Keywords 5-HT3 receptor antagonist - breast cancer - chemotherapy-induced nausea and vomiting
- highly emetogenic chemotherapy - NK-1 receptor antagonist
Introduction
Cancer as a noncommunicable disease presents a tremendous burden on patients, their
caregivers, and society. The currently estimated burden of cancer worldwide is touching
to 18 million in 2018 and is going to reach up to 29.5 million by 2040, with the leading
causes being tumors of the lung, breast, and prostate.[1 ]
In India, an estimated 1.15 million patients were diagnosed with cancer in the year
2018. The leading causes of cancer in males are cancers of the oral cavity and lip,
followed by lung and stomach cancer. In females, the most common cancer site affected
is the breast, followed by the oral cavity and lip and the cervix. An estimated 14%
of all newly diagnosed cancer cases are of breast tumors.[2 ]
For the treatment of breast cancer, the mainstay of treatment is surgery to remove
the tumor, followed by chemotherapy, radiotherapy, and hormonal therapy, depending
on the tumor type and stage. The chemotherapy commonly prescribed to these patients
is a combination of anthracycline–cyclophosphamide.
However, chemotherapy is fraught with a high frequency of serious and troublesome
adverse effects that compromise not only the quality of life of the patient but also
the patient compliance with the treatment. One of the most common and troublesome
adverse effects is associated with nausea and vomiting, which appears earliest, and
has a profound impact on the quality of life of the patient.[3 ]
Chemotherapy-induced nausea and vomiting (CINV) can be labeled as acute (within 24
h), delayed (beyond 24 h), anticipatory, breakthrough, and refractory, may present
in all permutations and combinations, that are substantially challenging for the physician
as well as to the patient.[4 ] Each chemotherapeutic agent used varies in its ability to induce emesis, with some
drugs such as cisplatin, cyclophosphamide (dose >1500 mg/m2 ) and anthracycline- cyclophosphamide combinations being implicated as highly emetogenic
and induce emesis in up to 90% of the patients receiving the drugs.[5 ]
It is imperative that nausea and vomiting occurring due to chemotherapy must be prevented
and treated optimally. For the prophylaxis of CINV, the drugs primarily included are
NK-1 receptor antagonists, such as aprepitant and fosaprepitant and 5HT3 receptor
antagonists such as ondansetron, granisetron and palonosetron, and dexamethasone.[6 ] Apart from this, other drugs used are olanzapine, metoclopramide, domperidone, etc.[7 ]
There is a dearth of data on the efficacy of the treatment of CINV from the Indian
subcontinent. There are no standard guidelines present from this region to suggest
the appropriate drug therapy for the prevention and treatment of CINV.
Thus, the present study was undertaken to observe the antiemetics prescribed to prevent
and treat CINV and their efficacy for patients with breast cancer planned to receive
highly emetogenic chemotherapy (HEC).
Subjects and Methods
The study was conducted over a period of 12 months in the Day Care Ward of the Cancer
Research Institute after obtaining written informed consent. The study was conducted
in accordance with the principles of the Declaration of Helsinki and after obtaining
clearance from the institutional ethics committee. A total of 71 patients diagnosed
with breast cancer were included in the study and were followed up until the third
cycle of chemotherapy.
Previously untreated patients (chemotherapy-naïve) female patients in the age group
18–65 years, newly diagnosed with breast cancer, post-surgery for tumor removal, and
planned to receive HEC were included in the study after obtaining written informed
consent.
Any patients planned to receive concurrent radiotherapy, patients with metastatic
tumors, patients with a history of previous exposure to chemotherapy, and pregnant
or lactating females were excluded from the study.
Demographic details including the age, weight, height, body mass index, and body surface
area were recorded in case recording forms and any relevant medical and personal history
was collected from the patients as well as caretakers. This included a history of
motion sickness and morning sickness. The patients were prescribed antiemetic regimens
as per the physician's preference and could be modified in subsequent cycles depending
upon the experience of the patient.
The intensity of nausea was assessed based on a 10-point visual analog scale (VAS).
