Overview
An estimated 8590 new cases of testicular cancer will be diagnosed in the United States in 2012.1 Germ cell tumors (GCTs) constitute 95% of malignant tumors arising in the testes. These tumors also occur occasionally in extragonadal primary sites, but they are still managed the same as testicular GCTs. Although GCTs are uncommon tumors that constitute only 2% of all human malignancies, they are the most common solid tumor in men between 15 and 34 years of age. In addition, the worldwide incidence of these tumors has more than doubled in the past 40 years.
Several risk factors for GCT development have been identified, including history of a GCT, positive family history, cryptorchidism, testicular dysgenesis,
NCCN Clinical Practice Guidelines in Oncology for Testicular Cancer
NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. and Klinefelter syndrome. GCTs are classified as seminoma or nonseminoma. Nonseminomatous tumors often include multiple cell types, including embryonal cell carcinoma, choriocarcinoma, yolk sac tumor, and teratoma. Teratomas are considered to be either mature or immature, depending on whether adult-type differential cell types or partial somatic differentiation, similar to that present in the fetus, is found. Rarely, a teratoma histologically resembles a somatic cancer, such as sarcoma or adenocarcinoma, and is then referred to as a teratoma with malignant transformation.
The serum tumor markers alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and β-human chorionic gonadotropin (β-HCG) are critical in diagnosing GCTs, determining prognosis, and assessing treatment outcome. These should be determined before, during, and after treatment and throughout the follow-up period. Serum tumor markers are useful for monitoring all stages of nonseminomas. They are also useful in monitoring metastatic seminomas, because elevated marker levels is the early sign of relapse.
LDH is a less-specific marker than AFP and β-HCG. AFP is a serum tumor marker produced by nonseminomatous cells (embryonal carcinoma, yolk-sac tumor) and may be seen at any stage. The approximate half-life of AFP is 5 to 7 days. A non-seminoma, therefore, is associated with elevated serum concentrations of AFP. When patients with a histologically “pure” testicular seminoma have an elevated level of AFP, it is generally assumed that an undetected focus of nonseminoma is present.2,3 An elevated serum concentration of β-HCG, which has a half-life of approximately 1 to 3 days, may also be present with seminomatous and nonseminomatous tumors. The elevations of β-HCG must be interpreted with caution, because hypogonadism and marijuana use may cause benign serum elevations of β-HCG.
NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer Version 1:2012
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Nonseminoma is the more clinically aggressive tumor. When both seminoma and elements of a non-seminoma are present, management follows that for a nonseminoma. Therefore, the diagnosis of a seminoma is restricted to pure seminoma histology and a normal serum concentration of AFP.
More than 90% of patients diagnosed with GCTs are cured, including 70% to 80% with advanced tumors who are treated with chemotherapy. A delay in diagnosis correlates with a higher stage at presentation. Standard therapy has been established at essentially all stages of management and must be closely followed to ensure the potential for cure.
Clinical Presentation
A painless solid testicular mass is pathognomonic for testicular tumor. More often, patients present with testicular discomfort or swelling suggestive of epididymitis or orchitis. A trial of antibiotics may be given in this circumstance, but persistent tenderness, swelling, or any palpable abnormality warrants further evaluation.
Diagnosis and Workup
If an intratesticular mass is identified, complete blood count, creatinine, electrolytes, and liver enzymes should be obtained. Further evaluation includes measurement of serum tumor markers and a chest radiograph. Testicular ultrasound serves to confirm the presence of a testicular mass and to explore the contralateral testis; it is sensitive and has an important role in determining whether a mass is intra- or extratesticular.4
Serum tumor markers are critical in assignment of prognosis and also management during treatment. Serum tumor markers are prognostic factors and contribute to diagnosis and staging.5 Markers are assessed before orchiectomy and repeated after orchiectomy. Elevated values of β-HCG, LDH, or AFP should be followed up with repeated tests to allow precise staging.
Biopsy may also be considered if a suspicious intratesticular abnormality, such as a hypoechoic mass or macrocalcification, is identified on ultrasound. In contrast, if microcalcifications without any other abnormality can be observed, testicular biopsy is not necessary.
In patients of reproductive age, sperm banking must be discussed.6,7 It must be discussed with the patients before undergoing any therapeutic intervention that may compromise fertility, including surgery, radiation therapy, and chemotherapy.8–10 If sperm banking is desired, it may be performed either before or after orchiectomy, but certainly before subsequent therapy.
Inguinal orchiectomy is considered the primary treatment for most patients who present with a suspicious testicular mass.11 An open inguinal biopsy of the contralateral testis is not routinely performed, but can be considered when a cryptorchid testis or marked atrophy is present.12 The extent of primary tumor is classified after orchiectomy, and therefore pathological (p) stage is assigned to the primary tumor (T).
