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Clinical Trial Results:
ESPAC-5F: European Study Group for Pancreatic Cancer - Trial 5F Four arm, prospective, multicentre, randomised feasibility trial of immediate surgery compared with neoadjuvant chemotherapies and neoadjuvant chemoradiotherapy.

Summary
EudraCT number	2013-003932-56
Trial protocol	GB DE IE FI
Global end of trial date	03 Feb 2021

Results information
Results version number	v1(current)
This version publication date	12 Feb 2022
First version publication date	12 Feb 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

UoL000726

ISRCTN number

ISRCTN89500674

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

University of Liverpool

Sponsor organisation address

1-3 Brownlow Street, Liverpool, United Kingdom, L69 3GL

Public contact

Ms Charlotte Rawcliffe , University of Liverpool, +44 1517948167, espac5@liverpool.ac.uk

Scientific contact

Professor Paula Ghaneh, University of Liverpool, +44 1517064062, paula@liverpool.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

31 Dec 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Dec 2019

Global end of trial reached?

Yes

Global end of trial date

03 Feb 2021

Was the trial ended prematurely?

Main objective of the trial

1. Recruitment Rate: Is it feasible to recruit and randomise patients with borderline resectable pancreatic cancer to receive immediate surgical exploration versus neoadjuvant chemotherapies or chemoradiotherapy? 2. Resection Rate: Resection rate will be measured using the total number of patients in the arm as baseline and, secondly, using the number of patients having explorative surgery. R0 (resection margins free of tumour) and R1 (Tumour within 1 mm of resection margin) resection margins will be included in the resection rate but not R2 resection (tumour present at resection margin).

Protection of trial subjects

Surgery Immediate surgery is standard practice and the risks to the patient are as expected for that treatment. Mortality rate is < 5% in specialist centres. The overall complication rate even in specialist centres is 18-54%. Reviews of large series of pancreatic resections shows an incidence of common complications of 10.4% for fistula, 9.9% for delayed gastric emptying, 4.8% for bleeding, 4.8% for wound infection and 3.8% for intra-abdominal abscess . The median hospital stay is 13-18 days in different series. The re-operation rate varies from 4 to 9% with a mortality rate of 23 to 67%. Major complications are a significant factor in post-operative mortality, especially if they require re-operation. The use of octreotide or somatostatin to prevent complications is supported by several multicentre, double-blind, randomized controlled trials. The best way to improve outcome is to concentrate pancreatic cancer care in regional specialist centre as was implemented in this trial. Gemcitabine and Capecitabine and Folinic acid, 5-Fluorouracil, Oxaliplatin and Irinotecan The planned chemotherapy used in the study has a well described toxicity profile when used within the terms of its marketing authorisation and administered in experienced tertiary care centres Radiotherapy The risks of upper abdominal radiotherapy are significant because of the proximity of gross tumour volume (GTV) to several critical structures. The optimum balance between efficacy and toxicity will be achieved by employing strict protocol defined target definition and strict CRT QA and will be carefully documented.

Background therapy

Arm A: Immediate surgery: Patients will undergo a pylorus preserving or classical Kausch Whipple resection with standard lymphadenectomy. Total pancreatectomy will be accepted if clinically indicated. Surgery alone with no neoadjuvant chemotherapy or chemoradiotherapy was the established standard of care in the Uk for this group of patients at the point of study commencement.

Evidence for comparator

At the point of designing this study there was no clear evidence to indicate if either neoadjuvant chemotherapy (CT) or chemoradiotherapy (CRT) is superior. At this stage a randomized neoadjuvant trial should include both CT and CRT arms to evaluate the relative merits/demerits of either modality. The proposed CT and CRT arms have demonstrated the best survival and response rates in Phase III trials +/- meta-analyses. Arm B: Gemcitabine plus capecitabine (GEMCAP): GEMCAP versus gemcitabine demonstrated significantly improved objective response rate (19.1% v 12.4%; P = .034) and progression-free survival (hazard ratio [HR], 0.78; 95% CI, 0.66 to 0.93; P = .004) in patients with advanced pancreatic cancer. Meta-analysis of two additional studies involving 935 patients showed a significant survival benefit in favour of GEM-CAP (HR, 0.86; 95% CI, 0.75 to 0.98; P = .02) versus gemcitabine. Neoadjuvant GEMCAP has been used in forty-three patients (18 with BR disease and 25 with LA disease). The radiologic response rate was 18.6%, median overall survival was 23.1 months in patients who underwent surgery and 13.2 months in patients unable to complete surgery (P = .017). Arm C: Oxaliplatin, irinotecan, fluorouracil, and Folinic acid (FOLFIRINOX): A Phase III trial of patients with metastatic pancreatic cancer comparing FOLFIRINOX with gemcitabine; demonstrated median overall survival of 11.1 months with FOLFIRINOX versus 6.8 months with gemcitabine (HR, 0.57; 95% [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months with FOLFIRINOX versus 3.3 months with gemcitabine (HR, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% with FOLFIRINOX versus 9.4% with gemcitabine (P<0.001) [29]. The majority of patients in this trial had body and tail tumours and good performance status. Arm D: Capecitabine based chemoradiotherapy (CRT): Chemoradiotherapy [CRT] has been the commonest modality tested in neoadjuvant therapy to date.

Actual start date of recruitment

01 Apr 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 90

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

The aim was to recruit 100 patients in a ratio of 2:1:1:1 between surgery and the three neoadjuvant interventions. The minimum acceptable sample size was 75, 30 for Arm A, 15 for Arms B, C and D. The minimum acceptable sample size was achieved, with 90 patients randomised in the ratio 33:20:20:17.

Screening details

Number of subjects started

542 ^[1]

Intermediate milestone: Number of subjects

Central Review: 158

Number of subjects completed

Reason: Number of subjects

Patients deemed unsuitable at screening: 384

Reason: Number of subjects

Patients unsuitable at central review: 68

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The majority of patients presenting with pancreatic cancer are not suitable for surgery (~80%), thus while 542 patients were screened, only 90 were deemed to be suitable. Of those 90, 86 started treatment.

Period 1 title

Treatment Phase (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Immediate Surgery

Arm description

Patients will undergo a pylorus preserving or classical Kausch Whipple resection with standard lymphadenectomy. Total pancreatectomy will be accepted if clinically indicated. Surgery alone with no neoadjuvant chemotherapy or chemoradiotherapy was the established standard of care in the Uk for this group of patients at the point of study commencement.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

GEMCAP

Arm description

Within two weeks of randomisation, eligible patients will commence neoadjuvant gemcitabine, 1000mg/m2 iv infusion over 30 minutes, days 1, 8 and 15 of a 28 day cycle and capecitabine 830mg/m2 BD PO for 21 out of 28 days (one cycle) for 2 cycles i.e. 8 weeks. Four to six weeks after completion of chemotherapy patients will undergo staging CT scan. If there has been no progression patients will then undergo surgical exploration within two weeks as in Arm A (surgery alone)

Arm type

Experimental

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

SUB02324MIG

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1000mg/m2 iv infusion over 30 minutes, days 1, 8 and 15 of a 28 day cycle for 2 cycles, i.e. 8 weeks.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

SUB12474MIG

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

capecitabine 830mg/m2 BD orally for 21 out of 28 day (one cycle) for 2 cycles, i.e. 8 weeks

FOLFIRINOX

Arm description

Within two weeks of randomisation, eligible patients will commence neoadjuvant oxaliplatin 85mg/m2 , irinotecan 180mg/m2 , folinic acid given according to local practice for both the drug and the dose, 5-FU 400mg/m2 bolus injection followed by 2400mg/m2 46 hour infusion, repeated every 2 weeks for 4 cycles i.e. 8 weeks. Growth factor support may be administered at the investigator’s discretion. Four to six weeks after completion of chemotherapy patients will undergo staging CT scan. If there has been no progression patients will then undergo surgical exploration within two weeks as in Arm A (surgery alone)

Arm type

Experimental

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

SUB09490MIG

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

85mg/m2 IV infusion over 2 hours on day one repeated every 2 weeks (1 cycle) for 4 cycles. i.e. 8 weeks

Investigational medicinal product name

Irinotecan

Investigational medicinal product code

SUB02772MIG

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

180mg/m2 IV over 30 to 90 minutes on day 1 repeated every 2 weeks (one cycle) for 4 cycles. i.e. 8 weeks.

