Table 2 summarizes the comparative studies among different antiemetic regimens for chemotherapy side effects evaluating their impact on HRQL.

Twelve out of 13 studies are randomized, and 9 of them were double-blind.

The first randomized double-blind study comparing different antiemetic prophylactic treatments for chemotherapy side effect that evaluated the impact on quality of life was carried out on breast cancer patients submitted to the first cycle of a cyclophosphamide-containing regimen [17]. Ondansetron (8 mg i.v. followed by 8 mg oral dosing three times daily for 5 days) was compared to metoclopramide (60 mg i.v. followed by 20 mg oral dosing three times daily for 5 days) during 6 cycles of chemotherapy. Both antiemetics were combined to a 16 mg single dose i.v. of dexamethasone before chemotherapy. Nausea and vomiting were recorded daily on a diary card while quality of life was assessed before each chemotherapy treatment and at the end of each 5-day chemotherapy treatment period using the Rotterdam Symptom Checklist questionnaire [18]. This includes 38 items summarized in three subscales (physical, psychological and functional activity). Each item of the physical and psychological subscales is rated on a four-point scale (0 = not at all, 1 = a little, 2 = somewhat, 3 = very much) as well as the items related to functional activity (0 = unable, 1 = only with help, 2 = without help, with difficulty, 3 = without help). A separate analysis was performed for the psychological, physical and functional activity subscales. The "lack of sexual interest" and ability to "go to work" questions were excluded from the analyses since > 5% of patients failed to complete them.

Due to much missing data, the mean and not the total of each subscale was considered. The study showed that at the first cycle of chemotherapy ondansetron plus dexamethasone was significantly superior to metoclopramide plus dexamethasone (complete protection from vomiting over the 5-day chemotherapy treatment period in 81% and 48% of patients, respectively). Furthermore, ondansetron induced a statistically significant improvement in the psychological subscale scores with respect to metoclopramide. No differences were observed in the physical and functional activity subscales. Interestingly, patients' psychological distress was stronger before chemotherapy than after. This was probably due to the apprehension in receiving chemotherapy for the first time. Instead, physical parameters worsened to the same degree after chemotherapy reflecting associated side effects. During the 6 cycles of chemotherapy 67% of patients receiving ondansetron and 28% of patients receiving metoclopramide had less than 3 emetic episodes. Over the 6 chemotherapy cycles quality of life results revealed a more pronounced difference in favour of ondansetron in the psychological subscale score as well as trends in favour of ondansetron in the physical and functional activity subscales. Unfortunately, quality of life data were not available for all patients for all 6 cycles of chemotherapy; therefore, a possible selection bias favouring ondansetron cannot be excluded, especially considering that the analysis of the 6 cycles refers to 475 assessments of ondansetron-treated patients and 380 assessments of metoclopramide-treated patients.

Another randomized, double-blind study evaluating the impact of CIE (Chemotherapy-induced emesis) on HRQL (Health-related Quality of life) compared oral ondansetron (8 mg every 8�12 hours for 3�5 days starting 2 hours before chemotherapy) with alizapride (150 mg i.v. followed by 50 mg orally administered every 8�12 hours for 3�5 days starting 2 hours before moderately-highly emetogenic chemotherapy) [19]. Nausea and vomiting episodes were recorded on a diary card, while quality of life was assessed using the FLIC and the FLIE questionnaires filled out by the patients before chemotherapy and 4 days after the chemotherapy. The total score for each questionnaire was obtained by calculating the average score for each item. Complete control of acute (57% versus 31%) and delayed (62% versus 48%) emesis was significantly superior in the ondansetron group than in alizapride group. Both groups experienced deterioration in FLIC and FLIE score from pretreatment to day 4. No difference in quality of life scores was shown between the ondansetron and alizapride groups when quality of life was measured by the FLIC, but when quality of life was measured by the FLIE, ondansetron was found superior to alizapride in preventing a decrease in quality of life following chemotherapy (mean difference in the scores for each question was 1.45 with ondansetron and 1.93 with alizapride, P < 0.04).

