Nuances of Testicular Cancer Care: More Work Needed

With many patients achieving cure, clinicians turn to the few who relapse and address survivorship care.

The incidence of testicular cancer is increasing, both globally and in the United States, and has been for several decades.¹ Fortunately, despite the increasing rates, testicular cancer is largely a disease of young and middle-aged men, and death rates have been stable or even marginally improved in Western countries.²

Within those statistics are emerging trends that require more research, like possible links between microplastics or cell phone carrying and testicular cancer or a rising incidence of the disease among certain racial/ethnic minorities in the United States,^3,4 but much of the field’s attention has turned to a myriad of topics focused on prolonging and improving the lives of patients diagnosed with testicular cancer.

“This is a young patient population and in addition to avoiding death, we also need to consider the long-term toxicities of the treatments we choose,” said Sia Daneshmand, MD, a professor of urology at Keck School of Medicine, University of Southern California. “There has been a shift in focus from curing the disease, which we know we can do in 95% of cases, to managing the burden of disease, de-escalating the intensity of treatment when possible, and finding more effective upfront treatments for those [who] need therapy.”

GU Oncology Now recently caught up with several physicians involved in the treatment of patients with testicular cancer to discuss current practices and challenges related to staging, treatment, and survivorship.

Diagnostic Workup

The most common sign of testicular cancer is a painless, enlarging scrotal mass, said Aditya Bagrodia, MD, FACS, an associate professor of urology at the University of California, San Diego. That should prompt a visit to a health care provider.

If seen in the emergency department or by a urologist, the patient should undergo a physical exam to confirm the mass and be asked relevant questions about family history, personal history, or undescended testicles.

The patient should undergo an ultrasound of the scrotum and have blood drawn for evaluation of serum tumor markers: alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (HCG), and lactate dehydrogenase (LDH).

“The serum tumor markers can provide us with some suggestion of whether or not the mass is a cancer,” Dr. Bagrodia said, adding that these markers are not perfect. “If they are elevated in the context of a testicular mass, it is more indicative of cancer, and it can indicate histology as well.”

For instance, beta-HCG is almost always produced by choriocarcinoma—a type of nonseminoma—and elevated in certain seminomas; AFP is never produced by seminomas but often elevated in nonseminomas, Dr. Bagrodia said.

“Not all testicular germ cell tumors will have elevated tumor markers, though,” said Julian Chavarriaga, MD, of the University of Toronto, Princess Margaret Cancer Centre in Canada. “Only about 20% of seminoma will have elevated markers, and patients with teratoma theoretically will not have any elevation of tumor markers.”

If suspicion of testicular cancer is high, radical inguinal orchiectomy is performed.

“It is important to know a patient’s tumor markers before orchiectomy because after the procedure they should normalize,” Dr. Chavarriaga said. “If they don’t go back to normal this raises suspicion that there is disease somewhere else, like the retroperitoneum.”

After surgery, further staging occurs with a computed tomography (CT) scan with intravenous contrast of the chest, abdomen, and pelvis. Once imaging is received, patients can be assigned a clinical stage.

Staging, Management

Clinical staging of testicular cancer is divided into disease that is confined to the testis and spermatic cord (clinical stage I), disease that involves lymph nodes in the retroperitoneum (clinical stage II), and distant metastatic disease in nonregional nodes or viscera (clinical stage III).⁵

“All of these stages have different variations,” said Dr. Chavarriaga. “A patient will be assigned to clinical stage IA or IB depending on pathological tumor stage and on lymphovascular invasion status. They will be classified as clinical stage IIA, B, or C, depending on the number and size of the affected lymph nodes in the retroperitoneum, and clinical stage IIIA, B, or C depending on where the cancer has spread to or the levels of tumor markers.”

Once a patient’s clinical stage is established, treatment can be offered.

“Broadly speaking, we observe patients with clinical stage I disease since among all-comers about 70% will be cured by testicular removal alone for nonseminoma and close to 85% for seminoma,” Dr. Bagrodia said, adding that there are rare exceptions.

After surgery, patients with clinical stage I nonseminoma can undergo surveillance with regular CT scans, physical exams, and tumor marker tests. A minority of patients may elect to undergo retroperitoneal lymph node dissection (RPLND). If no cancer is found in the lymph nodes, risk of recurrence is about 10%.⁶

“Recently, there has been more interest in the use of RPLND to avoid chemotherapy or radiation therapy and the long-term toxicities associated with them,” Dr. Bagrodia said.

Some patients may undergo adjuvant chemotherapy after orchiectomy. These regimens usually include one cycle of bleomycin, etoposide, and cisplatin (BEP) chemotherapy. Adjuvant chemotherapy is controversial because although it may reduce the risk of recurrence, the majority of patients will have been cured from orchiectomy and will have unnecessarily undergone chemotherapy.⁶

Patients with stage I seminoma have similar treatment options, with the majority of patients followed with surveillance. Because seminoma is “exquisitely sensitive” to radiation therapy, according to Dr. Bagrodia, early-stage seminoma can also be effectively treated with radiation, which lowers the risk of recurrence, but this option is largely historic, since a majority of patients will be cured with surgery alone.⁶

For patients with clinical stage II disease, clinicians will consider the size and number of involved lymph nodes, Dr. Bagrodia said.

