MEDICINE CASE WRITE UP

Syed Talha
2023-089
Patient Profile:
Name: Noor Muhammad
Age: 38 years
Gender: Male
Residence: Quetta
Marital Status: Married with 8 Children

Presenting Complain;
Excessive vomiting since the last 2 months
History of Presenting Complain;
Patient was is in usual state of health when this complaint of vomiting started one and a half
years ago but it has exacerbated in the last 2 months. He's had no oral take since that time.
Vomiting is projectile and green in colour. The quantity of vomiting depends upon the quantity
of food intake. He also complained of episodes of hematemesis in the last two months.
He also complained of heart burn which was aggrevated by eating and relieved by omeprazole.
He has constipation since the start of these symptoms.
He has lost 45 kg in the last 4 to 5 months. He also complained of fever that include 15 episodes
in the last two months. There is no associated pain in abdomen

Review of Systems

CNS;
Head Trauma: N/A Headache: N/A
Dizziness: N/A Fainting: N/A
Convulsions: N/A Numbness: N/A
Hearing Impairment: N/A Vision Impairment: N/A

Cardiovascular System;
Hypertension: +N/A
Palpitations: N/A Pedal Oedema: N/A
Exertional Dyspnoea: N/A Orthopnoea: N/A
Cyanosis: N/A

Respiratory System:
Dyspnoea: N/A Cough:N/A
Sputum: N/A Haemoptysis: N/A
Wheezing: N/A Night Sweats: N/A
Paroxysmal Nocturnal Dyspnoea: N/A Chest pain on respiration: N/A

Gastrointestinal Tract;
Nausea: N/A Vomiting: N/A
Dysphagia: N/A Hematemesis: N/A
Jaundice: N/A Abdominal Distension: N/A
Diarrhoea: N/A Constipation: N/A
Melena: N/A Heart Burn: N/A

Genitourinary Tract;
Burning Micturition: N/A Dysuria: N/A
Haematuria: N/A Frequency: N/A
Incomplete Voiding: N/A Nocturia: N/A
Urgency: N/A Pyuria: N/A
Hesitancy: N/A Incontinence: N/A
Polyuria: N/A Genital Discharge: N/A

Musculoskeletal System;
Joint Pain: N/A Bone Pain: N/A
Muscle Ache: N/A Stiffness: N/A
Joint Swelling: N/A Gait: Stable before stroke

Endocrine System;
Polydipsia: N/A Polyphagia: N/A
Glucose Intolerance: N/A Tremors: N/A
Neck Swelling: N/A Heat/Cold Intolerance: N/A

Medical and Surgical History;

Not Significant

Drug/Allergy History;
Not Significant

Family History;
Mother had DM, HTN, Asthma

Socioeconomic History;
Patient is resident of Quetta, lives in joint family system.
He lives on 1st floor with 6 rooms which are shared by his wife, 3 children and 3 brother.
4 persons are earning.
Takes balanced diet.

Personal History;
Does not drink or smoke

General Physical Examination

A middle-aged man lying in his bed who seemed mildly agitated . He had cannula on his left
forearm for IV fluids and medications. Foley’s catheter was attached.

Vitals;
Pulse: 90 beats/min, normal rhythm, good volume pulse R.R: 24 breaths/min
Temperature: Afebrile Weight: 85 KGs
Blood pressure: 110/80 mmHg

Face;
Central Cyanosis: N/A Pallor: - N/A
Jaundice: N/A Oral Hygiene: Normal
Nasal Congestion: N/A Ear Congestion: N/A
Tongue Muscle Wasting: N/A Tonsils: N/A
Neck;
Thyroid Swelling: N/A
Lymph Nodes: Not enlarged Trachea: Central

Hands;
Cyanosis: N/A Clubbing: N/A
Thenar/Hypothenar Wasting: - Koilonychias: N/A
Tremors: N/A Capillary Refill: N/A
Rash: N/A Normal Shamroth’s Window
Pedal Oedema: N/A Peripheral Pulses: Normal

Abdominal Examination
Inspection;
Symmetry: Normal Abdominal Distension: +ve

Palpation;
Superficial: Non-tender Deep: +ve
Visceromegaly: N/A

Percussion;
Liver Span: 9 cm Shifting Dullness: N/A
Fluid Thrill: N/A

Auscultation;
Bowel Sounds: Positive Aortic Bruit: N/A

Respiratory Examination
Inspection;
Symmetry: N/A Shape: N/A
Palpation;
Apex Beat: Normal Chest Expansion: Normal
Percussion; N/A
Auscultation;
Breath Sounds: Vesicular, No crackles or wheezes

Cardiovascular Examination
Normal S1 + S2
JVP not raised

Eye Examination
Pupils are Round, Regular and Reaction to light
Slight scleral icterus

ENT Examination
Tonsils not enlarged

Nervous System Examination

GCS: 15/15
Power: Right Arm: 5/5
Right Leg: 5/5
Left Arm: 5/5
Left Leg: 5/5
No Sensory loss in any dermatome

Investigations;

HB: 8
AST: 53
ALT: 47
ALP: 498
Gamma G.T: 77
Albumin: 2.7
Total Bilirubin: 1.0

Ultrasound Abdomen:
Significantly distended gall bladder. No stone. Homogeneous mass of
intermediate echogenicity with a peripheral hypoechoic halo of
compressed liver parenchyma.
Summary
38 y/o male, with no known comorbids. He presented with excessive vomiting since the last 2
months. Has a history of weight loss of 45 kg in the last 4-5 months. There is no oral intake.
Differentials:
• Cholangiocarcinoma
• Duodenal adenocarcinoma
• Acalculous cholecystitis