The third double-blind randomized study compared ondansetron (8 mg orally b.i.d. for 3 days) with prochlorperazine (10 mg orally b.i.d. for 3 days) in breast cancer and lymphoma patients submitted to moderately emetogenic chemotherapy [20]. Patients completed the FLIC and FLIE questionnaires before and at the end of the 3-day study period (day 4). Total scores were transformed to standardized scores so that the highest possible score on either scale equated to 100. Ondansetron was significantly superior to prochlorperazine in the complete control of emesis during the three days (60% versus 21%). Quality of life was evaluated in only 57 of 133 patients (34 receiving ondansetron and 23 prochlorperzine). Baseline scores of the FLIE did not differ between groups. Vomiting subscale scores were significantly different between groups (from 97.1 pre to 89.2 post treatment with ondansetron and from 96.7 pre to 70.4 post with prochlorperazine, P < 0.01). No significant difference was seen for the nausea subscale scores. There were no significant differences between groups in FLIC scores at baseline or at the end of the 3-day study period.

In two randomized double-blind studies quality of life was evaluated with the EORTC QLQ-C30. In the first [21], carried out in patients submitted to moderately emetogenic chemotherapy, the efficacy of dolasetron and ondansetron on day 1 and on day 1�7 was compared as well as the efficacy of the addition of dexamethasone to both. In the first 24 hours dolasetron was significantly less effective than ondansetron but no difference was shown between the two drugs over 7 days. The addition of dexamethasone significantly improved the efficacy of both drugs during the entire period.

There were no statistically significant differences between ondansetron and dolasetron at baseline for any of the HRQL domains assessed. Post-treatment, there were no significant changes in global quality of life or other domains, except for diarrhoea (more common with dolasetron) and constipation (more common with ondansetron). Dexamethasone-treated patients fared significantly better with respect to global quality of life, physical functioning and social functioning and nausea, anorexia, diarrhoea, fatigue and pain.

In the second study [22] the efficacy of 5-HT₃ antagonists, ondansetron or dolasetron added to dexametasone versus dexamethasone alone in the prevention of delayed emesis induced by moderately emetogenic chemotherapy was evaluated. Patients received in the first 24 hours a combination of a 5-HT₃ receptor antagonist plus dexamethasone. The continuation of the 5-HT₃ receptor antagonist improved slightly but not significantly, the complete control of delayed emesis (47% versus 41%). Minimal differences in quality of life were observed. Social functioning deteriorated significantly more in patients treated with dexamethasone alone than in those receiving the combination (-6.0 points versus -0.8 points in the combination). On the other hand, patients taking 5-HT₃ receptor antagonists reported a significantly greater increase in constipation (+26 points versus +13 points). Unfortunately, there is no method for weighting the sub-components of the QLQ-C30 with respect to their overall importance and, therefore, to balance symptomatic changes in one direction against functional changes in another.

A randomised double-blind study was carried out in advanced malignant melanoma patients submitted to dacarbazine administered in 1, 5 or 10 days, evaluating HRQL by unidimensional linear scales [23]. Two different doses of tropisetron were compared: 5 and 10 mg iv. Patients evaluated their mood, food intake and quality of life by recording scores in a diary card every day from the day before chemotherapy until the end of the chemotherapy cycle. The scores ranged from 0 (very bad) to 8 (very good). The two dosages of tropisetron prevented vomiting in 93% and 98% of patients with 5 mg and 10 mg, respectively.

Their well being was maintained during the cycle of chemotherapy; in fact, mood and quality of life of the patients remained good as well as food intake.

In another study the efficacy of three antiemetic regimens (ondansetron 8 mg i.v. followed by 8 mg orally every 8 hours for 3 days vs ondansetron as above plus metoclopramide 10 mg every 8 hours for 3 days vs ondansetron 8 mg i.v. single dose) in breast cancer patients submitted to CMF or FEC chemotherapy was evaluated [24].

Quality of life impact was assessed by FLIC questionnaires completed by the patients during a 5-day period following chemotherapy. Chemotherapy cycles, and not patients, were considered as a statistical unit. Responses were evaluated in 182 cycles: in 116 cycles patients received CMF and in 66 FEC. The high-dose ondansetron regimen was similar (CMF-treated patients) or superior (FEC-treated patients) to the combination of ondansetron plus metoclopramide and always superior to the single dose of ondansetron. Quality of life was always worse with ondansetron single dose i.v. while no differences were shown between ondansetron for three days versus ondansetron plus metoclopramide.

A double-blind multicentre study evaluated two antiemetic regimens, in patients with vomiting or moderate to severe nausea in the previous cycle of cisplatin based chemotherapy despite antiemetic treatment with a combination of a 5-HT₃ antagonist plus a corticosteroid: ondansetron plus methylprednisolone versus ondansetron plus methylprednisolone plus metopimazine [25]. The impact on the patient's quality of life was assessed using the FLIC and the FLIE that were joined together in a single questionnaire. This questionnaire consisted of 28 items (all 22 of the FLIC and 6 of the FLIE) and was filled out by the patient prior to the start of chemotherapy and at the end of the third day of antiemetic treatment.

