Revised 08 May 2013

T1-3 N0 M0 S0-S3 (clinical stage I and IS)

The cure rate of patients with non-seminoma clinical stage I is 99%. Vascular invasion (VI) of the primary tumour is the most important prognostic indicator for relapse. Patients with VI have a risk of 48% to develop metastatic disease, whereas only 14–22% of patients without VI will relapse. The evidence and percentage of embryonal carcinoma of the total tumour volume is the second most relevant prognostic factor, with an increase in risk correlating to the proportion of embryonal carcinoma within the primary tumour.

Treatment Options:

Three treatment options exist for clinical stage I patients:

Surveillance, which is the preferred treatment option irrespective of the risk status. Adjuvant chemotherapy or retroperitoneal lymph node dissection (RPLND) are alternate options, but only for patients unwilling or unable to undergo surveillance,

Management details:

1. Surveillance (preferred treatment option)
• All staging is unequivocally normal;
• patient is considered reliable and available for close follow up including serial CT scans of the retroperitoneum; and
• surveillance is acceptable to the referring urologist, the patient and the oncologist.
2. Retroperitoneal lymph node dissection (nerve-sparing).This surgical technique is intended to preserve the contralateral sympathetic nerves which allows ejaculation in most patients. However, where lymphadenopathy is encountered intraoperatively, a full bilateral block dissection should be performed. Relapses after RPLND occur mainly in the lungs (approximately 10%). Discussion in the multidisciplinary GU tumour conference and referral to an experienced centre is strongly recommended for consideration of RPLND and for the operation itself when indicated.
3. Adjuvant chemotherapy with one (or two cycles of BEP) may be considered in selected high risk patients unwilling or unable to undergo surveillance. There is no randomized comparison or 1 versus 2 cycle of BEP in this setting. Both strategies are associated with a low relapse rate of approximately 4-5% (8,9,10). These patients should therefore be discussed at the multidisciplinary conference. Referral to an experienced centre is advised.

For patients with clearly elevated and rising tumour markers after orchiectomy (ie T1N0 S 1-3 disease), BEP for 3 cycles is recommended. Such cases should be discussed at multi-disciplinary tumour board before commencing chemotherapy.

T0-4 N1-2 M0 S0 (clinical stage II and "good prognosis" according to the IGCCCG classification)

The cure rate for CS IIA and IIB non-seminoma is close to 98%.

Treatment should be selected to provide the best chance of cure with a single modality, as this will minimize morbidity. Early referral for assessment is preferred.

1. Primary chemotherapy according to the IGCCCG classification is recommended. For patients with "good prognosis" disease according to IGCCCG criteria, standard treatment is three cycles BEP. In case of contraindications to bleomycin, four cycles of cisplatin and etoposide (EP) can be given. Patients with a retroperitoneal mass ≥ 2 cm (stage IIB) and/or positive markers should receive primary chemotherapy followed by resection of residual lesions of ≥ 1 cm. Patients with residual mass < 1 cm after chemotherapy are considered low risk of relapse and routine resection is not warranted.
2. The treatment of patients with marker-negative stage IIA remains controversial. Up to 50% of patients (ref: Stephenson et al) have false positive lymph nodes and are pathological stage I disease. For these patients, an observation period with short-term CT follow up (e.g. repeat CT after 6-8 weeks) is recommended in order to allow the disease to declare itself. Growing lesions as well as positive tumour markers will be treated according to the IGCCCG classification. Regressing lymph nodes should be observed. If lymph nodes remain unchanged but suspicious a primary retroperitoneal lymph node dissection may be indicated. All RPLNDs should be done in an expert centre.

References:

1. Vergouwe Y, Steyerberg EW, Eijkemans MJ, et al: Predictors of occult metastasis in clinical stage I nonseminoma: a systematic review.[see comment]. Journal of Clinical Oncology 21:4092-9, 2003

2. Albers P, Siener R, Kliesch S, et al: Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German Testicular Cancer Study Group Trial. Journal of Clinical Oncology 21:1505-12, 2003

3. Donohue JP, Foster RS, Rowland RG, et al: Nerve-sparing retroperitoneal lymphadenectomy with preservation of ejaculation. J Urol. 144:287-291, 1990

4. Donohue JP, Thornhill JA, Foster RS, et al: The role of retroperitoneal lymphadenectomy in clinical stage B testis cancer: the Indiana University experience (1965 to 1989). J Urol 153:85-89, 1995

