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  Volume 95
Numero 6
novembre-dicembre 2009 		I documenti sono in formato PDF, consultabili utilizzando Acrobat Reader
 
Thalidomide improves prevention of chemotherapy-induced gastrointestinal side effects following a modified FOLFOX7 regimen: results of a prospective randomized crossover study

Yunpeng Liu, Jingdong Zhang, Yuee Teng, Lingyun Zhang, Ping Yu, Bo Jin, Mingfang Zhao, Jing Shi, Shizhou Liu, Na Song, Zhi Li
Department of Medical Oncology, the First Hospital, China Medical University, Shenyang City, China

Key words: chemotherapy-induced nausea and vomiting (CINV), ramosetron, thalidomide.

abstract

Aims and background. Thalidomide was firstly evaluated for the control of chemotherapy-induced gastrointestinal side effects following a modified FOLFOX7 (mFOLFOX7) regimen.
Methods and study design. Chemotherapy-naive patients with malignant tumors were randomized into two groups: A-B group (A, 0.3 mg of ramosetron plus 10 mg of dexamethasone on day 1, was given intravenously in the first cycle, and B, 0.3 mg of ramosetron plus 10 mg of dexamethasone on day 1 intravenously plus 150 mg orally twice daily of thalidomide on days 2 through 5, in the second cycle) and B-A group (those drugs were given in the reverse sequence). The primary end point was the efficacy of thalidomide in controlling delayed (days 2 through 5) chemotherapy-induced nausea and vomiting (CINV). The secondary end point was the safety of thalidomide.
Results. Of 52 patients enrolled, 50 patients (96%) were assessable. Complete response rates of delayed nausea (no nausea) were higher with group B than group A (52% vs 24%, P = 0.004 on day 2; 58% vs 24%, P =0.001 on day 3; and 60% vs 36%, P = 0.016 on day 4). Complete response rates of delayed emesis (no emetic episodes, no rescue therapy) for group B and A also showed significance (86% vs 66%, P = 0.019 on day 2 and 76% vs 56%, P = 0.035 on day 3). Complete response rates on anorexia for group B were higher than those for group A on days 2 through 5. More patients in group B reported sedation or dizziness than in group A (42% vs 9.6%; P = 0.000). 
Conclusions. Thalidomide improves prevention of chemotherapy-induced gastrointestinal side effects following the mFOLFOX7 regimen. It is a safe, effective antiemetic.

Introduction
Chemotherapy-induced nausea and vomiting (CINV) is one of the most common side effects of cancer chemotherapy. Clinical consequences of CINV such as malnutrition, acid-base and electrolyte changes, and patient refusal to continue chemotherapeutic cycles decrease health-related quality of life1 and compromise treatment efficacy. In the meantime, CINV has a considerable economic impact2. During the last 20 years, many agents have been studied to establish their efficacy in controlling CINV. Antiemetic agents include serotonin (5-HT3) receptor antagonists (ondansetron, granisetron, ramosetron and dolasetron), NK-1 receptor antagonist (eg, aprepitant), dexamethasone, phenothiazines and antihistamines. Most patients receiving moderately (e.g., oxaliplatin >75 mg/m2) to highly (e.g., cisplatin ≥50 mg/m2) emetogenic chemotherapy3 will not experience acute emesis (which occurs within 24 h postchemotherapy) with the combination of a 5-HT3 receptor antagonist and corticosteroids. However, 5-HT3 antagonists and corticosteroids control less than 50% of delayed CINV episodes, which occur 24 h or more after the start of chemotherapy4.
Among those antiemetic agents, dexamethasone is clearly effective in preventing emesis in both acute and delayed phases5. A recent meta-analysis of randomized controlled trials found that adding a 5-HT3 antagonist to dexamethasone did not improve the antiemetic effect of dexamethasone in preventing delayed emesis. The introduction of aprepitant and palonosetron represented an important advance in the prevention of delayed CINV6-8. Nevertheless, the control of delayed CINV was still not satisfactory. Therefore, further progress depends on innovative approaches and agents. 
Thalidomide, a derivative of glutamic acid, was introduced in Europe in 1954 as a sedative/hypnotic agent and was used to ameliorate nausea in pregnancy. Although thalidomide was well tolerated, a large increase in the incidence of limb malformations in newborn children was observed as a result of thalidomide use during pregnancy. Thalidomide was withdrawn from the market in Europe by the end of 1961. Since that time, new studies and uses for the drug have emerged, including the treatment of erythema nodosum leprosum9, aphthous ulcers of Behçet’s disease10, wasting and oral ulcers associated with the human immunodeficiency syndrome11,12, and graft-versus-host disease13. Moreover, thalidomide has already become part of the standard therapy for the treatment of patients with relapsed and refractory multiple myeloma14,15. It has also been found to have varying degrees of benefit in various other malignancies16.
However, it is not clear whether or not thalidomide is effective in controlling delayed CINV. We thus undertook a prospective randomized crossover controlled study to evaluate thalidomide in controlling of chemotherapy-induced gastrointestinal side effects following a mFOLFOX7 regimen. The primary hypothesis was that addition of thalidomide to a ramosetron plus dexamethasone regimen would be superior to ramosetron plus dexamethasone in controlling delayed CINV.

