Hiccups commonly occur in patients undergoing chemotherapy for lung cancer and may diminish their motivation for treatment. Therefore, it is important to characterize the hiccups and their risk factors. We examined the medical records of 120 patients with lung cancer during their initial chemotherapy and extracted data on the patients’ profiles and the onset, duration, and severity of their hiccup episodes. We found the incidence of hiccups to be 19.2% among the patients. Hiccups appeared within 3 days of beginning the chemotherapy and disappeared within 4 days. Hiccups hindered sleep in two patients. The characteristics of the hiccups episodes in our study were not different from those of previous studies. We also investigated distinctive features of the patients who developed hiccups. The occurrence of hiccups was associated with gender, age, and the treatment with platinum agents. Antiemetic agents, dexamethasone and neurokinin-1 receptor antagonists, also showed significant effects on hiccup episodes. Although the dose-responsive effect of dexamethasone on hiccups was insignificant and the effects of two neurokinin-1 receptor antagonists, aprepitant and fosaprepitant, on hiccups appeared identical. From these results, we suggest that a high incidence of hiccups may be anticipated with a prophylactic use of antiemetic agents, dexamethasone and neurokinin-1 receptor antagonists.
Hiccups are common physical phenomena noted by a specific “hic” sound that is produced by involuntary contractions of respiratory muscles (including diaphragm and intercostal and anterior scalene muscles) followed by a sudden closure of the vocal cords [
Indeed, rare intractable hiccups may indicate the existence of serious underlying problems in patients. Some pharmacological agents are also known to be risk factors for hiccups [
This is a single-center retrospective cohort study investigating the characteristics and associated risk factors of hiccups during the first chemotherapy cycle in patients with lung cancer.
We retrospectively examined the medical records of all inpatients who received their first chemotherapy cycle for lung cancer in the National Hospital Organization East Saitama Hospital from October 2011 to March 2013. Participants were followed 3 weeks after the beginning of chemotherapy. Exclusion criteria were as follows: those who tolerated chemotherapy poorly and those already with hiccups episodes before the beginning of their chemotherapy. All patients were treated with cisplatin, carboplatin, or with non-platinum-based antineoplastic drugs (non-Pt). Cisplatin was injected at doses of 70 to 90 mg/m2 on day 1. Carboplatin was injected at doses of 5 - 6 AUC on day 1. In addition, all patients received antiemetics including dexamethasone, 5-hydroxytryptamine receptor antagonist (5-HT3RA), and/or neurokinin-1 receptor antagonist (NK1RA) before and during chemotherapy to prevent or minimize chemotherapy-related emesis. One of two doses of dexamethasone was administered to each patient. In dexamethasone 6.6 mg group (DEX 6.6 mg), 6.6 mg of dexamethasone was injected on day 1 while in dexamethasone 16.5 mg group (DEX 16.5 mg), 16.5 mg of dexamethasone was injected on day 1 and 6.6 mg on day 2 and 3. Regarding 5HT3 RA administration, granisetron was injected at a dose of 3 mg on day 1 or palonosetron was injected at a dose of 0.75 mg on day 1. For NK1RA, aprepitant was orally administered at a dose of 125 mg on day 1 and 80 mg on day 2 and 3 or fosaprepitant was injected at a dose of 150 mg on day 1. Neuroleptic agents were also used according to clinical needs.
In this cohort, we tried to answer two questions related to hiccups during anticancer treatment: 1) what were the characteristics of the hiccups and 2) what factors influenced the occurrence of hiccups. The severity of hiccups was determined using a grading scale created by the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0), consisting of three grades: Grade 1 includes only the hiccups and does not require treatment, Grade 2 includes hiccups that require treatment, and Grade 3 includes hiccups that significantly hinder sleep and daily life. Information on patient clinical characteristics, laboratory data, and medication were collected from the medical records. Data on the occurrence, frequency, duration, and severity of hiccups were all used in the analysis. Medical records of hiccups used in the present study were carefully monitored on the bed side.
