A postal survey of maternal sleep in late pregnancy

Lynne Hutchison
Peter R Stone
Lesley Me Mccowan
Alistair W Stewart
John Md Thompson
Edwin A Mitchell
A postal survey of maternal sleep in late pregnancy
R E S E A R C H A R T I C L E Open Access
Background: Sleep disturbances in late pregnancy are common. This study aimed to survey sleep problems in third trimester pregnant women and to compare sleep in the pre-pregnancy period with the third trimester. Methods: Third-trimester women (n=650) were sent a postal survey containing questions relating to sleep experience, including perceived sleep quality, sleep difficulties, night waking, sleep environment, snoring, daytime tiredness and daytime napping. Time periods reported on were before pregnancy and in the last week. Results: Respondents numbered 244 (38%). Before pregnancy, the mean reported duration of night-time sleep was 8.1 (SD 1.1) hours; in the last week this had decreased to 7.5 (SD 1.8) hours (p<.0001). Only 29% rated their sleep quality in the last week as very good or fairly good, compared with 82% rating their sleep this way before the pregnancy. The main reasons for sleeping difficulties were discomfort (67%) and pain (36%). Snoring increased significantly over the course of the pregnancy, with 37% reporting snoring often or every night in the last week. Those with a pre-pregnancy body mass index of greater than 25 were significantly more likely to snore (p=.01). Only 4% of women had an abnormal Epworth Sleepiness Scale score (i.e. >10) prior to pregnancy, whereas in the last week 33% scored in the abnormal range. Likewise, 5% had regularly napped during the daytime before pregnancy, compared with 41% in the last week.Conclusions: Sleep problems are common in women in late pregnancy, and increase markedly compared with before pregnancy.

Background

Sleep problems in pregnancy are common, with most pregnant women reporting declining sleep quality and increased night waking especially in the third trimester [1][2][3][4][5][6]. Studies have found that 82-98% of women in late pregnancy report waking at night [2,3,6], and 64% -86% report problems with sleep quality during pregnancy [4]. Insomnia and increased wakefulness after sleep onset can result from a large number of potential causes including gastro-oesophageal reflux, discomfort, frequent micturition, and dyspnoea [1,2,5]. Poor sleep quality and lowered sleep duration have been associated with a higher incidence of preterm birth [7] and glucose intolerance and gestational diabetes in pregnancy [8,9]. Furthermore, a number of studies have shown an increased frequency of snoring and sleep disordered breathing as pregnancy progresses which may contribute to the increased incidence of glucose intolerance [9] and pregnancy induced hypertension [10].

This study aimed to assess sleep practices and sleep quality in women in the last trimester of pregnancy, and to document self-reported changes that occurred between the pre-pregnancy period and the last trimester of pregnancy.

Methods

In September 2011, survey questionnaires were posted to 650 pregnant women randomly selected from all women (n=1597) who were between 27 and 38 weeks gestation on the booking list at National Women's Health (NWH), a large maternity unit in Auckland, New Zealand. The questionnaire contained questions relating to their sleep experience both before becoming pregnant and in the last week. Questions included maternal demographics, perceived sleep quality, sleep difficulties, night waking, snoring, daytime tiredness, and daytime napping. Questions relating to sleep quality were based on the Pittsburgh Sleep Quality Index (PSQI), a 9-question self-rated test intended to measure sleep disturbances and quality of sleep [11]. Sleep disordered breathing questions were based on the Berlin Sleep Questionnaire (BSQ), a 10-item screening test designed to predict sleep apnea and sleep disordered breathing [12]. Participants also completed the Epworth Sleepiness Scale (ESS) to assess daytime sleepiness [13]. The ESS asks people to rate, on a 4-point scale (0 -3), their usual chances of dozing off or falling asleep in eight different situations or activities that most people engage in as part of their daily lives. The total ESS score is the sum of 8 item-scores and can range between 0 and 24. The higher the score, the higher the person's level of daytime sleepiness. We did not use questions from the PSQI and BSQ relating to blood pressure and areas already covered in the ESS. Additional questions were also posed in order to expand understanding of the respondents' experience specific to pregnancy. Additionally, the questionnaire asked the mother to report on her height, pre-pregnancy weight, ethnicity, smoking status at the time of the survey, parity and due date.

Statistical analysis was carried out using SAS (Version 9.1, SAS Institute Inc., Cary, NC, USA). Chi-squared analysis was used for categorical variables and t-tests were performed for continuous variables. The study complied with the Helsinki Declaration and was approved by the NZ Ministry of Health's Northern Regional X Ethics Committee; reference number NTX/11/EXP/172.

Results

In total, 650 survey forms were mailed; 252 were returned. Eight forms were excluded as these women reported they had already delivered their infants by the time they received the questionnaire, leaving 244 (38%) completed surveys included in the study. Apart from gestational age, no information was available on the non-respondents. Respondents were mostly of NZ European ethnicity, with a median age of 33 years and a median gestation of 36 weeks. Forty-five percent had no previous children; a further 37% had one child and 15% had two children. Characteristics of the respondents are outlined in Table 1.