Patients and methods
Patients
Chemotherapy-naive patients in our institution with histological or cytological confirmed malignancies who were scheduled to receive chemotherapy were randomized into the A-B group and B-A group. Other inclusion criteria were age between 18 and 70 years, ECOG (Eastern Cooperative Oncology Group) performance status of 0-2, and anticipated survival of more than 3 months. Patients were excluded if they were unable to understand or cooperate with study procedures. Other exclusion criteria were as follows: primary CNS malignancy or brain metastases, known seizure disorder, clinically significant neuromuscular disorder or degenerative disorder of the nervous system, clinically significant endocrine abnormalities not controlled with current therapy, history of thrombosis, history of significant hypersensitivity to thalidomide or the 5-HT3 receptor antagonist, use of any other medication with potential antiemetic action within 24 hr of chemotherapy, radiation therapy to the abdominal or pelvic areas within 48 hr before the study period, and pregnancy or lactation. Fertile patients had to be using effective contraception. The study was confirmed by the local Ethics Committee.

Chemotherapy regimen
The patients were scheduled to receive a moderately emetogenic mFOLFOX7 regimen (oxaliplatin, 100-130 mg/m2 intravenously over 2 hr on day 1; leucovorin, 200 mg/m2 intravenously over 2 hr on day 1; followed by 46-hr 2,400 mg/m2 5-fluorouracil continuous infusion, every 3 weeks).

Study design
The primary end point was the efficacy of thalidomide in controlling delayed CINV. The secondary end point was the safety of thalidomide. A prospective, randomized, open, crossover design was used. All patients were randomized into two groups: A-B group (group A, ramosetron plus dexamethasone on day 1 was given in the first cycle; and group B, the same antiemetic regimen as group A on day 1 plus thalidomide on days 2 through 5 in the second cycle) and B-A group (the same drugs were given in the reverse sequence). All the patients received ramosetron (0.3 mg intravenously) combined with dexamethasone (10 mg intravenously) 30 min prior to chemotherapy on day 1 for prophylaxis against acute emesis. In group B, additional thalidomide was given as 150 mg orally twice a day on days 2 through 5. Chemotherapy drug usage and dosage were consistent in the two consecutive periods.
Patients in both groups were permitted to receive an intravenous rescue dose of dexamethasone (10 mg) if vomiting occurred more than 2 times (National Cancer Institute Common Terminology Criteria for Adverse Events V2.017, NCI-CTCAE V2.0 grade 2) within 24 hr. Patients who required rescue therapy were to receive enough supportive therapy if still troubled by vomiting of more than 5 times within 24 hr (NCI-CTCAE V2.0 grade 3 or 4).
Patients were withdrawn from the study if they were not satisfied with the antiemetic treatment, or the chemotherapy was changed for the reason of uncontrolled side effects. The study was conducted according to the Declaration of Helsinki, and each patient gave a written informed consent before any study-related procedures were performed.