Investigational medicinal product name

Fluorouracil

Investigational medicinal product code

SUB27520

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

400mg/m2 bolus injection followed by 2400mg/m2 infusion over 46 hours. Repeated every 2 weeks for 4 cycles. i.e. 8 weeks

Investigational medicinal product name

Folinic acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

400mg/m2 IV on day 1 repeated every 2 weeks for 4 cycles. i.e. 8 weeks

ChemoRadiotherapy

Arm description

Within two weeks of randomisation, eligible patients will commence neoadjuvant chemoradiotherapy (CRT) delivering a total dose of 50.4Gy in 28 daily fractions over 5 1/2 weeks (1.8Gy/fraction, Mon to Fri) with capecitabine 830mg/m2 BD PO (Mon to Fri) throughout radiotherapy. Four to six weeks after completion of CRT patients will undergo a staging CT scan. If there has been no progression patients will then undergo surgical exploration within two weeks as in Arm A (surgery alone)

Arm type

Experimental

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

SUB12474MIG

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine 830mg/m2 twice daily orally on days of radiotherapy only. i.e. total of 28 days

Number of subjects in period 1	Immediate Surgery	GEMCAP	FOLFIRINOX	ChemoRadiotherapy
Started	33	20	20	17
Total number started treatment	31	19	20	16
Completed all treatment	30	17	15	11
Completed	9	13	15	9
Not completed	24	7	5	8
Physician decision	2	-	1	2
Consent withdrawn by subject	-	1	-	-
Advanced illness	-	-	1	-
Death	18	4	3	5
Did not start treatment	2	1	-	1
Withdrawn from surgery	1	-	-	-
Lost to follow-up	1	-	-	-
Refused chemotherapy during trial period	-	1	-	-

Baseline characteristics

Top of page

Reporting group title

Immediate Surgery

Reporting group description

Reporting group title

GEMCAP

Reporting group description

Reporting group title

FOLFIRINOX

Reporting group description

Reporting group title

ChemoRadiotherapy

Reporting group description

Reporting group values	Immediate Surgery	GEMCAP	FOLFIRINOX	ChemoRadiotherapy	Total
Number of subjects	33	20	20	17	90
Age categorical
Units: Subjects
In utero					0
Preterm newborn infants (gestational age < 37 wks)					0
Newborns (0-27 days)					0
Infants and toddlers (28 days-23 months)					0
Children (2-11 years)					0
Adolescents (12-17 years)					0
Adults (18-64 years)					0
From 65-84 years					0
85 years and over					0
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	61 (54 to 66)	63 (58 to 70)	64 (63 to 70)	66 (59 to 69)	-
Gender categorical
Units: Subjects
Female	19	10	10	9	48
Male	12	9	10	7	38
Not recorded	2	1	0	1	4
Diabetic Status
Units: Subjects
No	23	13	7	12	55
Type II	4	4	8	3	19
Type II (on insulin)	4	2	5	1	12
Not recorded	2	1	0	1	4
Smoking Status
Units: Subjects
Current	7	4	2	3	16
Past	10	7	3	8	28
Never	14	8	15	5	42
Not recorded	2	1	0	1	4
WHO Performance Status
Units: Subjects
Zero	16	6	8	9	39
One	15	13	12	7	47
Not recorded	2	1	0	1	4
T Stage
Units: Subjects
T1	0	0	1	0	1
T2	2	4	4	0	10
T3	24	12	13	16	65
T4	5	3	2	0	10
Not recorded	2	1	0	1	4
N Stage
Units: Subjects
N0	11	10	10	5	36
N1	18	9	9	11	47
nX	2	0	1	0	3
Not recorded	2	1	0	1	4
Cytology/EUS Biopsy
Units: Subjects
Adenocarcinoma	31	19	20	16	86
Not recorded	2	1	0	1	4
Surgical characteristic- Operation type
Units: Subjects
Pylorus preserving Whipples	15	5	11	6	37
Standard Whipples	2	5	0	1	8
Total pancreatectomy	4	1	0	1	6
Bypass	6	0	5	2	13
Open and Close	1	2	1	0	4
No Surgery	3	6	3	6	18
Not recorded	2	1	0	1	4
Extent of resection
Within 51 resected patients
Units: Subjects
Resection with extended lyphadenectomy	5	5	1	2	13
Standard resection	16	6	10	6	38
Not recorded	12	9	9	9	39
Vein resection
Within 51 resected patients
Units: Subjects
No	7	5	5	2	19
Yes	14	6	6	6	32
Not recorded	12	9	9	9	39
Tumour Stage
From 51 resected patients
Units: Subjects
pT1	0	0	3	2	5
pT2	4	3	0	2	9
pT3	17	8	8	4	37
Not recorded	12	9	9	9	39
Nodes
Units: Subjects
Negative	2	4	3	6	15
Positive	19	7	8	2	36
Not recorded	12	9	9	9	39
Metastases
Units: Subjects
M0	21	11	11	8	51
Not recorded	12	9	9	9	39
R Status
Units: Subjects
R0	3	2	2	3	10
R1	18	9	9	5	41
Not recorded	12	9	9	9	39
Differentiation
Units: Subjects
Undifferentiated	0	1	0	0	1
Poor	6	1	4	2	13
Moderate	15	4	6	2	27
Well	0	2	1	1	4
Not assessed	0	3	0	3	6
Not recorded	12	9	9	9	39
Total lymph nodes
Units: Subjects
0-9	0	0	1	2	3
10-19	9	3	5	1	18
20+	12	8	5	5	30
Not recorded	12	9	9	9	39
Positive lymph nodes
Units: Subjects
Zero	2	4	3	6	15
One	7	3	2	2	14
Two or more	12	4	6	0	22
Not recorded	12	9	9	9	39
Resection Margin
More than one resection margin can refer to the same patient. For the purposes of presenting the correct data in a format the website will accept, 4 subject analysis sets are defined as "Armname for resection margin". The data presented in the four overall reporting groups are meaningless for this variable.
Units: Subjects
Posterior	0	0	0	0	0
Anterior	0	0	0	0	0
SMV Groove	0	0	0	0	0
Pancreatic Neck	0	0	0	0	0
Bile Duct	0	0	0	0	0
Duodenal Resection	0	0	0	0	0
Gastric Resection	0	0	0	0	0
Other	33	20	20	17	90
CA19-9
Data available for 82 patients split 29:18:19:16.
Units: kU/L
median (inter-quartile range (Q1-Q3))	802.0 (183 to 1854.7)	503.6 (234.2 to 1364.8)	622.5 (75.5 to 1294.5)	321.5 (67.4 to 717.0)	-
Haemoglobin
Data available for 85 patients split 31:18:20:16.
Units: g/L
median (inter-quartile range (Q1-Q3))	124.0 (115.5 to 130.0)	129.0 (124.5 to 144.5)	123.0 (119.8 to 128.8)	137.0 (122.8 to 142.0)	-
Platelets
Data available for 85 patients split 31:18:20:16.
Units: x10^9/L
median (inter-quartile range (Q1-Q3))	272.0 (229.5 to 390.0)	268.0 (201.0 to 321.0)	296.5 (214.5 to 321.0)	279.0 (219.5 to 340.0)	-
Absolute Neutrophil Count
Data available for 85 patients split 31:18:20:16.
Units: x10^9/L
median (inter-quartile range (Q1-Q3))	5.1 (4.0 to 6.7)	4.8 (4.2 to 6.5)	5.0 (4.1 to 5.8)	4.8 (4.2 to 5.4)	-
White Blood Cell Count
Data available for 85 patients split 31:18:20:16.
Units: x10^9/L
median (inter-quartile range (Q1-Q3))	7.7 (6.2 to 10.1)	8.1 (7.0 to 8.8)	7.6 (6.3 to 8.4)	8.1 (6.9 to 9.3)	-
Lymohocytes
Data available for 85 patients split 31:18:20:16.
Units: x10^9/L
median (inter-quartile range (Q1-Q3))	1.7 (1.3 to 2.3)	1.8 (1.4 to 2.2)	1.8 (1.4 to 2.1)	2.3 (1.8 to 2.9)	-
Sodium
Data available for 85 patients split 30:19:20:16.
Units: mmol/L
median (inter-quartile range (Q1-Q3))	139 (136.2 to 140.0)	137.0 (135.0 to 138.5)	137.0 (133.8 to 141.0)	138.5 (136.8 to 139.2)	-
Potassium
Data available for 84 patients split 30:19:20:15.
Units: mmol/L
median (inter-quartile range (Q1-Q3))	4.3 (4.1 to 4.6)	4.4 (4.0 to 4.8)	4.1 (3.6 to 4.4)	4.5 (4.3 to 4.7)	-
Calcium
Data available for 83 patients split 30:19:19:15.
Units: mmol/L
median (inter-quartile range (Q1-Q3))	2.4 (2.3 to 2.5)	2.4 (2.3 to 2.4)	2.4 (2.4 to 2.4)	2.4 (2.3 to 2.5)	-
Urea
Data available for 84 patients split 30:18:20:16.
Units: mmol/L
median (inter-quartile range (Q1-Q3))	4.0 (3.6 to 5.2)	4.2 (3.2 to 5.5)	4.5 (3.9 to 5.5)	5.0 (4.3 to 5.3)	-
Creatinine
Data available for 70 patients split 24:15:18:13.
Units: μmol/L
median (inter-quartile range (Q1-Q3))	65.0 (51.6 to 70.4)	64.0 (54.0 to 68.5)	67.6 (61.8 to 74.5)	61.5 (54.8 to 69.5)	-
Abumin
Data available for 70 patients split 24:15:18:13.
Units: g/L
median (inter-quartile range (Q1-Q3))	40.0 (38.0 to 44.2)	42.0 (37.0 to 43.0)	39.0 (35.0 to 44.8)	42.5 (37.6 to 44.1)	-
Bilirubin
Data available for 70 patients split 24:15:18:13.
Units: μmol/L
median (inter-quartile range (Q1-Q3))	15.0 (9.0 to 26.0)	17.0 (12.5 to 24.0)	19.8 (11.5 to 28.0)	19.5 (8.8 to 26.8)	-
AST
Either AST or ALT were required, all patients had at least one of the two. 70 patients had AST, split 24:15:18:13.
Units: IU/L
median (inter-quartile range (Q1-Q3))	30.5 (23.8 to 61.2)	28.0 (24.0 to 42.5)	42.5 (21.2 to 76.8)	31.0 (26.0 to 85.0)	-
ALT
Either AST or ALT were required. All patients had at least one of the two. 60 patients had ALT, split 23:14:12:11.
Units: IU/L
median (inter-quartile range (Q1-Q3))	26.0 (19.5 to 41.5)	26.5 (22.0 to 41.5)	28.5 (18.2 to 53.5)	29.0 (25.0 to 36.5)	-
ALK Phosphatase
Units: IU/L
median (inter-quartile range (Q1-Q3))	145.0 (111.5 to 213.5)	136.0 (105.5 to 194.5)	180.0 (111.0 to 238.0)	149.5 (106.2 to 207.0)	-
Maximum Tumour Dimension
Units: mm
median (inter-quartile range (Q1-Q3))	36 (32 to 45)	30 (30 to 42)	30 (22 to 35)	32 (22 to 43)	-

