Paclitaxel, cisplatin and gemcitabine in treatment of carcinomas of unknown primary site, a phase II study

Figures & data

Table I. Patient characteristics (n=98).

Characteristics	No.		%
Age, years
Median		54
Range		26–65
Sex
Men	50		51
Women	48		49
ECOG performance status
0	49		50
1	49		50
Histology
Adenocarcinoma	67		68
Poorly differentiated carcinoma	24		25
Squamous cell carcinoma	7		7
No. of metastatic sites
1	17		17
2	28		29
>2	53		54
Site of disease
Lung	40		41
Lymph nodes	74		75
Liver	49		50
Peritoneum	9		9
Adrenal glands	10		10
Bones	24		25
Skin	5		5
Alkaline phosphatase
Normal	44		45
Elevated	54		55
Lactatdehydrogenase (LDH)
Normal	44		45
Elevated	54		55

Table II. Treatment-related toxicities* (No of courses = 535) - rates in brackets.

	Grade 1	Grade 2	Grade 3	Grade 4
Hematological toxicity
Anemia	274 (51.2)	194 (36.3)	5 (0.9)	1 (0.2)
Thrombocytopnia	198 (37.0)	82 (15.3)	73 (13.6)	38 (7.1)
Neutropenia	55 (10.3)	115 (21.5)	154 (28.8)	75 (14.0)
Febrile neutropenia				19 (3.6)
Non-hematological toxicity
Nausea/vomiting	218 (40.7)	88 (16.4)	17 (3.2)	–
Mucositis	52 (9.7)	6 (1.1)	–	–
Diarrhoea	57 (10.7)	15 (2.8)	5 (0.9)	–
Myalgia	100 (18.7)	23 (4.3)	–	–

*According to National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 2.0.

Figure 1. Kaplan-Meier estimates of progression-free survival in all enrolled patients (n=98). Median PFS was 6.6 months (95% CI: 5.2–7.9).

Table III. Responses to therapy for patients with measurable disease (n=91).

Response	N	%	95% CI
Complete response^a	5	5.5	2.3–12.5
Partial response^a	34	37.4	28.1–47.7
Stable disease^b	27	29.7	21.2–39.8
Progressive disease	18	19.8	10.7–26.7
Treatment discontinuation prior to evaluation	7	7.7	3.7–15.2
Treatment-related death	3
Patient refusal	1
Intercurrent unrelated illness	1
Severe toxicity	1
Primary tumour identification	1

CI: confidence interval.

^aRefers to confirmed objective responses.

^bRefers to at least 6 weeks duration of stable disease.

Figure 2. Kaplan-Meier estimates of overall survival in all enrolled patients (n=98). Median OS was 10.7 months (95% CI: 8.0–13.4).

Table IV. Two-drug regimens containing platinum, taxane or gemcitabine.

Regimen	Number of patients	Response rate (%)	Median Survival (months)	The 1-year and 2- year survival (%)	Reference
DXP vs. DXCB	73	26 vs. 22	8 vs. 8	42 vs. 29 (1-year)	Greco et al. 2000 [23]
PLCB	77	39^a	13	NR	Briasoulis et al. 2000 [19]
DXP	22	33	8	NR	Bouleuc et al. 2001 [18]
PG vs. PIR	80	55 vs. 38^a	8 vs. 6	NR	Culine et al. 2003 [20]
GDX	36	40	10	43 and 7	Pouessel et al. 2004 [33]
PLP	37	43^a	11	38 and 11	Park et al. 2004 [30]
CBPL	22	23^a	6.5	27 (1-year)	El-Rayes et al. 2005 [21]
PLCB vs. GVL	92	24 vs. 20	11 vs. 7	38 vs. 29 (1-year)	Huebner et al. 2005 [28]
GCB	50	31	7.8	26 and 12	Pittman et al. 2006 [32]
PL(weekly)CB	42	18	8.5	33 and 17	Berry et al. 2007 [17]
DXCB	47	32^a	16.2	NR	Pentheroudakis et al. 2008 [31]
PG vs. P	52		11 vs. 8	46 vs. 35 (1-year)	Gross-Goupil et al. 2008 [26]
Mean		32.2	9.8	37 and 12

P: cisplatin; G: gemcitabine; C_B: carboplatin; P_L: paclitaxel; D_X: docetaxel; I_R: irinotecan; V_L: vinorelbine. NR: not reported. ^aResponse rate calculated by intention-to treat analysis.

