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Despite the development of more effective antiemetic regimens in the last 30 years, nausea and vomiting continue to be two of the most frequently experienced and distressing side effects of chemotherapy.1 Prophylaxis is the mainstay of therapy, and if it is not managed appropriately, patients can develop anxiety about the potential of nausea and vomiting recurring with future cycles. This not only affects patients’ quality of life but also potentially interrupts their treatment schedules and impairs treatment efficacy.2

Various guidelines and recommendations on antiemetic regimens have been developed based on the emetogenicity of chemotherapy agents. Notably, key updates have been made recently to the European Society of Medical Oncology (ESMO) and the Multinational Association of Supportive Care in Cancer (MASCC) guidelines for prevention of chemotherapy-induced nausea and vomiting (CINV) in 2016 and the American Society of Clinical Oncology (ASCO) guideline on antiemetics in 2017. Two of the key recommendations are (1) adding a neurokinin receptor antagonist (NK1 RA) to a 5-hydroxytryptamine type 3 receptor antagonist (5-HT3 RA) plus dexamethasone in patients receiving carboplatin area under the curve (AUC) ≥4 mg/mL per minute, and (2) offering a four-drug combination of an NK1 RA, 5-HT3 RA, dexamethasone and olanzapine to patients who are treated with an anthracycline combined with cyclophosphamide (AC).3,4

Carboplatin has previously been considered a moderately emetogenic chemotherapy (MEC), and a two-drug combination of 5-HT3 RA plus dexamethasone was traditionally offered as antiemetic prophylaxis. However, carboplatin AUC≥4 is now thought to have an emetic potential greater than that of many other MEC agents. Without antiemetic prophylaxis, 89% of carboplatin-treated patients experienced some degree of nausea, and 82% of patients vomited.5,6 It is important to improve CINV prophylaxis in this group of patients. One major study evaluating this was a post-hoc analysis comparing an NK1 RA with placebo in addition to 5-HT3 RA plus dexamethasone among 401 carboplatin-treated patients in a phase 3 randomised trial by Hesketh et al. Superior responses were shown by the measures of no emesis, no nausea and complete response (defined as no emesis and no use of rescue medication) in the NK1 RA group.7 Other studies have also demonstrated the benefit of adding an NK1 RA to improve CINV in carboplatin-treated patients.8–12

AC combination chemotherapy has been reclassified as highly emetogenic since 2011 and a three-drug combination of NK1 RA, 5-HT3 RA and dexamethasone was considered the standard prophylactic antiemetic regimen. A phase 3 placebo-controlled randomised trial by Navari et al has evaluated the addition of olanzapine to this regimen in patients receiving highly emetogenic chemotherapy, with the majority of patients in this trial receiving AC combination chemotherapy. Olanzapine was shown to significantly improve nausea prevention and complete response.13 A 2016 meta-analysis of olanzapine for prophylaxis and rescue of CINV by Chiu et al also suggested a similar benefit.14 It is worth noting that most studies excluded patients receiving R-CHOP for lymphoma.

Adherence to evidence-based antiemetic guidelines is important to improve patient outcomes. However, a recent retrospective analysis has shown that less than half of physicians achieved greater than 90% adherence to antiemetic guidelines. For carboplatin, 62% of physicians had up to 10% compliance, and another 17% of physicians had between 11% and 20% compliance. Adherence was higher in the AC combination group, but just 56% of physicians had greater than 90% compliance to the guidelines.15 Healthcare professionals also tend to underestimate CINV incidence and severity.16 Therefore, an audit to assess the rate of CINV is important.

Currently in MidCentral Regional Cancer Treatment Service (MRCTS), the standard prophylactic antiemetic regimen used in carboplatin-treated patients is the two-drug combination of ondansetron (a 5-HT3 RA) 8mg twice daily for three doses plus dexamethasone 8mg once daily from day one to three. Aprepitant (an NK1 RA) is not considered as part of standard prophylactic antiemetic regimen in carboplatin-treated patients, although the addition of aprepitant can be considered if other risk factors for emesis, such as history of travel sickness or moderate to severe motion sickness, are present. AC-treated patients are given the three-drug combination of aprepitant 125mg on day one and 80mg on days two and three, ondansetron 8mg twice daily from day one to day two and dexamethasone 8mg once daily from day one to day three. Olanzapine is used in AC-treated breast cancer patients as a rescue medication and given on a ‘as required basis’ prescription, but not as a part of standard prophylactic antiemetic regimen.17

The prophylactic antiemetic regimen used in lymphoma patients treated with R-CHOP chemotherapy was less well defined in MRCTS. Aprepitant was a part of standard prophylactic emetic regimen in R-CHOP-treated patients. However, its role seemed to be less prominent when compared to that in AC-treated breast cancer patients.

The aim of this audit was to assess current use of prophylactic antiemetics and rate of CINV in patients under the care of MRCTS receiving carboplatin AUC≥4 or combination AC chemotherapy, and to determine whether the updated antiemetic regimens recommended by international guidelines should be adopted by MRCTS. We also took the opportunity to assess whether aprepitant should be added to the prophylactic antiemetic regimen in R-CHOP treated patients.

Methods

All patients considered in this prospective audit were being treated under MRCTS with either:

  1. carboplatin AUC≥ 4 either as single agent or as combination with other chemotherapy agents; or
  2. AC combination chemotherapy either in the form of FEC (containing epirubicin 100mg/m2 and cyclophosphamide 500mg/m2) as neoadjuvant or adjuvant breast cancer treatment, or R-CHOP (containing cyclophosphamide 750mg/m2 and doxorubicin 50mg/m2) as treatment for lymphoma.

These included patients from MidCentral District Health Board (DHB), Whanganui DHB, Hawke’s Bay DHB and Taranaki DHB. The study received approval from a local ethics committee and all patients provided written informed consent.

Eligible patients were recruited during their clinic appointments before commencement of chemotherapy or on their first day of chemotherapy administration. To minimise confounding variables, only patients receiving their first cycle of chemotherapy in the outpatient setting were recruited. Patients requiring chemotherapy as inpatients are generally more unwell and potentially have other factors that could cause nausea or vomiting.

Assessment was done by the means of a questionnaire adopted from the Hesketh et al study (Appendix Figure 1). Patients recorded all events of emesis and use of antiemetics in a daily diary during the first 120 hours (five days) after administration of first cycle of chemotherapy only. Patients also self-evaluated nausea daily with a 100-mm horizontal visual analogue scale (VAS). As per the study by Hesketh et al,7 we defined nausea as maximum VAS score ≥5mm, significant nausea as maximum VAS score ≥25mm, emesis as dry retching or vomiting and complete response as no emesis and no use of rescue medication. This was evaluated in the acute phase (≤24 hours), delayed phase (>24–120 hours) and overall phase (0–120 hours). Other data collected included each patient’s gender, age, types of chemotherapy agents, carboplatin AUC dose, primary tumour site and previous exposure to chemotherapy.

Results

Carboplatin-treated patients

Patients

Between 15 September 2018 and 10 August 2019, a total of 66 patients from MidCentral DHB and Whanganui DHB received carboplatin AUC≥4 (Figure 1). Thirty-seven patients were not included in the final audit results, as seven were treated in the inpatient setting, 14 did not return questionnaires and 16 were not recruited due to unknown reasons. As Taranaki DHB and Hawke’s Bay DHB did not have an electronic system similar to that used in MidCentral DHB to record the number of patients receiving chemotherapy, it was not known how many patients received carboplatin during that period at Taranaki and Hawke’s Bay DHBs. A total of 12 patients from Hawke’s Bay DHB and three patients from Taranaki DHB returned their questionnaires and were included. Forty-four carboplatin-treated patients were included in the final analysis.

