Can baseline quality of life scores predict for morbidity and survival after CRS and HIPEC: a prospective study of 151 patients

Data collection

EORTC-QLQ-C30 was used. We included QLQ-CR29 and QLQ-OV28 for patients with colorectal and ovarian primary cancers, respectively. Both English and Chinese versions of questionnaire were used. To ensure standardised interpretation of questionnaire, our research assistants, who were not involved in patients’ care, administered questionnaires. This was also useful for illiterate patients.

Questionnaire was administered at baseline before surgery and thereafter at 3, 6 and 12 months.

Surgical procedure and data

Details of our operative and follow-up protocols were recorded in our previous publication [15]. Information on baseline characteristics, surgical procedures, complications and recurrence was obtained from our prospectively maintained database. We also collected data on the presence of stoma at various time-points. Morbidity was evaluated using common terminology criteria for adverse events version 3.0 of National Institute Health criteria.

Statistical analysis

Disease-free survival (DFS) was defined as time from CRS and HIPEC procedure to disease recurrence or death from disease. OS was defined as time from the first CRS and HIPEC procedure to death. In the event that multiple CRS and HIPEC procedures were performed on an individual patient, OS was calculated from the first CRS and HIPEC.

QLQ-C30 and QLQ-CR29 scores were derived according to EORTC scoring manual [16]. Function and symptom summary scores were derived from the mean of individual scores.

Subscale and summary scores were summarised by time-point. Change from baseline scores was derived and analysed using a repeated measures model adjusting for time and baseline-by-time interaction. An unstructured covariance matrix was used in the model.

To assess the association between QoL and selected clinical variables, global health status score, function summary score and symptom summary score were summarised by time-point for each category of each variable.

We also performed an analysis of patients who underwent CRS and HIPEC procedures that had QoL questionnaires completed at all four time-points (completers only analysis). Completers were defined as patients with QoL questionnaires completed at all four time-points (baseline, 3 months, 6 months and 12 months post-op). Non-completers had procedures that were performed more than one year before data cut-off date of 18 Apr 2017 (window of 30 days given), but did not have four questionnaires completed.

The following procedures were excluded from analysis:

1. Procedures which were performed less than one year (+30 days window) before data cut-off date of 18 Apr 2017 (i.e. not reached one year mark yet).

2. If a patient completed questionnaires for all four time-points, but one or more of these were completed outside time window of ±1 month (i.e. 3 ± 1 months, 6 ± 1 months and 12 ± 1 months), then the procedure was taken as a completer, but questionnaires that were taken outside time window were excluded from analysis.

The association between ECOG performance status and morbidity or major morbidity was assessed using Pearson’s chi-squared test or Fisher’s exact test, where appropriate. The association between baseline QoL and morbidity or major morbidity was assessed using Wilcoxon rank-sum test. Only patients who did not have any previous CRS and HIPEC procedures were included in analysis. OS rates by ECOG performance status were estimated using Kaplan–Meier method. The association between ECOG performance status, baseline QoL and OS was assessed using Cox proportional hazards model. The association between QoL and death within one year was assessed using Wilcoxon rank-sum test for continuous variables and Fisher’s exact test for categorical variables.

Two-sided p-value of less than 0.05 was taken as statistically significant. Analyses were performed in Stata 15.0 (StataCorp, Texas, USA) and SAS 9.4 (SAS institute, Cary, NC, USA).

Participants characteristics

Table 1 shows patients’ characteristics. One hundred and fifty one patients underwent 155 surgeries. Four patients underwent two surgeries. In all the analyses we treat patients who underwent two surgeries as two patients. We do not account for the fact that they are actually the same patient. Among four patients who underwent two surgeries, one patient had no stoma at the baseline of the first surgery but had the stoma at the baseline of the second surgery; another patient had the stoma at the baseline of the first surgery but had no stoma at the baseline of the second surgery. The number of patients with a stoma at baseline was 50.

