ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of mixed or non-seminomatous germ cell tumors (NSGCT)

Annals of Oncology 16 (Supplement 1): i37 – i39, 2005 doi:10.1093/annonc/mdi817

ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of mixed or non-seminomatous germ cell tumors (NSGCT) Incidence .

The crude incidence rate of testicular cancer in Europe is 4.8/100 000 males/year, the mortality 0.35/100 000 males/year. About 60% of these testicular cancers are mixed or non-seminomatous tumors, 2 –3% present as bilateral tumors.

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Diagnosis should be based on histology of testis mass removed by inguinal orchiectomy [IV, B]. Biopsy (trucut or by mediastinoscopy) is needed in patients presenting with retroperitoneal or mediastinal primary [IV, B]. A cancer of unknown primary has to be ruled out by positive results of tumor markers. Patients with multiple lung or other extensive metastases should be considered for urgent chemotherapy. In these cases, patients may be diagnosed by typical clinical picture and raised markers [a-fetoprotein (aFP), b-human chorionic gonadotropin (bHCG)] [IV, B].

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Response evaluation .

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Patients on surveillance

Staging and risk assessment .

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Full blood count, urea, electrolytes, and liver function tests. Tumor markers, (aFP, bHCG, LDH), pre and post orchiectomy, and a CT-scan of chest and abdomen [III, A]. A MRI (or CT-scan if not available) of the brain if bHCG > 10 000 IU/l or >10 lung metastases [IV, B]. A bone scan in patients with metastatic disease [IV, B]. Contralateral testis biopsy should be considered, especially in patients with testicular atrophy (<16 ml) [III, A]. Staging according to the TNM system with optional listing of the Royal Marsden Hospital Staging and mandatory establishing of the prognostic group according to the International Germ Cell Consensus Classification (Table 1). Stage I patients are subdivided into low risk, (20% relapse rate) or high risk, (40–50% relapse rate), according to absence or presence of vascular, (lymphatic or venous) invasion. Prognosis is excellent, (98–100%), whichever management option is used. The choice is made on consideration of relative toxicities. For patients intended for chemotherapy or testicular radiotherapy sperm cryopreservation should be considered.

q 2005 European Society for Medical Oncology

Response is assessed by tumor marker measurement at least prior to each treatment cycle and repeat CT-scans post treatment [III, A]. Patients with residual masses post chemotherapy should have them resected wherever possible by a specialist surgeon [IV, A].

Follow-up .

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Patients should be treated by an oncologist with experience in testicular cancer treatment [II, B]. Treatment options are summarised in Table 2. Patients with testicular intraepithelial neoplasia, TIN, of the testis may be treated with radiotherapy to the affected testis (20Gy/10 fractions in 2 weeks) [III, B], orchiectomy, or initial surveillance.

Clinical review, chest X-ray, and tumor markers monthly for 1 year, 2 monthly for 2nd year, 4 monthly 3rd year, then 6 monthly to 5 years. CT-scans after 3, 6, 9, 12, and 24 months [III, B].

Post-chemotherapy patients .

Clinical review, chest X-ray, and tumor markers 2 monthly for 1 year, 3 monthly for 2nd year, then 6 monthly to 5 years, and then annually. CT-scans only as clinically indicated [V, D].

Note Levels of Evidence [I–V] and Grades of Recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.

Literature 1. Harland SJ, Cook PA, Fossa SD et al. Intratubular germ cell neoplasia of the contralateral testis in testicular cancer: defining a high risk group. J Urol 1998; 160: 1353–1357.

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Diagnosis

Treatment

i38 Table 1. Stage grouping according to the TNM 2002 system Stage

T

N

M

International Germ Cell Consensus Classification S

Good prognosis: all of the following

Stage 0

PTis

N0

M0

S0

– aFP <1000 ng/ml and bHCG <5000 IU/l (<1000 ng/l)

and

Stage I

pT1-4

N0

M0

SX

LDH < 1.5 upper limit of normal (ULN)