Further management is dictated by histology, a diagnosis of pure seminoma or nonseminoma (includes mixed seminoma tumors and seminoma histology with elevated AFP), and the stage. Although rare, when a patient presents with rapidly increasing β-HCG, symptoms related to disseminated disease, and a testicular mass, chemotherapy can be initiated immediately without waiting for a biopsy diagnosis.
Risk Classification for Advanced Disease
In 1997, the International Germ Cell Cancer Consensus Group (IGCCCG) defined a prognostic factor–based classification system based on identification of some clinically independent prognostic features, such as extent of disease and levels of serum tumor markers postorchiectomy. Postorchiectomy markers are used to classify the patient according to the IGCCCG risk classification. This classification categorizes patients with pure seminoma and non-seminoma GCT into good-, intermediate-, or poor-risk groups.13
Stage and risk classification are assigned according to the American Joint Committee on Cancer (AJCC) and IGCCCG classification.
Pure Seminoma
If a GCT is found, an abdominopelvic CT scan is performed. Abdominopelvic CT scanning is used to assess the retroperitoneal nodes.14 A chest CT is indicated if the abdominopelvic CT shows retroperitoneal adenopathy or the chest radiograph shows abnormal results. A chest CT scan is a sensitive way to evaluate the thorax and mediastinal nodes.15
The panel members recommend a brain MRI or bone scan only if metastases to these organs is suspected.
Elevated values of β-HCG, LDH, or AFP should be followed up with repeated tests. Serum concentrations of β-HCG and LDH may be elevated in patients with seminoma. An elevated AFP level indicates nonseminoma, and patients should be managed accordingly. Initial management of pure seminoma involves a radical inguinal orchiectomy. Orchiectomy is both diagnostic and therapeutic. Patients with seminoma arising from an extragonadal site, such as the mediastinum, are treated with standard chemotherapy regimens according to risk status.
Pure Seminoma Stages IA and IB
Primary Treatment for Pure Seminoma Stages IA and IB: For patients with stages IA and IB pure seminoma, the standard treatment options after initial orchiectomy include surveillance, radiotherapy, or chemotherapy with 1 or 2 cycles of carboplatin. The disease-specific survival for stage I disease is 99%, irrespective of the management strategy used.16 Several prospective nonrandomized studies of surveillance have been conducted.17–20 The relapse rate seen in these studies is 15% to 20% at 5 years, and most of the relapses are first detected in infradiaphragmatic lymph nodes.18–20 Some studies report tumor size greater than 4 cm and rete testis invasion as risk factors for relapse.19,21,22 However, a validation study by Chung et al.23,24 showed that tumor size greater than 4 cm and rete testis invasion were not predictors of relapse. Therefore, the panel members discourage risk-adapted management based on tumor size greater than 4 cm and rete testis invasion for stage I pure seminoma. Surveillance is listed as the preferred option (category 1) for patients with pT1 and pT2 disease.
If surveillance is not applicable, alternatives are either adjuvant carboplatin or adjuvant radiotherapy, as described later. Each approach has distinct advantages and disadvantages. The physicians should discuss these with the patients and their families and pick the best approach on a case-by-case basis.
Oliver et al.25 reported on the results of a trial that randomized 1477 patients with stage I testicular cancer to undergo either radiotherapy or one injection of carboplatin. In the study, carboplatin (area under the cure [AUC] × 7) was administered intravenously. The dose was calculated by the formula 7 × (glomerular filtration rate [GFR, mL/min] + 25 mg). With a median follow-up of 4 years, the relapse-free survival rates were similar for both groups.25 Late relapses and secondary GCTs can occur beyond 5 and 10 years. Therefore, the investigators continued to follow these patients. The updated results reported noninferiority of single-dose carboplatin versus radiation therapy.26 In an intent-to-treat analysis, the relapse-free rates at 5 years were 94.7% for the carboplatin arm and 96% for the radiotherapy arm (hazard ratio, 1.25; P = .37). Two cases of contralateral GCTs were seen in the carboplatin arm versus 15 in the radiation therapy arm, with hazard ratio of 0.22; the contralateral GCT-free rates at 5 years are 99.8% and 98.8%, respectively. The authors concluded that a single dose of carboplatin is less toxic and as effective in preventing disease recurrence as adjuvant radiotherapy in men with stage I pure seminoma after orchiectomy.26 Two courses of adjuvant carboplatin have also been reported to reduce the relapse rate.27 The panel recommends either 1 or 2 cycles of carboplatin AUC × 7 as a category 1 recommendation for patients with stages IA and IB pure seminoma.