“With nonseminoma, if they are small [in] volume and limited in number then options include RPLND,” Dr. Bagrodia said.

RPLND is used when tumor markers have returned to normal, none of the lymph nodes are larger than 2 cm, and there are fewer than 5 enlarged lymph nodes.⁶

Chemotherapy is typically used in some stage II seminoma and nonseminoma when tumor markers have remained elevated after surgery.

Historically, standard options for patients with stage II seminoma included either radiation therapy to lymph nodes in the abdomen and pelvis or systemic chemotherapy. Recently, there has been renewed interest in RPLND for this clinical scenario to avoid long-term toxicities associated with chemotherapy and radiation. RPLND for small-volume seminoma has started to enter national and international practice guidelines.

Patients with stage III disease and beyond will undergo systemic chemotherapy regardless of whether they have seminoma or nonseminoma. The most common chemotherapy regimen is BEP given in 3-week cycles for 3 or 4 cycles. In some cases, patients may receive etoposide, ifosfamide, and cisplatin if bleomycin is contraindicated.

“Patients who receive chemotherapy and have tumor markers normalize but still have masses greater than 1 cm may require further postchemotherapy RPLND to remove any radiographic sites of disease,” Dr. Bagrodia said.

Addressing Fertility

Fertility preservation should be discussed with any patient with suspected testicular cancer before surgery, if possible.

“We don’t even necessarily know what the mass is yet, but we still discuss fertility,” Dr. Chavarriaga said. “Some of these patients are very young, haven’t had children, and plan to in the future.”

Past studies indicated that only about 50% of patients of childbearing age with cancer were referred for fertility preservation in the United States,⁷ while another study of 200 patients with testicular cancer found that 70% chose not to bank sperm.⁸ It should be noted that the cost of fertility preservation in the United States could be prohibitive, with estimates for males ranging from $500 to $1000 for sperm cryopreservation, plus the annual cost of storage.⁹

“Fertility issues are definitely important for patients, and in Denmark, we have quite a good set-up,” explained Mikkel Bandak, MD, of Copenhagen University Hospital Rigshospitalet. “In our public health system all patients are offered to donate semen for cryopreservation, and if later they are not able to conceive a child, they have the chance to do [in vitro fertilization] for free and use the cryopreserved sperm, if possible.”

When fertility is addressed with the patient, the availability of testicular prosthesis should also be discussed, Dr. Bagrodia said.

“Offering a prosthetic can alleviate anxiety, depression, and body issues, but it is frequently not done,” Dr. Bagrodia said. “Survey-level data indicate that anywhere from 70% to 80% of patients did not have prosthetic offered, which is not acceptable.”

Although according to Dr. Bandak and Jakob Lauritsen, MD, of Copenhagen University Hospital, Rigshospitalet, this concern may be uniquely cultural.

“In Denmark, very few patients receive prosthesis even though they are offered free of charge,” Dr. Lauritsen said. “I would say maybe 1% to 2% of patients ask for it.”

Relapse Risk

After surgery for testicular cancer, patients are monitored for relapse using imaging and serum tumor markers. An estimated one-fifth to one-quarter of patients will relapse within 5 years.¹⁰ Unlike many other solid tumors, a large percentage of patients with germ cell tumors can still achieve cure with second- or third-line chemotherapy and/or radiotherapy after disease progression. For those reasons, it is important for clinicians to have accurate predictors of relapse risk.

Drs. Lauritsen and Bandak together with colleagues in Denmark recently published a study of patients with clinical stage I seminoma that assessed prognostic factors for relapse in an unselected nationwide population-based setting. The study found that 16% of the close to 1000 patients relapsed at a median follow-up of approximately 6 years. Independent predictors of relapse included invasion of the testicular hilum, lymphovascular invasion, and elevated preorchiectomy levels of beta-HCG and LDH. Risk was as low as 5% among patients with no risk factors but was as high as 62% in those with all 4 risk factors plus tumor extension into the hilar soft tissue of the testicular rhilum.¹¹

“Our main finding in this study was that for the quite a lot of patients with very low risk of relapse, we might do less intensive workup,” Dr. Bandak said. “We are looking into if they should have fewer CT scans or measurements of tumor markers because the risk of relapse is so low.”

Drs. Bandak and Lauritsen said that their group is discussing how to best approach those patients found to be at the highest risk for relapse.

“We still don’t think adjuvant treatment is the right approach because it is not very effective,” Dr. Bandak said. “We need to find a better type of adjuvant treatment before we can recommend it.”

The survival rates are still very high, even in this group at the highest risk for relapse, Dr. Lauritsen said.

“It is a matter of identifying the best way forward for each patient,” Dr. Lauritsen said. “If you administer adjuvant therapy to too large of a group of patients you might induce late effects and side effects that could have a high impact on quality of life. We need to determine a [cutoff] point for administering adjuvant treatment.”