Sleep duration and quality

Before pregnancy, the mean number of hours of night-time sleep was reported by mothers to be 8.1 (SD 1.1) hours; in the last week this had decreased to 7.5 (SD 1.8) hours (p<.0001). Thirty-two percent reported sleeping less than 7 hours per night and 16% had slept less than 6 hours per night in the last week, compared with reported rates of 9% and 2% respectively before pregnancy (p=<.0001). Using paired t-tests, it was seen that overall the participants' mean sleep duration had reduced by a mean of 35.8 (SE 0.10) per night minutes in the last week compared with before pregnancy (p=.0001). Individually however, 31% of women reported an increase in night time sleep hours.

Perceived sleep quality deteriorated over the course of the pregnancy, with 82% rating their sleep quality as very good or fairly good before pregnancy, compared with 29% rating their sleep this way in the last week. Thirty-eight percent rated their sleep as fairly bad or very bad in the last week, compared with only 4% before pregnancy. Likewise, in the last week 96% of respondents reported needing to go to the toilet during the night and for 65% of these women this was at least twice a night. Difficulty falling asleep and getting back to sleep, restless sleep, and needing to change sleep positions during the night were all problems that worsened during the pregnancy (Table 2). Women in the later stages of the last trimester woke significantly more often at night than those in the earlier stages (p=0.04). Compared to those at 28 to 32 weeks gestation (mean wakings 2.1 [SD 1.2]), the number of reported night wakings of women at 32 to 36, 34 to 36, 36 to 38 and ≥38 weeks was significantly higher, at 2.8 (SD 1.5), 3.3 (SD 2.0), 3.0 (SD 1.6), and 3.4 (SD 2.1) respectively ( Figure 1).

Reasons for difficulty sleeping

Before pregnancy, the predominant reason for having trouble sleeping was "things on my mind" (51%); however, by the third trimester, this was superseded by discomfort (67%), although pain and "things on my mind" still featured in 36% of respondents. Other physical discomforts such as heartburn, feeling hot, and trouble breathing comfortably were also significantly increased in the last week (Table 3). When asked "What usually wakes you in the morning?" the most common reason in the last week was the need to go to the toilet (33%), whereas before pregnancy this accounted for only 3% of awakenings.

Snoring

One hundred and fifty three women (63%) had ever been told they snored. Snoring increased significantly over the course of the pregnancy, with 28% reporting snoring three or more nights in the last week compared with 4% prior to pregnancy (Table 4). Snoring loudness also increased over this period, but being told that they had stopped breathing while snoring was reported in very few women either before pregnancy or in the last week. Of those who snored in the last week, 58% said it did not bother others. Those with a pre-pregnancy body mass index (BMI) ≥25 were significantly more likely to snore than those whose BMI was <25 (78% vs 59% respectively; p=.01).

Daytime sleepiness

Approximately half of the mothers were still tired after their night sleep compared with only 10% of them reporting that they had felt this way before pregnancy. In the last week, 41% had napped during the daytime, with the median nap time being 90 minutes [IQR=(60, 120)]. However, the total reported hours of sleep per 24 hours (daytime naps plus nighttime sleep hours) before pregnancy and in the last week did not differ significantly: 8.6 (SD 1.3) versus 8.7 (SD 2.0) hours respectively. Paired t-tests of the total scores on the Epworth Sleepiness Scale revealed that women's Epworth scores reduced overall by 4.4 (SE 0.28, p<0.0001) in the period between prior to pregnancy and the last week. Only 6.5% of women had an increased Epworth score in the last week compared with before pregnancy. When categorised according to the official ESS criteria (i.e. total score of 0 -10 is normal and greater than 10 is abnormal) [14], 4% of women had an abnormal score prior to pregnancy, whereas 33% scored in the abnormal range in the last week (Table 5).

Discussion

Sleep problems in late pregnancy are common. In this study we have provided an in-depth survey of sleep practices and symptoms in the third trimester of pregnancy and compared this with pre-pregnancy sleep in the same women.

Compared with pre-pregnancy, and consistent with other studies [2,3,6,9,15], we have shown a reduction in maternal sleep quality in the third trimester compared with before pregnancy. Much of the reduction in quality appears to be the result of night waking, which was almost universal in this group of mothers, particularly in the latter part of the third trimester, for reasons of nocturia, discomfort, pain and general restlessness.

Sleep duration decreased in the third trimester compared with before pregnancy, dropping from a mean of 8.1 hours to 7.5 hours a night. This contrasts with Hedman et al. [6] whose Finnish respondents reported a sleep duration of 7.8 hours both before pregnancy and in the third trimester. Facco et al. in Chicago analysed self-administered questionnaires from women in early pregnancy and again in the third trimester and showed that mean sleep duration dropped from 7.4 hours early in pregnancy to 7 hours in late pregnancy [9]. In a small Taiwanese study using actigraphy to measure sleep duration in nulliparous women the mean duration of total night time sleep in the third trimester was 6.4 (± 1.0) hours [16].

Those who reported snoring often or every night in the last week comprised 28%, slightly higher than others have shown using self-reported data (10% -25%) [1,2,6]; however, Izci et al. used partner reports to determine the presence and frequency of snoring, and found that 35% to 39% were frequent snorers [17,18]. That group also investigated the pathophysiology of snoring and showed that in the third trimester of pregnancy the upper airways are significantly narrower than in non-pregnant women [18], and that the difference was only in the seated position but not when the subjects were supine [19]. This possibly acts  as a protective mechanism against the effects of supine position on upper airways in late pregnancy. Daytime fatigue also increased significantly over the course of the pregnancy with 33% of third-trimester women having an ESS total score >10. Consistent with this finding, Pien et al. from the University of Pennsylvania showed that in the month of delivery 45% of pregnant women scored >10 [4] while in a Scottish study 23% of third trimester women scored >10 [17]. In an Australian study, 11% of non-pregnant adults without evidence of a chronic sleep disorder scored >10 [14]. Whether variations in sleep duration and daytime fatigue relate to local lifestyle factors in different parts of the world is unknown.

