Gemcitabine and cisplatin in locally advanced and metastatic bladder cancer; 3- or 4-week schedule?

Figures & data

Table I.  Baseline clinical patient characteristics.

	3-week n (%)	4-week n (%)	p-value
Age (years) median (range)	63.7 (32.7–78.6)	61.4 (47.9–79.1)	0.17
Sex
male	124 (82.1)	42 (68.9)	0.034
female	27 (17.9)	19 (31.1)
PS (ECOG)
0–1	135 (89.4)	54 (88.5)	0.85
≥ 2	16 (10.6)	7 (11.5)
Hemoglobin
normal	59 (40.4)	21 (35.0)	0.47
low	87 (59.6)	39 (65.0)
P-alkaline phosphatase
normal	107 (74.3)	34 (56.7)	0.013
elevated	37 (25.7)	26 (43.3)
Stage
M0
T4b, N2-3	69 (44.4)	16 (26.2)	<0.0001
M1
extra-pelvine lymph nodes	31 (20.5)	7 (11.5)
visceral metastases	51 (33.7)	38 (62.2)

Figure 1.  Survival for all patients. a) Overall survival, 3-week vs. 4-week schedule; b) Progression-free survival, 3-week vs. 4-week schedule.

Table II.  Survival parameters.

	3-week (n = 151) No.	4-week (n = 61) No.
Overall survival
Events (death)	126 (83.5%)	52 (85.3%)
Censored patients	25 (16.5%)	9 (14.7%)
Median survival (95% CI)	12.50 (10.3–14.7)	14.7 (10.8–18.7)
12 months survival rate	51.7%	54.1%
36 months survival rate	21.2%	11.8%
60 months survival rate	14.9%	11.8%
HR*	0.87 (0.63–1.20) Walds p = 0.40
Progression-free survival
Events (progression)	131 (86.8%)	56 (91.8%)
Censored patients	20 (13.2%)	5 (8.2%)
Median survival (95% CI)	9.77 (8.3–11.2)	8.60 (7.0–10.2)
12 months survival rate	39.1%	32.8%
36 months survival rate	18.5%	8.6%
60 months survival rate	13.1%	8.6%
HR*	0.79 (0.58–1.08) Walds p = 0.14

Abbreviations: HR, Hazard Ratio; CI, Confidence Interval.

*A HR <1 indicates a better outcome for the 3-week schedule.

Table III.  Summary of efficacy outcomes.

			Treatment effect			Treatment effect when adjusted for prognostic factors
	3-week	4-week	HR 3- vs. 4- week	95% CI	p	HR 3- vs. 4-week	95% CI	p
Median overall survival (95% CI)	12.5 (10.3–14.7)	14.7 (10.8–18.7)	0.87	0.63–1.20	0.40	1.16	0.82–1.62	0.39
Median progression-free survival (95% CI)	9.77 (8.3–11.2)	8.60 (7.0–10.2)	0.79	0.58–1.08	0.14	1.00	0.72–1.38	0.98
			RR 3-/4-week			RR 3-/4-week
Overall response rate	59.7%	55.6%	1.07	0.81–1.41	0.61	0.91	0.69–1.19	0.64
Complete response rate	21.7%	21.8%	0.99	0.55–1.81	0.99	0.64	0.36–1.13	0.20

Abbreviations: CI, Confidence Intervals; HR, Hazard Ratio; RR, Risk Ratio.

A HR <1 indicates a better outcome for the 3-week schedule. The final model included performance status (HR = 2.02; 95% CI 1.26–3.24), presence and absence of visceral metastases (HR = 1.81; 95% CI 1.33–2.47), level of hemoglobin (HR = 1.57; 95%CI 1.16–2.13) and schedule.

Table IV.  Toxicity ratios, n = 212.