Subject analysis set title

Centre

Subject analysis set type

Per protocol

Subject analysis set description

Recruitment to randomisation, split by site.

Subject analysis set title

Baseline Patients

Subject analysis set type

Per protocol

Subject analysis set description

Full dataset incorporating all four arms

Subject analysis set title

Explorative Surgery Patients

Subject analysis set type

Per protocol

Subject analysis set description

Patients who had undergone explorative surgery

Subject analysis set title

Immediate Surgery for Resection Margin

Subject analysis set type

Per protocol

Subject analysis set description

Immediate surgery including repeated patients

Subject analysis set title

GEMCAP for resection margin

Subject analysis set type

Per protocol

Subject analysis set description

GEMCAP with repeated patients

Subject analysis set title

FOLFIRINOX for resection margin

Subject analysis set type

Per protocol

Subject analysis set description

FOLFIRINOX with repeated patients

Subject analysis set title

Chemoradiotherapy for resection margin

Subject analysis set type

Per protocol

Subject analysis set description

Chemoradiotherapy with repeated patients

Subject analysis set title

Baseline Patients Immediate Surgery

Subject analysis set type

Per protocol

Subject analysis set description

Baseline patients randomised to immediate surgery

Subject analysis set title

Baseline Patients Neoadjuvant Therapies

Subject analysis set type

Per protocol

Subject analysis set description

Baseline patients randomised to neoadjuvant therapies

Subject analysis set title

Explorative Surgery Immediate Surgery

Subject analysis set type

Per protocol

Subject analysis set description

Patients that underwent exploratory surgery who were randomised to immediate surgery

Subject analysis set title

Explorative Surgery Neoadjuvant Therapies

Subject analysis set type

Per protocol

Subject analysis set description

Patients that underwent explorative surgery who were randomised to neoadjuvant therapies

Subject analysis sets values	Centre	Baseline Patients	Explorative Surgery Patients	Immediate Surgery for Resection Margin	GEMCAP for resection margin	FOLFIRINOX for resection margin	Chemoradiotherapy for resection margin	Baseline Patients Immediate Surgery	Baseline Patients Neoadjuvant Therapies	Explorative Surgery Immediate Surgery	Explorative Surgery Neoadjuvant Therapies
Number of subjects	90	86	68	40	17	15	7	31	55	28	40
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))
Gender categorical
Units: Subjects
Female
Male
Not recorded
Diabetic Status
Units: Subjects
No
Type II
Type II (on insulin)
Not recorded
Smoking Status
Units: Subjects
Current
Past
Never
Not recorded
WHO Performance Status
Units: Subjects
Zero
One
Not recorded
T Stage
Units: Subjects
T1
T2
T3
T4
Not recorded
N Stage
Units: Subjects
N0
N1
nX
Not recorded
Cytology/EUS Biopsy
Units: Subjects
Adenocarcinoma
Not recorded
Surgical characteristic- Operation type
Units: Subjects
Pylorus preserving Whipples
Standard Whipples
Total pancreatectomy
Bypass
Open and Close
No Surgery
Not recorded
Extent of resection
Within 51 resected patients
Units: Subjects
Resection with extended lyphadenectomy
Standard resection
Not recorded
Vein resection
Within 51 resected patients
Units: Subjects
No
Yes
Not recorded
Tumour Stage
From 51 resected patients
Units: Subjects
pT1
pT2
pT3
Not recorded
Nodes
Units: Subjects
Negative
Positive
Not recorded
Metastases
Units: Subjects
M0
Not recorded
R Status
Units: Subjects
R0
R1
Not recorded
Differentiation
Units: Subjects
Undifferentiated
Poor
Moderate
Well
Not assessed
Not recorded
Total lymph nodes
Units: Subjects
0-9
10-19
20+
Not recorded
Positive lymph nodes
Units: Subjects
Zero
One
Two or more
Not recorded
Resection Margin
More than one resection margin can refer to the same patient. For the purposes of presenting the correct data in a format the website will accept, 4 subject analysis sets are defined as "Armname for resection margin". The data presented in the four overall reporting groups are meaningless for this variable.
Units: Subjects
Posterior				12	3	2	2
Anterior				8	3	2	0
SMV Groove				13	6	5	3
Pancreatic Neck				4	3	3	0
Bile Duct				0	1	1	0
Duodenal Resection				1	1	0	2
Gastric Resection				0	0	0	0
Other				2	0	2	0
CA19-9
Data available for 82 patients split 29:18:19:16.
Units: kU/L
median (inter-quartile range (Q1-Q3))
Haemoglobin
Data available for 85 patients split 31:18:20:16.
Units: g/L
median (inter-quartile range (Q1-Q3))
Platelets
Data available for 85 patients split 31:18:20:16.
Units: x10^9/L
median (inter-quartile range (Q1-Q3))
Absolute Neutrophil Count
Data available for 85 patients split 31:18:20:16.
Units: x10^9/L
median (inter-quartile range (Q1-Q3))
White Blood Cell Count
Data available for 85 patients split 31:18:20:16.
Units: x10^9/L
median (inter-quartile range (Q1-Q3))
Lymohocytes
Data available for 85 patients split 31:18:20:16.
Units: x10^9/L
median (inter-quartile range (Q1-Q3))
Sodium
Data available for 85 patients split 30:19:20:16.
Units: mmol/L
median (inter-quartile range (Q1-Q3))
Potassium
Data available for 84 patients split 30:19:20:15.
Units: mmol/L
median (inter-quartile range (Q1-Q3))
Calcium
Data available for 83 patients split 30:19:19:15.
Units: mmol/L
median (inter-quartile range (Q1-Q3))
Urea
Data available for 84 patients split 30:18:20:16.
Units: mmol/L
median (inter-quartile range (Q1-Q3))
Creatinine
Data available for 70 patients split 24:15:18:13.
Units: μmol/L
median (inter-quartile range (Q1-Q3))
Abumin
Data available for 70 patients split 24:15:18:13.
Units: g/L
median (inter-quartile range (Q1-Q3))
Bilirubin
Data available for 70 patients split 24:15:18:13.
Units: μmol/L
median (inter-quartile range (Q1-Q3))
AST
Either AST or ALT were required, all patients had at least one of the two. 70 patients had AST, split 24:15:18:13.
Units: IU/L
median (inter-quartile range (Q1-Q3))
ALT
Either AST or ALT were required. All patients had at least one of the two. 60 patients had ALT, split 23:14:12:11.
Units: IU/L
median (inter-quartile range (Q1-Q3))
ALK Phosphatase
Units: IU/L
median (inter-quartile range (Q1-Q3))
Maximum Tumour Dimension
Units: mm
median (inter-quartile range (Q1-Q3))

