Hyperthermic intraoperative peritoneal chemotherapy and cytoreductive surgery for people with peritoneal metastases: a systematic review and cost-effectiveness analysis

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Chapter 1 Background and rationale

Sections of this chapter have been reproduced from Gurusamy et al. ,1 under licence CC-BY-4.0.

Chapter 2 Aims and objectives

The overarching aim of this project is to answer the following research questions:

Does HIPEC + CRS improve survival and/or quality of life (QoL) compared to CRS ± systemic chemotherapy or systemic chemotherapy alone in people with peritoneal metastases (from colorectal, gastric or stage III or greater epithelial ovarian cancers) who can withstand major surgery, and is it cost-effective in the NHS setting?

Chapter 3 Systematic review methods

Chapter 4 Cost-effectiveness analysis methods

We followed the National Institute for Health and Care Excellence (NICE) methodological standards for conducting our cost-effectiveness analysis. 54

Chapter 5 Results

Systematic review

Results of search

We identified 7938 records through electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (Wiley) (n = 1169), MEDLINE Ovid (n = 3405), Embase Ovid (n = 930), Science Citation Index Expanded and Conference Proceedings Citation Index-Science (n = 1758), ClinicalTrials.gov (n = 152) and WHO Trials register (n = 524). There were 6019 records after removing duplicates. We excluded 5855 clearly irrelevant records through reading titles and abstracts. We retrieved a total of 164 full-text records for further assessment in detail. We included a total of eight trials for this review13,14,60–65 (see Table 1). We excluded 58 records for the reasons stated in Appendix 4. 12,66–122 We identified 38 records of ongoing trials123–160 (see Appendix 5). While some ongoing studies are clearly on people with peritoneal metastases, in other trials, a subset of participants would be eligible for a future review on the same topic. Additional reports of included, excluded and ongoing studies (60 records)16,62,161–218 are listed in Appendix 6. The reference flow is shown in Figure 1.

TABLE 1 - Characteristics of included studies

Study name	Type of primary cancer	Other major inclusion/exclusion criteria	Number randomised	Post-randomisation exclusions	Mean or median age	Number of females (proportion)	Intervention vs. control	Follow-up in months
Quénet62	Colorectal cancer	Adults ≤ 70 years. Minor or moderate peritoneal carcinomatosis with a Sugarbaker Peritoneal Cancer Index score ≤ 25. Macroscopically complete R1 surgical tumour reduction or of residual thickness not exceeding 1 mm (R2). Absence of extraperitoneal metastases (other than ovarian or retroperitoneal lymph node metastases).	265	0	60	133 (50.2%)	HIPEC + CRS ± systemic chemotherapy vs. CRS ± systemic chemotherapy	Median: 64
Verwaal14	Colorectal cancer	Adults < 71 years. No other distant metastases.	105	0	54	47 (44.8%)	HIPEC + CRS ± systemic chemotherapy vs. systemic chemotherapy	Median: 22
Yang13	Gastric cancer	Adults of 20–75 years. No other metastases other than to peritoneum.	68	0	50	33 (48.5%)	HIPEC + CRS ± systemic chemotherapy vs. CRS ± systemic chemotherapy	Median: 32
Rau63	Gastric cancer	No other metastases other than to peritoneum or ovary. Possibility of 80% tumour reduction at CRS during diagnostic laparoscopy or exploratory laparotomy.	105	Not stated	Not stated	Not stated	HIPEC + CRS ± systemic chemotherapy vs. CRS ± systemic chemotherapy	Not stated
Rudloff64	Gastric cancer	Potential for complete resection. No other metastases other than to peritoneum, liver or lung.	17	0	48	7 (41.2%)	HIPEC + CRS ± systemic chemotherapy vs. systemic chemotherapy	Minimum: 24
Van Driel65	Ovarian cancer	Abdominal disease was too extensive for primary CRS or because surgery had been performed but was incomplete (i.e. after surgery, one or more residual tumours measuring > 1 cm in diameter were present). No extra-abdominal metastases.	245	0	62	245 (100.0%)	HIPEC + CRS ± systemic chemotherapy vs. CRS ± systemic chemotherapy	Median: 57
Antonio60	Ovarian cancer	No extraperitoneal metastases.	79	8 (unresectable)	61	79 (100.0%)	HIPEC + CRS ± systemic chemotherapy vs. CRS ± systemic chemotherapy	Median: 32
Lim61	Ovarian cancer	Adults < 75 years. Residual tumours < 1 cm. Extraperitoneal metastases.	184	0	53	184 (100.0%)	HIPEC + CRS ± systemic chemotherapy vs. CRS ± systemic chemotherapy	Median: 70

FIGURE 1.

Study flow diagram.

Because of the nature of the comparisons involved, we did not identify any non-randomised studies at low or moderate risk of bias, as such studies compare outcomes in completely different groups of individuals: participants likely to withstand major surgery and had limited metastases received HIPEC + CRS + systemic chemotherapy, while participants unlikely to withstand major surgery or had more extensive metastases did not receive HIPEC.

We did not identify any trial which compared CRS + systemic chemotherapy versus systemic chemotherapy alone in addition to supportive care for people with peritoneal metastases from colorectal or gastric cancer. While there were trials comparing CRS + systemic chemotherapy versus systemic chemotherapy alone in addition to supportive care in women with ovarian cancer, it was not clear whether any of these participants had peritoneal metastases, or even when it was clear that some people would have had peritoneal metastases, no separate outcome data were available for such participants. Therefore, such studies were excluded.

Characteristics of included studies

The characteristics of included studies are summarised in Table 1. Further details of HIPEC and systemic chemotherapy in these studies are summarised in Appendix 3, Tables 15 and 16. We included a total of eight trials (1068 participants) in this review. 13,14,60–65 Of the participants included in the studies, eight were excluded after randomisation as they were unresectable, leaving a total of 1060 participants included in this review. Of these, 955 participants from seven trials were included in quantitative analysis. 13,14,60–62,64,65 Two trials (370 participants) were conducted in people with peritoneal metastases from colorectal cancer,14,62 three trials (190 participants; 85 participants from two trials were included in quantitative analysis) were conducted in people with peritoneal metastases from gastric cancer13,63,64 and three trials (508 participants; 500 participants included in analysis) were conducted in people with stage III or greater epithelial ovarian cancer. 60,61,65 The follow-up period in the trials ranged from 22 months to 70 months in the seven trials that reported this information. 13,14,60–62,64,65

Participants

All trials included only adults. The mean or median age of the trial participants was between 48 and 62 years in the seven trials that reported this information. 13,14,60–62,64,65 The proportion of trial participants who were females was between 41.2% and 50.2% in the four trials on colorectal or gastric cancers that reported the number of female trial participants. 13,14,62,64

Most trials excluded participants who had extraperitoneal metastases, and because of the nature of the comparisons in this systematic review, they included only participants who were eligible to undergo major surgery and chemotherapy.

Comparisons

The comparisons in the trials were: HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy in six trials13,60–63,65 and HIPEC + CRS + systemic chemotherapy versus systemic chemotherapy in the remaining two trials. 14,64

Outcomes

All-cause mortality was reported in an analysable format in seven trials. 13,14,60–62,64,65 Overall HRQoL was reported in one trial. 60 Serious adverse events were reported in analysable format in five trials. 13,60–62,65 Progression-free survival was reported in analysable format in four trials. 60–62,65 None of the trials reported non-serious adverse events or patient-reported outcome measures in analysable format.

Risk of bias in the trials

The overall risk of bias in the trials was low in six trials for all-cause mortality. 14,60–62,64,65 Of the remaining two trials, one was based on a conference abstract,63 and it is quite probable that this trial would also be at low risk of bias when fully published. The risk of bias in the different domains for mortality is shown in Table 2. It should be noted that most trials did not have a published protocol or a protocol that predated recruitment available from the trial register. Nevertheless, all-cause mortality was reported in most of the trials in the way it is expected. Therefore, we have considered that the risk of bias in the trials was low for all-cause mortality in most trials. Subjective outcomes such as HRQoL and serious adverse events would have been rated as some concerns as none of the trials used outcome assessor blinding. Only two trials reported participant blinding. 60,61 In the remaining trials, participants were aware of the treatment groups.

