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.

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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.810 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.1720 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.1820 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.2932 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.3032

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.3941 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 BEP4749 or 4 cycles of EP5052 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.55,5761

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.6466 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.810 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: surveillance7276 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.7985 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,76,82,8690 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.9196 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.100104 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%.108,113118

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.128130 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.131133

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.140145

The recommendation for gemcitabine and oxaliplatin is based on data from phase II studies140142 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.140142

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 oxaliplatin140142; 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

T1

References

  • 1

    SiegelRNaishadhamDJemalA. Cancer statistics, 2012. CA Cancer J Clin2012;62:1029.

  • 2

    NazeerTRoJYAmatoRJ. Histologically pure seminoma with elevated alpha-fetoprotein: a clinicopathologic study of ten cases. Oncol Rep1998;5:14251429.

    • Search Google Scholar
    • Export Citation
  • 3

    WeissbachLBussar-MaatzRMannK. The value of tumor markers in testicular seminomas. Results of a prospective multicenter study. Eur Urol1997;32:1622.

    • Search Google Scholar
    • Export Citation
  • 4

    KimWRosenMALangerJE. US MR imaging correlation in pathologic conditions of the scrotum. Radiographics2007;27:12391253.

  • 5

    KleinEA. Tumor markers in testis cancer. Urol Clin North Am1993;20:6773.

  • 6

    RagniGSomiglianaERestelliL. Sperm banking and rate of assisted reproduction treatment: insights from a 15-year cryopreservation program for male cancer patients. Cancer2003;97:16241629.

    • Search Google Scholar
    • Export Citation
  • 7

    SaitoKSuzukiKIwasakiA. Sperm cryopreservation before cancer chemotherapy helps in the emotional battle against cancer. Cancer2005;104:521524.

    • Search Google Scholar
    • Export Citation
  • 8

    BrydoyMFossaSDKleppO. Paternity following treatment for testicular cancer. J Natl Cancer Inst2005;97:15801588.

  • 9

    HuygheEMatsudaTDaudinM. Fertility after testicular cancer treatments: results of a large multicenter study. Cancer2004;100:732737.

  • 10

    GordonWJrSiegmundKStanisicTH. A study of reproductive function in patients with seminoma treated with radiotherapy and orchidectomy: (SWOG-8711). Int J Radiat Oncol Biol Phys1997;38:8394.

    • Search Google Scholar
    • Export Citation
  • 11

    JonesRHVaseyPA. Part I: testicular cancer--management of early disease. Lancet Oncol2003;4:730737.

  • 12

    FossaSDChenJSchonfeldSJ. Risk of contralateral testicular cancer: a population-based study of 29,515 U.S. men. J Natl Cancer Inst2005;97:10561066.

    • Search Google Scholar
    • Export Citation
  • 13

    International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol1997;15:594603.

    • Search Google Scholar
    • Export Citation
  • 14

    LeibovitchLFosterRSKopeckyKKDonohueJP. Improved accuracy of computerized tomography based clinical staging in low stage nonseminomatous germ cell cancer using size criteria of retroperitoneal lymph nodes. J Urol1995;154:17591763.

    • Search Google Scholar
    • Export Citation
  • 15

    SeeWAHoxieL. Chest staging in testis cancer patients: imaging modality selection based upon risk assessment as determined by abdominal computerized tomography scan results. J Urol1993;150:874878.

    • Search Google Scholar
    • Export Citation
  • 16

    MeadGMFossaSDOliverRT. Randomized trials in 2466 patients with stage I seminoma: patterns of relapse and follow-up. J Natl Cancer Inst2011;103:241249.

    • Search Google Scholar
    • Export Citation
  • 17

    GrollRJWardePJewettMA. A comprehensive systematic review of testicular germ cell tumor surveillance. Crit Rev Oncol Hematol2007;64:182197.

    • Search Google Scholar
    • Export Citation
  • 18

    AparicioJGarcia del MuroXMarotoP. Multicenter study evaluating a dual policy of postorchiectomy surveillance and selective adjuvant single-agent carboplatin for patients with clinical stage I seminoma. Ann Oncol2003;14:867872.

    • Search Google Scholar
    • Export Citation
  • 19

    WardePSpechtLHorwichA. Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. J Clin Oncol2002;20:44484452.

    • Search Google Scholar
    • Export Citation
  • 20

    ChungPParkerCPanzarellaT. Surveillance in stage I testicular seminoma: risk of late relapse. Can J Urol2002;9:16371640.

  • 21

    von der MaaseHSpechtLJacobsenGK. Surveillance following orchidectomy for stage I seminoma of the testis. Eur J Cancer1993;29A:19311934.

    • Search Google Scholar
    • Export Citation
  • 22

    WardePGospodarowiczMKBanerjeeD. Prognostic factors for relapse in stage I testicular seminoma treated with surveillance. J Urol1997;157:17051709; discussion 1709–1710.

    • Search Google Scholar
    • Export Citation
  • 23

    ChungPWDaugaardGTyldesleyS. Prognostic factors for relapse in stage I seminoma managed with surveillance: a validation study [abstract]. J Clin Oncol2010;28:Abstract 4535.

    • Search Google Scholar
    • Export Citation
  • 24

    ChungPWardeP. Stage I seminoma: adjuvant treatment is effective but is it necessary?J Natl Cancer Inst2011;103:194196.

  • 25

    OliverRTMasonMDMeadGM. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet2005;366:293300.

    • Search Google Scholar
    • Export Citation
  • 26

    OliverRTMeadGMRustinGJ. Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214). J Clin Oncol2011;29:957962.

    • Search Google Scholar
    • Export Citation
  • 27

    AparicioJGermaJRGarcia del MuroX. Risk-adapted management for patients with clinical stage I seminoma: the Second Spanish Germ Cell Cancer Cooperative Group study. J Clin Oncol2005;23:87178723.

    • Search Google Scholar
    • Export Citation
  • 28

    GarmezyBPagliaroLC. Choosing treatment for stage I seminoma: who should get what?Oncology (Williston Park)2009;23:753 759.

  • 29

    JonesWGFossaSDMeadGM. Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I testicular seminoma: a report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer trial 30942 (ISRCTN18525328). J Clin Oncol2005;23:12001208.

    • Search Google Scholar
    • Export Citation
  • 30

    FossaSDHorwichARussellJM. Optimal planning target volume for stage I testicular seminoma: a Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group. J Clin Oncol1999;17:1146.

    • Search Google Scholar
    • Export Citation
  • 31

    DinniwellRChanPCzarnotaG. Pelvic lymph node topography for radiotherapy treatment planning from ferumoxtran-10 contrast-enhanced magnetic resonance imaging. Int J Radiat Oncol Biol Phys2009;74:844851.

    • Search Google Scholar
    • Export Citation
  • 32

    McMahonCJRofskyNMPedrosaI. Lymphatic metastases from pelvic tumors: anatomic classification, characterization, and staging. Radiology2010;254:3146.

    • Search Google Scholar
    • Export Citation
  • 33

    MartinJMPanzarellaTZwahlenDR. Evidence-based guidelines for following stage 1 seminoma. Cancer2007;109:22482256.

  • 34

    SouchonRHartmannMKregeS. Interdisciplinary evidence-based recommendations for the follow-up of early stage seminomatous testicular germ cell cancer patients. Strahlenther Onkol2011;187:158166.

    • Search Google Scholar
    • Export Citation
  • 35

    TolanSVespriniDJewettMA. No role for routine chest radiography in stage I seminoma surveillance. Eur Urol2010;57:474479.

  • 36

    TRISST (MRC TE24) trial of imaging and schedule in seminoma testis. Available at: http://www.ctu.mrc.ac.uk/plugins/StudyDisplay/protocols/TRISST%20protocol%20version%203%209_MAR10.pdf. Accessed February 24 2012.

    • Search Google Scholar
    • Export Citation
  • 37

    LivseyJETaylorBMobarekN. Patterns of relapse following radiotherapy for stage I seminoma of the testis: implications for follow-up. Clin Oncol (R Coll Radiol)2001;13:296300.

    • Search Google Scholar
    • Export Citation
  • 38

    van AsNJGilbertDCMoney-KyrleJ. Evidence-based pragmatic guidelines for the follow-up of testicular cancer: optimising the detection of relapse. Br J Cancer2008;98:18941902.