Baseline characteristics of carboplatin-treated patients are shown in Table 1. The median age of the patients was 66 years, and more patients were female (66%) than male (34%). The primary malignancies of carboplatin-treated patients included lung (38.6%), ovary/fallopian tube/peritoneum (25%), gastrointestinal, including pancreatobiliary (11.4%), uterus (9%), urothelial (7%) and others such as breast, pleura, head and neck and thymus (9%). Eight patients (18%) had received chemotherapy previously.

Figure 1: Patients’ recruitment (carboplatin).

Table 1: Baseline characteristics.

Use of antiemetics and rate of CINV

Forty-two of the 44 patients completed their prophylactic antiemetic regimens appropriately as planned. Six patients were taking aprepitant, as they were thought to have high risk of developing CINV. The numbers of carboplatin-treated patients who developed nausea, significant nausea or emesis in the overall phase was 23 (52%), 18 (41%) and 11 (25%), respectively, with the same proportions in the delayed phase. Only a few patients developed CINV in the acute phase (seven with nausea, three with significant nausea and only one with emesis). In general, 22 patients (50%) had either emesis or significant nausea in the overall and delayed phase when treated with carboplatin AUC≥4, and only three (7%) in the acute phase (Figure 2).

Figure 2: Rate of CINV in carboplatin-treated patients.

Complete response (no emesis and no use of rescue medication) was observed in 21 patients (48%) in both delayed and overall phases and 33 patients (75%) in the acute phase (Figure 3). As shown in Figures 4 and 5, there were more patients with significant nausea on days four and five (12 and 11 patients, respectively) and with emesis on days three, four and five (five, seven and five patients, respectively).

Figure 3: Complete response (carboplatin-treated patients).

Figure 4: Number of patients with significant nausea (carboplatin).

Figure 5: Number of patients with Emesis (carboplatin).

We also evaluated other factors associated with risk of CINV, such as gender and age.18 Around half of both males and females experienced either emesis or significant nausea (8 of 15 males and 14 of 29 females; Table 2). A similar pattern was also observed across various age groups, primary tumour sites, carboplatin AUC doses and combination chemotherapy agents (Tables 3, 4 and 5). The patient numbers in these subgroups were small.

Table 2: CINV by gender and age.

Table 3: CINV by primary tumour site.

Table 4: CINV by carboplatin AUC doses.

Table 5: CINV by various combinations of chemotherapy agents.

C denotes carboplatin; TCH denotes docetaxel, carboplatin and trastuzumab.

In the six patients who had aprepitant as part of their prophylactic antiemetic regimens, five developed significant nausea and two developed emesis, which all occurred in the delayed phase. They were given aprepitant due to presence of other risk factors for CINV.

Combination anthraycline/cyclophosphamide (AC)-treated patients

Patients

Between 15 September 2018 and 15 June 2019, 30 AC-treated patients were included in the audit. Twenty-five patients had breast cancer and received FEC chemotherapy (Figure 6). They were all females (100%) and their median age was 52 years. Recruitment in this patient group ended earlier, as a phase 2 trial involving breast cancer patients started in July 2019. Five patients had lymphoma and were treated with R-CHOP chemotherapy.

Figure 6: Patients’ recruitment (combination AC).

Use of antiemetics and rate of CINV

All 25 FEC-treated patients completed their prophylactic antiemetic regimens appropriately as planned. Nine patients were taking olanzapine as rescue medication. The numbers of FEC-treated patients who developed nausea, significant nausea or emesis in the overall phase were 19 (76%), 14 (56%) and six (24%), respectively. Almost all patients in this group who experienced CINV developed their symptoms in the acute phase with a high proportion having ongoing CINV in the delayed phase. For example, 13 of the 14 patients with significant nausea developed this in the acute phase, and 10 of them in the delayed phase. A similar rate is seen in patients who developed emesis. Overall, 14 patients (56%) had either emesis or significant nausea in the overall phase when treated with FEC chemotherapy, mostly in the acute phase (13 patients) rather than in the delayed phase (nine patients) (Figure 7).

Figure 7: Rate of CINV in FEC-treated breast patients.

Figure 8 shows that complete response was only observed in six patients (24%) in the overall phase, seven patients in the delayed phase and 10 patients in the acute phase. As shown in Figures 9 and 10, most patients who experienced either significant nausea, or emesis developed their symptoms on day one of chemotherapy.

Figure 8: Complete response (FEC-treated patients).

Figure 9: Number of patients with significant nausea (FEC).

Figure 10: Number of patients with emesis (FEC).

In the R-CHOP-treated lymphoma patients group, none of the five patients who participated had any significant nausea or emesis. Only one of them had aprepitant as part of prophylactic antiemetic regimens.

Discussion

Carboplatin-treated patients

This audit shows that patients treated with carboplatin in our centre had high rates of nausea and vomiting despite use of existing prophylactic antiemetic regimen, especially in the overall and delayed phases. This finding is consistent with the study by Hesketh et al and several other larger studies.7,18–20 It was unclear why carboplatin-treated patients in our centre had higher rates of CINV, particularly on days four and five compared to days two and three. It is worth noting that our patients’ last doses of dexamethasone are on day three. It is difficult to draw conclusions as a recent systematic review showing that one-day dexamethasone is not inferior to three-day dexamethasone for prevention of CINV.21 However, the Hesketh study has shown that the use of NK1 RA provided a superior CINV protection, especially in the overall and delayed phases, and thus should be used as part of antiemetic regimen in carboplatin-treated patients.

There was no clear pattern in the proportion of carboplatin-treated patients who developed CINV when compared across age groups, genders, primary tumour sites, carboplatin AUC doses and combination chemotherapy agents. However, patient numbers in these subgroups were too small to draw a meaningful conclusion from.

It is acknowledged that six of the patients who participated in this audit were taking aprepitant. There remained a high rate of CINV in these six patients (five developed significant nausea and two developed emesis). However, these patients were started on aprepitant due to the presence of other risk factors of CINV and the numbers are small, and hence selection bias is highly likely.

Only two patients treated with carboplatin did not complete their prophylactic antiemetic regimens. However, more than 30 eligible patients either did not return their questionnaires or were not recruited. This raises the possibility of selection bias in our study population. Adherence rates to prophylactic regimen may be lower in routine clinical practice.

Combination anthracycline/cyclophosphamide-treated patients

This audit has also shown high rates of nausea and vomiting across all phases in breast cancer patients treated with combination anthracycline/cyclophosphamide.

The rate of CINV in both acute and delayed phases that we observed in this population is higher than what was observed by Navari et al. It is unclear why we have a higher rate of CINV in the acute phase compared to delayed phase; this differs from the findings of other studies.13,22 One possibility is the use of a newer generation of antiemetics in the larger trials. Regardless, it appears that antiemetic prophylaxis in this patient group in our centre is insufficient. Therefore, we should look at an additional antiemetic agent. Olanzapine has been shown to be effective in preventing CINV in both acute and delayed phases13,22–24 and therefore should be added to the usual three-drug regimen.

Other agents should also be considered for more effective prophylaxis of CINV. Currently, a phase 2 study is underway in New Zealand to evaluate the role of pantoprazole, a proton pump inhibitor, in the prophylaxis of delayed CINV in breast cancer patients receiving adjuvant chemotherapy. Its role in preventing delayed CINV in the carboplatin-treated patients will also need to be evaluated.

The numbers of patients treated with R-CHOP is too small for us to draw any meaningful conclusion. However, we have not observed any significant nausea in the five patients treated with R-CHOP, despite four of them not having aprepitant. Therefore, instead of aprepitant being given routinely as part of prophylactic antiemetic regimen, it should be considered in patients with high risk of developing CINV only. Possible explanations for lower rates of CINV in patients receiving R-CHOP chemotherapy in comparison to FEC chemotherapy include: a small sample size, the use of different dosages and drugs, the use of high-dose prednisone as part of treatment regimen and the younger age and gender of patients receiving FEC chemotherapy.18

Other limitations of this audit include the small numbers of patients and that a cost–benefit analysis was not performed. The study by Navari et al also included cisplatin-treated patients, although most patients (more than 60%) were treated with anthracycline/cyclophosphamide. A minority of patients in our study were also given aprepitant or olanzapine and this could potentially affect our data.