TABLE 2 - Risk of bias

Study name	Bias arising from the randomisation process	Bias due to deviations from intended interventions	Bias due to missing outcome data	Bias in measurement of the outcome	Bias in selection of the reported result	Overall risk of bias
Quénet62	Low risk	Low risk	Low risk	Low risk	Some concerns	Low risk
Verwaal14	Low risk	Low risk	Low risk	Low risk	Some concerns	Low risk
Yang13	Some concerns	Low risk	Low risk	Low risk	Some concerns	Some concerns
Rudloff64	Low risk	Low risk	Low risk	Low risk	Some concerns	Low risk
Rau63	Some concerns	Some concerns	Low risk	Low risk	Some concerns	Some concerns
Antonio60	Low risk	Low risk	Low risk	Low risk	Some concerns	Low risk
Van Driel65	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Lim61	Low risk	Low risk	Low risk	Low risk	Some concerns	Low risk

Effect estimates

Colorectal cancer

Of the two trials in colorectal cancer, one trial compared HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy,62 and another compared HIPEC + CRS + systemic chemotherapy versus systemic chemotherapy. 14 So, a meta-analysis was not performed. We did not calculate the indirect effect estimates because of the differences in the types of participants included in the two trials. In one trial, only participants who had macroscopically complete R₁ surgical tumour reduction or residual thickness not exceeding 1 mm were included,62 but in the other trial there was no such criterion for selection. 14 In the absence of IPD analysis or effect estimates in a subset of participants who were similar in the two trials, it may be inappropriate to calculate the indirect effect estimates of CRS + systemic chemotherapy versus systemic chemotherapy in addition to supportive treatment because of possible violation of transitivity assumption (i.e. the participants in the trials were reasonably similar to allow randomisation to any of the arms being evaluated). Therefore, we have presented only the effect estimates of the direct comparisons.

HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy forcolorectal peritoneal metastases

One trial (265 participants) was included in the analysis. 62 The outcomes of interest reported by the trial included all-cause mortality, serious adverse events and time to disease progression. The forest plots are available in Figures 2–4.

FIGURE 2.

Colorectal cancer (HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy): all-cause mortality. SE, standard error.

FIGURE 3.

Colorectal cancer (HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy): serious adverse events.

FIGURE 4.

Colorectal cancer (HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy): time to disease progression. SE, standard error.

The figure shows that there is probably little or no difference in all-cause mortality between HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy.

The figure shows that HIPEC + CRS + systemic chemotherapy may increase the serious adverse events compared to CRS + systemic chemotherapy.

The figure shows that there is probably little or no difference in time to disease progression between HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy.

All-cause mortality

The evidence suggests that HIPEC + CRS + systemic chemotherapy results in little to no difference in all-cause mortality compared to CRS + systemic chemotherapy [60.6% in HIPEC + CRS + systemic chemotherapy vs. 60.6% in CRS + systemic chemotherapy; median follow-up 64 months; HR 1.00, 95% confidence interval (CI) 0.63 to 1.58; one trial; 265 participants; moderate-certainty evidence].

Serious adverse events

The evidence suggests HIPEC + CRS + systemic chemotherapy may increase the number of people who developed serious adverse events compared to CRS + systemic chemotherapy (25.6% in HIPEC + CRS + systemic chemotherapy vs. 15.2% in CRS + systemic chemotherapy; RR 1.69, 95% CI 1.03 to 2.77; one trial; 265 participants; low-certainty evidence).

Disease progression

The evidence suggests that HIPEC + CRS + systemic chemotherapy may result in little to no difference in overall disease progression compared to CRS + systemic chemotherapy (81.2% in HIPEC + CRS + systemic chemotherapy vs. 84.1% in CRS + systemic chemotherapy; median follow-up 64 months; HR 0.91, 95% CI 0.72 to 1.16; one trial; 265 participants; low-certainty evidence).

HIPEC + CRS + systemic chemotherapy versus systemic chemotherapy for colorectalperitoneal metastases

One trial (105 participants) was included in the analysis. 14 The outcomes of interest reported by the trial included all-cause mortality. The forest plot is available in Figure 5.

FIGURE 5.

Colorectal cancer (HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy): all-cause mortality. Verwaal et al. 14 SE, standard error.

The figure shows that HIPEC + CRS + systemic chemotherapy probably decreases all-cause mortality compared to systemic chemotherapy alone.

All-cause mortality

The evidence suggests that HIPEC + CRS + systemic chemotherapy probably decreases all-cause mortality compared to systemic chemotherapy (40.8% in HIPEC + CRS + systemic chemotherapy vs. 60.8% in systemic chemotherapy alone; median follow-up 22 months; HR 0.55, 95% CI 0.32 to 0.95; one trial; 105 participants; moderate-certainty evidence).

Gastric cancer

Of the three trials in gastric cancer, two trials compared HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy,13,63 and one trial compared HIPEC + CRS + systemic chemotherapy versus systemic chemotherapy. 64 Of the two trials that compared HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy, one trial did not provide the outcomes of interest in an analysable format. 63 So, a meta-analysis was not performed. We did not calculate the indirect effect estimates because of the differences in the types of participants included in the two trials that provided quantitative data. In one trial, there was no restriction based on metastases to lung or liver,64 while in the other trial, people with metastases to lung or liver were excluded. 13 As for colorectal cancer, in the absence of IPD analysis or effect estimates in a subset of participants who were similar in the two trials, it may be inappropriate to calculate the indirect effect estimates of CRS + systemic chemotherapy versus systemic chemotherapy in addition to supportive treatment because of possible violation of transitivity assumption. Therefore, we have presented only the effect estimates of the direct comparisons.

HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy forgastric peritoneal metastases

The effect estimates for one trial (68 participants) that provided data in analysable format13 are presented below. The outcomes of interest reported by the trial included all-cause mortality and serious adverse events. The forest plots are available in Figures 6 and 7.

FIGURE 6.

Gastric cancer (HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy): all-cause mortality. SE, standard error.

FIGURE 7.

Gastric cancer (HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy): serious adverse events.

The trial that did not provide data in analysable format provided a narrative statement about all-cause mortality,63 which is also included below.

The figure shows that HIPEC + CRS + systemic chemotherapy may result in lower mortality than CRS + systemic chemotherapy. However, another trial which reported mortality data in a format that could not be used for analysis showed that there is little or no difference in all-cause mortality between the groups. Therefore, the effect of HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy on all-cause mortality is highly uncertain.

The figure shows that there is little or no difference in serious adverse events between the groups. Combined with the risk of bias in the trial and small size of the trial, there is high uncertainty about the effect of HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy on serious adverse events.

All-cause mortality

There is high uncertainty about the effect of HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy on all-cause mortality [73.8% in HIPEC + CRS + systemic chemotherapy vs. 97.1% in CRS + systemic chemotherapy; median follow-up 32 months; HR 0.38, 95% CI 0.21 to 0.70 based on the one trial (68 participants) that reported data in analysable format;13 very low-certainty evidence]. In the trial (105 participants) that did not report the data on all-cause mortality in an analysable way reported that there was no difference in all-cause mortality between HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy. 63

Serious adverse events

There is high uncertainty about the effect of HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy on serious adverse events (14.7% in HIPEC + CRS + systemic chemotherapy vs. 11.8% in CRS + systemic chemotherapy; RR 1.25, 95% CI 0.37 to 4.26; one trial; 68 participants; very low-certainty evidence).

HIPEC + CRS + systemic chemotherapy versus systemic chemotherapy for gastricperitoneal metastases

One trial (17 participants) was included in the analysis. 64 The outcomes of interest reported by the trial included all-cause mortality. The forest plot is available in Figure 8.

FIGURE 8.

Gastric cancer (HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy): all-cause mortality. SE, standard error.

The figure shows that HIPEC + CRS + systemic chemotherapy probably results in lower mortality than systemic chemotherapy alone.

All-cause mortality

The evidence suggests that HIPEC + CRS + systemic chemotherapy probably decreases all-cause mortality compared to systemic chemotherapy (40.8% in HIPEC + CRS + systemic chemotherapy vs. 100% in systemic chemotherapy alone; minimum follow-up 24 months; HR 0.40, 95% CI 0.30 to 0.52; one trial; 17 participants; moderate-certainty evidence).

Ovarian cancer (stage III or greater epithelial ovarian cancer requiring interval cytoreductive surgery)

Three trials (500 participants) compared HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy. 60,61,65 The outcomes of interest reported by all the three trials included all-cause mortality, serious adverse events and time to disease progression. Of these three trials, two reported number of people with serious adverse events,60,65 and another trial reported number of serious adverse events. 61 Health-related quality of life was reported in analysable format in one trial60 and in a format that could not be included in the analysis in another trial. 65 Therefore, we have not presented this information. The forest plots are available in Figures 9–13.

