It is commonly claimed that the nausea and vomiting accompanying cytotoxic chemotherapy have a negative impact on health-related quality of life. While this may seem self-evident, until a few years ago there was little empirical data demonstrating that the failure to control post-chemotherapy emesis affects aspects of quality of life.

In spite of their limitations, several observational studies showed that nausea and vomiting associated with chemotherapy induced a decrease in health-related quality of life with respect to patients without nausea and vomiting. This has also been demonstrated after the adjustment for health-related quality of life before chemotherapy that is an important prognostic factor of chemotherapy-induced nausea and vomiting.

Furthermore, one study suggests that the optimal time of assessment of quality of life to evaluate the impact of chemotherapy-induced nausea and vomiting is day 4 if a 3-day recall period is used or day 8 when the recall period is 7 days.

In double-blind studies the efficacy, tolerability and impact on quality of life of the 5-HT₃ receptor antagonists was superior with respect to metoclopramide, alizapride and prochlorperazine. Similar results have been achieved with the combination of ondansetron with dexamethasone, the standard treatment for the prevention of acute emesis induced by moderately emetogenic chemotherapy, with respect to the metoclopramide plus dexamethasone combination. Instead, in another double-blind study, in patients submitted to moderately emetogenic chemotherapy, a 5-HT₃ antagonist did not seem to significantly increase complete protection from delayed emesis and the patients' quality of life with respect to dexamethasone alone. In conclusion, the evaluation of quality of life in randomized trials comparing different antiemetic drugs for the prevention of chemotherapy-induced nausea and vomiting can add important information useful for the choice of the optimal antiemetic treatment.

Introduction

About 20 years ago vomiting and nausea ranked as the most distressing side effects of cancer chemotherapy from the patients' point of view [1]. Unfortunately, despite progress achieved with the 5HT₃ receptor antagonists chemotherapy-induced nausea and vomiting remains a distressing adverse event. In fact, in two studies carried out after their introduction in clinical practice, nausea still ranks number 1 as the adverse event of chemotherapy of most concern to patients, with vomiting ranking as the 3^rd and the 5^th most distressing symptom [2,3].

This is probably due to the unsatisfactory efficacy of the available antiemetic drugs to prevent delayed chemotherapy induced emesis, a phenomenon which has been arbitrarily defined as vomiting and/or nausea beginning, or persisting for, more than 24 hours after chemotherapy administration [4]. Another reason is that often the results of clinical research are not transferred to clinical practice [5].

Clinical consequences of chemotherapy-induced emesis (CIE) include oesophageal tear, fractures, malnutrition, acid-base and electrolyte changes and patients' refusal to continue chemotherapeutic cycles, thus decreasing health-related quality of life (HRQL) and compromising treatment efficacy [6].

In this paper we analyse the impact of CIE on HRQL. A search of published articles in English language in the MEDLINE electronic bibliographic databases from 1976 to 2002 was carried out.

Abstracts were considered relevant if the article: 1) described the development and validation of an HRQL instrument used to assess HRQL in CIE; 2) described the impact of CIE on HRQL; 3) compared HRQL between different antiemetic drugs for the prevention of CIE. The electronic search was supplemented by a manual review of the bibliographies of the references retrieved.

It is commonly claimed that the nausea and vomiting accompanying cytotoxic chemotherapy have a negative impact on HRQL (Health-Related Quality of Life). While this may seem self-evident, there is little empirical data demonstrating that the failure to control post-chemotherapy emesis affects aspects of quality of life other than directly related physical symptoms [6]. In fact, until 1992 studies that considered the impact of nausea and vomiting on a broader, multidimensional measure of quality of life were lacking. Furthermore, one study carried out in breast cancer patients showed that the important determinants of a good quality of life for them appear to be their ability to complete the activities of everyday living and their emotional well-being, while nausea and vomiting, when present, were not powerful independent predictors of variations in overall quality of life [7]. A possible criticism of this study is that most of these patients had not recently received chemotherapy and had no experience of nausea and vomiting. On the other hand, improvement in the control of nausea and vomiting lead to a smaller decrease in the quality of life of cancer patients in the few days following chemotherapy, but other issues can be more important determinants of quality of life in the long term.