Apart from the mechanical and physical effects of increased size and weight in late pregnancy, especially as these affect general fatigue and sleep disordered breathing, sleep in pregnancy may also be influenced by hormonal changes. While these changes were not measured in this survey, they are undoubtedly important. The hormones oestrogen, which decreases REM sleep, and progesterone, which increases non-REM sleep, ventilation and respiratory alkalosis, both increase markedly in pregnancy. In addition, a lowered cortisol-melatonin ratio in late pregnancy can result in poor quality of sleep [20]. It is important to consider however, that at this time in a woman's life it may not only be hormonal or physiological factors that are at play. For instance, although sleep duration decreased overall, 31% of the women reported increased sleep duration, perhaps due to stopping work, changing childcare demands, other lifestyle factors, or the perceived need to sleep more because of increased fatigue.

While pregnant women and their obstetric carers may regard pregnancy sleep disorders as normal and to be endured, there is evidence that disrupted sleep and changing sleep practices may influence adverse pregnancy outcomes, and several reviews have commented on this [5,7,21]. An increased risk of preterm delivery [7,22] and postpartum depression [7] have been linked with sleep deprivation, while sleep disordered breathing is associated with gestational diabetes [8,9,21], low birth weight, preterm and small for gestational age infants, caesarean section and preeclampsia [23]. In addition, short sleep duration and severely disrupted sleep are also more likely to be associated with unplanned caesarean deliveries after controlling for infant birth weight [24]. Increased daytime napping and fewer toilet visits at night have been implicated as risk factors for stillbirth [25]. Whilst Stacey et al. reported that daytime sleepiness per se was not related to the incidence of stillbirth [25], increased daytime napping has been associated with sleep disordered breathing, at least in the non-pregnant population [26], and it is not uncommon for patients to underestimate their levels of daytime sleepiness. The current study does not include polysomnography or  measures of fetal outcomes, so we are unable to comment on any potential associations between excessive daytime sleepiness, sleep disordered breathing and fetal health. Interventions to improve sleep and possible adverse pregnancy outcomes may thus be important and further studies are warranted to investigate this area.

The main limitation of this study was the retrospective nature of the questions leading to the possibility of recall bias, particularly for the questions relating to sleep prior to pregnancy. Preferably, the same survey administered to the women both before pregnancy and in the third trimester might have provided a more accurate picture of increased prevalence of sleep related behaviours of pregnancy. However, this would have increased the complexity of the study. Ideally, a polysomnogram would confirm the accuracy of maternal report.

In addition, there is no validated questionnaire for sleep disorders in pregnancy, and although we used questions from other validated tools such as the Pittsburgh Sleep Quality Index, the Berlin Sleep Questionnaire, and the Epworth Sleepiness Scale questionnaires, the relative contributions of common symptoms of pregnancy and true sleep disordered breathing are unclear. In fact, the Berlin questionnaire has been shown to poorly predict sleep disordered breathing in pregnant women [27]. Tiredness and reduced daytime functioning are frequently experienced by pregnant women [18,28], and this potentially compounds the problem of assessing the true prevalence of sleep problems in pregnancy. The validity of retrospective reporting of sleep questions prior to pregnancy has also not been established, although one study in a non-pregnant population has shown a high correlation between baseline ESS and a retrospective re-test 5 months later [29].

Another limitation may be that only 27% of our respondents were in the overweight or obese BMI categories, compared with 48% who were overweight or obese in the 2010 NWH annual report [30]; therefore, the incidence of sleep disordered breathing in our study may be lower than in the NWH population. Thus our results for snoring are likely conservative. Unfortunately we did not have access to information regarding gestational hypertension, pre-eclampsia, or gestational diabetes in the participants and so cannot comment on these conditions in relation to the sleep findings. Notwithstanding these limitations, this study has provided a clearer understanding of the problems, difficulties, and sleep practices experienced by third trimester pregnant women.

Conclusions

Sleep problems were common in this group of women in late pregnancy, and these disturbances were increased comparative to their pre-pregnancy experience. Evidence is emerging that sleep quality, sleep disordered breathing and sleep practices can affect maternal-fetal outcomes and it appears that improving these areas might lessen the impact of adverse fetal outcomes. However, definitive standards of good sleep hygiene for women experiencing the physiological and hormonal changes of late pregnancy have not yet been determined and should be the subject of future research.

Figure 1
1Mean number of times waking at night at each gestational age. Error bars denote standard error of mean.