Conclusion

This audit has shown that the rate of CINV in patients under the care of MRCTS receiving carboplatin AUC≥4 or combination anthracycline/cyclophosphamide is high. Therefore, we will add a neurokinin-1 antagonist to the antiemetic regimens for patients receiving carboplatin-based chemotherapy AUC≥4, and olanzapine for those receiving combination anthracycline/cyclophosphamide chemotherapy, in an attempt to improve the rates of CINV in these groups. Another repeat audit post-implementation of above recommendations will be important to assess for any improvement.

Appendix

Appendix Figure 1: Questionnaire: Nausea and Vomiting Diary.

Summary

Abstract

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) are two of the most frequently experienced and distressing side effects of cancer treatment. Recent updates by ESMO/MASCC and ASCO on guidelines for prevention of CINV have recommended the addition of a neurokinin-1 receptor antagonist to antiemetic regimens for patients receiving carboplatin-based chemotherapy area under the curve (AUC) ≥4 mg/mL per minute, and an addition of olanzapine for those receiving combination anthracycline/cyclophosphamide chemotherapy. AIMS: To assess current use of prophylactic antiemetics and rates of CINV in patients under the care of MidCentral Regional Cancer Treatment Service (MRCTS) receiving carboplatin AUC≥4 or combination anthracycline/cyclophosphamide. METHODS: Data was prospectively collected on patients under the care of MRCTS receiving carboplatin AUC≥4 or combination anthracycline/cyclophosphamide chemotherapy, including breast cancer patients receiving 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and lymphoma patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Questionnaires were given to eligible patients to be completed daily from day two to day six of first cycle of chemotherapy only. Data on each patient’s gender, age, types of chemotherapies, types of malignancies, presence of nausea or vomiting, number of dry retching or vomiting episodes and anti-emetics were recorded. RESULTS: From 15 September 2018 to 10 August 2019, a total of 44 patients receiving carboplatin-based chemotherapy AUC≥4 and 30 patients receiving combination anthracycline/cyclophosphamide were included. Twenty-two patients (50%) had either emesis or significant nausea in the overall and delayed phase when treated with carboplatin AUC≥4, and only three (7%) in the acute phase. Fourteen patients (56%) had either emesis or significant nausea in the overall phase when treated with FEC chemotherapy, mostly in the acute phase (13 patients) rather than in the delayed phase (9 patients). CONCLUSION: The rates of CINV are high with the existing antiemetic regimens used at MidCentral Regional Cancer Treatment Service. Therefore, in accordance with international guidelines, we will add a neurokinin-1 antagonist to the antiemetic regimens for patients receiving carboplatin-based chemotherapy AUC≥4, and olanzapine for those receiving combination anthracycline/cyclophosphamide chemotherapy, in an attempt to improve the rates of CINV in these groups. Repeating this audit post-implementation of above recommendations will be important to assess for any improvement.

Aim

Method

Results

Conclusion

Author Information

Edward Lo: Phase 1/Lung Research Fellow, Auckland Cancer Trials Centre, Auckland District Health Board. Malcolm Anderson: Regional Cancer Treatment Service, MidCentral District Health Board. Rebecca Carroll: Regional Cancer Treatment Service, MidCentral District Health Board. Garry Forgeson: Regional Cancer Treatment Service, MidCentral District Health Board. Richard Isaacs: Regional Cancer Treatment Service, MidCentral District Health Board. Jody Jordan: Regional Cancer Treatment Service, Hawke's Bay District Health Board. Liyana Satterthwaite: Regional Cancer Treatment Service, MidCentral District Health Board. Navin Wewala: Regional Cancer Treatment Service, MidCentral District Health Board. Jennifer Fernando: Regional Cancer Treatment Service, MidCentral District Health Board.

Acknowledgements

Correspondence

Edward Lo: Phase 1/Lung Research Fellow, Auckland Cancer Trials Centre, Auckland District Health Board

Correspondence Email

elo@adhb.govt.nz

Competing Interests

Nil.

1. De Boer-Dennert M, de Wit R, Schmitz P, et al. Patient perceptions of the side-effects of chemotherapy: the influence of 5HT3 antagonists. British Journal of Cancer. 1997; 76(8): 1055–1061.

2. Shankar A, Roy S, Malik A, et al. Prevention of Chemotherapy-Induced Nausea and Vomiting in Cancer Patients. Asian Pacific Journal of Cancer Prevention. 2015;16(15):6207-6213.

3. Einhorn L, Rapoport B, Navari R, et al. 2016 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting. Supportive Care in Cancer. 2016;25(1):303-308.

4. Hesketh P, Bohlke K, Kris M. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update Summary. Journal of Oncology Practice. 2017;13(12):825-830.

5. Martin M, Diaz-Rubio E, Sanchez A, et al. The natural course of emesis after carboplatin treatment. Acta Oncol.1990;29:593–595.

6. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Antiemesis. Version 2.2015. http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed September 16, 2019.

7. Hesketh P, Schnadig I, Schwartzberg L, et al. Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in patients receiving carboplatin-based chemotherapy. Cancer. 2016;122(15):2418-2425

8. Yahata H, Kobayashi H, Sonoda K, et al. Efficacy of aprepitant for the prevention of chemotherapy induced nausea and vomiting with a moderately emetogenic chemotherapy regimen : a multicenter, placebo controlled, double blind , randomized study in patients with gynecologic cancer receiving paclitaxel and carboplatin. Int J Clin Oncol. 2016;21(3):491-497.

9. Maehara M, Ueda T, Miyahara D, et al. Clinical Efficacy of Aprepitant in Patients with Gynecological Cancer after Chemotherapy Using Paclitaxel and Carboplatin. Anticancer Res. 2015;35:4527-4534.

10. Tanioka M, Kitao A, Matsumoto K, et al. A randomised, placebo-controlled, double-blind study of aprepitant in nondrinking women younger than 70 years receiving moderately emetogenic chemotherapy. Br J Cancer. 2013;109(4):859-865.

11. Ito Y, Karayama M, Inui N, et al. Aprepitant in patients with advanced non-small-cell lung cancer receiving carboplatin-based chemotherapy. Lung Cancer. 2014;84(3):259-264.

12. Kusagaya H, Inui N, Karayama M, et al. Evaluation of palonosetron and dexamethasone with or without aprepitant to prevent carboplatin-induced nausea and vomiting in patients with advanced non-small-cell lung cancer. Lung Cancer. 2015;90(3):410-416.