0 in the VAS corresponded to no nausea at all and 10 in the VAS corresponded to the
worst possible nausea. The VAS responses were recorded at 0 h, 6 h, 24 h, 48 h, and
120 h postchemotherapy.
The patients were given an Emesis Diary and were instructed on how to fill the diary.
The patients were instructed to record the frequency of vomiting episodes and any
need for rescue medications. The frequency of vomiting episodes and the need for rescue
medication were analyzed in the acute and delayed phase, as well as the overall phase
for the different antiemetic regimens given to the patients.
A detailed analysis of the antiemetic drugs prescribed was done based on feedback
given by the patient. Patients were similarly assessed at subsequent cycles, till
three cycles of chemotherapy.
Data management and statistical analysis
All of the data from the case recording forms and questionnaire were entered in a
master chart on Microsoft Excel for the analysis. The statistical analysis was based
on standard descriptive statistical tests using Microsoft Excel and Statistical Package
for the Social Sciences version 20.0 (SPSS, Inc.; Chicago, IL, USA) for Windows. The
demographic data and VAS scores were represented as mean ± standard deviation and
a history of morning and motion sickness was depicted in terms of frequency. The efficacy
of the antiemetic regimes was assessed by comparison of the mean scores of VAS by
the independent t -test. The chemotherapy regimens prescribed along with the antiemetic regimen used
are depicted in frequency and percentage. The vomiting frequency, need for rescue
medication, and complete response were expressed in frequency and percentages.
Results
Seventy-one patients recently diagnosed with Carcinoma Breast who received adjuvant
HEC were included in the study. All of these patients had undergone surgical tumor
removal before starting chemotherapy. All of these patients had been prescribed chemotherapy,
followed by hormone therapy and radiotherapy. Sixty-seven patients (94%) had been
diagnosed with infiltrating ductal carcinoma of the breast. The mean age of the patients
included in the study was 51.49 ± 10.81 years. The minimum age was 27 years and the
maximum age was 65 years. Forty-one patients reported a positive history of morning
sickness and 35 patients gave a positive history of motion sickness [Table 1 ].{Table 1}
Table 1
Demographic profile and clinical characteristics of patients with breast cancer receiving
highly emetogenic chemotherapy (n =71)
Criteria
Subjects (n =71)
Values expressed as mean±SD. SD: Standard deviation
Age (years)
51.49±10.81
Weight (kg)
63.28±11.22
Height (cm)
155.48±6.05
Body surface area (m2 )
1.64±0.16
Body mass index (kg/m2 )
26.22±4.36
History of morning sickness
41
History of motion sickness
35
History of motion and morning sickness
25
Of the 71 patients analyzed, 21 patients received a combination of Adriamycin and
cyclophosphamide and 50 patients received epirubicin along with cyclophosphamide [Table 2 ].
Table 2
Highly emetogenic chemotherapy regimens prescribed in patients with breast cancer,
along with mean doses prescribed (n =71)
Regimen number
Number of patients
Regimen
Dose (mg)
PET – Positron emission tomography
1
50
Epirubicin
154.2±9.18
Cyclophosphamide
925±136.5
2
21
Adriamycin
86.36±7.1
Cyclophosphamide
872±82.2
All patients (n = 71) were prescribed premedication in with at combination of ondansetron and dexamethasone
intravenously at a dose of 8 mg each or a dose of 16 mg each. Along with this, in
the first cycle, 48 patients were prescribed an aprepitant kit, given as 125 mg orally
on the 1st day of chemotherapy and followed by a maintenance dose of 80 mg orally
on days 2 and 3. The antiemetic regimens prescribed were as per the treating physician's
discretion and were modified in subsequent cycles based on the feedback given by the
patient as per her experience in the prior cycle. Thus, six patients in the second
cycle were escalated to a regimen containing aprepitant and four more in the third
cycle were prescribed additional aprepitant [Table 3 ]. In all cycles, the patients were given ondansetron three times a day for 5 days,
as well as rescue medication in case the patient experienced more nausea or increased
frequency of vomiting episodes. In case of severe nausea or vomiting, patients were
prescribed injection granisetron 3 mg intravenously.
