A prospective study of gastrointestinal radiation therapy-induced nausea and vomiting

Support Care Cancer (2014) 22:1493 1507 DOI 10.1007/s00520-013-2104-0 ORIGINAL ARTICLE A prospective study of gastrointestinal radiation therapy-induced nausea and vomiting Michael Poon & Kristopher Dennis & Carlo DeAngelis & Hans Chung & Jordan Stinson & Liying Zhang & Gillian Bedard & Marko Popovic & Nicholas Lao & Natalie Pulenzas & Shun Wong & Edward Chow Received: 21 October 2013 /Accepted: 12 December 2013 /Published online: 12 January 2014 # Springer-Verlag Berlin Heidelberg 2014 Abstract Objective and vomiting are common side effects from radiotherapy that can interfere with gastrointestinal (GI) cancer patients quality of life (QOL). A prospective study among patients with GI cancers was conducted to document the timing, incidence and risk factors of radiation therapyinduced nausea and vomiting (RINV). Methods Forty-eight patients planned to receive curative or palliative intent abdominal and/or pelvic radiotherapy alone or with concomitant chemoradiotherapy were followed prospectively. All episodes of nausea, vomiting, retching and antiemetic use were recorded daily for the entire treatment period and for the week following completion of therapy. QOL was assessed weekly using the Functional Living Index Quality of Life Tool and the EORTC QLQ-C30 core questionnaire. Results occurred in 83 % of patients and emesis in 54 %. Pancreatic cancer was significantly correlated to higher proportions of nausea and emesis (p=0.002 and p=0.0003) compared to other primary sites. There were no significant difference between concomitant chemoradiotherapy and radiotherapy only patients for nausea and emesis. Patients had significantly greater proportions of RINV during the first, M. Poon: C. DeAngelis : H. Chung : J. Stinson : L. Zhang : G. Bedard: M. Popovic : N. Lao : N. Pulenzas : S. Wong : E. Chow Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada K. Dennis Division of Radiation Oncology, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada E. Chow (*) Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5 e-mail: Edward.Chow@sunnybrook.ca second and fifth weeks of treatment and during the first week following treatment. Vomiting was found to impair patients usual recreation or leisure activities and enjoyment of their meals. Worse physical, role and social functioning and greater fatigue and appetite loss over the course of treatment correlated directly with the timing of RINV symptoms. Conclusion RINV worsened QOL and was experienced even after treatment was completed; physicians should therefore be cognizant and monitor patients in the week following radiotherapy. Concomitant chemoradiotherapy should potentially be included in the moderate emetogenic risk category. Keywords Radiotherapy-induced emesis. Radiotherapy-induced nausea and vomiting. Onset timing. Concomitant chemoradiotherapy Introduction and vomiting are common side effects of antineoplastic therapy. While supportive care of patients receiving systemic treatment has improved in the past 20 years [1], the body of research in radiotherapy-induced nausea and vomiting (RINV) remains limited in comparison to that for chemotherapy-induced nausea and vomiting (CINV). Depending on the anatomic area being irradiated, an estimated 40 80 % of patients treated with radiotherapy develop RINV [2], which can interfere with quality of life (QOL) and cause delays or interruptions of treatment [3]. Clinicians continue to underestimate the incidence of nausea, which is not as well controlled as emesis [4]. The updated ASCO antiemetic guidelines highlight RINV as an understudied area and recognize the need to improve symptom control [4]. The incidence and severity of RINV are thought to result from a combination of radiotherapy-related factors and patient-related factors [1]. These include the anatomic site of

1494 Support Care Cancer (2014) 22:1493 1507 radiation, volume of organs such as the small bowel irradiated, radiation dose and fractionation schedule, age, gender and concurrent or recent chemotherapy [2]. However, current antiemetic guidelines categorize radiation treatments only according to the anatomic area being irradiated [1, 4]. According to antiemetic practice guidelines, radiation treatments to the upper abdomen are considered moderately emetogenic, with an estimated risk of 60 90 % [5]. The largest sources of incidence data for emetogenic risk treatments were published in a pair of Italian observational studies [2]. Across 45 Italian centres, 1,020 patients undergoing radiotherapy to all body sites were followed prospectively. Of the 52 patients who received treatment to the upper abdomen, 48 % developed nausea and 21 % developed vomiting during radiotherapy. A prior investigation by the same research group documented a 67 % nausea rate and a 38 % vomiting rate among the 42 patients receiving upper abdominal radiotherapy [6]. These results were subsequently used to support current recommendations for prophylactic antiemetic medications for upper abdominal radiotherapy. Previous studies did not compare different GI radiotherapy targets. Furthermore, they enrolled very few patients who received concomitant chemoradiotherapy which may increase the risk of nausea and vomiting experienced beyond radiotherapy alone. The effect of RINV on patients QOL during and following completion of radiotherapy is also unclear. Finally, radiation oncologists do not categorize treatments in terms of emetogenic potential but rather in terms of primary cancer or anatomic site. Therefore, site-specific data would be helpful to further develop antiemetic guidelines. A prospective study of RINV among patients with GI cancers was conducted to better understand and document RINV timing, incidence, natural history and risk factors, all of which are needed in order to develop personalized and appropriate supportive care strategies in the future. Methods Patient characteristics Forty-eight patients with GI cancer that were planned to receive curative or palliative intent abdominal and/or pelvic radiotherapy alone or with concomitant chemotherapy were enrolled between May and October of 2012. All patients aged 18 years or older, with a Karnofsky Performance Status (KPS) of greater than 40, and a histologically, cytologically or radiologically proven GI tumor were considered eligible. Patients who had received prior radiotherapy to brain, abdominal and/ or pelvic structures were ineligible. Antiemetic treatment plans were left to the discretion of the most responsible treating oncologists. Five patients were not included in the study herein as their treatments were cancelled prematurely. Patient assessments Patients were followed daily from the day of their first radiation treatment to 7 days following the completion of their scheduled treatment. Patients were expected to record all episodes of nausea, vomiting, retching and antiemetic use on a diary. An individual episode was considered new only if it occurred at least 1 min following completion of the previous episode. On every treatment day, the patient met with a research assistant in-person to review all episodes of RINV. If the planned in-person meeting did not occur, attempts were made to contact the patient via telephone on the same day. QOL was assessed on a weekly basis beginning on the first day of treatment using the Functional Living Index Quality of Life Tool (FLIE) (Appendix I) and the EORTC QLQ-C30 (QLQ-C30) core questionnaire (Appendix II). This provided a nausea and vomiting-specific QOL assessment (18-item FLIE) commonly employed in antiemetic research [7 11], while still capturing overall QOL across functional scales (30-item QLQ-C30). Patients were followed until the seventh day after their final treatment, until their treatment was cancelled prematurely or until they requested to be taken off the study. Outcomes of interest The principal outcomes of interest were: 1) The cumulative incidence of episodes of nausea and emesis from the day of the first radiation treatment to the seventh day following the last radiation treatment, inclusive. 2) The proportion of patients experiencing any episodes of nausea and emesis on an individual day. Other outcomes of interest included the frequency of episodes of nausea and emesis on a daily basis, the proportion of patients receiving antiemetic medications, the changes in QOL from baseline to the weekly assessment periods and the incidence of nausea within the 7 days following the last radiation treatment. Statistical analyses Demographic information was summarized as mean, standard deviation (SD), median and range for continuous variables and as proportions for categorical variables. The incidences of symptoms were calculated as a proportion of patients. Vomiting and retching were combined together under emesis. In the current study, D0 was defined as day 0 (the rest of the day following a patient s first treatment), D1 as day 1 (the day after the first treatment) and so forth. and emetic episodes were classified into three categories to

