State-of-the-Art Management of Germ Cell Tumors Produces High Cure Rates

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Everything we do is to maximize the patient achieving a complete response. With 12 weeks of chemotherapy, we cure most patients.

—Pasquale W. Benedetto, MD

Pasquale W. Benedetto, MD, the Leonard M. Miller Professor of Medicine at the University of Miami/Sylvester Comprehensive Cancer Center, recently spoke at the 2015 New Orleans Summer Cancer Meeting about his approach to diagnosing and treating germ cell tumors in men.1 The ASCO Post was there to capture Dr. ­Benedetto’s insights.

The Basics

Germ cell tumors derive from an ovum or spermatozoon, or precursor cells thereof. While germ cell tumors are primarily gonadal (95%), they can arise in the mediastinum, retroperitoneum, or central nervous system, or constitute midline germ cell syndrome.

“These are curable malignancies in more than 90% of cases. Patients diagnosed with localized disease can be cured with surgery, but nonlocalized disease can also be cured,” Dr. ­Benedetto emphasized. “It is incumbent upon medical oncologists to identify these tumors, especially when the presentation is not typical, and to treat intensively to achieve complete remission.”

In men, germ cell tumors are broadly divided into seminoma and nonseminomatous disease. The most primitive form of the latter is embryonal carcinoma. Differentiation along embryonic lines gives rise to any of the three germ layers (endo-, ecto-, or mesoderm), which in aggregate is called teratoma. Differentiation along extraembryonic lines gives rise to choriocarcinoma or yolk sac tumor.

A distinction between seminoma and nonseminomatous lesions is important. Seminomas are biologically indolent, whereas nonseminomas can be aggressive and more likely to metastasize.

Signs Pointing to Germ Cell Tumor

“Any patient between the ages of 15 and 40 with an intratesticular mass has germ cell tumor until proven otherwise,” he said. Other possible presentations include anterior superior mediastinal mass and localized retroperitoneal mass.

In addition, oncologists should suspect a germ cell tumor in any male patient with a midline tumor described as “poorly differentiated carcinoma” without an obvious primary (ie, midline germ cell syndrome); with elevated alpha-fetoprotein or beta–human chorionic gonadotropin (hCG); or with a tumor of unknown origin with isochromosome 12p, a molecular feature characteristic of germ cell neoplasms.

Importantly, occult disease, including recurrences, can be documented by these serum markers. Both alpha-fetoprotein and beta-hCG can be elevated in nonseminomatous lesions. In seminomas, alpha-fetoprotein is never elevated, and beta-hCG may or may not be elevated.

Staging of Germ Cell Cancers

Germ cell tumors are limited to stage I disease in 85% of seminomas but in only 35% of nonseminomatous lesions. Fortunately, this distinction does not determine outcomes, he said.

“We can cure both these populations to the same degree. It’s simply the mechanism by which we get there or the relative need for any other treatment after the primary surgery,” Dr. Benedetto explained.

Tumors are best staged using the International Germ Cell Cancer Consensus Group classification system, which relies heavily on tumor marker levels and takes into account the presence and sites of metastases and magnitude of tumor marker elevations, risk-stratifying patients into good-, intermediate-, and poor-risk subsets. With seminomas, there is no category for “poor risk,” as all these patients “should be cured,” he added.

Understanding Tumor Markers

While tumor markers are vital components of assessment, in the case of seminoma they do not define the disease stage. “There is no such thing as a seminoma with [alpha-fetoprotein] elevation,” he said. Patients labeled as having “seminoma” who have elevated alpha-fetoprotein, without an alternative explanation, undoubtedly have a nonseminomatous component to their disease and should be treated according to the algorithm for nonseminomatous disease.

A marker can only be interpreted with an understanding of its half-life, which is 5 to 7 days for alpha-fetoprotein and 2 to 3 days for beta-hCG. This information helps monitor the patient without the use of imaging.

“A single assay is uninterpretable,” he said. “If a marker is elevated a few weeks after treatment, you don’t know what it means unless you have a previous report. You need at least two points to determine whether the difference between those points is within the predicted range, according to the half-life of the marker.”

A persistently elevated tumor marker after surgery or chemotherapy is “unequivocal evidence” of disease, suggesting that the patient has not achieved a complete remission. A rising level indicates persistent, recurrent, or new disease.