SOAP Criteria
Problem Subject Objective Analysis Plan Ask
list ive (Relevant (Logical differential list) (Diagnostic/Thera yourself
(Relate physical peutic, patient questions
d exam) education)
history)
Biological excessi Symmetry: • Cholangiocarcin 1.CT Abdomen
ve Normal oma 2.CBC Compariso
vomitin 3. Blood Culture n of
g since • Duodenal 4. Endoscopy adjuvant
adenocarcinom gemcitabin
the last
a e
2
chemother
months Abdo apy versus
• Acalculous
minal cholecystitis observatio
Distension: n in
+ve resected
bile duct
cancer
Superficial:
Non-tender

Deep:
+ve
Visceromegal
y: N/A
Psycholog The Counsel the patient
ical patient about this disease
seemed and tell him the
agitated possible treatment
due to and prognosis
his
ongoing
illness &
wanted
all of it
to end.

Preventiv
e
Patient: A 38 year old male with excessive vomiting since the last 2 months
Intervention: Adjuvant gemcitabine chemotherapy
Comparison: Resection of bile duct cancer
Outcome: The survival probability in patients with resected bile duct cancer was not
significantly different between the gemcitabine adjuvant chemotherapy group and the
observation group.

Source of evidence: PubMed.

Level of evidence: Randomized Control Trial
 Randomized clinical trial

Randomized clinical trial of adjuvant gemcitabine

chemotherapy versus observation in resected bile duct cancer
T. Ebata1 , S. Hirano4 , M. Konishi6 , K. Uesaka7 , Y. Tsuchiya9 , M. Ohtsuka10 , Y. Kaneoka11 ,
M. Yamamoto12 , Y. Ambo5 , Y. Shimizu2 , F. Ozawa13 , A. Fukutomi8 , M. Ando3 , Y. Nimura1 and
M. Nagino1 , on behalf of the Bile Duct Cancer Adjuvant Trial (BCAT) Study Group
1
Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 2 Department of Gastroenterological Surgery,
Aichi Cancer Centre Hospital, and 3 Centre for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, 4 Department of
Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, and 5 Department of Surgery, Teine-Keijinkai Hospital, Sapporo,

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6
Department of Hepatobiliary-Pancreatic Surgery, National Cancer Centre Hospital East, Kashiwa, Divisions of 7 Hepato-Biliary-Pancreatic Surgery
and 8 Gastrointestinal Oncology, Shizuoka Cancer Centre Hospital, Shizuoka, 9 Department of Surgery, Niigata Cancer Centre Hospital, Niigata,
10
Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, 11 Department of Surgery, Ogaki Municipal Hospital, Ogaki,
12
Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, and 13 Department of Hepato-Biliary-Pancreatic
Surgery, Saitama Medical Centre, Saitama Medical University, Saitama, Japan
Correspondence to: Professor M. Nagino, Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine,
65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan (e-mail: nagino@med.nagoya-u.ac.jp)

Background: Although some retrospective studies have suggested the value of adjuvant therapy, no
recommended standard exists in bile duct cancer. The aim of this study was to test the hypothesis that
adjuvant gemcitabine chemotherapy would improve survival probability in resected bile duct cancer.
Methods: This was a randomized phase III trial. Patients with resected bile duct cancer were assigned
randomly to gemcitabine and observation groups, which were balanced with respect to lymph node
status, residual tumour status and tumour location. Gemcitabine was given intravenously at a dose of
1000 mg/m2 , administered on days 1, 8 and 15 every 4 weeks for six cycles. The primary endpoint was
overall survival, and secondary endpoints were relapse-free survival, subgroup analysis and toxicity.
Results: Some 225 patients were included (117 gemcitabine, 108 observation). Baseline characteristics
were well balanced between the gemcitabine and observation groups. There were no significant differ-
ences in overall survival (median 62⋅3 versus 63⋅8 months respectively; hazard ratio 1⋅01, 95 per cent c.i.
0⋅70 to 1⋅45; P = 0⋅964) and relapse-free survival (median 36⋅0 versus 39⋅9 months; hazard ratio 0⋅93,
0⋅66 to 1⋅32; P = 0⋅693). There were no survival differences between the two groups in subsets stratified
by lymph node status and margin status. Although haematological toxicity occurred frequently in the
gemcitabine group, most toxicities were transient, and grade 3/4 non-haematological toxicity was rare.
Conclusion: The survival probability in patients with resected bile duct cancer was not significantly
different between the gemcitabine adjuvant chemotherapy group and the observation group. Registration
number: UMIN 000000820 (http://www.umin.ac.jp/).

Paper accepted 1 November 2017

Published online in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.10776

Introduction therapy has therefore been used widely after surgical

Surgical resection offers the best chance of prolonged sur-
vival and should be considered as the first-line treatment
for bile duct cancer. However, the disease often has neg-
ative prognostic features represented by larger tumour
size, vascular invasion, nodal metastasis or positive resec-
tion margins1 . Postoperative recurrence develops in over
50 per cent of patients2,3 , and 5-year survival remains
unfavourable with a rate of 10–40 per cent1,4 . Adjuvant
resection5,6 , although its optimal regimen has yet to be
established.
Gemcitabine has broad activity in a variety of tumours,
including bile duct cancer. Early studies7,8 on gemcitabine
in the unresectable/metastatic setting showed a response
rate of 7–18 per cent, with an acceptable toxic profile in
Japanese patients with unresectable biliary cancer. In 2007,
the Charité Onkologie (CONKO) 001 trial9 reported that
adjuvant gemcitabine therapy had minimal toxicity and