    • Search Google Scholar
    • Export Citation
  • 39

    ClassenJSchmidbergerHMeisnerC. Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial. J Clin Oncol2003;21:11011106.

    • Search Google Scholar
    • Export Citation
  • 40

    PattersonHNormanARMitraSS. Combination carboplatin and radiotherapy in the management of stage II testicular seminoma: comparison with radiotherapy treatment alone. Radiother Oncol2001;59:511.

    • Search Google Scholar
    • Export Citation
  • 41

    SchmidbergerHBambergMMeisnerC. Radiotherapy in stage IIA and IIB testicular seminoma with reduced portals: a prospective multicenter study. Int J Radiat Oncol Biol Phys1997;39:321326.

    • Search Google Scholar
    • Export Citation
  • 42

    DettiBLiviLScocciantiS. Management of stage II testicular seminoma over a period of 40 years. Urol Oncol2009;27:534538.

  • 43

    ChooRSandlerHWardeP. Survey of radiation oncologists: practice patterns of the management of stage I seminoma of testis in Canada and a selected group in the United States. Can J Urol2002;9:14791485.

    • Search Google Scholar
    • Export Citation
  • 44

    GospodarwiczMKSturgeonJFJewettMA. Early stage and advanced seminoma: role of radiation therapy, surgery, and chemotherapy. Semin Oncol1998;25:160173.

    • Search Google Scholar
    • Export Citation
  • 45

    DomontJMassardCPatrikidouA. A risk-adapted strategy of radiotherapy or cisplatin-based chemotherapy in stage II seminoma. Urol Oncolin press.

    • Search Google Scholar
    • Export Citation
  • 46

    Garcia-del-MuroXMarotoPGumaJ. Chemotherapy as an alternative to radiotherapy in the treatment of stage IIA and IIB testicular seminoma: a Spanish Germ Cell Cancer Group study. J Clin Oncol2008;26:54165421.

    • Search Google Scholar
    • Export Citation
  • 47

    de WitRRobertsJTWilkinsonPM. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol2001;19:16291640.

    • Search Google Scholar
    • Export Citation
  • 48

    LoehrerPJSrJohnsonDElsonP. Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group trial. J Clin Oncol1995;13:470476.

    • Search Google Scholar
    • Export Citation
  • 49

    SaxmanSBFinchDGoninREinhornLH. Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the Indian University experience. J Clin Oncol1998;16:702706.

    • Search Google Scholar
    • Export Citation
  • 50

    BajorinDFSarosdyMFPfisterDG. Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: a multiinstitutional study. J Clin Oncol1993;11:598606.

    • Search Google Scholar
    • Export Citation
  • 51

    XiaoHMazumdarMBajorinDF. Long-term follow-up of patients with good-risk germ cell tumors treated with etoposide and cisplatin. J Clin Oncol1997;15:25532558.

    • Search Google Scholar
    • Export Citation
  • 52

    KondaguntaGVBacikJBajorinD. Etoposide and cisplatin chemotherapy for metastatic good-risk germ cell tumors. J Clin Oncol2005;23:92909294.

    • Search Google Scholar
    • Export Citation
  • 53

    Tjan-HeijnenVCOosterhofGOde WitRDe MulderPH. Treatment in germ cell tumours: state of the art. Eur J Surg Oncol1997;23:110117.

  • 54

    de WitRLouwerensMde MulderPH. Management of intermediate-prognosis germ-cell cancer: results of a phase I/II study of Taxol-BEP. Int J Cancer1999;83:831833.

    • Search Google Scholar
    • Export Citation
  • 55

    BechererADe SantisMKaranikasG. FDG PET is superior to CT in the prediction of viable tumour in post-chemotherapy seminoma residuals. Eur J Radiol2005;54:284288.

    • Search Google Scholar
    • Export Citation
  • 56

    HinzSSchraderMKempkensteffenC. The role of positron emission tomography in the evaluation of residual masses after chemotherapy for advanced stage seminoma. J Urol2008;179:936940; discussion 940.

    • Search Google Scholar
    • Export Citation
  • 57

    CremeriusUWildbergerJEBorchersH. Does positron emission tomography using 18-fluoro-2-deoxyglucose improve clinical staging of testicular cancer?–results of a study in 50 patients. Urology1999;54:900904.

    • Search Google Scholar
    • Export Citation
  • 58

    AlbersPBenderHYilmazH. Positron emission tomography in the clinical staging of patients with stage I and II testicular germ cell tumors. Urology1999;53:808811.

    • Search Google Scholar
    • Export Citation
  • 59

    SpermonJRDe Geus-OeiLFKiemeneyLA. The role of (18)fluoro-2-deoxyglucose positron emission tomography in initial staging and re-staging after chemotherapy for testicular germ cell tumours. BJU Int2002;89:549556.

    • Search Google Scholar
    • Export Citation
  • 60

    De SantisMPontJ. The role of positron emission tomography in germ cell cancer. World J Urol2004;22:4146.

  • 61

    De SantisMBechererABokemeyerC. 2-18fluoro-deoxy-D-glucose positron emission tomography is a reliable predictor for viable tumor in postchemotherapy seminoma: an update of the prospective multicentric SEMPET trial. J Clin Oncol2004;22:10341039.

    • Search Google Scholar
    • Export Citation
  • 62

    EhrlichYBramesMJBeckSD. Long-term follow-up of cisplatin combination chemotherapy in patients with disseminated nonseminomatous germ cell tumors: is a postchemotherapy retroperitoneal lymph node dissection needed after complete remission?J Clin Oncol2010;28:531536.

    • Search Google Scholar
    • Export Citation
  • 63

    KollmannsbergerCDaneshmandSSoA. Management of disseminated nonseminomatous germ cell tumors with risk-based chemotherapy followed by response-guided postchemotherapy surgery. J Clin Oncol2010;28:537542.

    • Search Google Scholar
    • Export Citation
  • 64

    KondaguntaGVBacikJSheinfeldJ. Paclitaxel plus ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tumors. J Clin Oncol2007;25:8590.

    • Search Google Scholar
    • Export Citation
  • 65

    MillerKDLoehrerPJGoninREinhornLH. Salvage chemotherapy with vinblastine, ifosfamide, and cisplatin in recurrent seminoma. J Clin Oncol1997;15:14271431.

    • Search Google Scholar
    • Export Citation
  • 66

    LoehrerPJSrLauerRRothBJ. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med1988;109:540546.

    • Search Google Scholar
    • Export Citation
  • 67

    KondaguntaGVBacikJDonadioA. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol2005;23:65496555.

    • Search Google Scholar
    • Export Citation
  • 68

    SchmollHJJordanKHuddartR. Testicular seminoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol2010;21(Suppl 5):v140146.

    • Search Google Scholar
    • Export Citation
  • 69

    de WitMBrennerWHartmannM. [18F]-FDG-PET in clinical stage I/II non-seminomatous germ cell tumours: results of the German multicentre trial. Ann Oncol2008;19:16191623.

    • Search Google Scholar
    • Export Citation
  • 70

    HuddartRAO’DohertyMJPadhaniA. 18fluorodeoxyglucose positron emission tomography in the prediction of relapse in patients with high-risk, clinical stage I nonseminomatous germ cell tumors: preliminary report of MRC Trial TE22: the NCRI Testis Tumour Clinical Study Group. J Clin Oncol2007;25:30903095.

    • Search Google Scholar
    • Export Citation
  • 71

    SheinfeldJHerrHW. Role of surgery in management of germ cell tumor. Semin Oncol1998;25:203209.

  • 72

    CollsBMHarveyVJSkeltonL. Late results of surveillance of clinical stage I nonseminoma germ cell testicular tumours: 17 years’ experience in a national study in New Zealand. BJU Int1999;83:7682.

    • Search Google Scholar
    • Export Citation
  • 73

    ReadGStenningSPCullenMH. Medical Research Council prospective study of surveillance for stage I testicular teratoma. Medical Research Council Testicular Tumors Working Party. J Clin Oncol1992;10:17621768.

    • Search Google Scholar
    • Export Citation
  • 74

    KakiashviliDAnson-CartwrightLSturgeonJF. Non risk-adapted surveillance management for clinical stage I nonseminomatous testis tumors [abstract]. J Urol2007;177:Abstract 835.