FIGURE 9.

Ovarian cancer (HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy): all-cause mortality. SE, Standard error.

FIGURE 10.

Ovarian cancer (HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy): HRQoL. SE, standard error; SD, standard deviation.

FIGURE 11.

Ovarian cancer (HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy): serious adverse events (proportion).

FIGURE 12.

Ovarian cancer (HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy): serious adverse events (number per participant). SE, standard error.

FIGURE 13.

Ovarian cancer (HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy): time to disease progression. SE, standard error.

The figure shows that HIPEC + CRS + systemic chemotherapy probably results in lower mortality and disease progression than CRS + systemic chemotherapy.

The figure also shows that there may be little or no difference in the HRQoL between HIPEC + CRS + systemic chemotherapy and CRS + systemic chemotherapy.

The figure also shows that there may be little or no difference in the proportion of participants who developed serious adverse events between HIPEC + CRS + systemic chemotherapy and CRS + systemic chemotherapy.

The figure also shows that the number of serious adverse events was probably higher in HIPEC + CRS + systemic chemotherapy compared to CRS + systemic chemotherapy.

The figure shows that HIPEC + CRS + systemic chemotherapy probably results in lower disease progression than CRS + systemic chemotherapy.

All-cause mortality

The evidence suggests that HIPEC + CRS + systemic chemotherapy probably results in lower all-cause mortality compared to CRS + systemic chemotherapy (46.3% in HIPEC + CRS + systemic chemotherapy vs. 57.4% in CRS + systemic chemotherapy; median follow-up 32 to 70 months; HR 0.73, 95% CI 0.57 to 0.93; three trials; 500 participants; moderate-certainty evidence).

Health-related quality of life

The evidence suggests that HIPEC + CRS + systemic chemotherapy may result in little to no difference in the HRQoL (Global Health Status at 12 months) compared to CRS + systemic chemotherapy (MD 4.85, 95% CI −7.74 to 17.44; one trial; 71 participants; low-certainty evidence). In another trial where data were not reported in analysable format,65 HIPEC + CRS + systemic chemotherapy resulted in little to no difference in the HRQoL [European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 (QLQ-C30)] at 24 months.

Serious adverse events

The evidence suggests that HIPEC + CRS + systemic chemotherapy may result in little to no difference in number of people who developed serious adverse events compared to CRS + systemic chemotherapy (26.7% in HIPEC + CRS + systemic chemotherapy vs. 25.2% in CRS + systemic chemotherapy; RR 1.06, 95% CI 0.73 to 1.54; two trials; 316 participants; moderate-certainty evidence). The evidence suggests HIPEC + CRS + systemic chemotherapy probably increases the number of serious adverse events compared to CRS + systemic chemotherapy (41.4 events per 100 participants in HIPEC + CRS + systemic chemotherapy vs. 32.6 events per 100 participants in CRS + systemic chemotherapy; rate ratio 1.27, 95% CI 1.09 to 1.49; one trial; 184 participants; moderate-certainty evidence).

Disease progression

The evidence suggests that HIPEC + CRS + systemic chemotherapy may result in lower disease progression compared to CRS + systemic chemotherapy (75.8% in HIPEC + CRS + systemic chemotherapy vs. 85.7% in CRS + systemic chemotherapy; median follow-up 32–70 months; HR 0.73, 95% CI 0.60 to 0.89; three trials; 500 participants; low-certainty evidence).

Heterogeneity

There was no evidence of heterogeneity in any of the meta-analyses as indicated by good overlap of CIs of effect estimates from the trials, between-study standard deviation (τ = 0), I² = 0% and the p-value of chi-squared test for heterogeneity being not statistically significant (see Figures 9–13).

Sensitivity analysis

An exploratory panoramic meta-analysis revealed that HIPEC + CRS + systemic chemotherapy results in little to no difference in all-cause mortality compared to CRS + systemic chemotherapy, as indicated by the 95% credible intervals (CrI).

• Colorectal cancer: HR 1.00 (95% CrI 0.15 to 6.77).

• Gastric cancer: HR 0.38 (95% CrI 0.05 to 2.64).

• Ovarian cancer: HR 0.73 (95% CrI 0.24 to 2.18).

There was no evidence of differences in survival by cancer types [coefficient for cancer type: gastric cancer vs. colorectal cancer −0.96 (95% CrI −3.67 to 1.78) and ovarian cancer vs. colorectal cancer −0.32 (95% CrI −2.53 to 1.90), although the between-study standard deviation was 0.29 (95% CrI 0.01 to 3.08)].

Reporting bias

We have searched all the major databases for medical publications and clinical trial registers. We did not identify any registered and completed clinical trial which has not reported the results over an extended period of time.

Certainty of evidence

The certainty of evidence and the reasons for downgrading the evidence are available in Table 3. Most of the evidence related to all-cause mortality was of moderate certainty.

TABLE 3 - Certainty of evidence

GRADE, Grading of Recommendations, Assessment, Development and Evaluations; SC, Systemic chemotherapy.

Based on the control group proportions observed in the trials for colorectal and gastric cancer or mean control group proportions observed in the trials for ovarian cancer

Downgraded one level for imprecision.

Downgraded one level for lack of blinding for a subjective outcome (see Table 2).

Downgraded one level for unclear randomisation (see Table 2).

Downgraded one level for heterogeneity in the results between the study that reported data in analysable format compared to the trial that did not report data in analysable format.

Outcomes	Anticipated absolute effectsa (95% CI)		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with CRS + SC (or SC alone)	Risk with HIPEC + CRS + SC
Colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
All-cause mortality (median follow-up: 64 months)	606 per 1000	606 per 1000 (444 to 771)	HR 1.00 (0.63 to 1.58)	265 (1 RCT)	⨁⨁⨁◯ Moderateb
Serious adverse events (short term)	152 per 1000	256 per 1000 (156 to 420)	RR 1.69 (1.03 to 2.77)	265 (1 RCT)	⨁⨁◯◯ Lowb,c
Time to disease progression (median follow-up: 64 months)	841 per 1000	812 per 1000 (734 to 881)	HR 0.91 (0.72 to 1.16)	265 (1 RCT)	⨁⨁◯◯ Lowb,c
Colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone
All-cause mortality (median follow-up: 22 months)	608 per 1000	402 per 1000 (259 to 589)	HR 0.55 (0.32 to 0.95)	105 (1 RCT)	⨁⨁⨁◯ Moderateb
Gastric cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
All-cause mortality (median follow-up: 32 months)	971 per 1000	738 per 1000 (523 to 915)	HR 0.38 (0.21 to 0.70)	68 (1 RCT)	⨁◯◯◯ Very lowb,d,e	Another trial including 105 participants indicated that there was no difference in all-cause mortality between the two groups but could not be included in the analysis because the numbers were not reported in a format suitable for analysis
Serious adverse events (short term)	118 per 1000	147 per 1000 (44 to 501)	RR 1.25 (0.37 to 4.26)	68 (1 RCT)	⨁◯◯◯ Very lowb,c,d
Gastric cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone
All-cause mortality (minimum follow-up: 24 months)	1000 per 1000	1000 per 1000 (1000 to 1000)	HR 0.40 (0.30 to 0.52)	17 (1 RCT)	⨁⨁⨁◯ Moderateb
Ovarian cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
All-cause mortality (median follow-up: 32–70 months)	574 per 1000	463 per 1000 (385 to 547)	HR 0.73 (0.57 to 0.93)	500 (3 RCTs)	⨁⨁⨁◯ Moderateb
HRQoL assessed with Global Health Status Scale from 0 to 100 (mean follow-up: 12 months)	The mean HRQoL was 69.79	MD 4.85 more (7.74 fewer to 17.44 more)	-	71 (1 RCT)	⨁⨁◯◯ Lowb,c
Serious adverse events (proportion) (short term)	252 per 1000	267 per 1000 (184 to 387)	RR 1.06 (0.73 to 1.54)	316 (2 RCTs)	⨁⨁◯◯ Lowb,c
Serious adverse events (number per participant) (short term)	326 per 1000	414 per 1000 (355 to 486)	Rate ratio 1.27 (1.09 to 1.49)	184 (1 RCT)	⨁⨁⨁◯ Moderatec
Time to disease progression (median follow-up: 32–70 months)	857 per 1000	758 per 1000 (688 to 822)	HR 0.73 (0.60 to 0.89)	500 (3 RCTs)	⨁⨁◯◯ Lowb,c

Cost-effectiveness

The decision tree is available in Figure 14. The input parameters for the different comparisons are available in Tables 4–8. The cost estimates for different aspects of treatment and the sources of information for different comparisons are available in Appendix 7, Tables 17–21. The results of the analyses are available in Tables 9–13. The file that was used to perform the cost-effectiveness analysis is available as Report Supplementary Material 1. This file can be used to calculate the cost-effectiveness based on local cost estimates.

