Pegylated liposomal doxorubicin in the management of ovarian cancer

Figures & data

Figure 1. PRISMA chart showing the trial exclusion and inclusion process in the metaanalysis. SEER, Surveillance, Epidemiology, and End Results.

Table 1. Survival data extracted from analyzed clinical trials

Author	Year	No. pts	Arms	Phase	OS	PFS	OS P (log rank test)
					(HR)	(HR)
I line
Pignata et al.^39	2011	820	CPLD vs CP	III	0.82	0.95	0.58
					(0.72–1.12)	(0.81–1.13)
Bookman et al.^40	2009	862	CPLD vs CP	III	0.97	0.96	0.79
					(0.83–1.13)	(0.93–1.09)
II line
Bafaloukos et al.^44	2010	189	CPLD vs CP	II	-	1.15	-
						(0.78–1.66)
Kaye et al.^41	2011	97	PLD vs O	II	-	0.91	0.66
						(0.6–1.39)
Kaye et al.^41	2011	97	PLD vs O	II	-	0.86	0.66
						(0.56–1.3)
Albert et al.^43	2008	61	CPLD vs C	III	0.46	0.54	0.03
					(0.22–0.95)	(0.32–0.93)
CALYPSO^11	2010	976	CPLD vs CP	III	0.99	0.82	0.05
					(0.85–1.16)	(0.72–0.94)
Ferrandina et al.^28	2008	153	PLD vs G	III	-	-	0.411
Mutch et al.^20	2007	195	PLD vs G	III	1.02	-	0.87
					(0.71–1.42)
Gordon et al.^36	2004	474	PLD vs T	III	0.82	0.79	0.05
					(0.68–1)	(0.67–0.94)
III line
Colombo et al.^45	2012	829	PLD vs Patupilone	III	1.07	0.95
					(0.91–1.26)	(0.8–1.12)

Abbreviations: OS, overall survival; PFS, progression free survival; HR, hazard ratio; CPLD, carboplatin and pegylated liposomal doxorubicin; CP, carboplatin and paclitaxel; PLD, pegylated liposomal doxorubicin; O, olaparib; C, carboplatin; G, gemcitabine; T, topotecan.

Table 2. Response rate and toxicities data extracted from analyzed clinical trials

Author	Trial design	RR (%)	Hematologic toxicity
			TCP (%)	Anemia (%)	NTP (%)
I line
Pignata et al.^39	CPLD	57	16	10	43
	CP	59	2	4	50
Bookman et al.^40	CPLD	-	38	-	69
	CP	-	22	-	59
II line
CALYPSO^11	CPLD	-	16	8	35
	CP	-	6	5	45
Bafaloukos et al.^44	CPLD	51	11	-	35
	CP	57	2	-	30
Alberts et al.^43	CPLD	52	29	16	29
	C	29	10	0	3
Kaye et al.^41	PLD	25	-	0	-
	O	18	-	6	-
Kaye et al.^41	PLD	18	-	0	-
	O	31	-	13	-
Ferrandina et al.^28	PLD	16	0	7	6
	G	29	5	5	23
O’ Byrne et al.^48	PLD	17.8	-	-	-
	P	22.4	-	-	-
Mutch et al.^20	PLD	8	5	2	18
	G	6	6	3	38
Gordon et al.^36	PLD	20	1	28	12
	T	17	34	5	77
Rose et al.^47	PLD	10	-	-	-
	CC	32	-	-	-
Aurelia^46	PLD	7.9	-	-	-
	T	3.3	-	-	-
Aurelia^46	PLD	7.9	-	-	-
	P	12.6	-	-	-
III line
Vergote et al.^35	PLD	11	7	5	14
	Canfosfamide	4	5	11	8
Colombo et al.^45	PLD	7.9	-	3.7	10
	Patupilone	15.5	-	4.5	3

Abbreviations: OR, odds ratio; rr, risk ratio; CPLD, carboplatin and pegylated liposomal doxorubicin; CP, carboplatin and paclitaxel; PLD, pegylated liposomal doxorubicin; O, olaparib; C, carboplatin; G, gemcitabine; T, topotecan.