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Despite the development of more effective antiemetic regimens in the last 30 years, nausea and vomiting continue to be two of the most frequently experienced and distressing side effects of chemotherapy.1 Prophylaxis is the mainstay of therapy, and if it is not managed appropriately, patients can develop anxiety about the potential of nausea and vomiting recurring with future cycles. This not only affects patients’ quality of life but also potentially interrupts their treatment schedules and impairs treatment efficacy.2

Various guidelines and recommendations on antiemetic regimens have been developed based on the emetogenicity of chemotherapy agents. Notably, key updates have been made recently to the European Society of Medical Oncology (ESMO) and the Multinational Association of Supportive Care in Cancer (MASCC) guidelines for prevention of chemotherapy-induced nausea and vomiting (CINV) in 2016 and the American Society of Clinical Oncology (ASCO) guideline on antiemetics in 2017. Two of the key recommendations are (1) adding a neurokinin receptor antagonist (NK1 RA) to a 5-hydroxytryptamine type 3 receptor antagonist (5-HT3 RA) plus dexamethasone in patients receiving carboplatin area under the curve (AUC) ≥4 mg/mL per minute, and (2) offering a four-drug combination of an NK1 RA, 5-HT3 RA, dexamethasone and olanzapine to patients who are treated with an anthracycline combined with cyclophosphamide (AC).3,4

Carboplatin has previously been considered a moderately emetogenic chemotherapy (MEC), and a two-drug combination of 5-HT3 RA plus dexamethasone was traditionally offered as antiemetic prophylaxis. However, carboplatin AUC≥4 is now thought to have an emetic potential greater than that of many other MEC agents. Without antiemetic prophylaxis, 89% of carboplatin-treated patients experienced some degree of nausea, and 82% of patients vomited.5,6 It is important to improve CINV prophylaxis in this group of patients. One major study evaluating this was a post-hoc analysis comparing an NK1 RA with placebo in addition to 5-HT3 RA plus dexamethasone among 401 carboplatin-treated patients in a phase 3 randomised trial by Hesketh et al. Superior responses were shown by the measures of no emesis, no nausea and complete response (defined as no emesis and no use of rescue medication) in the NK1 RA group.7 Other studies have also demonstrated the benefit of adding an NK1 RA to improve CINV in carboplatin-treated patients.8–12

AC combination chemotherapy has been reclassified as highly emetogenic since 2011 and a three-drug combination of NK1 RA, 5-HT3 RA and dexamethasone was considered the standard prophylactic antiemetic regimen. A phase 3 placebo-controlled randomised trial by Navari et al has evaluated the addition of olanzapine to this regimen in patients receiving highly emetogenic chemotherapy, with the majority of patients in this trial receiving AC combination chemotherapy. Olanzapine was shown to significantly improve nausea prevention and complete response.13 A 2016 meta-analysis of olanzapine for prophylaxis and rescue of CINV by Chiu et al also suggested a similar benefit.14 It is worth noting that most studies excluded patients receiving R-CHOP for lymphoma.

Adherence to evidence-based antiemetic guidelines is important to improve patient outcomes. However, a recent retrospective analysis has shown that less than half of physicians achieved greater than 90% adherence to antiemetic guidelines. For carboplatin, 62% of physicians had up to 10% compliance, and another 17% of physicians had between 11% and 20% compliance. Adherence was higher in the AC combination group, but just 56% of physicians had greater than 90% compliance to the guidelines.15 Healthcare professionals also tend to underestimate CINV incidence and severity.16 Therefore, an audit to assess the rate of CINV is important.

Currently in MidCentral Regional Cancer Treatment Service (MRCTS), the standard prophylactic antiemetic regimen used in carboplatin-treated patients is the two-drug combination of ondansetron (a 5-HT3 RA) 8mg twice daily for three doses plus dexamethasone 8mg once daily from day one to three. Aprepitant (an NK1 RA) is not considered as part of standard prophylactic antiemetic regimen in carboplatin-treated patients, although the addition of aprepitant can be considered if other risk factors for emesis, such as history of travel sickness or moderate to severe motion sickness, are present. AC-treated patients are given the three-drug combination of aprepitant 125mg on day one and 80mg on days two and three, ondansetron 8mg twice daily from day one to day two and dexamethasone 8mg once daily from day one to day three. Olanzapine is used in AC-treated breast cancer patients as a rescue medication and given on a ‘as required basis’ prescription, but not as a part of standard prophylactic antiemetic regimen.17

The prophylactic antiemetic regimen used in lymphoma patients treated with R-CHOP chemotherapy was less well defined in MRCTS. Aprepitant was a part of standard prophylactic emetic regimen in R-CHOP-treated patients. However, its role seemed to be less prominent when compared to that in AC-treated breast cancer patients.

The aim of this audit was to assess current use of prophylactic antiemetics and rate of CINV in patients under the care of MRCTS receiving carboplatin AUC≥4 or combination AC chemotherapy, and to determine whether the updated antiemetic regimens recommended by international guidelines should be adopted by MRCTS. We also took the opportunity to assess whether aprepitant should be added to the prophylactic antiemetic regimen in R-CHOP treated patients.

Methods

All patients considered in this prospective audit were being treated under MRCTS with either:

  1. carboplatin AUC≥ 4 either as single agent or as combination with other chemotherapy agents; or
  2. AC combination chemotherapy either in the form of FEC (containing epirubicin 100mg/m2 and cyclophosphamide 500mg/m2) as neoadjuvant or adjuvant breast cancer treatment, or R-CHOP (containing cyclophosphamide 750mg/m2 and doxorubicin 50mg/m2) as treatment for lymphoma.

These included patients from MidCentral District Health Board (DHB), Whanganui DHB, Hawke’s Bay DHB and Taranaki DHB. The study received approval from a local ethics committee and all patients provided written informed consent.

Eligible patients were recruited during their clinic appointments before commencement of chemotherapy or on their first day of chemotherapy administration. To minimise confounding variables, only patients receiving their first cycle of chemotherapy in the outpatient setting were recruited. Patients requiring chemotherapy as inpatients are generally more unwell and potentially have other factors that could cause nausea or vomiting.

Assessment was done by the means of a questionnaire adopted from the Hesketh et al study (Appendix Figure 1). Patients recorded all events of emesis and use of antiemetics in a daily diary during the first 120 hours (five days) after administration of first cycle of chemotherapy only. Patients also self-evaluated nausea daily with a 100-mm horizontal visual analogue scale (VAS). As per the study by Hesketh et al,7 we defined nausea as maximum VAS score ≥5mm, significant nausea as maximum VAS score ≥25mm, emesis as dry retching or vomiting and complete response as no emesis and no use of rescue medication. This was evaluated in the acute phase (≤24 hours), delayed phase (>24–120 hours) and overall phase (0–120 hours). Other data collected included each patient’s gender, age, types of chemotherapy agents, carboplatin AUC dose, primary tumour site and previous exposure to chemotherapy.

Results

Carboplatin-treated patients

Patients

Between 15 September 2018 and 10 August 2019, a total of 66 patients from MidCentral DHB and Whanganui DHB received carboplatin AUC≥4 (Figure 1). Thirty-seven patients were not included in the final audit results, as seven were treated in the inpatient setting, 14 did not return questionnaires and 16 were not recruited due to unknown reasons. As Taranaki DHB and Hawke’s Bay DHB did not have an electronic system similar to that used in MidCentral DHB to record the number of patients receiving chemotherapy, it was not known how many patients received carboplatin during that period at Taranaki and Hawke’s Bay DHBs. A total of 12 patients from Hawke’s Bay DHB and three patients from Taranaki DHB returned their questionnaires and were included. Forty-four carboplatin-treated patients were included in the final analysis.

Baseline characteristics of carboplatin-treated patients are shown in Table 1. The median age of the patients was 66 years, and more patients were female (66%) than male (34%). The primary malignancies of carboplatin-treated patients included lung (38.6%), ovary/fallopian tube/peritoneum (25%), gastrointestinal, including pancreatobiliary (11.4%), uterus (9%), urothelial (7%) and others such as breast, pleura, head and neck and thymus (9%). Eight patients (18%) had received chemotherapy previously.

Figure 1: Patients’ recruitment (carboplatin).

Table 1: Baseline characteristics.

Use of antiemetics and rate of CINV

Forty-two of the 44 patients completed their prophylactic antiemetic regimens appropriately as planned. Six patients were taking aprepitant, as they were thought to have high risk of developing CINV. The numbers of carboplatin-treated patients who developed nausea, significant nausea or emesis in the overall phase was 23 (52%), 18 (41%) and 11 (25%), respectively, with the same proportions in the delayed phase. Only a few patients developed CINV in the acute phase (seven with nausea, three with significant nausea and only one with emesis). In general, 22 patients (50%) had either emesis or significant nausea in the overall and delayed phase when treated with carboplatin AUC≥4, and only three (7%) in the acute phase (Figure 2).

