From the Department of Urology, The University of Texas Southwestern Medical Center at Dallas.

Presented at the continuing medical education symposium, “Urology: Frontiers 2000,” held on March 10, 2000, at Baylor University Medical Center.

Corresponding author: Arthur I. Sagalowsky, MD, Department of Urology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9110.

When the histological types of testis cancer are considered, the incidence of seminoma peaks at a slightly later age group than does embryonal cell carcinoma or teratoma. In addition, the incidence rates of embryonal and choriocarcinoma have not changed; the increases are occurring among seminoma and teratoma primarily.

For the 7600 cases of this uniformly aggressive and potentially lethal malignancy, there are only about 400 deaths per year. Thus, the treatment is highly successful.

This article focuses on clinical stage 1 testis cancer. The following tables define the staging and list the treatment options by stage for testis cancer (Tables 1-4) (2). Clinical stage 1 is determined by a 3-pronged approach (Figure). Invasion outside of the testis, and particularly in the vascular or lymph channels, is the strongest prognostic factor for being beyond stage 1 disease. A variety of tools can help determine whether such invasion is present: specific and sensitive tumor markers, abdominal computed tomography (CT) scans, chest x-rays, and selective use of chest CT for patients at higher risk. The serum tumor markers alpha-fetoprotein and beta human chorionic gonadotropin also are important for staging testis tumors and for detecting recurrence.

With data from the past 3 decades, we have determined the natural course of clinical stage 1 testis cancer. Patients with prototypical clinical stage 1 cancer have a 75% chance of being cured by an orchiectomy. The remaining 25% of the patients have either microscopic stage 2 or stage 3 disease. They usually relapse in the retroperitoneal lymph nodes and the lungs.

In the remainder of this article, I present data to guide physicians in choosing the best treatment for clinical stage 1 testis cancer. I will start with 3 hypothetical cases, which I will return to at the end of the article. All 3 patients are recently married 26-year-old men who have no children but wish to have a family:

• Patient 1 had a 6-month history of an enlarged testis lump. When he had his orchiectomy, the histological results showed pure seminoma. No vascular invasion was present.
• Patient 2 had a testis mass removed, which proved to be a mixed germ cell tumor--40% embryonal carcinoma, 40% teratoma, and 20% seminoma. Some vascular channel invasion was present.
• Patient 3 had a testis mass removed, which was pure embryonal carcinoma with vascular channel invasion.

Treatment options include surveillance, retroperitoneal lymph node dissection (RPLND), and primary chemotherapy. The relative desirability of each option in the above cases is based on the specific features in each case.

RETROPERITONEAL LYMPH NODE DISSECTION

With RPLND, the retroperitoneal pericaval nodes, periaortic nodes, interaortocaval nodes, and the tissue extending behind the great vessels are removed. When I was a resident, I was taught to do a total bilateral dissection on all patients. This procedure caused nonejaculation from disruption of critical sympathetic nerves and ganglia and resulted in infertility. Since then, physicians have worked to limit treatment-related morbidity among patients who truly have stage 1 disease. One method is nerve-sparing node dissection.

At the American Urological Association in 1998, the Indiana group presented data from their experience over a 20-year period (3). With an equal number of right and left RPLNDs, every one of the patients available for follow-up maintained ejaculation. The pregnancy rates were somewhat lower, and semen analysis results were not available. However, the study showed that it is possible to do a proper RPLND and preserve ejaculation. That former major disadvantage of RPLND is largely avoidable.

It is important to remember that another treatment option, chemotherapy, results in total destruction of spermatogenesis for a variable period, usually 9 to 12 months. The return of good sperm quality takes close to a year and is unpredictable. Whether the physician is speaking to the patient about RPLND or primary chemotherapy, then, he or she should present the option of cryopreservation of the sperm. However, some patients are not good candidates for this procedure since they have a subfertile semen analysis at the time of presentation--possibly due to the psychological stress related to the cancer diagnosis or intrinsic subfertility.