Evaluation methods
Pretreatment evaluations included a complete medical history, physical examination, ECG and clinical laboratory profile within 1 week of the start of chemotherapy. An emetic episode was defined as one occurrence of vomiting or a sequence of occurrences in very close succession not relieved by a period of relaxation of at least 1 min, any number of episodes of unproductive emesis (retches) in a unique 5-min period, or an episode of retching of <5 min duration combined with vomiting not relieved by a period of relaxation of 1 min.
The observation period was 5 days. Patients recorded daily episodes of vomiting (number and time) and degree of nausea and anorexia. They also recorded side effects such as peripheral neurology, sedation, hot flushing, headache, dry mouth and rash. The side effects were graded by the investigator according to NCI-CTCAE V2.0.

Response criteria
Nausea score No nausea (–); slight nausea but no influence on food intake (+); obvious nausea, influence on food intake (++); serious nausea, no intake of food and patient bedridden (+++).
Antiemetic efficacy Complete response, no emetic episodes and no rescue therapy; partial response, 1-2 emetic episodes; minor response, 3-5 emetic episodes; treatment failure, >5 emetic episodes.
Anorexia score Normal food intake (–); intake of a little solid food (+); liquid diet (++); no food intake (+++).
The complete response rate was calculated as the percentage of complete response for vomiting, and the percentage of (–) for nausea and anoxia. The effective rate was calculated as the percentage of complete response and partial response for vomiting and the percentage of [(–) + (+)] for nausea and anorexia18.

Statistical analysis
Chi-squared and Fisher’s exact test were applied for analysis of categorical variables. If the expected frequency in table cells was under 5 or total sample size was under 20, Fisher’s exact test was used. All P values were based on two-sided tests. P <0.05 was considered statistically significant. Statistical analysis was performed using statistical software (SPSS for Windows, Ver: 13.0).

Results
Patient characteristics
A total of 52 patients were enrolled from October 2006 to December 2007. All patients completed the study except for 2 patients in group A-B who did not receive the second cycle for bad compliance, and side effects were moderate in both patients. Fifty patients were evaluated for efficacy, and all 52 patients were included in the toxicological evaluation. Demographic data and patient characteristics are presented in Table 1.

Table 1 - Demographic characteristics of the two groups (n = 52)

 

A-B (n = 26)

B-A (n = 26)

 

 

 

Sex

 

 

Male

18

17

Female

 8

 9

Median age, yr (range)

55.5 (28-69)

54 (31-70)

ECOG performance status

 

 

0

15

12

1

11

14

Primary tumor

 

 

Gastric cancer

 8

13

Colorectal cancer

16

11

Others

 2

 2


Efficacy on acute nausea
The complete response rates and effective rates of group B for acute nausea (on day 1) were similar to those of group A; differences were not statistically significant (Table 2).
Efficacy on delayed nausea
The complete response rates and effective rates of group B on days 2 through 4 were higher than those of group A (Table 2), and the differences were statistically significant. The complete response rates and effective rates for both groups on day 5 were high and showed no significance.

Table 2 - Efficacy of both groups on nausea

Observation

Group

Nausea score

CRR

ER

period

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

-

+

++

+++

%

P

%

P

 

 

 

 

 

 

 

 

 

 

Day 1

A

34

10

 6

0

68.0

0.373

88.0

0.505

 

B

38

 8

 4

0

76.0

 

92.0

 

Day 2

A

12

21

17

0

24.0

0.004

66.0

0.009

 

B

26

18

 5

1

52.0

 

88.0

 

Day 3

A

12

20

16

2

24.0

0.001

64.0

0.005

 

B

29

15

 4

2

58.0

 

88.0

 

Day 4

A

18

17

12

3

36.0

0.016

70.0

0.053

 

B

30

13

 7

0

60.0

 

86.0

 

Day 5

A

27

12

10

1

54.0

0.309

78.0

0.050

 

B

32

14

 4

0

64.0

 

92.0

 

 

 

 

 

 

 

 

 

 

 

CRR，complete response rate, calculated as the percentage of no nausea (-); ER, effective rate, calculated as the percentage of sum of no nausea (-) and slight nausea but no influence on food intake (+), namely [(-) + (+ )].


Efficacy on acute vomiting
As shown in Table 3, there was no significant difference between the two groups for the complete response rates and effective rates on day 1.
Efficacy on delayed vomiting
The complete response rates for group B on delayed vomiting were higher than those for group A, as shown in Table 3, and the differences were statistically significant on days 2 and 3. The complete response rates for group B on days 4 and 5 were higher than those for group A, but the differences were not statistically significant.