Milestones That Inform Current Treatment

Dr. Benedetto described several discoveries and milestones in the treatment of these tumors that have informed the current standard of care:

  • The efficacy of cisplatin is critical to inducing complete remission in disseminated testis cancer; carboplatin should not be substituted.
  • Intensity of treatment, not length of treatment, matters.
  • Complete remissions are durable, and maintenance therapy is unnecessary.
  • Risk-assessment criteria are based on the Indiana staging system, classifying disseminated disease as minimal-, moderate-, or high-risk.
  • Bleomycin/etoposide/cisplatin is equivalent to cisplatin/vinblastine/bleomycin, is less toxic, and remains the standard of care.
  • For good-risk patients, three cycles of bleomycin/etoposide/cisplatin are equivalent to four cycles, and for poor-risk patients, four cycles of bleomycin/etoposide/cisplatin are better than four cycles of cisplatin/vinblastine/bleomycin.
  • Etoposide/ifosfamide/cisplatin or upfront high-dose chemotherapy and stem cell transplantation is not better than bleomycin/etoposide/cisplatin as first-line therapy for poor-risk patients.

“Everything we do is to maximize the patient achieving a complete response,” he elaborated. “With 12 weeks of chemotherapy, we cure most patients.”

Practical Treatment Tips

Dr. Benedetto offered a number of clinical pearls for treating germ cell ­tumors:

  • Treat good-risk patients with 9 weeks of bleomycin/etoposide/cisplatin; treat poor-risk patients for 12 weeks.
  • Maintain treatment intensity over the 21-day cycles. Do not get off schedule; do not initiate on a Wednesday unless you can treat the patient over the weekend.
  • Do not hold any dose of chemotherapy for a low absolute neutrophil count, as these patients typically do not develop febrile neutropenia.
  • Do not give growth factors to the average patient.
  • Do not repeat computed tomography (CT) imaging during chemotherapy; simply repeat tumor marker assessments at the beginning of each cycle. If markers are decreasing predictably, do not change treatment.

Treatment of Stage I Disease

Since most patients with stage I disease are cured by the primary surgery, adjuvant chemotherapy is not warranted for most, if not all, patients. After orchiectomy, 70% of patients with nonseminomatous disease are cured. Most of the 30% who relapse will do so within a few months, and their recurrences occur with good-risk features. Therefore, they are highly, essentially universally, curable.

“There is nothing to be lost with surveillance and nothing to be gained with intervention,” Dr. Benedetto maintained. “It’s better to wait for the few patients who will relapse, and then treat them for cure with chemotherapy and avoid overtreatment of many who are destined never to have a ­recurrence.”

The only patient for whom adjuvant treatment might be considered is one who may not be compliant with surveillance. His surveillance strategy involves CT scans of the abdomen only (not the lungs or pelvis) and chest x-rays.

Imaging, Residual Masses

Dr. Benedetto emphasized, “CT scans in the middle of chemotherapy will only confuse you…. All you really need to know is whether tumor markers are going down with treatment.”

Postchemotherapy retroperitoneal exploration may be the key to achieving long-term remission in patients with a residual mass > 1 cm or after salvage therapy, he said.

Residual masses in nonseminomatous patients will be viable germ cell tumor in only 8%, teratoma in 50%, and fibrosis in 43%. Teratomas must be removed, as they can dedifferentiate and become resistant tumors.

For nonseminomas, positron-emission tomography (PET) scanning is not necessary for staging or for evaluating outcomes, as PET cannot distinguish between teratoma and cancer and cannot predict for relapse, he said. For seminoma, however, PET can predict for residual disease > 3 cm with 100% accuracy; therefore, it is useful for gauging response but not for initial staging.

Predicting, Treating Recurrences

“You don’t want to need salvage therapy, since we don’t cure many patients that way. Do things right the first time,” Dr. Benedetto exhorted ­attendees.

While first-line chemotherapy is almost 100% curative, the cure rate drops to less than 40% in the second-line setting. Salvage chemotherapy should be ifosfamide-based, preferably including paclitaxel, ifosfamide, and platinum. The use of transplant can be discussed with patients. ■

Disclosure: Dr. Benedetto reported no potential conflicts of interest.


1. Benedetto PW: How do I treat a patient diagnosed with a seminoma and a non-seminoma testicular cancer: State-of-the-art management to obtain a high cure rate. 2015 New Orleans Summer Cancer Meeting. Presented July 18, 2015.