Support Care Cancer (2014) 22:1493 1507 1495 demonstrate frequency of events. Patients who experienced no nausea on a given calendar day were classified as No, 1 2 episodes of nausea were classified as Occasional and 3 or more episodes of nausea in a day were classified under Frequent. The same also applied to emetic episodes. The overall incidence of symptoms and the incidences of symptoms falling in the aforementioned categories were plotted over time. To investigate time trends of nausea and emesis, the generalized estimating equations (GEEs) methodology was employed [12]. Because the responses of RINV were ordinal variables (1=none, 2=occasional, 3=frequent), multinomial distribution with cumulative logit link function and an independent working correlation matrix were used. Independent variables included the time in days and categorical variable of period (baseline, during treatment and post-treatment). To assess significant differences between groups of patients, some categorical covariates were added in the GEE model, such as radiotherapy treatment (radiotherapy only vs. concomitant chemoradiotherapy), emetogenic risk (low vs. moderate) and primary cancer site. To investigate weekly RINV, nausea and emetic episodes were summed per patient per week and a Poisson s distribution was used with GEE modeling to compare between weeks. General linear mixed models (GLMM) were used to investigate time trends of QOL. Natural logtransformation was applied for time-dependent QOLs. pvalues less than 0.05 were considered statistically significant. Kaplan Meier time to events curves were plotted from baseline to first occurrence of nausea and first occurrence of emesis, respectively. Analyses were performed using the Statistical Analysis Software package (SAS version 9.3 for Windows), GENMOD and Mixed procedures. Results Overall incidence of nausea and emesis Demographics, treatment and antiemetic details of the 48 study patients are outlined in Table 1. The mean length of time on study was 26 days (including non-treatment days) and ranged from 0 to 57 days. The most common primary sites of cancer were the pancreas (29 %), the esophagus (15 %) and the liver (15 %). All treatments had either a low or moderate emetogenic risk level as defined by MASCC/ASCO guidelines, with the majority presenting a moderate risk since the upper abdomen was irradiated (73 %; Table 1). Twenty of the patients received concurrent chemotherapy, the majority of which was considered of low emetogenic risk (85 %) [1]. Across all 48 patients, 1499 daily dairies of nausea, vomiting and retching were collected. Of the 1,499 daily symptom assessment records, 4 % of nausea records, 4 % of vomiting records and 4 % of retching records were Table 1 Patient demographics, radiotherapy (RT), chemotherapy, and anti-emetic details Characteristic Number of patients 48 Age (years) N 48 Mean±SD 64.7±12.8 Median (range) 65 (32 92) Karnofsky performance status N 39 Mean±SD 78.5±11.2 Median (range) 80 (60 100) Sex Female 24 (50.0 %) Male 24 (50.0 %) Primary cancer site Pancreas 14 (29.2 %) Esophagus 7 (14.6 %) Liver 7 (14.6 %) Colon 5 (10.4 %) Stomach 5 (10.4 %) Kidney 3 (6.2 %) Others 7 (14.6 %) Previous unrelated cancer or GI disorder/surgery No 21 (46.6 %) Yes 25 (54.4 %) Anxiety disorder No 44 (93.6 %) Yes 3 (6.4 %) Alcohol consumption No 34 (77.3 %) Yes 10 (22.7 %) Previous RT No 43 (91.5 %) Yes 4 (8.5 %) Previous chemotherapy No 31 (64.6 %) Yes 17 (35.4 %) Previous CINV No 6 (35.3 %) Yes 11 (64.7 %) RT RT duration (days) N 48 Mean±SD 25.5±16.4 Median (range) 21 (0 57) Anatomic site of RT Pancreas 14 (29.2 %) Liver 10 (20.8 %) Esophagus 7 (14.6 %) Upper abdomen 6 (12.5 %)