FIGURE 14.

Decision tree (HIPEC + CRS + systemic chemotherapy vs. control). Please see detailed description of this decision tree in the text.

TABLE 4 - Input parameters in decision tree model: colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy

ln, natural logarithm.

Parameters	Type of distribution	Mean (uniform), number with event (dichotomous)	Number without event (dichotomous)	Lower limit	Upper limit	Source/notes
Complications (HIPEC + CRS)	Beta	34	99	0	0.5	Systematic review (from Quénet et al. 202162)
Short-term mortality (HIPEC + CRS)	Beta	2	131	0	0.1	Quénet et al. 202162
Survival ln (HR)	Continuous	0	0.2345605	−2	2	Systematic review (from Quénet et al. 202162)
Complications (control)	Beta	20	112	0	0.5	Systematic review (from Quénet et al. 202162)
Short-term mortality (control)	Beta	2	130	0	0.1	Quénet et al. 202162
5-year mortality (control)	Beta	80	53	0	1	Systematic review (from Quénet et al. 202162)
Cost (HIPEC + CRS) complicated	Uniform	16,308.92895		11,416.25	21,202	See Appendix 7, Table 17
Cost (HIPEC + CRS) uncomplicated	Uniform	11,939.472		8357.63	15,521	See Appendix 7, Table 17
Cost (control) complicated	Uniform	10,568.45695		7397.92	13,739	See Appendix 7, Table 17
Cost (control) uncomplicated	Uniform	6199		4339.3	8058.7	See Appendix 7, Table 17
QoL (complicated HIPEC + CRS) (short term)	Beta	0.43	0.57	0.1	0.9	Hypothetical 0.1 less in complicated
QoL (uncomplicated HIPEC + CRS) (short term)	Beta	0.53	0.47	0.1	0.9	Leimkuhler et al. 2020;219 EORTC CLQ30 mapped to 5Q5D using Kim et al. 2012220
QoL (complicated CRS) (short term)	Beta	0.43	0.57	0.1	0.9	Hypothetically same as HIPEC group
QoL (uncomplicated CRS) (short term)	Beta	0.53	0.47	0.1	0.9	Hypothetically same as HIPEC group
QoL (long term) HIPEC	Beta	0.785	0.215	0.1	0.9	Malcolm et al. 2021221
QoL (long term) control	Beta	0.785	0.215	0.1	0.9	Malcolm et al. 2021221

TABLE 5 - Input parameters in decision tree model: colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone

ln, natural logarithm.

Parameters	Type of distribution	Mean (uniform), number with event (dichotomous)	Number without event (dichotomous)	Lower limit	Upper limit	Source/notes
Complications (HIPEC + CRS)	Beta	34	99	0	0.5	No information from Verwaal et al. 2003;14 therefore used details from Quénet et al. 202162
Short-term mortality (HIPEC + CRS)	Beta	4	50	0	0.1	Verwaal et al. 200314
Survival ln (HR)	Continuous	−0.597837001	0.2775921	−2	2	Systematic review (from Verwaal et al. 200314)
Complications (control)	Beta	10	41	0	0.5	Estimated from (Verwaal et al. 200314)
Short-term mortality (control)	Beta	0	51	0	0.1	Verwaal et al. 200314
5-year mortality (control)	Beta	80	53	0	1	Systematic review (Verwaal et al. 200314)
Cost (HIPEC + CRS) complicated	Uniform	24,432.82095		17,102.97	31,763	See Appendix 7, Table 18
Cost (HIPEC + CRS) uncomplicated	Uniform	20,063.364		14,044.35	26,082	See Appendix 7, Table 18
Cost (control) complicated	Uniform	13,072.25695		9150.58	16,994	See Appendix 7, Table 18
Cost (control) uncomplicated	Uniform	8702.8		6091.96	11,314	See Appendix 7, Table 18
QoL (complicated HIPEC + CRS) (short term)	Beta	0.43	0.57	0.1	0.9	Hypothetical 0.1 less in complicated
QoL (uncomplicated HIPEC + CRS) (short term)	Beta	0.53	0.47	0.1	0.9	Leimkuhler et al. 2020;219 EORTC CLQ30 mapped to 5Q5D using Kim et al. 2012220
QoL (complicated CRS) (short term)	Beta	0.57	0.43	0.1	0.9	Hypothetical 0.1 less in complicated
QoL (uncomplicated CRS) (short term)	Beta	0.67	0.33	0.1	0.9	Flyum et al. 2021222
QoL (long term) HIPEC	Beta	0.785	0.215	0.1	0.9	Malcolm et al. 2021221
QoL (long term) control	Beta	0.67	0.33	0.1	0.9	Flyum et al. 2021222

TABLE 6 - Input parameters in decision tree model: gastric cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy

ln, natural logarithm.

Parameters	Type of distribution	Mean (uniform), number with event (dichotomous)	Number without event (dichotomous)	Lower limit	Upper limit	Source/notes
Complications (HIPEC + CRS)	Beta	5	29	0	0.5	Systematic review (from Yang et al. 201113)
Short-term mortality (HIPEC + CRS)	Beta	0	34	0	0.1	No information
Survival ln (HR)	Continuous	−0.446287103	0.4782931	−2	2	Systematic review (from Yang et al. 201113)
Complications (control)	Beta	4	30	0	0.5	Systematic review (from Yang et al. 201113)
Short-term mortality (control)	Beta	0	34	0	0.1	No information
5-year mortality (control)	Beta	33	1	0	1	Systematic review (from Yang et al. 201113)
Cost (HIPEC + CRS) complicated	Uniform	20,727.35891		14,509.15	26,946	See Appendix 7, Table 19
Cost (HIPEC + CRS) uncomplicated	Uniform	16,357.90196		11,450.53	21,265	See Appendix 7, Table 19
Cost (control) complicated	Uniform	17,397.58591		12,178.31	22,617	See Appendix 7, Table 19
Cost (control) uncomplicated	Uniform	13,028.12896		9119.69	16,937	See Appendix 7, Table 19
QoL (complicated HIPEC + CRS) (short term)	Beta	0.43	0.57	0.1	0.9	Hypothetical 0.1 less in complicated
QoL (uncomplicated HIPEC + CRS) (short term)	Beta	0.53	0.47	0.1	0.9	Leimkuhler et al. 2020;219 EORTC CLQ30 mapped to 5Q5D using Kim et al. 2012220
QoL (complicated CRS) (short term)	Beta	0.43	0.57	0.1	0.9	Hypothetically same as HIPEC group
QoL (uncomplicated CRS) (short term)	Beta	0.53	0.47	0.1	0.9	Hypothetically same as HIPEC group
QoL (long term) HIPEC	Beta	0.85	0.15	0.1	0.9	van der Wielen et al. 2022223
QoL (long term) control	Beta	0.85	0.15	0.1	0.9	van der Wielen et al. 2022223

TABLE 7 - Input parameters in decision tree model: gastric cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone

ln, natural logarithm.

Parameters	Type of distribution	Mean (uniform), number with event (dichotomous)	Number without event (dichotomous)	Lower limit	Upper limit	Source/notes
Complications (HIPEC + CRS)	Beta	5	29	0	0.5	No information from Rudloff et al. 2014;64 therefore used details from Yang et al. 201113
Short-term mortality (HIPEC + CRS)	Beta	0	9	0	0.1	Rudloff et al. 201464
Survival ln (HR)	Continuous	−0.916290732	0.1403205	−2	2	Systematic review (from Rudloff et al. 201464)
Complications (control)	Beta	0	8	0	0.5	No information
Short-term mortality (control)	Beta	0	8	0	0.1	No information
5-year mortality (control)	Beta	8	0	0	1	Systematic review (from Rudloff et al. 201464)
Cost (HIPEC + CRS) complicated	Uniform	32,325.51895		22,627.86	42,023	See Appendix 7, Table 20
Cost (HIPEC + CRS) uncomplicated	Uniform	27,956.062		19,569.24	36,343	See Appendix 7, Table 20
Cost (control) complicated	Uniform	22,785.41695		15,949.79	29,621	See Appendix 7, Table 20
Cost (control) uncomplicated	Uniform	18,415.96		12,891.17	23,941	See Appendix 7, Table 20
QoL (complicated HIPEC + CRS) (short term)	Beta	0.43	0.57	0.1	0.9	Hypothetical 0.1 less in complicated
QoL (uncomplicated HIPEC + CRS) (short term)	Beta	0.53	0.47	0.1	0.9	Leimkuhler et al. 2020;219 EORTC CLQ30 mapped to 5Q5D using Kim et al. 2012220
QoL (complicated CRS) (short term)	Beta	0.54	0.46	0.1	0.9	Hypothetical 0.1 less in complicated
QoL (uncomplicated CRS) (short term)	Beta	0.64	0.36	0.1	0.9	Carter et al. 2015224
QoL (long term) HIPEC	Beta	0.85	0.15	0.1	0.9	van der Wielen et al. 2022223
QoL (long term) Control	Beta	0.64	0.36	0.1	0.9	Carter et al. 2015224

TABLE 8 - Input parameters in decision tree model: ovarian cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy

ln, natural logarithm.