Table 1
1Characteristics of respondentsCharacteristic
Category
n (%) or
mean (SD)

Maternal age (missing=3)
<20
6 (2.5)

20-34
138 (57.3)

>35
97 (40.3)

Ethnicity (missing=3)
European
150 (62.2)

Other
59 (24.5)

Maori
17 (7.1)

Pacific
15 (6.2)

Marital status (missing=40)
Married
168 (82.3)

De facto
28 (13.7)

Single
8 (3.9)

Current smoker (missing=4)
Yes
10 (4.2)

Sleep with partner (missing=0)
Yes
200 (82.0)

Gestation (weeks) (missing=11)
35.0 (2.7)

Gestation, categorised (weeks)
28 to<32
25 (10.8)

32 to <34
49 (21.1)

34 to <36
42 (18.1)

36 to <38
73 (31.5)

≥38
43 (18.5)

Parity (missing=6)
0
108 (45.4)

1
87 (36.6)

2
35 (14.7)

≥3
8 (3.4)

Pre-pregnancy BMI, calculated (missing=19)
23.8 (4.5)

Pre-pregnancy BMI categorised (missing=19) <18.5
6 (2.7)

18.5 -24.9 159 (70.7)

25.0 -29.9 36 (16.0)

≥30
24 (10.7)

Table 2
2Sleep qualityVariable
Response
Before pregnancy n (%)
In last week n (%)
P-value

Difficulty falling asleep
Never/rarely/
sometimes
218 (90.1)
180 (74.4)
<.0001

Often/every night
24 (9.9)
62 (25.6)

Difficulty getting back to sleep
Never/rarely/
sometimes
224 (92.4)
145 (59.7)
<.0001

Often/every night
19 (7.8)
98 (40.2)

Wake up at night
Yes
66 (27.2)
234 (96.3)
<.0001

Go to toilet at night
Yes
101 (41.9)
232 (95.8)
<.0001

If yes, number of times up to toilet
1
82 (86.3)
77 (35.0)
<.0001

2
7 (7.4)
66 (30.0)

≥3
6 (6.4)
77 (35.1)

Are you a restless sleeper?
No/a little/average
211 (87.2)
105 (43.3)
<.0001

More than average
19 (7.8)
76 (31.4)

Very restless
12 (5.0)
61 (25.2)

Changed sleep position at night
Not lots*
196 (80.9)
105 (43.8)
<.0001

Lots
46 (19.0)
135 (56.3)

Sleep quality self-rating
Very good
124 (51.2)
17 (7.0)
<.0001

Fairly good
75 (31.0)
52 (21.5)

Average
33 (13.6)
81 (33.5)

Fairly bad
10 (4.1)
74 (30.6)

Very bad
0
18 (7.4)

Table 3
3Reasons for difficulty sleepingReason
Before pregnancy n (%)
In the last week n (%)
P-value

Uncomfortable
13 (5.4)
163 (67.1)
<.0001

Pain
5 (2.1)
87 (35.8)
<.0001

Things on my mind
123 (50.6)
87 (35.8)
0.001

Heartburn
1 (0.4)
69 (28.4)
<.0001

Too hot
28 (11.5)
70 (28.8)
<.0001

Can't breathe comfortably
4 (1.6)
56 (23.0)
<.0001

Partner snoring
69 (28.4)
46 (18.9)
0.01

Noise
34 (14.0)
19 (7.8)
0.03

Too cold
29 (11.9)
14 (5.8)
0.02

Partner turning
25 (10.3)
16 (6.6)
0.14

Bad dreams
32 (13.2)
37 (15.2)
0.51

Cough
21 (8.6)
27 (11.1)
0.36

Other
13 (5.4)
30 (12.4)
0.007

Table 4
4Snoring before pregnancy and in the last weekQuestion
Response
Before pregnancy n (%)
In last week n (%)
P-value

How frequently do you snore?
No snoring
116 (51.6)
103 (47.7)
<.0001

1 -2 nights per week
99 (44.0)
52 (24.1)

3 or more nights per week
10 (4.4)
61 (28.2)

Missing
19
28

How loud is your snoring?
No snoring
119 (55.1)
103 (49.5)
<.0001

Minimal / soft
77 (35.6)
47 (22.6)

As loud as talking / very loud
20 (9.3)
58 (27.9)

Missing
28
36

Table 5
5Daytime sleepiness, daytime napping and ESS score ESS = Epworth Sleepiness Scale.Question
Response
Before pregnancy n (%)
In last week n (%)
P-value

How often are you tired after night sleep? (missing=6)
0 -2 times a week
213 (89.5)
113 (47.1)
<.0001

3 -7 times a week
25 (10.5)
127 (53.0)

How often are you tired during day? (missing=6)
0 -2 times a week
218 (91.6)
95 (40.1)
<.0001

3 -7 times a week
20 (8.4)
142 (59.9)

How often do you nap during day? (missing=4)
0 -2 times a week
229 (95.4)
143 (59.3)
<.0001

3 -7 times a week
11 (4.6)
98 (40.7)

Categorised ESS total score
Normal (0 -10)
222 (96.1)
157 (67.1)
<.0001

Abnormal (>10)
9 (3.9)
77 (32.9)

http://www.biomedcentral.com/1471-2393/12/144
* This category consists of the following subcategories: 0, possibly once, possibly twice, >twice but not lots.
AcknowledgementsWe express thanks to the mothers who participated in this survey and to Cure Kids for funding the study. We also acknowledge valuable input from the members of the Maternal Sleep in Pregnancy Study Group: EA MitchellAbbreviations BMI: Body mass index; NWH: National Women's Health; ESS: Epworth Sleepiness Scale; SD: Standard deviation; SE: Standard error; IQR: Inter-quartile range.Competing interestsThe authors declare that they have no competing interests.Authors' contributions BLH developed the questionnaire, carried out the data collection and data entry, performed basic statistical analysis, and drafted the manuscript. LMEM and PRS participated in the planning of the study and contributed to the manuscript. AWS and JMDT contributed to the statistical analysis. EAM conceived of the study, participated in its design and oversaw the project. All authors read and approved the final manuscript.Submit your next manuscript to BioMed Central and take full advantage of:
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Safety and efficacy of cytotoxic chemotherapy in hepatocellular carcinoma after first-line treatment with sorafenib

