From OncoLog, October 2012, Vol. 57, No. 10

Compass: Early-Stage Testicular Cancer
Postsurgical treatment varies according to tumor stage and histology

By Sunni Hosemann

Introduction

Inguinal orchiectomy is the standard initial treatment for patients who present with a testicular mass considered suspicious. The diagnosis and staging of testicular cancers are then made by pathological analysis, and subsequent management decisions are guided by the tumor’s histologic subtype and assigned stage.

Most testicular cancers (95%) are germ cell tumors—either seminomas (40%) or non-seminomas (60%)—and this discussion is limited to those types. Tumors are considered non-seminomas if they contain any histological component that is not pure seminoma.

Serum tumor markers—specifically, the beta subunit of human chorionic gonadotropin (β-hCG) and alpha fetoprotein (AFP)—also have a role in staging and treatment decisions for testicular cancers. According to Louis Pisters, M.D., a professor in the Department of Urology at The University of Texas MD Anderson Cancer Center, elevated β-hCG levels may be seen in patients with seminomas or non-seminomas, but elevated AFP levels are seen only in patients with non-seminomas. Therefore, tumors are categorized and treated as non-seminomas when increased AFP is present, even if pathological analysis has not detected a non-seminoma tumor component.

In this discussion, early-stage disease refers to stages IA and IB (pT1–pT4, N0, M0). These stages include primary tumors that are limited to the testis and those that involve adjacent structures (tunica albuginea, tunica vaginalis, spermatic cord, or scrotum) with or without evidence of lymphovascular invasion (LVI) but have not involved regional lymph nodes or metastasized to distant sites.

Testicular cancer

The National Cancer Institute estimates that 8,590 new cases of testicular cancer and 360 testicular cancer–related deaths will occur this year. Testicular cancer is highly treatable and curable and is often detected early. The survival rate for all men with testicular cancers is 95%; for men with early-stage disease, it is over 99%. “The cure rate for stage I disease approaches 100%, and even metastatic disease is curable,” Dr. Pisters said. “But it is not 100%, and we still see patients who die of both seminoma and non-seminoma.”

More than half of the testicular cancer cases in the United States are diagnosed in men between the ages of 20 and 34 years. Testicular cancers in older men are more commonly found to be seminomas. Non-seminomas tend to be more aggressive.

Testicular cancers follow a very predictable pattern of spread via the retroperitoneal lymph nodes, which are located behind all the major organs in the abdomen and extend upward along the aorta and vena cava. The lymphatic vessels of the testes follow the gonadal blood vessels as they ascend through the spermatic cord and continue upward along the aorta and vena cava to the renal hila. These lymphatic vessels’ location deep in the abdomen, their proximity to major organs, and the distance they span have implications for both surgical and radiation therapies. It is important to note that this pattern of spread initially bypasses the pelvic nodes; therefore, disease in the retroperitoneal lymph nodes would be considered regional.

Notably, the pattern of lymph drainage from the scrotum is different from that of lymph drainage from the testes. Lymph in the scrotum first drains to the lower extremities; thus, it is prudent to avoid enabling the escape of cancer cells from a diseased testicle into the scrotum, which would result in two potential pathways of spread. This is why needle biopsies of the testicle are avoided and orchiectomy is performed via the inguinal route rather than through the scrotum.

Treatment overview

After orchiectomy, the question becomes: is further treatment warranted at this time, or is active surveillance a better option?

For early-stage testicular cancers, the objective of additional treatment is to prevent disease relapse due to subclinical or occult metastases. Thus, postoperative treatment modalities are aimed at the retroperitoneal lymph nodes where the cancer first spreads. Disease recurs in 25%–30% of patients with non-seminomas and 15%–20% of patients with seminomas. Fortunately, the cure rate is very high in patients treated for recurrent disease, and their survival is equivalent to that achieved with pre-emptive treatment. However, compared with preemptive treatment, treatment for recurrent disease is more intense and carries higher risks of long-term sequelae.