However, it was less clear precisely how important nausea and vomiting may be and to what extent their effects are independent of the other toxicities of chemotherapy and indeed of the effects of the diagnosis and disease itself [7]. Some studies have tried to answer to these questions (Table 1).

Chemotherapy Side Effects Studies without comparative purpose

Lindley et al. evaluated 122 patients with various cancers submitted to different emetogenic chemotherapies and different antiemetic prophylaxis [8]. Emesis (one or more episodes of vomiting and/or a nausea severity of 2.0 cm or more on a 10 cm visual analogue scale) was reported by 56% of patients. To evaluate emesis and its impact on quality of life three instruments were used before chemotherapy and 3 days after: a diary card where the number of vomiting and retching episodes occurring every day was recorded as well the severity of nausea, sedation and anxiety experienced by the patients; the Functional Living Index – Cancer (FLIC) a validated instrument to assess the patient's quality of life [9]; the Functional Living Index – Emesis (FLIE), an instrument created, pre-tested and revised prior the study, with questions modelled after those of the FLIC but specifically addressing the impact of chemotherapy induced nausea and vomiting on the physical activities, social and emotional function and ability to enjoy meals. The score of the FLIC (FLIE) was determined by summing the responses to the 22 (18) questions on a 7 point analogue scale and, therefore, the range of total scores possible is between 22 (18), all 1 responses on each scale, and 154 (126), all 7 responses on each scale. A higher score corresponds to a higher quality of life (less negative impact on the patient's functional living by nausea and vomiting).

The mean quality of life score for patients of the FLIC decreased significantly from 121 before to 110 three days after chemotherapy, but it was statistically significant only in those patients experiencing emesis (from 119 to 101) while in those not reporting emesis the score was not different following chemotherapy (from 124 to 122). Similar results were obtained with the FLIE: the mean score decreased from 118 before to 101 three days after chemotherapy, but the decrease was dramatic in patients who experienced emesis (from 115 to 85) as compared to a constant level for the non-emesis patient group. Chemotherapy and antiemetic therapy seem to contribute significantly to changes in quality of life observed. In fact, of patients who experienced chemotherapy-induced emesis, 23% were unable to go to work due to emesis, 22% reported they were unable to prepare meals due to emesis; 12% reported that emesis made them unable to care for themselves; 12% reported that they were unable to take prescribed medications on at least two occasions due to emesis.

In another study, 109 patients that had previously experienced nausea and vomiting and/or side effects with the use of standard antiemetic agents were submitted in the following cycle of a similar chemotherapy regimen to a compassionate-use program of ondansetron (0.15 mg/kg i.v. every 4 hours for three daily doses) [10]. Two assessment tools were used to evaluate patient's conditions: a score ranging from 1 to 10 for physician's assessment and the FLIE questionnaire filled out by the patient. In this case the score for the 18 items of FLIE was added and transposed to a 100-point scale to give a final score, with a higher score indicating a better quality of life. The mean score was significantly better with ondansetron than with standard antiemetics (65.5 versus 39.5). The FLIE scores were higher for 76% of patients during ondansetron treatment as compared to previous chemotherapy with standard antiemetics. Possible criticisms are that (i) the difference in scores is probably overestimated because of the time of assessment (both after treatment with ondansetron), and (ii) the shortcomings in the study design (neither randomised, nor double-blind).

One study evaluated the effect of chemotherapy-induced nausea and vomiting on health-related quality of life before the 5-HT₃ antagonists became available [11]. In 92 patients submitted to moderately and highly emetogenic chemotherapy the incidence of nausea and vomiting for 5 consecutive days and their impact on quality of life was evaluated. Quality of life was assessed by the FLIE that was completed before chemotherapy, and on day 2 and 5 after. The summed scores were standardized to a 100 point-scale. Over the 5 days of the survey 72 patients (78%) reported nausea or at least one emetic episode. The FLIE scores indicated significant worsening of functional status associated with chemotherapy, but an improvement after the first 24 hours following chemotherapy, an improvement that was greater for emesis than for nausea. On day 2 the main impact was from emesis, particularly with regard to leisure activities, household tasks and hardship on the family. On the other hand, nausea had a significantly greater impact than emesis on overall functioning, enjoyment of eating and hardship on the patient.