		3-week-schedule (n = 151) Cycles (n = 799)	4-week- schedule (n = 61) Cycles (n = 314)			Correction for absence or presence of visceral metastases
	Numbers accessible for evaluation (3-week/4-week)			RR 3 vs. 4^# 95% CI	χ^2 p	Corrected RR^# 3 vs. 4 (95% CI)	M-H weighted χ^2 p
Neutropenia grade 3 and 4 % of patients	206 (145/61)	54.9%	77.0%	0.71 (0.56–0.89)	0.003	0.66 (0.53–0.82)	0.001
Thrombocytopenia grade 3 and 4 % of patients	206 (145/61)	44.8%	72.1%	0.62 (0.49–0.79)	<0.001	0.61 (0.47–0.79)	0.001
Infection grade 3 and 4 % of patients	212 (151/61)	26.5%	31.1%	0.85 (0.54–1.34)	0.49	0.92 (0.57–1.47)	0.86
Neutropenic fever % of patients	212 (151/61)	4.6%	11.5%	0.40 (0.14–1.10)	0.07	0.33 (0.11–1.01)	0.08
Renal toxicity leading to dose-reduction % of patients	212 (151/61)	14.6%	18.0%	0.80 (0.41–1.56)	0.53	0.67 (0.33–1.37)	0.39
Transfusions RBC % of all cycles	212 (151/61)	23.7%	42.6%		<0.001*		0.001*
Transfusions platelets % of all cycles	212 (151/61)	1.6%	2.9%		0.18*		0.26*

Abbreviations: RR, Risc Ratio; CI, Confidence Intervals.

^#A RR <1 indicates a better outcome for the 3-week schedule. *) Mann-Whitney U-test.

Table V.  Dose intensity and compliance.

	gemcitabine		cisplatin
DI* (mg/m^2/week)	3-week (n = 151)	4-week (n = 61)	3-week (n = 151)	4-week (n = 61)
Planned dose	666	750	23.3	17.5
Received dose	639.7	605.6	21.5	16.4
Relative DI (%)	96.0	80.7	92.0	93.0

Abbreviations: DI, dose intensity.

Figure 2.  Overall survival for all patients according to the administration of cisplatin.

Figure 3.  Effect of chemotherapy on renal function. Each line illustrates the pre-treatment GFR value and the GFR value after the last treatment cycle for each patient.

Table VI.  Treatment compliance.

	3-week (n = 151)	4-week (n = 61)	p-value - χ^2
	No.	No.
Planned cycles	906	366
Delivered cycles	799 (88%)	314 (85%)	0.24
Modified in dose	153 (19%)	197 (62%)	<0.0001
Day 15 omissions		149 (47%)
Modified in timing	37 (5%)	59 (19%)	<0.0001

Table VII.  Presentation of 3- and 4-week GC Schedules.

	n	gemcitabine mg/m^2	day	cisplatin mg/m^2	day	dose adjustments	relative dose-intensity gemcitabine	OR/CR	median survival (months)	grade 3–4 neutropenia	grade 3–4 thrombo-cytopenia
4-week GC schedule
Kaufman et al. [3]	46	1000	1,8,15	75	1	30%		41%/22%	14.3	63%	60%
Moore et al. [5]	31	1000	1,8,15	70	2	100%	69%	57%/21%	13.2	39%	55%
Lorusso et al. [4]	54	1000	1,8,15	70	2	46.7%		48%/15%	12.5	39%	20%
von der Maase et al. [1]	203 (405)	1000	1,8,15	70	2	37%	80%	49%/12%	13.8	71%	57%
Present study	61 (212)	1000	1,8,15	70	2	62%	76.9%	55%/22%	14.7	77%	72%
Parra et al. [6]	54 (107)	1000	1,8,15	70	2	51%	79%	Lung cancer		27.8%	29.5%
3-week GC schedule
Hussain et al. [14]	32	1000–1200	1,8	35–45	1,8	–	–	65%/13%	16.0	34%	47%
Adamo et al. [11]	27	1200	1,8	75	2	8%	–	48%/20%	13.2	0	24%
Flechon et al. [19]	30	1250	1.8	70	1	40%	88%	Adjuvant		73%	23%
Present study	151 (212)	1000	1,8	70	2	19.5%	96%	59%/21%	12.5	54.9%	44.8%
Parra et al. [6]	53 (107)	1000	1,8	70	2	19%	88.5%	Lung cancer		22.5	5.5

Abbreviations: OR, Overall response Rate; CR, Complete response Rate.

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