Improvement of Adherence to Guidelines for Antiemetic Medication Enhances Emetic Control in Patients with Colorectal Cancer Receiving Chemotherapy of Moderate Emetic Risk HIRONORI FUJII 1, HIROTOSHI IIHARA 1, MASASHI ISHIHARA 1, TAKAO TAKAHASHI 2, KAZUHIRO YOSHIDA 2 and YOSHINORI ITOH 1 1 Department of Pharmacy, Gifu University Hospital, Gifu, Japan; 2 Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan Abstract. Prevention of chemotherapy-induced nausea and vomiting (CINV) according to the clinical practice guidelines is particularly important. In the present study, we investigated the adherence to the guidelines for antiemetic medication and the control of CINV in 61 patients with colorectal cancer receiving the first course of chemotherapy of moderate emetic risk at our outpatient cancer chemotherapy clinic. Furthermore, we carried out intervention to improve evidence-based antiemetic medication in another 64 patients. The rate of adherence to the antiemetic guidelines was only 6.6%; non-adherence was due mostly to the lack of dexamethasone treatment on days 2 and 3. In the interventional group, antiemetic medication adherence was markedly enhanced to 89%, which led to a significant enhancement of complete protection from nausea and vomiting during-delayed period (days 2-5 after chemotherapy) from 54% to 74% (p<0.05), although the daily dose of dexamethasone was 4 mg, lower than that recommended by the guidelines (8 mg). Finally, we evaluated the effect of dexamethasone at a daily dose of 4 mg, since little is known about the efficacy of such dose. Dexamethasone at this dose was found to be effective at elevating the rate of complete protection from nausea and vomiting during-delayed period (increase of 20%, p<0.05). These findings suggest that medication intervention to reduce the gap between guidelines and clinical practice improves the emetic control in patients with colorectal cancer receiving moderately-emetic chemotherapy. CThis article is freely accessible online. orrespondence to: Hironori Fujii, Department of Pharmacy, Gifu University Hospital, Yanagido 1-1, Gifu 501-1194, Japan. Tel: +81 582307080, Fax: +81 582307093, e-mail: h_fujii@gifu-u.ac.jp Key Words: Colorectal cancer, moderately emetic chemotherapy, chemotherapy-induced nausea and vomiting, adherence, dexamethasone. Chemotherapy-induced nausea and vomiting (CINV) is a serious side-effect that reduces patient quality of life and impairs patient adherence to medication (1, 2). However, the recent development of several novel classes of antiemetic agents, such as neurokinin NK1 receptor antagonists and second-generation 5-hydroxytryptamine-3 (5-HT3) receptor antagonist has greatly improved the control of CINV (3). Several clinical practice guidelines for the use of antiemetic agents to prevent CINV have been provided by American Society of Clinical Oncology (ASCO) (4), Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology (MASCC/ESMO) (5), and National Comprehensive Cancer Network (NCCN) (6), in which chemotherapy agents are classified into four categories; highly emetic risk (HEC), moderately emetic risk (MEC), low emetic risk and minimal emetic risk, and appropriate use of antiemetic agents based on the emetic risk of chemotherapy are recommended. However, the guidelines are not always followed in clinical practice. Burmeister et al. showed by a retrospective study of 299 patients receiving cancer chemotherapy that the adherence to MASCC guidelines was 61%, while it was only 11% for prevention of acute and delayed CINV, respectively (7). Gomez et al. also reported that for 4,566 patients with lung cancer who received platinum-containing chemotherapy, the prevalence of the use of aprepitant was less than 10% in contrast to moderate-to-high prevalence (60-90%) of the use of 5-HT3 antagonists and dexamethasone (8). On the other hand, Chan et al. demonstrated that the adherence to the antiemetic guideline was 42% in 361 breast cancer patients receiving chemotherapy containing anthracyclines, in which the complete protection from delayed CINV was significantly higher in patients who took appropriate antiemetic agents (27%) than in those who did not (16%) (9). Aapro et al. also reported similar data in 991 patients receiving HEC or MEC: the adherence was 55%, 46% and 29% for antiemesis during acute, delayed and overall periods, respectively (10). Moreover, they showed that the 0250-7005/2013 $2.00+.40 5549
