High dose chemotherapy with stem cell support in the treatment of testicular cancer

Table 1 Prognostic criteria for metastatic germ cell tumors[3]

	Good prognosis group	Intermediate prognosis group	Poor prognosis group
Seminoma	90% of cases 5 yr PFS 82% 5 yr OS 86% All of the following criteria: Any primary site No non-pulmonary visceral metastases Normal AFP Any hCG Any LDH	10% of cases 5 yr PFS 67% 5 yr OS 72% Any of the following criteria: Any primary site Non-pulmonary visceral metastases Normal AFP Any hCG Any LDH	-
Non-seminoma	56% of cases 5 yr PFS 89% 5 yr OS 92% All of the following criteria: Testis/retroperitoneal primary Non non-pulmonary visceral metastases AFP < 1000 ng/mL hCG < 5000 IU/L (1000 ng/mL) LDH < 1.5 × ULN	28% of cases 5 yr PFS 75% 5 yr OS 80% Testis/retroperitoneal primary Non non-pulmonary visceral metastases AFP 1000-10000 ng/mL hCG 5000-50000 IU/L (1000 ng/mL) LDH 1.5-10 × ULN	28% of cases 5 yr PFS 75% 5 yr OS 80% Any of the following criteria: Mediastinal primary Non-pulmonary visceral metastases AFP > 10000 ng/mL hCG > 50000 IU/L (1000 ng/mL) LDH > 10 × ULN

AFP: Alpha-fetoprotein; hCG: Human chorionic gonadotrophin; LDH: Lactate dehydrogenase; PFS: Progression free survival; OS: Overall survival.

Table 2 Studies of first line high dose chemotherapy for poor prognosis patients

Ref.	Type of study	Number of patients	Protocol	OS (%)	PFS (%)	Medianfollow-up (mo)
Motzer et al[15]	Phase II, prospective	28	VAB-6 × 2 + HD-CE × 2	57	46	31
Motzer et al[16]	Phase II, prospective	30	VIP × 2 + HD-CEC × 2	48 (5 yr)	48 (5 yr)	60
Bokemeyer et al[17]	Comparative, retrospective	147 (HDCT) vs 309 (SDCT)	VIP × 2 + HD-VIP × 2 vs BEP/VIP × 4	82 vs 72 (2 yr) P = 0.0184	75 vs 59 (2 yr) P = 0.0056	21
Schmoll et al[18]	Phase I/II, prospective	221	VIP + HD-VIP × 3-4	73 (5 yr)	68 (5 yr)	48
Hartmann et al[19]	Phase I/II, prospective	52	VIP + T-HD-VIP	75 (5 yr)	64 (5 yr)	41
Motzer et al[20]	Phase III, prospective	108 (HDCT) vs 111 (SDCT)	BEP × 2 + HD-CEC × 2 vs BEP × 4	71 vs 72 (2 yr)	60 vs 57 (2 yr)	33
Daugaard et al[23]	Phase III, prospective	65 (HDCT) vs 66 (SDCT)	VIP + HD-VIP × 3 vs BEP × 4	86.1 vs 83 (2 yr)	66.1 vs 48 (1 yr)	NR
Necchi et al[22]	Phase II, prospective	43 (HDCT) vs 42 (SDCT)	BEP × 2 + HD-CpE + HD-Carbo vs BEP × 4	54.8 vs 55.8 (5 yr)	59.3 vs 62.8 (5 yr)	114

BEP: Bleomycin, etoposide, cisplatin; HD: High dose; HD-CE: High dose carboplatin, etoposide; HD-CEC: High dose carboplatin, etoposide, cyclophosphamide; HDCT: High dose chemotherapy; HD-VIP: High dose, etoposide, ifosfamide, cisplatin; NR: Not reported; OS: Overall survival; PFS: Progression free survival; SDCT: Standard-dose chemotherapy; VAB: Actinomycin D, vinblastine, cyclophosphamide, bleomycin, cisplatin.

Table 3 High dose chemotherapy as second line treatment

Ref.	Type of study	Number of patients	Protocol	OS (%)	PFS (%)	Median follow-up (mo)
Rodenhuis et al[26]	Phase II, prospective	35	Conventional chemotherapy + HD-CTC × 2	NR	54	37
Bhatia et al[27]	Phase II, prospective	65	VeIP × 1-2 + HD-CE × 2	NR	57	39
Motzer et al[28]	Phase II, prospective	37	TI × 2 + HD-CE × 3	54	49	31
Rick et al[29]	Phase II, prospective	62	TIP × 3 + HD-CET × 1	30 (3 yr)	25 (2 yr)	36
Pico et al[30]	Phase III, prospective, randomized	135 (HDCT) vs 128 (SDCT)	VIP/VeIP × 3 + HD-CE × 1 vs VIP/VeIP × 4	53 vs 53 (3 yr)	42 vs 35 (3 yr)	45
Einhorn et al[31]	Retrospective	135	HD-CE × 2	NR	70	48
Lorch et al[32]	Phase II, prospective, randomized	111 (sequentional HDCT) vs 105 (single HDCT)	VIPx 1 + HD-CE × 3 vs VIP × 3 + HD-CE × 1	47 vs 45 (5 yr)	49 vs 39 (5 yr) P = 0.057	90
Feldman et al[33]	Phase I/II, prospective	107	TI × 2 + HD-CE × 3	52 (5 yr)	48 (5 yr)	61
Lorch et al[34]	Comparative, retrospective	821 (HDCT) vs 773 (SDCT)		53.2 vs 40.8 (5 yr) P < 0.001	49.6 vs 27.8 (2 yr) P < 0.001	NR
Selle et al[36]	Phase II, prospective	45	Epi-Tax × 2 + HD Thio-Tax + HD-ICE × 2	66% (2 yr)	50% (2 yr)	26
Berger et al[37]	Comparative, retrospective	95 (HDCT) vs 48 (SDCT)	HDCT vs SDCT	P = 0.931	Median 8 vs 42 mo P < 0.001	NR
Nieto et al[64]	Phase II, prospective	42	BEC-GDMC + BEV + HD-ICE	65% (2 yr)	63% (2 yr)	NR