1496 Support Care Cancer (2014) 22:1493 1507 Table 1 (continued) Characteristic Stomach 4 (8.3 %) Pelvis 4 (8.3 %) Colon 3 (6.25) RT emetogenicity risk level Low 13 (27.1 %) Moderate 35 (72.9 %) RT technique IMRT 30 (62.5 %) Field based 7 (20.19 %) SBRT 8 (16.7 %) Conventional 3DRT 3 (6.2 %) Discrepancy between prescribed and received RT dose? No 44 (91.6 %) Yes RT cancelled prematurely 2 (4.2 %) Yes one extra fraction received 2 (4.2 %) Chemotherapy (CT) treatment CT planned concurrently No 28 (58.3 %) Yes 20 (41.7 %) CT received Capecitabine 7 (35.0 %) 5-Fluorouracil 8 (45.0 %) FU/Mitomycin + RT 2 (10.0 %) FUCISP 3 (15.0 %) CT emetogenicity risk level High 3 (15.0 %) Low 17 (85.0 %) Antiemetic use Antiemetic use during radiation No 13 (27.1 %) Yes 35 (72.9 %) FU fluorouracil, RT radiotherapy, FUCISP fluorouracil cisplatin, IMRT intensity modulated radiotherapy, SBRTstereotactic body radiotherapy incomplete. Antiemetic use was documented in 35 of the 48 patients and 445 daily records during the follow-up period. In these patients antiemetics were used consistently throughout treatment. However, due to the inconsistencies in patient reporting, daily antiemetic use was not analysed in relation to nausea or emetic episodes. Among all available records, 78 % and 90 % of daily symptom assessment diaries reported no nausea and emesis, respectively. Fourteen percent of events were classified as occasional nausea and 7 % as occasional emesis. Eight percent and 3 % of events were categorized as frequent for nausea and emesis, respectively. Overall, 83 % of patients experienced an episode of nausea and 54 % experienced an emetic episode. No nausea or emesis occurred in 15 % of patients during treatment, 60 % during post-treatment and 13 % over the entire period (Table 2). Daily and weekly trends of nausea and emesis The daily percentage of patients experiencing nausea ranges from 0 % to 50 % and emesis values range from 0 % to 23 % (Fig. 1a, b). On any given day, an average of 22 % of patients experienced nausea and 5 % of patients experienced emesis. There were no significant overall time trends for nausea or emesis in all patients. However, significant differences can be seen for symptom experiences at different time periods. Patients had significantly more episodes of nausea during the treatment phase compared to baseline (p=0.03). In addition, patients had significantly higher proportions of emesis during treatment when compared to baseline (p=0.04) and at the post-treatment phase compared to baseline (p=0.03; Table 3). In Table 3, nausea and emesis differences between baseline and during treatment hold true when the binary covariate of radiotherapy treatment is applied to the model (p=0.03 and p= 0.04, respectively). Upon stratification, there was no significant difference between concomitant chemoradiotherapy and radiotherapy only patients for either nausea or emesis. Patients with concurrent chemotherapy had similar proportions of both nausea and emesis over time (Fig. 1c, d). However, patients on chemotherapy had a lower probability of nausea over time (Fig. 1c). In a similar stratification for antiemetics, patients who received antiemetics had significantly higher probabilities of nausea over time (p<0.0001; Fig. 1e). However, no such trend was seen with emesis (Fig. 1f). A significant difference was seen between baseline and during treatment nausea and emesis values (p=0.03 and 0.04, respectively) when different cancer sites were analysed (Table 3). Patients with a pancreatic cancer site were found to have significantly higher proportions of both nausea and emesis (p=0.002 and p=0.0003, respectively). Finally, patients with low emetogenic risk radiotherapy had significantly fewer episodes of nausea compared to patients with moderate risk (p=0.02). Weekly incidences of nausea and emesis indicated that patients had a higher probability of nausea during weeks 1 and 5 as compared to other weeks (p=0.006 and 0.01, respectively). For emesis, patients experienced significantly more symptoms at week 1 (p=0.0004), week 2(p=0.01) and posttreatment (p=0.009; Table 3). Kaplan Meier (KM) curves were plotted from baseline to first occurrence of nausea and emesis (Fig. 2a, b). There was a censored rate of 17 % for nausea. The median time to first occurrence of nausea from KM curve was 4 days with 95 % confidence intervals of 2 to 17 days. The range of time to event was from 0 to 57 days. There were 28 subjects with emesis among 48 total subjects and 22 subjects did

Support Care Cancer (2014) 22:1493 1507 1497 Table 2 Descriptive analysis of overall percentages of patients Overall patient level descriptive analysis During treatment (N=48) Post-treatment (N=42) During+post-treatment (N=48) Yes 39/48 (81.3 %) 14/42 (33.3 %) 40/48 (83.3 %) No 9/48 (18.8 %) 28/42 (66.7 %) 8/48 (16.7 %) Yes 24/48 (50.0 %) 10/42 (23.8 %) 26/48 (54.2 %) No 24/48 (50.0 %) 32/42 (76.2 %) 22/48 (45.8 %) and emesis Any nausea and/or any emesis 41/48 (85.4 %) 17/42 (40.5 %) 42/48 (87.5 %) None 7/48 (14.6 %) 25/42 (59.5 %) 6/48 (12.5 %) Descriptive analysis of RT only patients and RT+CT patients RT only (N=28) RT+CT (N=20) Yes 24/28 (85.7 %) 16/20 (80.0 %) No 4/28 (14.3 %) 4/20 (20.0 %) Yes 19/28 (67.9 %) 7/20 (35.0 %) No 9/28 (32.1 %) 13/20 (65.0 %) and emesis Any nausea and/or any emesis 26/28 (92.9 %) 16/20 (80.0 %) None 2/28 (7.1 %) 4/20 (20.0 %) Descriptive analysis of RT patients with or without antiemetics No antiemetics (N=13) Antiemetics (N=35) Yes 7/13 (53.9 %) 33/35 (94.3 %) No 6/13 (46.1 %) 2/35 (5.7 %) Yes 6/13 (46.2 %) 20/35 (57.1 %) No 7/13 (53.8 %) 15/35 (42.9 %) and emesis Any nausea and/or any emesis 9/13 (69.2 %) 33/35 (94.3 %) None 4/13 (30.8 %) 2/35 (5.7 %) Descriptive analysis by primary cancer site Pancreas (N=14) Esophagus (N=7) Colon (N=5) Stomach (N=5) Other (N=17) Yes 14 (100 %) 4 (57.1 %) 5 (100 %) 5 (100 %) 12 (70.6 %) No 0 (0 %) 3 (42.9 %) 0 (0 %) 0 (0 %) 5 (29.4 %) Yes 9 (64.3 %) 4 (57.1 %) 4 (80.0 %) 1 (20.0 %) 8 (47.1 %) No 5 (35.7 %) 3 (42.9 %) 1 (20.0 %) 4 (80.0 %) 9 (52.9 %) and emesis Any nausea and/or any emesis 14 (100 %) 6 (85.7 %) 5 (100 %) 5 (100 %) 12 (70.6 %) None 0 (0 %) 1 (14.3 %) 0 (0 %) 0 (0 %) 5 (29.4 %) not have any emesis over the time with a censored rate of 46 %. The median time to first occurrence of emesis from KM curve was 16 days with 95 % confidence intervals of 7 to 57 days. FLIE and C30 QOL With regards to the FLIE, the responses to item-11 ( Has vomiting affected your ability to maintain usual recreation or

1498 Support Care Cancer (2014) 22:1493 1507 a b c d e f Fig. 1 a Percentage of patients with no nausea, any nausea, occasional nausea or frequent nausea over time. D = day. b Percentage of patients with no emesis, any emesis, occasional emesis or frequent emesis over time. D = day. c Percentage of patients who experienced nausea while receiving concurrent chemotherapy with RT or RT without chemotherapy over time. D = day. d Percentage of patients who experienced emesis while receiving concurrent chemotherapy with RT or RT without chemotherapy over time. D = day. e Percentage of patients who experienced nausea with and without antiemetics over time. D = day. f Percentage of patients who experienced emesis with and without antiemetics over time. D =day leisure activities in the past 3 days? ) significantly decreased over time (p=0.04; Appendix III), indicating emesis was associated with increasing problems with recreation or leisure activities over time. In addition, item-13 response demonstrates that vomiting hindered patients ability to enjoy their meals (p=0.04). QLQ-C30 functional scores indicated worse physical (p=0.001), role (p=0.0003) and social functioning (p=0.002), but better emotional functioning (p=0.02) over the course of radiotherapy treatment. C30 symptom scores indicated that patients had increasing fatigue (p=0.0008) and appetite loss (p<0.0001) over time (Table 4). Patients who experienced nausea or emesis had significantly higher scores for all FLIE items. The significant interaction