A total of 472 QoL questionnaires were completed. Questionnaire completion was 80.0% at 3 months, 69.7% at 6 months and 54.8% at 12 months. A total of 4.5%, 9.7% and 20.6% of procedures had not reached 3 month, 6 month and 12 month time-point at the time of data cut-off, respectively.

Attrition due to death was 0.7% at 3 months, 3.6% at 6 months and 7.3% at 12 months. Procedures where 3, 6 or 12 month time-points were not reached yet were excluded from denominator. Questionnaires that were completed outside the allowed time window of ±1 month were considered attrition and counted under “Attrition due to other reasons”.

About 98.7% of patients had a completeness of cytoreduction (CC) score of 0 or 1.69 (44.5%) patients had no post-operative complications. Of 86 patients that suffered complications, only 21 (13.5%) had grade 3 or 4 complications while the remaining 86.5% had grade 1 or 2 complications.

The median follow-up duration was 18.9 months (95%CI, 15.0–20.7). Median DFS was 16.5 months (95%CI, 13.8–22.2). Median OS was not reached. Three year DFS and OS were 24.0% (95%CI, 14.9–34.3) and 73.0% (95%CI, 58.5–83.1), respectively.

QoL scores change after CRS and HIPEC

Global health status score significantly increased at 3, 6 and 12 months after CRS and HIPEC (Figure 1A). At 12 months, the score increased by an average of 4.8 points (95%CI, 1.0–8.7; p=0.015) compared to baseline.

Figure 1:

Plots of adjusted mean change from baseline-by-time for (A) global health status, functional scale scores and symptom scale scores, (B) functional scale scores, and (C) symptom scale scores. Global health status score significantly increased at 3, 6 and 12 months after CRS and HIPEC. The decreases in functional scales recovered to baseline by one year post-surgery. At 12 months, both emotional and social functioning scores improved compared to baseline. Insomnia and constipation symptoms were improved and more or less sustained up to 12 months. Diarrhoea symptoms increased.

For functional scales (Figure 1B), the largest increase was observed in emotional functioning at 3 months after CRS and HIPEC (+6.1 points; 95%CI, 3.8–8.4; p<0.001), which was sustained at 6 and 12 months. Decreases in physical and role functioning was observed at 3 months, but had recovered by 6 months. At 12 months, both emotional and social functioning scores improved compared to baseline.

For symptom scales (Figure 1C), the largest post-operative improvements at 3 months were observed in insomnia (−5.0 points; 95% CI, from −8.4 to −1.6; p=0.005) and constipation (−5.3 points; 95%CI, from −8.0 to −2.5; p<0.001) symptoms, which were more or less sustained up to 12 months. However, diarrhoea symptoms increased (+4.0 points; 95%CI, 1.0–6.9; p=0.009).

One hundred and two CRS and HIPEC procedures (performed on 100 patients) with QoL questionnaires were completed at all four time-points. Thirteen procedures were classified as non-completers. Of these 13 procedures, four had baseline QoL only (no post-operative QoL data available). Thirty two procedures were performed within one year (+30 days window) of the data cut-off date, hence had not reached one year time-point yet. For eight procedures, patient died within one year. These 40 procedures were excluded from completers vs. non-completers analysis. The results were mostly similar to the analysis with all subjects. There appeared to be a larger increase in global health status and functional scale scores at 6 months for completers.

The association between clinical variables and QoL scores

The following groups of patients had significantly lower global health status scores at 6 months compared to other patients at the same time-point (Table 2A): PCI score ≥15, SICU stay ≥1 day, presence of post-operative complications and patients who died within one year. Every 10 min increase in duration of peritonectomy was associated with a decrease of 0.28 points on average in global health status score at post-operative 6 months (95% CI, from −0.51 to −0.05; p=0.016) (Table 2B). By 12 months, the differences in scores between groups were no longer significant.