Complete protection from vomiting throughout the cycle of chemotherapy was achieved more frequently by patients receiving the triple combination (53% versus 38%, P < 0.008).

Modification in quality of life (FLIC questionnaire) was similar between the two treatment groups. The FLIE showed a decrease in quality of life that was inferior albeit not significantly with the triple combination.

In another double-blind study the role of tropisetron in the prevention of cisplatin-induced delayed emesis was evaluated. On the first day all patients received 5 mg oral tropisetron and then were randomly assigned to receive either tropisetron or placebo on days 2 through 5 [26]. A newly developed quality of life questionnaire was employed that consisted of seven scales: physical scale, mental and related symptom scale, respiratory condition related scale, social scale, an active scale, a scale for the influence of nausea and vomiting on patient's daily life, and a global scale [27]. This questionnaire was printed in diary form and filled out every morning.

The rate of complete protection from delayed emesis in the tropisetron group and placebo group was respectively 46.3% and 36.5%.

All scales, except social well being, changed immediately in both groups and reached a nadir on days 2�3, after that returning to the control levels during the two weeks after cisplatin administration. Tropisetron treated patients showed significantly better physical wellbeing, mental wellbeing, functional wellbeing and global quality of life scores with respect to placebo-treated patients.

Finally two open, randomized, multicenter studies have been published [28,29]. The first compared tropisetron (5 mg i.v. on day 1 followed by 5 mg oral every day on days 2�6) with a metoclopramide-cocktail (metoclopramide 3 mg/kg i.v. plus dexamethasone 20 mg i.v. plus lorazepam 1 mg oral on day 1 followed by metoclopramide 10 mg orally or 20 mg as suppositories three times a day on days 2�6) in patients submitted to consecutive cycles of cisplatin chemotherapy [28]. Nausea and vomiting were recorded on a diary card while quality of life was assessed by a non-validated questionnaire consisting of 18 questions about various symptoms and 5 questions about appetite and social life.

On day 1 of the first cycle complete control of vomiting was not significantly different (63% with tropisetron versus 64% with metoclopramide cocktail) while complete control of nausea was significantly superior with the cocktail (40% versus 61%). The rate of complete control of vomiting and nausea increased from day 1 to day 6 with both antiemetic regimens, and this also happened at the second chemotherapy cycle. Before both cisplatin chemotherapy cycles, the two groups did not differ in the responses to the 23 questions. In posttreatment evaluations in both treatment groups, the patients reported more nausea, vomiting, being ill, being tired or sleepy, and having more problems with eating than was reported in the pretreatment evaluation. Patients receiving tropisetron experienced significantly more constipation and headache than did those treated with the metoclopramide cocktail.

Another open, randomized, multicentre study compared tropisetron (5 mg i.v. day 1 and 2 followed by 10 mg orally until two days after the end of chemotherapy) with tropisetron (as above) plus dexamethasone (20 mg i.v. on day 1 and 2 followed by 4 mg i.v. or orally until two days after the end of chemotherapy) and with tropisetron (as above) plus metoclopramide (20 mg i.v. plus 10 mg orally b.i.d on day 1 followed by 10 mg t.i.d. orally until two days after the end of chemotherapy) in patients submitted to highly and moderately emetogenic chemotherapy [29]. Quality of life in this study was documented using a newly developed, validated but not yet published, colour scale. Tropisetron plus dexamethasone was significantly superior to tropisetron alone and tropisetron plus metoclopramide for both acute and delayed emesis. Quality of life was rated as "very good", or "good" by more than half the patients before starting therapy. The assessment after the first chemotherapy cycle did not reveal any general deterioration. No statistical difference was detectable between the groups; altogether 41% of the patients reported an improvement in their quality of life after the first cycle, while 33% stated their quality of life was unchanged and 33% deteriorated.

In these last two studies no data were reported in the paper either on the number of patients evaluated for quality of life or on the missing values. Considering that the evaluation is carried out in open studies the risk of selection bias and confounding is high.

Another open study compared in cisplatin-treated ovarian cancer patients the antiemetic efficacy of ondansetron, granisetron, and metoclopramide.

