I. Clinical manifestations
Painless testicular swelling is a typical symptom of testicular cancer. In addition, patients with testicular discomfort or swelling suspected of epididymitis or orchitis may be treated with experimental antibiotics. Persistent tenderness, swelling, or palpable abnormalities suggest further examination with testicular ultrasound. In most cases, testicular ultrasound is required to identify the lesion, but it is used as an alternative when physical examination is sufficient (TEST-1).
If an intra-testicular mass is identified, further testing includes serum AFP, lactate dehydrogenase (LDH), and beta-human chorionic gonadotropin (beta-HCG) testing and chest radiographs. elevated beta-HCG, LDH, or AFP should be repeated for accurate staging. Transinguinal orchiectomy is the most radical treatment for most patients with suspected testicular masses. If a GCT is found, abdominopelvic computed tomography (CT) is required. Serum HCG and LDH may be elevated in patients with seminoma, whereas elevation of AFP is suggestive of non-seminomatous tumors and should be managed accordingly.
CT of the chest should be performed if CT of the abdominopelvic cavity shows retroperitoneal adenopathy or if the chest radiograph shows abnormal findings. Open transinguinal biopsy of the contralateral testis is not routinely performed unless cryptorchidism or significant atrophy is present. Biopsy should be performed when there is a suspected intra-testicular abnormality, such as a hypoechoic mass or large calcifications confirmed by ultrasound. Conversely, testicular biopsy is not necessary if no abnormalities are seen other than microcalcifications. These tests, as well as other tests with clinical indications, can determine the clinical stage and guide further management. If clinical signs of metastasis are present, brain magnetic resonance imaging (MRI) and bone scan should also be performed.
Further treatment is determined jointly based on histology, the diagnosis of seminomatous or nonseminomatous cell tumor, and staging. Patients should consider sperm preservation prior to any therapeutic interventions that may affect fertility, such as radiation therapy, surgery, and chemotherapy.
II. Treatment
Seminogenic cell tumors
Stages IA and IB
Patients in stages IA and IB receive radiotherapy (20-30 Gy) to the subdiaphragmatic region, including para-aortic lymph nodes ± ipsilateral ileo-inguinal region lymph node radiation. Prophylactic mediastinal radiotherapy is not recommended, as recurrence is rare in this region.
Existing studies have used single administration of carboplatin as an alternative to radiotherapy.5 Oliver et al5 reported the results of a randomized clinical trial in which 1477 patients with stage 1 testicular cancer received either radiotherapy or a single injection of carboplatin. The dose of carboplatin administered in the study was AUC=7. The median follow-up time was 4 years, and recurrence-free survival was similar in both groups. Because late recurrence or secondary germ cell tumors may occur after 5 or 10 years, the authors continued to follow these patients. updated follow-up results for these 1,148 patients were reported at the 2008 ASCO Annual Meeting.
In an intention-to-treat analysis, the 5-year recurrence-free survival rate was 94.7% in the carboplatin group and 96% in the radiotherapy group (risk ratio, 1.25; P = .37). The incidence of new germ cell tumors differed significantly between the two groups (2 in the carboplatin group vs 15 in the radiotherapy group) with a risk ratio (HR) of 0.22 (95% CI 0.05, 0.95 p = 0.03). The authors concluded that a single dose of carboplatin was as effective as adjuvant radiotherapy in preventing disease recurrence with less toxicity in patients with stage I post-orchiectomy spermatocytoma, and therefore the NCCN panel now recommends a single dose of carboplatin (class 1) as an alternative to radiotherapy in patients with stages IA and IB.
If adjuvant radiotherapy is not administered after orchiectomy, approximately 15-20% of patients with spermatocytoma will recur. The median time to recurrence is about 12 months, but recurrence is still possible 5 years after orchiectomy. Because both radiotherapy and chemotherapy may lead to late recurrence, surveillance is also an option for the management of patients with stage I seminoma (category 1).