    • Search Google Scholar
    • Export Citation
  • 75

    ZunigaAKakiashviliDJewettMA. Surveillance in stage I nonseminomatous germ cell tumours of the testis. BJU Int2009;104:13511356.

  • 76

    OliverRTOngJShamashJ. Long-term follow-up of Anglian Germ Cell Cancer Group surveillance versus patients with stage 1 nonseminoma treated with adjuvant chemotherapy. Urology2004;63:556561.

    • Search Google Scholar
    • Export Citation
  • 77

    de BruinMJOosterhofGODebruyneFM. Nerve-sparing retroperitoneal lymphadenectomy for low stage testicular cancer. Br J Urol1993;71:336339.

    • Search Google Scholar
    • Export Citation
  • 78

    StephensonAJBoslGJMotzerRJ. Retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer: impact of patient selection factors on outcome. J Clin Oncol2005;23:27812788.

    • Search Google Scholar
    • Export Citation
  • 79

    BohlenDBornerMSonntagRW. Long-term results following adjuvant chemotherapy in patients with clinical stage I testicular nonseminomatous malignant germ cell tumors with high risk factors. J Urol1999;161:11481152.

    • Search Google Scholar
    • Export Citation
  • 80

    BohlenDBurkhardFCMillsR. Fertility and sexual function following orchiectomy and 2 cycles of chemotherapy for stage I high risk nonseminomatous germ cell cancer. J Urol2001;165:441444.

    • Search Google Scholar
    • Export Citation
  • 81

    ChevreauCMazerollesCSoulieM. Long-term efficacy of two cycles of BEP regimen in high-risk stage I nonseminomatous testicular germ cell tumors with embryonal carcinoma and/or vascular invasion. Eur Urol2004;46:209214.

    • Search Google Scholar
    • Export Citation
  • 82

    CullenMHStenningSPParkinsonMC. Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report. J Clin Oncol1996;14:11061113.

    • Search Google Scholar
    • Export Citation
  • 83

    OliverRTRajaMAOngJGallagherCJ. Pilot study to evaluate impact of a policy of adjuvant chemotherapy for high risk stage 1 malignant teratoma on overall relapse rate of stage 1 cancer patients. J Urol1992;148:14531455.

    • Search Google Scholar
    • Export Citation
  • 84

    PontJAlbrechtWPostnerG. Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: long-term results of a prospective trial. J Clin Oncol1996;14:441448.

    • Search Google Scholar
    • Export Citation
  • 85

    StuderUEFeyMFCalderoniA. Adjuvant chemotherapy after orchiectomy in high-risk patients with clinical stage I non-seminomatous testicular cancer. Eur Urol1993;23:444449.

    • Search Google Scholar
    • Export Citation
  • 86

    SharirSFosterRSDonohueJPJewettMA. What is the appropriate follow-up after treatment?Semin Urol Oncol1996;14:4553.

  • 87

    StuderUEFeyMFCalderoniA. Adjuvant chemotherapy after orchiectomy in high-risk patients with clinical stage I non-seminomatous testicular cancer. Eur Urol1993;23:444449.

    • Search Google Scholar
    • Export Citation
  • 88

    BohlenDBornerMSonntagRW. Long-term results following adjuvant chemotherapy in patients with clinical stage I testicular nonseminomatous malignant germ cell tumors with high risk factors. J Urol1999;161:11481152.

    • Search Google Scholar
    • Export Citation
  • 89

    PontJAlbrechtWPostnerG. Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: long-term results of a prospective trial. J Clin Oncol1996;14:441448.

    • Search Google Scholar
    • Export Citation
  • 90

    ChevreauCMazerollesCSoulieM. Long-term efficacy of two cycles of BEP regimen in high-risk stage I nonseminomatous testicular germ cell tumors with embryonal carcinoma and/or vascular invasion. Eur Urol2004;46:209214.

    • Search Google Scholar
    • Export Citation
  • 91

    MeinardiMTGietemaJAvan der GraafWT. Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol2000;18:17251732.

    • Search Google Scholar
    • Export Citation
  • 92

    BergerCCBokemeyerCSchneiderM. Secondary Raynaud’s phenomenon and other late vascular complications following chemotherapy for testicular cancer. Eur J Cancer1995;31A:22292238.

    • Search Google Scholar
    • Export Citation
  • 93

    StrumbergDBruggeSKornMW. Evaluation of long-term toxicity in patients after cisplatin-based chemotherapy for non-seminomatous testicular cancer. Ann Oncol2002;13:229236.

    • Search Google Scholar
    • Export Citation
  • 94

    BokemeyerCBergerCCKuczykMASchmollHJ. Evaluation of long-term toxicity after chemotherapy for testicular cancer. J Clin Oncol1996;14:29232932.

    • Search Google Scholar
    • Export Citation
  • 95

    HuddartRANormanAShahidiM. Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol2003;21:15131523.

    • Search Google Scholar
    • Export Citation
  • 96

    BajorinDFMotzerRJRodriguezE. Acute nonlymphocytic leukemia in germ cell tumor patients treated with etoposide-containing chemotherapy. J Natl Cancer Inst1993;85:6062.

    • Search Google Scholar
    • Export Citation
  • 97

    AlbersPSienerRKregeS. Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I nonseminomatous testicular germ cell tumors: AUO Trial AH 01/94 by the German Testicular Cancer Study Group. J Clin Oncol2008;26:29662972.

    • Search Google Scholar
    • Export Citation
  • 98

    CulineSTheodoreCTerrier-LacombeMJDrozJP. Primary chemotherapy in patients with nonseminomatous germ cell tumors of the testis and biological disease only after orchiectomy. J Urol1996;155:12961298.

    • Search Google Scholar
    • Export Citation
  • 99

    DavisBEHerrHWFairWRBoslGJ. The management of patients with nonseminomatous germ cell tumors of the testis with serologic disease only after orchiectomy. J Urol1994;152:111113; discussion 114.

    • Search Google Scholar
    • Export Citation
  • 100

    StephensonAJBoslGJMotzerRJ. Nonrandomized comparison of primary chemotherapy and retroperitoneal lymph node dissection for clinical stage IIA and IIB nonseminomatous germ cell testicular cancer. J Clin Oncol2007;25:55975602.

    • Search Google Scholar
    • Export Citation
  • 101

    WeissbachLBussar-MaatzRFlechtnerH. RPLND or primary chemotherapy in clinical stage IIA/B nonseminomatous germ cell tumors? Results of a prospective multicenter trial including quality of life assessment. Eur Urol2000;37:582594.

    • Search Google Scholar
    • Export Citation
  • 102

    DonohueJPThornhillJAFosterRS. Clinical stage B non-seminomatous germ cell testis cancer: the Indiana University experience (1965-1989) using routine primary retroperitoneal lymph node dissection. Eur J Cancer1995;31A:15991604.

    • Search Google Scholar
    • Export Citation
  • 103

    PizzocaroG. Retroperitoneal lymph node dissection in clinical stage IIA and IIB nonseminomatous germ cell tumours of the testis. Int J Androl1987;10:269275.

    • Search Google Scholar
    • Export Citation
  • 104

    CulineSTheodoreCCourtBH. Evaluation of primary standard cisplatin-based chemotherapy for clinical stage II non-seminomatous germ cell tumours of the testis. Br J Urol1997;79:258262.

    • Search Google Scholar
    • Export Citation
  • 105

    RabbaniFSheinfeldJFarivar-MohseniH. Low-volume nodal metastases detected at retroperitoneal lymphadenectomy for testicular cancer: pattern and prognostic factors for relapse. J Clin Oncol2001;19:20202025.

    • Search Google Scholar
    • Export Citation
  • 106

    StephensonAJBoslGJBajorinDF. Retroperitoneal lymph node dissection in patients with low stage testicular cancer with embryonal carcinoma predominance and/or lymphovascular invasion. J Urol2005;174:557560; discussion 560.

    • Search Google Scholar
    • Export Citation
  • 107

    CarverBSShayeganBEggenerS. Incidence of metastatic nonseminomatous germ cell tumor outside the boundaries of a modified postchemotherapy retroperitoneal lymph node dissection. J Clin Oncol2007;25:43654369.

    • Search Google Scholar
    • Export Citation
  • 108

    WilliamsSDStableinDMEinhornLH. Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer. N Engl J Med1987;317:14331438.

