EŠects of Serum Sodium Concentrations on Nausea and Vomiting after Moderately Emetogenic Chemotherapy

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1 Vol. 138, No. 8 YAKUGAKU ZASSHI 138, (2018) 1095 Regular Article EŠects of Serum Sodium Concentrations on Nausea and Vomiting after Moderately Emetogenic Chemotherapy Shiro Hatakeyama,, a,b Noriko Suzuki, c Kazuya Abe, c Noboru Konno, a Toshiyuki Kaneko, c Teiko Toyoguchi, a,b and Tadashi Shiraishi a,b a Division of Pharmacy, Yamagata University Hospital; Iida-nishi, Yamagata , Japan: b Department of Pharmaceutical Science, Faculty of Medicine, Yamagata University; Iida-nishi, Yamagata , Japan: and c Department of Pharmacy, Okitama Public General Hospital; 2000 Oaza-Nishiotsuka, Kawanishi-machi, Higashiokitama-gun, Yamagata , Japan. (Received February 1, 2018; Accepted April 15, 2018) Chemotherapy-induced nausea and vomiting (CINV) is the most unbearable adverse ešect of chemotherapy. The antiemesis guidelines of the National Comprehensive Cancer Network indicate that hyponatremia is a risk factor for CINV, although the relationship between the incidence of CINV and hyponatremia has not been su ciently studied. This two-center prospective observational study evaluated whether low serum sodium concentrations were a risk factor for CINV. The study included 34 patients who were scheduled to receive ˆrst-line carboplatin- or oxaliplatin-based chemotherapy for gynecological or colorectal cancers. Patient diaries were used to record the daily incidences of CINV events during a 5-day period. The patients were divided based on the median serum sodium concentration into a low Na + group (<141 meq/l) and a high Na + group ( 141 meq/l). The incidences of delayed nausea were 27.8% in the high Na + group and 62.5% in the low Na + group (p=0.042), with complete control rates (no vomiting, rescue medication, or grade 2 nausea) of 77.8% and 43.8%, respectively (p=0.042). The time to complete control failure in each group was analyzed using the Kaplan-Meier method, which revealed a signiˆcantly shorter time in the low Na + group (p=0.03). Therefore, these results indicate that low serum sodium concentrations may increase the risk of CINV. Key words chemotherapy-induced nausea and vomiting; hyponatremia; risk factor; moderately emetogenic chemotherapy INTRODUCTION Chemotherapy-induced nausea and vomiting (CINV) is the most unbearable adverse ešect of chemotherapy. 1) Various antiemetic agents can be used to prevent CINV, such as dexamethasone, 5- hydroxytryptamine (5-HT 3 ) antagonists, and neurokinin-1 (NK 1 ) receptor antagonists. The international guidelines regarding antiemetictherapy recommend that the speciˆc antiemetic agent should be selected based on the emetogenic risk of the chemotherapy drugs, 2 4) and the 2010 Japanese guideline has also provided recommendations regarding the appropriate use of antiemetic agents. 5) However, some cancer patients continue to experience CINV despite improvements in antiemetic therapy. The incidence of CINV is associated with treatment-related and patient-related risk factors. For example, the patient-related risk factors include female sex, younger age, and alcohol consumption. 6 10) The s.hatakeyama@med.id.yamagata-u.ac.jp standard treatment-related risk factor is the emetogenicity of the anticancer drugs, which can be classi- ˆed as high, moderate, low, or minimal emetogenicity. Nevertheless, it can be di cult to accurately assess the severity of CINV and its ešects on the patient's daily life, 11) especially for moderately emetogenic chemotherapy (MEC), which causes CINV in 30 90% of cases. The National Comprehensive Cancer Network guidelines indicate that electrolyte disturbances, such as hyponatremia, could be a risk factor for CINV. 3) Furthermore, the prevalence of hyponatremia is high among cancer patients, which indicates that patients with hyponatremia may frequently receive chemotherapy. 12) However, the association between the incidence of CINV and hyponatremia remains unclear, and it would be useful to understand whether serum sodium concentrations in uence CINV among patients receiving chemotherapy. Therefore, this prospective two-center observational study investigated whether lower serum sodium concentrations were associated with the incidence of CINV among 2018 The Pharmaceutical Society of Japan