Figure 2: Rate of CINV in carboplatin-treated patients.

Complete response (no emesis and no use of rescue medication) was observed in 21 patients (48%) in both delayed and overall phases and 33 patients (75%) in the acute phase (Figure 3). As shown in Figures 4 and 5, there were more patients with significant nausea on days four and five (12 and 11 patients, respectively) and with emesis on days three, four and five (five, seven and five patients, respectively).

Figure 3: Complete response (carboplatin-treated patients).

Figure 4: Number of patients with significant nausea (carboplatin).

Figure 5: Number of patients with Emesis (carboplatin).

We also evaluated other factors associated with risk of CINV, such as gender and age.18 Around half of both males and females experienced either emesis or significant nausea (8 of 15 males and 14 of 29 females; Table 2). A similar pattern was also observed across various age groups, primary tumour sites, carboplatin AUC doses and combination chemotherapy agents (Tables 3, 4 and 5). The patient numbers in these subgroups were small.

Table 2: CINV by gender and age.

Table 3: CINV by primary tumour site.

Table 4: CINV by carboplatin AUC doses.

Table 5: CINV by various combinations of chemotherapy agents.

C denotes carboplatin; TCH denotes docetaxel, carboplatin and trastuzumab.

In the six patients who had aprepitant as part of their prophylactic antiemetic regimens, five developed significant nausea and two developed emesis, which all occurred in the delayed phase. They were given aprepitant due to presence of other risk factors for CINV.

Combination anthraycline/cyclophosphamide (AC)-treated patients

Patients

Between 15 September 2018 and 15 June 2019, 30 AC-treated patients were included in the audit. Twenty-five patients had breast cancer and received FEC chemotherapy (Figure 6). They were all females (100%) and their median age was 52 years. Recruitment in this patient group ended earlier, as a phase 2 trial involving breast cancer patients started in July 2019. Five patients had lymphoma and were treated with R-CHOP chemotherapy.

Figure 6: Patients’ recruitment (combination AC).

Use of antiemetics and rate of CINV

All 25 FEC-treated patients completed their prophylactic antiemetic regimens appropriately as planned. Nine patients were taking olanzapine as rescue medication. The numbers of FEC-treated patients who developed nausea, significant nausea or emesis in the overall phase were 19 (76%), 14 (56%) and six (24%), respectively. Almost all patients in this group who experienced CINV developed their symptoms in the acute phase with a high proportion having ongoing CINV in the delayed phase. For example, 13 of the 14 patients with significant nausea developed this in the acute phase, and 10 of them in the delayed phase. A similar rate is seen in patients who developed emesis. Overall, 14 patients (56%) had either emesis or significant nausea in the overall phase when treated with FEC chemotherapy, mostly in the acute phase (13 patients) rather than in the delayed phase (nine patients) (Figure 7).

Figure 7: Rate of CINV in FEC-treated breast patients.

Figure 8 shows that complete response was only observed in six patients (24%) in the overall phase, seven patients in the delayed phase and 10 patients in the acute phase. As shown in Figures 9 and 10, most patients who experienced either significant nausea, or emesis developed their symptoms on day one of chemotherapy.

Figure 8: Complete response (FEC-treated patients).

Figure 9: Number of patients with significant nausea (FEC).

Figure 10: Number of patients with emesis (FEC).

In the R-CHOP-treated lymphoma patients group, none of the five patients who participated had any significant nausea or emesis. Only one of them had aprepitant as part of prophylactic antiemetic regimens.

Discussion

Carboplatin-treated patients

This audit shows that patients treated with carboplatin in our centre had high rates of nausea and vomiting despite use of existing prophylactic antiemetic regimen, especially in the overall and delayed phases. This finding is consistent with the study by Hesketh et al and several other larger studies.7,18–20 It was unclear why carboplatin-treated patients in our centre had higher rates of CINV, particularly on days four and five compared to days two and three. It is worth noting that our patients’ last doses of dexamethasone are on day three. It is difficult to draw conclusions as a recent systematic review showing that one-day dexamethasone is not inferior to three-day dexamethasone for prevention of CINV.21 However, the Hesketh study has shown that the use of NK1 RA provided a superior CINV protection, especially in the overall and delayed phases, and thus should be used as part of antiemetic regimen in carboplatin-treated patients.

There was no clear pattern in the proportion of carboplatin-treated patients who developed CINV when compared across age groups, genders, primary tumour sites, carboplatin AUC doses and combination chemotherapy agents. However, patient numbers in these subgroups were too small to draw a meaningful conclusion from.

It is acknowledged that six of the patients who participated in this audit were taking aprepitant. There remained a high rate of CINV in these six patients (five developed significant nausea and two developed emesis). However, these patients were started on aprepitant due to the presence of other risk factors of CINV and the numbers are small, and hence selection bias is highly likely.

Only two patients treated with carboplatin did not complete their prophylactic antiemetic regimens. However, more than 30 eligible patients either did not return their questionnaires or were not recruited. This raises the possibility of selection bias in our study population. Adherence rates to prophylactic regimen may be lower in routine clinical practice.

Combination anthracycline/cyclophosphamide-treated patients

This audit has also shown high rates of nausea and vomiting across all phases in breast cancer patients treated with combination anthracycline/cyclophosphamide.

The rate of CINV in both acute and delayed phases that we observed in this population is higher than what was observed by Navari et al. It is unclear why we have a higher rate of CINV in the acute phase compared to delayed phase; this differs from the findings of other studies.13,22 One possibility is the use of a newer generation of antiemetics in the larger trials. Regardless, it appears that antiemetic prophylaxis in this patient group in our centre is insufficient. Therefore, we should look at an additional antiemetic agent. Olanzapine has been shown to be effective in preventing CINV in both acute and delayed phases13,22–24 and therefore should be added to the usual three-drug regimen.

Other agents should also be considered for more effective prophylaxis of CINV. Currently, a phase 2 study is underway in New Zealand to evaluate the role of pantoprazole, a proton pump inhibitor, in the prophylaxis of delayed CINV in breast cancer patients receiving adjuvant chemotherapy. Its role in preventing delayed CINV in the carboplatin-treated patients will also need to be evaluated.

The numbers of patients treated with R-CHOP is too small for us to draw any meaningful conclusion. However, we have not observed any significant nausea in the five patients treated with R-CHOP, despite four of them not having aprepitant. Therefore, instead of aprepitant being given routinely as part of prophylactic antiemetic regimen, it should be considered in patients with high risk of developing CINV only. Possible explanations for lower rates of CINV in patients receiving R-CHOP chemotherapy in comparison to FEC chemotherapy include: a small sample size, the use of different dosages and drugs, the use of high-dose prednisone as part of treatment regimen and the younger age and gender of patients receiving FEC chemotherapy.18

Other limitations of this audit include the small numbers of patients and that a cost–benefit analysis was not performed. The study by Navari et al also included cisplatin-treated patients, although most patients (more than 60%) were treated with anthracycline/cyclophosphamide. A minority of patients in our study were also given aprepitant or olanzapine and this could potentially affect our data.

Conclusion

This audit has shown that the rate of CINV in patients under the care of MRCTS receiving carboplatin AUC≥4 or combination anthracycline/cyclophosphamide is high. Therefore, we will add a neurokinin-1 antagonist to the antiemetic regimens for patients receiving carboplatin-based chemotherapy AUC≥4, and olanzapine for those receiving combination anthracycline/cyclophosphamide chemotherapy, in an attempt to improve the rates of CINV in these groups. Another repeat audit post-implementation of above recommendations will be important to assess for any improvement.

Appendix

Appendix Figure 1: Questionnaire: Nausea and Vomiting Diary.