    • Search Google Scholar
    • Export Citation
  • 109

    SheinfeldJMotzerRJRabbaniF. Incidence and clinical outcome of patients with teratoma in the retroperitoneum following primary retroperitoneal lymph node dissection for clinical stages I and IIA nonseminomatous germ cell tumors. J Urol2003;170:11591162.

    • Search Google Scholar
    • Export Citation
  • 110

    VogelzangNJFraleyEELangePH. Stage II nonseminomatous testicular cancer: a 10-year experience. J Clin Oncol1983;1:171178.

  • 111

    BehniaMFosterREinhornLH. Adjuvant bleomycin, etoposide and cisplatin in pathological stage II non-seminomatous testicular cancer. The Indiana University experience. Eur J Cancer2000;36:472475.

    • Search Google Scholar
    • Export Citation
  • 112

    KondaguntaGVSheinfeldJMazumdarM. Relapse-free and overall survival in patients with pathologic stage II nonseminomatous germ cell cancer treated with etoposide and cisplatin adjuvant chemotherapy. J Clin Oncol2004;22:464467.

    • Search Google Scholar
    • Export Citation
  • 113

    MotzerRJSheinfeldJMazumdarM. Etoposide and cisplatin adjuvant therapy for patients with pathologic stage II germ cell tumors. J Clin Oncol1995;13:27002704.

    • Search Google Scholar
    • Export Citation
  • 114

    DonohueJPThornhillJAFosterRS. The role of retroperitoneal lymphadenectomy in clinical stage B testis cancer: the Indiana University experience (1965 to 1989). J Urol1995;153:8589.

    • Search Google Scholar
    • Export Citation
  • 115

    HartlappJHWeissbachLBussar-MaatzR. Adjuvant chemotherapy in nonseminomatous testicular tumour stage II. Int J Androl1987;10:277284.

  • 116

    HorwichANormanAFisherC. Primary chemotherapy for stage II nonseminomatous germ cell tumors of the testis. J Urol1994;151:7277.

  • 117

    LogothetisCJSwansonDADexeusF. Primary chemotherapy for clinical stage II nonseminomatous germ cell tumors of the testis: a follow-up of 50 patients. J Clin Oncol1987;5:906911.

    • Search Google Scholar
    • Export Citation
  • 118

    SternbergCN. Role of primary chemotherapy in stage I and low-volume stage II nonseminomatous germ-cell testis tumors. Urol Clin North Am1993;20:93109.

    • Search Google Scholar
    • Export Citation
  • 119

    BoslGJGellerNLBajorinD. A randomized trial of etoposide + cisplatin versus vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin in patients with good-prognosis germ cell tumors. J Clin Oncol1988;6:12311238.

    • Search Google Scholar
    • Export Citation
  • 120

    WilliamsSDBirchREinhornLH. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med1987;316:14351440.

    • Search Google Scholar
    • Export Citation
  • 121

    EinhornLHWilliamsSDLoehrerPJ. Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. J Clin Oncol1989;7:387391.

    • Search Google Scholar
    • Export Citation
  • 122

    de WitRStoterGKayeSB. Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. J Clin Oncol1997;15:18371843.

    • Search Google Scholar
    • Export Citation
  • 123

    HorwichASleijferDTFossaSD. Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol1997;15:18441852.

    • Search Google Scholar
    • Export Citation
  • 124

    JonesRHVaseyPA. Part II: testicular cancer: management of advanced disease. Lancet Oncol2003;4:738747.

  • 125

    de WitRStoterGSleijferDT. Four cycles of BEP vs four cycles of VIP in patients with intermediate-prognosis metastatic testicular non-seminoma: a randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group. European Organization for Research and Treatment of Cancer. Br J Cancer1998;78:828832.

    • Search Google Scholar
    • Export Citation
  • 126

    FrohlichMWSmallEJ. Stage II nonseminomatous testis cancer: the roles of primary and adjuvant chemotherapy. Urol Clin North Am1998;25:451459.

    • Search Google Scholar
    • Export Citation
  • 127

    NicholsCRCatalanoPJCrawfordED. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B study. J Clin Oncol1998;16:12871293.

    • Search Google Scholar
    • Export Citation
  • 128

    TonerGCPanicekDMHeelanRT. Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection. J Clin Oncol1990;8:16831694.

    • Search Google Scholar
    • Export Citation
  • 129

    KuczykMMachtensSStiefCJonasU. Management of the post-chemotherapy residual mass in patients with advanced stage non-seminomatous germ cell tumors (NSGCT). Int J Cancer1999;83:852855.

    • Search Google Scholar
    • Export Citation
  • 130

    HartmannJTSchmollHJKuczykMA. Postchemotherapy resections of residual masses from metastatic non-seminomatous testicular germ cell tumors. Ann Oncol1997;8:531538.

    • Search Google Scholar
    • Export Citation
  • 131

    MotzerRJGellerNLTanCC. Salvage chemotherapy for patients with germ cell tumors. The Memorial Sloan-Kettering Cancer Center experience (1979-1989). Cancer1991;67:13051310.

    • Search Google Scholar
    • Export Citation
  • 132

    EinhornLHWilliamsSDChamnessA. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med2007;357:340348.

    • Search Google Scholar
    • Export Citation
  • 133

    LorchABeyerJBascoul-MolleviC. Prognostic factors in patients with metastatic germ cell tumors who experienced treatment failure with cisplatin-based first-line chemotherapy. J Clin Oncol2010;28:49064911.

    • Search Google Scholar
    • Export Citation
  • 134

    LoehrerPJSrGoninRNicholsCR. Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol1998;16:25002504.

    • Search Google Scholar
    • Export Citation
  • 135

    LorchARickOWundischT. High dose chemotherapy as salvage treatment for unresectable late relapse germ cell tumors. J Urol2010;184:168173.

    • Search Google Scholar
    • Export Citation
  • 136

    LorchANeubauerAHackenthalM. High-dose chemotherapy (HDCT) as second-salvage treatment in patients with multiple relapsed or refractory germ-cell tumors. Ann Oncol2010;21:820825.

    • Search Google Scholar
    • Export Citation
  • 137

    MotzerRJBoslGJ. High-dose chemotherapy for resistant germ cell tumors: recent advances and future directions. J Natl Cancer Inst1992;84:17031709.

    • Search Google Scholar
    • Export Citation
  • 138

    FeldmanDRSheinfeldJBajorinDF. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. J Clin Oncol2010;28:17061713.

    • Search Google Scholar
    • Export Citation
  • 139

    WoodDPJrHerrHWMotzerRJ. Surgical resection of solitary metastases after chemotherapy in patients with nonseminomatous germ cell tumors and elevated serum tumor markers. Cancer1992;70:23542357.

    • Search Google Scholar
    • Export Citation
  • 140

    De GiorgiURostiGAietaM. Phase II study of oxaliplatin and gemcitabine salvage chemotherapy in patients with cisplatin-refractory nonseminomatous germ cell tumor. Eur Urol2006;50:10321038; discussion 1038–1039.

    • Search Google Scholar
    • Export Citation
  • 141

    KollmannsbergerCBeyerJLierschR. Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: a study of the German Testicular Cancer Study Group. J Clin Oncol2004;22:108114.

    • Search Google Scholar
    • Export Citation
  • 142

    PectasidesDPectasidesMFarmakisD. Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell tumors: a phase II study. Ann Oncol2004;15:493497.

    • Search Google Scholar
    • Export Citation
  • 143

    BokemeyerCOechsleKHoneckerF. Combination chemotherapy with gemcitabine, oxaliplatin, and paclitaxel in patients with cisplatin-refractory or multiply relapsed germ-cell tumors: a study of the German Testicular Cancer Study Group. Ann Oncol2008;19:448453.

    • Search Google Scholar
    • Export Citation
  • 144

    EinhornLHBramesMJJuliarBWilliamsSD. Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol2007;25:513516.

    • Search Google Scholar
    • Export Citation
  • 145

    MulherinBPBramesMJEinhornLH. Long-term survival with paclitaxel and gemcitabine for germ cell tumors after progression following high-dose chemotherapy with tandem transplants [abstract]. J Clin Oncol2011;29:Abstract 4562.

    • Search Google Scholar
    • Export Citation
  • 146

    FossaSDBokemeyerCGerlA. Treatment outcome of patients with brain metastases from malignant germ cell tumors. Cancer1999;85:988997.