© 2018 BJS Society Ltd BJS 2018; 105: 192–202

Published by John Wiley & Sons Ltd
Adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer
improved disease-free survival compared with observation
in Western patients with resected pancreatic cancer9 . As
extrahepatic bile duct cancer partly shares embryological,
clinical and pathological features with pancreatic cancer10 ,
this favourable effect of gemcitabine prompted the present
authors to conduct a randomized study in patients with
bile duct cancer. The aim of this study was to prove the
superiority of adjuvant gemcitabine over observation in
patients who underwent resection for extrahepatic bile duct
cancer.
Methods
The Bile Duct Cancer Adjuvant Trial (BCAT) was a ran-
domized, open-label, multicentre phase III trial conducted
at 48 Japanese hospitals. The trial was completed in accor-
dance with the Declaration of Helsinki and the Ethical
Guidelines for Clinical Studies of the Ministry of Health,
Labour and Welfare of Japan. All associated medical
procedures were covered by the Japanese national social
insurance system. The study protocol was approved by
institutional review boards in all participating centres and
registered in the University Hospital Medical Information
Network (http://www.umin.ac.jp; registration number
ID 000000820). All patients provided written informed
consent.
The primary endpoint was overall survival, and the
secondary endpoints were relapse-free survival, subgroup
analysis and toxicity. The trial was monitored by a data
monitoring committee, which functioned independently of
the investigators. Data were collected using the web-based
clinical trial management system at the data centre (EPS,
Osaka, Japan).
Patient eligibility
Patients with histologically proven extrahepatic bile
duct cancer (perihilar and distal cholangiocarcinomas)
who underwent macroscopically curative resection were
enrolled in this study within 10 weeks after surgery.
Other eligibility criteria for participants were pathological
tumour stage I, II or III according to the UICC system,
sixth edition11 , and absence of distant metastasis or malig-
nant ascites. Participants also had to fulfil the following
criteria: possibility of adequate oral intake; aged 20 years
or older; Eastern Cooperative Oncology Group (ECOG)
performance status of 0 or 1; no history of chemotherapy
or radiotherapy within the past 5 years; and adequate
organ function (leucocyte count at least 3000/μl and not
more than 12 000/μl; platelet count 100 000/μl or higher;
haemoglobin concentration at least 8⋅0 g/dl; total bilirubin
© 2018 BJS Society Ltd
Published by John Wiley & Sons Ltd
193
concentration 2⋅0 mg/dl or less; aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) concentrations
100 units/dl or below; and serum creatinine concentration
1⋅5 mg/dl or less).
Exclusion criteria comprised: confirmed recurrence
before registration; clinically significant pleural effusion
or ascites; pulmonary fibrosis or interstitial pneumonia;
uncontrollable diarrhoea; severe heart failure or myocar-
dial infarction within 6 months before registration; active
infectious disease; blood transfusion within 2 weeks before
trial registration; severe surgical complications; other
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concomitant malignant disease; pregnant or lactating
women; childbearing potential; or other serious disorders
incompatible with the trial, based on the investigator’s
judgement.
Procedures
Standard surgical procedures, including pancreatoduo-
denectomy3 , hepatobiliary resection12 , hepatopancreato-
duodenectomy13 or bile duct resection, were performed
with or without vascular resection14,15 , depending on
tumour extension and institutional guidelines. Regional
lymphadenectomy was carried out routinely. All required
sections of a case record form were sent by fax to the
coordinating data centre.
Patients were assigned randomly to either the gem-
citabine or observation (surgery alone) group in a 1 : 1
ratio by a modified minimization method; participants were
stratified into groups by residual tumour status (R0 versus
R1), lymph node status (pN0 versus pN1), tumour loca-
tion (hilar versus distal) and enrolment centre. Patients and
investigators were aware of the group assignment and no
placebo was used. Treatment allocation was performed cen-
trally through a web-based randomization system managed
by the data centre.
Patients assigned to the gemcitabine group received
intravenous gemcitabine at a dose of 1000 mg/m2 over
30 min on days 1, 8 and 15, followed by a rest period of
1 week (1 cycle). The dosing of gemcitabine was delayed
according to the following criteria: leucocyte count below
2500/μl; platelet count less than 100 000/μl; haemoglobin
concentration under 6⋅5 g/dl; total bilirubin concentra-
tion below 3⋅0 mg/dl; AST and ALT concentrations over
150 units/dl; pyrexia of 38 ∘ C or higher; uncontrolled
diarrhoea; and other non-haematological adverse events
which made administration of gemcitabine inappropriate.
The subsequent dose of gemcitabine was reduced to 80
per cent of the initial dose and then to 60 per cent, if
any of the following events occurred: leucocyte count
less than 1000/μl; platelet count below 25 000/μl; serious
www.bjs.co.uk BJS 2018; 105: 192–202
194
Assessed for eligibility
n = 228
Enrolment
Randomized
n = 226
Allocated to gemcitabine n = 117
Allocation
Received intervention n = 114
Did not receive intervention n = 3
Withdrawal of consent n = 3
Analysed n = 117
Analysis
Lost to follow-up n = 1
Excluded from safety analysis n = 1
Insufficient data on adverse events n = 1
Fig. 1 Trial flow chart
non-haematological adverse events; or two consecutive
skips of the second dose. Gemcitabine was given every
4 weeks until a total of 18 doses had been given, which was
defined as completion of protocol treatment. The observa-
tion group received no anticancer treatment after surgery
until disease relapse was confirmed. Protocol treatment
was discontinued if any of the following occurred: recur-
rence; adverse events requiring further dose reduction
to below 60 per cent of the intended dose; delaying the
next dose for 28 days or more; patient request; difficulty
in continuing the protocol treatment because of a change
in the patient’s personal circumstances; or other medical
conditions, as judged by the investigators.
During protocol treatment, laboratory tests and clin-
ical symptoms were assessed weekly (excluding the rest
week) in the gemcitabine group and monthly in the con-
trol group. Tumour markers were measured monthly; chest
radiography and abdominal CT were performed every
3 months. After the period of protocol treatment, measure-
ment of tumour markers, chest radiography and abdom-
inal CT were repeated every 3 months during the first
3 years after enrolment, and every 6 months thereafter
until the end of follow-up (at least 5 years from regis-
tration). Adverse events were assessed according to the
National Cancer Institute Common Terminology Crite-
ria for Adverse Events, version 3.016 . Disease relapse was
diagnosed based on radiological and/or cytological exami-
nations. An increasing level of tumour markers alone was
not considered relapse. Treatment for relapse was not pre-
scribed by the protocol.
© 2018 BJS Society Ltd
Published by John Wiley & Sons Ltd
T. Ebata, S. Hirano, M. Konishi, K. Uesaka, Y. Tsuchiya, M. Ohtsuka et al.
Excluded n = 2
Did not meet inclusion criteria n = 2
Allocated to observation n = 109
Excluded owing to stage 0 disease n = 1
Received intervention n = 106
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Did not receive intervention n = 2
Withdrawal of consent n = 2
Analysed n = 108
Lost to follow-up n = 1
Statistical analysis
The results of earlier Japanese studies17,18 served as the
basis for determining the required number of patients,
and the 5-year overall survival rate in the observation
group was assumed to be 30 per cent. The present authors
expected a hazard ratio (HR) for mortality of 0⋅85 in
the gemcitabine group compared with the observation
group, and calculated that 189 events were needed to
reject the null hypothesis with a statistical power of 80
per cent and two-sided α of 5 per cent. The total required
sample size was 300 patients with an enrolment of 2 years,
followed by an additional follow-up of 5 years. It was
predefined in the protocol that survival was to be assessed
in the full analysis set and in prespecified subpopula-
tions (according to margin status, lymph node status
and tumour location). Toxicity was assessed in the safety
analysis population in which relevant data collection was
completed.
Efficacy was evaluated in an interim analysis, which was
performed by an independent data and safety monitor-
ing committee, when 200 patients had been enrolled in
the study. To control the overall α error at less than 0⋅05,
multiplicity for the primary endpoint was adjusted using
the O’Brien–Fleming type α spending function19 . After
interim analysis, the authors revised the protocol to extend
the initial recruitment period of 2 years by 16 months
owing to delayed recruitment.
Continuous data are expressed as median (i.q.r.) unless
specified otherwise. Pretreatment variables between
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Adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer 195

