Treatment
Treatment of Stage I or II Disease
In patients with clinical stage I disease (normal serum markers and normal CT scans of the chest and abdomen), the risk of relapse is 15% to 20% and the majority of relapses occur in the retroperitoneum. Tumor size greater than 4 cm is the strongest and most reliable risk factor for recurrence. The presence of lymphovascular space invasion, young age, and rete testis invasion have also been associated with increased risk of relapse; however, the results have been inconsistent among various independent series. A pooled-analysis of data from the Royal Marsden Hospital, Danish Testicular Cancer Study Group, Princess Margaret Hospital, and the Royal London Hospital (Warde et al: J Clin Oncol 2002) initially suggested risk-based prognostic groups based on tumor size and rete testis invasion may enable a risk-adapted treatment approach for stage I seminoma. However, a study that used an independent data set with 687 patients and median follow-up of 4 years has found that tumor size is the only factor that predicts relapse and that rete testis invasion is not of prognostic importance. The preferred management post-orchiectomy for stage I seminoma is surveillance. Alternatively, adjuvant radiotherapy is highly effective for patients who are unable or unwilling to participate in a surveillance program. Adjuvant single-agent carboplatin(Drug information on carboplatin), one or two cycles, has also been investigated. Salvage for patients who recur while on surveillance are excellent and achieve about a 100% cure rate with three cycles of BEP (bleomycin, etoposide(Drug information on etoposide), cisplatin(Drug information on cisplatin)) or four cycles of EP (etoposide, cisplatin).
Surgery
Initial intervention for testicular cancer is radical inguinal orchiectomy. Orchiectomy may be deferred temporarily in patients with advanced-stage disease in whom the diagnosis of NSGCT can be made on clinical grounds (elevated markers). In such patients, an orchiectomy must be performed sooner or later, because there is incomplete penetration of chemotherapy into the testes.
Further therapy hinges on the pathologic diagnosis. In general, most clinical stage I tumors are typically followed with surveillance (see discussion later). In more advanced stages of the disease, patients with pure seminomas are treated with radiotherapy or chemotherapy, whereas patients with NSGCTs are treated with surgery and/or chemotherapy.
Inguinal orchiectomy. In addition to removal of the testis, the spermatic cord is dissected high into the retroperitoneum. The vas deferens is isolated from the testicular vessels and ligated separately with a permanent suture. Also, the testicular vessels are freed from the peritoneum and carefully ligated with a permanent suture.
Retroperitoneal lymph node dissection (RLND) for NSGCTs. For patients with NSGCTs and either no evidence or a small volume of disease on CT (stage I [N0] or stage II [N1, N2a, N2b] disease), RLND was generally indicated because it (1) accurately and definitively defines the presence or absence of retroperitoneal metastases and (2) removes the retroperitoneum as a site of recurrence, thus obviating the need for surveillance with CT. Today, most patients undergo surveillance or primary chemotherapy (see discussion later in this chapter).
RLND can be accomplished transperitoneally or retroperitoneally through a thoracoabdominal approach. The thoracoabdominal approach is more technically difficult but eliminates the risk of postoperative small-bowel obstruction and usually requires a shorter hospital stay.
Follow-up schedule for germ cell tumor• Nerve-sparing surgery—Regardless of the approach, urologic oncologists recommend a unilateral, nerve-sparing procedure. For right-sided tumors, the medial border of the template is the midpoint of the aorta, and for left-sided tumors, the medial border is the midpoint of the inferior vena cava (IVC). The sympathetic trunks responsible for normal bladder neck closure during ejaculation course lateral to the aorta on the left side and behind the IVC on the right side. Below the inferior mesenteric artery, both sympathetic trunks send branches to the region anterior to the aorta. The branches coalesce and then pass to the bladder neck.
Critical aspects of nerve-sparing surgery include preservation of the ipsilateral sympathetic nerve trunk and bilateral preservation of branches below the level of the inferior mesenteric artery. In our experience and that of other authors, it is possible to maintain normal ejaculatory function in virtually all patients using this technique. With a template dissection, there is some risk of disease outside the template. Eggener et al at MSKCC have reported good recovery of ejaculation with bilateral dissection using a nerve-sparing approach.