Table 3. Quality assessment

Included studies	Method of randomization	Allocation concealment	Blindness	Withdrawal and dropout	Baseline	Quality level
Pignata et al.^39	Centralized	Central office	No	Detailed criteria	Identical baseline	A
Bookman et al.^40	Centralized	Not detailed	No	Detailed criteria	Identical baseline	B
CALYPSO^11	Centralized	Central office	No	Detailed criteria	Identical baseline	A
Bafaloukos et al.^44	Centralized	Central office	No	Detailed criteria	Identical baseline	A
Alberts et al.^43	Centralized	Not detailed	No	Detailed criteria	Identical baseline	B
Kaye et al.^41	Centralized	Central office	No	Not detailed	Identical baseline	B
Ferrandina et al.^28	Centralized	Central office	Yes	Detailed criteria	Identical baseline	A
Mutch et al.^20	Centralized	Not detailed	No	Detailed criteria	Identical baseline	B
Gordon et al.^36	Centralized	Central office	No	Detailed criteria	Identical baseline	A
O’Byrne et al.^48	Not reported	Not detailed	No	Not detailed	Identical baseline	C
AURELIAl^46	Centralized	Central office	No	Detailed criteria	Identical baseline	A
Colombo et al.^45	Centralized	Central office	No	Detailed criteria	Identical baseline	A
Vergote et al.^35	Centralized	Central office	No	Detailed criteria	Identical baseline	A
Rose et al.^47	Centralized	Not detailed	No	Not detailed	Identical baseline	B

Figure 2. Comparison of OS and PFS, according to treatment line (A andB respectively) or platinum sensitivity (C and D respectively), between patients treated with a PLD-containing regimen vs. any other PLD-free schedule. Abbreviation: OS, overall survival; PFS, progression free survival; HR, hazard ratio; CPLD, carboplatin and pegylated liposomal doxorubicin; CP, carboplatin and paclitaxel; PLD pegylated liposomal doxorubicin; O, olaparib; C, carboplatin; G, gemcitabine; T, topotecan.

Figure 3. Comparison of RR and Ca125 response, according to treatment line (A and B respectively) or platinum sensitivity (C andD respectively), between patients treated with a PLD-containing regimen vs. any other PLD-free schedule. Abbreviation: OR, odds ratio; rr, risk ratio; CPLD, carboplatin and pegylated liposomal doxorubicin; CP, carboplatin and paclitaxel; PLD, pegylated liposomal doxorubicin; O, olaparib; C, carboplatin; G, gemcitabine; T, topotecan.

Table 4. Most common adverse events analyzed in the metaanalysis

Adverse events	Overall risk ratio (95% CI)	P value
Anemia	0.94 (0.42–2.11)	0.88
Neutropenia	0.89 (0.57–1.39)	0.61
Thrombocytopenia	1.34 (0.62–2.90)	0.45
Neurotoxicity	0.48 (0.16–1.41)	0.18
Palmar–plantar erythrodysesthesia	26.33 (11.76–58.99)	<0.01
Alopecia	0.22 (0.10–0.46)	<0.01

Figure 4. Funnel plot (Begg test) assessing publication bias.

Pignata S, Scambia G, Ferrandina G, Savarese A, Sorio R, Breda E, Gebbia V, Musso P, Frigerio L, Del Medico P, et al. Carboplatin plus paclitaxel versus carboplatin plus pegylated liposomal doxorubicin as first-line treatment for patients with ovarian cancer: the MITO-2 randomized phase III trial. J Clin Oncol 2011; 29:3628 - 35; http://dx.doi.org/10.1200/JCO.2010.33.8566; PMID: 21844495

 PubMed Web of Science ®Google Scholar

Bookman MA, Brady MF, McGuire WP, Harper PG, Alberts DS, Friedlander M, Colombo N, Fowler JM, Argenta PA, De Geest K, et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a Phase III Trial of the Gynecologic Cancer Intergroup. J Clin Oncol 2009; 27:1419 - 25; http://dx.doi.org/10.1200/JCO.2008.19.1684; PMID: 19224846

 PubMed Web of Science ®Google Scholar

Bafaloukos D, Linardou H, Aravantinos G, Papadimitriou C, Bamias A, Fountzilas G, Kalofonos HP, Kosmidis P, Timotheadou E, Makatsoris T, et al. A randomized phase II study of carboplatin plus pegylated liposomal doxorubicin versus carboplatin plus paclitaxel in platinum sensitive ovarian cancer patients: a Hellenic Cooperative Oncology Group study. BMC Med 2010; 8:3; http://dx.doi.org/10.1186/1741-7015-8-3; PMID: 20055981

