Japanese Journal of Clinical Oncology Advance Access originally published online on December 5, 2008
Japanese Journal of Clinical Oncology 2009 39(2):111-115; doi:10.1093/jjco/hyn140
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© The Author (2008). Published by Oxford University Press. All rights reserved
Ramosetron for the Prevention of Nausea and Vomiting During 5-Fluorouracil-Based Chemoradiotherapy for Pancreatico-biliary Cancer
1 Department of Radiation Oncology
2 Department of Surgery
3 Department of Internal Medicine, Seoul National University College of Medicine, Seoul
4 Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea
For reprints and all correspondence: Eui Kyu Chie, Department of Radiation Oncology, Seoul National University College of Medicine, 101 Daehangno, Jongno-gu, Seoul 110-744, Republic of Korea. E-mail: ekchie93{at}snu.ac.kr
Received September 16, 2008; accepted November 10, 2008
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Abstract |
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Objective: The aim of the study was to evaluate the role of ramosetron for the prevention of chemoradiotherapy-induced nausea and vomiting (CRINV) in patients receiving upper abdominal irradiation with concurrent 5-fluorouracil chemotherapy.
Methods: Between November 2006 and April 2007, 25 patients with pancreatico-biliary cancer underwent adjuvant chemoradiotherapy. A total dose of 40 Gy was delivered using 2 Gy/fraction, 5 days a week, with 2 weeks of planned rest after 20 Gy. Concomitant 5-fluorouracil (500 mg/m2/day i.v. bolus) was administered for the first 3 days of each split course. During the first course of chemoradiotherapy, all patients had prophylactic metoclopramide before treatment and those refractory to metoclopramide received rescue medication with ondansetron. During the second course of chemoradiotherapy, prophylactic ramosetron was given to patients who were refractory to ondansetron. Response to antiemetics was scored in four tiers: none, no CRINV; mild, did not interfere with normal daily life; moderate, interfered with normal daily life and severe, patient bedridden because of CRINV.
Results: Fifty-six percent of the patients (14 of 25) had moderate CRINV despite metoclopramide, and received ondansetron. Ten patients who experienced moderate CRINV despite the ondansetron had prophylactic ramosetron, and 60% of the patients (6 of 10) had the symptom improved.
Conclusions: Ramosetron proved to be an effective alternative for the control of CRINV during upper abdominal irradiation with concurrent 5-fluorouracil chemotherapy.
Key Words: chemoradiotherapy • nausea and vomiting • ramosetron
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INTRODUCTION |
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Radiotherapy-induced nausea and vomiting (RINV) is one of the most frequently observed complications during radiotherapy (1). RINV usually decreases the compliance of patients to the treatment and may result in treatment interruption, which may even compromise the treatment outcome (2). Therefore, appropriate treatment of RINV is mandatory for better treatment outcome and patients' quality of life (2,3). Based on the results of randomized clinical trials (4–6), several oncology societies recommend the prophylactic use of antiemetics, and a 5-hydroxytryptamine (5-HT3) receptor antagonist is recommended in most cases (7). At the present time, two 5-HT3 receptor antagonists, namely ondansetron and granisetron, are widely used as potent antiemetics, and these two agents are thought to have equivalent effect at prescribed doses (8). However, there is little consensus on the treatment of nausea and vomiting during chemoradiotherapy, which is a commonly employed combination therapy, especially in the gastrointestinal tract malignancies. Recently, Morita et al. (9) noted excellent antiemetic effect with ramosetron, a recently developed 5-HT3 receptor antagonist, in the treatment of esophageal cancer with chemoradiotherapy combined with hyperthermia.
In this study, we evaluated the preventive role of ramosetron on chemoradiotherapy-induced nausea and vomiting (CRINV) in patients receiving upper abdominal irradiation with concurrent 5-fluorouracil chemotherapy who experienced CRINV despite the use of metoclopramide and ondansetron.