Table Ⅰ. Patients demographics. Observational Interventional p-value (n=61) (n=64) Age, mean (range) 61.5 (37-82) 66.9 (34-86) 0.010 a Gender (male/female) 45/16 43/21 0.440 b Body surface area (m 2 ) 1.63±0.18 1.56±0.17 0.049 c Alanine aminotransferase (IU/l) 27.1±13.4 30.2±19.8 0.305 c Aspartate aminotransferase (IU/l) 24.4±15.4 24.2±24.3 0.972 c Serum creatinine (mg/dl) 0.7±0.2 0.7±0.2 0.270 c White blood cells (10 4 /mm 3 ) 6200±1833 5752±1787 0.169 c Hemoglobin (g/dl) 12.3±1.7 11.7±1.8 0.055 c Platelet (10 6 /mm 3 ) 24.2±9.2 21.8±8.2 0.119 c Chemotherapy regimen L-OHP-based 35 37 0.591 b Irinotecan-based 26 27 Relative dose intensity (%) 85.4±16.6 99.4±5.1 <0.01 c Data represent the mean±sd. a Mann-Whitney U-test; b Chi-square test; c t-test. complete response, defined as no emesis and no rescue treatment, was significantly higher in the adherent than in the non-adherent group (60% versus 51%, p=0.008). In addition, Koch et al. in a study of 113 patients with colorectal cancer receiving MEC or low-emetic risk chemotherapy, demonstrated that the adherence to the MASCC/ESMO guideline was extremely low (3%), the predominant cause of which was the lack of dexamethasone prescription on days 2 and 3 (43%), or throughout the overall chemotherapy period (45%). In the present study, the adherence to the national guideline for the use of antiemetic agents was investigated in 61 patients with colorectal cancer who received MEC (oxaliplatin- or irinotecan-based chemotherapy) at our outpatient cancer chemotherapy clinic. Subsequently, an intervention to improve medication adherence was carried out in another group of 64 patients, and the clinical outcomes were evaluated. Patients and Methods Patients. Sixty-one outpatients with colorectal cancer who received the first course of MEC during April 2009 and March 2010 were the subjects of the present observational study, while another 64 patients with colorectal cancer receiving similar chemotherapy for the first time during April 2010 and March 2011 were the subjects of the present interventional study. Chemotherapy included oxaliplatin/5- fluorouracil/levofolinate combination regimen (modified FOLFOX6), irinotecan therapy, and irinotecan/5-fluorouracil/levofolinate combination regimen (FOLFIRI). The present study was carried out in accordance with the guidelines for the Care for Human study adopted by the Ethics Committee of the Gifu Graduate School of Medicine, and notified by the Japanese Government (approval no. 22-156 of the Institutional Review Board). Medication adherence. According to the clinical practice guideline for antiemesis, the use of a combination of 5-HT3 antagonist and dexamethasone is recommended before chemotherapy for the prevention of acute CINV, and oral dexamethasone (daily dose of 8 mg) on days 2 and 3 for the prevention of delayed CINV. Antiemetic adherence during acute and delayed periods was investigated from medical records. Medical intervention. Intervention was made to enhance the prevalence of the use of the antiemetic medication based on the clinical practice guidelines. For this purpose, the dosage and administration of antiemetic drugs used before and after (days 2-4) chemotherapy based on the guidelines were verified and described in a view format. The evidence-based antiemetic medication was notified to the physicians by showing them the view format. Evaluation of the control of CINV. The primary endpoint was complete protection from nausea and vomiting during the delayed period (2-5 days after chemotherapy). Complete protection during the acute period (within 24 h), complete protection from nausea and complete protection from vomiting during the acute and delayed periods were also evaluated. First of all, the prevalence of antiemetic medication and the rate of control of CINV were compared between the observational and the interventional groups. Subsequently, the effect of dexamethasone given on days 2 and 3 after chemotherapy was examined by comparing the data with dexamethasone in an interventional group against those without dexamethasone obtained from an observational group. Statistical analyses. Data were analyzed using Statistics Program for Social Science for Windows (SPSS II; ver. 11, SPSS Inc., Chicago, IL, USA). Parametric variables were analyzed using the t- test, while nonparametric data were analyzed by the Mann-Whitney U-test or chi-square-test. A p-value of less than 0.05 was considered statistically significant. 5550