groups were compared by the Pearson χ2 test or Table 1 Baseline patient and tumour characteristics
Mann–Whitney U test, as appropriate. Gemcitabine Observation
Overall survival was defined as the time from random- (n = 117) (n = 108)
ization to death from any cause. Relapse-free survival was Age (years)
defined as the time between randomization and the date ≥ 70 65 (55⋅6) 46 (42⋅6)
of relapse or death from any cause. Data for patients who < 70 52 (44⋅4) 62 (57⋅4)
Sex
did not have an event were censored at the date of the final M 77 (65⋅8) 82 (75⋅9)
observation. The Kaplan–Meier method was used to esti- F 40 (34⋅2) 26 (24⋅1)
mate cumulative survival, and the log rank test for compar- Performance status
isons between the two test groups. HRs with 95 per cent 0 12 (10⋅3) 14 (13⋅0)
1 105 (89⋅7) 94 (87⋅0)
confidence intervals were estimated by the Cox propor-

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Tumour location
tional hazards model. All tests were two sided and P < 0⋅050 Perihilar 51 (43⋅6) 51 (47⋅2)
was considered statistically significant. All statistical calcu- Distal 66 (56⋅4) 57 (52⋅8)
Surgical procedures
lations were performed using SAS® version 9.4 (SAS Insti-
Pancreatoduodenectomy 63 (53⋅8) 49 (45⋅4)
tute, Cary, North Carolina, USA). Hepatobiliary resection 44 (37⋅6) 51 (47⋅2)
Hepatopancreatoduodenectomy 8 (6⋅8) 7 (6⋅5)
Bile duct resection 2 (1⋅7) 1 (0⋅9)
Results Combined portal vein resection 16 (13⋅7) 19 (17⋅6)
CA19-9 (units/ml)* 11⋅1 (6⋅4–27⋅1) 12⋅9 (7⋅0-26⋅1)
Between 1 September 2007 and 31 January 2011, a total Interval between surgery and 50 (35–59) 50 (37–59)
randomization (days)*
of 226 patients were enrolled in 48 hospitals; 117 patients
Primary tumour classification†
were assigned randomly to the gemcitabine group and 109 pT1 22 (18⋅8) 16 (14⋅8)
to the observation group (Fig. 1). After randomization, one pT2 30 (25⋅6) 33 (30⋅6)
patient was found to be ineligible because of stage 0 disease. pT3 52 (44⋅4) 48 (44⋅4)
pT4 13 (11⋅1) 11 (10⋅2)
The analysis included 117 patients in the gemcitabine Lymph node status†
group and 108 in the observation group. pN0 75 (64⋅1) 72 (66⋅7)
Patient demographics and tumour characteristics were pN1 42 (35⋅9) 36 (33⋅3)
Pathological tumour stage†
well balanced in the two groups (Table 1). There were
I 40 (34⋅2) 34 (31⋅5)
102 perihilar and 123 distal tumours. The surgical pro- II 60 (51⋅3) 60 (55⋅6)
cedures included pancreatoduodenectomy (112 patients), III 17 (14⋅5) 14 (13⋅0)
hepatobiliary resection (95), hepatopancreatoduodenec- Residual tumour status†
R0 106 (90⋅6) 94 (87⋅0)
tomy (15) and bile duct resection alone (3). Hepatectomy
R1 11 (9⋅4) 14 (13⋅0)
was performed in 110 patients (48⋅9 per cent), 108 of Histological type
whom underwent major hepatectomy (right hepatectomy Tubular adenocarcinoma 105 (89⋅7) 103 (95⋅4)
51, left hepatectomy 43, left trisectionectomy 11, right Papillary adenocarcinoma 11 (9⋅4) 4 (3⋅7)
Adenosquamous carcinoma 1 (0⋅9) 1 (0⋅9)
trisectionectomy 3). Portal vein resection was undertaken Histological grade
in 35 patients (15⋅5 per cent). Pathologically, the incidence Well differentiated 49 (41⋅9) 31 (28⋅7)
of T3/4 tumour, lymph node metastasis and positive resec- Moderately differentiated 53 (45⋅3) 64 (59⋅3)
Poorly differentiated 15 (12⋅8) 13 (12⋅0)
tion margins (R1) was 55⋅1 per cent (124 patients), 34⋅7
per cent (78) and 11⋅1 per cent (25) respectively. Values in parentheses are percentages, unless indicated otherwise; *values
are median (i.q.r.). †According to the UICC TNM Classification of
Malignant Tumours (6th edition)11 . CA, carbohydrate antigen.
Toxicity and drug delivery
Grade 3/4 haematological toxicities occurred frequently in and 53 patients discontinued treatment for the following
the gemcitabine group (Table 2); abnormal neutrophil lev- reasons: need for dose reduction to below 60 per cent (18),
els were most common (58⋅4 per cent), followed by abnor- patient refusal (9), disease relapse (8), physician decision
mal levels of leucocytes (29⋅2 per cent), haemoglobin (7⋅1 (8), delay to next dose of more than 28 days (6) and change
per cent) and platelets (7⋅1 per cent). Non-haematological of residence (4). The remaining 61 patients (52⋅1 per cent)
adverse events were rare, and comparable between the two completed protocol therapy with (20) or without (41) dose
groups. reduction. Overall, 85 patients (72⋅6 per cent) received
Among 117 patients allocated to the gemcitabine group, 12 or more doses of gemcitabine. The median weekly
three did not receive gemcitabine as they withdrew consent dose of gemcitabine was 651 (i.q.r. 513–764) mg/m2

© 2018 BJS Society Ltd www.bjs.co.uk BJS 2018; 105: 192–202

Published by John Wiley & Sons Ltd
196 T. Ebata, S. Hirano, M. Konishi, K. Uesaka, Y. Tsuchiya, M. Ohtsuka et al.

Table 2 Adverse events in safety analysis population

Gemcitabine (n = 113) Observation (n = 106)
Grade 1/2 Grade 3 Grade 4 Grade 3/4 Grade 1/2 Grade 3 Grade 4 Grade 3/4 P*
Haematological toxicity
Leucocytes 66 33 0 33 (29⋅2) 19 2 0 2 (1⋅9) < 0⋅001
Neutrophils 32 51 15 66 (58⋅4) 17 4 0 4 (3⋅8) < 0⋅001
Haemoglobin 85 8 0 8 (7⋅1) 61 1 0 1 (0⋅9) 0⋅036
Platelets 73 8 0 8 (7⋅1) 32 0 0 0 (0) 0⋅007
AST 47 2 0 2 (1⋅8) 32 2 0 2 (1⋅9) 1⋅000
ALT 45 1 0 1 (0⋅9) 31 1 0 1 (0⋅9) 1⋅000
Bilirubin 17 0 0 0 (0) 10 3 1 4 (3⋅8) 0⋅053
Creatinine 9 0 0 0 (0) 10 0 0 0 (0) 1⋅000

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Non-haematological toxicity
Fatigue 43 5 1 6 (5⋅3) 26 1 0 1 (0⋅9) 0⋅120
Anorexia 38 4 2 6 (5⋅3) 12 2 0 2 (1⋅9) 0⋅282
Nausea 31 1 0 1 (0⋅9) 5 0 0 0 (0) 1⋅000
Vomiting 11 1 0 1 (0⋅9) 4 1 0 1 (0⋅9) 1⋅000
Diarrhoea 12 0 0 0 (0) 6 0 0 0 (0) 1⋅000
Fever 33 3 1 4 (3⋅5) 16 0 0 0 (0) 0⋅122
Febrile neutropenia - 0 0 0 (0) - 0 0 0 (0) 1⋅000

Values in parentheses. are percentages. Adverse events were defined according to the Common Terminology Criteria for Adverse Events of the National
Cancer Institute, version 3.016 . AST, aspartate aminotransferase; ALT, alanine aminotransferase. *Comparison of grade 3/4 adverse events between
gemcitabine and observation groups (Pearson χ2 test).

