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New Treatments for Testicular Cancer

Testicular cancer is a relatively uncommon malignancy. There’s only about 7,000 cases per year in the United States, but it affects men at a young age. The peak incidence of testicular cancer is in the age group of 15-35. It’s highly curable. Nowadays about 90% of patients will be cured, crossing all stages. It’s a model malignancy because multi-modality therapy is used, as we’ll talk about. The cure rates for testicular cancer have improved dramatically over the past 30 years, increasing from 60-65% in the 60’s up to about 90% in the 1990’s. This is attributable to a few factors, probably the most important of which is the development of effective cisplatin-based chemotherapy for testicle cancer.

The etiology of testicular cancer is not known but there are several risk factors that are important. The most important of which is cryptorchidism. Cryptorchidism is seen in about 10% of patients with testicular cancer. When you see cryptorchidism there is anywhere from a five to fifty-fold increased risk of developing testicular cancer in that person’s lifetime. Interestingly, about 25% of the malignancies that occur in the context of cryptorchidism occur in the contralateral testicle. There are some interesting associations with testicular cancer. First of all, rarely do we see families with multiple members having testicular cancer. Testicular cancer can occur bilaterally in about 2-3% of patients, more commonly with seminoma than with non-seminoma. There is a distinct marker in the tumor associated with testicular cancer.

A typical presentation of testicular cancer is painless enlargement of the testes, although pain may occur when there is bleeding within the testicle or rapid growth within the testicle. A testicular ultrasound is the most important test to do. It will distinguish an intratesticular mass from an extra-testicular mass 98% of the time. If in intratesticular mass is seen, it’s testicular cancer until proven otherwise. Once the diagnosis is established pathologically it’s important to sub-group these tumors. About two-thirds of these tumors are mixed tumors.

The staging process involves some assessment of the abdomen, usually a CT scan. Some assessment of the chest which could be a chest x-ray or a chest CT scan, as well as serum markers. There’s probably no other disease where serum markers are as useful as in testicular cancer. One of the markers is the alpha-fetoprotein is elevated in about 50% of the cases.

Now let’s talk about treatment of different subtypes of testicular cancer. First of all, stage I seminoma. Orchiectomy is performed. The pathologist says this is a pure seminoma. The alpha-fetoprotein has never been elevated. If the alpha-fetoprotein is elevated in the context of a seminoma it is categorically considered a non-seminoma. So for pure seminoma, stage I.

For stage II seminomas, that is, involvement of the lymph nodes, the treatment is dependent on the size of the lymph nodes. If the lymph node mass is solitary and is 5 cm or less the standard of care in the United States is radiation in a hockey-stick distribution with a boost of radiation.

The story is a lot more complicated for stage I non-seminomas where there are several choices involved in the treatment of these patients. And I just want to go through these briefly in some amount of detail. Surveillance, retroperitoneal lymph node dissection and chemotherapy are the three alternatives. The standard in the United States for many years, particularly before effective chemotherapy was developed for non-seminomas.

Now how effective is the retroperitoneal lymph node dissection in curing patients with stage I testicular cancer? The largest study ever conducted was a multi-institution study called the Testicular Cancer Intergroup Study, conducted between 1979 and 1984 in which over 500 patients from multiple institutions underwent a retroperitoneal lymph node dissection. In that study 284 patients were found to have pathological stage I disease.

But if we look at how effective retroperitoneal lymph node dissection is at actually curing disease, one has to look at the studies in a little more detail. Look at the studies in which a retroperitoneal lymph node dissection was performed, disease was found in the lymph nodes, and no subsequent therapy was undertaken. What was the cure rate in those patients? Overall, the retroperitoneal lymph node dissection with no subsequent chemotherapy is curative.

Now an alternative approach to patients with stage I non-seminoma is surveillance. This is a look at multiple studies in which patients with non-seminomas were observed, subsequently may have relapsed, and ultimately treated with chemotherapy. In this conglomerate of studies, as one would anticipate, about 28% of patients relapsed and ultimately with chemotherapy the majority of those patients are cured. Overall the results of surveillance, if done well, are very similar to a retroperitoneal lymph node dissection. Typically if one watches a patient with stage I seminoma and they relapse, they will do so very quickly; 50% by five months, 80% by two years.

Now on the basis of the surveillance studies and the retroperitoneal lymph node dissection studies that have been published over the last 20 years, one can stratify patients into two basic subgroups; good risk patients and poor risk patients. Good risk patients are those patients that in their orchiectomy specimen have no lymphatic or venous invasion.

An alternative therapy for patients with stage I seminoma, which might be appropriate for patients who are in the high risk group is adjuvant chemotherapy. That is, chemotherapy when the markers are normal after orchiectomy. Now for high risk features, if patients have high risk features and a greater than 50% relapse, this is an appropriate alternative therapy. This has been proven now in three studies, one of which is shown here.

One of the issues that comes up in the treatment of seminomas with chemotherapy is the presence of a residual mass after treatment. In distinction to non-seminomas where teratoma is an issue, teratoma is not an issue with seminoma, and the issue here is whether there is residual seminoma or carcinoma in the residual mass or is it all just fibrosis. The vast majority of the time the mass is residual fibrosis. There have been strategies in the United States, and Europe as well, of resecting the residual mass or giving radiation for the residual mass, but I think that in 2006 the standard of care in general is observation. This is a non-randomized study from England that looked at the utility of giving radiation to these masses after chemotherapy. This is a study of 302 consecutive men with metastatic seminoma, treated with chemotherapy.

Now shifting over to non-seminomas; the sub-grouping is a little more complex. This is now the consensus, the world consensus, in terms of stratification. These are good risk non-seminomas. These patients have to have testicular primaries or retroperitoneal primaries, no non- pulmonary visceral metastases and low markers. These patients are cured over 90% of the time. Intermediate risk patients; no non-pulmonary visceral metastases, retroperitoneal or testicular.

Two studies looking at carboplatin. One done at Memorial Sloan-Kettering. Higher failure rate with carboplatin although no difference in overall survival as a result of salvage. A European study, 598 men. Good risk. Difference in complete response was seen and there is ultimately differences in treatment failure and in survival, although this was not statistically significant.

Now here is a patient, a fairly typical patient, who has multiple pulmonary metastases and high tumor markers, treated with chemotherapy. Tumor markers normalize. The masses clear up completely. Complete response, no further therapy is necessary, the patient is observed. This is a patient who received chemotherapy, markers normalized and was left with this large, irregular retroperitoneal mass. This started out as a non-seminoma in the testes. So the standard of care in the United States for residual masses, after tumor marker normalization, is resection of the residual mass. In 2006 what one finds in these residual masses 10% of the time is residual cancer. If residual cancer is seen, further chemotherapy is necessary. The standard has been two further cycles of the same chemotherapy, although salvage chemotherapy is appropriate here as well.

If scar tissue is seen, the patient obviously has a great prognosis. So further therapy is necessary. Forty-five percent of the time a mature teratoma will be seen. If it is seen, no further chemotherapy is necessary but there needs to be close surveillance in these patients for the possibility of other teratomas arising in other locations. For patients who were treated with primary chemotherapy and ultimately relapse with marker elevation and/or progression of tumor masses, some of those patients can still be cured with subsequent chemotherapy. For a patient who has received standard chemotherapy, about 20% of patients will be cured.

Finally, last but not least, there are some patients who become chemotherapy-resistant who ultimately can be cured with third line surgery. These are chemotherapy refractory patients who generally have resectable disease, hopefully single site disease, generally late relapsers. There tends to be teratoma in the original pathology.