If radiation therapy is delivered, the panel recommends a total dose of 20 Gy (midplane) in 10 daily 2.0-Gy fractions,28 given to an infradiaphragmatic area, including para-aortic lymph nodes; in special circumstances, this area may include the ipsilateral ilioinguinal nodes.29–32 Patients for whom radiation therapy is generally not given include those at higher risk for morbidity from radiation therapy, such as those with a history of pelvic surgery. Prophylaxis to the mediastinum is not provided, because relapse rarely occurs at this site. For patients with stages IA and IB pure seminoma, adjuvant radiation therapy to include the para-aortic nodes is also a category 1 recommendation, although active surveillance is preferred (see Principles of Radiotherapy for Pure Testicular Seminoma, pages 513–516).
Follow-Up After Primary Treatment for Pure Seminoma Stages IA and IB: For follow-up, the different risk of recurrence associated with each treatment modality is important to distinguish (surveillance vs. adjuvant therapy). An analysis of more than 5000 patients with stage I seminoma from various trials showed that, independent of the treatment modality, the risk of recurrence is highest in the first 2 years and decreases after that.33
Follow-up during surveillance includes a history and physical, with measurement of postorchiectomy serum tumor markers (AFP, β-HCG, and LDH), performed every 3 to 4 months for 1 to 2 years, every 6 to 12 months for years 3 to 4, and annually thereafter.34, 35
Controversy exists regarding how many imaging studies must be performed in patients on active surveillance. The panel recommends abdominal/pelvic CT every 6 months for years 1 to 2, every 6 to 12 months for year 3, and then annually for years 4 to 5. The most common site of relapse in patients managed with surveillance or adjuvant chemotherapy is the retroperitoneal nodes. Chest radiographs may be obtained as clinically indicated for years 1 to 5. The clinical trial TRISST (MRC TE24/Trial of Imaging and Schedule in Seminoma Testis) in the United Kingdom is currently studying whether a reduced CT schedule or MRI could be used as a safe and effective alternative to standard CT-based surveillance in the management of stage I seminoma.36
The risk of recurrence 5 years after adjuvant treatment is less than 0.3% annually.33 Follow-up of patients treated with carboplatin includes a history and physical, with measurement of post orchiectomy serum tumor markers (AFP, β-HCG, and LDH) performed every 3 months the first year, every 4 months the second year, every 6 months the third year, and annually thereafter.
The panel recommends abdominal/pelvic CT annually for the first 3 years after radiotherapy or carboplatin. In a recently published meta-analysis of 2466 patients, Mead et al.16 reported that recurrence rarely occurred after more than 3 years from treatment with either radiotherapy or carboplatin. Relapse occurred after 3 years only in 4 of the 2466 patients (0.2%).16 They recommend that CT scans of the pelvis and chest can be omitted in these patients as part of routine follow-up. The panel recommends that chest radiographs be obtained only as clinically indicated.
Follow-up of patients treated with radiotherapy includes a history and physical, with measurement of postorchiectomy serum tumor markers (AFP, β-HCG, and LDH). Follow-up should be performed every 4 months for 1 to 2 years, and then annually for 3 to 10 years.33 Para-aortic radiation therapy is recommended when patients with stage I seminoma are irradiated (see pages 513–516). Patients treated with para-aortic radiation therapy have a slightly higher rate of pelvic relapse than those treated with “dog-leg” radiograph.30,33,37,38 Some NCCN Member Institutions obtain a CT scan of the pelvis only every 6 months for 3 years after para-aortic radiotherapy.33 Others obtain CT scans of the pelvis and abdomen annually for 3 years.30 The panel’s consensus recommendation is for abdominal and pelvic CT scans annually for 3 years in patients treated with para-aortic radiotherapy. Chest radiographs should be obtained only when clinically indicated. Recurrences are treated according to the stage at relapse.16
Pure Seminoma Stage IS
Primary Treatment for Pure Seminoma Stage IS: According to the AJCC definition, stage IS requires persistent elevation of serum tumor markers (LDH, AFP, and β-HCG) after orchiectomy. Stage IS is uncommon and patients are generally treated with radiation to an infradiaphragmatic area, including para-aortic lymph nodes with or without radiation to the ipsilateral ilioinguinal nodes.30–32
Follow-Up After Primary Radiation Treatment for Pure Seminoma Stage IS: Follow-up recommendations by the panel for patients with stage IS treated with adjuvant radiation therapy are similar to those for patients with stages IA and IB treated with adjuvant radiation therapy. Recurrences are treated according to the stage at relapse.
Pure Seminoma Stages IIA and IIB
Primary Treatment for Pure Seminoma Stages IIA and IIB: Stage IIA is defined as metastatic disease to lymph nodes, with a lymph node mass measuring less than 2 cm in diameter in greatest dimension on CT scan, whereas stage IIB is disease measuring 2 to 5 cm in maximum diameter.
