Japanese Journal of Clinical Oncology

Patients and Exclusion Criteria

From January 1994 to April 1995, 29 patients with histologically confirmed locally invasive bladder cancer were entered into the study. On entry, patients had to be scheduled to receive at least two cycles of cisplatin-containing intraarterial chemotherapy, with an identical dose of cisplatin to be administered during each course. Eligible patients were inpatients of 16-80 years of age and performance status (PS) 0-3 according to World Health Organization (WHO) criteria, who gave written informed consent, which was subject to approval by the Ethics Committee, Institute of Clinical Medicine, University of Tsukuba. Exclusion criteria were (1) clinical evidence of severe cardiac, renal, hepatic or hematological disease; (2) confirmed or suspected pregnancy; (3) clinical evidence of bowel obstruction; (4) concomitant cerebral tumor or epilepsy; (5) emetic symptoms or use of antiemetic drugs prior to chemotherapy; and (6) other conditions deemed by attending physicians to make entry into the study inappropriate.

Pretreatment and Follow-up Examinations

Pretreatment evaluation included a complete medical history and physical examination. Complete blood cell counts, 12-channel biochemical profiles, determination of serum electrolytes and creatinine, 24 h urine collection for creatinine determination, electrocardiography and chest roentgenography were performed before patients received treatment. Follow-up laboratory examinations were performed at least twice in the first week after treatment and weekly thereafter.

Chemotherapy Regimens

All patients were hospitalized in order to receive three courses of cisplatin-containing intraarterial chemotherapy regimens. Cisplatin 50 mg/m² and methotrexate 30 mg/m² were administered over 60 min every 3 weeks through intraarterial catheters placed in the bilateral internal iliac arteries using the Seldinger method (9). Intravenous hydration with 2-3 l of 5% dextrose in 0.45% sodium chloride at a rate of 150-200 ml/h was given 3-6 h before chemotherapy until 12 h after cisplatin administration. All patients also received 200 ml of 10% mannitol solution intravenously at the time of cisplatin administration.

Antiemetic Treatment

The randomization sequence was computer generated, with treatment being assigned to blocks of four patients. Patients were classified into two groups: granisetron treatment (group G) or no treatment (group NG) with the first course of chemotherapy, crossing over with the second course at least 3 weeks later. The patients in group G received granisetron 40 µg/kg dissolved in 100 ml of physiological saline by intravenous infusion 30 min before CDDP administration. Patients in group NG received physiological saline only.

Evaluation Techniques

Before analyzing the efficacy of treatment, we checked for treatment-period interactions and period effects every day during the study (10). To evaluate the treatment-period interaction, we divided the patients into two groups based on whether treatment effectiveness was the same or different in the two treatment periods and then subdivided each based on the presence or absence of granisetron administration. To evaluate the period effect, we divided the patients who showed different treatment effectiveness in the two treatment periods into two groups based on the period in which effectiveness was observed. These groups were further subdivided based on the difference in treatment during the first and second treatment period (treatment or no treatment).

Effectiveness was evaluated based on patient and physician assessments of the degree of nausea and frequency of vomiting, including dry retching. All patients were observed in hospital, with the period of observation including the 24 h after cisplatin administration as the acute emetic phase and from the second to fifth day after cisplatin administration as the delayed emetic phase. Both patients and physicians made global assessments of nausea and treatment effectiveness. The degree of nausea was scored as follows: 0, none; 1, mild (no interference with normal daily life); 2, moderate (interference with normal daily life); and 3, severe (confinement to bed due to nausea). The score was recorded every 12 h during the acute emetic phase and daily during the late emetic phase. Nausea was graded as shown in Table 1.

The timing and number of episodes of vomiting and dry retching were recorded in the same way as nausea by the patients, cross-checked by physicians and entered on the clinical record form. Total clinical effectiveness was evaluated as being very effective (VE), effective (E), somewhat effective (SE) or not effective (NE) by combining nausea grade and the number of emetic episodes as shown in Table 2.

Table 1. Grading of nausea

Nausea grade	Total score
	0-12 h	0-24 h	Days 2-5
A	0-1	0-2	0-1
B	2	3-4	2
C	3	5-6	3

Table 2. Clinical effectiveness

Frequency of vomiting (times/day)*	Nausea grade
	A	B	C
0	VE	VE	E
1-2	VE	E	SE
3-4	E	SE	NE
[ge]5	NE	NE	NE

VE, very effective; E, effective; SE, somewhat effective; NE, not effective.
*Includes dry retching.

Table 3. Patients' characteristics

Characteristic	Group
	NG	G
No. of patients	13	16
Male/female	10/3	12/4
Age (years)
Median	67.5	68.5
Range	47-80	48-82
Performance status
0	10	12
1	2	3
2	1	0
3	0	1
Previous chemotherapy
Yes	0	1
No	13	15

Each group is categorized by the treatment in the first course.

`Complete control of emesis' was defined as no emetic episodes with no or mild nausea and the duration of this state after chemotherapy was recorded. Based on this, the proportion of patients in each group who did not experience vomiting was calculated.

Side-effects were recorded and the safety of treatment was evaluated.

Statistical Analyses

For each course of treatment, efficacy was assessed separately for the acute and delayed phases. Patients were included in a crossover analysis of a relevant variable if data for that variable were available for both courses of treatment. The Mann-Whitney U-test and Cox log rank test were used to test for differences between group G and group NG with a level of significance of 5%.

