosis. Within that range, men with nonseminomatous primary tumors appear to have lower risk than men with seminoma.

Several other numbers belong on a survivorship list:

• Fertility. In two large studies, roughly 70% of patients fathered children after treatment. Many did so without using banked sperm. NCI advises waiting at least 3 months after finishing chemotherapy before conceiving, unless using sperm frozen beforehand.
• Second leukemias. Standard etoposide doses, meaning under 2 g/m² in total, carry a relative risk of 15 to 25. But that works out to a cumulative leukemia rate under 0.5% at 5 years. Early data suggest doses above 2 g/m² may carry higher risk.
• Kidneys. Creatinine clearance drops about 15% on average during platinum-based therapy. It then appears to stay stable long-term.
• Hearing. Cisplatin causes hearing loss in both ears. It generally hits 4 kHz to 8 kHz, outside the range of conversational speech. Hearing aids are rarely needed at standard cisplatin doses.

Related pages: testicular cancer covers the disease overview. Cancer staging explains the system behind these categories. And fear of recurrence covers the part no marker measures.

• Which markers are being followed, at what interval, and what were the values before orchiectomy?
• Is the histology seminoma, nonseminoma, or mixed — and does an AFP result change that classification?
• If beta-hCG is up, has the luteinizing hormone cross-reaction been ruled out, and has marijuana use been considered?
• Is this a first relapse after first-line chemotherapy, or a later one?
• Was the original tumor testicular or extragonadal?
• Has 2 years passed since complete remission, and does that make surgery the better option?
• If salvage chemotherapy is proposed, which of ifosfamide plus cisplatin plus etoposide or vinblastine, and why that choice?
• What is the cumulative etoposide dose so far, in g/m²?

This page is a planning aid drawn from NCI's published summary. It is not a prediction, and it does not replace the instructions of a treating team.

Relapse here is usually found by a blood test rather than a symptom. Even so, some things should not wait for the next marker draw.

• Call 911 or go to an emergency department if you have chest pain, sudden breathlessness, or you cough up blood. The lungs are the commonest site of spread, and a clot in the lung causes the same signs.
• Call 911 or go to an emergency department if you become confused, start hallucinating, or have trouble speaking or keeping your balance while on ifosfamide. Ifosfamide can cause a serious brain reaction called encephalopathy.
• Ring your care team immediately, at any hour, if you have a temperature of 100.4°F (38°C) or higher, or shaking chills, during salvage chemotherapy. Salvage regimens drive neutrophils very low, so this counts as an emergency and needs antibiotics within the hour. If you cannot reach them fast, go to an emergency department rather than leaving a message with the clinic.
• Call your care team the same day if you see blood in your urine, or urination becomes painful or urgent, on ifosfamide. This can mean bladder irritation from the drug.
• Call your care team within a day or two if you have new or worsening back pain, a swollen painful leg, or a new lump in the remaining testicle. Back pain led to the imaging that found a retroperitoneal relapse in one of the cases described above.

• NCI PDQ — Testicular Cancer Treatment, health professional version
• MedlinePlus — Ifosfamide Injection
• MedlinePlus — Deep venous thrombosis
• NCI — Infections and Neutropenia during Cancer Treatment
• CDC — Fever and Cancer Treatment