Support Care Cancer (2014) 22:1493 1507 1499 Table 3 Daily and weekly nausea and emesis trend analysis in all patients and in sub-groups Symptom (none vs. nausea or emesis) Coefficient Standard error p value All patients Period: baseline vs. during treatment 1.10 0.51 0.03 Period: baseline vs. during treatment 1.95 0.98 0.04 Baseline vs. post-treatment 3.82 1.75 0.03 RT only vs. RT+CT Period: baseline vs. during treatment 1.11 0.51 0.03 Period: baseline vs. during treatment 1.95 0.98 0.04 Pancreas vs. other cancer sites Period: baseline vs. during treatment 1.19 0.54 0.03 Primary cancer site of pancreas vs. other 1.42 0.46 0.002 Period: baseline vs. during treatment 2.08 1.00 0.04 Baseline vs. post-treatment 4.29 1.75 0.01 Primary cancer site of pancreas vs. other 1.91 0.53 0.0003 Emetogenic risk of RT (low vs. moderate) RT emetogenicity (low vs. moderate) 1.45 0.63 0.02 Weekly nausea and emesis Weeks Baseline vs. other weeks 21.97 4.08 <0.0001 Week 1 vs. other weeks 5.37 1.95 0.006 Week 5 vs. other weeks 4.71 1.86 0.01 Weeks Baseline vs. other weeks 22.80 7.04 0.001 Week 1 vs. other weeks 6.37 1.81 0.0004 Week 2 vs. other weeks 5.73 2.21 0.01 Post-treatment vs. other weeks 5.18 1.98 0.009 terms for questions 10, 12, 14 and 16, and the overall summary score indicated that patients with emesis experienced increasingly detrimental effects over time as a result of vomiting. Additionally, patients with nausea or vomiting had increased trouble with fatigue, nausea/vomiting symptoms and appetite loss, but less trouble with insomnia according to the QLQ-C30. Social functioning, fatigue and appetite loss also all got worse over time with RINV. Patients with any nausea reported worse physical functioning compared to patients with no nausea (p=0.01). A similar relationship was seen with patients who experienced emesis. These patients had worse physical and role functioning compared to patients with no emesis over time (p=0.003, 0.002). Lastly, patients with emesis had more trouble with the nausea/vomiting symptoms score on the QLQ- C30 (Tables 4 and 5). Discussion RINV may be underappreciated by radiation oncologists and many consider its incidence negligible when compared to the incidence caused by chemotherapy. Consequently, radiation oncologists tend to prophylactically prescribe antiemetics

1500 Support Care Cancer (2014) 22:1493 1507 Fig. 2 a Kaplan Meier curve of time to first episode of nausea. b Kaplan Meier curve of time to first emetic episode only to a minority of patients [2]. In the present study, nausea and emesis was reported by 75 % and 42 % of patients, respectively. In addition, up to 50 % and 23 % of patients experience nausea and emesis respectively on any given day of treatment. Our data agrees with the estimate that 50 80 % of GI patients treated with radiation experience RINV [5]. However, the observed incidences of nausea and emesis (76 % and 49 %, respectively) were somewhat greater than what was previously reported. In the two prospective observational trials from the Italian Group for Antiemetic Research, of the 92 patients who received treatment to the upper abdomen, 56 % developed nausea and 29 % developed vomiting [2]. In a retrospective study of patients treated with chemoradiotherapy from Germany, of the 14 patients irradiated in the upper abdomen, 50 % and 43 % experienced at least one episode of nausea and vomiting, respectively [13]. Discrepancies may arise from study design differences. Our in person meeting Table 4 Weekly FLIE and EORTC QLQ-C30 QOL trends analysis in all patients using general linear mixed model Quality of life (QOL) over time (weeks) Coefficient (standard error) p value FLIE QOL RINV Q11 0.011 (0.006) 0.04 RINV Q13 0.014 (0.007) 0.04 C30 QOL C30 physical functioning 1.06 (0.32) 0.001 C30 role functioning 1.56 (0.43) 0.0003 C30 emotional functioning 0.68 (0.29) 0.02 C30 social functioning 1.18 (0.37) 0.002 C30 fatigue 0.06 (0.02) 0.0007 C30 nausea/vomiting 0.06 (0.03) 0.02 C30 appetite loss 0.17 (0.03) <0.0001 with patients on a daily basis may have increased the capture rate of events as compared to solely using diaries. In trend analysis, several patterns for RINV timing are statistically significant. A clear difference in nausea and vomiting at baseline compared to during treatment was found. Interestingly, significantly greater proportions of emesis posttreatment compared to baseline were also seen. This demonstrated a significant RINV post-treatment phase in the 7 days following treatment, similar to that with chemotherapy and in palliative radiotherapy [14 18]; physicians should therefore be cognizant and monitor their patients accordingly in the first week following radiotherapy treatment. 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonists are the current standard of antiemetic therapy for RINV. There is clear evidence supporting their superiority over dopamine receptor antagonists or older agents [19 21]. However, not much is known with regards to the optimal timing of antiemetics or how RINV develops [22]. RINV is suspected to occur through a mechanism involving serotonin-mediated emetic response, but it is not clear whether every fraction of radiotherapy triggers an emetic response or if 5-HT release diminishes over time after the first few fractions [22]. Clinical and preclinical data suggest that 5-HT 3 receptor antagonists lose their effectiveness in the prophylaxis of RINV beyond the first 48 h [23 25]. This means that 5-HT 3 receptor antagonists would not be effective for the entirety of treatment, especially in protracted schedules of radiotherapy. Therefore, timing of symptom onset may provide potential periods where more efficacious antiemetics could be used; such as weeks 1, 2 and 5 and the first week post-treatment as was found in the current investigation. However, further study is needed to define therapeutic approaches for preventing and treating RINV over protracted treatments. Multivariable analysis indicated no significant difference between concomitant chemoradiotherapy and radiotherapy only patients for either nausea or emesis. Both groups have