  • 147

    BokemeyerCNowakPHauptA. Treatment of brain metastases in patients with testicular cancer. J Clin Oncol1997;15:14491454.

  • 148

    HartmannJBambergMAlbersP. Multidiciplinary treatment and prognosis of patients with central nervous metastases (CNS) from testicular germ cell tumour (GCT) origin [abstract]. Proc Ann Soc Clin Oncol2003;22:400.Abstract 1607.

    • Search Google Scholar
    • Export Citation

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    NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer Version 1:2012

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    Version1.2012, 01-17-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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References

  • 1

    SiegelRNaishadhamDJemalA. Cancer statistics, 2012. CA Cancer J Clin2012;62:1029.

  • 2

    NazeerTRoJYAmatoRJ. Histologically pure seminoma with elevated alpha-fetoprotein: a clinicopathologic study of ten cases. Oncol Rep1998;5:14251429.

    • Search Google Scholar
    • Export Citation
  • 3

    WeissbachLBussar-MaatzRMannK. The value of tumor markers in testicular seminomas. Results of a prospective multicenter study. Eur Urol1997;32:1622.

    • Search Google Scholar
    • Export Citation
  • 4

    KimWRosenMALangerJE. US MR imaging correlation in pathologic conditions of the scrotum. Radiographics2007;27:12391253.

  • 5

    KleinEA. Tumor markers in testis cancer. Urol Clin North Am1993;20:6773.

  • 6

    RagniGSomiglianaERestelliL. Sperm banking and rate of assisted reproduction treatment: insights from a 15-year cryopreservation program for male cancer patients. Cancer2003;97:16241629.

    • Search Google Scholar
    • Export Citation
  • 7

    SaitoKSuzukiKIwasakiA. Sperm cryopreservation before cancer chemotherapy helps in the emotional battle against cancer. Cancer2005;104:521524.

    • Search Google Scholar
    • Export Citation
  • 8

    BrydoyMFossaSDKleppO. Paternity following treatment for testicular cancer. J Natl Cancer Inst2005;97:15801588.

  • 9

    HuygheEMatsudaTDaudinM. Fertility after testicular cancer treatments: results of a large multicenter study. Cancer2004;100:732737.

  • 10

    GordonWJrSiegmundKStanisicTH. A study of reproductive function in patients with seminoma treated with radiotherapy and orchidectomy: (SWOG-8711). Int J Radiat Oncol Biol Phys1997;38:8394.

    • Search Google Scholar
    • Export Citation
  • 11

    JonesRHVaseyPA. Part I: testicular cancer--management of early disease. Lancet Oncol2003;4:730737.

  • 12

    FossaSDChenJSchonfeldSJ. Risk of contralateral testicular cancer: a population-based study of 29,515 U.S. men. J Natl Cancer Inst2005;97:10561066.

    • Search Google Scholar
    • Export Citation
  • 13

    International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol1997;15:594603.

    • Search Google Scholar
    • Export Citation
  • 14

    LeibovitchLFosterRSKopeckyKKDonohueJP. Improved accuracy of computerized tomography based clinical staging in low stage nonseminomatous germ cell cancer using size criteria of retroperitoneal lymph nodes. J Urol1995;154:17591763.

    • Search Google Scholar
    • Export Citation
  • 15

    SeeWAHoxieL. Chest staging in testis cancer patients: imaging modality selection based upon risk assessment as determined by abdominal computerized tomography scan results. J Urol1993;150:874878.

    • Search Google Scholar
    • Export Citation
  • 16

    MeadGMFossaSDOliverRT. Randomized trials in 2466 patients with stage I seminoma: patterns of relapse and follow-up. J Natl Cancer Inst2011;103:241249.

    • Search Google Scholar
    • Export Citation
  • 17

    GrollRJWardePJewettMA. A comprehensive systematic review of testicular germ cell tumor surveillance. Crit Rev Oncol Hematol2007;64:182197.

    • Search Google Scholar
    • Export Citation
  • 18

    AparicioJGarcia del MuroXMarotoP. Multicenter study evaluating a dual policy of postorchiectomy surveillance and selective adjuvant single-agent carboplatin for patients with clinical stage I seminoma. Ann Oncol2003;14:867872.

    • Search Google Scholar
    • Export Citation
  • 19

    WardePSpechtLHorwichA. Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. J Clin Oncol2002;20:44484452.

    • Search Google Scholar
    • Export Citation
  • 20

    ChungPParkerCPanzarellaT. Surveillance in stage I testicular seminoma: risk of late relapse. Can J Urol2002;9:16371640.

  • 21

    von der MaaseHSpechtLJacobsenGK. Surveillance following orchidectomy for stage I seminoma of the testis. Eur J Cancer1993;29A:19311934.

    • Search Google Scholar
    • Export Citation
  • 22

    WardePGospodarowiczMKBanerjeeD. Prognostic factors for relapse in stage I testicular seminoma treated with surveillance. J Urol1997;157:17051709; discussion 1709–1710.

    • Search Google Scholar
    • Export Citation
  • 23

    ChungPWDaugaardGTyldesleyS. Prognostic factors for relapse in stage I seminoma managed with surveillance: a validation study [abstract]. J Clin Oncol2010;28:Abstract 4535.

    • Search Google Scholar
    • Export Citation
  • 24

    ChungPWardeP. Stage I seminoma: adjuvant treatment is effective but is it necessary?J Natl Cancer Inst2011;103:194196.

  • 25

    OliverRTMasonMDMeadGM. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet2005;366:293300.

    • Search Google Scholar
    • Export Citation
  • 26

    OliverRTMeadGMRustinGJ. Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214). J Clin Oncol2011;29:957962.

    • Search Google Scholar
    • Export Citation
  • 27

    AparicioJGermaJRGarcia del MuroX. Risk-adapted management for patients with clinical stage I seminoma: the Second Spanish Germ Cell Cancer Cooperative Group study. J Clin Oncol2005;23:87178723.

    • Search Google Scholar
    • Export Citation
  • 28

    GarmezyBPagliaroLC. Choosing treatment for stage I seminoma: who should get what?Oncology (Williston Park)2009;23:753 759.

  • 29

    JonesWGFossaSDMeadGM. Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I testicular seminoma: a report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer trial 30942 (ISRCTN18525328). J Clin Oncol2005;23:12001208.

    • Search Google Scholar
    • Export Citation
  • 30

    FossaSDHorwichARussellJM. Optimal planning target volume for stage I testicular seminoma: a Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group. J Clin Oncol1999;17:1146.

    • Search Google Scholar
    • Export Citation
  • 31

    DinniwellRChanPCzarnotaG. Pelvic lymph node topography for radiotherapy treatment planning from ferumoxtran-10 contrast-enhanced magnetic resonance imaging. Int J Radiat Oncol Biol Phys2009;74:844851.

    • Search Google Scholar
    • Export Citation
  • 32

    McMahonCJRofskyNMPedrosaI. Lymphatic metastases from pelvic tumors: anatomic classification, characterization, and staging. Radiology2010;254:3146.

    • Search Google Scholar
    • Export Citation
  • 33

    MartinJMPanzarellaTZwahlenDR. Evidence-based guidelines for following stage 1 seminoma. Cancer2007;109:22482256.

  • 34

    SouchonRHartmannMKregeS. Interdisciplinary evidence-based recommendations for the follow-up of early stage seminomatous testicular germ cell cancer patients. Strahlenther Onkol2011;187:158166.

    • Search Google Scholar
    • Export Citation
  • 35

    TolanSVespriniDJewettMA. No role for routine chest radiography in stage I seminoma surveillance. Eur Urol2010;57:474479.

  • 36

    TRISST (MRC TE24) trial of imaging and schedule in seminoma testis. Available at: http://www.ctu.mrc.ac.uk/plugins/StudyDisplay/protocols/TRISST%20protocol%20version%203%209_MAR10.pdf. Accessed February 24 2012.

    • Search Google Scholar
    • Export Citation
  • 37

    LivseyJETaylorBMobarekN. Patterns of relapse following radiotherapy for stage I seminoma of the testis: implications for follow-up. Clin Oncol (R Coll Radiol)2001;13:296300.

    • Search Google Scholar
    • Export Citation
  • 38

    van AsNJGilbertDCMoney-KyrleJ. Evidence-based pragmatic guidelines for the follow-up of testicular cancer: optimising the detection of relapse. Br J Cancer2008;98:18941902.