Radiotherapy has been the mainstay of treatment in patients with stage IIA and IIB seminoma.39–41 The standard radiation field compared with stage I is extended from the para-aortic region to include an ipsilateral iliac field. The relapse rates are moderate (5%–6% for stage IIA) and overall survival is almost 100%.39,41,42
For patients with stage IIA or IIB seminoma, the panel recommends radiation therapy to an infradiaphragmatic area, including para-aortic and ipsilateral iliac lymph nodes in 2 anteroposterior–posteroanterior phases. The initial phase consists of radiation to modified dog-leg fields at a dose of 20 Gy (midplane) in 10 daily 2.0-Gy fractions29 or 25.5 Gy in 15 daily 1.7-Gy fractions.43 The panel prefers modified ‘dog-leg’ fields as described by Classen et al.39 For details on field arrangement, see pages 513–516. The second phase (cone down) of radiotherapy consists of daily 2.0-Gy fractions to a cumulative total dose of approximately 30 Gy for stage IIA and 36 Gy for stage IIB.39 As with the management of stage I disease, prophylactic mediastinal radiation therapy is not indicated for stage II disease.44
For selected patients with stage IIB seminoma, such as those with adenopathy measuring more than 3 cm,45 chemotherapy with 4 courses of etoposide and cisplatin (EP) or 3 cycles of bleomycin, etoposide, and cisplatin (BEP) is an alternative to radiotherapy.42,46
Follow-Up for Stages IIA and IIB Pure Seminoma After Primary Treatment: The recommended follow-up schedules for patients with stage IIA/B seminoma after radiation therapy include a history and physical, with measurement of postorchiectomy serum tumor markers (AFP, β-HCG, and LDH) performed every 3 months for year 1, every 6 months for years 2 to 5, and then annually for years 6 to 10.
Chest radiograph is recommended every 6 months for the first 2 years. An abdominal CT scan is recommended every 6 months in years 1 to 2 and annually in year 3 after radiotherapy. In patients who have undergone retroperitoneal lymph node dissection (RPLND), it is recommended between 3 to 6 months postsurgery and then as clinically indicated.39
The follow-up of patients with stage IIB seminoma after chemotherapy is similar to follow-up after chemotherapy for patients with stages IIC and III seminoma, as discussed in Follow-Up for Pure Seminoma Stages IIB, IIC, and III After Chemotherapy on page 525.
Pure Seminoma Stages IIC and III
Primary Treatment for Pure Seminoma Stages IIC and III: Patients with stage IIC or III disease are those considered at either good or intermediate risk. All stage IIC and stage III seminoma is considered good-risk disease, except for stage III disease with nonpulmonary visceral metastases (e.g., bone, liver, brain), which is considered intermediate-risk. Standard chemotherapy is used for both groups of patients. However, for patients with good risk, 3 cycles of BEP47–49 or 4 cycles of EP50–52 are recommended. In contrast, more intensive chemotherapy (i.e., 4 cycles of BEP) is recommended for those with intermediate-risk disease.53,54 All of these chemotherapy options are category 1 recommendations according to the panel.
Postchemotherapy Management of Pure Seminoma Stages IIB, IIC, and III: After initial chemotherapy, patients with stage IIB, IIC, and III disease are evaluated with serum tumor markers and a CT scan of the chest abdomen and pelvis. Patients are then classified according to the presence or absence of a residual mass and the status of serum tumor markers. Patients with normal markers and either no residual mass or residual mass of 3 cm or less need no further treatment. They should undergo surveillance, as discussed in Follow-Up for Pure Seminoma Stages IIB, IIC, and III After Chemotherapy, on page 525.
In cases of residual tumor larger than 3 cm and marker levels that are normal, a PET scan is recommended to assess whether residual viable tumor is present.55 A PET scan has high positive and negative predictive values with regard to the question of remaining disease in patients with residual masses after chemotherapy.56 To reduce the incidence of false-positive results, the PET scan is typically performed at least 6 weeks after completion of chemotherapy. Notably, granulomatous disease, such as sarcoid, is a source of false-positive results. The panel recommends a PET scan in patients with seminoma, a residual mass larger than 3 cm, and normal levels of markers, approximately 6 weeks after chemotherapy to determine whether to continue with surveillance or resume treatment.55,57–61
If the PET scan is negative, no further treatment is needed; however, the patient should undergo follow-up,62,63 as discussed in the next section on Follow-Up for Pure Seminoma Stages IIB, IIC, and III After Chemotherapy.
Because a positive PET scan is a strong indicator of residual active tumor, resection should be considered. Therefore, if technically feasible, RPLND may be considered (category 2A). The other option, if resection is not feasible, is second-line chemotherapy (category 2A). Cisplatin-based combination chemotherapy is used for second-line treatment.64–66 The regimens are 4 cycles of TIP (paclitaxel, ifosfamide, cisplatin)67 or 4 cycles of VeIP (vinblastine, ifosfamide, cisplatin).65,66
According to these NCCN Guidelines, second-line therapy for seminoma and nonseminoma is similar. This is discussed in Second-Line Therapy for Metastatic GCTs, on page 528. The follow-up of these patients is also described later.