Support Care Cancer (2014) 22:1493 1507 1501 comparable probabilities of nausea and emesis over time. This is likely because the majority of patients received a low emetogenic potential chemotherapy and therefore did not add to the emetic stimulus of the radiation. These similarities supports the previous suggestion by Maranzano et al. that patients submitted to low risk concomitant chemoradiotherapy should be included in the moderate emetogenic risk category [2]. Results of multivariate analyses on primary cancer site and emetogenic risks concur with the current categorization of emetogenic risks and suggest that prophylactic antiemetics are indicated for patients with pancreatic cancer receiving radiation. The 18-item FLIE scores demonstrate a role for nausea and vomiting on QOL impairment. and vomiting interference scores properly reflect the symptom data for all items. Vomiting could impair patients ability to maintain usual recreation or leisure and enjoy their meals. In addition, patients treated with radiotherapy for GI cancer showed worse physical, role and social functioning and more fatigue and appetite loss over the course of their treatment, all of which were found to correlate with the timing of RINV symptoms. It is for these reasons that RINV management is imperative and guidelines have been calling for the prophylactic management of these symptoms [26, 27]. This study is limited by a small sample size of 48. Given the heterogeneity of the study population, more patients are needed to confirm our findings. Patients were treated with various radiotherapy dose fractionation schedules to different anatomic sites. Different antiemetic compounds and a wide range of doses were used in the study herein; the inconsistency of which prevents analysis of antiemetic efficacy. We did not record RINV symptoms past 1 week after the completion of radiation treatment. Nonetheless, our results provide valuable information regarding RINV and clearly demonstrate the need to improve symptom control. More detailed incidence data will help to further identify populations at risk and the times during which antiemetic therapy could be most helpful. In addition, with developing knowledge of the side effects of 5- HT3 receptor antagonists (e.g., constipation), alternative agents with more favorable GI adverse effect profiles should be considered for study. and vomiting are commonly experienced amongst patients receiving radiotherapy and chemoradiotherapy. We encourage future studies to further elucidate how RINV is experienced in order to optimize supportive care strategies in the future. Acknowledgements We thank the generous support of Bratty Family Fund, Michael and Karyn Goldstein Cancer Research Fund, Joseph and Silvana Melara Cancer Research Fund and Ofelia Cancer Research Fund. Appendix I. FLIE 1. How much nausea have you had in the past 3 days? None 2. Has nausea affected your ability to maintain usual recreation or leisure activities in the past 3 days? None 3. Has nausea affected your ability to make a meal or do minor household repairs during the past 3 days? 4. How much has nausea affected your ability to enjoy a meal in the past 3 days? 5. How much has nausea affected your ability to enjoy liquid refreshment in the past 3 days? 6. How much has nausea affected your willingness to see and spend time with family and friends, in the past 3 days? 7. Has nausea affected your daily functioning in the past 3 days? 8. Rate the degree to which your nausea has imposed a hardship on you (personally) in the past 3 days. 9. Rate the degree to which your nausea has imposed a hardship on those closest to you in the past 3 days. 10. How much vomiting have you had in the past 3 days? None 11. Has vomiting affected your ability to maintain usual recreation or leisure activities in the past 3 days? 12. Has vomiting affected your ability to complete your usual household tasks during the past 3 days? 13. How much has vomiting affected your ability to enjoy a meal in the past 3 days? 14. How much has vomiting affected your ability to enjoy liquid refreshment in the past 3 days? Conflict of interest Appendices None. 15. How much has vomiting affected your willingness to see and spend time with friends, in the past 3 days?

1502 Support Care Cancer (2014) 22:1493 1507 Appendix II. EORTC C30 Not at A Quite Very All Little a Bit Much 1. Do you have any trouble doing strenuous activities, 1 2 3 4 like carrying a heavy shopping bag or a suitcase? 2. Do you have any trouble taking a long walk? 1 2 3 4 3. Do you have any trouble taking a short walk outside of the house? 1 2 3 4 4. Do you need to stay in bed or a chair during the day? 1 2 3 4 5. Do you need help with eating, dressing, washing 1 2 3 4 yourself or using the toilet? During the past week: Not at A Quite Very All Little a Bit Much 6. Were you limited in doing either your work or other daily activities? 1 2 3 4 7. Were you limited in pursuing your hobbies or other 1 2 3 4 leisure time activities? 8. Were you short of breath? 1 2 3 4 9. Have you had pain? 1 2 3 4 10. Did you need to rest? 1 2 3 4 11. Have you had trouble sleeping? 1 2 3 4 12. Have you felt weak? 1 2 3 4 13. Have you lacked appetite? 1 2 3 4 14. Have you felt nauseated? 1 2 3 4 15. Have you vomited? 1 2 3 4 16. Have you been constipated? 1 2 3 4 17. Have you had diarrhea? 1 2 3 4 18. Were you tired? 1 2 3 4 19. Did pain interfere with your daily activities? 1 2 3 4 During the past week: Not at A Quite Very All Little a Bit Much 20. Have you had difficulty in concentrating on things, like reading a newspaper or watching television? 1 2 3 4 21. Did you feel tense? 1 2 3 4 22. Did you worry? 1 2 3 4 23. Did you feel irritable? 1 2 3 4 24. Did you feel depressed? 1 2 3 4 25. Have you had difficulty remembering things? 1 2 3 4 26. Has your physical condition or medical treatment interfered with your family life? 1 2 3 4 27. Has your physical condition or medical treatment interfered with your social activities? 1 2 3 4 28. Has your physical condition or medical treatment caused you financial difficulties? 1 2 3 4 For the following questions please circle the number between 1 and 7 that best applies to you 29. How would you rate your overall health during the past week? Very poor Excellent 30. How would you rate your overall quality of life during the past week? Very poor Excellent

Support Care Cancer (2014) 22:1493 1507 1503 Appendix III Table 5 QOL in patients receiving radiotherapy for gastrointestinal cancer as assessed by the QLQ-C30 and FLIE N Mean Standard dev. Median Q1 Q3 Min Max FLIE 18 items and summary scores RINV nausea summary score Visit week Visit 38 12.58 10.43 9.0 9.0 9.0 9.0 55.0 1 Week 1 26 20.31 19.73 9.0 9.0 24.0 9.0 63.0 2 Week 2 21 16.57 14.77 9.0 9.0 19.0 9.0 63.0 3 Week 3 14 14.14 11.37 9.0 9.0 10.0 9.0 47.0 4 Week 4 12 13.33 8.18 9.0 9.0 15.0 9.0 32.0 5 Week 5 8 15.88 13.07 9.0 9.0 20.0 9.0 42.0 6 Week 6 5 16.40 10.19 9.0 9.0 26.0 9.0 29.0 7 End week 39 19.31 16.90 9.0 9.0 26.0 3.0 63.0 8 Follow-up week 36 15.11 14.39 9.0 9.0 9.0 7.0 63.0 RINV vomiting summary score Visit week Visit 38 10.34 5.64 9.0 9.0 9.0 9.0 42.0 1 Week 1 26 15.73 14.61 9.0 9.0 9.0 9.0 57.0 2 Week 2 21 13.24 11.19 9.0 9.0 9.0 9.0 50.0 3 Week 3 14 9.00 0.00 9.0 9.0 9.0 9.0 9.0 4 Week 4 12 9.08 0.29 9.0 9.0 9.0 9.0 10.0 5 Week 5 8 11.25 6.36 9.0 9.0 9.0 9.0 27.0 6 Week 6 5 9.00 0.00 9.0 9.0 9.0 9.0 9.0 7 End week 37 14.68 13.93 9.0 9.0 9.0 9.0 63.0 8 Follow-up week 36 13.25 12.02 9.0 9.0 9.0 9.0 62.0 FLIE 18-item summary score Visit week Visit 38 22.92 14.24 18.0 18.0 18.0 18.0 88.0 1 Week 1 26 36.04 32.72 18.0 18.0 33.0 18.0 114.0 2 Week 2 21 29.81 23.54 18.0 18.0 31.0 18.0 113.0 3 Week 3 14 23.14 11.37 18.0 18.0 19.0 18.0 56.0 4 Week 4 12 22.42 8.39 18.0 18.0 24.0 18.0 42.0 5 Week 5 8 27.13 18.59 18.0 18.0 29.0 18.0 69.0 6 Week 6 5 25.40 10.19 18.0 18.0 35.0 18.0 38.0 7 End week 39 33.23 29.21 18.0 18.0 35.0 12.0 126.0 8 Follow-up week 36 28.36 24.75 18.0 18.0 23.5 16.0 125.0 C30 functioning and symptoms scores Physical functioning Visit week Visit 43 73.76 25.38 80.0 66.7 93.3 6.7 100.0 1 Week 1 34 78.43 22.26 85.0 66.7 96.7 6.7 100.0 2 Week 2 27 80.56 18.85 86.7 60.0 100.0 40.0 100.0 3 Week 3 19 74.50 23.23 86.7 53.3 93.3 33.3 100.0 4 Week 4 18 77.10 21.28 83.3 53.3 93.3 40.0 100.0 5 Week 5 12 73.06 19.63 74.2 59.2 90.0 33.3 100.0 6 Week 6 5 72.33 15.17 66.7 66.7 83.3 53.3 91.7 7 End week 42 70.95 29.82 81.7 53.3 93.3 0.0 100.0 8 Follow-up week 43 65.25 28.69 66.7 44.4 91.7 6.7 100.0 Role functioning Visit week Visit 42 65.48 29.77 66.7 33.3 100.0 0.0 100.0 1 Week 1 33 75.76 26.05 83.3 66.7 100.0 0.0 100.0 2 Week 2 27 78.40 24.81 83.3 66.7 100.0 33.3 100.0 3 Week 3 19 71.05 31.84 83.3 33.3 100.0 0.0 100.0