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PATIENTS AND METHODS |
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Twenty-five patients who underwent adjuvant chemoradiotherapy for pancreatico-biliary cancer between November 2006 and April 2007 are the subjects of this study. All patients received external beam radiotherapy to the tumor bed and regional lymph nodes by 3-dimensional conformal technique. A total dose of 40 Gy was delivered using 2 Gy/fraction, 5 days a week, with 2 weeks of planned rest after 20 Gy. Concomitant 5-fluorouracil (500 mg/m2/day i.v. bolus) was administered for the first 3 days of each 2 weeks of radiotherapy.
During the first course of chemoradiotherapy, all patients had prophylactic metoclopramide (5 mg, p.o., t.i.d for 5 days) before the initiation of chemoradiotherapy, and rescue ondansetron (8 mg, p.o., b.i.d) was given to patients who were refractory to metoclopramide within 2 days of the treatment initiation. All patients recovered from the treatment-related morbidities during the 2-week rest period after the first course of the treatment. Patients who were refractory to ondansetron during the first course received prophylactic ramosetron (0.1 mg, p.o., q.d) for the first 3 days of the second course of chemoradiotherapy.
Response to antiemetic medication was assessed at least once a week during the treatment. CRINV was graded by the modified criteria from those for RINV of the Italian Group for Antiemetic Research in Radiotherapy: none, no CRINV; mild, did not interfere with normal daily life; moderate, interfered with normal daily life and severe, patient bedridden because of CRINV (1). For statistical analysis, patients with no or mild CRINV were considered as responders, whereas those with moderate or severe CRINV were considered as non-responders. Statistical analysis was performed using SPSS software (release 12.0.1. SPSS Inc. Chicago, IL, USA). Differences in categorical variables between parameters were compared using Fisher's exact test.
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RESULTS |
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The characteristics including age, sex, alcohol consumption, site of tumor and the planning target volume of all the patients are summarized in Table 1.
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During the first course of chemoradiotherapy, CRINV after prophylactic metoclopramide was none in nine patients and mild in two patients. The remaining 14 patients with moderate CRINV received ondansetron as rescue medication, and four patients had symptom improved to mild CRINV. During the second course of chemoradiotherapy, 10 patients who were refractory to ondansetron had prophylactic ramosetron, and the response was as follows: none in four patients, mild in two and moderate in four (Fig. 1). Fifteen patients who responded to metoclopramide ± ondansetron were managed with the two agents on the second course of chemoradiotherapy, and their CRINV was well controlled: none in nine patients and mild in six.
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There was no difference in the characteristics between the responders and non-responders to metoclopramide ± ondansetron during the first course of chemoradiotherapy (Table 2). However, the response to ramosetron was associated with patients' age, with those younger than 60 years not responding to ramosetron (Table 3).
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There were no noticeable complications associated with the antiemetic medication, including ramosetron, and there were no definite changes in the serum chemistry profiles either.
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DISCUSSION |
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Treatment-related nausea and vomiting is one of the most frequently observed complications during upper abdominal irradiation, with the incidence of 50–80% (1). According to the current guidelines on the use of antiemetics by several oncology societies, such as American Society of Clinical Oncology (ASCO) and Multinational Association of Supportive Care in Cancer (MASCC), upper abdominal radiotherapy is categorized as moderate risk group for RINV, and the prophylaxis with the 5-HT3 receptor antagonist is recommended (7,8). In addition to the irradiated site, age, sex, alcohol consumption, previous nausea and vomiting history, and/or anxiety can also affect the occurrence of RINV (10). Furthermore, concurrent chemotherapy should also be considered for the risk assessment of RINV, as there is no evidence that emetogenic effect of chemotherapy and radiotherapy is protective and not additive or even synergistic. At the present time, only National Comprehensive Cancer Network (NCCN) provides guidelines for the management of nausea and vomiting due to chemoradiotherapy, which is defined as CRINV in our study (11). In this guideline, it is recommended that management principle should follow that of chemotherapy. 5-Fluorouracil, the commonly employed chemotherapeutic agent during concurrent chemoradiotherapy for gastrointestinal tract malignancies, is categorized as low risk group, and dexamethasone or metoclopramide is recommended. However, such a recommendation seems suboptimal, considering the high incidence of RINV for upper abdominal irradiation. Our study followed the NCCN guidelines in the first course of chemoradiotherapy and showed that prophylactic metoclopramide was less effective for controlling CRINV. Although radiotherapy is generally considered to be less emetogenic than chemotherapy, these results suggest that risk assessment should not be based solely on chemotherapeutic agent and should at least follow those of more emetogenic treatment. This is particularly important for patients with cancer of upper gastrointestinal tract, as radiotherapy to the area involved is categorized as moderate risk group, whereas frequently used chemotherapeutic agent, which is a 5-fluorouracil derivative, is categorized as low risk group in aforementioned guidelines.