Follow-Up for Pure Seminoma Stages IIB, IIC, and III After Chemotherapy: Recommended follow-up schedules include a history and physical with chest radiograph and measurement of postorchiectomy serum tumor markers every 2 months for the first year, every 3 months for the second year, every 6 months for the third and fourth years, and annually thereafter through the tenth year. An abdominal/pelvic CT scan is recommended as clinically indicated in all patients, except those who have undergone RPLND, in whom it is recommended between 3 and 6 months postsurgery and then as clinically indicated.68 A PET scan may be performed as clinically indicated.
Nonseminoma
Similar to the workup for seminoma, if nonseminoma is found, CT of the abdomen and pelvis should be performed with chest imaging if needed. MRI of the brain and a bone scan should be conducted in the case of clinical indicators (symptoms) of involvement. PET scanning does not contribute and routine use is not recommended for patients with nonseminoma.69,70
Elevated values of β-HCG, LDH, or AFP should be followed up with repeated tests. Nonseminoma includes mixed seminoma tumors and seminoma histology with elevated AFP. Postorchiectomy serum markers are important for classifying patients with nonseminoma into good-, intermediate- and poor-risk groups according to the IGCCCG risk classification.13
In patients of reproductive age, sperm banking must be discussed6,7 before any therapeutic intervention is performed that may compromise fertility, including surgery, radiation therapy, or chemotherapy.8–10 If sperm banking is desired, it may be performed either before or after orchiectomy, but certainly before adjuvant therapy.
Stage-dependent treatment options after inguinal orchiectomy include surveillance, chemotherapy, and RPLND. Although the timing of the RPLND may vary, most patients with nonseminoma will undergo an RPLND for either diagnostic or therapeutic purposes at some point during treatment. The major morbidity associated with bilateral dissection is retrograde ejaculation, resulting in infertility. Nerve dissection techniques preserve antegrade ejaculation in 90% of cases.71
Nonseminoma Stage IA
Primary Treatment of Nonseminoma Stage IA: According to the panel, 2 management options exist for patients with stage IA disease after orchiectomy: surveillance72–76 and nerve-sparing RPLND. The cure rate with either approach exceeds 95%, although with surveillance, this depends on adherence to periodic follow-up examinations and subsequent chemotherapy for the 20% to 30% of patients who experience relapse. Patients who choose surveillance should agree to be compliant with follow-up. RPLND should be performed using a nerve-sparing technique.77,78 According to these guidelines, the nerve-sparing RPLND is recommended within 4 weeks of a CT scan and within 7 to 10 days of repeat serum marker testing to ensure accurate presurgical staging.
Management of Nonseminoma Stage IA After RPLND: After RPLND, if the dissected lymph nodes are not involved with a tumor (pN0), no adjuvant chemotherapy is given and the patients should undergo surveillance. However, if the resected lymph nodes involve tumor, the decision whether to use adjuvant chemotherapy is based on the degree of nodal involvement. Surveillance is preferred over chemotherapy for patients with pN1 disease. Chemotherapy is preferred in patients with pN2 or pN3 disease. Surveillance is an option for patients with pN2 but not for those with pN3 disease. Recommended chemotherapy regimens include either EP or BEP. Two cycles of either regimen (EP or BEP) are recommended for patients with pN1 or pN2 disease.79–85 For patients with pN3 disease, longer courses of chemotherapy with 4 cycles of EP or 3 cycles of BEP is recommended.
Follow-Up for Nonseminoma Stage IA: In the current guidelines, the long-term follow-up tests for patients with stage IA disease electing primary surveillance or who have undergone RPLND or chemotherapy include serum marker assessment, chest radiograph, and an abdominal CT scan. The frequency of these tests is outlined in Follow-Up for Nonseminoma, page 511.
Nonseminoma Stage IB
Primary Treatment of Nonseminoma Stage IB: After orchiectomy, either nerve-sparing RPLND or adjuvant chemotherapy is an option to reduce the risk of relapse in patients with stage IB disease.
Several studies using 2 cycles of BEP as primary treatment for patients with stage I nonseminoma have reported relapse-free survival in more than 95% of patients,76,82,86–90 leading the panel to consider this approach a category 2A recommendation. Late consequences of cisplatin-based chemotherapy have been reported based on long-term follow-up of patients.91–96 A trial by Albers et al.97 randomized patients with stage I disease after orchiectomy to undergo unilateral RPLND (n = 191) or one adjuvant course of BEP (n = 191). After a median follow-up of 4.7 years, 2 relapses were reported in the group of patients treated with one course of adjuvant BEP and in 13 patients with relapse in the arm treated with RPLND (P =.0011). This study indicates that one course of BEP is active, and could be an option in patients unable to tolerate the toxicity of treatment. The comparator arm in this trial (unilateral RPLND) is not the standard treatment approach. Therefore, although the results of this study are promising, this approach merits further investigation comparing 1 cycle of BEP versus 2 cycles with longer follow-up. The panel considers 1 cycle of BEP a category 2B option as primary therapy.