RPLND can be performed laparoscopically. In 1998, the Austrian group presented their experience with 47 patients, 36 of whom were pathologic stage 1 and 11 of whom were pathologic stage 2 (4). The stage 1 patients were followed after surgery, and the stage 2 patients received adjuvant chemotherapy. All patients had no evidence of disease upon follow-up. If laparoscopic node dissections were failing to sample the nodes adequately, we would expect to see some relapses. Laparoscopic procedures are tedious and lengthy, but they are an option.

SURVEILLANCE

Surveillance is an option for many patients because 1) three fourths of clinical stage 1 cases are pathologic stage 1, and 2) for those cases that relapse, highly effective chemotherapy is available. Thus, surveillance offers the possibility of maintaining a high cure rate while avoiding the morbidity associated with immediate further treatment.

Surveillance also presents some disadvantages. Some patients may not maintain proper follow-up and compliance, and some physicians may not recommend the necessary rate of follow-up. There is the potential for bulk relapse and an accompanying decrease in overall survival. If patients relapse, the total amount of chemotherapy required is higher than if the drugs were given preemptively. Based on this, researchers have debated which option presents the least cumulative morbidity. Another consideration is that some patients cannot emotionally tolerate the uncertainty of a 25% risk of having untreated and potentially spreading cancer.

How reliable is CT staging? If we could be 95% to 98% sure that clinical stage 1 is stage 1, it would be foolish to offer any further treatment. Through the years, the false-negative rate has been in the range of 25%. Even with third- and fourth-generation CT scans, the clinical staging error remains similar. Interpretation errors are also made. The radiologist generally checks the CT scan to determine if any lymph nodes are >2 cm. However, if the radiologist does not see large nodes (according to the definition) but sees an entire vertical column of nodes that are 11/2 to 2 cm in the primary tumor landing zone, that should raise a red flag.

If a patient has an abnormal CT scan, the risk of a chest x-ray being a false negative is roughly 25%. So if patients' markers and abdominal CT scans are normal, plain chest x-ray is sufficient. If, instead, patients have abnormal nodes on abdominal CT scan or unexplained positive tumor markers, they should receive a chest CT.

DEFINING AND TREATING HIGH-RISK GROUPS OF CLINICAL STAGE 1 PATIENTS

Using data from testis cancer studies, we can identify which patients are at high risk for not having true stage 1 disease. Sogani from Memorial Sloan Kettering Cancer Center followed a large number of cases for 11 years (5). Of the patients who started off with clinical stage 1 disease, 74% remained continuously free of disease. Those who relapsed did so within 2 years. Testis cancer grows rapidly and has the shortest doubling time of any tumor. The sites of relapse were the retroperitoneal nodes and the lungs. The factors that best predicted relapse were vascular channel invasion first of all and then predominance of embryonal carcinoma on histology. Only 12% of the entire group of relapsers lacked one of these risk factors.

The overall survival of this group of patients remained excellent. Among the relapsers, 3 were cured by RPLND; 6, by chemotherapy alone; and the remaining 15, by RPLND and chemotherapy. Based on these results, Sogani and colleagues concluded that although surveillance and chemotherapy for relapse results in an excellent survival rate, patients with the above-mentioned risk factors should receive RPLND rather than surveillance.

David Swanson and colleagues from M. D. Anderson Cancer Center presented their outcomes in high-risk clinical stage 1 mixed germ cell tumors (6). High risk was defined as an alpha-fetoprotein >80 ng/dL, a high percentage of embryonal carcinoma, or vascular invasion. All of the patients underwent RPLND. In keeping with other reports, 7 of 26 (27%) had positive nodes, and 4 of these 7 patients (57%) relapsed and therefore required chemotherapy. Of the 19 who had negative nodes but were high-risk patients, 7 (37%) also relapsed. So in the high-risk patients who underwent RPLND, 42% ended up receiving chemotherapy. In 1999, Swanson showed that in another cohort of high-risk patients, 46% subsequently relapsed and required chemotherapy. Based on their experience, then, the M. D. Anderson group has begun offering 2 courses of primary platinum-based chemotherapy, avoiding the intervening step of RPLND.