Acute Emetic Phase

Clinical effectiveness was evaluated daily for 5 days after CDDP administration (Table 4). Granisetron administration significantly reduced nausea and vomiting during the acute emetic phase (an evaluation of treatment as VE or E was made in 89.7% of patients in group G and 33.3% of patients in group NG; P < 0.001).

Table 4. Distribution of patients according to the clinical effectiveness of granisetron (%)

Time after chemotherapy	Group	n	No. of cases with		Effectiveness (%)				P
			Nausea	Vomiting	VE	E	SE	NE
0-12 h	NG	27	20	17	51.9	14.8	22.2	11.1	0.003
	G	29	9	1	93.1	0	6.9	0
0-24 h	NG	27	22	20	25.9	3.7	7.4	63.0	<0.001
	G	29	11	3	86.3	6.9	3.4	3.4
Day 2	NG	27	15	4	92.6	0	3.7	3.7	0.68
	G	29	13	5	89.7	0	0	10.3
Day 3	NG	27	9	2	96.3	0	0	3.7	0.20
	G	29	12	4	86.2	0	0	13.8
Day 4	NG	27	4	1	100	0	0	0	0.09
	G	29	8	3	89.7	6.9	0	3.4
Day 5	NG	27	3	0	96.3	0	0	3.7	0.63
	G	29	5	0	93.2	3.4	0	3.4

VE, very effective; E, effective; SE, somewhat effective; NE, not effective.

Delayed Emetic Phase

The effectiveness of treatment was evaluated as VE in [sim]90% of patients in groups G and NG during the delayed phase (P = not significant) (Table 4).

Complete Control of Emesis

The total clinical effectiveness of treatment, which was judged by the combined evaluation technique shown in Table 2, is shown in Fig. 1. Complete control of emesis was achieved in 68 and 18% of patients in groups G and NG, respectively. This difference was statistically significant (P < 0.0001).

Figure 1. Proportion of patients showing complete control of emesis at various times after CDDP-containing intraarterial chemotherapy. Solid line, group G; dashed line, group NG.

Side-effects

In one patient, slightly elevated liver enzyme levels were recorded during both courses of therapy, but these events were considered by the investigator to be probably unrelated to granisetron treatment. No central nervous system effects or serious adverse events were observed in group G.

DISCUSSION

CDDP-containing intraarterial chemotherapy produces an excellent local response and high survival rates in locally invasive bladder cancer (5-7,11-13), producing a response rate 2-10-fold that of intravenous administration (14). This is explained theoretically by intraarterial administration producing higher local peak concentrations, thereby augmenting the effectiveness of chemotherapy (15). In addition, because CDDP is rapidly bound to protein after administration, it should be most effective when delivered intraarterially (14,16). Furthermore, intraarterial CDDP administration may be less toxic if it has been protein bound or extracted during a first pass through a tumor bed (5,6), although it has been reported that the emetic side-effects of CDDP-containing intraarterial chemotherapy are similar to those of intravenous chemotherapy (11).

In a study by Kris et al. (17), all 15 patients (100%) receiving CDDP 50 mg/m² i.v. vomited, with the median number of emetic episodes being 7. In our study of the same CDDP dose administered intraarterially, CDDP appeared to be less emetogenic than it is on intravenous administration. However, gastrointestinal toxicities such as nausea, vomiting and anorexia are noted in almost all patients receiving CDDP-containing intraarterial chemotherapy; these toxicities reduce the quality of life and are dose limiting in some patients (8,18).

Recently, the efficacy of antiemetic therapy in controlling gastrointestinal toxicities has been studied and 5-HT₃ receptor antagonists have been found to be effective in controlling those caused by intravenous CDDP administration (4,19). However, neither the severity of gastrointestinal toxicity nor the efficacy of 5-HT₃ receptor antagonists against the emesis induced by CDDP-containing intraarterial chemotherapy has been evaluated in a prospective randomized trial. Therefore, this study represents the first randomized, placebo-controlled crossover trial assessing the antiemetic efficacy and safety of the 5-HT₃ antagonist granisetron in the prevention of CDDP-containing intraarterial chemotherapy-induced emesis. This study demonstrates that in patients receiving CDDP-containing chemotherapy, a single prophylactic dose of granisetron 40 µg/kg can prevent or control nausea and vomiting in the acute emetic phase. Granisetron also completely controlled emesis in a majority of patients.

Intravenous CDDP-containing chemotherapy is known to cause delayed emesis (20,21), but this was observed infrequently in the present study. From these results, CDDP-containing intraarterial chemotherapy may cause less delayed emesis than intravenous administration. This may be explained by the difference in the nature of delayed and acute emesis (20).

In conclusion, this is the first randomized, placebo controlled, crossover study of the use of the 5-HT₃ antagonist granisetron against emesis caused by intraarterial CDDP-containing chemotherapy. Although intraarterial CDDP administration produced less emesis than intravenous CDDP administration at the same concentration, gastrointestinal toxicity is still the most unpleasant side-effect for patients. A single prophylactic infusion of granisetron 40 µg/kg was effective in preventing the nausea and vomiting associated with intraarterial CDDP-containing chemotherapy.

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Received July 24, 1998; accepted November 9, 1998
For reprints and all correspondence: Katsunori Uchida, Department of Urology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
Abbreviations: CDDP, cisplatin; 5-HT₃, 5-hydroxytryptamine type 3; PS, performance status; WHO, World Health Organization; group G, granisetron treatment group; group NG, no granisetron treatment group; VE, very effective; E, effective; SE, somewhat effective; NE, not effective

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