Surveillance alone may be offered to selected patients with T2 disease (category 2B). Vascular invasion is a significant predictor of relapse when orchiectomy is followed by surveillance alone.11 Surveillance is generally not recommended for T2 disease with vascular invasion because of the 50% chance of relapse. Exceptions are made according to individual circumstances. When surveillance is opted in selected patients with T2 disease, both the patient and physician must be compliant with follow-up recommendations.
Management of Nonseminoma Stage IB After Primary Treatment: The adjuvant treatment after primary nerve-sparing RPLND for patients with IB disease is similar to that described for stage IA in Management of Nonseminoma Stage IA After RPLND, page 525.
Management after primary chemotherapy in patients with normal values of serum tumor markers may be nerve-sparing RPLND or surveillance. The panel considers nerve-sparing bilateral RPLND a category 2A recommendation for patients with residual mass of 1 cm or greater and a category 2B recommendation if the residual mass is smaller than 1 cm. Surveillance is category 2B for both populations. In the current guidelines, the long-term follow-up tests for patients electing surveillance include serum marker assessment, chest radiograph, and abdominal CT scan. The frequency of these tests is outlined in Follow-Up for Nonseminoma, on page 511.
Nonseminoma Stage IS
Patients with stage IS disease exhibit a persistent elevation of serum tumor markers postorchiectomy but no radiographic evidence of disease. The elevated levels of AFP and β-HCG after orchiectomy must be interpreted with caution, because these may be from causes other than disseminated nonseminoma, such as hepatobiliary disease, marijuana use, and hypogonadism.
Primary Treatment of Nonseminoma Stage IS: The panel consensus recommendation is that these patients be treated with standard chemotherapy with either 4 cycles of EP or 3 cycles of BEP. Either regimen is preferable to initial RPLND, because these patients nearly always have disseminated disease.98,99
Management of Stage IS Nonseminoma Postprimary Treatment: The management of patients with stage IS nonseminoma after primary treatment with chemotherapy is similar to the management schema outlined for patients with good-risk nonseminoma, including stages IIB, IIC, and IIIA, described in the following sections.
Nonseminoma Stage IIA
Primary Treatment of Nonseminoma Stage IIA: Treatment for patients with stage IIA nonseminoma depends on postorchiectomy serum tumor marker levels.
For patients with stage IIA disease and normal postorchiectomy levels of AFP and β-HCG, the panel considers either primary RPLND (category 2A) or chemotherapy (category 2B) as treatment options.100–104 The chemotherapy regimens include 4 cycles of EP or 3 cycles of BEP. Chemotherapy is considered particularly appropriate if the patient has multifocal disease.
For patients with persistently elevated AFP or β-HCG levels, the panel recommends induction chemotherapy, based on data from 2 retrospective studies of patients with low-stage nonseminoma treated with RPLND.105,106 The presence of elevated postorchiectomy AFP or β-HCG levels was associated with a high risk of relapse.105,106
Management after primary chemotherapy and RPLND is discussed in the following sections.
Management After Primary Treatment of Nonseminoma Stage IIA: After primary chemotherapy, subsequent management depends on marker levels and the residual mass on CT scan. Therefore, patients must undergo a CT scan before treatment is decided. Lesions smaller than 1 cm on CT scan may represent false-positives and must be interpreted with caution. The options listed by the panel for managing patients with stage IIA disease after primary chemotherapy include nerve-sparing bilateral RPLND or surveillance.
The panel considers nerve-sparing bilateral RPLND a category 2A recommendation for patients with a residual mass of 1 cm or greater, and a category 2B recommendation if the residual mass is less than 1 cm. A bilateral RPLND involves removal of lymphatic tissue between both ureters, spanning from the diaphragmatic crus to the bifurcation of the common iliac arteries. The rationale for this extended region of dissection is the greater likelihood of bilateral disease with greater tumor burden.107 Referral to high-volume centers must be considered for RPLND postchemotherapy. Surveillance, however, is a category 2B recommendation for both populations.