Table 3 - Efficacy of both groups on vomiting

Observation

Group

Antiemetic efficacy

CRR

ER

period

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CR

PR

MR

F

%

P

%

P

 

 

 

 

 

 

 

 

 

 

Day 1

A

44

 5

1

0

88.0

0.485

98.0

1.000*

 

B

47

 2

1

0

94.0

 

98.0

 

Day 2

A

33

12

5

0

66.0

0.019

90.0

0.433*

 

B

43

 5

2

0

86.0

 

96.0

 

Day 3

A

28

14

7

1

56.0

0.035

84.0

0.110

 

B

38

 9

3

0

76.0

 

94.0

 

Day 4

A

33

11

5

1

66.0

0.068

88.0

0.505

 

B

41

 5

4

0

82.0

 

92.0

 

Day 5

A

43

 5

1

1

86.0

0.182

96.0

1.000*

 

B

47

 2

1

0

94.0

 

98.0

 

 

 

 

 

 

 

 

 

 

 

CR, complete response; PR, partial response; MR, minor response; F, treatment failure; CRR, complete response rate; ER, effective rate, the percentage of (CR+PR).

*Continuity correction.


Efficacy on anorexia
Table 4 shows that the complete response rates on anorexia for group B were higher than those for group A on days 2 through 5, and the differences were statistically significant.
Additional antiemesis drug administration
On day 1 of the two cycles, 3 patients in group A and 2 patients in group B received an additional administration of dexamethasone (10 mg) due to unsatisfactory control. After 24 hr, 14 patients in group A and 6 in group B were administered a rescue dose of dexamethasone (P = 0.046). Two patients in group A and 1 patient in group B received metochopramide/prochlorperazine and support treatment.

Table 4 - Efficacy of both groups on anorexia

Observation

Group

Anorexia score

CRR

ER

period

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

-

+

++

+++

%

P

%

P

 

 

 

 

 

 

 

 

 

 

Day 1

A

33

12

5

0

66.0

0.271

90.0

0.712*

 

B

38

9

3

0

76.0

 

94.0

 

Day 2

A

15

25

10

0

30.0

0.009

80.0

0.084

 

B

28

18

3

1

56.0

 

92.0

 

Day 3

A

12

19

17

2

24.0

0.001

62.0

0.000

 

B

29

17

2

2

58.0

 

92.0

 

Day 4

A

12

24

11

3

24.0

0.004

72.0

0.022

 

B

26

19

5

0

52.0

 

90.0

 

Day 5

A

20

18

11

1

40.0

0.046

76.0

0.004

 

B

30

18

2

0

60.0

 

96.0

 

 

 

 

 

 

 

 

 

 

 

CRR, complete response rate, the percentage of anorexia score (-); ER, effective rate, the percentage of anorexia score [(-)+(+)].

*Continuity correction.


Adverse effect
Adverse events occurring in 5% or more of patients in either treatment group are shown in Table 5. Generally, adverse effects were mostly mild to moderate (grade 1-2, NCI-CTC V2.0), and there was no grade 3-4 toxicity in any of the chemotherapy cycles. There was no significance difference in the adverse events of the two treatment groups except for frequency of the sedation, which occurred more frequently in group B than in group A.

Table 5 - Summary of adverse events occurring in 5% or more of patients in the two treatment groups [no.(%)]

 

Group A (n = 52)

Group B (n = 50)

P

 

 

 

 

Constipation

12 (23.1)

10 (20)

0.706

Headache

 6 (11.5)

 5 (10)

0.802

Peripheral neurology

11 (21.2)

 9 (18)

0.688

Hot flushing

 9 (17.3)

 8 (16)

0.859

Sedation/dizziness

 5 (9.6)

21 (42)

0.000

 

 

 

 

In parenthesis, percentage.