Table V. Three-drug regimens containing platinum, taxane and/or gemcitabine.

Regimen	Number of patients	Response rate (%)	Median Survival (months)	The 1-year and 2-year survival (%)	Reference
PLCBE	55	47	13.4	NR	Hainsworth et al. 1997 [27]
PLCBE	71	48	11	48 and 20	Greco et al. 2000 [22]
GCBPL	120	25	9	42 and 23	Greco et al. 2002 [24]
PEG	30	37^a	7.2	26 (1-year)	Balaña et al. 2003 [16]
PLCBE and GIR	132	30	9.1	35 and 16	Greco et al. 2004 [25]
DXCBG	63	37^a	11.8	NR	Mel et al. 2006 (abstact) [29]
PGPL vs. PGVL	66	49 vs. 42^a	9.6 vs. 13.6	NR	Palmeri et al. 2006 [15]
CBGCA	33	39^a	7.6	36 and 14	Schneider et al. 2007 [34]
PLPG	98	43^a	10.7	42 and 14	Møller et al., current study
Mean		39.4	9.9	38 and 17

P: cisplatin; G: gemcitabine; C_B: carboplatin; P_L: paclitaxel; D_X: docetaxel; I_R: irinotecan; V_L: vinorelbine; E: etoposid; C_A: capecitabine. NR: not reported.

^aResponse rate calculated by intention-to treat analysis.

Greco FA, Erland JB, Morrissey LH, Burris HA, III, Hermann RC, Steis R, . Carcinoma of unknown primary site: Phase II trials with docetaxel plus cisplatin or carboplatin. Ann Oncol 2000;11:211–5.

 PubMed Web of Science ®Google Scholar

Briasoulis E, Kalofonos H, Bafaloukos D, Samantas E, Fountzilas G, Xiros N, . Carboplatin plus paclitaxel in unknown primary carcinoma: A phase II Hellenic Cooperative Oncology Group Study. J Clin Oncol 2000;18:3101–7.

 PubMed Web of Science ®Google Scholar

Bouleuc C, Saghatchian M, Di Tullio L, Louvet C, Levy E, Di Palma M, . A multicenter phase II study of docetaxel and cisplatin in the treatment of cancer of unknown primary site (CUP). Proc Am Soc Clin 2001;20:abstact 2300.

 Google Scholar

Culine S, Lortholary A, Voigt JJ, Bugat R, Theodore C, Priou F, . Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown primary site: Results of a randomized phase II study–trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01). J Clin Oncol 2003;21:3479–82.

 PubMed Web of Science ®Google Scholar

Pouessel D, Culine S, Becht C, Ychou M, Romieu G, Fabbro M, . Gemcitabine and docetaxel as front-line chemotherapy in patients with carcinoma of an unknown primary site. Cancer 2004;100:1257–61.

 PubMed Web of Science ®Google Scholar

Park YH, Ryoo BY, Choi SJ, Yang SH, Kim HT. A phase II study of paclitaxel plus cisplatin chemotherapy in an unfavourable group of patients with cancer of unknown primary site. Jpn J Clin Oncol 2004;34:681–5.

 PubMed Web of Science ®Google Scholar

El-Rayes BF, Shields AF, Zalupski M, Heilbrun LK, Jain V, Terry D, . A phase II study of carboplatin and paclitaxel in adenocarcinoma of unknown primary. Am J Clin Oncol 2005;28:152–6.

 PubMed Web of Science ®Google Scholar

Huebner G, Link H, Kohne CH, Stahl M, Kretzschmar A, Steinbach S, . Paclitaxel and carboplatin vs gemcitabine and vinorelbine in patients with adeno- or undifferentiated carcinoma of unknown primary: a randomised prospective phase II trial. Br J Cancer 2009;100:44–49.