    • Search Google Scholar
    • Export Citation
  • 39

    ClassenJSchmidbergerHMeisnerC. Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial. J Clin Oncol2003;21:11011106.

    • Search Google Scholar
    • Export Citation
  • 40

    PattersonHNormanARMitraSS. Combination carboplatin and radiotherapy in the management of stage II testicular seminoma: comparison with radiotherapy treatment alone. Radiother Oncol2001;59:511.

    • Search Google Scholar
    • Export Citation
  • 41

    SchmidbergerHBambergMMeisnerC. Radiotherapy in stage IIA and IIB testicular seminoma with reduced portals: a prospective multicenter study. Int J Radiat Oncol Biol Phys1997;39:321326.

    • Search Google Scholar
    • Export Citation
  • 42

    DettiBLiviLScocciantiS. Management of stage II testicular seminoma over a period of 40 years. Urol Oncol2009;27:534538.

  • 43

    ChooRSandlerHWardeP. Survey of radiation oncologists: practice patterns of the management of stage I seminoma of testis in Canada and a selected group in the United States. Can J Urol2002;9:14791485.

    • Search Google Scholar
    • Export Citation
  • 44

    GospodarwiczMKSturgeonJFJewettMA. Early stage and advanced seminoma: role of radiation therapy, surgery, and chemotherapy. Semin Oncol1998;25:160173.

    • Search Google Scholar
    • Export Citation
  • 45

    DomontJMassardCPatrikidouA. A risk-adapted strategy of radiotherapy or cisplatin-based chemotherapy in stage II seminoma. Urol Oncolin press.

    • Search Google Scholar
    • Export Citation
  • 46

    Garcia-del-MuroXMarotoPGumaJ. Chemotherapy as an alternative to radiotherapy in the treatment of stage IIA and IIB testicular seminoma: a Spanish Germ Cell Cancer Group study. J Clin Oncol2008;26:54165421.

    • Search Google Scholar
    • Export Citation
  • 47

    de WitRRobertsJTWilkinsonPM. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol2001;19:16291640.

    • Search Google Scholar
    • Export Citation
  • 48

    LoehrerPJSrJohnsonDElsonP. Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group trial. J Clin Oncol1995;13:470476.

    • Search Google Scholar
    • Export Citation
  • 49

    SaxmanSBFinchDGoninREinhornLH. Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the Indian University experience. J Clin Oncol1998;16:702706.

    • Search Google Scholar
    • Export Citation
  • 50

    BajorinDFSarosdyMFPfisterDG. Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: a multiinstitutional study. J Clin Oncol1993;11:598606.

    • Search Google Scholar
    • Export Citation
  • 51

    XiaoHMazumdarMBajorinDF. Long-term follow-up of patients with good-risk germ cell tumors treated with etoposide and cisplatin. J Clin Oncol1997;15:25532558.

    • Search Google Scholar
    • Export Citation
  • 52

    KondaguntaGVBacikJBajorinD. Etoposide and cisplatin chemotherapy for metastatic good-risk germ cell tumors. J Clin Oncol2005;23:92909294.

    • Search Google Scholar
    • Export Citation
  • 53

    Tjan-HeijnenVCOosterhofGOde WitRDe MulderPH. Treatment in germ cell tumours: state of the art. Eur J Surg Oncol1997;23:110117.

  • 54

    de WitRLouwerensMde MulderPH. Management of intermediate-prognosis germ-cell cancer: results of a phase I/II study of Taxol-BEP. Int J Cancer1999;83:831833.

    • Search Google Scholar
    • Export Citation
  • 55

    BechererADe SantisMKaranikasG. FDG PET is superior to CT in the prediction of viable tumour in post-chemotherapy seminoma residuals. Eur J Radiol2005;54:284288.

    • Search Google Scholar
    • Export Citation
  • 56

    HinzSSchraderMKempkensteffenC. The role of positron emission tomography in the evaluation of residual masses after chemotherapy for advanced stage seminoma. J Urol2008;179:936940; discussion 940.

    • Search Google Scholar
    • Export Citation
  • 57

    CremeriusUWildbergerJEBorchersH. Does positron emission tomography using 18-fluoro-2-deoxyglucose improve clinical staging of testicular cancer?–results of a study in 50 patients. Urology1999;54:900904.

    • Search Google Scholar
    • Export Citation
  • 58

    AlbersPBenderHYilmazH. Positron emission tomography in the clinical staging of patients with stage I and II testicular germ cell tumors. Urology1999;53:808811.

    • Search Google Scholar
    • Export Citation
  • 59

    SpermonJRDe Geus-OeiLFKiemeneyLA. The role of (18)fluoro-2-deoxyglucose positron emission tomography in initial staging and re-staging after chemotherapy for testicular germ cell tumours. BJU Int2002;89:549556.

    • Search Google Scholar
    • Export Citation
  • 60

    De SantisMPontJ. The role of positron emission tomography in germ cell cancer. World J Urol2004;22:4146.

  • 61

    De SantisMBechererABokemeyerC. 2-18fluoro-deoxy-D-glucose positron emission tomography is a reliable predictor for viable tumor in postchemotherapy seminoma: an update of the prospective multicentric SEMPET trial. J Clin Oncol2004;22:10341039.

    • Search Google Scholar
    • Export Citation
  • 62

    EhrlichYBramesMJBeckSD. Long-term follow-up of cisplatin combination chemotherapy in patients with disseminated nonseminomatous germ cell tumors: is a postchemotherapy retroperitoneal lymph node dissection needed after complete remission?J Clin Oncol2010;28:531536.

    • Search Google Scholar
    • Export Citation
  • 63

    KollmannsbergerCDaneshmandSSoA. Management of disseminated nonseminomatous germ cell tumors with risk-based chemotherapy followed by response-guided postchemotherapy surgery. J Clin Oncol2010;28:537542.

    • Search Google Scholar
    • Export Citation
  • 64

    KondaguntaGVBacikJSheinfeldJ. Paclitaxel plus ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tumors. J Clin Oncol2007;25:8590.

    • Search Google Scholar
    • Export Citation
  • 65

    MillerKDLoehrerPJGoninREinhornLH. Salvage chemotherapy with vinblastine, ifosfamide, and cisplatin in recurrent seminoma. J Clin Oncol1997;15:14271431.

    • Search Google Scholar
    • Export Citation
  • 66

    LoehrerPJSrLauerRRothBJ. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med1988;109:540546.

    • Search Google Scholar
    • Export Citation
  • 67

    KondaguntaGVBacikJDonadioA. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol2005;23:65496555.

    • Search Google Scholar
    • Export Citation
  • 68

    SchmollHJJordanKHuddartR. Testicular seminoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol2010;21(Suppl 5):v140146.

    • Search Google Scholar
    • Export Citation
  • 69

    de WitMBrennerWHartmannM. [18F]-FDG-PET in clinical stage I/II non-seminomatous germ cell tumours: results of the German multicentre trial. Ann Oncol2008;19:16191623.

    • Search Google Scholar
    • Export Citation
  • 70

    HuddartRAO’DohertyMJPadhaniA. 18fluorodeoxyglucose positron emission tomography in the prediction of relapse in patients with high-risk, clinical stage I nonseminomatous germ cell tumors: preliminary report of MRC Trial TE22: the NCRI Testis Tumour Clinical Study Group. J Clin Oncol2007;25:30903095.

    • Search Google Scholar
    • Export Citation
  • 71

    SheinfeldJHerrHW. Role of surgery in management of germ cell tumor. Semin Oncol1998;25:203209.

  • 72

    CollsBMHarveyVJSkeltonL. Late results of surveillance of clinical stage I nonseminoma germ cell testicular tumours: 17 years’ experience in a national study in New Zealand. BJU Int1999;83:7682.

    • Search Google Scholar
    • Export Citation
  • 73

    ReadGStenningSPCullenMH. Medical Research Council prospective study of surveillance for stage I testicular teratoma. Medical Research Council Testicular Tumors Working Party. J Clin Oncol1992;10:17621768.

    • Search Google Scholar
    • Export Citation
  • 74

    KakiashviliDAnson-CartwrightLSturgeonJF. Non risk-adapted surveillance management for clinical stage I nonseminomatous testis tumors [abstract]. J Urol2007;177:Abstract 835.