Radiation therapy for stage I seminomas
Chemotherapy regimens for testicular cancerSeminomas of the testes are exquisitely sensitive to irradiation. This characteristic, combined with their predictable lymphatic spread, makes these cancers amenable to radiotherapy. Since low radiation doses are used, acute and late side effects are few, although second primary malignancies in the radiation field and coronary vascular disease (when mediastinal fields have been used) have been reported. Radiotherapy is not indicated in patients with NSGCT, except in the palliative setting.
Fields and doses. The radiotherapy portals have traditionally included the retroperitoneal lymph nodes, which are the primary drainage of the testis, from T10 to L5 and the ipsilateral hemipelvis, including the inguinal scar. However, studies that reduced the size of the retroperitoneal field and omitted hemipelvis irradiation in select patients (eg, those who have not undergone prior orchiopexy or other pelvic, inguinal, or scrotal surgery) favor smaller treatment volumes. The T10 study that randomized 478 men with stage I seminomas to receive irradiation of the para-aortics (T11 to L5) and ipsilateral hemipelvis (dogleg) or irradiation of the para-aortics only was recently updated, with a median follow-up of more than 10 years. The actuarial rate of 5-year freedom from relapse was about 96% for both groups. There were four pelvic relapses in patients given retroperitoneal radiation therapy only (two with additional systemic relapse) vs no relapses in the dogleg arm. Otherwise, the few failures observed following radiotherapy most often occurred in the next level of lymph node drainage sites, such as the mediastinum or left supraclavicular fossa. A single seminoma-related death was recorded in the para-aortic radiation-only arm. In the interest of minimizing the field size, together with data from Bruns et al that demonstrates a very low risk of recurrences above T12, the para-aortic field can be further reduced to the bottom of T11 to the bottom of L5.
The smaller treatment volume reduces the dose to the remaining testicle and probably the risk of secondary malignancy. The ipsilateral hemipelvis is treated only when there is a history of ipsilateral inguinal surgery. Violation of the inguinal region can alter the testicular lymphatic drainage pathway to the para-aortic region. The hemiscrotum is often treated if the tumor has penetrated the tunica albuginea, a trans-scrotal incision was performed, or orchiopexy was performed for cryptorchidism. This practice has been questioned, however, since the incidence of scrotal failure is low, even in the presence of these risk factors. In fact, some surgeons advocate the use of trans-scrotal exploration to rule out benign lesions.
The T18/T19 study randomized 1,094 patients with clinical stage 1 seminoma to receive adjuvant para-aortic radiation therapy at 30 Gy or 20 Gy. The relapse-free rates at 5 years with these two radiation doses were 95.1% and 96.8%, respectively, and 20 Gy is preferred.
Side effects. The acute side effects of radiotherapy are limited to nausea, vomiting, and infrequently, diarrhea, all of which usually can be readily controlled with medication. Long-term complications reported at the University of Texas MD Anderson Cancer Center demonstrated increased mortality ratios for overall, cardiac-specific, and secondary cancer deaths for men treated with radiation therapy for seminoma between 1951 and 1999. No difference in mortality risk was noted in the first 15 years following treatment; however, over the entire period, the all-cause mortality risk was 1.59. The cardiac-specific mortality rate after 15 years was 1.61, and the secondary cancer mortality rate was 1.91.
Permanent infertility from scattered irradiation to the contralateral testis is uncommon, whereas prolonged aspermia for more than 1 year may occur, especially with irradiation of the hemiscrotum. Nevertheless, sperm banking is recommended for patients concerned about childbearing.
Follow-up. Relapse following adjuvant radiotherapy occurs in 2% to 5% of patients, and the great majority of recurrences occur within the first 2 to 3 years after treatment. Recurrences are typically found in lymph nodes of the pelvis, abdomen, groin, mediastinum, supraclavicular fossa, and neck. Physical examination of these areas and CT evaluations of the abdomen and pelvis can aid with the detection of recurrence.
Owing to increasing concerns about late effects related to radiographic studies, two evidence-based studies have suggested fewer follow-up evaluations than have traditionally been performed. Follow-up with imaging studies two or three times a year during the first 3 to 4 years of follow-up has been suggested. The additional value of chest imaging and tumor markers (AFP, β-hCG, and lactate dehydrogenase) has been questioned, because few recurrences are detected on the basis of these evaluations alone. However, these studies are routinely done, because solitary pulmonary recurrences can occur and because these tumor markers may also support the suspicion of recurrence indicated on physical examination or imaging. Chest radiography is the preferred method for imaging the chest, because the radiation exposure is lower than that with CT. Late recurrences are well documented, and annual follow-up until at least year 6 has been suggested, a point in time at which the risk of recurrence falls below 0.3% per year.