 PubMed Web of Science ®Google Scholar

Pittman KB, Olver IN, Koczwara B, Kotasek D, Patterson WK, Keefe DM, . Gemcitabine and carboplatin in carcinoma of unknown primary site: A phase 2 Adelaide Cancer Trials and Education Collaborative study. Br J Cancer 2006;95: 1309–13.

 PubMed Web of Science ®Google Scholar

Berry W, Elkordy M, O'Rourke M, Khan M, Asmar L. Results of a phase II study of weekly paclitaxel plus carboplatin in advanced carcinoma of unknown primary origin: A reasonable regimen for the community-based clinic? Cancer Invest 2007;25:27–31.

 PubMed Web of Science ®Google Scholar

Pentheroudakis G, Briasoulis E, Kalofonos HP, Fountzilas G, Economopoulos T, Samelis G, . Docetaxel and carboplatin combination chemotherapy as outpatient palliative therapy in carcinoma of unknown primary: A multicentre Hellenic Cooperative Oncology Group phase II study. Acta Oncol 2008;47:1148–55.

 PubMed Web of Science ®Google Scholar

Gross-Goupil M, Fourcade A, Blot F, Penel N, Negrier S, Culine S, . A randomized trial of cisplatin with or without gemcitabine in patients (pts) with carcinoma of an unknown primary (CUP) and without poor prognostic factors: Results of GEFCAPI 02. Ann Oncol 2008;19 Suppl 8: abstract 798P.

 Google Scholar

Hainsworth JD, Erland JB, Kalman LA, Schreeder MT, Greco FA. Carcinoma of unknown primary site: Treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide. J Clin Oncol 1997;15:2385–93.

 PubMed Web of Science ®Google Scholar

Greco FA, Burris HA, III, Erland JB, Gray JR, Kalman LA, Schreeder MT, . Carcinoma of unknown primary site. Cancer 2000;89:2655–60.

 PubMed Web of Science ®Google Scholar

Greco FA, Burris HA, III, Litchy S, Barton JH, Bradof JE, Richards P, . Gemcitabine, carboplatin, and paclitaxel for patients with carcinoma of unknown primary site: A Minnie Pearl Cancer Research Network study. J Clin Oncol 2002;20:1651–6.

 PubMed Web of Science ®Google Scholar

Balana C, Manzano JL, Moreno I, Cirauqui B, Abad A, Font A, . Phase II study of cisplatin, etoposide and gemcitabine in an unfavourable group of patients with carcinoma of unknown primary site. Ann Oncol 2003;14:1425–9.

 PubMed Web of Science ®Google Scholar

Greco FA, Rodriguez GI, Shaffer DW, Hermann R, Litchy S, Yardley DA, . Carcinoma of unknown primary site: Sequential treatment with paclitaxel/carboplatin/etoposide and gemcitabine/irinotecan: A Minnie Pearl Cancer Research Network phase II trial. Oncologist 2004;9:644–52.

 PubMed Web of Science ®Google Scholar

Mel JPM, Balaña C, López-Vega J, Casado A, Segura A, Cervera J, . Phase II study of Docetaxel (D), Carboplatin (C) and Gemcitabine (G), in advanced tumors of unknown primary site. J Clin Oncol 2006;4 Suppl 18: abstract 12028.

 Google Scholar

Palmeri S, Lorusso V, Palmeri L, Vaglica M, Porta C, Nortilli R, . Cisplatin and gemcitabine with either vinorelbine or paclitaxel in the treatment of carcinomas of unknown primary site: Results of an Italian multicenter, randomized, phase II study. Cancer 2006;107:2898–905.

 PubMed Web of Science ®Google Scholar

Schneider BJ, El-Rayes B, Muler JH, Philip PA, Kalemkerian GP, Griffith KA, . Phase II trial of carboplatin, gemcitabine, and capecitabine in patients with carcinoma of unknown primary site. Cancer 2007;110:770–5.

 PubMed Web of Science ®Google Scholar