Chemotherapy-induced nausea and vomiting in daily clinical practice: a community hospital-based study

This prospective, multicenter, observational study was conducted in the departments of medical oncology of nine hospitals in the wider Amsterdam region of the Netherlands (see Appendix).

The study sample was composed of a consecutive series of chemotherapy naive patients treated during a 2-year period. Patients had to be scheduled for treatment with either HEC, MEC containing anthracycline, or MEC not containing anthracycline (see paragraph ‘Data collection and study measures’ for more details). Patients were excluded if they lacked basic proficiency in the Dutch language, if they were younger than 18 years of age, or exhibited overt psychopathology or serious cognitive problems that would impede their ability to take part in the study. Eligible patients were given both oral and written information about the study prior to obtaining their informed consent. The institutional review boards of the participating hospitals approved the study. Patient inclusion took place between May 2005 and May 2007.

Patients recorded episodes of nausea, vomiting, and use of antiemetics in a diary for the day prior to and for 7 days following each of three consecutive chemotherapy cycles. Patients were instructed to use the diary everyday to record each emetic episode and to provide daily nausea assessments using a 100-mm visual analogue scale (VAS) to rate the severity of nausea experienced during the preceding 24 h. Patients also recorded all rescue antiemetic medication taken in addition to what was prescribed at baseline to prevent nausea and vomiting. Only the research team had access to the patient diaries. Treatment decisions were based on the physicians' usual patient assessment practice.

Using previously published decision rules, no nausea was defined as a VAS score of less than 5 mm on the 100-mm scale. A patient was considered to have had acute nausea or acute emesis if nausea (VAS > = 5 mm), or at least one episode of vomiting was reported during the first 24 h after start of chemotherapy [3, 5, 14]. Any episode of nausea and/or vomiting thereafter up to 5 days after chemotherapy was considered delayed [5, 14, 15].

In addition, on day 5 after each chemotherapy cycle, patients were asked to complete the 18-item Functional Living Index-Emesis (FLIE), a validated self-report questionnaire designed to evaluate the impact of CINV on patients' daily lives [16, 17] Response categories range from one to seven on a modified linear analogue scale. The total score, calculated by summing the responses to the 18 items, ranges from 18 to 126, with higher scores representing better health outcomes (i.e., less impact of CINV on daily life) [18]. Following Bloechl-Daum et al., an individual item score of six or more, and a total FLIE score of 108 or more were considered evidence of no or minimal impact of CINV on daily life [5].

Sociodemographic and clinical information were obtained via interview, nurse ratings, and/or from the medical records. This included age, sex, country of origin, WHO performance status, alcohol intake, prior pregnancy-related emesis, problems with motion sickness, cancer diagnosis, type of chemotherapy, radiotherapy, and emetogenicity.

Emetogenicity was defined as HEC (i.e., at least one chemotherapeutic agent of Hesketh level 5 emetic potential, such as cisplatin in combination with other chemotherapy), MEC containing anthracycline (i.e.. at least one anthracycline (doxorubicin, epirubicin) in combination with non-platinum containing chemotherapy), or MEC not containing anthracycline (i.e., at least one chemotherapeutic agent of Hesketh level 3 or 4 emetic potential) [15, 19] Prescribed antiemetics were recorded by the nurses at each chemotherapy cycle.

For interpretation of the use of antiemetics, combinations of antiemetics were categorized in accordance with international guidelines. Table 1 summarizes the 2007 NCCN guidelines on antiemetics. From these guidelines, six combinations can be defined:

A non-respondent analysis using logistic regression was performed to compare patient and treatment characteristics of patients returning all three diaries with those of patients returning less than three diaries.

Descriptive statistics (means, standard deviations, percentages) are reported for patient background characteristics and prevalence of CINV. To evaluate the influence of patient characteristics and type of antiemetic on CINV, a series of logistic regression analyses was performed with acute nausea, delayed nausea, acute vomiting, delayed vomiting, and FLIE scores as dependent variables, and age, gender, emetogenicity, antiemetic schedule, and alcohol use as independent variables.

Logistic regression analysis was also used to evaluate the influence of patient and treatment characteristics on adding antiemetics across treatment cycles. Independent variables included age, gender, emetogenicity, CINV, and alcohol use. Where use of logistic regression was not possible due to missing cells, the chi-square statistic was used.