100 100

Relapse-free survival (%)

80 80
Overall survival (%)

60 60

40 40
Gemcitabine
20 Observation 20

0 1 2 3 4 5 0 1 2 3 4 5
Time after randomization (years) Time after randomization (years)
No. at risk No. at risk
Gemcitabine 117 107 89 79 65 60 Gemcitabine 117 90 69 59 54 53
Observation 108 98 80 70 65 55 Observation 108 72 59 55 50 46

a Overall survival b Relapse-free survival

Fig. 2 Kaplan–Meier estimates of a overall and b relapse-free survival in gemcitabine and observation groups. a P = 0⋅997, b P = 0⋅717
(log rank test)

and the median relative dose intensity (RDI) was 82⋅2
(45⋅6–100) per cent. The RDI did not differ significantly
between patients with versus without hepatectomy: 82⋅2
(46⋅1–100) versus 83⋅3 (39⋅2–100) per cent respectively
(P = 0⋅913).
Survival analysis
At last follow-up in April 2016, median follow-up was
79⋅4 months. One patient in each group was lost to
follow-up within 5 years after randomization. During the
study interval, 62 patients in the gemcitabine group and
57 in the observation group died. The overall survival rate
was 68⋅1 per cent at 3 years and 51⋅7 per cent at 5 years,
with a median survival time (MST) of 62⋅3 months, in
the gemcitabine group; it was 65⋅7 per cent at 3 years and
51⋅6 per cent at 5 years, with an MST of 63⋅8 months, in
the observation group (Fig. 2a). The HR for death in the
gemcitabine group, compared with the observation group,
was 1⋅01 (95 per cent c.i. 0⋅70 to 1⋅45; P = 0⋅964). The
relapse-free survival rate was 50⋅9 per cent at 3 years and
45⋅7 per cent at 5 years, with an MST of 36⋅0 months, in
the gemcitabine group; it was 52⋅6 per cent at 3 years and
44⋅0 per cent at 5 years, with an MST of 39⋅9 months, in the

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Published by John Wiley & Sons Ltd
Adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer 197

Men
Women
Age <70 years
Age ≥70 years
Performance status 0
Performance status 1
pT1–2
pT3–4
Stage I–II
Stage III

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N0
N1
R0
R1
Pancreatoduodenectomy
Hepatectomy/others
CA19-9 < 12 units/ml
CA19-9 ≥ 12 units/ml
Well differentiated
Moderately differentiated
Poorly differentiated
0·1 0·2 1 5 10
Favours gemcitabine Favours observation
Hazard ratio
a Overall survival

Men
Women
Age < 70 years
Age ≥ 70 years
Performance status 0
Performance status 1
pT1–2
pT3–4
Stage I–II
Stage III
N0
N1
R0
R1
Pancreatoduodenectomy
Hepatectomy/others
CA19-9 < 12 units/ml
CA19-9 ≥ 12 units/ml
Well differentiated
Moderately differentiated
Poorly differentiated
0·1 0·2 1 5 10
Favours gemcitabine Favours observation
Hazard ratio
b Relapse-free survival

Fig. 3 Subset analysis of gemcitabine versus observation using a Cox regression model for a overall and b relapse-free survival

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Published by John Wiley & Sons Ltd
198 T. Ebata, S. Hirano, M. Konishi, K. Uesaka, Y. Tsuchiya, M. Ohtsuka et al.

100 100

80 80

Overall survival (%)

Overall survival (%)

60 60

40 Gemcitabine 40
Observation
20 20

0 1 2 3 4 5 0 1 2 3 4 5
Time after randomization (years) Time after randomization (years)

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No. at risk No. at risk
Gemcitabine 75 71 64 61 53 51 Gemcitabine 42 36 25 18 12 9
Observation 72 69 61 55 50 43 Observation 36 29 19 15 15 12

a No lymph node metastasis b With lymph node metastasis

100 100

80 80

Overall survival (%)

Overall survival (%)

60 60

40 40

20 20

0 1 2 3 4 5 0 1 2 3 4 5
Time after randomization (years) Time after randomization (years)
No. at risk No. at risk
Gemcitabine 106 97 82 73 60 56 Gemcitabine 11 10 7 6 5 4
Observation 94 87 71 61 57 49 Observation 14 11 9 9 8 6

c Negative resection margin d Positive resection margin

Fig. 4Kaplan–Meier estimates of overall survival, stratified by node status and margin status: a patients without lymph node metastasis,
b patients with lymph node metastasis, c patients with negative resection margins and d patients with resection positive margins.
a P = 0.723, b P = 0.839, c P = 0.965, d P = 0.657 (log rank test)

observation group (Fig. 2b). The HR for relapse in patients
receiving gemcitabine, compared with observation, was
0⋅93 (0⋅66 to 1⋅32; P = 0⋅693).
Subgroup analyses, stratified according to lymph node
status (pN0 versus pN1), resection margin status (R0 versus
R1), tumour location (hilar versus distal) and other factors
did not demonstrate significant differences in postopera-
tive survival between the two groups (Figs 3 and 4; Table
S1, supporting information). However, there were trends
towards a benefit for women, and lack of benefit among
patients with ECOG performance status 1.
Recurrence pattern
After 5 years of follow-up, recurrence was observed in 63
patients (53⋅8 per cent) in the gemcitabine group and 61
(56⋅5 per cent) in the observation group (P = 0⋅691) (Table
S2, supporting information). The location of first relapse
was not significantly different between the two groups;
liver was the most common site, followed by a local site,
peritoneum and abdominal lymph nodes. Of the 124
patients with disease relapse, 102 (82⋅3 per cent) received
treatment as follows: chemotherapy in 92, radiotherapy in
nine, and surgical resection in eight patients, with some
overlap.
Discussion
Because of the rarity of bile duct cancer and the exten-
sive surgical resection for this disease, the number of
surgical resections for the disease per centre has been