 PubMed Web of Science ®Google Scholar

Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, Amnon A, Bell-McGuinn KM, Chen LM, Friedlander M, et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 2012; 30:372 - 9; http://dx.doi.org/10.1200/JCO.2011.36.9215; PMID: 22203755

 PubMed Web of Science ®Google Scholar

Alberts DS, Liu PY, Wilczynski SP, Clouser MC, Lopez AM, Michelin DP, Lanzotti VJ, Markman M, Southwest Oncology Group. Randomized trial of pegylated liposomal doxorubicin (PLD) plus carboplatin versus carboplatin in platinum-sensitive (PS) patients with recurrent epithelial ovarian or peritoneal carcinoma after failure of initial platinum-based chemotherapy (Southwest Oncology Group Protocol S0200). Gynecol Oncol 2008; 108:90 - 4; http://dx.doi.org/10.1016/j.ygyno.2007.08.075; PMID: 17949799

 PubMed Web of Science ®Google Scholar

Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, Gebski V, Heywood M, Vasey PA, Volgger B, Vergote I, Pignata S, Ferrero A, et al. Pegylated liposomal Doxorubicin and Carboplatin compared with Paclitaxel and Carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol 2010; 28:3323 - 9; http://dx.doi.org/10.1200/JCO.2009.25.7519; PMID: 20498395

 PubMed Web of Science ®Google Scholar

Ferrandina G, Ludovisi M, Lorusso D, Pignata S, Breda E, Savarese A, Del Medico P, Scaltriti L, Katsaros D, Priolo D, et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol 2008; 26:890 - 6; http://dx.doi.org/10.1200/JCO.2007.13.6606; PMID: 18281662

 PubMed Web of Science ®Google Scholar

Mutch DG, Orlando M, Goss T, Teneriello MG, Gordon AN, McMeekin SD, Wang Y, Scribner DR Jr., Marciniack M, Naumann RW, et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol 2007; 25:2811 - 8; http://dx.doi.org/10.1200/JCO.2006.09.6735; PMID: 17602086

 PubMed Web of Science ®Google Scholar

Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 2001; 19:3312 - 22; PMID: 11454878

 PubMed Web of Science ®Google Scholar

Colombo N, Kutarska E, Dimopoulos M, Bae DS, Rzepka-Gorska I, Bidzinski M, Scambia G, Engelholm SA, Joly F, Weber D, et al. Randomized, open-label, phase III study comparing patupilone (EPO906) with pegylated liposomal doxorubicin in platinum-refractory or -resistant patients with recurrent epithelial ovarian, primary fallopian tube, or primary peritoneal cancer. J Clin Oncol 2012; 30:3841 - 7; http://dx.doi.org/10.1200/JCO.2011.38.8082; PMID: 22987083

 PubMed Web of Science ®Google Scholar

O'Byrne KJ. A phase III study of Doxil/Caelyx versus paclitaxel in platinum-treated, taxane-naive relapsed ovarian cancer. Proc Am Soc Clin Oncol 2002; 21:203a

 Google Scholar

Rose P, Edwards R, Finkler N, Seiden M, Duska L, Krasner C, Cappuccini F, Kolevska T, Brand E, Brown G, et al. Phase 3 Study: Canfosfamide (C, TLK286) plus carboplatin (P) vs liposomal doxorubicin (D) as 2nd line therapy of platinum (P) resistant ovarian cancer (OC). ASCO Meeting Abstracts 2007; 25:LBA5529.

 Google Scholar

Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, Sorio R, Vergote IB, Witteveen P, Bamias A, et al. AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC). ASCO Meeting Abstracts 2012; 30:LBA5002.

 Google Scholar

Vergote I, Finkler N, del Campo J, Lohr A, Hunter J, Matei D, Kavanagh J, Vermorken JB, Meng L, Jones M, et al, ASSIST-1 Study Group. Phase 3 randomised study of canfosfamide (Telcyta, TLK286) versus pegylated liposomal doxorubicin or topotecan as third-line therapy in patients with platinum-refractory or -resistant ovarian cancer. Eur J Cancer 2009; 45:2324 - 32; http://dx.doi.org/10.1016/j.ejca.2009.05.016; PMID: 19515553

 PubMed Web of Science ®Google Scholar