Data are expressed as mean ± standard deviation. Categorical variables are expressed as numbers, frequencies, and percentages. Comparisons between the group with hiccups and the group without hiccups were performed using the Mann-Whitney U-test, chi-square test or the fisher’s exact test, as appropriate. To identify risk factors for hiccups. A P value of <0.05 was considered significant. All statistical analyses were performed using JMP® Pro 13.1.0 (SAS Institute Inc., Cary, NC, USA).
This retrospective study using medical records was undertaken with the approval of the Ethics Committee of the hospital. We complied with the Declaration of Helsinki and the Ethical Guidelines for Epidemiological Research.
Of a total of 120 Japanese patients admitted for receiving their first chemotherapy cycle for lung cancer, none was excluded based on the exclusion criteria. Hiccups were observed in 23 of 120 patients undergoing the initial chemotherapy cycle for lung cancer. All patients developed hiccups within 3 days of beginning the chemotherapy, and the episodes lasted for a maximum of 4 days (
patients, 2 days in eleven patients, 3 days in six patients, and 4 days in one patient (
Regarding the severity of hiccups, eleven patients had grade level 1 hiccups, ten patients grade level 2, and two patients grade level 3 (
The baseline characteristics of the patients who experienced hiccups were similar to those of the patients without hiccups, except for gender, age and use of anticancer agents and antiemetics agents (
The incidence of hiccups increased in patients using dexamethasone as an antiemetic. For details, the incidence of hiccups in patients treated with 6.6 mg of dexamethasone as well as the cisplatin based chemotherapy was 38.9% and that in patients using carboplatin was 20.0%, whereas the incidence of hiccups in patients using non platinum based chemotherapy was 12.5% (
Parameter | No. of Patients | Patients with Hiccups | ||
---|---|---|---|---|
No. of Patients | % | P | ||
Total | 120 | 23 | 19.2 | |
Gender | 0.006 | |||
Male | 97 | 23 | 23.7 | |
Female | 23 | 0 | 0.0 | |
Age | 71.6 ± 8.2 | 68.5 ± 6.5 | 0.045 | |
Staging | 0.520 | |||
1 | 4 | 1 | 25.0 | |
2 | 8 | 0 | 0.0 | |
3 | 30 | 7 | 23.3 | |
4 | 78 | 15 | 19.2 | |
Performance Status | 0.093 | |||
1 | 106 | 18 | 17.0 | |
2 | 8 | 2 | 25.0 | |
3 | 5 | 2 | 40.0 | |
4 | 1 | 1 | 100.0 | |
Lung surgery | 65 | 9 | 39.1 | 0.108 |
Brain metastasis | 17 | 3 | 13.0 | 0.864 |
Diaphragm metastasis | 28 | 6 | 26.1 | 0.728 |
Medication history | ||||
Platinum antitumor agent | 77 | 20 | 26.3 | 0.014 |
Antiemetic agent | ||||
DEX | 101 | 23 | 22.8 | 0.022 |
5HT3RA | 107 | 23 | 21.5 | 0.154 |
NK1RA | 87 | 21 | 24.1 | 0.048 |
DEX, dexamethasone; 5HT3RA, 5-hydroxytryptamine receptor antagonists; NK1RA, Neurokinin 1 receptor antagonists.