Discussion
Development of the 5-HT3 receptor antagonists represents a significant advance in antiemetic therapy in controlling CINV19. Preclinical studies have shown that the pharmacological action of ramosetron was long lasting20,21. Moreover, ours and another previous clinical study found that ramosetron showed longer-lasting effects than granisetron22,23.
Although both palonosetron and aprepitant have been shown to be effective to some degree in preventing delayed emesis, lack of adequate CINV control continues to trouble cancer patients. Moreover, neither of the two drugs is commercially available in China, so delayed CINV is still bothersome for Chinese patients.
Even though thalidomide was withdrawn from the market following reports of teratogenicity for pregnant women, its availability in a well-tolerated oral form and its importance of angiogenesis in development, growth, and metastasis of malignant tumors prompted the initiation of thalidomide clinical trials in the treatment of cancer. Based on the satisfactory efficiency of thalidomide in controlling nausea and vomiting in pregnant women, we hypothesized that thalidomide may be effective in controlling delayed CINV in cancer patients. This is the first randomized crossover controlled study in which thalidomide was evaluated for the control of chemotherapy-induced gastrointestinal side effects, and the results confirmed our hypothesis.
Our study was aimed to observe the efficiency of thalidomide in controlling delayed CINV. Therefore, on day 1, antiemetic regimens for both groups were the same, and there was no significant difference between two groups in incidence of acute CINV. In group B, rates of delayed CINV were obviously lower than those in group A on days 2 through 4. Addition of thalidomide increased 34% of complete response rates of delayed nausea and 20% of complete response rates of delayed emesis on day 3. The rates of anorexia were significantly lower for group B than for group A on days 2 through 5. The result was encouraging and showed that addition of thalidomide to ramosetron plus dexamethasone could control delayed CINV satisfactorily and also improve the quality of life. Actually, the chemotherapeutic regimen consisted of 46-hr 5-fluorouracil continuous infusion, so, the gastrointestinal side effects on days 2-3 may also result from acute CINV from 5-fluorouracil. The finding also indicates that thalidomide may also be effective in controlling acute CINV.
On day 1, 3 patients in group A and 2 in group B required additional antiemetic drug administration, which indicated the high efficacy of both regimens on acute nausea and vomiting. However, on days 2 through 5, 14 and 6 patients in group A and B, respectively, received additional antiemetic therapy. The difference between the two groups was significant, which further supported that thalidomide could improve control of delayed CINV.
Most of the clinical trials in cancer have used thalidomide doses of 200 to 800 mg/d16. In our study, the thalidomide dose of 150 mg orally twice a day was shown to be tolerated in cancer patients. The adverse effects were mostly mild, and there was no grade 3-4 toxicity in any of the chemotherapy cycles. The main complaint was sedation/dizziness (21/50, 42%). In general, thalidomide is a safe, effective antiemetic drug.
In our study, a crossover design was used instead of a parallel design. It is well known that in a crossover study, dropouts tend to occur frequently and a carryover effect is the main shortcoming of a crossover design. Nevertheless, crossover designs have been widely used in antiemetic studies. The dropout rate in our study was low (3.8%, 2/52), and the washout period was long enough to avoid the presence of a carryover effect. Thus, the efficacy of cycles 1 and 2 could be combined for analysis.
Additional larger randomized, double-blind, multi-center trials are indicated to confirm the clinical value of thalidomide in the control of delayed CINV.