In particular, certain specific patients should be closely monitored, such as patients with T1 or T2 (category 2B) who require long-term follow-up (TEST-3). The presence of a relapse after the observation period actually indicates an extension of the treatment lead time. Therefore, these patients are treated according to the stage at the time of relapse. Patients who did not undergo radiotherapy included those at high risk of disease after radiotherapy, meaning patients with stage IA and IB with horseshoe kidney or pelvic ectopic kidney, inflammatory bowel disease, and patients with a history of prior radiotherapy.
Follow-up includes history taking and physical examination, as well as serum tumor marker testing, every 3-4 months in the first year, every 6 months in the second year, and annually thereafter. More intensive follow-up is recommended for patients who have not undergone radiotherapy – history taking and physical examination, as well as serum tumor markers, should be performed every 3-4 months for the first 3 years, every 6 months for the next 3 years, and annually thereafter. For patients treated with para-aortic radiotherapy, annual pelvic CT is recommended for the first 3 years, while for patients treated with a single dose of carboplatin or during the surveillance period, abdominal/pelvic CT with intermittent chest radiographs is recommended at each follow-up visit until the full 10 years.
IS stage
Patients in stage IS should undergo radiotherapy (25-30 Gy) to the subdiaphragmatic region, including the para-aortic lymph nodes ± ipsilateral ileo-inguinal region lymph nodes.4 Recommendations for follow-up are similar to those for patients in stages 1A and 1B. If advanced dissemination of the lesion is suspected, the entire process should be performed according to the guidelines for high-risk GCT.
Stages IIA and IIB
Stage IIA is defined as a lesion less than 2 cm in diameter on CT scan, while stage IIB is defined as a lesion between 2 and 5 cm in maximum diameter.
For stage IIA and IIB patients, 35-40 Gy of radiotherapy should be given to the subdiaphragmatic region, including the para-aortic lymph nodes ± the ipsilateral ileo-inguinal region lymph nodes. As with the management of stage I lesions, prophylactic mediastinal zone radiotherapy is not recommended.
Patients with stages IIA and IIB, where radiotherapy is relatively contraindicated, cannot be supervised alone. Instead, 4 cycles of etoposide and cisplatin (EP) therapy are recommended.
Follow-up of stage IIA and IIB patients includes history taking, and physical examination and serum tumor marker testing, which should be performed every 3-4 months for the first 3 years, every 6 months for the fourth year, and annually thereafter. An abdominal CT is recommended after 4 months of the first year.
Stage IIC or III
Patients with stage IIC or III are defined as high or intermediate risk. All stage IIC or III lesions were defined as intermediate risk, except stage III with visceral metastases other than lung.
Standard chemotherapy was administered in both groups, but for high-risk patients, 4 cycles of EP or 3 cycles of bleomycin, etoposide and cisplatin (BEP) were recommended, whereas for intermediate-risk patients, 4 cycles of BEP were recommended. these recommendations were all category 1 evidence. After starting chemotherapy, patients with stage IIC or III were evaluated using serum tumor markers and CT scans of the chest, abdomen, and pelvis.
Patients were classified according to the presence of a residual mass and serum tumor marker status. If no residual lesions were present and tumor markers were normal then surveillance was performed without further treatment. For patients with residual lesions but normal tumor markers, positron emission tomography (PET) is recommended to evaluate the tumor activity of the residual lesions. To minimize the incidence of false-positive results, PET scans should be performed within 6 weeks after the end of chemotherapy. It is important to note that granulomatous disease, such as nodular disease, is often the cause of false-positive results. If the PET scan is negative, no further treatment is required, but this patient should be closely monitored for recurrence. If the result is positive, surgical excisional biopsy (category 2B), or rescue therapy should be considered. Radiotherapy (category 2B) may also be considered.