Fujii et al: Adherence to Guidelines and Emetic Control Figure 1. Comparison of adherence to the national guidelines for prevention of chemotherapy-induced nausea and vomiting (A), complete protection from nausea plus vomiting (B), nausea (C), and vomiting (D) in patients with colorectal cancer receiving moderately emetic chemotherapy (MEC) at the outpatient cancer chemotherapy clinic between the observational and the interventional groups. Intervention was carried out to facilitate antiemetic medication based on the clinical practice guidelines. *p<0.05, **p<0.01 by Chi-square test. Results Patients demographics. The demographics of patients were compared between the observational and interventional groups. As shown in Table I. The mean age was significantly higher in patients of the interventional group than in those in the observational group (66.9 versus 61.5 years, p=0.01). Body surface area was significantly smaller in patients of the interventional group (1.56 versus 1.63 m 2, p=0.049). The relative dose intensity for chemotherapy was significantly 5551
higher in the interventional group (99% versus 85%, p<0.01), indicating that higher dose of oxaliplatin or irinotecan was administered. Gender and laboratory data were not different between the two groups. Adherence to the antiemetic guideline and control of CINV. In the observational group, the adherence to the antiemetic guidelines in patients receiving the first course of MEC was 100% in the acute period, while that in the delayed period was only 6.6% (Figure 1A). Non-adherence was due exclusively to the lack of dexamethasone use on days 2 and 3. On the other hand, in an interventional group, the treatment of dexamethasone on days 2 and 3 was carried out in 57 of 64 patients (89%) (Figure 1A), although the daily dose of dexamethasone (4 mg) was lower than the guidelinerecommended dose (8 mg). Control of CINV. Complete protection from both nausea and vomiting during the delayed period (2-5 days) was 20% higher (p<0.05) in an interventional group than in an observational group, although the rate of complete protection during the acute period was rather significantly (p<0.01) lower by 15% in an interventional group (Figure 1B). In addition, the rate of complete protection from nausea alone during the delayed period was significantly (p<0.05) higher by 19% in an interventional group than in an observational group (Figure 1C), while the rate of complete protection from vomiting alone was not significantly different between the two groups (Figure 1D). Effect of delayed treatment with dexamethasone on complete protection from nausea and vomiting. To determine the antiemetic effect of dexamethasone given on days 2 and 3, the data without treatment of dexamethasone in an interventional group were compared to those with treatment of dexamethasone in an observational group. Complete protection during the delayed period was significantly (p<0.05) higher by 18% in the dexamethasone treatment group, while the rate of acute CINV being significantly (p<0.01) lower by 13% (Figure 2A). Moreover, the rate of complete control of nausea alone during the delayed period was also significantly (p<0.05) higher by 18% in the dexamethasone-treatment group. No significant difference in the complete control of vomiting alone was observed between the two groups. Since the control of CINV during the acute period was different between the two groups, the effect of dexamethasone on delayed CINV was re-evaluated in patients who showed no signs of acute CINV. As shown in Figure 2B, complete protection from nausea and vomiting was significantly (p<0.05) higher by 20% in the dexamethasone-treatment group. This effect of dexamethasone was predominantly due to the enhanced control of nausea but not vomiting. Comparison of other adverse events. As shown in Table II, the incidence and grade of hematological toxicities and nonhematological toxicity (constipation) were compared in the two groups. Although the incidence of severe (grade 3 or more) toxicities were limited and did not differ between the two groups, the incidence of leukopenia of all grades was significantly higher in the interventional group (42.2% versus 23.0%, p=0.024). There were no significant differences in the incidence or grade of other toxicities between the two groups. Discussion A number of evidence-based therapeutic measures and diagnostic techniques have been developed for a variety of diseases in recent years since the theory of evidence-based medicine was originally advocated by Gordon H. Guyatt in 1991 (12, 13). However, literature has highlighted that evidence-based guidelines or medicine have not been fullyutilized in actual clinical practice (the so-called evidence practice gap) (14). McGlynn et al. investigated adherence to the recommended