References
 1. Bloechl-Daum B, Deuson RR, Mavros P, Hansen M, Herrstedt J: Delayed nausea and vomiting continue to reduce patients’ quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment. J Clin Oncol, 24: 4472-4478, 2006.
 2. Martin CG, Rubenstein EB, Elting LS, Kim YJ, Osoba D: Measuring chemotherapy-induced nausea and emesis. Cancer, 98: 645-655, 2003.
 3. Hesketh PJ, Kris MG, Grunberg SM, Beck T, Hainsworth JD, Harker G, Aapro MS, Gandara D, Lindley CM: Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol, 15: 103-109, 1997.
 4. Kris MG, Gralla R, Clark RA, Tyson LB, O’Connell JP, Wertheim MS, Kelsen DP: Incidence, course and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J Clin Oncol, 3: 1379-1384, 1985.
 5. Ioannidis JP, Hesketh PJ, Lau J: Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: a meta-analysis of randomized evidence. J Clin Oncol, 18: 3409-3422, 2000.
 6. Aapro MS, Grunberg SM, Manikhas GM, Olivares G, Suarez T, Tjulandin SA, Bertoli LF, Yunus F, Morrica B, Lordick F, Macciocchi A: A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol, 17: 1441-1449, 2006.
 7. Eisenberg P, Figueroa-Vadillo J, Zamora R, Charu V, Hajdenberg J, Cartmell A, Macciocchi A, Grunberg S: Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer, 98: 2473-2482, 2003.
 8. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, Julie Ma G, Eldridge K, Hipple A, Evans JK, Horgan KJ, Lawson F: Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer, 97: 3090-3098, 2003.
 9. Sheskin J: Thalidomide in the treatment of lepra reactions. Clin Pharmacol Ther, 6: 303-306, 1965.
10. Hamuryudan V, Mat C, Saip S, Ozyazgan Y, Siva A, Yurdakul S, Zwingenberger K, Yazici H: Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med, 128: 443-450, 1998.
11. Jacobson JM, Greenspan JS, Spritzler J, Ketter N, Fahey JL, Jackson JB, Fox L, Chernoff M, Wu AW, MacPhail LA, Vasquez GJ, Wohl DA: Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. N Engl J Med, 336: 1487-1493, 1997.
12. Reyes-Teran G, Sierra-Madero JG, Martinez del Cerro V, Arroyo-Figueroa H, Pasquetti A, Calva JJ, Ruiz-Palacios GM: Effects of thalidomide on HIV-associated wasting syndrome: A randomized, double-blind, placebo-controlled clinical trial. AIDS, 10: 1501-1507, 1996.
13. Parker PM, Chao N, Nademanee A, O’Donnell MR, Schmidt GM, Snyder DS, Stein AS, Smith EP, Molina A, Stepan DE, Kashyap A, Planas I, Spielberger R, Somlo G, Margolin K, Zwingenberger K, Wilsman K, Negrin RS, Long GD, Niland JC, Blume KG, Forman SJ: Thalidomide as salvage therapy for chronic graft-versus-host disease. Blood, 6: 3604-3609, 1995.
14. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med, 341: 1565-1571, 1999.
15. Barlogie B, Desikan R, Eddlemon P, Spencer T, Zeldis J, Munshi N, Badros A, Zangari M, Anaissie E, Epstein J, Shaughnessy J, Ayers D, Spoon D, Tricot G: Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: Identification of prognostic factors in a phase 2 study of 169 patients. Blood, 98: 492-494, 2001.
16. Kumar S, Witzig TE, Rajkumar SV: Thalidomid: current role in the treatment of non-plasma cell malignancies. J Clin Oncol, 22: 2477-2488, 2004. 
17. Trotti A: The evolution and application of toxicity criteria. Semin Radiat Oncol,12: 1-3, 2002.
18. Shi Y, He X, Yang S, Ai B, Zhang C, Huang D, Dong M, Liu P, Zhou S, Han X: Ramosetron versus ondansetron in the prevention of chemotherapy-induced gastrointestinal side effects: A prospective randomized controlled study. Chemotherapy, 53: 44-50, 2007.
19. Hesketh PJ, Gandara DR: Serotonin antagonists: A new class of antiemetic agents. J Natl Cancer Inst, 83: 613-620, 1991.
20. Fujihara A, Tanaka S, Suzuki M, Yamamoto M, Asano M: The effect of YM060, a novel 5-HT3 receptor antagonist, on cisplatin-induced emesis in ferrets. Clin Rep, 28: 2337-2347, 1994.
21. Akuzawa S, Ito H, Yamaguchi T: Comparative study of [3H]ramosetron and [3H]granisetron binding in the cloned human 5-hydroxytryptamine 3 receptors. Jpn J Pharmacol, 78: 381-384,1998.
22. Zhang JD, Liu YP, Teng YE, Shi J: Preventive effects of ramosetron and granisetron in prevention of gastrointestinal reaction associated with chemotherapeutic agents: a comparative study. Zhonghua Yi Xue Za Zhi, 83: 2058-2060, 2003.
23. Kang YK, Park YH, Ryoo BY, Bang YJ, Cho KS, Shin DB, Kim HC, Lee KH, Park YS, Lee KS, Heo DS, Kim SY, Cho EK, Lim HY, Kim WK, Lee JA, Kim TY, Lee JC, Yoon HJ, Kim NK: Ramosetron for the prevention of cisplatin-induced acute emesis: a prospective randomized comparison with granisetron. J Int Med Res, 30: 220-229, 2002.



 
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