End points

Top of page

Reporting group title

Immediate Surgery

Reporting group description

Reporting group title

GEMCAP

Reporting group description

Reporting group title

FOLFIRINOX

Reporting group description

Reporting group title

ChemoRadiotherapy

Reporting group description

Subject analysis set title

Centre

Subject analysis set type

Per protocol

Subject analysis set description

Recruitment to randomisation, split by site.

Subject analysis set title

Baseline Patients

Subject analysis set type

Per protocol

Subject analysis set description

Full dataset incorporating all four arms

Subject analysis set title

Explorative Surgery Patients

Subject analysis set type

Per protocol

Subject analysis set description

Patients who had undergone explorative surgery

Subject analysis set title

Immediate Surgery for Resection Margin

Subject analysis set type

Per protocol

Subject analysis set description

Immediate surgery including repeated patients

Subject analysis set title

GEMCAP for resection margin

Subject analysis set type

Per protocol

Subject analysis set description

GEMCAP with repeated patients

Subject analysis set title

FOLFIRINOX for resection margin

Subject analysis set type

Per protocol

Subject analysis set description

FOLFIRINOX with repeated patients

Subject analysis set title

Chemoradiotherapy for resection margin

Subject analysis set type

Per protocol

Subject analysis set description

Chemoradiotherapy with repeated patients

Subject analysis set title

Baseline Patients Immediate Surgery

Subject analysis set type

Per protocol

Subject analysis set description

Baseline patients randomised to immediate surgery

Subject analysis set title

Baseline Patients Neoadjuvant Therapies

Subject analysis set type

Per protocol

Subject analysis set description

Baseline patients randomised to neoadjuvant therapies

Subject analysis set title

Explorative Surgery Immediate Surgery

Subject analysis set type

Per protocol

Subject analysis set description

Patients that underwent exploratory surgery who were randomised to immediate surgery

Subject analysis set title

Explorative Surgery Neoadjuvant Therapies

Subject analysis set type

Per protocol

Subject analysis set description

Patients that underwent explorative surgery who were randomised to neoadjuvant therapies

Primary: Recruitment Rate

Top of page

End point title

Recruitment Rate ^[1]

End point description

Recruitment rate will be measured by (i) recruitment rate by centre (ii) overall recruitment rate and (iii) a graph comparing expected versus actual cumulative recruitment. The recruitment target is 100 patients in 39 months. Recruitment rate per site is defined as the number of patients recruited at a site divided by the amount of time the site has been open to recruit. Recruitment rate (per site) = number of patients recruited in the site / (date of data lock – site green light date) Similarly, overall recruitment rate is defined as the number of patients recruited in the trial divided by the amount of the trial has been open to recruit. Recruitment rate (overall) = total number of patients recruited in the trial / (date of data lock –trial green light date)

End point type

Primary

End point timeframe

52 months

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This was a feasibility trial, and thus this endpoint was analysed by whether it met its minimum recruitment target within the study-period.

End point values	Centre
Number of subjects analysed	90
Units: Patients/unit time
number (confidence interval 95%)
Royal Liverpool and Clatterbridge	8.74 (6.18 to 11.99)
University Hospital of Heidelberg	4.80 (2.48 to 8.38)
Weston Park Hospital (Sheffield)	2.00 (0.80 to 4.12)
Hammersmith Hospital (London)	1.36 (0.44 to 3.18)
The Beatson WoSCC and Glasgow RI	1.55 (0.50 to 3.61)
Ninewells Hospital (Dundee)	1.32 (0.36 to 3.37)
The Christie and Manchester Royal Infirmary	1.40 (0.38 to 3.59)
Velindre and Singleton and Morriston	1.28 (0.35 to 3.27)
King's College and Guy's and St Thomas	0.92 (0.19 to 2.70)
Aberdeen Royal Infirmary	0.59 (0.07 to 2.13)
Queen Alexandra and Southampton General Hospital	0.68 (0.08 to 1.88)
Royal Marsden Hospital (London and Sutton)	0.52 (0.06 to 1.88)
Churchill and the Great Western Swindon	0.27 (0.01 to 1.52)
Queen Elizabeth Hospital (Birmingham)	0.27 (0.01 to 1.48)
Royal Free Hospital (London)	0.00 (0.00 to 2.18)
University Hospital Coventry	0.00 (0.00 to 1.14)
Overall	20.69 (16.64 to 25.43)

Attachments

Observed Recruitment

No statistical analyses for this end point

Primary: Resection Rate

Top of page

End point title

Resection Rate

End point description

An overall resection rate will be measured using the total number of patients at baseline. A second resection rate will also be measured using only the patients who undergo explorative surgery. R1 and R0 resection margins will be used when measuring the resection rate – R2 resection margins will be excluded. Resection rate is thus defined as the total number of resected R0 or R1 patients divided by the total number of patients at baseline or the total number of patients undergone surgery (two rates will be measured). Resection Rate (baseline pts) = number of R0 or R1 resected patients / number of patients at baseline Resection Rate (surgery pts) = number of R0 or R1 resected patients / number of patients undergone explorative surgery

End point type

Primary

End point timeframe

52 Months

End point values	Baseline Patients	Explorative Surgery Patients	Baseline Patients Immediate Surgery	Baseline Patients Neoadjuvant Therapies	Explorative Surgery Immediate Surgery	Explorative Surgery Neoadjuvant Therapies
Number of subjects analysed	86	68	31	55	28	40
Units: Resection Rate
number (confidence interval 95%)
Overall	0.59 (0.48 to 0.70)	0.75 (0.63 to 0.85)	0.68 (0.49 to 0.83)	0.55 (0.41 to 0.68)	0.75 (0.55 to 0.89)	0.75 (0.59 to 0.87)

Resection Rate (overall)

Statistical analysis description

A Chi-square test is performed to compare the resection rate of combined neoadjuvant therapies with that for immediate surgery.

Comparison groups

Baseline Patients Immediate Surgery v Baseline Patients Neoadjuvant Therapies

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[2]

P-value

> 0.05

Method

Chi-squared

Confidence interval

Notes
[2] - Investigation of recruitment to surgery, comparing immediate surgery with all neoadjuvant therapy arms.

Resection rate (explorative surgery)

Statistical analysis description

A Chi-square test is performed to compare the resection rate of combined neoadjuvant therapies with that for immediate surgery, for patients who had undergone exploratory surgery.

