Revised 08 May 2013
AFP negative, moderate elevations of LDH or bHCG acceptable (any AFP elevation in a “pure” seminoma would prompt treatment according to nonseminoma guidelines).
N0 M0 (clinical stage I)
Despite normal CT scans, a 20% risk of clinical occult metastatic disease in locoregional lymph nodes with subsequent disease progression remains, if no adjuvant treatment is applied after orchiectomy. Nevertheless, the cure rate in CS I seminoma patients is almost 100% after salvage of relapse. The primary management strategy after inguinal orchiectomy is surveillance with administration of irradiation or chemotherapy at time of relapse. Adjuvant radiation treatment, or adjuvant chemotherapy with single agent carboplatin are options , but are rarely the best option and surveillance is almost always the preferred strategy.
Surveillance is the current standard management strategy after an orchiectomy, but initial assessment at a cancer centre is strongly recommended. The potential advantage of surveillance is that patients are spared acute and late radiation toxicity and possibly an associated increased risk of secondary malignancies. Surveillance is labour-intensive and requires long-term follow-up in highly motivated patients. The exceptional patient that is not available or unwilling to undergo prolonged and close follow-up are not candidates for a surveillance strategy. Reported relapse rate on surveillance are approximately 20%. Almost all relapses should be salvageable with further therapy (either chemotherapy or radiotherapy). As a result, adjuvant radiotherapy and adjuvant chemotherapy are very rarely the recommended management.
Adjuvant radiotherapy of the para-aortic or para-aortic plus pelvic region was historically the most frequently used adjuvant treatment resulting in a relapse rate of 3-4% at 10 years. Almost all of these recurrences are located outside the irradiated area, mostly in the pelvis (1.7%) (if only para-aortic fields are used) or close to the border of the radiation fields. Total radiation dose is 20-25 Gy in 10 to 20 fractions. When used the standard fractionation is 25 Gy in 15 fractions to the para-aortic nodes alone. Due to the risk for secondary malignancies and the increased risk for cardiotoxicity, adjuvant radiation is no longer recommended as a standard management option and should be reserved for the exceptional patients with contraindications for active surveillance or adjuvant carboplatin.
Adjuvant chemotherapy with single agent Carboplatin is an alternative to radiation therapy or surveillance for stage I seminoma. A large phase III trial comparing one cycle of adjuvant carboplatin with adjuvant radiation demonstrated non-inferiority of Carboplatin to adjuvant radiation. Relapses in the Carboplatin arm, however, occurred mainly in the retroperitoneum. In the rare event that adjuvant carboplatin is chosen, one cycle at a dose of AUC (Area under the curve) 7 is considered standard of care.
Consultation with a specialized centre regarding the optimal treatment strategy in an individual patient is strongly recommended.
Studies of surveillance have identified tumour size (4 cm vs. >4 cm, hazard ratio 2.0) and rete testis invasion (hazard ratio 1.7) as important predictors of relapse in multivariate analysis. Other factors which may increase relapse rates include younger age (<34 years), lymphatic or vascular invasion, and undifferentiated histology. However, strategies to stratify patients into high and low risk groups to decide on surveillance or adjuvant therapies based on these risk factors (ie a risk adapted approach) have not been consistently validated (5,6). Even those patients with high risk features (eg size greater than 4 cm) can be managed with surveillance. In general, the majority of STAGE I SEMINOMA PATIENTS SHOULD BE OFFERED SURVEILLANCE AS THE PRIMARY RECOMMENDATION after inguinal orchiectomy regardless of these risk factors. Other groups have recently made similar recommendations for primary management (7,8). Adjuvant chemotherapy or adjuvant radiotherapy may be appropriate options in exceptional circumstances.
Jones WG, Fossa SD, Mead GM, et al. A randomised trial of 30 versus 20 Gy in the adjuvant treatment of stage I testicular seminoma: A report on Medical Research Council Trial TE 18, EORTC 30942. J Clin Onc 2005, 23: 1200-1208.