Summary

Abstract

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) are two of the most frequently experienced and distressing side effects of cancer treatment. Recent updates by ESMO/MASCC and ASCO on guidelines for prevention of CINV have recommended the addition of a neurokinin-1 receptor antagonist to antiemetic regimens for patients receiving carboplatin-based chemotherapy area under the curve (AUC) ≥4 mg/mL per minute, and an addition of olanzapine for those receiving combination anthracycline/cyclophosphamide chemotherapy. AIMS: To assess current use of prophylactic antiemetics and rates of CINV in patients under the care of MidCentral Regional Cancer Treatment Service (MRCTS) receiving carboplatin AUC≥4 or combination anthracycline/cyclophosphamide. METHODS: Data was prospectively collected on patients under the care of MRCTS receiving carboplatin AUC≥4 or combination anthracycline/cyclophosphamide chemotherapy, including breast cancer patients receiving 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and lymphoma patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Questionnaires were given to eligible patients to be completed daily from day two to day six of first cycle of chemotherapy only. Data on each patient’s gender, age, types of chemotherapies, types of malignancies, presence of nausea or vomiting, number of dry retching or vomiting episodes and anti-emetics were recorded. RESULTS: From 15 September 2018 to 10 August 2019, a total of 44 patients receiving carboplatin-based chemotherapy AUC≥4 and 30 patients receiving combination anthracycline/cyclophosphamide were included. Twenty-two patients (50%) had either emesis or significant nausea in the overall and delayed phase when treated with carboplatin AUC≥4, and only three (7%) in the acute phase. Fourteen patients (56%) had either emesis or significant nausea in the overall phase when treated with FEC chemotherapy, mostly in the acute phase (13 patients) rather than in the delayed phase (9 patients). CONCLUSION: The rates of CINV are high with the existing antiemetic regimens used at MidCentral Regional Cancer Treatment Service. Therefore, in accordance with international guidelines, we will add a neurokinin-1 antagonist to the antiemetic regimens for patients receiving carboplatin-based chemotherapy AUC≥4, and olanzapine for those receiving combination anthracycline/cyclophosphamide chemotherapy, in an attempt to improve the rates of CINV in these groups. Repeating this audit post-implementation of above recommendations will be important to assess for any improvement.

Aim

Method

Results

Conclusion

Author Information

Edward Lo: Phase 1/Lung Research Fellow, Auckland Cancer Trials Centre, Auckland District Health Board. Malcolm Anderson: Regional Cancer Treatment Service, MidCentral District Health Board. Rebecca Carroll: Regional Cancer Treatment Service, MidCentral District Health Board. Garry Forgeson: Regional Cancer Treatment Service, MidCentral District Health Board. Richard Isaacs: Regional Cancer Treatment Service, MidCentral District Health Board. Jody Jordan: Regional Cancer Treatment Service, Hawke's Bay District Health Board. Liyana Satterthwaite: Regional Cancer Treatment Service, MidCentral District Health Board. Navin Wewala: Regional Cancer Treatment Service, MidCentral District Health Board. Jennifer Fernando: Regional Cancer Treatment Service, MidCentral District Health Board.

Acknowledgements

Correspondence

Edward Lo: Phase 1/Lung Research Fellow, Auckland Cancer Trials Centre, Auckland District Health Board

Correspondence Email

elo@adhb.govt.nz

Competing Interests

Nil.

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8. Yahata H, Kobayashi H, Sonoda K, et al. Efficacy of aprepitant for the prevention of chemotherapy induced nausea and vomiting with a moderately emetogenic chemotherapy regimen : a multicenter, placebo controlled, double blind , randomized study in patients with gynecologic cancer receiving paclitaxel and carboplatin. Int J Clin Oncol. 2016;21(3):491-497.

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Despite the development of more effective antiemetic regimens in the last 30 years, nausea and vomiting continue to be two of the most frequently experienced and distressing side effects of chemotherapy.1 Prophylaxis is the mainstay of therapy, and if it is not managed appropriately, patients can develop anxiety about the potential of nausea and vomiting recurring with future cycles. This not only affects patients’ quality of life but also potentially interrupts their treatment schedules and impairs treatment efficacy.2

Various guidelines and recommendations on antiemetic regimens have been developed based on the emetogenicity of chemotherapy agents. Notably, key updates have been made recently to the European Society of Medical Oncology (ESMO) and the Multinational Association of Supportive Care in Cancer (MASCC) guidelines for prevention of chemotherapy-induced nausea and vomiting (CINV) in 2016 and the American Society of Clinical Oncology (ASCO) guideline on antiemetics in 2017. Two of the key recommendations are (1) adding a neurokinin receptor antagonist (NK1 RA) to a 5-hydroxytryptamine type 3 receptor antagonist (5-HT3 RA) plus dexamethasone in patients receiving carboplatin area under the curve (AUC) ≥4 mg/mL per minute, and (2) offering a four-drug combination of an NK1 RA, 5-HT3 RA, dexamethasone and olanzapine to patients who are treated with an anthracycline combined with cyclophosphamide (AC).3,4

Carboplatin has previously been considered a moderately emetogenic chemotherapy (MEC), and a two-drug combination of 5-HT3 RA plus dexamethasone was traditionally offered as antiemetic prophylaxis. However, carboplatin AUC≥4 is now thought to have an emetic potential greater than that of many other MEC agents. Without antiemetic prophylaxis, 89% of carboplatin-treated patients experienced some degree of nausea, and 82% of patients vomited.5,6 It is important to improve CINV prophylaxis in this group of patients. One major study evaluating this was a post-hoc analysis comparing an NK1 RA with placebo in addition to 5-HT3 RA plus dexamethasone among 401 carboplatin-treated patients in a phase 3 randomised trial by Hesketh et al. Superior responses were shown by the measures of no emesis, no nausea and complete response (defined as no emesis and no use of rescue medication) in the NK1 RA group.7 Other studies have also demonstrated the benefit of adding an NK1 RA to improve CINV in carboplatin-treated patients.8–12

AC combination chemotherapy has been reclassified as highly emetogenic since 2011 and a three-drug combination of NK1 RA, 5-HT3 RA and dexamethasone was considered the standard prophylactic antiemetic regimen. A phase 3 placebo-controlled randomised trial by Navari et al has evaluated the addition of olanzapine to this regimen in patients receiving highly emetogenic chemotherapy, with the majority of patients in this trial receiving AC combination chemotherapy. Olanzapine was shown to significantly improve nausea prevention and complete response.13 A 2016 meta-analysis of olanzapine for prophylaxis and rescue of CINV by Chiu et al also suggested a similar benefit.14 It is worth noting that most studies excluded patients receiving R-CHOP for lymphoma.

Adherence to evidence-based antiemetic guidelines is important to improve patient outcomes. However, a recent retrospective analysis has shown that less than half of physicians achieved greater than 90% adherence to antiemetic guidelines. For carboplatin, 62% of physicians had up to 10% compliance, and another 17% of physicians had between 11% and 20% compliance. Adherence was higher in the AC combination group, but just 56% of physicians had greater than 90% compliance to the guidelines.15 Healthcare professionals also tend to underestimate CINV incidence and severity.16 Therefore, an audit to assess the rate of CINV is important.

Currently in MidCentral Regional Cancer Treatment Service (MRCTS), the standard prophylactic antiemetic regimen used in carboplatin-treated patients is the two-drug combination of ondansetron (a 5-HT3 RA) 8mg twice daily for three doses plus dexamethasone 8mg once daily from day one to three. Aprepitant (an NK1 RA) is not considered as part of standard prophylactic antiemetic regimen in carboplatin-treated patients, although the addition of aprepitant can be considered if other risk factors for emesis, such as history of travel sickness or moderate to severe motion sickness, are present. AC-treated patients are given the three-drug combination of aprepitant 125mg on day one and 80mg on days two and three, ondansetron 8mg twice daily from day one to day two and dexamethasone 8mg once daily from day one to day three. Olanzapine is used in AC-treated breast cancer patients as a rescue medication and given on a ‘as required basis’ prescription, but not as a part of standard prophylactic antiemetic regimen.17

The prophylactic antiemetic regimen used in lymphoma patients treated with R-CHOP chemotherapy was less well defined in MRCTS. Aprepitant was a part of standard prophylactic emetic regimen in R-CHOP-treated patients. However, its role seemed to be less prominent when compared to that in AC-treated breast cancer patients.