Leonardo Gomes Da Fonseca
Guilherme Nader
Marta
Maria Ignez Freitas
Melro Braghiroli
Aline Lopes Chagas
FlairJose Carrilho
Paulo Marcelo Hoff
Jorge Sabbaga
Safety and efficacy of cytotoxic chemotherapy in hepatocellular carcinoma after first-line treatment with sorafenib
10.1186/s12885-018-5173-0R E S E A R C H A R T I C L E Open Access
Background: Before the targeted therapies era, cytotoxic chemotherapy (CCT) was an option for advanced hepatocellular carcinoma (HCC), even with the lack of supporting evidence. Since the last decade, sorafenib has been established as the first-line therapy. Although new agents are being incorporated, CCT is still considered in regions where new drugs are not available or for patients who progressed through the approved therapies and remain in good clinical condition. We aimed to describe our experience regarding the use of CCT as second-line treatment after sorafenib. Methods: A database of 273 patients was evaluated. Patients that received CCT after sorafenib progression were selected for the analysis. Descriptive statistics was used for categorical and continue variables. Median survival was estimated with Kaplan-Meier curves. Variables were found to be significant if the two-sided p value was ≤ 0.05 on multivariate testing using the Cox regression model.Results: Forty-five patients received CCT; 33 (73.3%) had Child-Pugh classification A, and 34 (75.6%) had stage C according to the Barcelona Clinic Liver Cancer (BCLC) staging system. The most used regimen was doxorubicin in 25 patients (55.6%). Median overall survival (OS) was 8.05 months (95% confidence interval [CI] 2.73 -9.88 months). The 6-month and 1-year survival probability was 52.4% and 27.36%, respectively. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and disease control with sorafenib was independently associated with better OS in patients treated with CCT. Any-grade toxicities were observed in 82.2% and grade 3-4 in 44.4% of the patients. Conclusion: In accordance with previous studies, CCT had a notable rate of adverse events. The poor prognosis of this cohort suggests that CCT may not alter the natural history of HCC after sorafenib progression.

Background

Hepatocellular carcinoma (HCC) is the sixth most common neoplasm and the third leading cause of cancer-related death [1]. This high rate of mortality is mainly associated with the coexistence of underlying cirrhosis and the considerable proportion of patients diagnosed in advanced stage [2].

For patients in advanced stage and for those who are refractory or have contraindications to locoregional therapies, systemic treatment is recommended. Sorafenib, a multi-kinase inhibitor, showed consistent overall survival (OS) improvement in two phase III placebo-controlled trials and is considered the standard first-line therapy [3,4]. Lenvatinib was shown to be non-inferior to sorafenib in a phase III non-inferiority trial [5]. In the second-line setting, regorafenib improved OS over placebo in patients who were tolerant and progressed on sorafenib [6]. Cabozantinib was also shown to be superior to placebo in terms of OS after at least one previous systemic therapy, including sorafenib, and can be an alternative in the second-line [7].

Before the targeted therapies era, cytotoxic chemotherapy (CCT) was considered a treatment option for advanced HCC. Indeed, in regions where the new agents are not available or for patients who progressed after the available therapies and remain in good clinical condition, CCT is still being considered albeit there is no high level of evidence.

Historically, doxorubicin was widely adopted in clinical practice although there was no proven benefit in terms of OS and safety [8]. Likewise, polychemotherapy with the PIAF regimen (cisplatin, interferon, doxorubicin and 5-fluorouracil) did not show significant survival benefit over doxorubicin and was associated with increased treatment-related toxicities [9]. In a phase III trial conducted in Asia that compared FOLFOX4 with doxorubicin, the median progression-free survival (PFS) favoured FOLFOX4, but there was no difference in OS between the two arms [10].

Even though the published results on CCT for HCC are disappointing, there are no randomised prospective trials that addressed a head-to-head comparison between CCT and sorafenib in the first-line setting or with other drugs as second-line therapy. Evolving therapies for HCC, such as immunotherapies and new target agents, will probably be incorporated into the treatment armamentarium in the near future. In this context, the role of CCT should be reviewed. We aimed to evaluate our single-centre experience regarding the safety and efficacy of CCT as second-line treatment in patients with HCC after sorafenib.

Methods

Patients and methods

A database of 273 consecutive HCC patients treated with sorafenib at Instituto do Cancer do Estado de São Paulo, Universidade de São Paulo, Brazil, from July 2009 to January 2017 was retrospectively evaluated after approval by the local ethics committee. All patients met diagnostic criteria for HCC based on radiological and/or histological findings [11].

From this dataset, we selected the patients that had received sorafenib as initial systemic treatment and were treated with CCT regimens, according to physician choice and local availability, after sorafenib discontinuation.

Relevant data from the clinical records were collected, including age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), pre-existing hepatopathy, Child-Pugh score, extrahepatic spread, vascular invasion, serum laboratory findings (alpha-fetoprotein, bilirubin, alkaline phosphatase and albumin), prior treatments for HCC, sorafenib treatment duration, CCT regimen, median CCT treatment duration, toxicity and OS. Outcome data were last updated on November 27, 2017.

