Controversies in the Management of Stage I Seminoma

Introduction

In the United States, an estimated 7,200 new cases of testicular cancer were diagnosed in 1997, but only 340 deaths were attributable to this cancer.[1] Seminoma represents about 50% of all germ-cell tumors and is the most common histologic type of testicular cancer. Seminoma has long been recognized as a radiosensitive and chemosensitive neoplasm.

Stage I testicular cancer includes all patients without lymph node involvement or distant metastatic spread (T1-4 N0 M0) and represents 70% of all cases of seminoma.[2] A new staging system for testicular cancer now includes the presence of vascular lymphatic invasion and marker elevation, as shown in Table 1. The stage groupings have also been modified in this new system.

The management of stage I testicular cancer has followed the lead of other successfully treated cancers, including Hodgkin’s disease and various pediatric malignancies. The primary end point of many ongoing studies in these tumors is not to improve efficacy, but rather, to lessen toxicity from equally effective therapies. Several older studies have shown that the mediastinum can be omitted from the treatment volume of irradiated patients, even those with stage IIA disease, thus eliminating the potential toxicity associated with thoracic radiotherapy (RT).

The management of stage I seminoma continues to evolve. Currently, there are significant controversies regarding the relative roles of adjuvant RT, surveillance, and adjuvant single-agent chemotherapy. This review focuses on the changing management of this very curable neoplasm and addresses the results and toxicity of standard-volume RT, reduced-volume RT, surveillance, and adjuvant single-agent chemotherapy after orchiectomy. Potential salvage therapies for rare primary treatment failures are also discussed.

Standard Adjuvant Therapy: Para-aortic and Pelvic RT

Standard therapy for all patients with early-stage seminoma includes radical inguinal orchiectomy with high ligation of the spermatic cord. Scrotal violation has never been shown to compromise survival, but may preclude patients from the option of postoperative surveillance and may alter RT volumes, leading to the delivery of unnecessary dose to normal tissues, including the remaining testicle. Any additional therapy besides orchiectomy in stage I seminoma is adjuvant in nature and is designed to treat subclinical nodal or micrometastatic spread.

Radiation therapy has been a standard adjuvant treatment for early-stage seminoma. The patterns of dissemination include progressive spread from the retroperitoneum to the mediastinum and supraclavicular lymph nodes. This was the rationale for extended-field RT in early-stage seminoma, which often included elective treatment of the mediastinum and supraclavicular lymph nodes. Prior to the advent of cisplatin(Drug information on cisplatin) (Platinol), extensive-field RT cured a significant number of patients, even those with lymphadenopathy.

Hanks et al found that 27% of patients with clinical stage I seminoma treated in the US Patterns of Care Study received supradiaphragmatic RT, and more than half received subdiaphragmatic doses > 30 Gy.[3] In the Norwegian Radium Hospital series (1970 to 1982), radiation was delivered to a median dose of 40 Gy prior to 1980, with only one field treated each day.[4] Since current RT doses and volumes are much lower, interpretation of the toxicity data from series with the longest follow-up must take this into account.

Efficacy

Table 2 summarizes the relapse-free survival rates of stage I seminoma patients treated with standard ipsilateral pelvic and para-aortic RT in several studies.[3-11] Many of these reports included some patients treated in the 1950s and ’60s. Overall, about 95% to 97% of patients were relapse-free after standard adjuvant RT. Most of the deaths from seminoma in these series occurred in the precisplatin era. The patterns of failure after RT indicated that seminoma is a very radiosensitive neoplasm.

Dosmann et al found no recurrences in the treatment field in 282 patients with stage I seminoma treated with adjuvant RT.[5] Similar results have been seen in other institutions.[7]

Toxicity

Delayed toxicity after RT, although generally occurring at a low frequency, is important given the high likelihood of disease control. Toxic events related to RT include infertility, cardiotoxicity, gastrointestinal toxicity, second neoplasms, and immunosuppression.

Infertility is an important issue for many men with seminoma. The average patient with seminoma is approximately 35 years old. Whether infertility is the result of surgery, adjuvant therapy, a coexisting testicular abnormality, or a combination of all of these factors is unknown.

Southwest Oncology Group (SWOG) trial 8711 prospectively followed 53 patients treated with orchiectomy and adjuvant pelvic and para-aortic irradiation.[12] Over half (54%) of the patients with baseline sperm counts were subfertile. Lower testicular doses (< 0.79 Gy) were achieved when testicular shields were used, and this protection was associated with beneficial effects on 1-year sperm counts. Sperm count recovered 1 year after RT in the low-testicular-dose group but was delayed in patients who received higher doses. Similar changes were seen in serum follicle-stimulating hormone (FSH) concentration but not in serum testosterone level.

Cardiotoxicity--Elective mediastinal RT was associated with an excessive number of cardiac deaths in the Patterns of Care series.[13] The cardiac toxicity of mediastinal RT was subsequently confirmed in Hodgkin’s disease.