At the American Urological Association meeting in 1998, Hermans and colleagues from Indiana University indicated that they were offering primary chemotherapy for high-risk clinical stage 1 patients as well (7). This decision was based on data that showed that 11% of the pathological stage 1 patients undergoing RPLNDs relapsed, and 30% of the stage 2 patients who did not receive postsurgical chemotherapy relapsed. In contrast, none of the 33 stage 2 patients who received the chemotherapy after RPLND relapsed.

Judd Moul developed a computer-model program to decide which patients with clinical stage 1 disease are at high risk to relapse (8). Others have tried to develop additional markers to determine risk, but none of those are sufficiently sensitive or specific to change clinical practice.

PRIMARY, ADJUVANT CHEMOTHERAPY

The primary chemotherapy offered by the M. D. Anderson group consisted of carboplatin (instead of cisplatin) along with etopiside and bleomycin (9). Carboplatin was chosen so that the patients could receive the chemotherapy on an outpatient basis. Carboplatin is less nephrotoxic but slightly more myelotoxic than cisplatin. However, in every clinical trial of advanced disease, carboplatin has been inferior therapeutically to cisplatin.

The results with the primary chemotherapy protocol have been excellent: 48 of 52 high-risk patients received chemotherapy, and 47 of these remained continuously free of disease. One patient relapsed with teratoma and required surgery. The overall treatment-related toxicities were relatively mild. Carboplatin reduces white blood cell count significantly and results in a higher rate of myelosuppression; however, none of the patients required hospitalization for myelosuppression or sepsis. Swanson and colleagues concluded that primary chemotherapy in this group of patients at high risk for relapse was safe, offered a high cure rate, and rarely required additional therapy.

Kratzik et al from Vienna, Austria, gave primary chemotherapy with single-agent carboplatin for seminoma (10). Although carboplatin as a single agent would not be chosen for therapy of known persistent disease, their outcome to date is indisputably excellent. However, one must keep in mind that approximately 75% of patients likely were stage 1 and did not require any chemotherapy.

Physicians should inform patients of the risks of chemotherapy, just as they review the risks of surgery. Among the enduring toxicities is the decreased oxygen diffusion capacity of the lungs caused by bleomycin. Investigators in several clinical trials of low-volume stage 2 disease attempted to eliminate bleomycin from the regimen, but this led to decidedly inferior results. Currently we do not know how to prevent the peripheral neuropathy of platinum. Chemotherapy may also lead to alteration in semen analysis and to long-term bone marrow damage, which may predispose to secondary malignancies. Just as we would not want to do a node dissection if we knew there was a 0% chance of positive nodes, we have to weigh the risks of primary chemotherapy in the same 60% to 70% of patients who are going to have negative nodes.

Only now--26 years into the platinum era--are we beginning to see data on long-term survival in patients with advanced disease. Most of the secondary tumors have been in patients who received alkylating agents or radiotherapy. A 1997 study showed a 4.9% incidence of secondary tumors in testis cancer patients who had received either radiation or chemotherapy (11). That rate is much higher than what would be expected among men in the general population. Among the secondary tumors, the most common was acute lymphoblastic leukemia.

Researchers have also studied the risk of developing a contralateral testicular tumor. Leibovitch presented prospective data on annual ultrasonography of the remaining testis for patients treated for testis cancer (12). His group found a 4% incidence of ultrasound abnormality in the opposite testis within 2 to 6 years; 80% of the time the abnormality turned out to be a germ cell tumor. The long-term clinical occurrence rate of contralateral testis tumor is 2% to 3%. When identified by usual clinical means, such as palpation and tumor markers, the outcome is no different from that of first-time testis tumor patients. While there is an ongoing, cumulative risk, it is low, and I do not think one can recommend routine follow-up scrotal ultrasound.

CONCLUSION

In conclusion, let us return to the 3 hypothetical patients.

Patient 1 with pure seminoma had a 6-month history, which is a long duration. I would recommend infradiaphragmatic radiation. It has a 99% cure rate, and the balance between cure and toxicity with this treatment seems better than that for chemotherapy. This patient is a legitimate contender for surveillance as well.