Differences in the prevalence of CINV and the impact of CINV on daily life over the three chemotherapy cycles were analyzed using McNemar's test for correlated proportions [20].

Chemotherapy-induced nausea and vomiting have a clear impact on the daily lives of cancer patients. Antiemetic therapy is aimed at preventing, ameliorating or minimizing CINV. Most studies of the effects of CINV have been characterized by narrow patient selection criteria and have investigated well-defined, protocol-based chemotherapy, and antiemetic regimens.

The results of this study of CINV and antiemetic use in routine clinical practice indicate that CINV and particularly delayed symptoms, impact significantly on patients' daily life, despite the use of different combinations of antiemetics. Our findings are consistent with those of other studies, in which the prevalence of delayed nausea and vomiting is higher than acute nausea and vomiting [5].

However, contrary to expectations, we found that patients receiving treatment with moderately emetogenic chemotherapy containing anthracyclines (MEC-A) suffered more from CINV than patients receiving HEC.

A previous study in daily clinical practice by Bloechl-Daum reported no significant differences in the rate of acute and delayed nausea between patients treated with HEC and MEC, while significantly more patients receiving HEC than MEC reported that CINV had a negative impact on daily life (52.8% and 35.5%, p = 0.027) [5]. However, Mollassiotis et al. reported that patients receiving MEC experienced higher levels of CINV compared to patients receiving HEC in a large, single center study in the UK [21]. These two studies were conducted before antiemetic guidelines incorporated the use of NK-1 receptor antagonist containing regimens for patients receiving HEC. After completion of our study, antiemetic guidelines for MEC-A were also updated. Currently, a three-drug combination regimen, including an NK-1 receptor antagonist, is also recommended for MEC-A regimens [1]. Our finding that patients who received MEC treatment faired particularly poorly in terms of CINV symptoms may be explained, at least in part, by the fact that these patients did not receive newer and more effective antiemetic treatment including aprepitant. Additional studies are needed to determine the effectiveness in daily clinical practice of newer antiemetic treatments among patients receiving MEC-A.

Various other factors, in addition to the emetogenicity of the chemotherapy, have been identified that influence both the prevalence and the severity of CINV. These include age, gender, alcohol use, history of motion sickness, and history of pregnancy-related vomiting. In our study, the first three of these risk factors were found to be associated significantly with CINV, but not the latter two. It is unclear why this is the case. It may be that once female gender, which was a strong predictor variable, entered the logistic regression model, motion sickness and pregnancy-related vomiting did not have any additional predictive value.

Interestingly, in a recent analysis of data from two phase III trials of aprepitant in patients receiving cisplatin-based chemotherapy, female gender was not found to be a significant risk factor for CINV [22]. It would be of interest to determine if this also holds true for patients receiving MEC-A, because the majority of these patients are women being treated for breast cancer with anthracycline-containing regimens.

Given the finding that patients lost to follow-up were younger and significantly more likely to receive HEC, patients' level of CINV after multiple treatment cycles might be underestimated in our study because of the increased risk of CINV associated with these risk factors.

The current study is, to the best of our knowledge, the first to investigate change in antiemetic use, and specifically, the use of additional antiemetics, during consecutive cycles of chemotherapy. Previous studies on CINV over multiple treatment cycles have been carried out in well-defined patient populations using predefined antiemetic regimens that were held constant throughout the chemotherapy treatment [23]. In our study, we found that patients experiencing acute vomiting were significantly more likely to have antiemetics added in subsequent chemotherapy cycles than those not experiencing acute vomiting. However, no significant association was observed between other symptoms of CINV and the use of additional antiemetics during subsequent treatment cycles. Additionally, our results indicate that delayed CINV had no effect on subsequent antiemetic treatment. This may be due, in part, to the fact that physicians and nurses often underestimate the incidence of delayed nausea and vomiting [13]. The introduction of standardized, clinic- and home-based symptom monitoring (the latter via interactive voice recognition systems or internet-based data capture) could provide health care providers with real time information on delayed CINV, which, in turn, could have a salutary effect on symptom management.