Comparison groups

Explorative Surgery Immediate Surgery v Explorative Surgery Neoadjuvant Therapies

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Chi-squared

Confidence interval

Secondary: R0 Resection Rate

Top of page

End point title

R0 Resection Rate

End point description

An overall R0 resection rate will be measured using the total number of patients at baseline. A second resection rate will also be measured using only the patients who undergo explorative surgery. The R0 resection margin is recorded according to the Royal College of Pathologists report on Standards and datasets for reporting cancers. Resection rate is defined as the total number of resected R0 patients divided by the total number of patients recruited or the total number of patients undergone surgery (two rates will be measured). R0 Resection Rate (baseline pts) = number of R0 resected patients / number of patients at baseline R0 Resection Rate (surgery pts) = number of R0 resected patients / number of patients undergone explorative surgery

End point type

Secondary

End point timeframe

52 months

End point values	Baseline Patients	Explorative Surgery Patients	Baseline Patients Immediate Surgery	Baseline Patients Neoadjuvant Therapies	Explorative Surgery Immediate Surgery	Explorative Surgery Neoadjuvant Therapies
Number of subjects analysed	86	68	31	55	28	40
Units: Resection Rate
number (confidence interval 95%)
Overall	0.12 (0.06 to 0.20)	0.15 (0.07 to 0.25)	0.10 (0.02 to 0.26)	0.13 (0.05 to 0.24)	0.11 (0.02 to 0.28)	0.18 (0.07 to 0.33)

R0 Resection Rate (overall)

Statistical analysis description

A Fisher’s exact test is performed to compare the rate of combined neoadjuvant therapies with that for immediate surgery.

Comparison groups

Baseline Patients Neoadjuvant Therapies v Baseline Patients Immediate Surgery

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Chi-squared

Confidence interval

R0 Resection Rate (Explorative Surgery)

Statistical analysis description

A Fisher’s exact test is performed to compare the rate of combined neoadjuvant therapies with that for immediate surgery, for patients who had undergone exploratory surgery.

Comparison groups

Explorative Surgery Immediate Surgery v Explorative Surgery Neoadjuvant Therapies

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Chi-squared

Confidence interval

Secondary: Post-operative complications rate

Top of page

End point title

Post-operative complications rate

End point description

Post-operative complications will be measured using morbidity and mortality rates. Post-operative morbidity will be recorded following surgery and classified according to existing guidelines. Post-operative mortality will be recorded as the 30 day mortality rate. Post-operative complications rates are defined as morbidity and 30-days mortality rates. The denominator of both measures will be the total number of patients undergone surgery. Morbidity Rate = number of patients with complications / number of patients undergone explorative surgery 30-days Mortality Rate = number of patients died within 30 days from surgery / number of patients undergone explorative surgery

End point type

Secondary

End point timeframe

Morbidity- any patient deemed to have post-operative morbidity before censoring Mortality- 30 days post-operative

End point values	Immediate Surgery	GEMCAP	FOLFIRINOX	ChemoRadiotherapy
Number of subjects analysed	28	13	17	10
Units: Complications Rate
number (confidence interval 95%)
Post-operative morbidity	0.50 (0.31 to 0.69)	0.38 (0.14 to 0.68)	0.29 (0.10 to 0.56)	0.50 (0.19 to 0.81)
Post-operative mortality (30 days)	0 (0 to 0.12)	0 (0 to 0.25)	0 (0 to 0.20)	0 (0 to 0.31)

Morbidity

Statistical analysis description

A Chi-square test is performed to compare the rates on a regimen basis.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Chi-squared

Confidence interval

Secondary: Response rate

Top of page

End point title

Response rate ^[3]

End point description

An overall response rate will be measured using the number of patients at baseline. Response will be assessed in accordance with RECIST 1.1 guidelines (www.recist.com/files/Recist-1.1-Fanbook.pdf) and those patients achieving partial or complete response with disease control will be compared. The response rate is defined as the number of complete response or partial response or stable disease or progression disease divided the total number of patients at baseline. e.g. Complete Response Rate = number of patients showing complete response at re-staging / number of patients at baseline In the same way, the rates for partial response, stable disease and progression disease will be calculated. Furthermore, an overall response rate will be measured pulling together complete and partial responders. Overall Response Rate = number of complete responders + number of partial responders / number of patients at baseline

End point type

Secondary

End point timeframe

Diagnosis of response will occur at post-surgery restaging.

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Response rate is reported for neo-adjuvant arms only.

End point values	GEMCAP	FOLFIRINOX	ChemoRadiotherapy
Number of subjects analysed	17	17	12
Units: Response Rate
number (not applicable)
Complete Response Rate	0.00	0.00	0.00
Partial Response Rate	0.12	0.23	0.00
Stable Disease Rate	0.70	0.71	0.75
Disease Progression Rate	0.18	0.06	0.25
Overall Response Rate (CR+PR)	0.12	0.24	0.00

Complete response

Statistical analysis description

A Fisher’s exact test is performed to compare the rates on a regimen basis.

Comparison groups

GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Fisher exact

Confidence interval

Partial Response

Statistical analysis description

A Fisher's exact test is performed to comper the rates on a regimen basis.

Comparison groups

GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Fisher exact

Confidence interval

Stable Disease

Statistical analysis description

A Chi-square test is performed as appropriate to compare the rates on a regimen basis.

Comparison groups

GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Chi-squared

Confidence interval

Disease Progression

Statistical analysis description

A Fisher's exact test is performed to compare the rates on a regimen basis.

Comparison groups

GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Fisher exact

Confidence interval

Secondary: Overall Survival

Top of page

End point title

Overall Survival

End point description

Overall survival is defined as follow: Overall survival (months) = (min(censoring data, date of death) – date of randomisation)/ 30.44 The final – administrative – censoring date (at which the trial terminates) will be the date of most recent randomisation + 12 month. Patients will otherwise be censored at the date last know alive.

End point type

Secondary

End point timeframe

Days between date of randomisation and date of death, 12 months from date of randomisation, or date of last follow-up if not followed up for a full 12 months.

End point values	Immediate Surgery	GEMCAP	FOLFIRINOX	ChemoRadiotherapy
Number of subjects analysed	31	19	20	16
Units: 12 month survival rate
number (confidence interval 95%)	40 (25 to 63)	78 (60 to 100)	84 (70 to 100)	60 (37 to 97)

Attachments

Overall Survival Kaplan-Meier

Overall Survival

Statistical analysis description

Log-rank test is applied to investigate the difference in survival outcomes among the arms. Kaplan-Meier curve is plotted to visualise any differences over time.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.05

Method

Logrank

Confidence interval

Secondary: Disease or local disease-free survival

Top of page

End point title

Disease or local disease-free survival

End point description

Disease and local disease free survival rate will be measured for the patients who undergo explorative surgery. Disease and local disease free survival are defined as the number of days between the date of surgery and disease or local disease recurrence, respectively. Disease and local disease free survival are defined as follow: Time to recurrence* (month) = (min(censoring date, date of recurrence) – date of surgery) / 30.44 * Localised, metastatic or both Time to local recurrence (month) = (min(censoring date, date of recurrence) – date of surgery) / 30.44 Patients who do not have confirmed recurrence at CT and patients who are not assessed by CT will be censored for recurrence at the later of current visit or last follow up. Patients who die without confirmed recurrence will be censored at their date of death.

End point type

Secondary

End point timeframe

Date of surgery to disease recurrence, or date of most recent follow-up after surgery.

End point values	Immediate Surgery	GEMCAP	FOLFIRINOX	ChemoRadiotherapy
Number of subjects analysed	28	12	17	10
Units: Disease-free survival rate
number (confidence interval 95%)
Disease-free survival	41 (24 to 69)	73 (51 to 100)	41 (24 to 69)	73 (51 to 100)
Local disease-free survival	91 (80 to 100)	100 (100 to 100)	91 (80 to 100)	100 (100 to 100)

Attachments

Disease-free survival Kaplan-Meier
Local disease-free survival K-M

Disease-free survival

Statistical analysis description

Log-rank test is applied to investigate the difference in disease-free survival among arms. Kaplan-Meier curve is also plotted.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Logrank

Confidence interval

Local disease-free survival

Statistical analysis description

Log rank test is applied to investigate the difference in local disease-free survival among arms. Kaplan-Meier curve is also plotted.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Logrank