For patients who cannot have PET scan, post-chemotherapy management is based on the CT scan results. When the residual lesion is larger than 3 cm, there is controversy regarding the best management, as approximately 25% of these patients have a fertile seminoma or a previously unidentified nonseminomatous tumor. Options for management include surgery (category 2B), radiotherapy (category 2B), and observation. If surgery is chosen, excision of the residual lesion or multi-point biopsy is performed. Complete bilateral or modified retroperitoneal lymph node dissection (RPLND) is not performed, due to technical difficulties in patients with seminoma on the one hand and the potential for increased pathogenicity due to extensive fibrosis on the other. If the residual lesion is ≤3 cm, the patient is placed under observation.
Treatment of recurrent lesions is initiated according to the stage at the time of recurrence. Rescuing treatment is recommended for patients with elevated tumor markers or CT scans suggesting an enlarged mass. Rescuing treatment for seminomas and non-seminomas is similar and will be further discussed in the section on non-seminomas.
Patients with seminomatous cell tumors arising in extra-gonadal sites, such as the mediastinum, are treated with standard chemotherapy regimens based on risk stratification. Approximately 90% of patients with advanced seminomas are cured with platinum-containing regimens of chemotherapy.
Non-seminomatous cell tumors
Treatment options according to staging after transinguinal orchiectomy include observation, chemotherapy, and RPLND. although the timing of RPLND varies, most patients with non-seminomatous cell tumors will undergo RPLND at some point during treatment for diagnostic or therapeutic reasons. the primary sequelae of bilateral resection are retrograde ejaculation, which can lead to infertility. The nerve-splitting technique preserves ejaculatory function in 90% of patients. Stencil resection avoids the contralateral sympathetic trunk, postganglionic sympathetic fibers, and the inferior ventral plexus, thereby preserving ejaculatory function in 80% of patients. In conclusion, open nerve-preserving RPLND rather than laparoscopic RPLND treatment is recommended.
There are concerns about incomplete sampling leading to false-negative results, and there are no reports on the efficacy of laparoscopic resection. Since the recommended number of chemotherapy cycles is based on the number of positive lymph nodes, incomplete sampling may lead to under-treatment.
Stage IA
There are two management options for patients with stage IA after orchiectomy: (1) supervised (for patients with good compliance) or (2) open nerve-preserving RPLND. each approach has a cure rate of more than 95%. However, the high cure rate in patients who opt for supervision is dependent on patient compliance with regular follow-up examinations and follow-up chemotherapy after relapse in 20-30% of patients. Supervised follow-up examinations included abdominopelvic CT scans every 2-3 months in the first year and every 3-4 months in the second year. Tumor markers and chest radiographs were performed every 1-2 months in the first year and every 2 months in the second year.
Patients who cannot cooperate are treated with RPLND. Open nerve-preserving RPLND is often performed within 4 weeks after CT scan and 7-10 days after repeat serum tumor marker testing to ensure accurate preoperative staging. If no tumor metastases are found in the resected lymph nodes (pN0), adjuvant chemotherapy is not required after RPLND. However, if tumor is found in the resected lymph nodes, the decision to administer adjuvant chemotherapy depends on the grade of lymph node invasion and the patient’s compliance to supervision. Chemotherapy is preferred over surveillance for patients with pN2 or pN3. Recommended regimens include EP or BEP; two cycles of either regimen are recommended for patients with pN1 or pN2, while patients with pN3 should be treated with 4 cycles of EP and 3 cycles of BEP (preferably).
Phase IB
Open nerve-preserving RPLND is one of the treatment options for stage IB patients and the subsequent adjuvant therapy is similar to that for IA patients. Another option is open nerve-preserving RPLND or supervision (TEST-8) after two cycles of BEP regimens (Class 2B). Ultimately, supervision only (category 2B) can be performed in T2 patients with good compliance. In patients undergoing supervision alone after orchiectomy, vascular invasion is an important prognostic factor for recurrence. Supervision is generally not recommended in patients with T2 with vascular invasion, as 50% of patients will recur. Exceptions may be made for patients with good compliance on an individual basis. When supervision is chosen for patients with T2 lesions, both patients and physicians should follow the recommendations for follow-up.