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Published by John Wiley & Sons Ltd
Adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer
limited1,4 , making it difficult to implement a random-
ized trial of adjuvant chemotherapy. There has been
only one phase III study20 , which was carried out over
25 years ago. This study had the following problems:
outdated regimen using mitomycin C and 5-fluorouracil;
inclusion of pancreatic and biliary cancers; and survival
benefit found only in patients with gallbladder cancer,
which could complicate its interpretation. The present
randomized trial evaluated the routine use of adjuvant
chemotherapy in bile duct cancer with follow-up over
5 years. This study, which was conducted in 48 centres
in a single country, failed to demonstrate a significant
difference in overall survival or relapse-free survival
between the gemcitabine and observation groups. These
findings clearly indicate that gemcitabine, which is used
widely in the metastatic setting for extrahepatic bile duct
cancer, probably does not work in the adjuvant setting.
Thus, simple observation should be the standard approach
to postoperative care in bile duct cancer, and adjuvant
chemotherapy should be undertaken only in the setting of a
clinical trial.
For adjuvant use of gemcitabine in pancreatic cancer,
the completion rate was approximately 60 per cent and
the relative dose intensity around 80 per cent9,21 . The
most frequent grade 3/4 adverse event was an abnormal
neutrophil level, with an incidence of approximately 70 per
cent21,22 . Interestingly, the present study showed similar
results regarding dose intensity and toxicity, even though
the profile of the surgical procedures differed between
the studies, as half of the patients here underwent major
hepatectomy. Although the optimal dose modification of
gemcitabine in patients who have undergone hepatectomy
has rarely been addressed23 , the present findings suggest
that patients who underwent extended hepatectomy were
able to tolerate gemcitabine therapy alone and support
the previous observation that the pharmacokinetics of
gemcitabine in patients were comparable after major
hepatectomy versus pancreatoduodenectomy24 . In this
context, toxicity-associated low dose intensity is unlikely
to affect the present survival results.
Several retrospective studies25 – 32 have evaluated the
effect of adjuvant chemotherapy in resected biliary tract
cancer. These reports have many flaws, including hetero-
geneous disease, limited numbers of patients, long study
period and a variety of regimens. Importantly, the conclu-
sions regarding survival benefits are conflicting. According
to a systematic review5 , a beneficial effect of adjuvant ther-
apy was not evident in the overall analysis, but was observed
in subgroups according to lymph node involvement and
resection margin status. Recently, a retrospective propen-
sity score matching analysis33 of node-positive perihilar
© 2018 BJS Society Ltd
Published by John Wiley & Sons Ltd
199
cholangiocarcinoma reported an increase in 5-year sur-
vival rate by 28 per cent in the adjuvant gemcitabine
group compared with the observation group. Both the
latter study33 and the systematic review5 recommended
adjuvant chemotherapy in node-positive disease follow-
ing resection. In contrast, the subset analysis limited to
node-positive patients in the present study showed no dif-
ference in overall survival between the gemcitabine and
observation groups. Rather, overall survival in the gem-
citabine group was worse than in the observation group
at 3 years. These results do not support the efficacy of
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adjuvant gemcitabine in node-positive patients. However,
this subset analysis was a secondary result with a limited
number of patients. Therefore, the efficacy of adjuvant
chemotherapy in such a high-risk population cannot be
completely ruled out.
In this study, the observed 5-year survival rate was
approximately 50 per cent, which was higher than the
expected rate of 30 per cent. This favourable long-term
outcome can be explained by several factors relating to
the trial design. Surgical outcomes generally improve over
time owing to refinements in surgical technique, peri-
operative management or surgical indication12 . In addi-
tion, the present study included only patients treated
for extrahepatic cholangiocarcinoma, excluding gallblad-
der cancer. The study also excluded patients with dis-
tant metastatic disease, those who underwent R2 resection,
patients with severe surgical complications and those who
died in hospital. These selection criteria may have con-
tributed to favourable survival in the present trial com-
pared with that of the entire patient cohort who under-
went resection. In fact, the number of deaths was lower
than anticipated in the initial 5 years after surgery. In this