Parameters	Type of distribution	Mean (uniform), number with event (dichotomous)	Number without event (dichotomous)	Lower limit	Upper limit	Source/notes
Complications (HIPEC + CRS)	Beta	42	115	0	0.5	Systematic review (from van Driel et al. 201865 and Antonio et al. 202260)
Short-term mortality (HIPEC + CRS)	Beta	1	156	0	0.1	From: van Driel et al. 201865 and Antonio et al. 202260
Survival ln (HR)	Continuous	−0.314710745	0.124887	−2	2	Systematic review (from van Driel et al. 2018,65 Antonio et al. 2022,60 Lim et al. 202261)
Complications (control)	Beta	40	119	0	0.5	Systematic review (from van Driel et al. 201865 and Antonio et al. 202260)
Short-term mortality (control)	Beta	2	157	0	0.1	From: van Driel et al. 201865 and Antonio et al. 202260
5-year mortality (control)	Beta	123	92	0	1	Systematic review (from van Driel et al. 201865 and Lim et al. 202261). The number of deaths was reported only in these two trials, but the HRs were reported in the three trials
Cost (HIPEC + CRS) complicated	Uniform	15,964.05095		11,174.84	20,753	See Appendix 7, Table 21
Cost (HIPEC + CRS) uncomplicated	Uniform	11,594.594		81,16.216	15,073	See Appendix 7, Table 21
Cost (control) complicated	Uniform	12,336.65695		8635.66	16,038	See Appendix 7, Table 21
Cost (control) uncomplicated	Uniform	7967.2		5577.04	10,357	See Appendix 7, Table 21
QoL (complicated HIPEC + CRS) (short term)	Beta	0.5013	0.4987	0.1	0.9	Hypothetical 0.1 less in complicated
QoL (uncomplicated HIPEC + CRS) (short term)	Beta	0.6013	0.3987	0.1	0.9	Antonio et al. 2022,60 converted using Kim et al. 2012220
QoL (complicated CRS) (short term)	Beta	0.504612	0.495388	0.1	0.9	Hypothetical 0.1 less in complicated
QoL (uncomplicated CRS) (short term)	Beta	0.604612	0.395388	0.1	0.9	Antonio et al. 2022,60 converted using Kim et al. 2012220
QoL (long term) HIPEC	Beta	0.606	0.394	0.1	0.9	Antonio et al. 2022,60 converted using Kim et al. 2012220
QoL (long term) control	Beta	0.606	0.394	0.1	0.9	Antonio et al. 2022,60 converted using Kim et al. 2012220

Colorectal cancer

HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy for colorectal peritoneal metastases

The results of the cost-effectiveness analysis are presented in Tables 9–13 and Figures 15–17. The deterministic results show that HIPEC + CRS + systemic chemotherapy results in more costs and similar QALYs as CRS + systemic chemotherapy. The incremental NMBs at willingness to pay (WTP) of £20,000 and £30,000 were −£6162.83 and −£6164.19, respectively, that is, incremental NMB was < 0, indicating that HIPEC + CRS + systemic chemotherapy was not cost-effective compared to CRS + systemic chemotherapy in NHS (see Table 9).

TABLE 9 - Net monetary benefits (deterministic results)

Calculated at willingness-to-pay thresholds of £20,000 and £30,000 per QALY gained.

Treatment	Costs	QALYs	NMBa
			£20,000	£30,000
Colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
HIPEC + CRS + chemotherapy	£13,021	6.3270	£113,519.32	£176,789.54
CRS + chemotherapy	£6861	6.3272	£119,682.14	£182,953.73
Incremental	£6160	−0.0001	−£6162.83	−£6164.19
Colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone
HIPEC + CRS + chemotherapy	£21,074	8.9770	£158,465.13	£248,234.86
Chemotherapy	£9560	3.0058	£50,555.67	£80,613.28
Incremental	£11,515	5.9712	£107,909.46	£167,621.58
Gastric cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
HIPEC + CRS + chemotherapy	£16,930	17.1311	£325,692.76	£497,004.04
CRS + chemotherapy	£13,542	16.2530	£311,518.04	£474,048.15
Incremental	£3388	0.8781	£14,174.73	£22,955.89
Gastric cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone
HIPEC + CRS + chemotherapy	£28,563	18.6927	£345,289.89	£532,216.48
Chemotherapy	£18,416	14.0955	£263,493.51	£404,448.25
Incremental	£10,147	4.5972	£81,796.38	£127,768.23
Ovarian cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
HIPEC + CRS + chemotherapy	£12,657	6.5189	£117,721.33	£182,910.73
CRS + chemotherapy	£9066	4.0013	£70,959.52	£110,972.50
Incremental	£3591	2.5176	£46,761.81	£71,938.23

FIGURE 15.

Scatterplot (colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy). The scatterplot shows that the points are clustered in the north-east and north-west quadrants, indicating that HIPEC + CRS + systemic chemotherapy results in more costs and similar QALYs as CRS + systemic chemotherapy.

FIGURE 16.

Cost-effectiveness acceptability curve (colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy). The cost-effectiveness acceptability curve indicates that the likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to CRS + systemic chemotherapy was around 50% at WTP thresholds up to £60,000.

FIGURE 17.

Tornado plot (colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy). The univariate sensitivity analysis reveals that the major uncertainties relate to the effectiveness of HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy in terms of survival and long-term HRQoL. ln, natural logarithm.

The PSA revealed that there was considerable uncertainty in the incremental NMB (see Table 10). The scatterplot revealed that the points were clustered in the north-east and north-west quadrants, confirming that HIPEC + CRS + systemic chemotherapy results in more costs and similar QALYs as CRS + systemic chemotherapy (see Figure 15).

TABLE 10 - Net monetary benefits (probabilistic results)

Calculated at willingness-to-pay thresholds of £20,000 and £30,000 per QALY gained.