According to Dr. Pisters, risk stratification is possible for non-seminomas using serum tumor markers and pathological characteristics. Predictors of a high risk for relapse include evidence of LVI or embryonal carcinoma cells’ making up more than 80% of the tumor. Relapse occurs in about half of patients with high-risk characteristics.

Postoperative treatment options

Postoperative treatment options for stage IA and IB seminomas include active surveillance, radiation therapy, or chemotherapy. For non-seminomas, the standard options for stage IA disease are active surveillance or retroperitoneal lymph node dissection (RPLND). The options for stage IB non-seminomas are active surveillance (for T2 only), RPLND, or chemotherapy.

Active surveillance is an option for patients with stage IA or IB seminomas or stage IA non-seminomas. Surveillance is generally not recommended for patients with stage IB non-seminomas because the disease will recur in 50% of these patients, but it is an option for selected patients who are compliant with follow-up. Active surveillance consists of follow-up visits at specified intervals. Evaluations at these visits include abdominal pelvic computed tomography, chest radiography, and monitoring of serum tumor marker levels. Patients with seminomas remain on active surveillance for 10 years, and those with non-seminomas are monitored for 5 years. The time span of these clinic visits is a limiting issue for some patients.

Radiation therapy has long been a standard option for stage IA and IB seminomas. However, according to Karen Hoffman, M.D., an associate professor in the Department of Radiation Oncology, the treatment paradigm for these tumors has changed over time. Historically, pre-emptive radiation therapy was delivered to lymph nodes in the paraaortic and ipsilateral pelvic regions. “This produced excellent survival rates—near 100%,” she said. Thus, for a time, it was standard procedure to treat patients with radiation therapy after orchiectomy.

“However, it became known that the incidence of second malignant neoplasms occurring later in life was increased in these patients and in some cases caused premature deaths,” Dr. Hoffman said. Over time, studies confirmed that the radiation field could be reduced to exclude the ipsilateral pelvic nodes and that the radiation dose to para-aortic nodes could be decreased from 30 to 20 Gy without compromising survival. “This was important because we believe that this reduction in field size and radiation dose reduced the risk of radiation-related second malignancies,” Dr. Hoffman added.

Advances such as computed tomography–based planning and proton radiation therapy have resulted in a more precisely targeted delivery of radiation. However, some risk remains, so although radiation is still used elsewhere, it is no longer a preferred option at MD Anderson in patients with no known lymph node involvement. Dr. Hoffman instead discusses the option of active surveillance with all her patients with early-stage disease for whom it is an option.

“Currently, if I treat an early-stage seminoma patient with radiation at all, I use proton therapy,” Dr. Hoffman said. Proton beams have a lower entrance dose than conventional photon radiation, deliver the therapeutic dose over a discrete area, and have no exit dose. Therefore, proton radiation treatment of the para-aortic lymph nodes delivers a lower dose to adjacent organs, including the pancreas and gastrointestinal tract. “Although proton therapy has not been around long enough to gauge its long-term effects and has not been compared head-to-head with conventional radiation delivery, we know that it reduces the unnecessary radiation dose to tissues outside the target field, which should decrease longterm side effects,” she said.

RPLND is a standard option for patients with stage IA or IB non-seminomas, in whom the surgery usually provides definitive treatment.

RPLND is usually done through a large transabdominal midline incision and involves removing lymphatic tissue from around the great vessels. In the past, the operation involved a full bilateral dissection and usually resulted in nerve damage that caused loss of ejaculation and emission capability. Today, smaller dissection fields are used to spare these nerve bundles and retain as much function as possible.

Standard options for patients with stage IA non-seminomas are pre-emptive RPLND or active surveillance. Some patients who opt for active surveillance will not need further treatment, and those who undergo RPLND when disease recurs have outcomes similar to those of patients who undergo early surgery.

Patients with stage IB non-seminomas who require or want additional treatment rather than surveillance must choose between RPLND and chemotherapy. “The surgery is a large and serious operation—an extensive abdominal surgery,” Dr. Pisters said. “Most patients prefer the chemotherapy.”