IS stage
Patients in the IS stage present with persistent elevation of markers but no imaging evidence of lesions. These patients should undergo standard chemotherapy with 4 cycles of EP or 3 cycles of BEP (TEST-6). Either regimen is preferable to initial open nerve-preserving RPLND, as these patients almost always have disseminated lesions.
Stages IIA and IIB
Treatment of patients with stage IIA nonseminomatous cell tumors depends on the level of serum tumor markers. When tumor marker levels are consistently elevated, chemotherapy with 4 cycles of EP or 3 cycles of BEP followed by open nerve-preserving RPLND or surveillance should be administered.
When tumor markers are negative, there are two options for treatment. Patients may be treated with chemotherapy with 4 cycles of EP or 3 cycles of BEP (category 2B) followed by open nerve-preserving RPLND or supervision (TEST-7). This treatment is most appropriate when the patient has multiple lesions. In addition, patients may be treated with open nerve-preserving RPLND followed by adjuvant chemotherapy or supervision, depending on the number of positive lymph nodes identified and the patient’s compliance. For example, supervision is preferred in pN1 patients with good compliance, while chemotherapy is preferred in pN2 patients and supervision is not recommended in pN3 patients. The recommended chemotherapy consists of two cycles of BEP or EP with a relapse-free survival rate of nearly 100%.
Treatment of stage II patients depends on tumor marker levels and imaging results. When tumor markers are negative, CT findings determine the duration of treatment. If the abnormal imaging findings are limited to the lymphatic drainage area, there are two treatment options. One is open nerve-preserving RPLND, while stage II A patients should undergo adjuvant chemotherapy (TEST-9). The second option is chemotherapy with 4 cycles of EP or 3 cycles of BEP followed by open nerve-preserving RPLND or surveillance (TEST-8). If the metastatic lesion is not confined to the lymphatic drainage area (e.g., multiple lymph node metastases outside the lymphatic drainage area), it is recommended that similar chemotherapy be administered first instead of open RPLND.
Stages IIC and III
Stage IIC and III patients are treated with chemotherapy according to risk stratification. Similarly, patients with a primary site outside the gonads, either retroperitoneal or mediastinal, are treated with initial chemotherapy. Risk stratification stems from studies of chemotherapy aimed at reducing toxicity while maintaining maximum efficacy.
Early chemotherapy combinations containing cisplatin, vincristine, and bleomycin studied in the 1970s achieved complete remission in 70-80% of patients with metastatic GCT. These regimens were associated with serious adverse effects, including neuromuscular toxicity, death due to myelosuppression or bleomycin-associated pulmonary fibrosis, and Raynaud’s phenomenon.
The high cure rates and toxicity of cisplatin, vincristine and bleomycin regimens have led to the stratification of patients according to risk. Disease extent and serum tumor marker levels were identified as important prognostic factors, and models were established to classify patients into low- and high-risk categories.
Low-risk (stage IIC and IIIA) non-seminomatous cell tumors
Treatment plans for low-risk GCT are designed with a focus on reducing toxicity while ensuring maximum efficacy. Randomized clinical trials have shown that this can be achieved by replacing etoposide with vincristine,24,25 or by reducing or not using bleomycin.25,26 Currently, in the United States, there are two standard treatment regimens for patients with low-risk GCT: 4 cycles of EP or 3 cycles of BEP (TEST-B). These two regimens are well tolerated and have a cure rate of approximately 90% in low-risk patients.
Intermediate-risk (stage IIIB) and high-risk (stage IIIC) non-seminomatous cell tumors
Between 20% and 30% of patients with metastatic GCT are not cured by conventional platinum-based therapy. For these patients, poor prognostic factors at diagnosis include extrapulmonary visceral metastases and high serum tumor markers or non-seminomatous cell tumors originating in the mediastinum.28 For patients with these risk factors, clinical trials are aimed at improving outcomes.
