Stage I nonseminoma is highly curable (>99%). Orchiectomy alone will cure about 70% of patients but the remaining 30% will relapse and require additional treatment. The relapses are highly curable, and thus post-orchiectomy surveillance is a standard treatment option, but some physicians and patients prefer to reduce the risk of relapse by having the patient undergo either a retroperitoneal lymph node dissection (RPLND) or one or two cycles of chemotherapy. Each of these three approaches has unique advantages and disadvantages, and none has been shown to result in longer survival or superior quality of life.
- Radical inguinal orchiectomy followed by a regular and frequent surveillance schedule.
Typically, patients are seen monthly during the first year, every 2 months during the second year, every 3 months during the third year, every 4 months during the fourth year, every 6 months during the fifth year, and annually for the subsequent 5 years.[23,24,25] At each visit, the history is reviewed, a physical examination is given, determination of serum markers are performed, and a chest x-ray is obtained (sometimes at alternating visits). An additional key aspect of surveillance involves abdominal or abdominopelvic CT scans, but the preferred frequency of such scans is controversial.
A randomized controlled trial (MRC-TE08) compared a schedule that used only two scans at 3 months and 12 months to a schedule that used five scans at 3, 6, 9, 12 and 24 months. With over 400 randomly assigned patients and a median follow-up of 40 months, all relapsing patients had either good- or intermediate-risk disease, and there were no differences in the stage or extent of disease at relapse between the two arms. No deaths were reported. Nonetheless, some organizations recommend CT scans every 3 to 4 months during the first 3 years of follow-up and continuing but less-frequent CT scans thereafter. While this study would appear to indicate that scans at 3 and 12 months are adequate during the first year, longer follow-up will be needed to assess whether discontinuing scans after 12 months is safe.[Level of evidence: 1iiA] With regard to chest imaging, disease recurrence is rarely detected by chest x-ray alone, so chest x-ray may play little or no role in routine surveillance but is nonetheless included in the mainstream surveillance schedules.
The need for long-term follow-up has not been adequately investigated. Surveillance series with long follow-up have reported that fewer than 1% of clinical stage I patients relapse after 5 years.[27,28] Late relapses often occur in the retroperitoneum when they do occur. Hence, some schedules discontinue CT scans after 12 months, while others recommend at least annual scans for 10 years.
The option of a radical inguinal orchiectomy followed by a regular and frequent surveillance schedule should be considered only if:
- CT scan and serum markers are negative.
- The patient accepts the need for and commits to frequent surveillance visits. Children are adequately followed by serum markers alpha-fetoprotein (AFP), chest x-rays, and clinical examination.
- The physician accepts responsibility for seeing that a follow-up schedule is maintained as noted.
- Removal of the testicle through the groin followed (in adults) by RPLND.
A nerve-sparing RPLND that preserves ejaculation in virtually every patient has been described in clinical stage I patients and appears to be as effective as the standard RPLND.[30,31,32] Surgery should be followed by monthly determination of serum markers and chest x-rays for the first year and every other month determinations for the second year.
Men undergoing RPLND who are found to have pathological stage I disease have a roughly 10% risk of relapsing subsequently, whereas men with pathological stage II disease (i.e., those who are found to have lymph node metastases at RPLND) have as much as a 50% risk of relapse without further treatment.Two cycles of post-RPLND chemotherapy using either bleomycin, etoposide, and cisplatin (BEP) or etoposide plus cisplatin (EP) lowers the risk of relapse in men with pathological stage II disease to about 1%.[34,35] The vast majority of reported patients in studies of RPLND underwent the operation at a center of excellence with a urological surgeon who had performed hundreds of such operations. The ability of less-experienced urologists to achieve similar results is unknown.
In patients with pathologic stage I disease after RPLND, the presence of lymphatic or venous invasion or a predominance of embryonal carcinoma in the primary tumor appears to predict for relapse.[36,37,38] In a large Testicular Cancer Intergroup Study, the relapse rate among men with pathological stage I disease was 19% in those with vascular invasion versus 6% in those without vascular invasion. One study reported that the relapse rate for men with pathological stage I disease was 21.2% (18 of 85 men relapsed) if their tumors were predominantly embryonal carcinoma and 29% if there was a predominance of embryonal carcinoma plus lymphovascular invasion, versus 3% (5 of 141 men relapsed) if there was not a predominance of embryonal carcinoma.[36,37]
Among pathological stage II patients, the relapse rate was 32% among men with embryonal carcinoma-predominant tumors compared with15.6% in the other stage II patients. The risk of metastatic disease (i.e., either pathological stage II disease or relapsed pathological stage I disease) in men with tumors showing a predominance of embryonal carcinoma plus lymphovascular invasion was 62% compared with 16% in men with neither risk factor.
These data have shown that high-risk patients undergoing RPLND have a substantial risk of subsequently receiving chemotherapy. Data from one institution have shown that about half of men with stage I pure embryonal carcinoma undergoing RPLND will subsequently receive cisplatin-based chemotherapy.
Retroperitoneal dissection of lymph nodes is not helpful in the management of children, and potential morbidity of the surgery is not justified by the information obtained. In men who have undergone RPLND, chemotherapy is employed immediately on first evidence of recurrence.
- Adjuvant therapy consisting of one or two courses of BEP chemotherapy in patients with clinical stage I disease.
A randomized controlled trial compared a single cycle of BEP chemotherapy to RPLND in 382 patients. The 2-year recurrence-free survival rates were 99.5% with chemotherapy versus 91.9% with RPLND (absolute difference = 7.6%; 95% confidence interval, 3.1%-12.1%). There were no treatment-related or cancer-specific deaths in either arm of the study.
A Swedish and Norwegian study reported results of a risk-adapted therapy protocol in which patients with nonseminomas with lymphovascular invasion underwent postorchiectomy chemotherapy with one or two cycles of BEP chemotherapy, while those without lymphovascular invasion underwent either surveillance or a single cycle of BEP. The study included 745 patients and, with a median follow-up of 4.7 years and 2-year follow-up of 89% of patients, there were no deaths from testicular cancer, although one patient died of a stroke immediately after completing chemotherapy for relapsed disease. Overall survival and cause-specific survival were 98.9% and 99.9%, respectively. Both of these studies were conducted at community-based hospitals and demonstrated that postorchiectomy chemotherapy could be delivered at a regional or national level without depending on centers of excellence.
Several phase II studies and case series reporting the results after two cycles of BEP in intermediate- or high-risk patients have reported relapse rates ranging from 0% to 4% (average = 2.4%). Fewer than 1% of patients in these series died of testicular cancer. While chemotherapy produces the lower relapse rate and a comparable disease-specific survival rate compared to RPLND or surveillance, it is unknown whether a brief course of chemotherapy results in late toxicity or an increased risk of late relapse. Longer follow-up is awaited.