Fossa A, Jones WG, Stenning S, Collaborateurs ftT. Quality of life (QL) after radiotherapy (RT) for stage I seminoma : results from a randomized trial of two RT schedules (MRC TE18). Proc Am Soc Clin Oncol 2002; 21: abstract # 750.
Warde P, Specht L, Horwich A, Oliver T, Panzarella T, Gospodarowicz M, von der Maase H.; Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. J Clin Oncol. 2002, 20: 4448-4452.
Oliver RT, Mead GM, Rustin G, et al: Randomized trial of Carboplatin versus radiotherapy for stage I seminoma: . J Clin Onc 2011, 29: 957-962.
Aparicio J, Maroto P, Garcia del Muro X. Risk-adapted treatment in Clnical stage I testicular seminoma: The third Spanish Germ Cell Cancer Group study. J Clin Onc 2011, 29: 4677-4681.
Chung P, Daugard G, Tyldesley S et al. Prognostic factors for relapse in stage I seminoma managed with surveillance: A validation study. J Clin Onc 2010, 28 (15s) abst: 4535.
Wood L, Kollmannsberger C, Jewett M, et al . Canadian consensus guidelines for the management of testicular germ cell cancer. Can Urol Assoc J. 2010, 4(2):e19-38.
Albers P, Albrecht W, Algaba F et al. EUA guidelines on testicular cancer: 2011 update. Eur Urol 2011, 60(2):304-319.
N1-3 M0 (Clinical stage II A/B/C)
Relapse-free survival for patients with stage II A / B seminoma is approximately 95% and 90% at 6 years, respectively. Post inguinal orchidectomy, radiation treatment to the para-aortic and ipsilateral pelvic area (25 Gy in 20 fractions, with a boost to the involved nodes to a further 10 Gy in 5 fractions) is the standard treatment option for stage II A and a treatment option for stage IIB. Where fertility is an issue, the remaining testicle is shielded in conjunction with sperm banking.
Chemotherapy with three cycles of standard-dose cisplatin, etoposide and bleomycin (BEP), or four cycles of etoposide, cisplatin (EP, in case of contraindication for bleomycin) represent an alternative treatment for patients and is emerging as the standard treatment option for stage IIB seminoma in order to avoid potential long-term complications of radiation therapy.
Practical considerations for the use of BEP and other chemotherapy regimens:
- When considering the use of any chemotherapy, including bleomycin, the treating physician should balance the relative risks and benefits of the particular regimens available, relative to the patient’s comorbidities and tolerance of that regimen.
- Relative contraindications to the use of bleomycin include: age over 40, poor renal function, high cumulative bleomycin dose, severe pre-existing lung disease, and anaphylactic reaction to prior bleomycin exposure.
- All patients should be informed that they should notify their oncologist if they develop pulmonary symptoms (shortness of breath, dry cough, etc).
- Patients should be asked if they have developed any of the aforementioned pulmonary symptoms regularly while on chemotherapy.
- Patients should be examined for respiratory signs (such as inspiratory lag, or rales) regularly while on chemotherapy.
- BEP should be abandoned in favour of EP or VIP when respiratory symptoms and signs of toxicity develop even in the absence of normal pulmonary function testing or lung imaging is normal.
- Pulmonary function tests are usually performed prior to commencing BEP and at the beginning of the 4th cycle.
- For those who are going onto post chemotherapy surgery, the 11th and 12th doses of bleomycin are usually held.
- If there has been a significant decline in the diffusion capacity (>30-40 %), bleomycin is held.
- Arbitrary neutrophil recovery should not delay the initiation of chemotherapy. Cycles should start every 21 days without dose adjustment or delay. Prophylactic GCS-F is recommended for all ifosfamide containing regimens, patients with intermediate or poor risk disease and patients with a previous episode of neutropenic fever and/or a significant delay in neutrophil recovery. In patients with good risk disease and treatment with BEP or EP, neutropenic fever is rare and the prophylactic use of GCS-F is at the discretion of the treating physician.