Confidence interval

Secondary: Quality of Life 24 weeks

Top of page

End point title

Quality of Life 24 weeks

End point description

Quality of life will be assessed for all patients with the EORTC Quality of Life Questionnaire version 3. The data will be scored according to the algorithm described in the EORTC scoring manual which linearly transforms the data from categorical scales to a score of 0-100. Summary measures of quality of life will be expressed as the direct difference in QoL scores between baseline and follow up assessment. EORTC questionnaire scores will be calculated in two steps, as described in the manual: Raw Score = RA = (I1 + I2 + … + In) / n where I1 + I2 + … + In are the component items Transformation into 0-100 score For Functional scales: Score = 1 - ((RS-1))/range x 100 For Symptom scales / items and Global health status / QoL: Score = ((RS-1))/range x 100 (dispersion parameter of difference is interquartile range)

End point type

Secondary

End point timeframe

Baseline and 24 weeks follow-up

End point values	Immediate Surgery	GEMCAP	FOLFIRINOX	ChemoRadiotherapy
Number of subjects analysed	12 ^[4]	12 ^[5]	14	6
Units: EORTC QoL index difference
number (confidence interval 50%)
Overall Q0L	4.2 (-10.4 to 10.4)	-8.3 (-16.7 to 16.7)	0.0 (0.0 to 12.5)	-4.2 (-20.8 to 12.5)
Physical functioning	-6.7 (-13.3 to -1.7)	-10 (-21.2 to -3.3)	-10.0 (-33.3 to 0.0)	-20.0 (-33.3 to -2.9)
Role functioning	0.0 (-16.7 to 16.7)	-8.3 (-37.5 to 16.7)	-16.7 (-33.3 to -4.2)	-41.7 (-50.0 to -33.3)
Emotional functioning	8.3 (-2.1 to 18.8)	2.8 (0.0 to 12.5)	0.0 (-8.3 to 8.3)	16.7 (0.0 to 31.3)
Cognitive functioning	0.0 (0.0 to 4.2)	0.0 (-25.0 to 0.0)	0.0 (-12.5 to 0.0)	0.0 (0.0 to 12.5)
Social functioning	0.0 (-20.8 to 16.7)	-16.7 (-25.0 to 0.0)	-8.3 (-33.3 to 0.0)	-41.7 (-50.0 to -8.3)
Fatigue	0.0 (-5.6 to 13.9)	5.6 (-16.7 to 13.9)	11.1 (0.0 to 19.4)	22.2 (11.1 to 33.3)
Nausea and vomiting	0.0 (-20.8 to 16.7)	0.0 (-4.2 to 0.0)	0.0 (-16.7 to 0.0)	0.0 (0.0 to 12.5)
Pain	-8.3 (-37.5 to 0.0)	0.0 (-16.7 to 20.8)	0.0 (-12.5 to 16.7)	8.3 (-37.5 to 29.2)
Dyspnoea	0.0 (0.0 to 33.3)	0.0 (0.0 to 0.0)	0.0 (0.0 to 0.0)	16.7 (0.0 to 33.3)
Insomnia	0.0 (-33.3 to 0.0)	0.0 (-33.3 to 41.7)	0.0 (-33.3 to 33.3)	0.0 (-25.0 to 0.0)
Appetite loss	0.0 (-41.7 to 8.3)	0.0 (-8.3 to 0.0)	0.0 (0.0 to 33.3)	16.7 (0.0 to 58.3)
Constipation	0.0 (-8.3 to 0.0)	0.0 (0.0 to 0.0)	0.0 (-33.3 to 0.0)	0.0 (-75.0 to 0.0)
Diarrhoea	0.0 (-8.3 to 33.3)	0.0 (0.0 to 66.7)	0.0 (0.0 to 25.0)	0.0 (0.0 to 25.0)
Financial difficulties	0.0 (0.0 to 0.0)	0.0 (0.0 to 0.0)	0.0 (0.0 to 58.3)	0.0 (0.0 to 25.0)

Notes
[4] - For some categories, subjects available is reduced to 11
[5] - For some categories, subjects available is reduced to 11 or 10

Overall QoL

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Physical functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Role functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Emotional functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Cognitive functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

GEMCAP v Immediate Surgery v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Social functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Fatigue

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Nausea and vomiting

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

GEMCAP v Immediate Surgery v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Pain

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Dyspnoea

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Insomnia

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Appetite loss

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Constipation

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Diarrhoea

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Financial difficulties

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Quality of Life 36 weeks

Top of page

End point title

Quality of Life 36 weeks

End point description

End point type

Secondary

End point timeframe

Baseline and 36 weeks follow-up

End point values	Immediate Surgery	GEMCAP	FOLFIRINOX	ChemoRadiotherapy
Number of subjects analysed	10	10 ^[6]	12	7
Units: EORTC QoL index difference
number (confidence interval 50%)
Overall QoL	0.0 (-31.2 to 6.2)	-16.7 (-33.3 to 0.0)	-8.3 (-27.1 to 16.7)	-8.3 (-25.0 to -4.2)
Physical functioning	-3.3 (-18.3 to 0.0)	-20.0 (-30.4 to -13.3)	-13.3 (-35.0 to 0.0)	-6.7 (-21.7 to -0.8)
Role functioning	-8.3 (-45.8 to 12.5)	-25.0 (-33.3 to -4.2)	0.0 (-37.5 to 0.0)	-33.3 (-33.3 to -16.7)
Emotional functioning	-11.1 (-22.9 to 6.3)	0.0 (-8.3 to 0.0)	0.0 (-8.3 to 25.0)	25.0 (-5.6 to 37.5)
Cognitive functioning	0.0 (-29.2 to 0.0)	0.0 (-16.7 to 0.0)	0.0 (-33.3 to 0.0)	0.0 (-16.7 to 0.0)
Social functioning	0.0 (-12.5 to 12.5)	0.0 (-16.7 to 0.0)	-16.7 (-37.5 to 4.2)	-16.7 (-33.3 to -16.7)
Fatigue	16.7 (-16.7 to 30.6)	16.7 (-16.7 to 33.3)	0.0 (-13.9 to 38.9)	11.1 (0.0 to 22.2)
Nausea and vomiting	0.0 (-25.0 to 12.5)	8.3 (0.0 to 29.2)	0.0 (-16.7 to 0.0)	0.0 (-8.3 to 8.3)
Pain	8.3 (-29.2 to 58.3)	16.7 (0.0 to 33.3)	8.3 (-16.7 to 37.5)	0.0 (-25.0 to 8.3)
Dyspnoea	0.0 (0.0 to 0.0)	0.0 (0.0 to 0.0)	0.0 (0.0 to 33.3)	0.0 (0.0 to 0.0)
Insomnia	16.7 (0.0 to 58.3)	0.0 (-25.0 to 0.0)	0.0 (-33.3 to 33.3)	0.0 (-16.7 to 16.7)
Appetite loss	0.0 (-33.3 to 25.0)	0.0 (-25.0 to 25.0)	0.0 (0.0 to 8.3)	0.0 (0.0 to 33.3)
Constipation	0.0 (0.0 to 0.0)	0.0 (0.0 to 0.0)	0.0 (-8.3 to 0.0)	0.0 (-33.3 to 33.3)
Diarrhoea	0.0 (0.0 to 33.3)	0.0 (0.0 to 33.3)	0.0 (-8.3 to 8.3)	0.0 (0.0 to 16.7)
Financial difficulties	0.0 (0.0 to 25.0)	0.0 (0.0 to 0.0)	0.0 (0.0 to 41.7)	0.0 (0.0 to 16.7)

Notes
[6] - For some categories, available subjects is reduced to 9

Overall QoL

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Physical functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Role functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Emotional functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Cognitive functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Social functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Fatigue