In patients using NK1RA as an antiemetic, the incidence of hiccups was increased as shown in
Patients with Hiccups (n = 23) | Patients without Hiccups (n = 97) | P | ||||||
---|---|---|---|---|---|---|---|---|
No. | % | No. | % | Within the group | vs. a | vs. b | vs. c | |
Non platinum based chemotherapy | NE | |||||||
None | 0 | 0.0 | 19 | 100.0 | ||||
DEX 6.6 mg | 3 | 12.5 | 21 | 87.5 | 0.164 | |||
DEX 16.5 mg | 0 | 0.0 | 0 | 0.0 | ||||
CBDCA based chemotherapy | NE | |||||||
None | 0 | 0.0 | 0 | 0.0 | ||||
DEX 6.6 mg | 11 | 20.0 | 44 | 80.0 | 0.029 | 0.323 | ||
DEX 16.5 mg | 2 | 50.0 | 2 | 50.0 | 0.208 | 0.024 | ||
CDDP based chemotherapy | NE | |||||||
None | 0 | 0.0 | 0 | 0.0 | ||||
DEX 6.6 mg | 7 | 38.9 | 11 | 61.1 | 0.003 | 0.053 | 0.970 | |
DEX 16.5 mg | 0 | 0.0 | 0 | 0.0 |
CDDP, cisplatin; DEX, dexamethasone; NE, not examined; a, None in the Non platinum based chemotherapy; b, DEX 6.6 mg in the Non platinum based chemotherapy; c, DEX 6.6 mg in the CBDCA based chemotherapy.
Patients with Hiccups (n = 20) | Patients without Hiccups (n = 62) | P | ||||
---|---|---|---|---|---|---|
No. | % | No. | % | Within the group | Between the groups | |
CBDCA based chemotherapy | 0.760 | |||||
Aprepitant | 5 | 22.7 | 17 | 77.3 | ||
Fosaprepitant | 8 | 19.5 | 33 | 80.5 | ||
CDDP based chemotherapy | 0.141 | |||||
Aprepitant | 4 | 57.1 | 3 | 42.9 | 0.108 | |
Fosaprepitant | 3 | 25.0 | 9 | 75.0 | 0.797 |
CBDCA, carboplatin; CDDP, cisplatin.
In the present study, hiccups developed in 23 patients with lung cancer during their first cycle of chemotherapy. Hiccups appeared within 3 days of beginning the chemotherapy, and the mean duration of hiccups was 3 days. The severity of hiccups varied from grade 1 to grade 3. Because female patients did not develop hiccups, there was definitely a male dominance. Comparison analyses between the group of patients with hiccups and the group of patients without them revealed that gender, age, platinum antitumor agents, dexamethasone, and NK1RA are associated with the increased incidence of hiccups in patients with lung cancer undergoing chemotherapy.
The characteristics of the hiccups episodes in our study were not different from those of previous studies. Hiccups occurred in 23 (19.2%) out of 120 patients, which is at an intermediate point in the reported 5% - 40% [
Hiccups observed during chemotherapy are considered medication-related symptoms. In the present study, we found an increased incidence of hiccups in patients on the platinum antitumor agents and on antiemetics agents including dexamethasone and NK1RA.Hiccups have been shown to be one of the adverse effects of platinum antitumor agents [
An antiemetic medication is recommended before the infusion of platinum antitumor agents [
The use of NK1RA may also have played a role in the development of hiccups because we observed an increased use of the agent in the group of patients with hiccups in the present study. Studies have shown the incidence of hiccups varied from 19% to 33% in patients who were treated with NK1RA [
Our study was a small-scale, retrospective, single-center study including older Japanese patients; thus, the results could not be directly extended to larger and younger populations or to other ethnic groups. However, medical records used in the present study were carefully monitored on the bed side. Because, mild hiccups are only occasionally reported on a self-reporting system.
In conclusion, we found that gender, age, and uses of platinum antitumor agents, dexamethasone, and NK1RA were risk factors for hiccups in patients with lung cancer. On the incidence of hiccups, we never observed dose responsive effects of dexamethasone or different effects between aprepitants and fosaprepitant. Therefore, to avoid hiccups in patients with lung cancer, we suggest caution on the use of dexamethasone and NK1RA in male and some certain-aged patients with lung cancer during their chemotherapy.
We declare that we have no conflict of interest.
The authors would like to thank K. Aoyama, and S. Ishibune for their help in preparing the manuscript.
Toriumi, S., Nakazawa1, K. and Shoji, M. (2018) Effect of Antiemetic Agents on Hiccups during Chemotherapy in Patients with Lung Cancer. Pharmacology & Pharmacy, 9, 124-133. https://doi.org/10.4236/pp.2018.94010