Patient 2 with a mixed tumor--40% embryonal, 40% teratoma, and 20% seminoma, with vascular invasion--still has the most to gain by a primary RPLND. Although teratoma by itself is less prone to relapse than embryonal carcinoma, the patient will pay a high price if the cancer is in the nodes. Following primary chemotherapy or surveillance and therapeutic chemotherapy for relapse, the teratoma will not be eliminated by chemotherapy alone. He will have a residual mass and end up receiving 3 or more courses of chemotherapy followed by surgical debulking. Postchemotherapy surgical debulking is a very difficult procedure.

The third patient, who had a pure embryonal carcinoma with vascular channel invasion, has a 30% or 40% risk of relapse, rather than the standard 25% risk. One might argue that RPLND and 2 courses of chemotherapy has less cumulative morbidity than surveillance and 4 courses of chemotherapy. However, I would treat this patient with primary chemotherapy, which has a high likelihood of cure, and avoid RPLND.

We are fortunate in testis tumor management to be able to discuss and argue over different treatment approaches, each of which should enjoy a 95% cure rate in clinical stage 1 patients.

1. SEER Cancer Statistics Review, NCI monograph, 1996.
2. Sagalowsky AI. Current considerations in the diagnosis and initial treatment of testicular cancer. Compr Ther 1994;20:688-694.
3. Foster RS, Ragan DC, Birhle R, Wahle GR, Hermans BP, Donohue JP. Fertility update on nerve sparing RPLND in clinical stage 1 nonseminoma. J Urol 1998;159:Ab174.
4. Janetschek G, Hobisch A, Peschel R, Hittmair A, Bartsch G. Laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous testicular carcinoma: long-term outcome. J Urol 2000;163:1793-1796.
5. Sogani PC, Perrotti M, Rabbani F, Herr HW, Fair WR, Bosl G. Long-term outcome of patients with clinical stage 1 testis cancer on surveillance. J Urol 1998;159:Ab184.
6. Swanson DA, von Eschenbach AC, Babian RJ, Dinney CPN, Pisters LL, Pettaway CA. Is retroperitoneal lymph node dissection (RPLND) alone optimal or sufficient therapy for clinical stage 1 nonseminomatous germ cell testicular tumors (NSGCTT) at high risk for relapse? J Urol 1998;159:Ab179.
7. Hermans BP, Sweeney CJ, Foster RS, Einhorn LE, Donohue JP. Risk of systemic metastases in clinical stage I nonseminoma germ cell testis tumor managed by retroperitoneal lymph node dissection. J Urol 2000;163:1721-1724.
8. Moul JW, Snow PB, Fernandez EB, Maher PD, Sesterhenn IA. Neural network analysis of quantitative histological factors to predict pathological stage in clinical stage I nonseminomatous testicular cancer. J Urol 1995;153:1674-1677.
9. Amato R, Banks E, Ro J, Swanson DA. Postorchiectomy adjuvant chemotherapy for patients with clinical stage 1 nonseminomatous germ cell tumors of the testis (NSGCTT) at high risk for relapse. J Urol 1999;161:Ab604.
10. Kratzik C, Reiter WJ, Schrey A. Ten years experience with adjuvant single-agent carboplatin therapy for clinical stage 1 seminoma. J Urol 1999;161:Ab700.
11. Travis LB, Curtis RE, Storm H, Hall P, Holowaty E, Van Leeuwen FE, Kohler BA, Pukkala E, Lynch CF, Andersson M, Bergfeldt K, Clarke EA, Wiklund T, Stoter G, Gospodarowicz M, Sturgeon J, Fraumeni JF Jr, Boice JD Jr. Risk of second malignant neoplasms among long-term survivors of testicular cancer. J Natl Cancer Inst 1997;89:1429-1439.
12. Leibovitch I, Ramon J, Hayman Z, Tel-Hashomer, Baniel J, Livne P, Petach-Tiqua, Vardi Y, Nativ O, Meretik S. Annual ultrasonographic screening of the remaining testis following unilateral radical orchiectomy for testicular germ cell tumor. A prospective multicenter study. J Urol 1999;161:Ab708.