    • Search Google Scholar
    • Export Citation
  • 75

    ZunigaAKakiashviliDJewettMA. Surveillance in stage I nonseminomatous germ cell tumours of the testis. BJU Int2009;104:13511356.

  • 76

    OliverRTOngJShamashJ. Long-term follow-up of Anglian Germ Cell Cancer Group surveillance versus patients with stage 1 nonseminoma treated with adjuvant chemotherapy. Urology2004;63:556561.

    • Search Google Scholar
    • Export Citation
  • 77

    de BruinMJOosterhofGODebruyneFM. Nerve-sparing retroperitoneal lymphadenectomy for low stage testicular cancer. Br J Urol1993;71:336339.

    • Search Google Scholar
    • Export Citation
  • 78

    StephensonAJBoslGJMotzerRJ. Retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer: impact of patient selection factors on outcome. J Clin Oncol2005;23:27812788.

    • Search Google Scholar
    • Export Citation
  • 79

    BohlenDBornerMSonntagRW. Long-term results following adjuvant chemotherapy in patients with clinical stage I testicular nonseminomatous malignant germ cell tumors with high risk factors. J Urol1999;161:11481152.

    • Search Google Scholar
    • Export Citation
  • 80

    BohlenDBurkhardFCMillsR. Fertility and sexual function following orchiectomy and 2 cycles of chemotherapy for stage I high risk nonseminomatous germ cell cancer. J Urol2001;165:441444.

    • Search Google Scholar
    • Export Citation
  • 81

    ChevreauCMazerollesCSoulieM. Long-term efficacy of two cycles of BEP regimen in high-risk stage I nonseminomatous testicular germ cell tumors with embryonal carcinoma and/or vascular invasion. Eur Urol2004;46:209214.

    • Search Google Scholar
    • Export Citation
  • 82

    CullenMHStenningSPParkinsonMC. Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report. J Clin Oncol1996;14:11061113.

    • Search Google Scholar
    • Export Citation
  • 83

    OliverRTRajaMAOngJGallagherCJ. Pilot study to evaluate impact of a policy of adjuvant chemotherapy for high risk stage 1 malignant teratoma on overall relapse rate of stage 1 cancer patients. J Urol1992;148:14531455.

    • Search Google Scholar
    • Export Citation
  • 84

    PontJAlbrechtWPostnerG. Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: long-term results of a prospective trial. J Clin Oncol1996;14:441448.

    • Search Google Scholar
    • Export Citation
  • 85

    StuderUEFeyMFCalderoniA. Adjuvant chemotherapy after orchiectomy in high-risk patients with clinical stage I non-seminomatous testicular cancer. Eur Urol1993;23:444449.

    • Search Google Scholar
    • Export Citation
  • 86

    SharirSFosterRSDonohueJPJewettMA. What is the appropriate follow-up after treatment?Semin Urol Oncol1996;14:4553.

  • 87

    StuderUEFeyMFCalderoniA. Adjuvant chemotherapy after orchiectomy in high-risk patients with clinical stage I non-seminomatous testicular cancer. Eur Urol1993;23:444449.

    • Search Google Scholar
    • Export Citation
  • 88

    BohlenDBornerMSonntagRW. Long-term results following adjuvant chemotherapy in patients with clinical stage I testicular nonseminomatous malignant germ cell tumors with high risk factors. J Urol1999;161:11481152.

    • Search Google Scholar
    • Export Citation
  • 89

    PontJAlbrechtWPostnerG. Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: long-term results of a prospective trial. J Clin Oncol1996;14:441448.

    • Search Google Scholar
    • Export Citation
  • 90

    ChevreauCMazerollesCSoulieM. Long-term efficacy of two cycles of BEP regimen in high-risk stage I nonseminomatous testicular germ cell tumors with embryonal carcinoma and/or vascular invasion. Eur Urol2004;46:209214.

    • Search Google Scholar
    • Export Citation
  • 91

    MeinardiMTGietemaJAvan der GraafWT. Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol2000;18:17251732.

    • Search Google Scholar
    • Export Citation
  • 92

    BergerCCBokemeyerCSchneiderM. Secondary Raynaud’s phenomenon and other late vascular complications following chemotherapy for testicular cancer. Eur J Cancer1995;31A:22292238.

    • Search Google Scholar
    • Export Citation
  • 93

    StrumbergDBruggeSKornMW. Evaluation of long-term toxicity in patients after cisplatin-based chemotherapy for non-seminomatous testicular cancer. Ann Oncol2002;13:229236.

    • Search Google Scholar
    • Export Citation
  • 94

    BokemeyerCBergerCCKuczykMASchmollHJ. Evaluation of long-term toxicity after chemotherapy for testicular cancer. J Clin Oncol1996;14:29232932.

    • Search Google Scholar
    • Export Citation
  • 95

    HuddartRANormanAShahidiM. Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol2003;21:15131523.

    • Search Google Scholar
    • Export Citation
  • 96

    BajorinDFMotzerRJRodriguezE. Acute nonlymphocytic leukemia in germ cell tumor patients treated with etoposide-containing chemotherapy. J Natl Cancer Inst1993;85:6062.

    • Search Google Scholar
    • Export Citation
  • 97

    AlbersPSienerRKregeS. Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I nonseminomatous testicular germ cell tumors: AUO Trial AH 01/94 by the German Testicular Cancer Study Group. J Clin Oncol2008;26:29662972.

    • Search Google Scholar
    • Export Citation
  • 98

    CulineSTheodoreCTerrier-LacombeMJDrozJP. Primary chemotherapy in patients with nonseminomatous germ cell tumors of the testis and biological disease only after orchiectomy. J Urol1996;155:12961298.

    • Search Google Scholar
    • Export Citation
  • 99

    DavisBEHerrHWFairWRBoslGJ. The management of patients with nonseminomatous germ cell tumors of the testis with serologic disease only after orchiectomy. J Urol1994;152:111113; discussion 114.

    • Search Google Scholar
    • Export Citation
  • 100

    StephensonAJBoslGJMotzerRJ. Nonrandomized comparison of primary chemotherapy and retroperitoneal lymph node dissection for clinical stage IIA and IIB nonseminomatous germ cell testicular cancer. J Clin Oncol2007;25:55975602.

    • Search Google Scholar
    • Export Citation
  • 101

    WeissbachLBussar-MaatzRFlechtnerH. RPLND or primary chemotherapy in clinical stage IIA/B nonseminomatous germ cell tumors? Results of a prospective multicenter trial including quality of life assessment. Eur Urol2000;37:582594.

    • Search Google Scholar
    • Export Citation
  • 102

    DonohueJPThornhillJAFosterRS. Clinical stage B non-seminomatous germ cell testis cancer: the Indiana University experience (1965-1989) using routine primary retroperitoneal lymph node dissection. Eur J Cancer1995;31A:15991604.

    • Search Google Scholar
    • Export Citation
  • 103

    PizzocaroG. Retroperitoneal lymph node dissection in clinical stage IIA and IIB nonseminomatous germ cell tumours of the testis. Int J Androl1987;10:269275.

    • Search Google Scholar
    • Export Citation
  • 104

    CulineSTheodoreCCourtBH. Evaluation of primary standard cisplatin-based chemotherapy for clinical stage II non-seminomatous germ cell tumours of the testis. Br J Urol1997;79:258262.

    • Search Google Scholar
    • Export Citation
  • 105

    RabbaniFSheinfeldJFarivar-MohseniH. Low-volume nodal metastases detected at retroperitoneal lymphadenectomy for testicular cancer: pattern and prognostic factors for relapse. J Clin Oncol2001;19:20202025.

    • Search Google Scholar
    • Export Citation
  • 106

    StephensonAJBoslGJBajorinDF. Retroperitoneal lymph node dissection in patients with low stage testicular cancer with embryonal carcinoma predominance and/or lymphovascular invasion. J Urol2005;174:557560; discussion 560.

    • Search Google Scholar
    • Export Citation
  • 107

    CarverBSShayeganBEggenerS. Incidence of metastatic nonseminomatous germ cell tumor outside the boundaries of a modified postchemotherapy retroperitoneal lymph node dissection. J Clin Oncol2007;25:43654369.

    • Search Google Scholar
    • Export Citation
  • 108

    WilliamsSDStableinDMEinhornLH. Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer. N Engl J Med1987;317:14331438.