Treatment and assessment

The chemotherapy regimens used were: weekly bolus 5-fluorouracil (5-FU) 370 mg/m 2 plus leucovorin 50 mg/ m 2 [12]; weekly oxaliplatin 85 mg/m 2 at weeks 1, 3 and 5, weekly bolus 5-FU 500 mg/m 2 with leucovorin 20 mg/m at weeks 1, 2, 3, 4, 5 and 6, then every 8 weeks (mFLOX) [13]; oxaliplatin 130 mg/m 2 on day 1 plus capecitabine 1,000 mg/m 2 twice daily on days 1 to 14, then every 3 weeks (CAPOX) [14]; doxorubicin 60-75 mg/m 2 every 3 weeks [8]; gemcitabine 1,000 mg/m 2 and oxaliplatin 85 mg/m 2 every 2 weeks (GEMOX) [15] and capecitabine 1,250 mg/m 2 twice daily for 2 weeks every 21 days and interferon (IFN)-alpha 3 million U three times a week. Usual dose reductions were done for managing adverse events depending on their type and severity. Treatment was continued until evidence of disease progression, unacceptable adverse event or death. The follow-up consisted of regular physical examination, laboratory assessment every 3-4 weeks and image studies (computed tomography or magnetic resonance) every 8-12 weeks. Assessment of response was based on the modified Response Evaluation Criteria in Solid Tumours [16]. OS was defined as the time from start of the CCT regimen treatment until death.

Statistical analyses

Data were evaluated using SPSS software version 23.0 (SPSS Chicago, IL). Continuous variables were expressed as means and ranges. Categorical variables were expressed as frequencies and compared using the chi-square test. We analysed pre-treatment clinical and laboratory markers potentially associated with outcome. Kaplan-Meier curves comparing OS and 95% confidence interval (95%CI) between groups were constructed, and log-rank testing was used for comparisons in univariate analysis. Variables were found to be significant if the two-sided p value was ≤ 0.05 on multivariate testing using a Cox regression test.

Results

Baseline characteristics

Between July 2009 and January 2017, a total of 273 patients who received sorafenib as first-line therapy for HCC were enrolled in this analysis. Of the 273 patients, 33 patients were excluded due to lack of sufficient information in data records. From the 240 patients included, 51 (18.7%) received a second-line systemic therapy, of which 45 (16.4%) received CCT and 6 were included in clinical trials.

Median age of the CCT group was 61.7 years (range 18.9-76.6 years), the majority of patients were male (75.6%), 41 (91.1%) had ECOG PS 0-1, 33 (73.3%) had Child-Pugh classification A and 34 (75.6%) had stage C according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Locoregional treatments had been previously delivered to 29 (64.4%) patients. The median duration of sorafenib treatment was 45 days (range 10-228 days). The most common reason for sorafenib discontinuation was progressive disease in 40 (88.9%) patients, while 4 (8.9%) patients discontinued sorafenib due to intolerance and 1 (2.2%) patient due to liver function deterioration. Doxorubicin was the regimen received by 25 (55.6%) patients, while the combination of fluoropyridine and oxaliplatin was received by 9 (20%) patients. The demographic and treatment characteristics are presented in Table 1.

Overall survival and response rate

At the time of the final analysis, 38 (84.4%) patients had died and 7 (15.6%) patients were still alive. The median follow-up was 6.31 months (95%CI 0.53 -21.62 months). The median OS from the start of CCT until death was 8.05 months (95%CI 2.73 -9.88 months) (Fig. 1a). The 6-month survival probability was 52.44% (95%CI 36.83 -65.89%) and 1-year survival probability was 27.36% (95%CI 14.90 -41.48%) from the start of CCT treatment. From the start of first-line sorafenib until death (sequence of sorafenib + CCT), the median OS was 15.86 months (95%CI 11.72 -22.99 months) (Fig. 1b). There was no OS difference between CCT regimens ( Table 2).

Thirty-two patients had available radiological responses: partial response was reported for 2 (4.4%) patients, 6 (13.3%) patients had stable disease and 24 (53.3%) patients had progressive disease. The reason for discontinuation of CCT was unacceptable toxicity in 20 (44.4%) patients, progressive disease in 17 (37.8%) patients and liver function decompensation in 3 (6.7%) patients. Five patients were still on treatment with CCT.

The   the treatment were reported. Table 3 lists the adverse events presented.

Prognostic factors

We performed univariate analysis to identify potential prognostic factors in the cohort of patients submitted to CCT. Child-Pugh classification A at the start of CCT (versus B-C), ECOG PS 0-1 at the start of CCT (versus 2-3) and disease control (stable disease + partial response) versus progressive disease as best responses while on first-line sorafenib showed significant better survival and were further evaluated in a multivariate model. In the multivariate analysis, only ECOG PS 0-1 at the start of CCT (p = 0.007) and disease control while on first-line sorafenib (p = 0.003) were independently associated with better survival (Table 4 and Fig. 2).

Discussion

In the present study, we described our experience with CCT in patients with HCC after discontinuation of sorafenib. We found a high rate of any-grade adverse    The systemic therapy for advanced HCC has changed since the results of the SHARP [4] and ASIA-PACIFIC trials [3] in which sorafenib delayed tumour progression, improved survival and became the first approved therapy for unresectable HCC. In the following years after these trials, many agents have been tested with disappointing results both in the first-and second-line setting [17][18][19].