For patients at intermediate risk, standard treatment with 4 cycles of BEP has a cure rate of approximately 70%. In contrast, in patients at high risk (stage IIIC), 4 cycles of BEP therapy resulted in sustained complete remission in less than 50% of patients, making clinical trials the treatment of choice. The panel recommends 4 cycles of etoposide, isocyclophosphamide and cisplatin (VIP regimen) for patients who cannot tolerate bleomycin.
Initial chemotherapy combined with radiotherapy should be administered to patients with detectable brain metastases. Surgery is also indicated for any clinical indication.
Post-chemotherapy management of stage IIC and IIIACIIIC non-seminomatous cell tumors
CT scans of the abdomen and pelvis and serum tumor marker analysis should be performed after induction chemotherapy. PET scans of residual lesions have some predictive value. If complete remission is achieved and tumor markers are negative, there are two management options: surveillance (category 2B) or open nerve-preserving RPLND (category 2B). If residual lesions remain but serum tumor markers are normal, all residual lesions should be removed. If only necrotic debris or mature teratoma is found, no further treatment is required and standard observation should be initiated. A further 15% of patients who still have a developable residual tumor will require two additional cycles of chemotherapy (EP, VelP [paclitaxel/isophosphamide/cisplatin], or TIP [vincristine/isophosphamide/cisplatin]).
Standard observation was initiated once patients entered disease-free survival. Rescuing therapy should be performed in patients who do not achieve complete remission with first-line therapy and in the presence of unresectable lesions.
Rescue therapy
Patients who do not achieve complete remission with first-line therapy are divided into two groups: those with a good prognosis and those with a poor prognosis. Good prognostic factors included tumor origin in the testis, complete remission with first-line therapy, low serum marker levels, and small size of the lesion. The standard treatment for patients with these characteristics was 4 cycles of cisplatin and isophosphamide combined with vincristine or paclitaxel (TEST-C). Fifty percent of patients who finished vincristine therapy achieved complete remission and 25% achieved sustained complete remission. High-dose chemotherapy with autologous stem cell support was preferred if patients remained in incomplete remission or relapsed after rescue therapy. Surgical rescue may be considered if resectable single-site metastases are present. Other options include participation in clinical trials or best supportive care.
Autologous stem cell-supported high-dose chemotherapy (Category 2B), participation in a clinical trial, or best supportive care may be considered for patients who have a poor prognosis with conventional dose rescue therapy (e.g., incomplete remission with first-line therapy) and for patients who require third-line rescue therapy. Third-line therapy is two cycles of high-dose cisplatin plus etoposide, ± cyclophosphamide (or isocyclophosphamide), which may result in complete remission in 15-20% of patients.
For patients considered for high-dose regimens, prognostic factors are applied to determine treatment. High-dose regimens are recommended for second-line therapy in patients whose primary site is the testis and whose markers are elevated during first-line therapy. Poor prognostic factors for high-dose chemotherapy with platinum-containing regimens include elevated serum HCG concentrations, primary in the mediastinum, and lack of sensitivity to cisplatin (absolutely refractory disease). Patients with these features often do not respond to this treatment and should be considered for investigational therapy or surgical resection – especially those with a mediastinal primary or single site metastases.
In patients who do not achieve complete remission with high-dose therapy, the disease is virtually incurable; the only exceptions are the rare patients with elevated serum tumor markers and substantial site metastases (often retroperitoneal) who undergo surgical resection.35 All other patients should be considered for palliative outpatient chemotherapy or radiation therapy. For germ cell tumors with prior intensive therapy, platinum resistance, and recurrence, one recommended palliative second-line relief regimen is gemcitabine in combination with oxaliplatin (class 2A). This recommendation is based on data from phase II trials. These trials investigated the efficacy and toxicity of gemcitabine plus oxaliplatin (GEMOX) in patients with relapsed or platinum-resistant GCT. The toxicity found was hematologic and manageable. These results show that gemcitabine combined with oxaliplatin is safe in patients with platinum-resistant testicular GCT and offers the opportunity for long-term survival.