When I see a patient with clinical stage I testicular cancer, the initial evaluation centers around three important factors:
First, review of CT scans to make sure that small volume lymph nodes in the primary landing zone in the retroperitoneum don’t indicate clinical Stage II disease.
Secondly, review of the pathology of the orchiectomy specimen by someone with significant experience in germ cell cancer is crucial, since subtle differences may make significant differences in treatment options presented to the patient (e.g. 99% seminoma + 1% nonseminoma = nonseminoma).
Finally, getting a handle on the rate of decline of serum tumor markers following orchiectomy (if they were elevated pre-orchiectomy) is important, as persistent elevation constitutes clinical Stage II disease, necessitating chemotherapy. Similarly, ANY elevation of alphafeto protein (AFP) indicates the presence of nonseminomatous elements, even if the orchiectomy specimen is read as pure seminoma.
Individuals with pure seminoma in the orchiectomy specimen, negative chest/abdomen/pelvis CT scans, normal physical examinations (specifically no evidence of supraclavicular adenopathy), and normal pre-op AFP, and for those with a minor elevation of HCG pre-orchiectomy (up to 200) normalization postoperatively, can all be appropriately labeled as having Stage I disease.
The relapse rate after orchiectomy is only 15%--therefore, 85% will already have been cured with their orchiectomy, and by definition will not benefit from additional therapy. I discuss two treatment options with those patients, either low-dose radiotherapy or active surveillance, and either approach should achieve a cure rate in excess of 95%.
Radiation Therapy for Clinical Stage I Seminoma
I tell patients that the major advantage of active therapy with radiation therapy is elimination of the retroperitoneum as a potential site of relapse, making routine abdominal imaging with CT scans unnecessary.
The administration of 2,600 cGy in a para-aortic strip plus the ipsilateral iliac nodes on the side of the primary tumor (the so-called “inverted hockey stick” distribution) results in minimal toxicity, including mild fatigue, and rarely, mild diarrhea, although some cases of focal pancreatitis or peptic ulcer disease have been reported.
Scatter radiotherapy to the contralateral testicle (despite lead shielding) may worsen preexisting oligospermia, with a potential long-term impact on fertility. There does not appear to be a significant increase of “in-field” second malignancies at this dose. Prophylactic supradiaphragmatic radiotherapy has demonstrated to be unnecessary.
Active Surveillance for Clinical Stage I Seminoma
However mild the side effects of radiotherapy for clinical stage I seminoma, 85% of patients have been cured by their orchiectomy and are receiving therapy unnecessarily. Since the vast majority of relapsing patients (95-99%) should be curable with combination chemotherapy, there is no medical mandate to give immediate therapy, making active surveillance a reasonable alternative in a motivated patient.
The downside of this approach is the frequency of follow-up visits and the need to perform routine abdominal imaging, both of which require a compliant patient.
I follow patients who have opted for surveillance monthly for the first year with physical examination, CXR, and serum tumor markers. I get routine tumor markers in follow-up, even in “marker-negative” seminoma patients for two reasons:
1. The diagnosis of “pure” seminoma might be incorrect, and a marker rise might be a first indication of recurrence of the previously unrecognized nonseminomatous elements
2. There is a 1.5% lifetime risk of a second primary germ cell tumor in the contralateral testicle, which might be first detected by elevation of serum tumor markers.
During the second year I perform these routine tests every two months, during Years 3 to 5 every six months, and then yearly thereafter.
In addition, I perform abdominal/pelvic CT scans every three months during the first year, every four months the second year, and every six months in Years 3-5.
The routine use of CT scans beyond Year 5 is controversial, and clearly of low yield, and I will present the data to the patient and involve him in that decision.
For the patient who is still nervous about relapse, it is not unreasonable to get one on an annual basis. For the patient primarily concerned about the radiation risks of multiple scans, it is equally reasonable to forego abdominal imaging beyond five years.
Chemotherapy for Clinical Stage I Seminoma
It has become somewhat fashionable over the past few years to offer a third option to patients with clinical stage I disease: abbreviated chemotherapy. In seminoma patients this has generally consisted of one or two doses of single-agent carboplatin. I do not personally ever recommend this approach, though, since I feel that the rationale behind this approach is fatally flawed, for the following reasons:
1. Randomized Phase III trials have clearly shown that carboplatin is inferior to cisplatin in the treatment of advanced germ cell tumors. It’s difficult to imagine that a single course of an inferior drug represents the best treatment option for the patient.