There have been many attempts to implement CCT as an option for systemic treatment of HCC. However, the published data failed to prove a convincing benefit. CCT was associated with low response rates, poor OS and a significant rate of adverse events. Currently, the main guidelines do not support the use of CCT in HCC [16,20].

A prospective randomised trial that assessed the efficacy of doxorubicin over no antitumour therapy reported an OS of 10.6 weeks and a response rate of less than 10% of the patients. In this trial, doxorubicin was associated with fatal complications in 25% of the patients, including septicaemia and cardiotoxicity [8].

Another prospective study compared doxorubicin and the PIAF regimen. There was no statistical difference in terms of OS between the two arms and a high rate of treatment-related toxicity was observed in patients treated with PIAF [9]. Additionally, FOLFOX4 did not show benefit in OS over doxorubicin in a phase III trial [10]. Finally, some observational studies evaluated GEMOX. The results often showed an acceptable toxicity profile, but the efficacy, in terms of prolonging survival, was not encouraging [15,21].

The combination of sorafenib and doxorubicin was also evaluated in a double-blind phase II study in which sorafenib plus doxorubicin resulted in prolonged PFS (6.0 vs. 2.7 months, p = 0.006) and OS (13.7 vs. 6.5 months, p = 0.006) compared with doxorubicin monotherapy [22]. Based on  the promising results of this phase II study, Cancer and Leukaemia Group B (CALGB) conducted a phase III trial randomising sorafenib plus doxorubicin compared to sorafenib alone. However, the preliminary report presented in 2016 demonstrated that the combination of sorafenib and doxorubicin was associated with shorter OS (9.3 vs. 10.5 months) and higher toxicity than sorafenib alone [23]. This disappointing results with CCT in HCC may be explained by the underlying liver cirrhosis, which limits the clinical management and imposes impairments in the drug metabolisation. This fact supports the high rate of grade 3-4 adverse events observed in our cohort and in the previously mentioned studies.

Recently, the multi-kinase inhibitor regorafenib improved survival in a phase III placebo-controlled trial in the second-line setting. Those patients treated with this agent had a median OS of 10.6 months versus 7.8 months for those randomised to the placebo arm. Based on these results, regorafenib was recommended as the first second-line therapy in HCC [6]. In a recently published randomised trial, cabozantinib was also superior to placebo in prolonging survival in patients with HCC, with median OS of 10.2 versus 8.0 months [7]. Although it is not fair to perform interstudy comparisons, these two second-line trials indicated that the OS for the placebo arm of selected patients was around 8 months. Our cohort was composed of selected patients who were considered by the physician to be in good clinical condition to receive additional treatment after sorafenib. However, our cohort achieved a median OS that was numerically similar to that observed in the placebo arms of the trials that tested cabozantinib and regorafenib in the second-line [6,7]. This result was consistent even with consider only the subgroup of our cohort with Child-Pugh A and BCLC C, that is the predominant subset of patients included in the mentioned second-line trials. Altogether, it suggests that CCT did not impact the natural history of HCC after sorafenib progression.

A limitation of our study is that we grouped different CCT regimens to evaluate outcomes and safety. The hypothesis that one of the regimens may be beneficial post-sorafenib cannot be determined owing to the small sample size of patients that received each regimen. However, even the regimens that were the most represented (mFLOX, CapOx and Doxorrubicin) did not show a median OS that suggested activity regarding the current scenario of second-line systemic therapies for HCC. Besides, previous published safety data of these regimens are not encouraging [8,10].

The use of CCT in HCC was motivated mainly because of an historic lack of effective therapies rather than based on solid evidence. However, the context seems to be changing, as we have positive phase III results for regorafenib and cabozantinib [6,7]. Additionally, new data on immunotherapy shows promising activity in HCC. The phase I/II trial CHECKMATE 040 reported a median OS of 15.0 months for patients treated with nivolumab after sorafenib [24]. Results of phase III trials of immunotherapy agents are being awaited, although the costs of these new therapies may delay their incorporation, especially in developing countries.

Conclusion

In accordance to previous published results, our results demonstrated that CCT has a notable rate of adverse events and seems to have a low efficacy in patients with HCC.

Safety
Thirty-seven (82.2%) patients presented any-grade adverse events, including 20 (44.4%) patients with grade 3-4 events. The most frequent adverse events were nausea/vomiting in 16 (36%) patients and asthenia in 12 (27%) patients. The most frequent grade 3-4 adverse events were nausea/vomiting in 9 (20%) patients and myelotoxicity in 8 (18%) patients. No deaths related to

Fig. 1
1Survival curves of the patients treated with chemotherapy. a shows the survival curve from the start of chemotherapy until death. b represent the survival curve from the start of first-line sorafenib (sorafenib + chemotherapy) until death

including a notable incidence of grade 3-4 adverse events, and an OS of approximately 8 months, denoting a poor prognosis in this cohort of HCC patients treated with CCT.