2 1096 YAKUGAKU ZASSHI Vol. 138, No. 8 (2018) patients who were going to receive carboplatin ( CBDCA )-based chemotherapy or oxaliplatin (L-OHP)-based chemotherapy. METHODS Study Design This prospective two-center observational study was conducted between May 2014 and March 2016 at the Yamagata University Hospital and Okitama Public General Hospital. The study protocol complied with the ethical guidelines for epidemiological studies, and was approved by the institutional review board of Yamagata University. All patients provided written informed consent for data collection before their enrollment. Study Subjects Patients were considered eligible for enrollment if they were scheduled to receive ˆrst-line CBDCA or L-OHP chemotherapy at the gynecological division of Yamagata University Hospital or the digestive surgery division of Okitama Public General Hospital. The median value for serum sodium concentration was used to create a low Na + group (below the median value) and a high Na + group (at or above the median value). Data Collection Patient diaries were used to identify all daily episodes of emesis and nausea, as well as the degree of dietary intake and the use of rescue antiemetic agents during a 5-day period. The investigators recorded the patients' demographic and clinical information, which included age, sex, cancer type, chemotherapy regimen, relative dose intensity (the ratio of delivered dose intensity to the standard dose intensity) of the platinum agent, details of any antiemetic agents, performance status (PS), serum sodium concentration, presence of hyponatremia, alcohol consumption habit, and history of motion sickness. Hyponatremia was deˆned as a serum sodium concentration of <138 meq/l based on version 4.0 of the Common Terminology Criteria for Adverse Events (CTCAE v4.0) and the lower limit for normal serum sodium concentration in the study hospitals. Assessment Nausea and vomiting were separately evaluated during the acute phase (ˆrst 24 h), delayed phase ( h), and overall treatment period. A vomiting episode was deˆned as any episode of emesis or retching. Rates of complete control (no vomiting, rescue medication, or grade 2 nausea) and complete response (no vomiting or rescue medication use) were evaluated during the overall treatment period. Nausea and vomiting were graded based on CTCAE v4.0. Statistical Analysis Categorical variables were analyzed using the chi-square test or Fischer's exact test. Continuous variables were analyzed using the Mann-Whitney U-test. The Kaplan-Meier method was used to compare the times to complete control failure. Hazard ratios and 95% conˆdential intervals were calculated for the time to complete control failure using a Cox proportional hazards model. In addition to serum sodium, chemotherapy regimen and several factors reported as risk factors for CINV previous studies (age, sex, use of aprepitant, performance status, alcohol intake, and motion sickness) 5,8,13,14) were chosen as variables for the Cox proportional hazards analysis. All p-values were determined using two-sided tests, and dišerences with a p-value of <0.05 were considered statistically signiˆcant. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama), 15) which is a graphical user interface for R software (The R Foundation for Statistical Computing, Vienna) that serves as a modiˆed version of R commander and includes common biostatistical functions. RESULTS Patient Characteristics This study included 20 patients with gynecological cancer and 14 patients with colorectal cancer. The median serum sodium concentration was meq/l, which was used to create the high Na + group ( 141 meq/l) and the low Na + group (<141 meq/l). Both groups had similar baseline characteristics (Table 1). The median serum sodium concentrations were meq/l in the high Na + group (interquartile range: meq/l) and meq/l inthelowna + group (interquartile range: meq/l). The prevalence of hyponatremia was 43.8% in the low Na + group. The proportions of CBDCA-based and L-OHP-based chemotherapy were similar ( p= 0.32), although the two groups had signiˆcantly dišerent chemotherapy regimens ( p<0.05). All patients received dexamethasone and 5-HT 3 receptor antagonists. The proportions of aprepitant use were 66.7% in the high Na + group and 50.0% in the low Na + group (p=0.32). No signiˆcant dišerences were observed in the two groups' other characteristics. Incidences of CINV Events The incidences of CINV events are shown in Table 2. The rates of