For these reasons, Dr. Pisters said, RPLND has fallen out of favor as a treatment for most of the early-stage testicular cancers discussed here and is rarely used at MD Anderson. The exception is a small subset of patients who have a teratoma with malignant transformation—a rare but very aggressive histologic type for which RPLND is the only option.

Chemotherapy is a standard option for patients with stage IA or IB seminomas or stage IB non-seminomas. According to Lance Pagliaro, M.D., a professor in the Department of Genitourinary Medical Oncology, chemotherapy is a safe and effective alternative to RPLND or radiation therapy.

For seminomas, the standard adjuvant chemotherapy is carboplatin, which has relatively mild side effects and can be administered on an outpatient basis either as a single dose or in two doses 3 weeks apart. A large randomized trial found equivalent rates of relapse-free survival in patients receiving single-dose carboplatin and patients receiving radiation therapy after orchiectomy.

“Two questions arise, however,” Dr. Pagliaro said. “The first is whether we can improve outcomes with two cycles instead of one, and the second is what are the effects after 10 or 20 years or longer?” Answering these questions will require data from follow-up visits over many years. In the meantime, noting that most recurrences are prevented with the first dose, he considers single-dose therapy safer. In the event of a recurrence during active surveillance or after chemotherapy, treatment outcomes are excellent, but either radiation therapy or intensive combination chemotherapy is required.

“I regard surveillance as the least morbid option for seminomas,” Dr. Pagliaro said. “Most are cured without the need for further treatment. Plus, we don’t have sufficient data about the long-term risks of some postoperative treatments.” However, Dr. Pagliaro believes that there are patients with early-stage seminomas for whom a single course of carboplatin should be strongly considered. These patients include:

• Patients with tumors larger than 4 cm classified as pT3. “These patients have a higher risk of recurrence—about 1 in 3,” he said.
• Patients 50 years or older, in whom seminomas are more common. These patients have fewer concerns about fertility or long-term sequelae.
• Patients of any age who are concerned about future access to health care. This includes men in their teens or early 20s who are currently covered by their parents’ insurance policies and whose future insurance coverage is uncertain.

Chemotherapy is also an option for patients with stage IB non-seminomas. For these patients, the most important risk factors are histological type and evidence of LVI. For patients who are considered to be at high risk of recurrence, the chemotherapy options are one or two cycles of bleomycin, etoposide, and cisplatin (BEP). “This is the same chemotherapy that is used for recurrence, but less is given if used up front,” Dr. Pagliaro said. “Although two cycles have not been proven clearly superior to one, we know that two cycles reduces recurrence risk from 50% with surveillance to 2%,” he said.

No study so far has compared one versus two cycles of BEP directly. However, a large risk-adapted trial that compared chemotherapy to surveillance after orchiectomy in patients with stage I non-seminomas found a 90% reduction in recurrence rate with only one cycle. Therefore, the difference in recurrence rates between patients who receive one and two cycles of BEP could be relatively small—4% versus 2%. Dr. Pagliaro’s current view is that because most recurrences are eliminated with one course, the benefit of less treatment outweighs the risk of treating 100 patients with a second course to prevent two recurrences.

For the average-risk patient with a stage IA non-seminoma, Dr. Pagliaro considers active surveillance the safest choice. But for select patients, such as those who might be less likely to tolerate chemotherapy later or those who have concerns about compliance with surveillance schedules, one course of BEP could be reasonable. “Most long-term chemotherapy effects are associated with three or more courses of therapy,” he said. “We have not seen serious treatment effects with only one course.”

Patient preferences

Treatment for stage I testicular cancers must be individualized, and substantial discussions are needed to help patients weigh the various options and choose between surveillance and postoperative treatment. In many cases, personal circumstances and preferences weigh as heavily in the decision as purely medical considerations. In all cases, sperm banking should be discussed before any treatment is initiated.

For more information, talk to your physician, visit www.mdanderson.org, or call askMDAnderson at 877-632-6789.

FURTHER READING

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