measures for prevention, diagnosis, therapy and follow-up for over 439 indicators of quality of care for 30 acute and chronic conditions by telephone interview and verification of medical records in more than 6,712 adults living in 12 metropolitan areas in the United States (15). They reported that adherence to the recommended care was 54.9%, and were little differences in the rates among preventive care, screening, diagnosis, treatment, and follow-up care. An evidence practice gap has also been reported for the control of CINV. Although several clinical practice guidelines for the use of antiemetic agents have been provided, the adherence to the guidelines has been reported to be low in the clinical setting from only 3% to 42% (7-11). The guidelines for antiemesis recommend the use of a combination of 5-HT3 antagonist and dexamethasone before chemotherapy and oral dexamethasone on days 2 and 3 for prevention of CINV associated with MEC. In the present study, the use of antiemetic drugs before chemotherapy did closely adhere to the guidelines. However, oral dexamethasone was used in only 6.6% of patients receiving MEC. Our data were generally consistent with those of Koch et al. who showed that the adherence to the MASCC/ESMO guideline was 3% in patients with colorectal cancer receiving MEC, in which dexamethasone was not prescribed in most cases (11). To promote use of evidence-based antiemetic medication, intervention was carried out. Patients were also instructed in the need for prevention of CINV and appropriate use of antiemetic drugs. As a consequence, dexamethasone was used on days 2 and 3 in 89% of patients in the intervention group, although the daily dose was lower than that recommended. 5552
Fujii et al: Adherence to Guidelines and Emetic Control Figure 2. Effect of delayed treatment with dexamethasone on days 2 and 3 on complete protection from nausea plus vomiting, nausea and vomiting during the acute (within 24 h) and delayed (days 2-5) periods in all patients with colorectal cancer (A), and in those who showed no signs of chemotherapy-induced nausea and vomiting during the acute period (B). Data without delayed dexamethasone treatment were obtained from the observational study and those with delayed dexamethasone treatment were from the interventional study. Patients were all pre-treated with a combination of intravenous 5-HT 3 receptor antagonist and intravenous dexamethasone (16-20 mg) before chemotherapy. *p<0.05, **p<0.01 by the Chi-square test. Such dosage selection was determined because of the increased risk of a variety of side-effects of dexamethasone, since patients with colorectal cancer receiving MEC are usually treated with chemotherapy every 2-3 weeks for a long period. Nevertheless, complete protection from nausea and vomiting during the delayed period was enhanced from 54% to 74% (p<0.05) by intervention with dexamethasone. The enhancement of complete protection was mostly due to the improvement of nausea not vomiting. On the other hand, there were significant differences in several patient characteristics in the two groups. The relative dose intensity was higher (p<0.01) in the interventional group, indicating that a higher amount of anticancer drug was administered. Such a difference in the relative dose 5553
Table Ⅱ. Comparison of other side-effects associated with chemotherapy in the observational and interventional groups. Observational Interventional p-value (N=61) (N=64) Adverse effect N Incidence (%) N Incidence (%) Constipation G0 53 86.9 52 81.3 G1 5 8.2 7 10.9 G2 3 4.9 5 7.8 All grades 8 13.1 12 18.8 0.468 Leukopenia G0 47 77.0 37 57.8 G1 6 9.8 5 7.8 G2 7 11.5 18 28.1 G 3 1 1.6 4 6.3 0.366 All grades 14 23.0 27 42.2 0.024 Anemia G0 24 39.3 22 34.4 G1 30 49.2 29 45.3 G2 6 9.8 11 17.2 G 3 1 1.6 2 3.1 0.973 All grades 37 60.7 42 65.6 0.100 Thrombocytopenia G0 50 82.0 44 68.8 G1 11 18.0 19 29.7 G2 0 0.0 1 1.6 G 3 0 0.0 0 0.0 All grades 11 18.0 20 31.3 0.583 Data were statistically compared by the chi-square test. intensity may contribute to the higher frequency of leukopenia (all grades) in this group (42% versus 23%, p<0.05). Moreover, in the present study, the control of acute CINV in the interventional group was inferior to that of the observational group. This may also be explained by the higher relative dose intensity of the interventional group. Even under such a condition, the control of CINV during the delayed period was significantly enhanced in the interventional group, thereby suggesting that the effect of the present intervention was underestimated. On the other