Testicular Cancer: Maintaining the High Cure Rate

As Dr. Raghavan has emphasized in his excellent overview of the current therapy for testis cancer, it is critical that the success of therapy for this disease not be compromised by a desire to avoid the complications of therapy. We would wholeheartedly agree with his assertion that modifications in therapy must be introduced with a thoughtful and structured approach to minimize the risk to efficacy. Clinicians who treat patients with testis cancer face a series of challenging questions. A clear understanding of the natural history of the disease and the risks associated with various treatment options is crucial to the goal of maximizing therapeutic efficacy while minimizing risks of recurrence and toxicity. We address four of these challenging questions below. Stage I Disease: Treat or Observe?
One of the most controversial issues in the management of germ cell tumors concerns the patient with disease confined to the testis. Traditionally, patients with nonseminoma underwent orchiectomy and retroperitoneal lymph node dissection. Large series have shown that a substantial majority (60% to 80%) of patients will have no nodal involvement at the time of resection, suggesting that surgery may often be avoidable. Prognostic factors have been identified to distinguish between patients with a low and high risk of relapse. The most important of these are the presence of vascular/lymphatic invasion and greater than 30% embryonal cell carcinoma.[1] Other factors include the absence of measurable levels of alpha-fetoprotein preorchiectomy, less than 50% teratoma in mixed germ cell tumors, and local extension into paratesticular structures. Patients without any of these risk factors can be observed safely with a low risk of recurrence. However, as emphasized by Dr. Raghavan, such observational strategies need to be rigorous, as a small but definite percentage of these patients will develop recurrent disease. A similar approach has been advocated for stage I seminoma, for which patients have traditionally been treated with orchiectomy followed by adjuvant radiotherapy. As with surgery in nonseminoma, the majority (75% to 80%) of these patients do not require any therapy beyond orchiectomy. Pooled data from over 600 patients identified tumor size and the presence of invasion of the rete testis as important prognostic factors for relapse in patients with seminoma.[ 2] Incorporation of these factors into clinical practice may allow the identification of a low-risk group similar to that seen in nonseminoma, making it feasible to observe selected stage I patients if a rigorous follow- up schedule is used. The rigor and discipline of observation require a serious commitment by both the clinician and patient. A major factor that the clinician must consider in making a recommendation for observation is the level of commitment by the individual patient and his ability to maintain the follow-up schedule. For some patients, initial therapy may be preferable based on these factors alone. When Should a Residual Mass Be Resected?
This question concerns the management of residual masses following successful treatment with chemotherapy. In this context, "successful treatment" refers to a substantial shrinkage in bulky adenopathy with resolution of any previously elevated serum markers. Residual masses are present in up to 60% of patients presenting with bulky seminoma. In general, these masses represent dense fibrotic residua, which are difficult to dissect from underlying structures. Residual abnormalities greater than 3 cm in size represented viable malignancy in 30% of the patients in a series from Memorial Sloan-Kettering, whereas no cancer was present in masses less than 3 cm in diameter.[ 3] Based on these data, some authors have recommended that all masses greater than 3 cm should be resected if technically feasible. In patients who have unresectable residual lesions or lesions less than 3 cm, careful surveillance should be undertaken. The majority of patients with nonseminoma and a residual mass have teratoma, although up to 20% may have residual malignancy.[4] These masses generally should be resected. The major risk is local complications due to growth of teratoma to the point where it may become unresectable. There is also a risk of malignant transformation into sarcoma and carcinoma, as well as a risk of late recurrence of the germ cell malignancy. Resection provides a definitive means of addressing these risks. Patients who are not resected must be observed closely to minimize these risks. How Should Poor-Risk Disease Be Managed?
The International Germ Cell Tumor Collaborative Group has defined prognostic factors that have been used to categorize patients into good, intermediate, and poor risk.[5] Management of the poor-prognosis group remains controversial, with some experts advocating new drug combinations and others high-dose chemotherapy regimens. Patients with negative prognostic factors should probably be referred to centers of excellence in the management of testis cancer for evaluation and therapy. It is clear from the literature that the best opportunity for cure in these individuals is with the initial therapy administered, and that questions regarding the efficacy of new regimens and high-dose chemotherapy should be answered in this setting. The role of high-dose chemotherapy with autologous stem cell support has yet to be defined. An ongoing Intergroup study is currently comparing high-dose chemotherapy to standard therapy in the high-risk population. How Should Long-Term Survivors Be Followed?
Dr. Raghavan has pointed out several of the late toxicities associated with treatment for testis cancer and summarized them in his Table 5. It is important to note that although the majority of testis cancer patients are cured of their disease, long-term follow- up is required.[6] This followup component to disease management should focus on both the late toxicities of the disease and detection of late relapses. Although testis cancer has been labeled a "model of curable neoplasm," it is important to note that, since these men will require medical observation over a prolonged period, in some ways this is a lifelong disease. As such, testis cancer may be better described as a model for converting an aggressive neoplasm to a chronic condition.