Two studies have been published by the Quality of Life and Symptom Control Committees of the National Cancer Institute of Canada Clinical Trials Group assessing whether pre-chemotherapy HRQL variables were associated with post-chemotherapy nausea and vomiting and their relationship to patient and treatment variables [12] and the effect of post-chemotherapy nausea and vomiting on HRQL [13] in 802 patients submitted to moderately and highly emetogenic chemotherapy. The HRQL used the questionnaire of the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) [14] completed by the patient from 0 to 7 days before chemotherapy (baseline) and at home 7 days after the chemotherapy (day 8) for both studies and on the first day of the second cycle of chemotherapy (day 15–29), for the second study.

The EORTC QLQ-C30 is a 30-item self-report questionnaire that contains questions exploring five functioning domains (physical, role, emotional, cognitive and social), an overall or "global" quality of life domain, three symptom domains (pain, fatigue, nausea/vomiting) and six single items (dyspnoea, insomnia, anorexia, diarrhoea, constipation, and financial difficulties). The raw scores for each domain and single item are transformed to give a score lying between 0 and 100. For the functioning domains and global quality of life, a higher score indicates a better or higher level of functioning; for the symptom domains and single items, a higher score indicates a greater level of symptoms or problems. The patients filled out a diary card for the assessment of nausea and vomiting.

In the first study [12] patients were divided into two groups: those who did not report nausea or vomiting and those who had nausea and one or more emetic episodes in the week after chemotherapy administration. More than 98% of patients completed the baseline questionnaire. Nausea was reported by 75.6% and vomiting by 55.7% of patients during the study period.

At the univariate analysis, the mean pretreatment scores in patients who suffered from chemotherapy-induced nausea were significantly lower for physical, role, emotional, cognitive, and social functioning than in patients without nausea. Patients with nausea also had significantly higher fatigue, preexisting nausea, pain, insomnia, constipation, financial difficulties and daytime drowsiness scores.

Patients who vomited after chemotherapy had significantly worse physical, role and social functioning, and global quality of life scores before chemotherapy than patients who did not vomit. Furthermore, patients who vomited had significantly higher fatigue, preexisting nausea, pain, anorexia, constipation, financial difficulties, and daytime drowsiness scores before chemotherapy than those who did not suffer from vomiting.

On the other hand, pretreatment quality of life scores were not found significantly correlated with the intensity of post-chemotherapy vomiting (1–2 episodes versus more than 2 episodes).

Five patient characteristics were positively associated with post-chemotherapy nausea (females, history of motion sickness, drowsiness and pre-chemotherapy nausea) and two with post-chemotherapy vomiting (ECOG performance status of 1 and 2 and consumption of 10 or less alcoholic drinks per week).

At the multivariate analysis, the variables remaining in the final model included low social functioning, pre-chemotherapy nausea, female gender, highly emetogenic chemotherapy and the lack of maintenance antiemetics after chemotherapy. A history of low alcohol intake was also associated with post-chemotherapy vomiting while increased fatigue and lower performance status were associated with post-chemotherapy nausea.

The risk of post-chemotherapy vomiting increased from 20% in patients having no risk factors to 76% in those having any four of a total of six risk factors.

The predictive value of certain health-related quality of life domains for post-chemotherapy vomiting showed in this study and not in the previous studies can be related to the different scoring systems of the EORTC and FLIC-FLIE questionnaires. In fact, the scoring of FLIC and FLIE questionnaires provides a single aggregate score as a measure of HRQL, whereas the scoring of the EORTC questionnaire provides separate scores for each domain and symptom. A single, aggregate score encompasses many domains and if only some of them have predictive value then those domains that do not have predictive value will mask the domains that do have predictive value. The result will be a dilution of the aggregate score that then, of itself, will not be predictive. This strongly supports the view that multidimensional instruments should be scored and analysed for the information provided by each of the separate domains. On the other hand, it is necessary to remember that the Canadian study is that with the largest number of patients enrolled and that the non-predictive value of HRQL scores of the previous studies could be due to the low number of patients evaluated.

In the second study [13] the patients were divided in four groups: those who experienced both nausea and vomiting, those with nausea without emetic episodes, those with no nausea but with vomiting, and those with neither nausea nor vomiting. To evaluate the impact of post-chemotherapy nausea and vomiting on HRQL the change in scores between the baseline and day 8 after chemotherapy administration was calculated for each domain and symptom of the questionnaire and compared in the four subgroups of patients. On day 8, 94.8% of patients filled out the questionnaire while about 70% completed it on the day of their second cycle of chemotherapy.