2. 85% of patients will be treated with chemotherapy unnecessarily, again having been cured by their orchiectomy, and with no compromise of overall cure rate by waiting to treat relapsing patients with combination chemotherapy.
3. Relapses do occur after this approach, meaning that frequent and long-term abdominal imaging is necessary.
4. Finally, in the MRC randomized trial of radiation therapy versus a single dose of carboplatin (reported as showing equivalent results), the trial (at full accrual) was designed to accept a 3% inferiority of chemotherapy, but because of under-accrual could have accepted a 7% inferiority and still been reported as showing equivalent results. Are we really willing to refer curable patients for a therapy that might be 7% inferior?
CLINICAL STAGE I NONSEMINOMA
For patients with clinical stage I nonseminomas, there are also two equally curative treatment options, and I will discuss thoroughly with patients both of these options. The first a nerve-sparing, modified template retroperitoneal lymph node dissection (RPLND), and the other is active surveillance.
RPLND in Clinical Stage I Nonseminoma
When I explain the pros and cons of surgery for clinical stage I nonseminoma, I tell patients that a major advantage is the removal of the retroperitoneum as a potential site of relapse, so that routine abdominal/pelvic CT scans are unnecessary. Other benefits include the knowledge gained from immediate pathologic staging (and immediate adjuvant chemotherapy for node-positive disease if the patient wishes) and the potential removal of teratoma, which responds only to surgical removal.
Disadvantages are that not every urologist can (or should) perform this procedure. The results reported in the literature reflect procedures done by surgeons trained in this technique and with a sufficient volume of cases to maintain their expertise. Additionally there is the upfront cost of surgery as well as weeks of down time for the patient during recovery from the procedure.
Active Surveillance in Clinical Stage I Non-Seminoma
Much of the rationale behind active surveillance in non-seminoma is similar to that for seminoma. However, the likelihood of having occult microscopic disease in the retroperitoneum (and therefore the likelihood of relapse with surveillance) is 30%, as opposed to the 15% for pure seminoma.
The patient must make a long-term commitment to this approach in terms of visits and abdominal/pelvic CT scans. Chemotherapy is given to any patient experiencing a serologic and/or radiographic relapse. Compliance with prescribed follow-up will mean a small volume relapse and cure rate in excess of 90% with three cycles of cisplatin + VP16 + bleomycin (BEP). While this approach makes the most medical sense in terms of preventing over-treatment, some patients may not be able to deal psychologically with a 30% risk of recurrence and might opt for immediate surgical intervention.
Combination Chemotherapy in Clinical Stage I Non-Seminoma
Although several groups have recommended 1 or 2 cycles of BEP in this clinical scenario, I once again never offer this as an option, the reasons being:
1. Seventy percent of patients will receive chemotherapy that they don’t need, because they have already been cured by their orchiectomy. If one gives two cycles of combination chemotherapy for clinical stage I disease and the standard treatment for recurrent disease is three cycles, then essentially 70% of patients receive chemotherapy that is unnecessary to spare the other 30% one additional course of therapy.
2. Such an approach may actually under-treat the 30% of patients who have microscopic disease and are destined to relapse. We have randomized, Phase III data in good-risk disease (including serologic-only recurrence) that three cycles of cisplatin + VP16 is inferior to three cycles of cisplatin + VP16 + bleomycin. Why would we think that one or two cycles of therapy is sufficient to cure microscopic disease in clinical stage I? Is the curability of someone who relapses after one or two cycles of therapy as high as the previously untreated patient? We have no idea.
3. We similarly don’t have sufficient information on the long-term impact of one or two cycles of chemotherapy in terms of fertility, VP16-related leukemia, neuropathy, Raynaud’s phenomenon, or cardiovascular disease.
In conclusion, clinical stage I germ cell tumors should be almost universally curable, with the appropriate attention to detail, particularly in terms of follow-up and imaging. The curability of recurrent disease is directly related to the volume of disease at the time of relapse, and the recommendations for follow-up maximize the chance of finding small-volume disease.
Bruce J. Roth, MD, is Professor of Medicine, Oncology Division, Washington University School of Medicine, St. Louis