hand, patients subjected to antiemetic medication intervention were significantly (p=0.01) older than those without intervention (66.9 versus 61.5 year-old). Younger age is reported to be a risk factor for CINV, although the cut-off for age differed among several reports: <40 years by Fraunholz et al. (16), <55 years by Sekine and Segawa (17), and <65 years by Hesketh et al. (18) and Hilarius et al. (19). Therefore, we cannot exclude the possibility that the emetic risk is lower due to age in patients of the interventional group than in those of the observational group. However, it is unlikely that age affected the incidence of CINV since the control of acute CINV was rather lower after intervention despite of older age and similar antiemetic medication before chemotherapy. Finally, we evaluated the effect of oral dexamethasone used at a daily dose of 4 mg on days 2 and 3 in patients receiving MEC, since little is known about the effect of dexamethasone at this dose for prevention of delayed CINV. Since the control of acute CINV was significantly lower in patients with dexamethasone treatment than in those without it, complete protection was compared in those who showed no signs of CINV during the acute period. Under such a condition, complete protection from nausea and vomiting during the delayed period was significantly (p<0.05) higher by 20% in the interventional group. This effect of dexamethasone was predominantly due to the improvement of nausea. The rates of no delayed nausea and no delayed vomiting were 57% and 91%, respectively, in patients without dexamethasone treatment. Our data for patients without dexamethasone were generally consistent with those reported by Hesketh et al. who showed that the rate of protection from delayed nausea and vomiting was 46% and 90%, respectively, in patients with colorectal cancer who received oxaliplatin-based chemotherapy but had no delayed antiemetic treatment (20). Roscoe et al. demonstrated by a randomized control trial in 1,021 patients receiving HEC or MEC for the first time that the addition of dexamethasone at a daily dose of 8 mg on days 2 and 3 to 5554
Fujii et al: Adherence to Guidelines and Emetic Control the standard acute antiemetic treatment (palonosetron-plusdexamethasone before chemotherapy) increased delayed nausea by approximately 20%, but not vomiting (21). Therefore, our data on the effect of dexamethasone at 4 mg/day on delayed CINV were very similar to those reported by Roscoe et al. Rolia et al. systematically reviewed randomized control trials and showed that dexamethasone at 8 mg/day on days 2-5 reduces the likelihood of the onset of delayed emesis (22). In contrast, Vardy et al. reported that delayed treatment with dexamethasone (8 mg/day) was not effective for prevention of CINV in 94 patients with breast cancer receiving anthracyclines and cyclophosphamide (delayed nausea: 81.6-83.8% for non-treatment group and 76.7-88.7% for the dexamethasone-treated group; delayed vomiting: 46.0-55.1% for the non-treatment group and 42.9-46.5% for the dexamethasone-treated group) (23). Therefore, larger randomized control trials in patients receiving MEC are required in order to clarify the effects of different doses of dexamethasone on the control of delayed CINV. In conclusion, adherence to the guidelines for antiemetic medication was investigated in patients with colorectal cancer receiving MEC and the adherence was found to be only 6.6%, mostly due to a lack of dexamethasone for prevention of delayed CINV. Subsequent intervention to improve evidence-based antiemetic medication increased adherence to 89% and resulted in better complete protection from delayed nausea and vomiting. Moreover, the addition of dexamethasone at a daily dose of 4 mg on days 2 and 3 increased the rate of complete protection from delayed nausea and vomiting by 20%. Source of Funding None declared. Conflicts of Interest The Authors have no conflicts of interest. References 1 Bloechl-Daum B, Deuson RR, Mavros P, Hansen M and 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 de Boer-Dennert M, de Wit R, Schmitz PI, Djontono J, Beurden V, Stoter G and Verweij J: Patient perceptions of the side-effects of chemotherapy: The influence of 5HT3 antagonists. Br J Cancer 76: 1055-1061, 1997. 3 Carelle N, Piotto E, Bellanger A, Germanaud J, Thuillier A and Khayat D: Changing patient perceptions of the side-effects of cancer chemotherapy. Cancer 95: 155-163, 2002. 