Treatment	Costs	QALYs	NMBa
			£20,000	£30,000
Colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
HIPEC + CRS + chemotherapy	£12,463 (95% CI £9331 to £15,582)	6.1718 (95% CI 1.1429 to 11.4222)	£110,973 (95% CI £10,397 to £215,978)	£172,691 (95% CI £21,843 to £330,246)
CRS + chemotherapy	£6528 (95% CI £4841 to £8204)	5.9786 (95% CI 1.1814 to 8.4504)	£113,045 (95% CI £17,077 to £162,529)	£172,832 (95% CI £28,877 to £247,011)
Incremental	£5936 (95% CI £2049 to £9811)	0.1932 (95% CI −5.8078 to 7.1457)	−£2073 (95% CI −£122,112 to £137,008)	−£141 (95% CI −£180,212 to £208,473)
Colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone
HIPEC + CRS + chemotherapy	£20,596 (95% CI £15,364 to £25,723)	8.6721 (95% CI 1.5551 to 14.0329)	£152,847 (95% CI £10,256 to £260,008)	£239,568 (95% CI £25,645 to £400,566)
Chemotherapy	£9130 (95% CI £6766 to £11,462)	2.8728 (95% CI 0.5562 to 4.5809)	£48,327 (95% CI £1970 to £82,345)	£77,055 (95% CI £7555 to £128,058)
Incremental	£11,467 (95% CI £5171 to £17,572)	5.7993 (95% CI −1.7495 to 11.8965)	£104,520 (95% CI −£46,759 to £227,057)	£162,513 (95% CI −£64,427 to £345,845)
Gastric cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
HIPEC + CRS + chemotherapy	£16,927 (95% CI £12,722 to £21,131)	15.7213 (95% CI 3.6692 to 18.1617)	£297,500 (95% CI £56,485 to £349,456)	£454,714 (95% CI £93,228 to £530,854)
CRS + chemotherapy	£13,543 (95% CI £10,127 to £16,957)	14.9190 (95% CI 3.4656 to 17.2325)	£284,836 (95% CI £55,791 to £333,592)	£434,025 (95% CI £90,434 to £505,718)
Incremental	£3383 (95% CI −£2643 to £9419)	0.8024 (95% CI −12.5666 to 13.6696)	£12,664 (95% CI −£254,806 to £270,104)	£20,688 (95% CI −£380,551 to £406,649)
Gastric cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone
HIPEC + CRS + chemotherapy	£28,156 (95% CI £20,712 to £35,662)	17.1404 (95% CI 3.9852 to 19.8173)	£314,651 (95% CI £51,404 to £374,273)	£486,055 (95% CI £91,213 to £572,129)
Chemotherapy	£18,427 (95% CI £13,186 to £23,673)	13.5237 (95% CI 2.4548 to 19.8082)	£252,046 (95% CI £30,970 to £380,426)	£387,282 (95% CI £55,213 to £578,093)
Incremental	£9729 (95% CI −£664 to £20,215)	3.6167 (95% CI −12.7241 to 16.9960)	£62,606 (95% CI −£263,733 to £330,185)	£98,773 (95% CI −£390,946 to £500,566)
Ovarian cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
HIPEC + CRS + chemotherapy	£12,054 (95% CI £9067 to £15,053)	6.3020 (95% CI 1.1644 to 11.2114)	£113,986 (95% CI £11,005 to £211,674)	£177,006 (95% CI £22,564 to £323,785)
CRS + chemotherapy	£8511 (95% CI £6380 to £10,625)	3.9277 (95% CI 0.7494 to 6.4870)	£70,044 (95% CI £6390 to £121,491)	£109,322 (95% CI £13,952 to £186,353)
Incremental	£3543 (95% CI −£463 to £7586)	2.3742 (95% CI −4.3425 to 8.9759)	£43,942 (95% CI −£90,407 to £176,080)	£67,684 (95% CI −£133,694 to £265,809)

The likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to CRS + systemic chemotherapy was 46.5% and 47.6% at WTP of £20,000 and £30,000, respectively. The CEAC curve indicated that the likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to CRS + systemic chemotherapy was around 50% at even higher thresholds (see Figure 16).

The univariate sensitivity analysis revealed that CRS + systemic chemotherapy was cost-effective (compared to HIPEC + CRS + systemic chemotherapy) for most of the parameters for the entire range tested (see Table 11). The main parameters when the intervention becomes cost-effective were when HIPEC + CRS + systemic chemotherapy results in better survival and better long-term HRQoL compared to CRS + systemic chemotherapy (see Table 11; Figure 17).

TABLE 11 - Threshold analysis

ln, natural logarithm.

Variable	Distribution	Range tested	Step	Threshold (WTP: £20,000 per QALY)	Threshold (WTP: £30,000 per QALY)
Colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
Complications (HIPEC + CRS)	Beta	0–0.5	0.05	Control is cost-effective for the range tested	Control is cost-effective for the range tested
Short-term mortality (HIPEC + CRS)	Beta	0–0.1	0.05	Control is cost-effective for the range tested	Control is cost-effective for the range tested
Survival ln (HR)	Continuous	−2 to 2	0.05	Control becomes cost-effective when value is 0	Control becomes cost-effective when value is 0
Complications (Control)	Beta	0–0.5	0.05	Control is cost-effective for the range tested	Control is cost-effective for the range tested
Short-term mortality (control)	Beta	0–0.1	0.05	Intervention becomes cost-effective when value is 0.1	Intervention becomes cost-effective when value is 0.05
5-year mortality (control)	Beta	0–1	0.05	Control is cost-effective for the range tested	Control is cost-effective for the range tested
Cost (HIPEC + CRS) complicated	Uniform	11,391.51–21,155.66	500	Control is cost-effective for the range tested	Control is cost-effective for the range tested
Cost (HIPEC + CRS) uncomplicated	Uniform	8332.89–15,475.37	500	Control is cost-effective for the range tested	Control is cost-effective for the range tested
Cost (control) complicated	Uniform	7397.92–13,738.99	500	Control is cost-effective for the range tested	Control is cost-effective for the range tested
Cost (control) uncomplicated	Uniform	4339.3–8058.7	500	Control is cost-effective for the range tested	Control is cost-effective for the range tested
QoL (complicated HIPEC + CRS) (short term)	Beta	0.1–0.9	0.05	Control is cost-effective for the range tested	Control is cost-effective for the range tested
QoL (uncomplicated HIPEC + CRS) (short term)	Beta	0.1–0.9	0.05	Control is cost-effective for the range tested	Control is cost-effective for the range tested
QoL (complicated CRS) (short term)	Beta	0.1–0.9	0.05	Control is cost-effective for the range tested	Control is cost-effective for the range tested
QoL (uncomplicated CRS) (short term)	Beta	0.1–0.9	0.05	Control is cost-effective for the range tested	Control is cost-effective for the range tested
QoL (long term) HIPEC	Beta	0.1–0.9	0.05	Intervention becomes cost-effective when value is 0.85	Intervention becomes cost-effective when value is 0.85
QoL (long term) Control	Beta	0.1–0.9	0.05	Control becomes cost-effective when value is 0.75	Control becomes cost-effective when value is 0.8
Colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone
Complications (HIPEC + CRS)	Beta	0–0.5	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Short-term mortality (HIPEC + CRS)	Beta	0–0.1	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Survival ln (HR)	Continuous	−2 to 2	0.05	Control becomes cost-effective when value is 0	Control becomes cost-effective when value is 0
Complications (control)	Beta	0–0.5	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Short-term mortality (control)	Beta	0–0.1	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
5-year mortality (control)	Beta	0–1	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (HIPEC + CRS) complicated	Uniform	17,028.75–31,624.83	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (HIPEC + CRS) uncomplicated	Uniform	13,970.13–25,944.54	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (control) complicated	Uniform	9150.58–16,993.93	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (control) uncomplicated	Uniform	6091.96–11,313.64	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (complicated HIPEC + CRS) (short term)	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (uncomplicated HIPEC + CRS) (short term)	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (complicated CRS) (short term)	Beta	0.1 to 0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (uncomplicated CRS) (short term)	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (long term) HIPEC	Beta	0.1–0.9	0.05	Intervention becomes cost-effective when value is 0.35	Intervention becomes cost-effective when value is 0.3
QoL (long term) control	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Gastric cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
Complications (HIPEC + CRS)	Beta	0–0.5	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Short-term mortality (HIPEC + CRS)	Beta	0–0.1	0.05	Control becomes cost-effective when value is 0.05	Control becomes cost-effective when value is 0.05
Survival ln (HR)	Continuous	−2 to 2	0.05	Control becomes cost-effective when value is −0.05	Control becomes cost-effective when value is 0
Complications (control)	Beta	0–0.5	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Short-term mortality (control)	Beta	0–0.1	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
5-year mortality (control)	Beta	0–1	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (HIPEC + CRS) complicated	Uniform	14,459.67–26,853.67	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (HIPEC + CRS) uncomplicated	Uniform	11,401.05–21,173.38	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (control) complicated	Uniform	12,178.31–22,616.86	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (control) uncomplicated	Uniform	9119.69–16,936.57	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (complicated HIPEC + CRS) (short term)	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (uncomplicated HIPEC + CRS) (short term)	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (complicated CRS) (short term)	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (uncomplicated CRS) (short term)	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (long term) HIPEC	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (long term) control	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Gastric cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone
Complications (HIPEC + CRS)	Beta	0–0.5	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Short-term mortality (HIPEC + CRS)	Beta	0–0.1	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Survival ln (HR)	Continuous	−2 to 2	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Complications (control)	Beta	0–0.5	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Short-term mortality (control)	Beta	0–0.1	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
5-year mortality (control)	Beta	0–1	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (HIPEC + CRS) complicated	Uniform	22,603.12–41,977.23	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (HIPEC + CRS) uncomplicated	Uniform	19,544.5–36,296.93	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (control) complicated	Uniform	15,949.79–29,621.04	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (control) uncomplicated	Uniform	12,891.17–23,940.75	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (complicated HIPEC + CRS) (short term)	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (uncomplicated HIPEC + CRS) (short term)	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (complicated CRS) (short term)	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (uncomplicated CRS) (short term)	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (long term) HIPEC	Beta	0.1–0.9	0.05	Intervention becomes cost-effective when value is 0.7	Intervention becomes cost-effective when value is 0.7
QoL (long term) control	Beta	0.1–0.9	0.05	Control becomes cost-effective when value is 0.85	Control becomes cost-effective when value is 0.85
Ovarian cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
Complications (HIPEC + CRS)	Beta	0–0.5	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Short-term mortality (HIPEC + CRS)	Beta	0–0.1	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Survival ln (HR)	Continuous	−2 to 2	0.05	Control becomes cost-effective when value is 0	Control becomes cost-effective when value is 0
Complications (control)	Beta	0–0.5	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Short-term mortality (control)	Beta	0–0.1	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
5-year mortality (control)	Beta	0–1	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (HIPEC + CRS) complicated	Uniform	11,100.62–20,615.43	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (HIPEC + CRS) uncomplicated	Uniform	8042–14,935.13	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (control) complicated	Uniform	8635.66–16,037.65	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
Cost (control) uncomplicated	Uniform	5577.04–10,357.36	500	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (complicated HIPEC + CRS) (short term)	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (uncomplicated HIPEC + CRS) (short term)	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (complicated CRS) (short term)	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (uncomplicated CRS) (short term)	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested
QoL (long term) HIPEC	Beta	0.1–0.9	0.05	Intervention becomes cost-effective when value is 0.4	Intervention becomes cost-effective when value is 0.4
QoL (long term) control	Beta	0.1–0.9	0.05	Intervention is cost-effective for the range tested	Intervention is cost-effective for the range tested