Table 3
Antiemetic regimens prescribed in patients with breast cancer, along with doses prescribed
(n =71)
Cycle
Ondansetron + dexamethasone (%)
Aprepitant kit + ondansetron + dexamethasone (%)
8 + 8 mg
16 + 16 mg
8 + 8 mg
16 + 16 mg
Cycle 1
2
21
0
48
Cycle 2
2
15
0
54
Cycle 3
0
13
2
56
Total (213)
4 (2)
49 (23)
2 (1)
158(74)
None of the patients in the first cycle required rescue with injection granisetron.
Two patients in the second cycle and one patient in the third cycle received granisetron
as rescue medication.
The mean scores for the intensity of nausea as per the VAS were higher for the patients
who were prescribed ondansetron and dexamethasone alone as compared to patients prescribed
Aprepitant plus ondansetron and dexamethasone. The VAS scores were highly significant
in the triple-drug regimen at 6 h, 24 h, and 48 h postchemotherapy as compared to
the two-drug regimen [Table 4a ]. In the second cycle and third cycles, the mean VAS scores were significantly lower
at 6 h, 24 h, and 48 h postchemotherapy for the patients receiving aprepitant as part
of the antiemetic regimen [Table 4b ] and [Table 4c ].
Table 4a
Comparison of visual analog scale score for intensity of nausea in cycle 1 in patients
receiving antiemetic regimens for highly emetogenic chemotherapy (n =71)
Time (h)
Ondansetron + dexamethasone (n =23)
Aprepitant + ondansetron + dexamethasone (n =48)
P
Independent t -test. Values expressed as mean±SD. SD: Standard deviation
At 0
0
0
At 6
5.30±1.69
2.85±1.01
0.000
At 24
6.13±1.18
4.56±1.24
0.000
At 48
5.57±1.04
3.40±1.16
0.000
At 120
2±0.67
1.65±0.93
0.109
Table 4b
Comparison of visual analog scale score for intensity of nausea in cycle 2 in patients
receiving antiemetic regimens for highly emetogenic chemotherapy (n =71)
Time (h)
Ondansetron + dexamethasone (n =17)
Aprepitant + ondansetron + dexamethasone (n =54)
P
Independent t -test. Values expressed as mean±SD. SD: Standard deviation
At 0
1.24±1.20
0.98±1.55
0.538
At 6
5.41±1.23
3.44±1.21
0.000
At 24
6.12±1.54
4.78±1.67
0.004
At 48
4.53±1.23
3.13±1.21
0.000
At 120
1.94±1.03
1.54±0.93
0.131
Table 4c
Comparison of visual analog scale score for intensity of nausea in cycle 3 in patients
receiving antiemetic regimens for highly emetogenic chemotherapy (n =71)
Time (h)
Ondansetron + dexamethasone (n =13)
Aprepitant + ondansetron + dexamethasone (n =58)
P
Independent t -test. Values expressed as mean±SD. SD: Standard deviation
At 0
0.92±1.12
0.71±1.20
0.554
At 6
5.15±1.21
3.17±1.30
0.000
At 24
6.69±1.75
3.98±0.98
0.000
At 48
4.31±1.55
2.69±0.86
0.003
At 120
2±1
1.41±0.96
0.05
In cycles 2 and 3, patients in both the regimens experienced nausea at 0 h of chemotherapy,
i.e., anticipatory nausea; however, we did not observe a statistically significant
difference in the extent of anticipatory nausea between the two regimens [Figure 1 ].
Figure 1: Visual analog scale scores for intensity of nausea in all cycles in patients
receiving antiemetic regimens for highly emetogenic chemotherapy (n = 71)
In the cycle 1 of chemotherapy, in the overall period (0–120 h), patients reporting
with no episodes of vomiting were higher in patients receiving aprepitant in addition
to ondansetron and dexamethasone as compared to patients who were not prescribed aprepitant
(52% in comparison to 0.4%). Similarly, in the acute phase (<24 h), 91.6% of the patients
receiving a regimen of aprepitant along with ondansetron and dexamethasone reported
no incidence of vomiting as compared to 47.8% of the patients in the ondansetron and
dexamethasone group. In the delayed phase (>24 h), 54% of the patients said that they
experienced no episode of vomiting when prescribed the aprepitant regimen, as compared
to 13% of patients on ondansetron and dexamethasone regimen. Similar results were
observed in the second and third cycles as well [Table 5 ].