The aim of this audit was to assess current use of prophylactic antiemetics and rate of CINV in patients under the care of MRCTS receiving carboplatin AUC≥4 or combination AC chemotherapy, and to determine whether the updated antiemetic regimens recommended by international guidelines should be adopted by MRCTS. We also took the opportunity to assess whether aprepitant should be added to the prophylactic antiemetic regimen in R-CHOP treated patients.

Methods

All patients considered in this prospective audit were being treated under MRCTS with either:

  1. carboplatin AUC≥ 4 either as single agent or as combination with other chemotherapy agents; or
  2. AC combination chemotherapy either in the form of FEC (containing epirubicin 100mg/m2 and cyclophosphamide 500mg/m2) as neoadjuvant or adjuvant breast cancer treatment, or R-CHOP (containing cyclophosphamide 750mg/m2 and doxorubicin 50mg/m2) as treatment for lymphoma.

These included patients from MidCentral District Health Board (DHB), Whanganui DHB, Hawke’s Bay DHB and Taranaki DHB. The study received approval from a local ethics committee and all patients provided written informed consent.

Eligible patients were recruited during their clinic appointments before commencement of chemotherapy or on their first day of chemotherapy administration. To minimise confounding variables, only patients receiving their first cycle of chemotherapy in the outpatient setting were recruited. Patients requiring chemotherapy as inpatients are generally more unwell and potentially have other factors that could cause nausea or vomiting.

Assessment was done by the means of a questionnaire adopted from the Hesketh et al study (Appendix Figure 1). Patients recorded all events of emesis and use of antiemetics in a daily diary during the first 120 hours (five days) after administration of first cycle of chemotherapy only. Patients also self-evaluated nausea daily with a 100-mm horizontal visual analogue scale (VAS). As per the study by Hesketh et al,7 we defined nausea as maximum VAS score ≥5mm, significant nausea as maximum VAS score ≥25mm, emesis as dry retching or vomiting and complete response as no emesis and no use of rescue medication. This was evaluated in the acute phase (≤24 hours), delayed phase (>24–120 hours) and overall phase (0–120 hours). Other data collected included each patient’s gender, age, types of chemotherapy agents, carboplatin AUC dose, primary tumour site and previous exposure to chemotherapy.

Results

Carboplatin-treated patients

Patients

Between 15 September 2018 and 10 August 2019, a total of 66 patients from MidCentral DHB and Whanganui DHB received carboplatin AUC≥4 (Figure 1). Thirty-seven patients were not included in the final audit results, as seven were treated in the inpatient setting, 14 did not return questionnaires and 16 were not recruited due to unknown reasons. As Taranaki DHB and Hawke’s Bay DHB did not have an electronic system similar to that used in MidCentral DHB to record the number of patients receiving chemotherapy, it was not known how many patients received carboplatin during that period at Taranaki and Hawke’s Bay DHBs. A total of 12 patients from Hawke’s Bay DHB and three patients from Taranaki DHB returned their questionnaires and were included. Forty-four carboplatin-treated patients were included in the final analysis.

Baseline characteristics of carboplatin-treated patients are shown in Table 1. The median age of the patients was 66 years, and more patients were female (66%) than male (34%). The primary malignancies of carboplatin-treated patients included lung (38.6%), ovary/fallopian tube/peritoneum (25%), gastrointestinal, including pancreatobiliary (11.4%), uterus (9%), urothelial (7%) and others such as breast, pleura, head and neck and thymus (9%). Eight patients (18%) had received chemotherapy previously.

Figure 1: Patients’ recruitment (carboplatin).

Table 1: Baseline characteristics.

Use of antiemetics and rate of CINV

Forty-two of the 44 patients completed their prophylactic antiemetic regimens appropriately as planned. Six patients were taking aprepitant, as they were thought to have high risk of developing CINV. The numbers of carboplatin-treated patients who developed nausea, significant nausea or emesis in the overall phase was 23 (52%), 18 (41%) and 11 (25%), respectively, with the same proportions in the delayed phase. Only a few patients developed CINV in the acute phase (seven with nausea, three with significant nausea and only one with emesis). In general, 22 patients (50%) had either emesis or significant nausea in the overall and delayed phase when treated with carboplatin AUC≥4, and only three (7%) in the acute phase (Figure 2).

Figure 2: Rate of CINV in carboplatin-treated patients.

Complete response (no emesis and no use of rescue medication) was observed in 21 patients (48%) in both delayed and overall phases and 33 patients (75%) in the acute phase (Figure 3). As shown in Figures 4 and 5, there were more patients with significant nausea on days four and five (12 and 11 patients, respectively) and with emesis on days three, four and five (five, seven and five patients, respectively).

Figure 3: Complete response (carboplatin-treated patients).

Figure 4: Number of patients with significant nausea (carboplatin).

Figure 5: Number of patients with Emesis (carboplatin).

We also evaluated other factors associated with risk of CINV, such as gender and age.18 Around half of both males and females experienced either emesis or significant nausea (8 of 15 males and 14 of 29 females; Table 2). A similar pattern was also observed across various age groups, primary tumour sites, carboplatin AUC doses and combination chemotherapy agents (Tables 3, 4 and 5). The patient numbers in these subgroups were small.

Table 2: CINV by gender and age.

Table 3: CINV by primary tumour site.

Table 4: CINV by carboplatin AUC doses.

Table 5: CINV by various combinations of chemotherapy agents.

C denotes carboplatin; TCH denotes docetaxel, carboplatin and trastuzumab.

In the six patients who had aprepitant as part of their prophylactic antiemetic regimens, five developed significant nausea and two developed emesis, which all occurred in the delayed phase. They were given aprepitant due to presence of other risk factors for CINV.

Combination anthraycline/cyclophosphamide (AC)-treated patients

Patients

Between 15 September 2018 and 15 June 2019, 30 AC-treated patients were included in the audit. Twenty-five patients had breast cancer and received FEC chemotherapy (Figure 6). They were all females (100%) and their median age was 52 years. Recruitment in this patient group ended earlier, as a phase 2 trial involving breast cancer patients started in July 2019. Five patients had lymphoma and were treated with R-CHOP chemotherapy.

Figure 6: Patients’ recruitment (combination AC).

Use of antiemetics and rate of CINV

All 25 FEC-treated patients completed their prophylactic antiemetic regimens appropriately as planned. Nine patients were taking olanzapine as rescue medication. The numbers of FEC-treated patients who developed nausea, significant nausea or emesis in the overall phase were 19 (76%), 14 (56%) and six (24%), respectively. Almost all patients in this group who experienced CINV developed their symptoms in the acute phase with a high proportion having ongoing CINV in the delayed phase. For example, 13 of the 14 patients with significant nausea developed this in the acute phase, and 10 of them in the delayed phase. A similar rate is seen in patients who developed emesis. Overall, 14 patients (56%) had either emesis or significant nausea in the overall phase when treated with FEC chemotherapy, mostly in the acute phase (13 patients) rather than in the delayed phase (nine patients) (Figure 7).

Figure 7: Rate of CINV in FEC-treated breast patients.

Figure 8 shows that complete response was only observed in six patients (24%) in the overall phase, seven patients in the delayed phase and 10 patients in the acute phase. As shown in Figures 9 and 10, most patients who experienced either significant nausea, or emesis developed their symptoms on day one of chemotherapy.

Figure 8: Complete response (FEC-treated patients).