1504 Support Care Cancer (2014) 22:1493 1507 Table 5 (continued) N Mean Standard dev. Median Q1 Q3 Min Max 4 Week 4 17 69.61 36.44 83.3 33.3 100.0 0.0 100.0 5 Week 5 13 61.54 38.12 66.7 33.3 100.0 0.0 100.0 6 Week 6 5 73.33 27.89 66.7 66.7 100.0 33.3 100.0 7 End week 42 60.32 36.06 66.7 33.3 100.0 0.0 100.0 8 Follow-up week 42 59.52 32.95 66.7 33.3 100.0 0.0 100.0 Emotional functioning Visit week Visit 43 72.87 22.65 75.0 58.3 91.7 16.7 100.0 1 Week 1 33 73.74 25.36 75.0 58.3 100.0 16.7 100.0 2 Week 2 27 81.17 21.75 91.7 66.7 100.0 25.0 100.0 3 Week 3 19 82.02 20.65 91.7 66.7 100.0 33.3 100.0 4 Week 4 17 85.29 14.89 83.3 75.0 100.0 58.3 100.0 5 Week 5 11 85.61 18.67 91.7 75.0 100.0 41.7 100.0 6 Week 6 5 85.00 16.03 91.7 83.3 91.7 58.3 100.0 7 End week 43 76.16 26.76 83.3 66.7 100.0 0.0 100.0 8 Follow-up week 43 78.68 23.52 83.3 66.7 100.0 0.0 100.0 Cognitive functioning Visit week Visit 43 87.60 19.28 100.0 83.3 100.0 0.0 100.0 1 Week 1 33 85.86 21.30 100.0 66.7 100.0 0.0 100.0 2 Week 2 27 89.51 16.11 100.0 66.7 100.0 50.0 100.0 3 Week 3 19 85.09 23.50 100.0 66.7 100.0 33.3 100.0 4 Week 4 18 81.48 22.06 83.3 83.3 100.0 33.3 100.0 5 Week 5 11 87.88 19.85 100.0 83.3 100.0 33.3 100.0 6 Week 6 5 83.33 23.57 100.0 66.7 100.0 50.0 100.0 7 End week 43 84.50 22.24 100.0 66.7 100.0 0.0 100.0 8 Follow-up week 43 87.98 19.36 100.0 83.3 100.0 16.7 100.0 Social functioning Visit week Visit 43 73.64 26.54 83.3 50.0 100.0 0.0 100.0 1 Week 1 33 77.78 28.77 100.0 66.7 100.0 0.0 100.0 2 Week 2 27 83.33 25.32 100.0 66.7 100.0 33.3 100.0 3 Week 3 19 77.19 30.03 100.0 66.7 100.0 0.0 100.0 4 Week 4 17 76.47 31.21 83.3 66.7 100.0 0.0 100.0 5 Week 5 11 81.82 26.30 100.0 66.7 100.0 33.3 100.0 6 Week 6 5 83.33 20.41 83.3 83.3 100.0 50.0 100.0 7 End week 42 63.89 35.10 66.7 33.3 100.0 0.0 100.0 8 Follow-up week 41 68.29 31.80 66.7 50.0 100.0 0.0 100.0 Global health status/qol Visit week Visit 43 56.30 24.39 50.0 41.7 75.0 0.0 100.0 1 Week 1 33 56.94 21.87 58.3 50.0 75.0 16.7 100.0 2 Week 2 27 60.03 17.99 58.3 50.0 66.7 16.7 100.0 3 Week 3 19 58.11 20.43 50.0 50.0 75.0 16.7 100.0 4 Week 4 18 57.64 17.05 58.3 50.0 66.7 16.7 91.7 5 Week 5 12 59.03 15.27 62.5 50.0 66.7 25.0 83.3 6 Week 6 5 70.00 18.26 66.7 66.7 66.7 50.0 100.0 7 End week 43 50.78 21.04 50.0 33.3 66.7 0.0 83.3 8 Follow-up week 43 56.40 17.89 50.0 50.0 66.7 16.7 83.3 Fatigue Visit week Visit 43 41.60 26.12 33.3 22.2 66.7 0.0 100.0 1 Week 1 33 46.97 27.68 44.4 33.3 66.7 0.0 100.0 2 Week 2 27 50.21 28.81 55.6 33.3 66.7 0.0 100.0 3 Week 3 19 45.03 31.75 33.3 22.2 66.7 0.0 100.0