Table 5
Comparison of frequency of no emesis in the acute, delayed, and overall phase in patients
receiving antiemetic regimens for highly emetogenic chemotherapy (n =71)
Cycle
Regimen (n )
Acute phase (<24 h) (%)
Delayed phase (24- 120 h) (%)
Overall phase (0- 120 h) (%)
At 1: Ondansetron + dexamethasone, At 2: Aprepitant + ondansetron + dexamethasone
Cycle 1
At 1 (23)
11 (47.8)
3 (13)
1 (0.4)
At 2 (48)
44 (91.6)
26 (54)
25 (52)
Cycle 2
At 1 (17)
11 (64.7)
3 (17.6)
3 (17.6)
At 2 (54)
44 (81.4)
37 (68.5)
34 (63)
Cycle 3
At 1 (13)
8(61.5)
4 (30.7)
3 (23)
At 2 (58)
53 (91.3)
46 (79.3)
40 (69)
Further, in our study, none of the patients prescribed either antiemetic regimen reported
a complete control of symptoms, i.e., no nausea, no emesis, and no need for rescue
medication across any of the cycles of chemotherapy.
In our study, five patients had adverse drug reactions which were possibly linked
to the antiemetic regimens used. Three patients reported urticaria after injection
ondansetron and were prescribed antihistaminic drugs for the same. Two patients reported
constipation, which likely could be due to ondansetron, and were treated with stool
softeners. None of the patients reported any serious adverse effects linked to the
antiemetic regimens.
Discussion
The impact of the diagnosis and treatment of cancer is not only on the physical domain
of well-being but also on the emotional, social, and spiritual aspects of a person.[8 ] Chemotherapy as such, by default, results in definite adverse effects as well as
long-term sequelae such as neutropenia, anemia, and bone marrow suppression along
with gastrointestinal adverse effects like nausea and vomiting, mucositis, and diarrhea.[9 ] All these adverse effects may translate to noncompliance to the treatment protocol
or a higher cost of treatment to be paid by the patient.[10 ]
Nausea and vomiting is a very distressing side effect induced by chemotherapy for
solid tumors which not only occurs very commonly in almost 70%–80% individuals but
is also recurrent, that is, the patient will experience it during every subsequent
cycle as well.[11 ] This can lead to nonadherence to the chemotherapeutic treatment, which can affect
disease progression and recurrence. Further, nausea and vomiting has severe effects
on the quality of life with impaired functioning, increased anxiety, or depression.[3 ]
Despite the best efforts to optimize the use of antiemetics, patients still experience
nausea and/or vomiting during and after chemotherapy, especially with HEC. The efficacy
of different antiemetics can vary according to various factors such as patient characteristics,
the type of chemotherapy received as well as the site of cancer tumors.[12 ] The addition of NK1 receptor antagonists to the antiemetic regimens has yielded
a better armament for tackling CINV.
The most frequently used antiemetic regimen in our study was a combination of NK1
receptor antagonist, aprepitant along with 5-HT3 receptor antagonist, ondansetron
and dexamethasone, followed by ondansetron with dexamethasone in all the three cycles
of solid tumors.
The NK1 receptor antagonist prescribed in our study was a 3-day regimen of oral aprepitant.
Along with this, patients were given premedication either with 8 mg or 16 mg each
of ondansetron and dexamethasone, both given intravenously. A maintenance dose of
oral ondansetron was also prescribed thrice a day for 5 days and to be taken as per
the requirement as rescue medication. All doses prescribed were as per the treating
physician's empirically based discretion.
We observed a deviation in the doses used for antiemetic drugs as compared to internationally
used regimens. In a study done by Dranitsaris et al ., patients were prescribed either a combination of ondansetron and dexamethasone
added to aprepitant or only a regimen of ondansetron and dexamethasone. However, the
regimen varied from our study as patients were premedicated with dexamethasone 12
mg given intravenously and ondansetron 8 mg given orally, repeated after 8 h.[13 ] A variation in the dosage regimen has reflected in the incomplete control of nausea
and vomiting with the antiemetic regimens used in our study.