Figure 9: Number of patients with significant nausea (FEC).

Figure 10: Number of patients with emesis (FEC).

In the R-CHOP-treated lymphoma patients group, none of the five patients who participated had any significant nausea or emesis. Only one of them had aprepitant as part of prophylactic antiemetic regimens.

Discussion

Carboplatin-treated patients

This audit shows that patients treated with carboplatin in our centre had high rates of nausea and vomiting despite use of existing prophylactic antiemetic regimen, especially in the overall and delayed phases. This finding is consistent with the study by Hesketh et al and several other larger studies.7,18–20 It was unclear why carboplatin-treated patients in our centre had higher rates of CINV, particularly on days four and five compared to days two and three. It is worth noting that our patients’ last doses of dexamethasone are on day three. It is difficult to draw conclusions as a recent systematic review showing that one-day dexamethasone is not inferior to three-day dexamethasone for prevention of CINV.21 However, the Hesketh study has shown that the use of NK1 RA provided a superior CINV protection, especially in the overall and delayed phases, and thus should be used as part of antiemetic regimen in carboplatin-treated patients.

There was no clear pattern in the proportion of carboplatin-treated patients who developed CINV when compared across age groups, genders, primary tumour sites, carboplatin AUC doses and combination chemotherapy agents. However, patient numbers in these subgroups were too small to draw a meaningful conclusion from.

It is acknowledged that six of the patients who participated in this audit were taking aprepitant. There remained a high rate of CINV in these six patients (five developed significant nausea and two developed emesis). However, these patients were started on aprepitant due to the presence of other risk factors of CINV and the numbers are small, and hence selection bias is highly likely.

Only two patients treated with carboplatin did not complete their prophylactic antiemetic regimens. However, more than 30 eligible patients either did not return their questionnaires or were not recruited. This raises the possibility of selection bias in our study population. Adherence rates to prophylactic regimen may be lower in routine clinical practice.

Combination anthracycline/cyclophosphamide-treated patients

This audit has also shown high rates of nausea and vomiting across all phases in breast cancer patients treated with combination anthracycline/cyclophosphamide.

The rate of CINV in both acute and delayed phases that we observed in this population is higher than what was observed by Navari et al. It is unclear why we have a higher rate of CINV in the acute phase compared to delayed phase; this differs from the findings of other studies.13,22 One possibility is the use of a newer generation of antiemetics in the larger trials. Regardless, it appears that antiemetic prophylaxis in this patient group in our centre is insufficient. Therefore, we should look at an additional antiemetic agent. Olanzapine has been shown to be effective in preventing CINV in both acute and delayed phases13,22–24 and therefore should be added to the usual three-drug regimen.

Other agents should also be considered for more effective prophylaxis of CINV. Currently, a phase 2 study is underway in New Zealand to evaluate the role of pantoprazole, a proton pump inhibitor, in the prophylaxis of delayed CINV in breast cancer patients receiving adjuvant chemotherapy. Its role in preventing delayed CINV in the carboplatin-treated patients will also need to be evaluated.

The numbers of patients treated with R-CHOP is too small for us to draw any meaningful conclusion. However, we have not observed any significant nausea in the five patients treated with R-CHOP, despite four of them not having aprepitant. Therefore, instead of aprepitant being given routinely as part of prophylactic antiemetic regimen, it should be considered in patients with high risk of developing CINV only. Possible explanations for lower rates of CINV in patients receiving R-CHOP chemotherapy in comparison to FEC chemotherapy include: a small sample size, the use of different dosages and drugs, the use of high-dose prednisone as part of treatment regimen and the younger age and gender of patients receiving FEC chemotherapy.18

Other limitations of this audit include the small numbers of patients and that a cost–benefit analysis was not performed. The study by Navari et al also included cisplatin-treated patients, although most patients (more than 60%) were treated with anthracycline/cyclophosphamide. A minority of patients in our study were also given aprepitant or olanzapine and this could potentially affect our data.

Conclusion

This audit has shown that the rate of CINV in patients under the care of MRCTS receiving carboplatin AUC≥4 or combination anthracycline/cyclophosphamide is high. Therefore, we will add a neurokinin-1 antagonist to the antiemetic regimens for patients receiving carboplatin-based chemotherapy AUC≥4, and olanzapine for those receiving combination anthracycline/cyclophosphamide chemotherapy, in an attempt to improve the rates of CINV in these groups. Another repeat audit post-implementation of above recommendations will be important to assess for any improvement.

Appendix

Appendix Figure 1: Questionnaire: Nausea and Vomiting Diary.

Summary

Abstract

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) are two of the most frequently experienced and distressing side effects of cancer treatment. Recent updates by ESMO/MASCC and ASCO on guidelines for prevention of CINV have recommended the addition of a neurokinin-1 receptor antagonist to antiemetic regimens for patients receiving carboplatin-based chemotherapy area under the curve (AUC) ≥4 mg/mL per minute, and an addition of olanzapine for those receiving combination anthracycline/cyclophosphamide chemotherapy. AIMS: To assess current use of prophylactic antiemetics and rates of CINV in patients under the care of MidCentral Regional Cancer Treatment Service (MRCTS) receiving carboplatin AUC≥4 or combination anthracycline/cyclophosphamide. METHODS: Data was prospectively collected on patients under the care of MRCTS receiving carboplatin AUC≥4 or combination anthracycline/cyclophosphamide chemotherapy, including breast cancer patients receiving 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and lymphoma patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Questionnaires were given to eligible patients to be completed daily from day two to day six of first cycle of chemotherapy only. Data on each patient’s gender, age, types of chemotherapies, types of malignancies, presence of nausea or vomiting, number of dry retching or vomiting episodes and anti-emetics were recorded. RESULTS: From 15 September 2018 to 10 August 2019, a total of 44 patients receiving carboplatin-based chemotherapy AUC≥4 and 30 patients receiving combination anthracycline/cyclophosphamide were included. Twenty-two patients (50%) had either emesis or significant nausea in the overall and delayed phase when treated with carboplatin AUC≥4, and only three (7%) in the acute phase. Fourteen patients (56%) had either emesis or significant nausea in the overall phase when treated with FEC chemotherapy, mostly in the acute phase (13 patients) rather than in the delayed phase (9 patients). CONCLUSION: The rates of CINV are high with the existing antiemetic regimens used at MidCentral Regional Cancer Treatment Service. Therefore, in accordance with international guidelines, we will add a neurokinin-1 antagonist to the antiemetic regimens for patients receiving carboplatin-based chemotherapy AUC≥4, and olanzapine for those receiving combination anthracycline/cyclophosphamide chemotherapy, in an attempt to improve the rates of CINV in these groups. Repeating this audit post-implementation of above recommendations will be important to assess for any improvement.

Aim

Method

Results

Conclusion

Author Information

Edward Lo: Phase 1/Lung Research Fellow, Auckland Cancer Trials Centre, Auckland District Health Board. Malcolm Anderson: Regional Cancer Treatment Service, MidCentral District Health Board. Rebecca Carroll: Regional Cancer Treatment Service, MidCentral District Health Board. Garry Forgeson: Regional Cancer Treatment Service, MidCentral District Health Board. Richard Isaacs: Regional Cancer Treatment Service, MidCentral District Health Board. Jody Jordan: Regional Cancer Treatment Service, Hawke's Bay District Health Board. Liyana Satterthwaite: Regional Cancer Treatment Service, MidCentral District Health Board. Navin Wewala: Regional Cancer Treatment Service, MidCentral District Health Board. Jennifer Fernando: Regional Cancer Treatment Service, MidCentral District Health Board.

Acknowledgements

Correspondence

Edward Lo: Phase 1/Lung Research Fellow, Auckland Cancer Trials Centre, Auckland District Health Board

Correspondence Email

elo@adhb.govt.nz

Competing Interests

Nil.

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