The EVPI between was £25 and £39 million per 1000 people (see Table 12). The expected value of perfect parameter information (EVPPI) could not be estimated because of insufficient computer memory.

TABLE 12 - Expected value for perfect information (per 1000 people)

Willingness-to-pay threshold
£20,000	£30,000
Colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
£25,489,715.67	£39,621,153.71
Colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone
£3,169,055.03	£4,155,359.80
Gastric cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
£31,579,625.20	£46,847,924.61
Gastric cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone
£29,220,352.71	£41,999,823.03
Ovarian cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
£12,781,413.10	£18,668,735.51

HIPEC + CRS + systemic chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases

The results of the cost-effectiveness analysis are presented in Tables 9–13 and Figures 18–21. The deterministic results show that HIPEC + CRS + systemic chemotherapy results in more costs and more QALYs than systemic chemotherapy alone. The incremental NMBs at WTP of £20,000 and £30,000 were £107,909.46 and £167,621.58, respectively, that is, incremental NMB was more than zero, indicating that HIPEC + CRS + systemic chemotherapy may be cost-effective compared to systemic chemotherapy alone in NHS (see Table 9).

FIGURE 18.

Scatterplot (colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone). The scatterplot shows that the points are clustered in the north-east quadrant, indicating that HIPEC + CRS + systemic chemotherapy results in more costs and more QALYs than systemic chemotherapy alone.

FIGURE 19.

Cost-effectiveness acceptability curve (colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone). The cost-effectiveness acceptability curve indicates that the likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to systemic chemotherapy alone was around 90% at WTP thresholds >£10,000 up to £60,000.

FIGURE 20.

Tornado plot (colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone). The univariate sensitivity analysis reveals that the major uncertainties relate to the effectiveness of HIPEC + CRS + systemic chemotherapy versus systemic chemotherapy alone in terms of survival and long-term HRQoL. ln, natural logarithm.

FIGURE 21.

Expected value of perfect parameter information (colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone).

The PSA revealed that there was some uncertainty in the incremental NMB (see Table 10). The scatterplot revealed that the points were clustered in the north-east quadrant, confirming that HIPEC + CRS + systemic chemotherapy results in more costs and more QALYs than systemic chemotherapy alone (see Figure 18).

The likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to systemic chemotherapy alone was 89.3% and 90.3% at WTP of £20,000 and £30,000, respectively. The CEAC curve indicated that the likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to systemic chemotherapy alone was around 90% at WTP thresholds >£10,000 up to £60,000 (see Figure 19).

The univariate sensitivity analysis revealed that HIPEC + CRS + systemic chemotherapy was cost-effective compared to systemic chemotherapy alone for most of the parameters for the entire range tested (see Table 11). The main parameters when the intervention becomes cost-effective was when HIPEC + CRS + systemic chemotherapy results in better survival and better long-term HRQoL compared systemic chemotherapy alone (see Table 11; Figure 20).

The EVPI was between £3 and £4 million per 1000 people (see Table 12). The EVPPI shows that the main uncertainties appear to be in the probabilities and costs (see Table 13; Figure 21).

TABLE 13 - Expected value for perfect parameter information (per 1000 people)

Not estimable because of computing power required.

Parameters	WTP threshold: £20,000	WTP threshold: £30,000
Colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
Probabilities	Not estimablea	Not estimablea
Costs	Not estimablea	Not estimablea
QoL	Not estimablea	Not estimablea
Colorectal cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone
Probabilities	£2,841,100.52	£3,744,343.32
Costs	£3,217,756.26	£4,247,070.12
QoL	£214,928.69	£219,547.80
Gastric cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
Probabilities	Not estimablea	Not estimablea
Costs	Not estimablea	Not estimablea
QoL	Not estimablea	Not estimablea
Gastric cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone
Probabilities	£29,139,433.25	£41,796,876.45
Costs	£29,196,348.60	£42,016,418.43
QoL	–	–
Ovarian cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy
Probabilities	£12,325,971.11	£17,989,799.71
Costs	£13,308,599.36	£19,451,913.17
QoL	£58,459.84	£71,190.49

Gastric cancer

HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy for gastric peritoneal metastases

The results of the cost-effectiveness analysis are presented in Tables 9–13, Figures 22–24. The deterministic results show that HIPEC + CRS + systemic chemotherapy results in more costs and more QALYs than CRS + systemic chemotherapy. The incremental NMBs at WTP of £20,000 and £30,000 were £14,174.73 and £22,955.89, respectively, that is, incremental NMB was more than zero, indicating that HIPEC + CRS + systemic chemotherapy may be cost-effective compared to CRS + systemic chemotherapy in NHS (see Table 9).

FIGURE 22.

Scatterplot (gastric cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy). The scatterplot shows that the points are clustered in the north quadrant, indicating that HIPEC + CRS + systemic chemotherapy results in more costs, but there is uncertainty in QALYs than CRS + systemic chemotherapy.

FIGURE 23.

Cost-effectiveness acceptability curve (gastric cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy). The cost-effectiveness acceptability curve indicates that the likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to CRS + systemic chemotherapy was around 70% at WTP thresholds >£10,000 up to £60,000.

FIGURE 24.

Tornado plot (gastric cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy). The univariate sensitivity analysis reveals that the major uncertainties relate to the effectiveness of HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy in terms of survival and long-term HRQoL. ln, natural logarithm.

The PSA revealed that there was considerable uncertainty in the incremental NMB (see Table 10). The scatterplot revealed that the points were clustered in the north quadrants, confirming that HIPEC + CRS + systemic chemotherapy results in more costs than CRS + systemic chemotherapy, but there is uncertainty in QALYs compared to CRS + systemic chemotherapy (see Figure 22).

The likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to CRS + systemic chemotherapy was 69.8% and 70.3% at WTP of £20,000 and £30,000, respectively. The CEAC curve indicated that the likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to CRS + systemic chemotherapy was around 70% at WTP thresholds >£10,000 up to £60,000 (see Figure 23).

The univariate sensitivity analysis revealed that HIPEC + CRS + systemic chemotherapy was cost-effective compared to CRS + systemic chemotherapy for most of the parameters for the entire range tested (see Table 11). The main parameters when the intervention becomes cost-effective was when HIPEC + CRS + systemic chemotherapy results in better survival and better long-term HRQoL compared to CRS + systemic chemotherapy (see Table 11; Figure 24).

The EVPI was between £32 million and £47 million per 1000 people (see Table 12). The EVPPI could not be estimated because of insufficient computer memory.

HIPEC + CRS + systemic chemotherapy versus systemic chemotherapy for gastric peritoneal metastases

The results of the cost-effectiveness analysis are presented in Tables 9–13, Figures 25–28. The deterministic results show that HIPEC + CRS + systemic chemotherapy results in more costs and more QALYs than systemic chemotherapy alone. The incremental NMBs at WTP of £20,000 and £30,000 were £81,796.38 and £127,768.23, respectively, that is, incremental NMB was more than zero, indicating that HIPEC + CRS + systemic chemotherapy may be cost-effective compared to systemic chemotherapy alone in the NHS (see Table 9).