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Nausea and vomiting

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Pain

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Dyspnoea

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Insomnia

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Appetite loss

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Constipation

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Diarrhoea

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Financial difficulties

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Quality of Life 48 weeks

Top of page

End point title

Quality of Life 48 weeks

End point description

End point type

Secondary

End point timeframe

Baseline and 48 weeks follow-up

End point values	Immediate Surgery	GEMCAP	FOLFIRINOX	ChemoRadiotherapy
Number of subjects analysed	5	7 ^[7]	10	4
Units: EORTC QoL index difference
number (confidence interval 50%)
Overall QoL	0.0 (-8.3 to 33.3)	8.3 (0.0 to 22.9)	0.0 (-8.3 to 16.7)	-8.3 (-18.8 to -4.2)
Physical functioning	-6.7 (-6.7 to 20.0)	-6.7 (-10.0 to 13.3)	0.0 (-11.7 to 0.0)	-23.3 (-26.7 to -16.7)
Role functioning	33.3 (0.0 to 33.3)	0.0 (-8.3 to 8.3)	-8.3 (-45.8 to 0.0)	-33.3 (-50.0 to -25.0)
Emotional functioning	8.3 (0.0 to 16.7)	8.3 (2.1 to 8.3)	0.0 (-12.5 to 25.0)	0.0 (-2.1 to 6.2)
Cognitive functioning	-16.7 (-16.7 to 16.7)	-16.7 (-16.7 to -4.2)	0.0 (-12.5 to 25.0)	-16.7 (-33.3 to 0.0)
Social functioning	33.3 (0.0 to 33.3)	16.7 (0.0 to 45.8)	0.0 (-25.0 to 16.7)	-33.3 (-41.7 to -29.2)
Fatigue	-11.1 (-33.3 to 0.0)	-11.1 (-27.8 to 22.2)	0.0 (-8.3 to 8.3)	38.9 (27.8 to 50.0)
Nausea and vomiting	-33.3 (-33.3 to -33.3)	0.0 (-16.7 to 0.0)	0.0 (-16.7 to 0.0)	8.3 (0.0 to 20.8)
Pain	-33.3 (-66.7 to -16.7)	0.0 (-33.3 to 8.3)	-16.7 (-16.7 to 0.0)	8.3 (-12.5 to 20.8)
Dyspnoea	0.0 (-66.7 to 0.0)	0.0 (-16.7 to 0.0)	0.0 (0.0 to 0.0)	0.0 (0.0 to 0.0)
Insomnia	0.0 (-33.3 to 0.0)	0.0 (-33.3 to 0.0)	0.0 (-25.0 to 0.0)	-50.0 (-66.7 to -16.7)
Appetite loss	-33.3 (-66.7 to -33.3)	0.0 (-50.0 to 0.0)	0.0 (0.0 to 33.3)	33.3 (25.0 to 41.7)
Constipation	0.0 (0.0 to 0.0)	0.0 (-50.0 to 0.0)	0.0 (-25.0 to 0.0)	-16.7 (-50.0 to 0.0)
Diarrhoea	0.0 (0.0 to 33.3)	0.0 (0.0 to 50.0)	0.0 (0.0 to 0.0)	0.0 (0.0 to 0.0)
Financial difficulties	0.0 (0.0 to 0.0)	0.0 (-25.0 to 0.0)	0.0 (0.0 to 33.3)	33.3 (0.0 to 66.7)

Notes
[7] - For some categories, available subjects is reduced to 6

Overall QoL

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Physical functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Role functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Emotional functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Cognitive functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Social functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Fatigue

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Nausea and vomiting

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Pain

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Dyspnoea

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Insomnia

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Appetite loss

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Constipation

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Diarrhoea

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Financial difficulties

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Quality of life 52 weeks

Top of page

End point title

Quality of life 52 weeks

End point description

End point type

Secondary

End point timeframe

Baseline and 52 weeks follow-up

End point values	Immediate Surgery	GEMCAP	FOLFIRINOX	ChemoRadiotherapy
Number of subjects analysed	4 ^[8]	7 ^[9]	6	2
Units: EORTC QoL index difference
number (confidence interval 50%)
Overall QoL	8.3 (4.2 to 10.4)	16.7 (4.2 to 29.2)	12.5 (2.1 to 47.9)	0.0 (0.0 to 0.0)
Physical functioning	10.0 (0.0 to 23.3)	-5.0 (-16.7 to 13.3)	-3.3 (-11.7 to 0.0)	-11.7 (-12.5 to -10.8)
Role functioning	41.7 (25.0 to 54.2)	0.0 (-33.3 to 33.3)	8.3 (-25.0 to 16.7)	-16.7 (-16.7 to -16.7)
Emotional functioning	8.3 (0.0 to 29.2)	12.5 (2.1 to 16.7)	16.7 (10.4 to 22.9)	15.3 (10.4 to 20.1)
Cognitive functioning	16.7 (12.5 to 20.8)	0.0 (-25.0 to 12.5)	0.0 (0.0 to 12.5)	0.0 (0.0 to 0.0)
Social functioning	33.3 (12.5 to 50.0)	16.7 (0.0 to 45.8)	16.7 (4.2 to 29.2)	-25.0 (-29.2 to -20.8)
Fatigue	-22.2 (-36.1 to -8.3)	0.0 (-22.2 to 11.1)	0.0 (0.0 to 8.3)	0.0 (0.0 to 0.0)
Nausea and vomiting	-33.3 (-41.7 to -25.0)	0.0 (-16.7 to 0.0)	0.0 (-12.5 to 0.0)	-8.3 (-12.5 to -4.2)
Pain	-25.0 (-50.0 to -12.5)	33.3 (-16.7 to 41.7)	-8.3 (-41.7 to 0.0)	8.3 (4.2 to 12.5)
Dyspnoea	-33.3 (-66.7 to 0.0)	0.0 (-16.7 to 0.0)	0.0 (0.0 to 0.0)	16.7 (8.3 to 25.0)
Insomnia	-33.3 (-66.7 to 8.3)	-33.3 (-33.3 to 16.7)	-16.7 (-33.3 to 25.0)	-50.0 (-58.3 to -41.7)
Appetite loss	-66.7 (-66.7 to -58.3)	-33.3 (-83.3 to -16.7)	-16.7 (-33.3 to 0.0)	0.0 (0.0 to 0.0)
Constipation	0.0 (-16.7 to 0.0)	-33.3 (-58.3 to -8.3)	0.0 (-25.0 to 0.0)	0.0 (0.0 to 0.0)
Diarrhoea	0.0 (0.0 to 8.3)	0.0 (0.0 to 25.0)	0.0 (0.0 to 0.0)	33.3 (16.7 to 50.0)
Financial difficulties	0.0 (-33.3 to 0.0)	0.0 (-25.0 to 0.0)	0.0 (0.0 to 25.0)	0.0 (0.0 to 0.0)

Notes
[8] - For some categories, subjects available is reduced to 3.
[9] - For some categories, subjects available is reduced to 6.

Overall QoL

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Physical functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Role functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Emotional functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Cognitive functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Social functioning

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Fatigue

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Nausea and vomiting

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Pain

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Dyspnoea

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Insomnia

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Appetite loss

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Constipation

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Diarrhoea

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Financial difficulties

Statistical analysis description

Wilcox test to assess the differences in QoL changes among the four arms.

Comparison groups

Immediate Surgery v GEMCAP v FOLFIRINOX v ChemoRadiotherapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Adverse events

Top of page

Timeframe for reporting adverse events

Throughout treatment phase

Adverse event reporting additional description

Overall, 1258 adverse events occurred during the course of the study (120, 401, 428 and 309 in the surgery, GEMCAP, FOLFIRINOX and ChemoRadiotherapy arms respectively). Adverse events were recorded at each visit and it is not possible to assess whether an event was ongoing from the previous visit or was a new one.

Assessment type

Systematic

Dictionary name

CTCAE

Dictionary version

Reporting group title

Immediate Surgery

Reporting group description

120 adverse events were recorded across patients

Reporting group title

GEMCAP

Reporting group description

401 adverse events were recorded across patients.

Reporting group title

FOLFIRINOX

Reporting group description

428 adverse events were recorded across patients.

Reporting group title

ChemoRadiotherapy

Reporting group description

309 adverse events were recorded across patients.