After primary nerve-sparing RPLND, treatment options include either surveillance or chemotherapy. The treatment choice depends on the number of positive lymph nodes identified. For example, because RPLND is likely a curative procedure in patients with pathologic stage N0 (pN0), surveillance is the only option listed for this group. Surveillance and chemotherapy are options for patients with pN1 and pN2 disease. RPLND is a curative procedure in 60% to 90% of patients with pN1 disease,106,108,109 and therefore the panel prefers surveillance over chemotherapy for these patients. The risk of relapse in patients with pN2 through pN3 disease is greater than 50%.106,108,110 With 2 cycles of adjuvant cisplatin-based chemotherapy, the risk of relapse after RPLND is generally less than 1%.106,111,112 The panel prefers 2 cycles of adjuvant chemotherapy for pN2 disease, and full-course chemotherapy (not surveillance) is recommended for pN3 disease. Recommended adjuvant chemotherapy regimens for pN1 and pN2 disease consists of 2 cycles of either BEP or EP,113 resulting in a relapse-free survival rate of nearly 100%. For pN3, the panel recommends a longer chemotherapy course consisting of either 4 cycles of EP or 3 cycles of BEP.
If patients with stage IIA disease have persistent marker elevation (i.e., stage IIA, S1), the primary treatment is chemotherapy as described later for good-risk nonseminoma.
Nonseminoma Stage IIB
Primary Treatment of Nonseminoma Stage IIB: Treatment for patients with stage IIB nonseminoma depends also on both postorchiectomy tumor marker levels and radiographic findings. When tumor markers are negative, the CT findings determine the proper course of treatment. If abnormal radiographic findings are limited to sites within the lymphatic drainage in the retroperitoneum (i.e., the landing zone), 2 management options are available. One option is to perform nerve-sparing RPLND and consider adjuvant treatment as described for patients with stage IIA disease. The second option is to treat with primary chemotherapy involving either 4 cycles of EP or 3 cycles of BEP, followed by nerve-sparing RPLND or surveillance.
Both options of primary chemotherapy or primary RPLND are comparable options in terms of outcome, but side effects and toxicity are different.101 The reported relapse-free survival with either approach is close to 98%.108,113–118
If metastatic disease (based on radiographic findings) is not confined to the lymphatic drainage (i.e., multifocal lymph node metastases outside the lymphatic drainage sites), chemotherapy is recommended with either 4 cycles of EP or 3 cycles of BEP, followed by nerve-sparing RPLND or surveillance.
For patients with stage IIB disease with persistent marker elevation (stage IIB, S1), the primary treatment is chemotherapy as described for good-risk nonseminoma, including stages IS, IIC, and IIIA in later sections. Initial RPLND is not recommended in this situation.
Management After Primary Treatment of Nonseminoma Stage IIB: The management of patients with stage IIB nonseminoma after primary treatment with either nerve-sparing bilateral RPLND or chemotherapy is similar to the management scheme outlined earlier for patients with stage IIA nonseminoma after primary treatment.
Advanced Metastatic Nonseminoma
The preferred primary chemotherapy regimens for patients with advanced disease depends on the IGCCCG risk classification.13 This classification categorizes patients as good-, intermediate-, or poor-risk.13 Also, patients with an extragonadal primary site, whether retroperitoneal or mediastinal, are treated with initial chemotherapy.
Primary Treatment of Good-Risk Nonseminoma: Based on the IGCCCG good-risk classification, this group includes patients with stages IS; IIA and IIB (with persistent marker elevation); IIC; and IIIA disease. Treatment for good-risk GCTs were designed to decrease toxicity while maintaining maximal efficacy. Randomized clinical trials showed that this can be achieved through either substituting etoposide for vinblastine,119,120 or eliminating or reducing the dose of bleomycin.119,121 Currently, 2 regimens are recommended by the panel: 4 cycles of EP51 or 3 cycles of BEP47,49,122,123 (both category 2A). Either regimen is well tolerated and cures approximately 90% of patients with good risk.124
Primary Treatment of Intermediate-Risk (Stage IIIB) Nonseminoma: For patients with intermediate risk (stage IIIB), the cure rate is approximately 70% with standard therapy using 4 cycles of BEP,125,126 and this is a category 2A recommendation by the panel.
Primary Treatment of Poor-Risk (Stage IIIC) Non-seminoma: Between 20% and 30% of all patients with poor-risk, (stage IIIC) metastatic GCTs are not cured with conventional cisplatin therapy, and fewer than one-half experience a durable complete response with 4 cycles of BEP, and therefore the panel lists treatment in a clinical trial as the preferred option.124
The standard chemotherapy regimen for poor-risk patients is 4 cycles of BEP. The regimen containing etoposide, ifosfamide, and cisplatin (VIP) was compared with BEP and found to be more toxic than BEP but equally as effective. Therefore, 4 cycles of VIP may be used for patients who may not tolerate bleomycin.127
Postchemotherapy Management for Good-, Intermediate-, and Poor-Risk Nonseminoma: At the conclusion of induction chemotherapy, CT scans of the abdomen and pelvis are indicated, along with serum tumor marker assays. PET scans for residual disease have limited predictive value. The frequency of these tests is outlined in Follow-Up for Nonseminoma, on page 511.