On day 8 the group with both nausea and vomiting showed statistically significant worse physical, cognitive and social functioning, global quality of life, fatigue, anorexia, insomnia and dyspnea as compared to the group with neither nausea nor vomiting. Patients with only nausea but no vomiting tended to have less worsening in functioning and symptoms than those having both nausea and vomiting.

Increased severity of vomiting (> 2 episodes) was associated with worsening only of global quality of life and anorexia compared with 1–2 episodes of vomiting.

After 2–4 weeks from the chemotherapy all quality of life scores either returned to their baseline levels or were better than baseline.

In this study the effect of chemotherapy-induced emesis on HRQL was evaluated taking into account the pre-chemotherapy health-related quality of life status. In fact, the authors first subtracted the baseline scores from the day 8 scores and then used the difference to compare the subgroups of patients with and without post-chemotherapy nausea and vomiting. In this way the non-emetogenic effects of chemotherapy on post-chemotherapy quality of life could also be considered at least in part; in fact, comparing the differences in changed scores between patients who vomited, it was assumed that the effects of chemotherapy or other variables were likely to be similar in the two groups because of the large sample size.

Finally, another possible explanation for the apparently different results of these two studies with respect to the previous ones is that post-chemotherapy quality of life was assessed 7 days after chemotherapy administration instead of 4 or 2 days.

The importance of the time of administration and of the time frame of quality of life assessment was evaluated in another Canadian study carried out in 650 patients submitted to moderately emetogenic chemotherapy [15]. The initial observation suggesting the necessity of this study was: despite the fact that patients who experienced greater nausea and vomiting reported a significantly worse quality of life, when quality of life was compared across treatment arms, which differed substantially in the control of emesis, no statistically significant difference in any quality of life outcome measures was found. The most likely explanation of this is that, as emesis is more intense in the first 2–3 days after chemotherapy, administering a questionnaire on day 8 (time frame: 7 days) could lead to attenuating the perceived effects of emesis on their HRQL.

In this study the participating centres were randomized to one of four quality of life assessment procedures. Patients in all centres completed a baseline questionnaire within 72 hours prior to study entry and a post-treatment assessment on either day 4 or 8 after chemotherapy. The selection of day 4 or 8 was randomized by centre. The time frames of the questionnaires were also randomly varied by centre to be either 7 days, as in the standard instrument, or 3 days, as a modified version.

When the quality of life questionnaire is administered on day 8, the changes in global quality of life are significantly greater when the recall period is 7 days than when it is 3 days (- 10.3 versus -1.2, P < 0.01) and when a 3 day recall period is used the changes are significantly greater when the questionnaire is administered on day 4 than on day 8 (-8.4 versus -1.2, P < 0.001). Furthermore, in this study the addition of dexamethasone to a 5-HT₃ antagonist significantly improved the control of emesis over the entire study period with respect to a 5-HT₃ antagonist alone. These results were parallel to those achieved on quality of life scores; in fact, patients receiving dexamethasone fared significantly better with respect to global quality of life, physical functioning and social functioning and symptom scales. Administering the questionnaire at the time of greatest symptoms, i.e. 3 days after chemotherapy, is the most sensitive means of detecting a treatment difference.

In another Canadian study, patients submitted to moderately emetogenic chemotherapy were monitored for nausea and vomiting and a modified version of the EORTC QLQC-30 questionnaire was administered before chemotherapy and on day 2 and day 6 to assess the impact nausea and vomiting had on quality of life of the patients [16].

Patients who experienced either nausea or vomiting had a decrease in quality of life from pre-chemotherapy levels on six functioning and five symptoms scale at day 2 and on four functioning and four symptom scales on day 6. Comparison of mean scores between the unmodified EORTC QLQC-30 and the nausea and vomiting versions demonstrated that the HRQL rating attributed to nausea and vomiting accounted for much, but not all, of the deterioration in HRQL scores in patients who experienced these chemotherapy side effects. Therefore, other reasons for some of the decrease in health-related quality of life must be identified in future studies.