and

Stage IA

pT1

N0

M0

S0

– Non-mediastinal primary

and

Stage IB

pT2-4

N0

M0

S0

– No non-pulmonary visceral metastases present

Stage IS

any pT/Tx

N0

M0

S1

Stage II

any pT/Tx

N1-3

M0

Sx

Intermediate prognosis: all of the following

Stage IIA

any pT/Tx

N1

M0

S0-1

– aFP 1000–10 000 ng/ml, or bHCG 5000–50 000 IU/l

Stage IIB

any pT/Tx

N2

M0

S0-1

or LDH 1.5–10 ULN

and and

any pT/Tx

N3

M0

S0-1

– Non-mediastinal primary site

Stage III

any pT/Tx

any N

M1a-b

SX

– No non-pulmonary visceral metastases present

Stage IIIA

any pT/Tx

any N

M1a

S0-1

Poor prognosis: any of the following

Stage IIIB

any pT/Tx

any N

M0

S2

– aFP >10 000 ng/ml or bHCG >50 000 IU/l or LDH >10 ULN

or

any pT/Tx

any N

M1a

S2

Stage IIIC

any pT/Tx

any N

M1a

S3

– Mediastinal primary site

or

any pT/Tx

any N

M1b

any S

– Non-pulmonary visceral metastases present

SX, marker studies not available (should not be accepted); M1a, non-regional nodal or pulmonary metastases; M1b, other metastases.

Table 2 Treatment options are summarized below Category

Recommended

Alternative

Evidence Grade

‘Low’ risk

Surveillance protocol

2BEP or retroperitoneal lymph node dissection (RPLND)

III, A

‘High’ risk

Adjuvant chemotherapy BEP2 cyclesa

Surveillance or RPLND

III, B

BEP3 cyclesa

PE4c

II, A

VIP4, entry into appropriate clinical protocols is encouraged

II, A

Localized (Clinical Stage I)

Metastatic (Clinical Stage II–III) Group: Good prognosis Group: Intermediate or Poor prognosis

a

BEP4

a

BEP, bleomycin 30 mg D1, 8, 15; etoposide 100 mg/m2 D1-5 (or 165 mg/m2 D1-3); cisplatin 20 mg/m2 D1-5 (or 50 mg/m2 D1, 2). For patients receiving adjuvant BEP; etoposide may be reduced to 360 mg/cycle [III, B]. c In order to avoid bleomycin toxicity. b

2. Group IGCC. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997; 15: 594–603. 3. Read G, Stenning SP, Cullen MH et al. Medical Research Council prospective study of surveillance for stage I testicular teratoma. Medical Research Council Testicular Tumors Working Party. J Clin Oncol 1992; 10: 1762– 1768. 4. Cullen MH, Stenning SP, Parkinson MC et al. Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: A Medical Research Council report. J Clin Oncol 1996; 14: 1106–1113. 5. Saxman SB, Finch D, Gonin R, Einhorn LH. 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 Oncol 1998; 16: 702 –706. 6. de Wit R, Roberts JT, Wilkinson PM et al. 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 Oncol 2001; 19: 1629– 1640. 7. Kaye SB, Mead GM, Fossa S et al. Intensive induction-sequential chemotherapy with BOP/VIP-B compared with treatment with BEP/EP for poor-prognosis metastatic nonseminomatous germ cell tumor: a Randomized Medical Research Council/European Organization for Research and Treatment of Cancer study. J Clin Oncol 1998; 16: 692–701. 8. Nichols CR, Catalano PJ, Crawford ED et al. 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 Oncol 1998; 16: 1287–1293. 9. Hendry WF, A’Hern RP, Hetherington JW et al. Para-aortic lymphadenectomy after chemotherapy for metastatic non-seminomatous germ

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Stage IIC

i39 cell tumors: prognostic value and therapeutic benefit. Br J Urol 1993; 71(2): 208–213. 10. Schmoll HJ, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377–1399. Coordinating authors for the ESMO Guidelines Task Force: R. A. Huddart1 & G. Purkalne2 1

Invited author, Institute of Cancer Research, 15 Cotswolds Rd, Sutton Surrey, SM7 1DN, UK; 2Assigned task force member, P. Stradins

University Hospital, Radiation & Chemotherapy Center, Pilsonu Str. 13, Riga, LV 1002, Latvia Approved by the ESMO Guidelines Task Force: April 2002, last update December 2004. Correspondence to: ESMO Guidelines Task Force ESMO Head Office Via La Santa 7 CH-6962 Viganello-Lugano Switzerland

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