Radiation therapy for stage II seminomas
Fields and doses. The radiotherapy fields are similar to those used for stage I disease, except that they are widened to include any retroperitoneal or pelvic adenopathy with a 2- to 3-cm margin. In the past, mediastinal and supraclavicular treatment was standard in patients with stage II disease. However, data from several series revealed only a 3% rate of mediastinal/supraclavicular relapse. In addition, late cardiac toxicity has been reported. Although treatment to supradiaphragmatic sites has largely been abandoned in these cases, one report indicates that the rate of failure in the left supraclavicular fossa is higher than was previously believed. An analysis from another group indicates the opposite, however—that supradiaphragmatic radiotherapy for stage IIA-B seminoma is unnecessary. The overall actuarial rate of freedom from disease at 5 years for patients with retroperitoneal adenopathy less than 2 cm (IIA) is 95%, 2 to 5 cm (IIB) is 90%, and more than 5 and less than 10 cm (IIC) is 85%.
Involved areas are usually treated with 30 (IIA) to 36 Gy (IIB), and uninvolved areas are treated with 20 Gy in 10 fractions or alternatively, 25 Gy in 15 fractions. There is no evidence of a dose-response effect above 25 Gy for uninvolved areas and above 36 Gy for involved areas. Failures within the irradiated volume are anecdotal.
Chemotherapy
Stage I seminomas. Several studies have evaluated the role of chemotherapy, typically carboplatin as adjuvant therapy, for clinical stage I seminoma. Single-cycle carboplatin (area under the curve [AUC] = 7) has been studied as an alternative to adjuvant radiotherapy in a randomized trial conducted by the United Kingdom Medical Research Council (UKMRC)/European Organisation for Research and Treatment of Cancer (EORTC). At a median follow-up of 6.5 years, the 5-year relapse-free survival rate among the 1,477 randomized patients was 96% and 94.7% after radiation therapy and carboplatin, respectively (hazard ratio of relapse = 1.25; 90% confidence interval [CI], 0.83–1.89; 95% CI, 0.77–2.03). First-echelon retroperitoneal nodal recurrences were more common in the chemotherapy group (67% vs <10%). Retroperitoneal nodal recurrences following radiotherapy are infrequent but typically are marginal misses at the edge of the treatment field.
Further questioning the role of single-cycle carboplatin in stage I disease, a pooled analysis of two randomized trials in advanced-stage disease demonstrated that single-agent carboplatin is inferior to cisplatin-based combination therapy. Phase II results evaluating two cycles of carboplatin (400 mg/m2) for prophylactic treatment of stage I seminomas were more promising. However, acute toxicity (ie, the degree of lethargy and time missed from work) is unlikely to be less than that of a 2-week course of radiotherapy.
• Adjuvant radiotherapy vs chemotherapy vs surveillance—On the basis of surveillance data, the overall incidence of disease failure without adjuvant therapy is 15% to 20% in stage I seminoma. This means that adjuvant therapy (radiation or carboplatin) will result in overtreatment in 80% to 85% of patients. A risk-adapted strategy that uses adjuvant treatment rather than surveillance for the highest-risk group (> 4-cm primary tumor and/or rete testes involvement) has been advocated by some clinicians, but it would result in overtreatment for at least 65% of men.
In addition, radiation therapy is associated with increased risk of secondary malignancies and cardiovascular disease. Surveillance CT scans of the abdomen are not needed after adjuvant radiation therapy, since retroperitoneal relapses are rare. One cycle of single-agent carboplatin is probably slightly less effective than radiation but appears to be safe with 6.5 years of follow-up (longer follow-up data is awaited). However, surveillance CT scans of the abdomen are still required after adjuvant treatment with carboplatin.
Follow-up in patients undergoing surveillance is rigorous and intended to identify disease before tumor is bulky or supradiaphragmatic requiring chemotherapy. Disease progression usually is not associated with symptoms until the tumor burden is large. Surveillance requires abdominopelvic CT scans and chest radiographs at 4-month intervals for 3 to 4 years and then annually for at least an additional 5 years. Late failures beyond 5 years have been observed. Salvage rates reported in patients who relapse while undergoing surveillance are approximately 90% initially, with ultimate salvage rates after relapse of 99% to 100%.