Quality of life was assessed before chemotherapy, on day 1 and during 5 days (every evening) using the Rotterdam Symptom Checklist. In the first cycle 85% of patients receiving ondansetron, 83% of those receiving granisetron and 60% of those receiving metoclopramide achieved complete protection from vomiting [30].

A statistically significant improvement in the psychological subscale scores after ondansetron and granisetron was observed with respect to metoclopramide. No differences were reported in the physical activity subscale.

In an open non-randomised study, breast cancer patients submitted to moderately emetogenic chemotherapy received an antiemetic prophylaxis based on ondansetron or metoclopramide. The selection of the regimen was left to the attending physician and represented current practice at the institution [31]. Complete control of acute emesis was 77% with ondansetron and 32% with metoclopramide in the first 24 hours and 83% and 55% on days 2�5, respectively.

With both antiemetic regimens the levels of quality of life 1 day after chemotherapy, assessed with the EORTC QLQ-C30, were lower than prior to chemotherapy on all five functional scales, except the emotional scale. On average, patients who received ondansetron had a better score on day 1 than prior to chemotherapy on this scale. The differences between groups were not statistically significant on any of the functional scales.

Global quality of life decreased more with metoclopramide than with ondansetron, but the difference was not statistically significant (-24 versus -17).

On day 3 all scores, except the emotional dimension, were lower than prior chemotherapy. Changes in scores on global quality of life were similar for both groups. For the role functioning scale, changes in scores were significantly better for ondansetron.

Conclusions

In spite of the fact that the impact of chemotherapy-induced nausea and vomiting on HRQL has a short-term effect, its evaluation can be useful for clinical decisions concerning the choice of antiemetic prophylaxis. Only the results of antiemetic randomized clinical trials can be used to reach this aim. Moreover, because of the subjectivity of the patient's answers, only a double-blind study can assure reliable results. Finally, only the correct choice of the antiemetic treatments to be compared can lead to useful results [32]. In fact, if the new antiemetic prophylaxis were compared to a treatment different from the best, no information about the differences between the mean scores of the two arms (new treatment and standard therapy) would be available. More precisely, the above mentioned difference could be due only to an inferior efficacy of the used comparator with respect to the standard antiemetic therapy. For similar reasons any comparison involving sub optimal antiemetic regimens could be regarded as useless for a specific clinical decision.

Only 9 out of 13 comparative studies identified in our research were randomized and double-blind; three of them were concerned with non-standard antiemetic therapies, and two were dose finding studies. Therefore, only the results of 4 studies can be regarded as useful for orienting the choice of an antiemetic prophylaxis.

Summarizing the results obtained by the comparative studies carried out until now, the efficacy, tolerability and impact on HRQL of antiemetic regimens containing 5-HT₃ receptor antagonists were found superior to those that referred to the earlier used antiemetic drugs (metoclopramide, alizapride and prochlorperazine). Furthermore, in one study the combination of ondansetron plus dexamethasone, still the standard treatment for the prevention of acute emesis induced by moderately emetogenic chemotherapy, was evaluated against metoclopramide plus dexamethasone. Its results show that the first antiemetic prophylaxis, allowing a better control of nausea and vomiting during the first 24 hours, also lead to an improvement in the patients HRQL.

Among the 13 comparative studies, a great heterogeneity of instruments aimed at evaluating HRQL was detected: in 4 studies FLIC and/or FLIE, in 3 the EORTC QLQ-C30, in 2 the Rotterdam Symptom Checklist, in 2 a uniscale, in 2 an ad hoc designed instrument was used. The reasons of the choice of the instrument to use to assess the influence of emesis on HRQL are clearly described by Uyl-deGroot et al. [32].

In conclusion, even if the number of the published studies specifically aimed to evaluate the impact of the chemotherapy-induced emesis on HRQL can be considered sufficiently high, those showing results that are reliable and useful to orient the clinical decision are few.

Also considering the improvement in antiemetic therapy for chemotherapy side effects obtained in the last few years, and the more frequent implementation of reliable antiemetic guidelines, as well as the recent increasing diffusion of lower emetogenic chemotherapies, more research should be performed to obtain results on the impact of CIE (Chemotherapy-induced emesis) on HRQL useful to orient the choice of antiemetic therapy.

List of abbreviations used

CIE: Chemotherapy-induced emesis, HRQL: Health-related quality of life

Authors' contributions

The paper is the result of the interactive collaboration between the authors.  All authors read and approved the final manuscript.