respect, the survival rate at 5 years of approximately 50
per cent in patients with extrahepatic bile duct cancer
can be used as the baseline rate in further randomized
studies.
Four other randomized studies of routine adjuvant
chemotherapy in biliary tract cancer are currently on-
going: BILCAP (capecitabine, since 2006)34 , PRODIGE
12-ACCORD 18 (gemcitabine and oxaliplatin, since
2009)35 , ASCOT (S-1, since 2013) and ACTICCA-1
(gemcitabine and cisplatin, since 2014)36 . These studies
will add important information on the role of adjuvant
chemotherapy for resected bile duct cancer. However,
the PRODIGE 12-ACCORD 18 trial35 showed no dif-
ference in relapse-free survival between the experimental
and observation groups (39 versus 33 per cent at 4 years;
P = 0⋅31), similar to the present study. In contrast, the BIL-
CAP trial37 demonstrated a longer overall survival time
in the capecitabine group compared with the observation
www.bjs.co.uk BJS 2018; 105: 192–202
200
group (51 versus 36 months; P = 0⋅028, in per-protocol
analysis), although the intention-to-treat analysis failed
to show the efficacy of adjuvant capecitabine therapy (51
versus 36 months; P = 0⋅097). The BILCAP study included
R1 resection, pN1 disease and gallbladder cancer in a
larger percentage of the cohort (35, 54 and 18 per cent
respectively) than in the present study (11⋅1, 34⋅7 and 0
per cent). The short follow-up of at least 2 years should be
considered in the BILCAP study. Overall, the results of
these studies, including BCAT, suggest that combination
chemotherapy does not always provide a survival benefit,
and the inclusion of patients with expected favourable
survival reduces the number of deaths, which potentially
leads to negative results. Therefore, further clinical trials
of adjuvant chemotherapy should not target all patients,
but should instead focus on patients with high-risk features
following resection.
A limitation of this study was that patient recruitment
was terminated before the number of patients reached
300, which may have led to an underpowered analysis.
Patient enrolment was considerably delayed after about
2009, mainly because most patients wanted to receive
adjuvant chemotherapy. However, the survival curves for
the gemcitabine and observation groups nearly overlapped.
With these data in mind, there was only a 2⋅8 per cent
probability of there being a statistically significant differ-
ence in overall survival even if the expected 189 deaths had
occurred. Therefore, it is highly unlikely that increasing
the number of patients to 300 would have affected the main
results.
Collaborators
Members of the BCAT Study Group: S. Nakamori (Osaka Medical Centre,
Osaka), T. Ajiki (Kobe University, Kobe), H. Baba (Kumamoto Univer-
sity, Kumamoto), R. Yamaguchi (Kasugai Municipal Hospital, Kasugai),
M. Kawai (Wakayama Medical University, Wakayama), H. Nagano (Yam-
aguchi University, Ube), F. Miura (Teikyo University, Tokyo), T. Arai
(Anjo Kosei Hospital, Anjo), Y. Nishiwaki (Hamamatsu Medical Cen-
tre, Hamamatsu), S. Kawasaki (Juntendo University, Tokyo), H. Shinchi
(Kagoshima University, Kagoshima), M. Shimoda (Dokkyo Medical Uni-
versity, Mibumachi), Y. Yamamoto (Akita University, Akita), I. Endo
(Yokohama City University, Yokohama), S. Isaji (Mie University, Tsu), T.
Otsubo (St Marianna University, Kawasaki), S. Ishihara (Fujita Health
University, Toyoake), T. Takahara (Iwate Medical University, Morioka),
M. Shimada (Tokushima University, Tokushima), M. Unno (Tohoku Uni-
versity, Sendai), M. Imamura (Sapporo Medical University, Sapporo),
N. Ohkochi (Tsukuba University, Tsukuba), Y. Murakami (Hiroshima
University, Hiroshima), J. Fujimoto (Hyogo Medical University, Nishi-
nomiya), S. Ikuta (Meiwa Hospital, Nishinomiya), Y. Fujino (Hyogo Can-
cer Centre, Akashi), M. Uebayashi (Kitami Red Cross Hospital, Kitami),
S. Ishiyama (Sendai Kosei Hospital, Sendai), N. Takakura (Fukuyama City
Hospital, Fukuyama), Y. Kumamoto (Kitasato University, Sagamihara),
T. Kato (Toyohashi Municipal Hospital, Toyohashi), I. Yoshioka (Toyama
© 2018 BJS Society Ltd
Published by John Wiley & Sons Ltd
T. Ebata, S. Hirano, M. Konishi, K. Uesaka, Y. Tsuchiya, M. Ohtsuka et al.
University, Toyama), S. Uemoto (Kyoto University, Kyoto) and K. Yanaga
(Jikei University, Tokyo).
Acknowledgements
The authors thank T. Nakashima (Japan Clinical Can-
cer Research Organization), T. Ikari (Tobu Chiiki
Hospital) and K. Aiba (Jikei University) for data and safety
monitoring.
The trial was supported by funding from the Nagoya
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Surgery Support Organization and Eli Lilly Japan K.K.,
which had no role in the study design, data collection, data
analysis, or data interpretation.
Disclosure: The authors declare no conflict of interest.
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Supporting information