FIGURE 25.

Scatterplot (gastric cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone). The scatterplot shows that the points are clustered in the north-east quadrant, indicating that HIPEC + CRS + systemic chemotherapy results in more costs and more QALYs than systemic chemotherapy alone.

FIGURE 26.

Cost-effectiveness acceptability curve (gastric cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone). The cost-effectiveness acceptability curve indicates that the likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to systemic chemotherapy alone was around 55–65% at WTP thresholds >£10,000 up to £60,000.

FIGURE 27.

Tornado plot (gastric cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone). The univariate sensitivity analysis reveals that the major uncertainties relate to the effectiveness of HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone in terms of long-term HRQoL. ln, natural logarithm.

FIGURE 28.

Expected value of perfect parameter information (gastric cancer: HIPEC + CRS + systemic chemotherapy vs. systemic chemotherapy alone).

The PSA revealed that there was considerable uncertainty in the incremental NMB (see Table 10). The scatterplot revealed that the points were clustered in the north-east quadrant, confirming that HIPEC + CRS + systemic chemotherapy results in more costs and more QALYs than systemic chemotherapy alone (see Figure 25).

The likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to systemic chemotherapy alone was 63.0% and 64.9% at WTP of £20,000 and £30,000, respectively. The CEAC curve indicated that the likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to systemic chemotherapy alone was around 55–65% at WTP thresholds >£10,000 up to £60,000 (see Figure 26).

The univariate sensitivity analysis revealed that HIPEC + CRS + systemic chemotherapy was cost-effective compared to systemic chemotherapy alone for most of the parameters for the entire range tested (see Table 11). The main parameters when the intervention becomes cost-effective was when HIPEC + CRS + systemic chemotherapy results in better long-term HRQoL compared to systemic chemotherapy alone (see Table 11; Figure 27).

The EVPI was between £29 and £42 million per 1000 people (see Table 12). The EVPPI shows that the main uncertainties appear to be in the probabilities and costs (see Table 13; Figure 28).

Ovarian cancer (stage III or greater epithelial ovarian cancer requiring interval cytoreductive surgery)

The results of the cost-effectiveness analysis are presented in Tables 9–13 and Figures 29–32. The deterministic results show that HIPEC + CRS + systemic chemotherapy results in more costs and more QALYs than CRS +systemic chemotherapy. The incremental NMBs at WTP of £20,000 and £30,000 were £46,761.81 and £71,938.23, respectively, that is, incremental NMB was more than zero, indicating that HIPEC + CRS + systemic chemotherapy was cost-effective compared to CRS +systemic chemotherapy in NHS (see Table 9).

FIGURE 29.

Scatterplot (ovarian cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy). The scatterplot shows that the points are clustered in the north-east quadrant, indicating that HIPEC + CRS + systemic chemotherapy results in more costs and more QALYs than CRS + systemic chemotherapy.

FIGURE 30.

Cost-effectiveness acceptability curve (ovarian cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy). The cost-effectiveness acceptability curve indicates that the likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to CRS + systemic chemotherapy was around 70% at WTP thresholds >£10,000 up to £60,000.

FIGURE 31.

Tornado plot (ovarian cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy). The univariate sensitivity analysis reveals that the major uncertainties relate to the effectiveness of HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy in terms of survival and long-term HRQoL. ln, natural logarithm.

FIGURE 32.

Expected value of perfect parameter information (ovarian cancer: HIPEC + CRS + systemic chemotherapy vs. CRS + systemic chemotherapy).

The PSA revealed that there was considerable uncertainty in the incremental NMB (see Table 10). The scatterplot revealed that the points were clustered in the north-east quadrant, confirming that HIPEC + CRS + systemic chemotherapy results in more costs and more QALYs than CRS + systemic chemotherapy (see Figure 29).

The likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to CRS + systemic chemotherapy was 71.9% and 72.4% at WTP of £20,000 and £30,000, respectively. The CEAC curve indicated that the likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to CRS + systemic chemotherapy was around 70% at WTP thresholds >£10,000 up to £60,000 (see Figure 30).

The univariate sensitivity analysis revealed that HIPEC + CRS + systemic chemotherapy was cost-effective compared to CRS + systemic chemotherapy for most of the parameters for the entire range tested (see Table 11). The main parameters when the intervention becomes cost-effective were when HIPEC + CRS + systemic chemotherapy results in better survival and better long-term HRQoL compared to CRS + systemic chemotherapy (see Table 11; Figure 31).

The EVPI was between £13 and £19 million per 1000 people (see Table 12). The EVPPI shows that the main uncertainties appear to be in the probabilities and costs (see Table 13; Figure 32).

Sensitivity analysis

Sensitivity analysis using real-life data did not make major changes to the conclusions of the cost-effectiveness analysis.

Summary of cost-effectiveness analysis

The summary of cost-effectiveness analysis is available in Table 14.

TABLE 14 - Summary of cost-effectiveness analysis (colorectal, gastric and stage III or greater epithelial ovarian cancers)

Intervention is HIPEC + CRS + systemic chemotherapy.

Cancer type	Controla	Probability of being cost-effective (%)	Incremental net benefits (deterministic analysis)	Incremental net benefits (PSA)
WTP threshold: £20,000
Colorectal cancer	CRS + systemic chemotherapy	46.5	−£6162.83	−£2073 (95% CI −£122,112 to £137,008)
Colorectal cancer	Systemic chemotherapy alone	89.3	£107,909.46	£104,520 (95% CI −£46,759 to £227,057)
Gastric cancer	CRS + systemic chemotherapy	69.8	£14,174.73	£12,664 (95% CI −£254,806 to £270,104)
Gastric cancer	Systemic chemotherapy alone	63.0	£81,796.38	£62,606 (95% CI −£263,733 to £330,185)
Ovarian cancer	CRS + systemic chemotherapy	71.9	£46,761.81	£43,942 (95% CI −£90,407 to £176,080)
WTP threshold: £30,000
Colorectal cancer	CRS + systemic chemotherapy	47.6	−£6164.19	−£141 (95% CI −180,212 to £208,473)
Colorectal cancer	Systemic chemotherapy alone	90.3	£167,621.58	£162,513 (95% CI −£64,427 to £345,845)
Gastric cancer	CRS + systemic chemotherapy	70.3	£22,955.89	£20,688 (95% CI −£380,551 to £406,649)
Gastric cancer	Systemic chemotherapy alone	64.9	£127,768.23	£98,773 (95% CI −£390,946 to £500,566)
Ovarian cancer	CRS + systemic chemotherapy	72.4	£71,938.23	£67,684 (95% CI −£133,694 to £265,809)

Chapter 6 Discussion

Chapter 7 Conclusions

Equality, diversity and inclusion

Other than the ovarian cancer trials, the proportion of women and men in the trials was similar, with women consisting of 40–50% of the overall sample size. There was no report in the trials about inclusion of people with disabilities. There was also no report of ethnicity in the trials. Therefore, we are unable to comment whether the proportion of trial participants who belonged to different ethnic groups was similar to that in the population.

Our research team was diverse, with representation from many ethnic groups and genders.

Additional information

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Appendix 1 Search strategies

Appendix 2 Methods for panoramic meta-analyses

Convergence

Unprocessed results

	Mean	SD	MC_error	val2.5pc	Median	val97.5pc	Start	Sample
B1	−0.9584	1.409	0.002573	−3.669	−0.9612	1.778	300,001	900,000
B2	−0.3165	1.139	0.002579	−2.527	−0.3176	1.897	300,001	900,000
d2.colorectal	−0.00277	0.9864	0.002052	−1.918	−1.95E-04	1.912	300,001	900,000
d2.gastric	−0.9611	1.008	0.001175	−2.906	−0.9611	0.9706	300,001	900,000
d2.ovarian	−0.3193	0.5703	7.91E-04	−1.431	−0.3175	0.7797	300,001	900,000
SD	0.5709	0.7729	0.00142	0.01214	0.2935	3.083	300,001	900,000
	Dbar	Dhat	DIC	pD
y	−0.4598	−4.684	3.765	4.224
total	−0.4598	−4.684	3.765	4.224

FIGURE 33.

Convergence

Appendix 3 Additional characteristics of included studies

Appendix 4 Excluded studies: reasons for exclusion

Appendix 5 Ongoing studies

Appendix 6 Additional records

Appendix 7 Calculation of costs used in the cost-effectiveness analysis