Support Care Cancer (2014) 22:1493 1507 1505 Table 5 (continued) N Mean Standard dev. Median Q1 Q3 Min Max 4 Week 4 18 44.75 26.16 44.4 33.3 55.6 0.0 100.0 5 Week 5 12 50.93 26.15 50.0 33.3 72.2 11.1 100.0 6 Week 6 5 53.33 29.81 66.7 33.3 77.8 11.1 77.8 7 End week 42 57.41 28.92 61.1 33.3 77.8 0.0 100.0 8 Follow-up week 42 58.20 30.24 55.6 33.3 77.8 0.0 100.0 /vomiting Visit week Visit 43 8.91 18.31 0.0 0.0 16.7 0.0 66.7 1 Week 1 34 20.10 30.09 0.0 0.0 33.3 0.0 100.0 2 Week 2 27 13.58 24.04 0.0 0.0 16.7 0.0 100.0 3 Week 3 19 15.79 20.39 0.0 0.0 33.3 0.0 66.7 4 Week 4 18 16.67 23.57 0.0 0.0 33.3 0.0 83.3 5 Week 5 12 19.44 33.21 0.0 0.0 33.3 0.0 100.0 6 Week 6 5 10.00 14.91 0.0 0.0 16.7 0.0 33.3 7 End week 42 25.00 29.73 16.7 0.0 33.3 0.0 100.0 8 Follow-up week 42 14.68 22.75 0.0 0.0 33.3 0.0 100.0 Pain Visit week Visit 43 28.88 28.66 16.7 0.0 50.0 0.0 100.0 1 Week 1 33 23.74 25.01 16.7 0.0 33.3 0.0 100.0 2 Week 2 27 19.75 20.17 16.7 0.0 33.3 0.0 83.3 3 Week 3 19 20.18 33.14 0.0 0.0 33.3 0.0 100.0 4 Week 4 18 25.00 29.84 16.7 0.0 50.0 0.0 100.0 5 Week 5 13 21.79 25.81 16.7 0.0 33.3 0.0 83.3 6 Week 6 5 16.67 20.41 16.7 0.0 16.7 0.0 50.0 7 End week 43 34.69 31.70 33.3 0.0 50.0 0.0 100.0 8 Follow-up week 44 31.44 30.55 16.7 16.7 50.0 0.0 100.0 Dyspnea Visit week Visit 43 10.08 21.25 0.0 0.0 0.0 0.0 100.0 1 Week 1 33 10.10 21.22 0.0 0.0 0.0 0.0 100.0 2 Week 2 27 17.28 29.77 0.0 0.0 33.3 0.0 100.0 3 Week 3 19 14.04 25.62 0.0 0.0 33.3 0.0 100.0 4 Week 4 18 13.89 23.04 0.0 0.0 33.3 0.0 66.7 5 Week 5 13 12.82 21.68 0.0 0.0 33.3 0.0 66.7 6 Week 6 5 6.67 14.91 0.0 0.0 0.0 0.0 33.3 7 End week 42 19.05 26.69 0.0 0.0 33.3 0.0 100.0 8 Follow-up week 43 13.95 24.38 0.0 0.0 33.3 0.0 100.0 Insomnia Visit week Visit 43 31.78 34.08 33.3 0.0 66.7 0.0 100.0 1 Week 1 33 30.30 30.46 33.3 0.0 66.7 0.0 100.0 2 Week 2 26 26.92 34.02 0.0 0.0 66.7 0.0 100.0 3 Week 3 19 35.09 37.64 33.3 0.0 66.7 0.0 100.0 4 Week 4 18 24.07 29.83 16.7 0.0 33.3 0.0 100.0 5 Week 5 12 38.89 37.15 33.3 0.0 66.7 0.0 100.0 6 Week 6 5 40.00 14.91 33.3 33.3 33.3 33.3 66.7 7 End week 42 29.37 31.41 33.3 0.0 33.3 0.0 100.0 8 Follow-up week 43 27.13 32.74 33.3 0.0 33.3 0.0 100.0 Appetite loss Visit week Visit 43 24.03 35.88 0.0 0.0 33.3 0.0 100.0 1 Week 1 33 30.30 41.13 0.0 0.0 66.7 0.0 100.0 2 Week 2 27 28.40 36.64 0.0 0.0 33.3 0.0 100.0 3 Week 3 19 33.33 40.06 33.3 0.0 66.7 0.0 100.0

1506 Support Care Cancer (2014) 22:1493 1507 Table 5 (continued) N Mean Standard dev. Median Q1 Q3 Min Max 4 Week 4 18 38.89 38.35 33.3 0.0 66.7 0.0 100.0 5 Week 5 12 41.67 42.94 33.3 0.0 83.3 0.0 100.0 6 Week 6 5 26.67 36.51 0.0 0.0 66.7 0.0 66.7 7 End week 41 42.28 37.29 33.3 0.0 66.7 0.0 100.0 8 Follow-up week 43 43.41 34.53 33.3 0.0 66.7 0.0 100.0 Constipation Visit week Visit 43 22.48 33.90 0.0 0.0 33.3 0.0 100.0 1 Week 1 34 23.53 36.26 0.0 0.0 33.3 0.0 100.0 2 Week 2 27 18.52 31.12 0.0 0.0 33.3 0.0 100.0 3 Week 3 18 14.81 28.52 0.0 0.0 33.3 0.0 100.0 4 Week 4 18 12.96 23.26 0.0 0.0 33.3 0.0 66.7 5 Week 5 12 2.78 9.62 0.0 0.0 0.0 0.0 33.3 6 Week 6 5 6.67 14.91 0.0 0.0 0.0 0.0 33.3 7 End week 42 20.63 32.89 0.0 0.0 33.3 0.0 100.0 8 Follow-up week 42 18.25 31.41 0.0 0.0 33.3 0.0 100.0 Diarrhea Visit week Visit 43 8.53 20.69 0.0 0.0 0.0 0.0 100.0 1 Week 1 34 16.67 26.27 0.0 0.0 33.3 0.0 100.0 2 Week 2 27 17.28 21.42 0.0 0.0 33.3 0.0 66.7 3 Week 3 19 17.54 23.22 0.0 0.0 33.3 0.0 66.7 4 Week 4 18 16.67 23.57 0.0 0.0 33.3 0.0 66.7 5 Week 5 12 13.89 22.29 0.0 0.0 33.3 0.0 66.7 6 Week 6 5 0.00 0.00 0.0 0.0 0.0 0.0 0.0 7 End week 41 10.57 21.65 0.0 0.0 0.0 0.0 100.0 8 Follow-up week 42 8.73 19.56 0.0 0.0 0.0 0.0 66.7 Financial problems Visit week Visit 43 21.71 28.99 0.0 0.0 33.3 0.0 100.0 1 Week 1 33 17.17 30.19 0.0 0.0 33.3 0.0 100.0 2 Week 2 27 17.28 31.17 0.0 0.0 33.3 0.0 100.0 3 Week 3 19 14.04 27.92 0.0 0.0 33.3 0.0 100.0 4 Week 4 17 19.61 33.46 0.0 0.0 33.3 0.0 100.0 5 Week 5 11 9.09 21.56 0.0 0.0 0.0 0.0 66.7 6 Week 6 5 6.67 14.91 0.0 0.0 0.0 0.0 33.3 7 End week 41 16.26 30.84 0.0 0.0 33.3 0.0 100.0 8 Follow-up week 40 20.00 30.94 0.0 0.0 33.3 0.0 100.0 References 1. Roila F, Herrstedt J, Gralla RJ, Tonato M (2011) Prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: guideline update and results of the Perugia consensus conference. Support Care Cancer 19(Suppl 1):S63 S65 2. Maranzano E, De Angelis V, Pergolizzi S, Lupattelli M, Frata P, Spagnesi S et al (2010) A prospective observational trial on emesis in radiotherapy: analysis of 1020 patients recruited in 45 Italian radiation oncology centres. Radiother Oncol 94(1):36 41 3. Naeim A, Dy SM, Lorenz KA, Sanati H, Walling A, Asch SM (2008) Evidence-based recommendations for cancer nausea and vomiting. J Clin Oncol 26(23):3903 3910 4. Basch E, Prestrud AA, Hesketh PJ, Kris MG, Feyer PC, Somerfield MR et al (2011) Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 29(31):4189 4198 5. Feyer PC, Maranzano E, Molassiotis A, Roila F, Clark-Snow RA, Jordan K et al (2011) Radiotherapy-induced nausea and vomiting (RINV): MASCC/ESMO guideline for antiemetics in radiotherapy: update 2009. Support Care Cancer 19(Suppl 1):S5 S14 6. Radiation-induced emesis: a prospective observational multicenter Italian trial. The Italian Group for Antiemetic Research in Radiotherapy. Int J Radiat Oncol Biol Phys 1999 Jun 1;44(3):619 625 7. Lindley CM, Hirsch JD, O Neill CV, Transau MC, Gilbert CS, Osterhaus JT (1992) Quality of life consequences of chemotherapyinduced emesis. Qual Life Res 1(5):331 340