If a complete response to chemotherapy is found through radiographic imaging and the tumor markers are negative, the panel lists 2 management options: surveillance (category 2B) or bilateral RPLND using nerve-sparing technique, if possible (category 2B).63
If a residual mass is found and the serum tumor markers (AFP and β-HCG) have normalized, then all sites of residual disease are resected.128–130 If only necrotic debris or mature teratoma is encountered, no further therapy is necessary and patients must be put under surveillance. If embryonal, yolk sac, choriocarcinoma, or seminoma elements are found in the residual mass, 2 cycles of conventionally dosed chemotherapy (EP, VelP, or TIP) are administered.
After patients are rendered disease-free, standard surveillance is initiated. The frequency of these follow-up tests is outlined in Follow-Up for Nonseminoma, on page 511.
Patients who experience an incomplete response to first-line therapy are treated with second-line therapy (see following section). The panel prefers that patients with recurrent nonseminoma be treated at centers with expertise in the management of this disease.
Second-Line Therapy for Metastatic GCTs
Patients who do not experience a durable complete response to first-line therapy or those who experience a recurrence can be divided into those with a favorable or unfavorable prognosis based on prognostic factors. Prognostic factors can be used in deciding whether a patient is a candidate for conventional-dose therapy or high-dose therapy with stem cell support as a second-line option. To determine the prognosis at initial diagnosis, the IGCCCG classification is used. However, for patients with progressive or relapsed disease after first-line treatment, several prognostic models have been reported.131–133
Favorable prognostic factors for conventional-dose second-line chemotherapy include a testicular primary site, prior complete response to first-line therapy, low levels of postorchiectomy serum tumor markers, and low-volume disease.131 Standard second-line therapy includes conventional-dose chemotherapy or high-dose chemotherapy. The conventional-dose regimen includes cisplatin and ifosfamide combined with either vinblastine or paclitaxel.134 In patients who experience an incomplete response or disease relapse after second-line conventional-dose chemotherapy, the preferred third-line option would be high-dose chemotherapy135,136 or chemotherapy in the context of a clinical trial.
Unfavorable prognostic features include incomplete response to first-line treatment, high levels of serum markers, high-volume disease, and presence of an extratesticular primary tumor. Patients with a testicular primary site and rising postorchiectomy serum tumor markers during first-line therapy are usually considered for high-dose programs. Chemotherapy options for patients with poor prognostic features include chemotherapy in the context of a clinical trial, conventional-dose second-line therapy (with VeIP or TIP), or high-dose chemotherapy (category 2B). Alternatively, patients may undergo best supportive care or salvage surgery if feasible.
The high-dose regimens include high-dose carboplatin plus etoposide followed by autologous stem cell transplant132,137 or paclitaxel plus ifosfamide followed by high-dose carboplatin plus etoposide with stem cell support (see Second-Line or Subsequent Chemotherapy Regimens for Metastatic Germ Cell Tumors, page 519).138
For patients who do not experience complete response to second-line, high-dose therapy, the disease is nearly always incurable; the only exception is the rare patient with elevated serum tumor markers and a solitary site of metastasis (usually retroperitoneal) that undergoes surgical resection.139 Other options are participation in a clinical trial or best supportive care.
Palliative Therapy
All patients with either persistent or recurrent disease should be considered for palliative chemotherapy or radiation therapy.
Palliative chemotherapy options for patients with intensively pretreated, cisplatin-resistant, or refractory GCTs are combinations of gemcitabine and paclitaxel and/or oxaliplatin.140–145
The recommendation for gemcitabine and oxaliplatin is based on data from phase II studies140–142 that investigated the efficacy and toxicity of gemcitabine and oxaliplatin in patients with relapsed or cisplatin-refractory GCTs. The results showed that the oxaliplatin and gemcitabine combination is safe for patients with cisplatin-refractory testicular GCTs, and may offer a chance of long-term survival.140–142
Gemcitabine and paclitaxel is another option that has shown promising results in a phase II study,144 and long-term follow-up results with this combination show long disease-free survival in rare patients who experienced progression after high-dose chemotherapy and had not received prior paclitaxel or gemcitabine.145
Furthermore, a phase II study of patients with treatment-refractory GCTs found the combination of gemcitabine, oxaliplatin, and paclitaxel to be effective, with acceptable toxicity.143
Therefore, for palliative therapy, the panel recommends gemcitabine with oxaliplatin140–142; gemcitabine with paclitaxel144,145; or gemcitabine with oxaliplatin and paclitaxel143 (all are category 2A recommendations).
Treatment of Brain Metastases
The prognosis of patients with brain metastasis is poor.146 Primary chemotherapy (using a cisplatin-based regimen) with radiotherapy is indicated for patients in whom brain metastases are detected.147,148 If clinically indicated and feasible, surgical resection of the metastasis should also be performed.
Individual Disclosures of the NCCN Testicular Cancer Panel
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