5. Weissbach L, Bussar MR, Flechtner H, et al: 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 Urol 37:582-594, 2000

6. Pont J, Holtl W, Kosak D, et al: Risk-adapted treatment choice in stage I nonseminomatous testicular germ cell cancer by regarding vascular invasion in the primary tumor: a prospective trial. Journal of Clinical Oncology 8:16-20, 1990

7. Amato RJ, Ro JY, Ayala AG, et al: Risk-adapted treatment for patients with clinical stage I nonseminomatous germ cell tumor of the testis. Urology 63:144-8; discussion 148-9, 2004

8. Albers P et al. 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 Oncol. 2008 Jun 20;26(18):2966-72.

9. Tansdstad T et al. Risk-adapted treatment in clinical stage I nonseminomatous germ cell testicular cancer: the SWENOTECA management program. J Clin Oncol. 2009 May 1;27(13):2122-8.

10. Pont J et al. Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: long-term results of a prospective trial. J Clin Onc. 14(2):441-8, 1996

Any T any N1-3 M0 S2,3; T any N any M1 S0-3 (Clinical stage III or "good", "intermediate" or "poor" prognosis according to the IGCCCG classification)

Induction chemotherapy followed by resection of residual masses is the standard approach for these patients. Because of the complexity and specialized nature of this treatment, referral to the BC Cancer Agency for opinion is strongly recommended.

For patients with "good prognosis" disease according to IGCCCG criteria, standard treatment is three cycles BEP. In case of contraindications against bleomycin, four cycles of cisplatin and etoposide (EP) can be given. Four cycles of BEP are the standard treatment for patients with intermediate or poor prognosis. Four cycles of etoposide, ifosfamide and cisplatin (VIP) are equally effective compared to BEP, but cause more acute myelotoxicity without offering additional benefits. VIP should however be considered in patients with contraindications for bleomycin or patients who are at high risk for bleomycin induced toxicity (age > 40 years; poor renal function; wide-spread metastatic disease; high cumulative bleomycin dose). VIP should also be considered for patients with extensive pulmonary metastases in whom secondary post-chemotherapy resections of residual lung lesions is expected.

In patients with a residual mass ≥1 cm and normalization of tumour markers, the residual masses have to be resected. Histological findings in subsequent surgery for residual masses after first line chemotherapy will reveal necrosis in about 50-60%, mature teratoma in 20-30% and vital cancer in 10-15%. The incidence of vital cancer is even higher after salvage chemotherapy. If technically feasible, all residual masses should be resected ( ie a full bilateral RPLND). In patients with residual masses at multiples sites, an individual decision should be made regarding number and extension of resections. If malignancy is evident in the resected specimen, two further cycles of intensive chemotherapy may be required.

Patients with brain metastases at initial presentation are still potentially curable and require multimodality therapy including neurosurgery, radiation oncology and medical oncology. Asymptomatic patients with brain metastases can be started on chemotherapy while the benefit of initial cranial irradiation remains unclear in these patients. The role of consolidating radiation in patients with good response in the brain to chemotherapy remains unclear and requires individualized treatment decision. All patients with brain metastases should be referred to a specialized centre.

Patients in whom brain metastases are discovered after an otherwise complete extracranial response to systemic chemotherapy, or persist after an otherwise complete extracranial response to chemotherapy, should have resectable lesions removed and proceed with curative intent cranial irradiation thereafter. When cranial irradiation is given with curative intent for non-seminoma the dose of radiation to the whole brain should be in the range of 40 to 45 Gy in 1.8 to 2 Gy fractions with a boost to gross disease to higher dose (typically a further 10 Gy). Brain metastases with seminoma is rare but more radiosensitive, and doses in the 30 to 40 Gy range are appropriate. Such cases should be discussed at multidisciplinary tumour board prior to cranial radiotherapy. Patients who relapse or progress with extracranial disease and brain metastases after previous chemotherapy have a poor prognosis. Treatment should include palliative cranial irradiation.

To maintain the highest chances for curability, all "poor-prognosis" patients should be transferred to a specialized centre without any delay to benefit from optimal interdisciplinary management and supportive care.

Reference:

1. O'Sullivan JM, Huddart RA, Norman AR, et al: Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours. Annals of Oncology 14:91-6, 2003