Fig. 2
2Survival curves representing prognostic factors associated with better survival in patients treated with chemotherapy. a shows the better survival for patients with ECOG-PS 0-1 vs ECOG-PS 2-3 (p=0.007). b shows that patients who presented disease control with first-line sorafenib had better survival versus those with progressive disease with sorafenib. (p=0.003)

Abbreviations 5 -
5FU: 5-fluorouracil; BCLC: Barcelona Clinic Liver Cancer; CALGB: Cancer and Leukaemia Group B; CAPOX: Oxaliplatin plus capecitabine regimen; CCT: Cytotoxic chemotherapy; ECOG PS: Eastern Cooperative Oncology Group performance status; GEMOX: Gemcitabine plus oxaliplatin regimen; HCC: Hepatocellular carcinoma; IFN: Interferon; mFLOX: Oxaliplatin plus 5fluorouracil regimen; OS: Overall survival; PFS: Progression-free survival

patients with BCLC C stage and Child-Pugh A (n=24) presented median OS of 8.05 months (95%CI
2.69-15.74) while those with Child-Pugh B (n=9) pre-
sented median OS of 1.91 months (95%CI 0.36-10.62).
Considering the patients with BCLC B and Child-Pugh
A (n=9), the median OS was 9.10 months (95%CI
1.49-9.88).

Table 1
1Baseline characteristics of the patients treated with chemotherapyBaseline characteristics
n=45

Gender, n (%)

Male
31 (75.6)

Female
14 (24.4)

Age, median years (min-max)
61.7 (18.9-76.6)

ECOG PS, n(%)

0-1
41 (91.1)

2-3
04 (8.9)

Child-Pugh classification, n (%)

A
33 (73.3)

B
11 (24.4)

C
1 (2.2)

BCLC stage, n(%)

B
11 (24.4)

C
34 (75.6)

Chronic Liver Disease Etiology, n(%)

HCV
20 (44.4)

HBV
9 (20.4)

Alcohol
8 (18.2)

NASH
3 (6.9)

Hemochromatosis
2 (4.5)

Auto-immune Hepatitis
2 (4.6)

Cryptogenic
1 (2.3)

Previous treatment, n (%) a

Resection
7 (15.6)

RFA
2 (4.4)

Transplantation
3 (6.7)

TACE
18 (40)

None
16 (35.6)

Extrahepatic spread, n(%)
30 (66.7)

Vascular invasion, n(%)
13 (28.9)

CCT regimen (%)

Doxorubicin
25 (55.6)

mFLOX/CapOx
9 (20)

5FU
8 (17.8)

GemOx
2 (4.4)

Capecitabine plus IFN
1 (2.2)

Ascites (%)
4 (8.9%)

Alpha fetoprotein, median ng/ml (IQI)
15514.4 (6683.5-24345.5)

Bilirubin median mg/dl (IQI)
1.27 (0.94 -1.6)

ECOG PS: Eastern Cooperative Oncology Group performance status; BCLC:
Barceona Clinic Liver Cancer; HBV: Hepatitis B virus; HCV: Hepatitis C
virus; NASH: Non-alcoholic steatohepatitis; RFA: radiofrequency ablation;
TACE: transarterial chemoembolization; CCT: cytotoxic chemotherapy;
mFLOX: modified 5-fluorouracil and oxaliplatin combination; CapOx:
capecitabine and oxaliplatin combination; 5FU: 5-fluorouracil; GemOX:
gencitabibe and oxaliplatin combination; IFN: interferon; IQI: interquartile
interval. a some patients may have been treated with more than one
previous treatment modality.

Table 2
2Overall survival according to the chemotherapy regimenChemotherapy regimen
N
Median months
95%CI months

Doxorubicin
25
8.05
2.33-10.22

mFLOX/CapOx
09
8.57
0.62-NA

GemOx
02
3.51
3.51-NA

Capecitabine plus IFN
01
NA
NA

5-Fluorouracil
08
2.73
0.36-NA

Total
45
8.05
2.73-9.89

95%CI: 95% confidence interval; mFLOX: modified 5-fluorouracil and
oxaliplatin combination; CapOx: capecitabine and oxaliplatin combination;
gencitabibe and oxaliplatin combination; IFN: interferon.

Table 3
3Rate of treatment-related adverse eventsAdverse event
N= 45

Mielotoxicity

Grade 1-2, n (%)
1(2)

Table 4
4Prognostic factors in patients treated with chemotherapyPrognostic factors
Median OS months (95%CI)
p univariate
p multivariate

Child-Pugh classification

A
8.31 (2.72-9.88)
0.0251
0.524

B-C
3.51 (0.52-14.12)

ECOG performance status

0-1
9.36 (2.79 -18.26)
<0.001
0.007

2-3
1.08 (0.36-2.01)

Best response to sorafenib

Progressive disease
2.73 (1.48-6.31)
0.0035
0.003

Disease control
9.89 (8.04-14.13)

OS: overall survival; 95%CI: 95% confidence interval; ECOG: Eastern Cooperative Oncology Group

AcknowledgementsNot applicable.FundingThis research received no specific funding.Availability of data and materialsThe dataset collected and analyzed in the present study are available from the corresponding author on request.Authors' contributionsLGF, GNM and JS developed the original idea for the study. LGF and GNM collected the data. LGF and GNM performed the statistical analysis and prepared figures and tables. LGF, GNM, MIFMB, ALC, FJC, PH and JS analyzed and interpreted data. LGF, GNM and JS were responsible for writing the manuscript. MIMFB, ALC, FJC, PH and JS revised the manuscript critically for important intellectual content. All authors have read and approved the manuscript.Ethics approval and consent to participateThe procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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