Ramosetron, a recently developed 5-HT3 receptor antagonist, has already been shown to have higher selectivity for serotonin receptors in comparison with ondansetron or granisetron in an animal study (12). Ramosetron has also been known to be equivalent to granisetron in the overall antiemetic effect and even superior to granisetron in the no-vomiting rate for patients receiving cisplatin (13). In a recent trial comparing ramosetron and ondansetron for patients receiving cisplatin-containing chemotherapy, the superior efficacy of ramosetron in the control of delayed nausea and vomiting was also noted (14). Moreover, ramosetron, in the formulation of orally disintegrating tablet, may increase patients’ compliance by enabling them to avoid swallowing water, which itself often leads to nausea and/or vomiting. Furthermore, once-daily dosing of ramosetron makes its administration more convenient.
However, there is no randomized trial demonstrating the antiemetic effect of ramosetron, and there are no data comparing ramosetron with other 5-HT3 receptor antagonists in the CRINV setting. The only observation concerning the role of ramosetron on CRINV was noted by Morita et al. (9). They reported that 79% of the patients had no CRINV with ramosetron during chemoradiotherapy and hyperthermia for esophageal cancer. In the current study, prophylactic ramosetron was prescribed to 10 patients who experienced moderate CRINV, despite the prophylactic metoclopramide and rescue ondansetron and in six of them (60%), CRINV was effectively controlled: none in four and mild in two patients. Prophylactic metoclopramide with or without rescue ondansetron achieved the similar results in 15 of 25 patients (60%). However, considering that the split course chemoradiotherapy was repeated with the same schedule for both radiotherapy and chemotherapy, that CRINV is more likely to develop in patients who experienced CRINV during the previous course of the treatment and that antiemetic effect of both metoclopramide and ondansetron during the initial cycle of the treatment was not satisfactory, patients receiving ramosetron might be at a higher risk for CRINV. Therefore, antiemetic effect of ramosetron may be at least equivalent, if not superior, over metoclopramide ± ondansetron in patients treated with the current setting. Even if the efficacy of the medication is equivalent, prophylactic use of ramosetron may be justified, considering the additive costs of two prescription agents as well as patient suffering (15).
However, the response to ramosetron was minimal in patients younger than 60 years. As mentioned earlier, young age is one of the well-known emetogenic risk factors (10). The Italian Group for Antiemetic Research in Radiotherapy also noted that young age was a potential risk factor affecting the development of RINV with borderline significance: the incidence of RINV was 45.5% in patients younger than 60 years versus 33.5% in those of 60 years or older (P = 0.0812) (1). However, the reason why young patients showed a higher incidence of RINV and a lower response to antiemetic agent is still unknown. More potent antiemetic therapy such as a combination of 5-HT3 receptor antagonist with other medication such as dexamethasone or aprepitant should be considered for these patients.
In conclusion, results from our study suggest that more attention should be paid on the selecting antiemetic medication during chemoradiotherapy, especially for the treatment of upper abdominal sites, and that prophylactic ramosetron is effective in the control of CRINV refractory to prophylactic metoclopramide and rescue ondansetron during upper abdominal irradiation with concurrent 5-fluorouracil chemotherapy and may be safely used as an alternative for CRINV in this group of patients.
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Funding |
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This work was supported by Seoul National University Hospital Research Fund (grant number 04-2008-117).
Conflict of interest statement
None declared.
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References |
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