4 Basch E, Prestrud AA, Hesketh PJ, Kris MG, Feyer PC, Somerfield MR, Chesney M, Clark-Snow RA, Flaherty AM, Freundlich B, Morrow G, Rao KV, Schwartz RN and Lyman GH: Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 29: 4189-4198, 2011. 5 Roila F, Herrstedt J, Aapro M, Gralla RJ, Einhorn LH, Ballatori E, Bria E, Clark-Snow RA, Espersen BT, Feyer P, Grunberg SM, Hesketh PJ, Jordan K, Kris MG, Maranzano E, Molassiotis A, Morrow G, Olver I, Rapoport BL, Rittenberg C, Saito M, Tonato M and Warr D: Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: Results of the Perugia consensus conference. Annal Oncol 21(suppl 5): v232-243, 2010. 6 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Antiemesis. Version I, 2013. Available at: http://www.nccn.org/professionals/physician_gls/ pdf/antiemesis.pdf. 7 Burmeister H, Aebi S, Studer C, Fey MF and Gautschi O: Adherence to ESMO clinical recommendations for prophylaxis of chemotherapy-induced nausea and vomiting. Support Care Cancer 20: 141-147, 2012. 8 Gomez DR, Liao KP, Giordano S, Nguyen H, Smith BD and Elting LS: Adherence to national guidelines for antiemesis prophylaxis in patients undergoing chemotherapy for lung cancer: A population-based study. Cancer 119: 1428-1436, 2013. 9 Chan A, Low XH and Yap KY: Assessment of the relationship between adherence with antiemetic drug therapy and control of nausea and vomiting in breast cancer patients receiving anthracycline-based chemotherapy. J Manag Care Pharm 18: 385-394, 2012. 10 Aapro M, Molassiotis A, Dicato M, Peláez I, Rodríguez-Lescure Á, Pastorelli D, Ma L, Burke T, Gu A, Gascon P and Roila F: The effect of guideline-consistent antiemetic therapy on chemotherapyinduced nausea and vomiting (CINV): the Pan European Emesis Registry (PEER). Ann Oncol 23: 1986-1992, 2012. 11 Koch S, Wein A, Siebler J, Boxberger F, Neurath MF, Harich H- D, Hohenberger W and Dörje F: Antiemetic prophylaxis and frequency of chemotherapyinduced nausea and vomiting in palliative first-line treatment of colorectal cancer patients: The Northern Bavarian IVOPAK I Project. Support Care Cancer 2013 (DOI 10.1007/s00520-013-1801-z). 12 Guyatt GH: Evidence-based medicine. ACP J Club 114(suppl 2): A-16, 1991. 13 Evidence-Based Medicine Working Group: Evidence-based medicine. A new approach to teaching the practice of medicine. JAMA 268: 2420-2425, 1992. 14 Buchan H. Gaps between best evidence and practice: Causes for concern. Med J Aust 180(6 suppl): 48-49, 2004. 15 McGlynn EA, Asch SM, Adams J, Keesey J, Hicks J, DeCristofaro A and Kerr EA: The quality of health care delivered to adults in the United States. New Engl J Med 348: 2635-2645, 2003. 16 Fraunholz I, Grau K, Weiss C and Rödel C: Patient- and treatment-related risk factors for nausea and emesis during concurrent chemoradiotherapy. Strahlenther Onkol 187: 1-6, 2011. 17 Sekine I, Segawa Y, Kubota K and Saeki T: Risk factors of chemotherapy-induced nausea and vomiting: Index for personalized antiemetic prophylaxis. Cancer Sci 104: 711-717, 2013. 5555
18 Hesketh PJ, Aapro M, Street JC and Carides AD: Evaluation of risk factors predictive of nausea and vomiting with current standard-of-care antiemetic treatment: Analysis of two phase III trials of aprepitant in patients receiving cisplatin-based chemotherapy. Support Care Cancer 18: 1171-1177, 2010. 19 Hilarius DL, Kloeg PH, van der Wall E, van den Heuvel JJ, Gundy CM and Aaronson NK: Chemotherapy-induced nausea and vomiting in daily clinical practice: A community hospitalbased study. Support Care Cancer 20: 107-117, 2012. 20 Hesketh PJ, Sanz-Altamira P, Bushey J and Hesketh AM: Prospective evaluation of the incidence of delayed nausea and vomiting in patients with colorectal cancer receiving oxaliplatinbased chemotherapy. Support Care Cancer 20: 1043-1047, 2012. 21 Roscoe JA, Heckler CE, Morrow GR, Mohile SG, Dakhil SR, Wade JL and Kuebler JP: Prevention of delayed nausea: A University of Rochester Cancer Center Community Clinical Oncology Program study of patients receiving chemotherapy. J Clin Oncol 30: 3389-3395, 2012. 22 Roila F, Warr D, Aapro M, Clark-Snow RA, Einhorn L, Gralla RJ, Herrstedt J, Saito M and Tonato M: Delayed emesis: Moderately emetogenic chemotherapy (single-day chemotherapy regimens only). Support Care Cancer 19(suppl 1): S57-62, 2011. 23 Vardy J, Pond G, Dodd A, Warr D, Seruga B, Clemons M, Bordeleau L, Goodwin P and Tannock IF: A randomized doubleblind placebo-controlled cross-over trial of the impact on quality of life of continuing dexamethasone beyond 24 h following adjuvant chemotherapy for breast cancer. Breast Cancer Res Treat 136: 143-151, 2012. Received September 26, 2013 Revised November 1, 2013 Accepted November 4, 2013 5556