3 Vol. 138, No. 8 (2018) YAKUGAKU ZASSHI 1097 Table 1. Patients' Demographic and Clinical Information High Na + group (n=18) Low Na + group (n=16) p-value Sex Male 3( 16.7) 5(31.2) b Female 15( 83.3) 11(68.8) Age (years) 68(62 71) 63(55 68) c Cancer type Gynecological cancer 12( 66.7) 8(50.0) a Colorectal cancer 6( 33.3) 8(50.0) Chemotherapy Regimen Carboplatin-based regimen 12( 66.7) 8(50.0) a (TC/DC) (5/7) (8/0) Oxaliplatin-based regimen 6( 33.3) 8(50.0) (FOLFOX/XELOX) (3/3) (5/5) RDI of the platinum agent (%) 99.0( ) 98.6( ) c Performance status 0 18(100.0) 15(93.8) b 1 0( 0.0) 1( 6.2) 3antiemetics Yes 12( 66.7) 8(50.0) a No 6( 33.3) 8(50.0) Alcohol consumption Yes 6( 33.3) 9(56.2) a No 12( 66.7) 7(43.8) Previous motion sickness Yes 3( 16.7) 5(31.2) b No 15( 83.3) 11(68.8) Serum sodium (meq/l) 142.0( ) 138.0( ) <0.05 c Hyponatremia Grade 0 18(100.0) 9(56.3) Grade 1 0( 0.0) 7(43.8) Data are shown median (interquartile range) or n (%), a chi-square test, b Fisher's exact test, c Mann-Whitney U-test, High Na + group: serum sodium concentration 141 meq/l, Low Na + group: <141 meq/l, RDI: relative dose intensity, TC: paclitaxel, carboplatin, DC: docetaxel, carboplatin, FOLFOX: levofolinate, uorouracil, oxaliplatin, XELOX: capecitabine, oxaliplatin, 3 antiemetics: dexamethasone, 5HT 3 receptor antagonist, neurokinin-1 receptor antagonist. delayed nausea were 27.8% in the high Na + group and 62.5% in the low Na + group (p=0.042),andthe ratesofgrade2delayednauseawere22.2% and 56.3%, respectively ( p=0.042). None of the patients experienced acute vomiting. Although the incidence of other CINV events was higher in the low Na + group than in the high Na + group, the dišerence was not statistically signiˆcant. During the overall treatment period, the low Na + group had a lower proportion of complete control than the high Na + group (43.8% vs. 77.8%, p=0.042). The complete response rates were 83.3% in the high Na + group and 68.8% in the low Na + group (p=0.43). There was no statistically signiˆcant dišerence in the proportion of CINV events between patients who received a CBDCA-based chemotherapy and those who received an L-OHPbased chemotherapy. Their rates of delayed nausea were 35.0% and 57.1% (p=0.20), respectively, and the complete control rates were 70.0% and 50.0% ( p=0.24), respectively. Similarly, there was no dišerence between patients with or without aprepitant. Their rates of delayed nausea were 57.1% and35.0% (p=0.20), respectively, and the complete control rates were 70.0% and 50.0% (p=0.24), respectively. There was no cessation of chemotherapy or reduction of anticancer agent dosage due to nausea and vomiting. The incidence of delayed nausea and the complete control rate were compared among patients in the high Na + group, patients with normal serum sodium

4 1098 YAKUGAKU ZASSHI Vol. 138, No. 8 (2018) Table 2. Incidence of Events Associated Chemotherapy Induced Nausea and Vomiting Nausea Acute phase High Na + group (n=18) Low Na + group (n=16) p-value All grade 1( 5.6) 3(18.8) b Grade 1/2/3/4 1/0/0/0 2/1/0/0 Delayed phase All grade 5(27.8) 10(62.5) a Grade 1/2/3/4 1/4/0/0 1/9/0/0 Vomiting Acute phase All grade 0( 0.0) 0( 0.0) Grade 1/2/3/4 0/0/0/0 0/0/0/0 Delayed phase All grade 2(11.1) 3(18.8) b Grade 1/2/3/4 1/1/0/0 2/1/0/0 Complete response 15(83.3) 11(68.8) b Complete control 14(77.8) 7(43.8) a Data are shown n (%), a chi-square test, b Fisher's exact test, High Na + group: serum sodium 141 meq/l, Low Na + group <141 meq/l, complete response: no vomiting or rescue medication use, complete control: no vomiting, rescue medication use, or grade 2 nausea. concentrations in the low Na + group, and patients with hyponatremia (Fig. 1). Theratesofdelayed nausea were 27.8%, 55.6%, and 71.4%, respectively (p=0.1), and the complete control rates were 77.8%, 44.4%, and 42.9%, respectively (p=0.12). Analysis of Time to Complete Control Failure and Its Risk Factors The Kaplan-Meier method revealed a signiˆcantly shorter time to complete