BEV: Bevacizumab; Epi-Tax: Epirubicine, paclitaxel; GDMC: Gemcitabine, docetaxel, melphalan, carboplatin; HD: High dose; HD-CE: High dose carboplatin, etoposide; HD-CET: High dose carboplatin, etoposide, thiotepa; HDCT: High dose chemotherapy; HD-CTC: High dose carboplatin, thiotepa, cyclophosphamide; HD-ICE: High dose ifosfamide, carboplatin, etoposide; NR: Not reported; OS: Overall survival: PFS: Progression free survival; SDCT: Standard-dose chemotherapy; Thio-Tax: Thiotepa, paclitaxel; TI: Paclitexel, ifosfamide; TIP: Paclitexel, ifosfamide, cisplatin; VeIP: Vinorelbine, ifosfamid, cisplatin; VIP: Etoposide, ifosfamide, cisplatin.

Table 4 High dose chemotherapy for third or subsequent lines, refractory/absolute refractory

Ref.	Type of study	Number of patients	Setting	Protocol	OS (%)	PFS (%)	Medianfollow-up (mo)
Vaena et al[38]	Retrospective	80	Second and subsequent lines, refractory	HD-CE × 2	40 (2 yr)	32 (2 yr)	24
Lotz et al[39]	Prospective	45	Second and subsequent lines, refractory/absolute refractory	Epi-Tax × 2 + HD Thio-Tax × 1 + HD-ICE × 2	23.5 (3 yr)	23.5 (3 yr)	36
Kondagunta et al[40]	Prospective	47	Second and third line, refractory/absolute refractory	TI × 2 + HD-CE × 3	NR	51	40
Einhorn et al[31]	Retrospective	49	Third or subsequent	HD-CE × 2	55	45	48
Lorch et al[41]	Retrospective	49	Third or subsequent, refractory	Various	17 (5 yr)	26 (5 yr)	48
Popovic et al[42]	Prospective	8	Forth or fifht line, refractory	Epi-Tax × 2-3 + HD-CE × 1-2	Median 11 mo	NR	NR

Epi-Tax: Epirubicine, paclitaxel; HD: High dose; HD-CE: High dose carboplatin, etoposide; HDCT: High dose chemotherapy; HD-ICE: High dose ifosfamide, carboplatin, etoposide; NR: Not reported; OS: Overall survival; PFS: Progression free survival; SDCT: Standard-dose chemotherapy; Thio-Tax: Thiotepa, paclitaxel; TI: Paclitexel, ifosfamide.

Table 5 High dose chemotherapy for extragodadal germ cell cancer

Ref.	Type of study	Number of patients	Setting	Protocol	OS (%)	PFS (%)	Medianfollow-up (mo)
Bokemeyer et al[44]	Phase I/II, prospective	28	PMNSGCT, first line	VIPx 1 + HD-VIP × 3	64 (5 yr)	56 (5 yr)	43
Banna et al[45]	Prospective	21	PMNSGCT, first line	BEP or VIP × 4 + HD-CEC × 1	41 (3 yr)	43 (5 yr)	52
Rosti et al[46]	Retrospective	22	EGCT, poor prognosi, first line	Various	75 (5 yr)	67 (5 yr)	50
Hartmann et al[47]	Retrospective	142	EGNSGCT, salvage	Various	12 (3 yr) (PMNSGCT only)	11 (3 yr) (PMNSGCT only)	45
De Giorgi et al[48]	Retrospective	59	EGNSGCT, salvage	Various	14 (PMNSGCT only)	14 (PMNSGCT only)	58

EGCT: Extragonadal germ cell tumor; EGNSGCT: Extragonadal non-seminomatous germ cell tumor; HD: High dose; HD-CEC: High dose carboplatin, etoposide, cyclophosphamide; HDCT: High dose chemotherapy; HD-ICE: High dose ifosfamide, carboplatin, etoposide; NR: Not reported; OS: Overall survival; PFS: Progression-free survival; PMNSGCT: Primary mediastinal non-seminomatous germ cell tumor.

Table 6 International Germ Cell Cancer Collaborative Group-2 prognostic criteria for relapsed germ cell cancer patients

Parameter	Score points
	0	1	2	3
Primary site	Gonadal	Extragonadal	-	Mediastinal non-seminoma
Prior response	CR/PRm-	PRm+/SD	PD	-
PFI, mo	> 3	≥ 3	-	-
AFP salvage	Normal	≤ 1000	> 1000
HCG salvage	≤ 1000	> 1000	-	-
LBB	No	Yes	-	-
Score sum (0-10) Regroup into categories: (0) = 0; (1 or 2) = 1; (3 or 4) = 2; (5 or more) = 3 Add histology points: Seminoma = -1; Non-seminoma or mixed = 1 Final prognostic score: -1 = Very low risk; 0 = Low risk; 1 = Intermediate risk; 2 = High risk; 3 = Very high risk

AFP: Alpha-fetoprotein; CR: Complete remission; HCG: Human chorionic gonadotrophin; LBB: Liver, brain, bone; PD: Progressive disease; PFI: Progression free interval; PRm-: Partial remission, markers negative; PRm+: Partial remission, markers positive; SD: Stable disease.