Support Care Cancer (2014) 22:1493 1507 1507 8. Decker GM, DeMeyer ES, Kisko DL (2006) Measuring the maintenance of daily life activities using the functional living index-emesis (FLIE) in patients receiving moderately emetogenic chemotherapy. J Support Oncol 4(1):35 41, 52 9. Clavel M, Soukop M, Greenstreet YL (1993) Improved control of emesis and quality of life with ondansetron in breast cancer. Oncology 50(3):180 185 10. Martin AR, Pearson JD, Cai B, Elmer M, Horgan K, Lindley C (2003) Assessing the impact of chemotherapy-induced nausea and vomiting on patients daily lives: a modified version of the Functional Living Index- (FLIE) with 5-day recall. Support Care Cancer 11(8):522 527 11. Martin AR, Carides AD, Pearson JD, Horgan K, Elmer M, Schmidt C et al (2003) Functional relevance of antiemetic control. Experience using the FLIE questionnaire in a randomised study of the NK-1 antagonist aprepitant. Eur J Cancer 39(10):1395 1401 12. Zeger SL, Liang KY (1986) Longitudinal data analysis for discrete and continuous outcomes. Biometrics 42(1):121 130 13. Fraunholz I, Grau K, Weiss C, Rodel C (2011) Patient- and treatmentrelated risk factors for nausea and emesis during concurrent chemoradiotherapy. Strahlenther Onkol 187(1):1 6 14. Dennis K, Nguyen J, Presutti R, DeAngelis C, Tsao M, Danjoux C et al (2012) Prophylaxis of radiotherapy-induced nausea and vomiting in the palliative treatment of bone metastases. Support Care Cancer 20(8):1673 1678 15. Koo WH, Ang PT (1996) Role of maintenance oral dexamethasone in prophylaxis of delayed emesis caused by moderately emetogenic chemotherapy. Ann Oncol 7(1):71 74 16. Kris MG, Gralla RJ, Clark RA, Tyson LB, O Connell JP, Wertheim MS et al (1985) Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J Clin Oncol 3(10):1379 1384 17. Ossi M, Anderson E, Freeman A (1996) 5-HT3 receptor antagonists in the control of cisplatin-induced delayed emesis. Oncology 53(Suppl 1):78 85 18. Kris MG, Gralla RJ, Tyson LB, Clark RA, Cirrincione C, Groshen S (1989) Controlling delayed vomiting: double-blind, randomized trial comparing placebo, dexamethasone alone, and metoclopramide plus dexamethasone in patients receiving cisplatin. J Clin Oncol 7(1):108 114 19. Horiot JC (2004) Prophylaxis versus treatment: is there a better way to manage radiotherapy-induced nausea and vomiting? Int J Radiat Oncol Biol Phys 60(4):1018 1025 20. Feyer P, Seegenschmiedt MH, Steingraeber M (2005) Granisetron in the control of radiotherapy-induced nausea and vomiting: a comparison with other antiemetic therapies. Support Care Cancer 13(9):671 678 21. Priestman TJ, Roberts JT, Upadhyaya BK (1993) A prospective randomized double-blind trial comparing ondansetron versus prochlorperazine for the prevention of nausea and vomiting in patients undergoing fractionated radiotherapy. Clin Oncol (R Coll Radiol) 5(6):358 363 22. Dennis K, Makhani L, Maranzano E, Feyer P, Zeng L, Angelis C et al (2013) Timing and duration of 5-HT3 receptor antagonist therapy for the prophylaxis of radiotherapy-induced nausea and vomiting: a systematic review of randomized and non-randomized studies. J Radiat Oncol 2(3):271 284 23. Bermudez J, Boyle EA, Miner WD, Sanger GJ (1988) The antiemetic potential of the 5-hydroxytryptamine3 receptor antagonist BRL 43694. Br J Cancer 58(5):644 650 24. de Wit R, Aapro M, Blower PR (2005) Is there a pharmacological basis for differences in 5-HT3-receptor antagonist efficacy in refractory patients? Cancer Chemother Pharmacol 56(3):231 238 25. Tramer MR, Reynolds DJ, Stoner NS, Moore RA, McQuay HJ (1998) Efficacy of 5-HT3 receptor antagonists in radiotherapyinduced nausea and vomiting: a quantitative systematic review. Eur J Cancer 34(12):1836 1844 26. ASHP Therapeutic Guidelines on the Pharmacologic Management of and Vomiting in Adult and Pediatric Patients Receiving Chemotherapy or Radiation Therapy or Undergoing Surgery. Am J Health Syst Pharm 1999 Apr 15;56(8):729 764 27. National Cancer Institute of Canada Clinical Trials Group (SC19), Wong RK, Paul N, Ding K, Whitehead M, Brundage M et al (2006) 5-hydroxytryptamine-3 receptor antagonist with or without shortcourse dexamethasone in the prophylaxis of radiation induced emesis: a placebo-controlled randomized trial of the National Cancer Institute of Canada Clinical Trials Group (SC19). J Clin Oncol 24(21):3458 3464