Long-term Considerations

Avoiding overtreatment is a priority among researchers and clinicians who are working to minimize treatment-related morbidity and long-term effects among this population of patients diagnosed with cancer at relatively young ages.

In addition to addressing fertility, testicular cancer survivors should be made aware of other possible survivorship issues.

Patients who received chemotherapy may be at increased risk for hearing loss, numbness or tingling, and more silent threats like cardiovascular disease and reduced lung function, Dr. Lauritsen said.

“All patients should be advised to stop smoking at once,” Dr. Lauritsen added. “You should also address common cardiovascular risk factors in survivors, who have an increased risk for metabolic syndrome.”

Testicular cancer survivors treated with platinum-based chemotherapy or radiation are also at increased risk for secondary malignancies.

“These malignancies can occur 10, 20, or 30 years after treatment,” Dr. Daneshmand said.

Patients cured of testicular cancer also have a small risk for developing cancer in the opposite testicle.¹²

“When I release a patient from surveillance, I sit them down and explain the potential risks,” Dr. Daneshmand said. “They are rare, but survivors should be vigilant for pain in their back or the other testicle.”

As many as 10% to 15% of survivors may also deal with testosterone deficiency, Dr. Bandak added.

“The majority of patients are able to produce enough testosterone from the other testicle, but it is important to address this [potential issue] by evaluating signs and symptoms of testosterone deficiency,” Dr. Bandak said.

Future Directions

Looking to the future of germ cell tumors, the community is focusing its attention on several areas. Firstly, everyone agreed that more accurate markers of disease are needed.

For example, Dr. Chavarriaga noted there needs to be a better, more reliable way to predict which patients with testicular masses and negative markers have benign or malignant disease.

“Some patients, particularly those with small testicular masses (<2 cm) get orchiectomy for a benign tumor,” Dr. Chavarriaga said. “If we had a marker to know which were benign or malignant, that would be helpful. The same is true for clinical stage I disease to predict risk of occult retroperitoneal disease.”

Another helpful scenario for accurate markers is in patients with clinical stage II disease with residual tumors after chemotherapy.

“Most of the time when we have residual masses we don’t know if the masses are fibrosis/necrosis or viable tumors,” Dr. Chavarriaga said. “It would be helpful if we could find more precise imaging modalities and markers like [circulating tumor (ct)DNA] that could predict residual masses after chemotherapy.”

In addition to the possibilities of ctDNA, a big area of interest in testes cancer today is microRNAs, said Dr. Chavarriaga.

Embryonic stem cells express various microRNA clusters, among them microRNA-371. One study of microRNA-371 in 20 patients with germ cell tumors found that levels decreased more than 300-fold postorchiemtomy,¹³ while a subsequent analysis showed that microRNA-371 had an 88.7% sensitivity and a 93.4% specificity for discrimination of testicular cancer.¹⁴

“It appears to be a highly sensitive blood-based biomarker, specifically in the preorchiectomy setting where it has a sensitivity and a specificity greater than 90%,” Dr. Bagrodia said. “In the postorchiectomy setting, it may be helpful with minimal residual disease but may not be sensitive enough to pick up microscopic sites of disease.”

Dr. Bagrodia called the wide availability and use of microRNA-371 potentially paradigm shifting.

There is currently a commercially available kit for measuring microRNA-371 that is certified by the European Union and can be used for quantification of microRNA in patients with testicular germ cell tumors.¹⁵ Dr. Bagrodia said that his lab is also fairly close to using this test for clinical decision-making.

Other key areas for future research include better options to treat the small percentage of patients with poor prognosis.

“The patients [who] die from testicular cancer are almost always from this group,” Dr. Lauritsen said.

Drs. Lauritsen and Bandak said they are eagerly awaiting the results of the TIGER study, a randomized phase 3 trial of paclitaxel, ifosfamide, and cisplatin versus paclitaxel plus ifosfamide followed by high-dose carboplatin plus etoposide with stem cell transplant as initial salvage chemotherapy for patients with germ cell tumors.¹⁶

“Although it is only a few patients, the patient who progress after second-line treatment are in a very poor situation, and we don’t have effective options,” Dr. Bandak said.

Dr. Daneshmand agreed that third-line options are a priority.

“Unfortunately, the whole field of immunotherapy with immune checkpoint inhibitors has been disappointing for germ cell tumors,” Dr. Daneshmand said. “We need more effective therapies in resistant patients.”

Finally, as with any cancer, the best way to save lives is to prevent the disease entirely. Greater research into risk factors for prevention is badly needed. In addition, Dr. Bagrodia called for more attention to be paid to the underlying sociodemographic impacts on testicular cancer care and outcomes. Although the U.S. Preventive Services Task Force does not currently recommend screening for testicular cancer, the community could do a better job of raising awareness about the disease among young and middle-aged men.

Because testes cancer is rare, Dr. Daneshmand said, making significant progress in answering questions related to prevention, management, and survivorship of the disease will take time and collaboration from the germ cell research community both nationally and internationally.

References

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