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Snapshot quiz

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Question: This 63-year-old man with chronic back pain also had long-standing intestinal obstruction. He had
intraoperative endoscopy after appendicectomy (a,b). What was the cause of the small bowel and colonic strictures
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a b c

The answer to the above question is found on p. 236 of this issue of BJS.
Landerholm K, Guy R: Department of Colorectal Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK
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 European Colorectal Congress
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2022

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28 November – 1 December 2022, St.Gallen, Switzerland
28

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Monday, 28 November 2022 Tuesday, 29 November 2022 Wednesday, 30 November 2022

09.50 9.00 9.00

Opening and welcome CONSULTANT‘S CORNER Advanced risk stratification in colorectal
Jochen Lange, St.Gallen, CH Michel Adamina, Winterthur, CH cancer – choosing wisely surgery and
adjuvant therapy
10.00 10.30 Philip Quirke, Leeds, UK
It is leaking! Approaches to salvaging an COFFEE BREAK
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Willem Bemelman, Amsterdam, NL 11.00 Predictors for Postoperative Complications
SATELLITE SYMPOSIUM and Mortality
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Andre D‘Hoore, Leuven, BE 11.45 Segmental colectomy versus extended
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Operative techniques to reduce 15.00
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Appendiceal neoplasia – when to opt for a Lars Pahlman lecture 15.00
minimal approach, when and how to go for Søren Laurberg, Aarhus, DK SATELLITE SYMPOSIUM
a maximal treatment
Tom Cecil, Basingstoke, Hampshire, UK

16.15 15.45
SATELLITE SYMPOSIUM COFFEE BREAK

16.15
Reoperative pelvic floor surgery –
17.00 er 2022 dealing with perineal hernia, reoperations,
Outcomes of modern induction therapies ecemb
ay, 1 D
and complex reconstructions
and Wait and Watch strategies, Hope or Hype h u rs d urgery
rectal S
T Guillaume Meurette, Nantes, FR
Antonino Spinelli, Milano, IT C o lo
class in y
Master logy Da 16.45
17.30 Procto Salvage strategies for rectal neoplasia
EAES Presidential Lecture - Use of ICG in Roel Hompes, Amsterdam, NL
colorectal surgery: beyond bowel perfusion
Salvador Morales-Conde, Sevilla, ES 17.15
Beyond TME – technique and results
of pelvic exenteration and sacrectomy
Paris Tekkis, London, UK
18.00
Get-Together with your colleagues 19.30
Industrial Exhibition FESTIVE EVENING

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