Thus, in summary, stage I seminoma is a highly curable disease with a disease-specific survival of 99% to 100%. Surveillance after orchiectomy is preferred, since any adjuvant therapy will result in overtreating the majority of patients who would have been cured with surgery alone. In patients who are poor follow-up candidates or who choose adjuvant therapy, radiation therapy (20 Gy to the para-aortic region) or a single dose of carboplatin (AUC = 7) can be used.
Chemotherapy treatment with three cycles of BEP or four cycles of EP is recommended in patients with stage IIC disease and multilevel stage IIB disease.
Stage I NSGCT. The risk of relapse after radical orchiectomy is about 30%. The main risk factors are lymphovascular invasion and embryonal carcinoma predominant disease (risk up to 40% to 50%). When patients on surveillance develop recurrent disease, the cure rate is about 100%. Adjuvant RLND and chemotherapy have been used to decrease the risk of recurrence. In a randomized clinical trial, patients with clinical stage I NSGCT underwent primary RLND (n = 191) or received one cycle of BEP (n = 191). Only two recurrences occurred in the BEP arm and 15 occurred in the RLND arm. All patients are currently without evidence of recurrence. Given the excellent cure rate achieved when recurrences are found during surveillance and to avoid overtreating the majority of patients with stage I NSGCT, surveillance is preferred whenever feasible (Table 4).
• Compliance and quality of surveillance—In a study of 75 patients with stage I NSGCTs, compliance with clinical examinations was 61.5% in year 1 and 35.5% in year 2, whereas compliance with abdominal/pelvic CT was only 25% and 11.8% in years 1 and 2, respectively. Careful selection of highly motivated patients for surveillance is indicated. The quality of surveillance for stage I testicular cancer in the community was reported from private insurance claims between 2002 and 2007. Seven hundred men underwent radical orchiectomy and 279 were managed with surveillance. Compliance with surveillance follow-up protocols recommended by referral centers was poor. Nearly 30% of all surveillance patients received no abdominal imaging, chest imaging, or tumor marker tests within the first year of diagnosis.
Stage II NSGCTs. Over the past several years, the threshold for primary surgery in patients with stage II disease on CT scans has changed. At present, masses larger than 3 cm in greatest cross-sectional diameter or those with more extensive longitudinal lymphatic spread are generally handled primarily with chemotherapy. For patients with tumors that are 3 cm or smaller, primary RLND is considered a standard approach. Up to 25% of patients with enlarged lymph nodes on CT scans will have pathologic stage I (false-positive) disease by RLND. In patients with serial rising markers (serologic stage II disease), chemotherapy is the standard of treatment.
• Adjuvant chemotherapy—Following RLND, the risk of systemic recurrence is 5% to 10% in patients with pathologic stage I nonseminomas, 15% to 30% in those with completely resected stage IIA (N2a) disease, and 30% to 50% in those with stage IIB (N2b) disease. Recurrence usually occurs in the lungs within the first 24 months after surgery. The risk of retroperitoneal recurrence in patients with stage I, IIA, or IIB disease is less than 1% after a properly performed RLND. Following RLND, patients with complete resection of stage II disease can be considered candidates for adjuvant chemotherapy.
The decision of whether or not to prescribe adjuvant chemotherapy following lymph node dissection is somewhat arbitrary and often depends on the patient's social circumstances and likelihood of adhering to close follow-up. A patient with completely resected carcinoma who undergoes RLND has a 70% chance of cure; thus, the majority of patients will never need chemotherapy. However, these patients must be monitored carefully with chest radiography and serum marker determinations every 2 months for 1 year, every 4 months for an additional year, and then every 6 months for the next 3 years. (CT scanning is not performed routinely unless clinically indicated, such as resection of teratoma.) The 30% of patients followed in such a manner who do develop recurrence will present with a tumor of low volume (eg, small pulmonary metastases or elevated serum markers); nearly 100% of these patients should be cured with appropriate systemic therapy.
However, some patients with resected stage II disease elect to receive adjuvant chemotherapy to minimize the risk of cancer recurrence. For such therapy, two cycles of BEP are recommended (Table 5). In a patient who agrees to close follow-up, the chance of dying of cancer should be negligible in either scenario. For patients who have persistently elevated or increasing serum markers following RLND or who have undergone incomplete lymph node dissection, three cycles of BEP are indicated.