control failure in the low Na + group than in the high Na + group ( p=0.03; Fig. 2). The univariate Cox proportional hazards model failed to detect signiˆcant risk factors for a short time to complete control failure (Table 3). DISCUSSION This study investigated the ešects of serum sodium concentration on CINV, and revealed that the low Na + group (<141 meq/l) had a signiˆcantly elevated incidence of delayed nausea and a signiˆcantly lower complete control rate than the high Na + group. Furthermore, other CINV events were also more common in the low Na + group, although this dišerence was not statistically signiˆcant. Moreover, the low Na + group had a shorter time to complete control failure than the high Na + group. All patients in the present study received prophylactic treatment using two antiemetics (dexamethasone and a 5-HT 3 antagonist) or three antiemetics (dexamethasone, a 5-HT 3 antagonist, and aprepitant). This is because the international guidelines for antiemetic therapy recommend using dexamethasone plus a 5-HT 3 antagonist in cases that will be treated using MEC, and adding a NK 1 receptor antagonist when the planned treatment involves CBDCA or L-OHP. 5) Nishimura et al. compared the e cacies of prophylactic treatment using two or three antiemetics for Japanese patients who received L-OHP chemotherapy, which revealed complete control rates of 69.4% and 79.7%, respectively, as well as com- Fig. 1. Proportions of Patients in Each Group with Delayed Nausea (A) and Who Achieved Complete Control during the Study Period (B) Groups were compared using Fisher's exact test.

5 Vol. 138, No. 8 (2018) YAKUGAKU ZASSHI 1099 Fig. 2. Kaplan-Meier Curves for Time to Failure of Complete Control during the First 120 h after Chemotherapy Administration The solid line indicates the high Na + group and the dashed line indicates the low Na + group. The log-rank test revealed that the dišerence was statistically signiˆcant (p=0.03). Table 3. Results of COX Proportional Hazards Analysis for Complete Control Failure Univariate analysis Variables HR (95%CI) p-value Age (>65) 0.80( ) Sex (female) 0.65( ) Oxaliplatin-based chemotherapy 1.83( ) Performance status 0.65( ) antiemetics 0.55( ) Alcohol intake 1.51( ) Motion sickness 0.55( ) Serum sodium (<141 meq/l) 3.24( ) Univariate (Cox proportional hazards model) analyses ware performed. HR: hazard ratio, CI: conˆdence interval, 3 antiemetics: dexamethasone, 5HT 3 receptor antagonist, neurokinin-1 receptor antagonist. plete response rates of 75.4% and 85.0%, respectively. 16) Furthermore, Rapoport et al.reported that dexamethasone plus 5-HT antagonist with/ without aprepitant provided complete response rates of 65.5% and 73.9%, respectively, for patients receiving MEC, and the incidences of vomiting were 28.7% and 16.8%, respectively. 17) Another prospective observational Japanese study of MEC revealed that the incidences of acute and delayed nausea were 6.7% and 41.7%, respectively, and that the incidences of acute and delayed vomiting were 1.7% and 15.9%, respectively. 13) However, those studies did not speciˆcally examine serum sodium concentrations. Relative to the previous studies, the present study revealed a comparable incidence of CINV in the high Na + group, although CINV was more common in the low Na + group. A large proportion of cancer patients may experience hyponatremia, as Doshi et al. have reported that 47% of hospitalized cancer patients had serum sodium concentrations of <135 meq/l. 12) Furthermore, Berghmans et al. reported that 3.7% of hospitalized cancer patients had serum sodium concentrations of <130 meq/l. 18) In the context, hyponatremia causes various symptoms, such as headache, convulsion, nausea, and vomiting. 19) The results of the present study indicate that the low Na + group had a higher incidence of CINV events than the high Na + group, and there was no signiˆcant dišerence in the proportion of CINV events between chemotherapy regimens, nor was there a dišerence with or without NK 1 receptor antagonist, which highlights the possibility that cancer patients with low serum sodium concentrationshave an elevated risk of developing nausea and vomiting. Based on the heterogeneity in the low Na + group, we performed a subanalysis which revealed that patients with hyponatre-