The patients reported anticipatory nausea as observed on the VAS in cycle 2 and cycle
3 at 0 h. The anticipatory nausea was lesser in the aprepitant containing regimen
as compared to the ondansetron and dexamethasone containing regimen.
In a study done by Molassiotis et al ., they explored the incidence of anticipatory nausea in patients in successive chemotherapy
cycles. They concluded that in patients receiving the second and third cycles of chemotherapy,
there was a significant increase in patients presenting with anticipatory nausea,
similar to our results.[14 ]
Profoundly symmetrical graphs are obtained when comparing VAS scores in the three
cycles. There is a very minor difference in the intensity of nausea between the three
cycles; thus, repeated exposure has not significantly reduced the susceptibility of
the patients to experience nausea.
In our study, in the acute phase of cancer chemotherapy, the incidence of no emesis
was better with the three-drug combination, containing aprepitant as compared to the
two-drug regimen over the acute, delayed as well as overall phase. Similar results
were observed across the second and third cycles of chemotherapy as well confirming
the results of a study by Hilarius et al . in their investigation in a community hospital in daily practice.[15 ] In their study, they observed that the control of emesis in the delayed phase did
not vastly differ between the regimens which contained aprepitant as compared to the
regimen without aprepitant. In contrast, we observed a marked difference in the delayed
phase, an effect that may be explained by the longer action of aprepitant which persists
beyond the acute phase.
Present guidelines for patients receiving HEC suggest the use of an NK 1 receptor
antagonist along with premedication with ondansetron and dexamethasone for the adequate
control of CINV, as well as additional prescription of olanzapine and dexamethasone
on the subsequent days.[5 ]
The primary reason for inadequate prescription of the NK1 receptor antagonist was
probably a lack of sensitization of physicians, as well as a lack of awareness of
the latest recommendations. Due to inadequate knowledge of the advantages of olanzapine
or dexamethasone, they were possibly not included in the antiemetic regimen of the
patients in the maintenance dose as suggested by international guidelines. A suboptimal
utilization of aprepitant as a prophylactic drug is most likely due to the socioeconomic
constraints of the patients. The addition of aprepitant increases the cost incurred
by the patient drastically as compared to a prescription of ondansetron–dexamethasone
alone. In a resource-poor setting like India, a due consideration has to be made for
the ability of the patients to afford the additional cost of aprepitant or other drugs
of the same class.[16 ]
Some of our study limitations were inadequate sample size, as well as a possible bias
due to the subjective nature of nausea. As our study sample consisted of only breast
cancer patients, the assessment for other cancers may be inadequate. Further, a cost
analysis can be performed to assess the economic impact of the control of CINV. This
study can further be expanded to include different emetogenicity of chemotherapeutic
regimens and different regimens of antiemetic drugs as well as can be investigated
by the specific site of cancer to get a better impression of the extent of CINV.
Conclusion
For any patient being treated for cancer, the occurrence of CINV is a disturbing and
immediate adverse effect that drastically effects the life of the patient. In our
study, a statistically significant difference in VAS scores between the regimens was
observed. In addition, we observed that with a combination of aprepitant, ondansetron,
and dexamethasone, the control of CINV was better as compared to a regimen without
aprepitant. Thus, more patients reported a better response, in terms of no emesis
when prescribed aprepitant. Still, a lot needs to be done to achieve a complete cure
in our setting. There is a constant need for constructing an evidence-based regimen
that can be uniformly applied to optimize the efforts to control and treat this disturbing
adverse effect of chemotherapy. Due consideration can be made to try and maximize
the effectiveness of the antiemetic regimen to ensure patient compliance to chemotherapy.
Acknowledgments
The authors would like to sincerely acknowledge the contribution of Himalayan Institute
of Medical Sciences and Cancer Research Institute, Himalayan Hospital Dehradun. The
authors humbly thank the guidance provided by the faculty and staff of the Department
of Pharmacology and Department of Medicine, HIMS, Dehradun. We would like to extend
our gratitude to all colleagues for the support and encouragement.