The following groups of patients had significantly lower function summary scores at post-operative 3 months, compared to other patients at the same time-point (Table 2A): presence of stoma at baseline and patients who died within one year. Every 10 min increase in duration of peritonectomy was associated with a decrease of 0.19 points on average in function summary score at post-operative 3 months (95%CI, from −0.35 to −0.04; p=0.015) (Table 2B). The differences observed in peritonectomy duration and presence of stoma were no longer significant at post-operative 6 months.

The following groups of patients had significantly higher symptom summary scores at post-operative 6 months, compared to other patients at the same time-point (Table 2A): SICU stay ≥1 day and patients who died within one year. The differences observed in SICU stay were no longer significant at 12 months post-op. The following groups of patients had significantly higher symptom summary scores at post-operative 12 months compared to other patients at the same time-point: PCI score ≥15 and presence of stoma at baseline.

At baseline, patients who died within one year tended to have higher appetite loss (p=0.030) and diarrhoea (p=0.026) scores compared to patients who were still alive at one year (Table 3). Primary tumour types distribution was significantly different between two groups (p=0.027). There was a stark contrast between two groups in global health status (p=0.001), physical functioning (p=0.023), role functioning (p=0.034), emotional functioning (p=0.037), fatigue (p=0.005), pain (p=0.025), appetite loss (p=0.017), symptom summary (p=0.034), nausea and vomiting (p=0.005) at three months; global health status (p=0.002), physical functioning (p=0.001), role functioning (p=0.008), social functioning (p=0.020), function summary (p=0.003), fatigue (p=0.022), pain (p=0.037), dyspnoea (p=0.018), appetite loss (p=0.018), symptom summary (p=0.004), nausea and vomiting (p=0.001) at six months.

The association between ECOG performance status, QoL at baseline and morbidity

All patients had an ECOG performance status of either 0 or 1 at baseline (Table 4). Total morbidity rate was 55.5%. Major morbidity rate was 13.5%. Patients with ECOG performance status of 1 at baseline were more likely to have major morbidity (27.8% vs. 11.8%), although not statistical significance (p=0.075).

Morbidity was associated with significantly lower global health status, physical functioning and role functioning scores, and significantly higher fatigue, nausea and vomiting, dyspnoea, appetite loss, constipation and financial difficulties scores at baseline. Symptom summary score at baseline was significantly higher in patients with morbidity.

Major morbidity was associated with significantly lower global health status and social functioning scores, and significantly higher fatigue and financial difficulties scores at baseline. Symptom summary score at baseline was also significantly higher in patients with major morbidity.

The association between baseline QoL and ECOG performance status with OS

Twenty-three died in 143 patients (16.1%). As only one patient died within 30 days, the association between baseline QoL and ECOG performance status with 30 day mortality was not assessed. Six patients were lost to follow-up before 30 days. Therefore, 30 day mortality rate was 0.7% (1/149).

Although patients with ECOG performance status of 1 at baseline had lower 2-year survival rates (Table 5), this was not statistically significant (p=0.476). Note that survival curves were not proportional (Figure 1). This might be due to immature data, since only 16.1% events were observed.

Social functioning score at baseline was significantly associated with OS (Table 5). For every 10-unit increase in social functioning score, the hazard of death decreased by 19% (HR=0.81; 95%CI, 0.70–0.94; p=0.006).

Pain, dyspnoea and symptom summary scores at baseline were also significantly associated with OS (Table 5). A 10-unit increase in pain score was associated with a 24% increase in hazard of death (HR=1.24; 95%CI, 1.04–1.49; p=0.019). A 10-unit increase in dyspnoea score was associated with a 57% increase in hazard of death (HR=1.57; 95%CI, 1.27–1.94; p<0.001). A 10-unit increase in symptom summary score was associated with 36% increase in hazard of death (HR=1.36; 95%CI, 1.01–1.84; p=0.041).