    • Search Google Scholar
    • Export Citation
  • 109

    SheinfeldJMotzerRJRabbaniF. Incidence and clinical outcome of patients with teratoma in the retroperitoneum following primary retroperitoneal lymph node dissection for clinical stages I and IIA nonseminomatous germ cell tumors. J Urol2003;170:11591162.

    • Search Google Scholar
    • Export Citation
  • 110

    VogelzangNJFraleyEELangePH. Stage II nonseminomatous testicular cancer: a 10-year experience. J Clin Oncol1983;1:171178.

  • 111

    BehniaMFosterREinhornLH. Adjuvant bleomycin, etoposide and cisplatin in pathological stage II non-seminomatous testicular cancer. The Indiana University experience. Eur J Cancer2000;36:472475.

    • Search Google Scholar
    • Export Citation
  • 112

    KondaguntaGVSheinfeldJMazumdarM. Relapse-free and overall survival in patients with pathologic stage II nonseminomatous germ cell cancer treated with etoposide and cisplatin adjuvant chemotherapy. J Clin Oncol2004;22:464467.

    • Search Google Scholar
    • Export Citation
  • 113

    MotzerRJSheinfeldJMazumdarM. Etoposide and cisplatin adjuvant therapy for patients with pathologic stage II germ cell tumors. J Clin Oncol1995;13:27002704.

    • Search Google Scholar
    • Export Citation
  • 114

    DonohueJPThornhillJAFosterRS. The role of retroperitoneal lymphadenectomy in clinical stage B testis cancer: the Indiana University experience (1965 to 1989). J Urol1995;153:8589.

    • Search Google Scholar
    • Export Citation
  • 115

    HartlappJHWeissbachLBussar-MaatzR. Adjuvant chemotherapy in nonseminomatous testicular tumour stage II. Int J Androl1987;10:277284.

  • 116

    HorwichANormanAFisherC. Primary chemotherapy for stage II nonseminomatous germ cell tumors of the testis. J Urol1994;151:7277.

  • 117

    LogothetisCJSwansonDADexeusF. Primary chemotherapy for clinical stage II nonseminomatous germ cell tumors of the testis: a follow-up of 50 patients. J Clin Oncol1987;5:906911.

    • Search Google Scholar
    • Export Citation
  • 118

    SternbergCN. Role of primary chemotherapy in stage I and low-volume stage II nonseminomatous germ-cell testis tumors. Urol Clin North Am1993;20:93109.

    • Search Google Scholar
    • Export Citation
  • 119

    BoslGJGellerNLBajorinD. A randomized trial of etoposide + cisplatin versus vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin in patients with good-prognosis germ cell tumors. J Clin Oncol1988;6:12311238.

    • Search Google Scholar
    • Export Citation
  • 120

    WilliamsSDBirchREinhornLH. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med1987;316:14351440.

    • Search Google Scholar
    • Export Citation
  • 121

    EinhornLHWilliamsSDLoehrerPJ. Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. J Clin Oncol1989;7:387391.

    • Search Google Scholar
    • Export Citation
  • 122

    de WitRStoterGKayeSB. Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. J Clin Oncol1997;15:18371843.

    • Search Google Scholar
    • Export Citation
  • 123

    HorwichASleijferDTFossaSD. Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol1997;15:18441852.

    • Search Google Scholar
    • Export Citation
  • 124

    JonesRHVaseyPA. Part II: testicular cancer: management of advanced disease. Lancet Oncol2003;4:738747.

  • 125

    de WitRStoterGSleijferDT. Four cycles of BEP vs four cycles of VIP in patients with intermediate-prognosis metastatic testicular non-seminoma: a randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group. European Organization for Research and Treatment of Cancer. Br J Cancer1998;78:828832.

    • Search Google Scholar
    • Export Citation
  • 126

    FrohlichMWSmallEJ. Stage II nonseminomatous testis cancer: the roles of primary and adjuvant chemotherapy. Urol Clin North Am1998;25:451459.

    • Search Google Scholar
    • Export Citation
  • 127

    NicholsCRCatalanoPJCrawfordED. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B study. J Clin Oncol1998;16:12871293.

    • Search Google Scholar
    • Export Citation
  • 128

    TonerGCPanicekDMHeelanRT. Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection. J Clin Oncol1990;8:16831694.

    • Search Google Scholar
    • Export Citation
  • 129

    KuczykMMachtensSStiefCJonasU. Management of the post-chemotherapy residual mass in patients with advanced stage non-seminomatous germ cell tumors (NSGCT). Int J Cancer1999;83:852855.

    • Search Google Scholar
    • Export Citation
  • 130

    HartmannJTSchmollHJKuczykMA. Postchemotherapy resections of residual masses from metastatic non-seminomatous testicular germ cell tumors. Ann Oncol1997;8:531538.

    • Search Google Scholar
    • Export Citation
  • 131

    MotzerRJGellerNLTanCC. Salvage chemotherapy for patients with germ cell tumors. The Memorial Sloan-Kettering Cancer Center experience (1979-1989). Cancer1991;67:13051310.

    • Search Google Scholar
    • Export Citation
  • 132

    EinhornLHWilliamsSDChamnessA. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med2007;357:340348.

    • Search Google Scholar
    • Export Citation
  • 133

    LorchABeyerJBascoul-MolleviC. Prognostic factors in patients with metastatic germ cell tumors who experienced treatment failure with cisplatin-based first-line chemotherapy. J Clin Oncol2010;28:49064911.

    • Search Google Scholar
    • Export Citation
  • 134

    LoehrerPJSrGoninRNicholsCR. Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol1998;16:25002504.

    • Search Google Scholar
    • Export Citation
  • 135

    LorchARickOWundischT. High dose chemotherapy as salvage treatment for unresectable late relapse germ cell tumors. J Urol2010;184:168173.

    • Search Google Scholar
    • Export Citation
  • 136

    LorchANeubauerAHackenthalM. High-dose chemotherapy (HDCT) as second-salvage treatment in patients with multiple relapsed or refractory germ-cell tumors. Ann Oncol2010;21:820825.

    • Search Google Scholar
    • Export Citation
  • 137

    MotzerRJBoslGJ. High-dose chemotherapy for resistant germ cell tumors: recent advances and future directions. J Natl Cancer Inst1992;84:17031709.

    • Search Google Scholar
    • Export Citation
  • 138

    FeldmanDRSheinfeldJBajorinDF. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. J Clin Oncol2010;28:17061713.

    • Search Google Scholar
    • Export Citation
  • 139

    WoodDPJrHerrHWMotzerRJ. Surgical resection of solitary metastases after chemotherapy in patients with nonseminomatous germ cell tumors and elevated serum tumor markers. Cancer1992;70:23542357.

    • Search Google Scholar
    • Export Citation
  • 140

    De GiorgiURostiGAietaM. Phase II study of oxaliplatin and gemcitabine salvage chemotherapy in patients with cisplatin-refractory nonseminomatous germ cell tumor. Eur Urol2006;50:10321038; discussion 1038–1039.

    • Search Google Scholar
    • Export Citation
  • 141

    KollmannsbergerCBeyerJLierschR. Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: a study of the German Testicular Cancer Study Group. J Clin Oncol2004;22:108114.

    • Search Google Scholar
    • Export Citation
  • 142

    PectasidesDPectasidesMFarmakisD. Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell tumors: a phase II study. Ann Oncol2004;15:493497.

    • Search Google Scholar
    • Export Citation
  • 143

    BokemeyerCOechsleKHoneckerF. Combination chemotherapy with gemcitabine, oxaliplatin, and paclitaxel in patients with cisplatin-refractory or multiply relapsed germ-cell tumors: a study of the German Testicular Cancer Study Group. Ann Oncol2008;19:448453.

    • Search Google Scholar
    • Export Citation
  • 144

    EinhornLHBramesMJJuliarBWilliamsSD. Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol2007;25:513516.

    • Search Google Scholar
    • Export Citation
  • 145

    MulherinBPBramesMJEinhornLH. Long-term survival with paclitaxel and gemcitabine for germ cell tumors after progression following high-dose chemotherapy with tandem transplants [abstract]. J Clin Oncol2011;29:Abstract 4562.

    • Search Google Scholar
    • Export Citation
  • 146

    FossaSDBokeme