6 1100 YAKUGAKU ZASSHI Vol. 138, No. 8 (2018) mia had a higher incidence of nausea than patients with non-hyponatremic serum sodium concentrations. A Cox proportional hazards model failed to detect signiˆcant risk factors for time to complete control failure in the present study. However, several studies have investigated patient-related risk factors for CINV, which revealed that female sex and younger age were associated with the risk of nausea. 6,7) In addition, female sex, younger age, poor PS, alcohol consumption, and previous morning sickness were risk factors for vomiting. 6,8 10) Furthermore, Tamura et al. revealed that, among Japanese patients with CINV, nausea was associated with female sex, younger age, and previous motion sickness, while delayed nausea was associated with alcohol consumption. The risk factors for acute vomiting were female sex and younger age, while only female sex was also associated with delayed vomiting, and sub-analysis of female patients revealed that previous morning sickness was associated all CINV events except acute vomiting. 13) Moreover, Sekine et al. reported that female sex, younger age (<55 years), poor PS, smoking, and alcohol consumption were risk factors for acute vomiting, although delayed vomiting was only associated with female sex. 14) It is possible that adding a NK 1 receptor antagonist was not a signiˆcant factor in the present study because of the small sample size and limited statistical power. The limitations of this study include the limited serum sodium concentration range, and the small sample size, which is associated with limited statistical power. In addition, we used the median serum sodium concentration as the cut-oš value, and it would be preferable to compare patients with and without hyponatremia in order to examine the relationship between serum sodium and CINV, although this approach was complicated by the small sample size and limited number of CINV events. These limitations indicate that further studies are needed to demonstrate that hyponatremia is an independent risk factor for CINV, using multivariate analysis, although the present study provides valuable preliminary evidence regarding the ešects of hyponatremia on the incidence of CINV. In conclusion, the ˆndings of the present study suggest that lower serum sodium concentrations could increase the risk of CINV. Therefore, monitoring serum sodium concentrations before chemotherapy, and monitoring to identify CINV, are needed to more appropriately manage CINV in this setting. Con icts of Interest The authors have no potential con icts of interest related to this report. REFERENCES 1) de Boer-Dennert M., de Wit R., Schmitz P. I., Djontono J., v Beurden V., Stoter G., Verweij J., Br.J.Cancer, 76, (1997). 2) Hesketh P. J., Bohlke K., Lyman G. H., Baasch E., Chesney M., Clark-Snow R. A., Danso M. A., Jordan K., Somerˆeld M. R., Kris M. G., J. Clin. Oncol., 34, (2016). 3) Ettinger D. S., Armstrong D. K., Barbour S., Berger M. J., Bierman P. J., Bradbury B., Ellis G., Kirkegaard S., Kloth D. D., Kris M. G., Lim D., Michaud L. B., Nabati L., Noonan K., Rugo H. S., Siler D., Sorscher S. M., Stelts S., Stucky-Marshall L., Todaro B., Urba S. G., J. Natl. Compr. Canc. Netw., 10, (2012). 4) RoilaF.,HerrstedtJ.,AaproM.,GrallaR.J., Einhorn L. H., Ballatori E., Bria E., Clark- Snow R. A., Espersen B. T., Feyer P., Grunberg S. M., Hesketh P. J., Jordan K., Kris M. G., Maranzano E., Molassiotis A., Morrow G., Olver I., Rapoport B. L., Rittenberg C., Saito M., Tonato M., Warr D., Ann. Oncol., 21, v232 v243 (2010). 5) Takeuchi H., Saeki T., Aiba K., Tamura K., Aogi K., Eguchi K., Okita K., Kagami Y., Tanaka R., Nakagawa K., Fujii H., Boku N., Wada M., Akechi T., Udagawa Y., Okawa Y., Onozawa Y., Sasaki H., Shima Y., Shimoyama N., Takeda M., Nishidate T., Yamamoto A., Ikeda T., Hirata K., Int. J. Clin. Oncol., 21, 1 12 (2016). 6) du Bois A., Meerpohl H. G., Vach W., Kommoss F. G., Fenzl E., P eiderer A., Eur. J. Cancer, 28, (1992). 7) Pater J., Slamet L., Zee B., Osoba D., Warr D., Rusthoven J., Support. Care Cancer, 2, (1994). 8) Pollera C. F., Giannarelli D., Cancer, 64, (1989). 9) WarrD.G.,StreetJ.C.,CaridesA.D.,Support. Care Cancer, 19, (2011).

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