- To minimize the risks of cisplatin-based chemotherapy on renal function, aggressive pre and post chemotherapy hydration is required. At least 1 litre of normal saline should be given prior to initiation of cisplatin and 1.5 to 2 additional litres after cisplatin daily. Patients should be encouraged to drink liquids aggressively and report significant vomiting immediately to their oncologist. Patients often gain a significant weight over the course of each five day session related to water intake, but this mobilizes rapidly and does not require diuretics for management.
- Bleomycin is an essential drug for optimal treatment of patients with testicular cancer, and can be given safely in the vast majority of patients and should not be withheld without clear cut contraindications to its use.
Advanced Seminoma - N3 >10 cm or M1 (Clinical stage IIC or III; "good" or "intermediate" prognosis acc. To the IGCCCG classification)
These patients will be treated with chemotherapy according to the IGCCCG classification. The standard approach is three cycles of BEP for patients with good risk disease, and 4 cycles of BEP for those with intermediate risk disease. When there are contraindications to bleomycin 4 cycles of EP is an alterative for patients with good risk disease, and 4 cycles of VIP is an alterative for patients with intermediate risk disease. A multi-disciplinary assessment is preferred before instigating therapy. These patients should have their evaluation and therapy expedited (visceral metastases from seminoma is rare).
Post treatment residual masses
Post-chemotherapy, as well as post-radiotherapy, the approach used at BCCCA for residual masses in seminoma patients is to closely follow by imaging investigations and tumour marker determinations rather than immediate resection, irrespective of the size of the mass. If close observation is not possible, residuals larger than 3 cm can be resected. PET scanning appears to be a promising tool in defining patients with residual lesions, in particular for lesions > 3 cm. It is important to perform the PET scan not earlier than 8 weeks after completion of chemotherapy in order to minimize false positive findings. This is the ONLY standard indication for PET scanning in testicular cancer management. The negative predictive value of PET-CT scans is high, and seminoma patients with PET-negative residuals should be followed irrespective of the size of the residual lesion. The positive predictive value of a PET-CT scan is less reliable (6). In PET-CT positive patients after chemotherapy either biopsy, close observation with serial CT scans, or, possibly, repeat PET-CT scans are recommended. If observed, residual masses are observed after therapy until there is definitive evidence of growth. Biopsy positive residual lesions or growing residual lesions should be resected whenever possible. The resection of growing residual seminoma lesions should be done in an experienced centre and by a surgeon experienced with this procedure. The resection of seminoma residual lesions is technically more difficult and associated with a higher complication rate as compared to the resection of nonseminoma lesions.
Routine use of radiotherapy for residual masses is not recommended (5), however, in the setting of clear isolated progression in a residual mass after chemotherapy, in a patient unable to undergo a resection, radiotherapy should be considered. Patients with residual masses after initial therapy should be discussed at the weekly multidisciplinary GU Tumour Case Conference.
Herr HW, Sheinfeld J, Puc HS et al. Surgery for a post-chemotherapy residual mass in seminoma. J Urol 1997; 157: 860-862.
Puc HS, Heelan R, Mazumdar M et al. Management of residual mass in advanced seminoma: results and recommendations from the Memorial Sloan-Kettering Cancer Center. J Clin Oncol 1996; 14: 454-460.
Albers P, Weissbach L, Krege S et al. Predictions of necrosis after chemotherapy of advanced germ cell tumors: results of a prospective multicenter trial of the German Testicular Cancer Study Group. J Urol 2004; 171: 1835-1838.
Mosharafa AA, Foster RS, Leibovich BC et al. Is post-chemotherapy resection of seminomatous elements associated with higher acute morbidity? Journal of Urology 2003; 169: 2126-2128.
Duchesne GM, Stenning SP, Aass N et al. Radiotherapy after chemotherapy for metastatic seminoma--a diminishing role. MRC Testicular Tumour Working Party. Eur J Cancer 1997; 33: 829-835.
De Santis M, Becherer A, Bokemeyer C et al. 2-18fluoro-deoxy-D-glucose Positron Emission Tomography Is a Reliable Predictor for Viable Tumor in Post Chemotherapy Seminoma: An Update of the Prospective Multicentric SEMPET Trial. J Clin Oncol 2004; 22: 1034-1039.