Current therapeutic strategies for invasive and metastatic bladder cancer

Figures & data

Table 1 Results of randomized clinical trials evaluating neoadjuvant chemotherapy for muscle-invasive bladder cancer

Study	N	Regimen	Comparator	pCR	OS
EORTC/MRC^Citation36	976	CMV (3 cycles) followed by cystectomy or RT (n = 491)	Cystectomy or RT (n = 485)	33%	5.5% in favor of CMV
INT 0080/SWOG 8710^Citation38	317	M-VAC (3 cycles) followed by cystectomy (n = 154)	Cystectomy (n = 153)	38%	Trend in benefit with M-VAC (P = 0.06)
Nordic^Citation39	325	CA (2 cycles) followed by cystectomy or RT (n = 151)	Cystectomy or RT (n = 160)	NR	No difference
Nordic 2^Citation37	317	CM (3 cycles) followed by cystectomy (n = 155)	Cystectomy (n = 154)	26.4%	No difference
Italy (GISTV)^Citation40	171	M-VEC (3 cycles) followed by cystectomy (n = 82)	Cystectomy (n = 71)	28%	No difference

Abbreviations: pCR, pathologic complete response; OS, overall survival; CMV, cisplatin + methotrexate + vinblastine; M-VAC, methotrexate + vinblastine + adriamycin + cisplatin; NR, not reported; CA, cisplatin + adriamycin; CM, cisplatin + methotrexate; M-VEC, methotrexate + vinblastine + epirubicin + cisplatin; SWOG, South West Oncology Group; RT, radiotherapy.

Table 2 Active clinical trials evaluating neoadjuvant chemotherapy for muscle invasive bladder cancer¹⁰⁰

Study identifier	Phase	Study drug	Start date	Primary endpoint
NCT00585689	II	gemcitabine + carboplatin + nab-paclitaxel	December 2007	pCR
NCT00706641	Pilot (0)	dasatinib	June 2008	Feasibility
NCT01245660	Pilot (0)	lapatinib	November 2010	Effect on EGF pathway
NCT00847015	II	gemcitabine + cisplatin + sunitinib	February 2009	pCR, safety
NCT00506155	II	M-VAC + bevacizumab	July 2007	pCR
NCT01222676	II	gemcitabine + cisplatin + sorafenib	October 2010	pCR
NCT01031420	II	dose-dense M-VAC	December 2009	pCR
NCT01094496 (N-ABLE)	II	gemcitabine + cisplatin ± CDX-1307 vaccine (for tumors expressing β-hcg)	March 2010	RFS
NCT00268450	II	neoadjuvant gemcitabine + cisplatin + bevacizumab, followed by surgery and adjuvant bevacizumab and paclitaxel	December 2005	pCR
NCT00749892	II	erlotinib	September 2008	pCR
NCT00136175	II	gemcitabine + carboplatin + paclitaxel	August 2005	pCR
NCT01093066	II	M-VAC follwed by optimal TURBT	April 2010	BPR

Abbreviations: pCR, pathologic complete response; EGF, epithelial growth factor; M-VAC, methotrexate + vinblastine + adriamycin + cisplatin; RFS, recurrence-free survival; BPR, bladder preservation rate; TURBT, transurethral resection of bladder tumor.

Figure 1 Dysregulated signaling pathways and targeted therapy in bladder cancer.

Abbreviations: EGF, Epithelial Growth Factor; VEGF, Vascular Endothelial Growth Factor; IGF-1, Insulin-like Growth Factor-1; RTK, Receptor Tyrosine Kinase; mTOR, mammalian Target of Rapamycin.

Table 3 Select active clinical trials for first-line therapy in advanced and metastatic bladder cancer¹⁰⁰

Study identifier	Phase	Study drug	Start date	Primary endpoint
NCT00461851	II	gemcitabine + carboplatin + sorafenib	April 2007	TTP
NCT01126749	I/II	eribulin + gemcitabine + cisplatin	May 2010	Safety
NCT00635726	II	methotrexate + vinblastine + doxorubicin + cisplatin followed by gemcitabine + cisplatin	March 2008	ORR
NCT00645593	II	gemcitabine + cisplatin ± cetuximab	March 2008	ORR
NCT00995488	II	nab-paclitaxel + gemcitabine + carboplatin	October 2009	Efficacy
NCT01118039	II	sunitinib (cisplatin ineligible patients)	May 2010	TTP and safety
NCT01191892	II	gemcitabine + carboplatin ± vandetanib	August 2009	PFS
NCT01089088	II	gemcitabine + cisplatin + sunitinib	March 2010	PFS
NCT01090466	I/II	gemcitabine + cisplatin + temsirolimus	March 2010	PFS and safety
NCT01215136	II	everolimus ± paclitaxel (cisplatin ineligible patients)	October 2010	ORR
NCT00949455	II/II	lapatinib maintenance in HER-2+ bladder cancer after first-line chemotherapy	July 2009	PFS
NCT00625664	II	larotaxel + cisplatin vs gemcitabine + cisplatin (CILAB)	February 2008	OS
NCT00942331	II	gemcitabine + cisplatin ± bevacizumab	July 2009	OS
NCT00022191	II	gemcitabine + cisplatin ± paclitaxel	August 2001	OS
NCT00089128	II	gemcitabine + irinotecan	August 2004	ORR
NCT00478361	II	gemcitabine + paclitaxel + doxorubicin with pegfligrastim	May 2007	ORR, TTP, and survival

Abbreviations: TTP, time to progression; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

Table 4 Select active clinical trials in second-line therapy for advanced and metastatic bladder cancer¹⁰⁰

Study identifier	Phase	Study drug	Start date	Primary endpoint
NCT01265940	I/II	pazopanib + vinflunine	Dec 2010	PFS
NCT00365157	I/II	E7389 (halichondrin B analog)	October 2010	Response rate and safety
NCT00683059	II	nab-paclitaxel	May 2008	Response rate
NCT00578526	II	sunitinib (SPRUCE)	December 2007	PFS
NCT01282463	II	Docetaxel ± ramucirumab or IMC-18F1	January 2011	PFS
NCT01234519	I/II	AEZS-108 in LHRH + urothelial cancers	November 2010	MTD
NCT00722553	II	pralatrexate	July 2008	ORR
NCT01031875	II	pazopanib	December 2009	ORR
NCT01108055	II	pazopanib + paclitaxel	April 2010	ORR
NCT00933374	II	everolimus + paclitaxel	July 2009	ORR

Abbreviations: PFS, progression-free survival; MTD, maximum tolerated dose; ORR, objective response rate; AEZS-108, luteinizing-hormone-releasing hormone linked to doxorubicin.

Table 5 Variants of invasive urothelial carcinoma

Squamous cell carcinoma Adenocarcinoma Nested pattern Microcystic Micropapillary Lympho-epithelioma-like Plasmacytoid and lymphoma-like Sarcomatoid/carcinosarcoma Giant cell Trophoblastic differentiation Clear cell Lipid cell Undifferentiated

Note: Adapted from World Health Organization Classification of Tumours. IARC Press: Lyon; 2004:359.¹⁰¹

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