Elective mediastinal therapy has no role in stage I seminoma, as relapse-free survival is excellent without it.[6] Only about 1.9% of patients with clinical stage I seminoma treated with standard pelvic and para-aortic RT will develop disease recurrence in the mediastinum or supraclavicular lymph nodes.[14] In stage II seminoma, the risk of mediastinal recurrence depends on the size of the para-aortic metastasis. In general, mediastinal therapy has been abandoned in patients with retroperitoneal tumors < 5 cm in favor of preservation of bone marrow for salvage chemotherapy, and in order to avoid late cardiac toxicity.

Gastrointestinal Toxicity--Late gastrointestinal toxicity has been reported after irradiation to the abdomen. In 365 stage I seminoma patients receiving relatively high doses of adjuvant RT, Fosså et al described 9 patients who developed gastric ulceration and 16 who experienced dyspepsia.[4] The median mid-plane dose in this study was 40 Gy. More conventional regimens, such as 25.5 Gy in 17 fractions, should have significantly lower rates of gastrointestinal toxicity.

Second Neoplasms--Much of the data on second malignancy after pelvic and para-aortic irradiation comes from large population registries or much smaller single-institution reports. Unfortunately, since many of the larger studies lack details on treatment, the relative contribution of RT is difficult to determine. Data are often combined for seminoma and other types of germ-cell tumors.

These limitations notwithstanding, the long-term toxicity data indicate that patients who have been irradiated for seminoma have a higher rate of second malignancy than age-matched controls. Second testicular tumors are probably not related to treatment, but rather, stem from a predisposition to germ-cell neoplasms. This phenomenon has been readily observed in patients with cryptorchid testes and has also been confirmed by large population studies.

Wanderås et al updated the Norwegian Radium Hospital experience with second germ-cell tumors, including 2,201 patients with primary germ-cell tumors.[15] In 1,135 patients with seminoma, the cumulative risk of a second germ-cell tumor was 3.4% at 15 years (relative risk [RR], 27.7). Age may be an important risk factor for posttherapeutic neoplasia. Patients diagnosed with a germ-cell tumor when they were under 30 years of age had a cumulative risk of 7.8% at 15 years.

Hanks et al found 14 second tumors among 387 patients treated with RT for stage I and II seminoma.[13] This corresponded to an 8% risk at 15 years (RR, 3.4). Of the 14 second malignancies, 2 were leukemias, 1 was an in-field melanoma, and 1 was a second testicular tumor. All of the remaining malignancies were marginal or out-of-field tumors.

A large, population-based study from Denmark included 3,256 patients with seminoma treated from 1943 to 1987 with various modalities.[16] For all second malignancy sites, the overall relative risk was 1.5 compared to the expected incidence in the overall population. A statistically significant increased risk was seen for cancers of the stomach (RR, 1.9), colon (RR, 1.7), pancreas (RR, 2.1), kidney (RR, 2.2), and bladder (RR, 2.1); nonmelanoma skin cancer (RR, 1.8); and leukemia (RR, 2.3). Only 1 of the 13 patients who developed leukemia had received chemotherapy.

What cannot be ascertained from these studies is whether RT causes a higher rate of second tumors, or whether seminoma patients are predisposed to developing second tumors even without RT. Three studies have compared the rate of second malignancy in patients who did and did not receive RT.

In a large, population-based study of second non-germ-cell tumors in patients from Norway, Wanderås et al found a relative risk of 1.58 (95% confidence interval [CI], 1.3 to 1.9) in patients who received RT without chemotherapy, 3.54 (95% CI, 2.0 to 5.8) in patients who received RT and chemotherapy, and 1.31 (95% CI, 0.4 to 3.4) in patients who received neither RT nor chemotherapy.[17] Even when second germ-cell tumors were excluded in this study, the relative risk of secondary malignancy was still greater than 1 in patients treated with surgery alone, possibly indicating that these patients are at an increased risk of second tumors even without cytotoxic therapy, (although the 95% CI included 1).

The Connecticut Tumor Registry data combined with the Surveillance, Epidemiology, and End Results (SEER) data of the National Cancer Institute (NCI) included 9,739 patients with testicular tumors (all histologies).[18] Ten-year survivors of seminoma were at increased risk for cancers of the pancreas (RR, 3.23), kidney (RR, 3.22), and bladder (RR, 2.94), as well as acute nonlymphocytic leukemia (RR, 5.77). This study confirmed the findings of the Norwegian population study that excess second tumors occur at a higher rate in patients treated with surgery alone (RR, 1.40).

Testicular cancer patients undergoing RT in the Netherlands had a relative risk of 4.4 for a second gastric cancer.[19] No increased risk was seen in patients who were treated with surgery alone, but since there were so few cases of gastric cancer, the 95% confidence intervals overlapped significantly. The relative risk of gastric cancer did increase with follow-up interval, suggesting that RT had some role in causation.

Unfortunately, follow-up from the more recent prospective surveillance studies is not long enough for an accurate assessment of second malignancies to be made. It is interesting to note that some of the tumors ascribed to RT, such as gastric cancer, have been seen in surveillance patients as well.[20]

Immunosuppression--Total lymphoid irradiation, as used in Hodgkin’s disease, is chronically immunosuppressive.[21] Alterations in CD4+ lymphocyte counts have been described in this setting. Similar changes may occur after para-aortic and pelvic RT for seminoma. Any role this potential immunosuppression may play in the pathogenesis of second malignancies is unknown.