Serious adverse events	Immediate Surgery	GEMCAP	FOLFIRINOX	ChemoRadiotherapy
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 28 (10.71%)	2 / 17 (11.76%)	5 / 19 (26.32%)	4 / 14 (28.57%)
number of deaths (all causes)	18	4	3	5
number of deaths resulting from adverse events
Investigations
Creatinine increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 17 (0.00%)	1 / 19 (5.26%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Gastric anastomotic leak
subjects affected / exposed	1 / 28 (3.57%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 28 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	0 / 28 (0.00%)	0 / 17 (0.00%)	1 / 19 (5.26%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Allergic reaction
subjects affected / exposed	0 / 28 (0.00%)	0 / 17 (0.00%)	1 / 19 (5.26%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 28 (0.00%)	0 / 17 (0.00%)	1 / 19 (5.26%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 28 (0.00%)	0 / 17 (0.00%)	1 / 19 (5.26%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroesophageal reflux disease
subjects affected / exposed	0 / 28 (0.00%)	1 / 17 (5.88%)	0 / 19 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 28 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 28 (0.00%)	0 / 17 (0.00%)	1 / 19 (5.26%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	2 / 28 (7.14%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Biliary tract infection
subjects affected / exposed	2 / 28 (7.14%)	0 / 17 (0.00%)	0 / 19 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic infection
subjects affected / exposed	0 / 28 (0.00%)	1 / 17 (5.88%)	0 / 19 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 28 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 28 (0.00%)	0 / 17 (0.00%)	2 / 19 (10.53%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
Metabolism and nutrition disorders
Diabetic ketoacidosis
subjects affected / exposed	0 / 28 (0.00%)	0 / 17 (0.00%)	0 / 19 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Immediate Surgery	GEMCAP	FOLFIRINOX	ChemoRadiotherapy
Total subjects affected by non serious adverse events
subjects affected / exposed	28 / 28 (100.00%)	17 / 17 (100.00%)	19 / 19 (100.00%)	14 / 14 (100.00%)
Investigations
All Events
Additional description: 1236 non-serious adverse events were reported across reporting groups. Granular data are not available but these events were split 117:399:423:305 by reporting group.
subjects affected / exposed	28 / 28 (100.00%)	17 / 17 (100.00%)	19 / 19 (100.00%)	14 / 14 (100.00%)
occurrences all number	28	17	19	14

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Were there any global substantial amendments to the protocol? Yes

05 Sep 2014

3. Protocol Updated to Version 3, dated 5 August 2014 Summary of changes: 1) Updated numbering of tables. 2) Contact details updated. 3) Inclusion criteria no. 8 modified from creatinine clearance to glomerular filtration rate. 4) Exclusion criteria no. 4 to allow exceptions case by case, e.g. methotrexate for rheumatoid arthritis. 5) Section 4: two additional procedures for the screening and randomisation process. 6) Section 7.3.1: allow pre-prepared vials/bags of solution as well as powder, as gemcitabine is now generic. 7) Section 7: clarification that there is a 2-day window for taking toxicity-assessment bloods. 8) Section 7: clarification regarding the use of G-CSF. 9) Section 7: clarification on managing patients with angina or angina-like pain. 10) Section 7.3.2: clarification of dose banding procedures. 11) Section 7.4.1, Arm C, FOLFIRINOX: folinic acid may now be either calcium or sodium folinate rather than Sodiofolin as previously specified. 12) Section 7.4.2, Arm C, FOLFIRINOX: folinic acid administration changed from 400mg/m2 to local practice. 13) Section 7.5, Chemoradiotherapy: re-written for improved clarity and with more detail. 14) Section 8.1: addition of pathology central core lab review to the schedules of procedures and other clarifications. 15) Section 8.5, Translational study: re-written for clarity and to reflect laboratory SOPs. 16) Section 8.6, Quality Assurance: further information added regarding the transfer of radiology images to the LCTU; radiotherapy paragraph also added. 17) Section 9.2: minimisation specified as the method of randomisation. 18) Section 12: regulatory approval details added. 19) Section 17: additional information regarding the publication policy. 20) Miscellaneous administrative changes.

28 Apr 2015

Protocol Updated to Version 4, dated 28.04.2015 1) Updated numbering of tables. 2) Contact details updated. 3) Exclusion Criteria No 2 modified to Previous or concurrent malignancy diagnoses, except: i) curatively treated basal cell carcinoma of skin, ii) carcinoma in situ of cervix, iii) previous cancers treated with curative intent, ending treatment ≥ 5 years ago. 4) Exclusion Criteria No 4 modified to Previous chemotherapy ending < 5 years ago (exceptions may be given case by case by the CI, such as methotrexate for rheumatoid arthritis). 5) Schematic of Study Design modified to show Review of staging MDCT scan by central laboratory will be included within the screening process. 6) Section 7.3.3 Dose Modifications: Information on treatment delays has been added to this section: Treatment delays should be avoided as far possible; the maximum allowable treatment omission is 3 weeks. Any patient whose treatment is omitted for longer than 3 weeks should discontinue therapy. All patients who withdraw from treatment should remain on followup within the trial. 7) Section 7.4.1 Active Ingredient Name /Dose for 5Fluorouracil modified typo to show correct 50 mg fluorouracil in 10 ml solution not 500mg. 8) Section 7.4.1 Irinotecan formulation modified to show Concentrate For Solution For Infusion not injection as per the approved SmPC for Irinotecan. 9) Section 7.4.3 Dose Modifications Information on treatment delays has been added to this section: Treatment delays should be avoided as far possible; the maximum allowable treatment omission is 3 weeks. Any patient whose treatment is omitted for longer than 3 weeks should discontinue therapy. All patients who withdraw from treatment should remain on followup within the trial. 10) Section 7.5.2 Optional PreRadiotherapy Investigations. Reworded to allow local standard of care using additional diagnostic assessments, as per institutional practice, may be of assistance in identifying disease not visible on CT

22 Mar 2016

1 - Exclusion Criteria Change Exclusion criteria change from • Previous or concurrent malignancy diagnoses, except: i) curatively-treated basal cell carcinoma of skin, ii) carcinoma in situ of cervix, iii) previous cancers treated with curative intent, ending treatment ≥ 5 years ago. To new suggested text • Previous or concurrent malignancy diagnoses, except curatively-treated (i) basal cell carcinoma of skin, ii) carcinoma in situ of cervix; breast; bladder; (iii) non muscle invasive transitional cell carcinoma of the bladder; iv) previous cancers treated with curative intent, ending treatment ≥ 3 years ago. Exclusion criteria change from • Previous chemotherapy ending < 5 years ago (exceptions may be given case by case by the CI, such as methotrexate for rheumatoid arthritis). To new suggested text • Previous chemotherapy ending < 3 years ago (exceptions may be given case by case by the CI, such as methotrexate for rheumatoid arthritis).

31 Jul 2017

Update to Protocol Version 6.0 1) Inserted additional information to section 5.1.2 ‘Ending Trial intervention Early’ to clarify how patients should be followed up 2) Amendments to the table of assessments was necessary to avoid confusion for sites. The information was adjusted to make it clear for research nurses at site 3) Protocol was updated to state that SAEs related to surgery, although should be reported, they would not be classed as ‘unexpected’ as all complications in surgery are expected. These will not be included in expedited reporting to the MHRA 4) Patients with 1.0 absolute neutrophil count should have 100% of the gemcitabine dose and there was no need for a dose reduction 5) The initial recruitment projection has been reviewed during the course of the study by the trial management group due to difficulties in opening centres and randomising patients in the first months of the trial. This created a need for an extension to recruitment and the statistical considerations have been updated to reflect this

05 Aug 2020

Update to Protocol Version 7 Amendment 1: Protocol Amendment End of Trial definition need amending Old Wording Section 8.8 Protocol Version 6.0 Dated 27/01/2017: The trial is closed when the required number of events for the secondary endpoints, disease and local disease free survival rate and overall survival, as defined in section 9.3.2, is reached and the database has been fully cleaned and frozen for each of these two final analyses.: New Wording Section 8.0: ‘The end of the trial is defined to be the date on which data for all participants is frozen and data entry privileges are withdrawn from the trial database’] Amendment 2: Protocol Amendment Extension of visit window Addition of + 90 days visit window on the week 52 follow-up visit on all arms. Amendment to Table 16 – 19

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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ESPAC-5F: European Study Group for Pancreatic Cancer - Trial 5F Four arm, prospective, multicentre, randomised feasibility trial of immediate surgery compared with neoadjuvant chemotherapies and neoadjuvant chemoradiotherapy.

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Clinical trials

Clinical Trial Results: ESPAC-5F: European Study Group for Pancreatic Cancer - Trial 5F Four arm, prospective, multicentre, randomised feasibility trial of immediate surgery compared with neoadjuvant chemotherapies and neoadjuvant chemoradiotherapy.

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Clinical Trial Results:
ESPAC-5F: European Study Group for Pancreatic Cancer - Trial 5F Four arm, prospective, multicentre, randomised feasibility trial of immediate surgery compared with neoadjuvant chemotherapies and neoadjuvant chemoradiotherapy.