University of

Auckland
Biological Science
for

Practice 742
Lecturer: Barbara
Daly
Sofia Krylova
ID 247366794
8 April 2016
Total Word count: 2745

Excluding: cover page

in text referencing of 199 words
Reference list of 864 words
and in text table
The use of neoadjuvant chemo-radiotherapy and surgery versus
surgery alone for treatment of operative oesophageal carcinoma.
Introduction
The focus of this paper is oesophageal carcinoma (OC).
Oesophageal cancer affects almost half a million people worldwide and
the incidence rates increase annually. It has a high mortality rate of 7585%. Oesophageal carcinoma is the eighth most common cancer in the
world with the sixth highest mortality rate (Pennathur, Gibson, Jobe, &
Luketich, 2013). Histologically the most common types of oesophageal
carcinoma are squamous-cell carcinoma (SCC) and adenocarcinoma
(ACA), which account for 90% of all OC, less prevalent are the small-cell
carcinoma, melanoma and leiomyosarcoma.
The incidence of OC differs geographically, highest rates found in
the Asian orogenic belt, southern and eastern Africa (Pennathur et al.,
2013). Ministry of Health (2011) state that the incidence rate of
oesophageal cancer in men peaks at 9 per 100,000 and 4 per 100,000 in
women. The mortality rates are three times higher in men than women.
According to the Ministry of Health (2011) Maori have almost double
the incidence and mortality rates of OC compared to the non-Maori.
According to Hill, Sarfati, Robson, and Blakely (2013) Maori have poorer
health outcomes post cancer diagnosis and are twice as likely to die from
the disease. While non-Maori and Maori are equally likely to be diagnosed
and receive staging, Maori are less likely to receive the cancer treatment
and have significantly longer waiting lists compared to non-Maori
(Stevens, Stevens, Kolbe, & Cox, 2008). Robson and Harris (2008) write
that indigenous populations and inequality in health care arise due to
socio-economic disparities as well as cost and education related barriers

which influence patient specific-situations. Family involvement and

support is fundamental in Maori health. Cancer treatment is a very
involved and complex process that affects not just a patient but the family
as a whole. The lack of Maori oncologists/healthcare providers may also
be a contributing factor.
Aye, Elwood, and Stevanovic (2014) state, that overall cancer
survival in New Zealand is lower compared to Australia, therefore further
improvements in management and early diagnosis is crucial. According to
American Cancer Society (2016b) in the 1960-1970 only 5% of patients
survived five years post diagnosis, now days about 20% survive up to the
five-year mark.
This assignment will explore the topics of epidemiology, etiology,
pathophysiology and pathogenesis, diagnosis/staging and treatment of
OC. Three randomised control trials (RCT) will be analysed and treatment
options such as neoadjuvant chemotherapy (NCT) and surgery versus
surgery alone will be compared in respect to effectiveness, reduction of
morbidity and mortality rates
Aetiology
Although the exact cause of OC is still unknown, several
predisposing factors associated with the development of oesophageal
cancer have been identified. The mucosal lining of the oesophagus is
made up of squamous-cells, the risk factors contributing to the cancer of
these cells are: smoking, alcohol consumption (considered to be the
strongest factor), low socio-economic status, mutation of ADH/ALDH
enzymes, achalasia, caustic injury, history of thoracic radiation, poor oral
hygiene, nutritional deficiencies and non-epidermolytic palmoplantar
keratoderma. Adenocarcinoma develops in the gland cells of the
oesophagus. In order for ACA to develop, squamous cells are replaced by
gland cells, as seen in Barretts oesophagus and often occurs in patients
with long-standing reflux disease (American Cancer Society, 2016b). The
risk factors associated with the developments ACA are: being male, older

age, tobacco use, Helicobacter pylori infection, symptomatic gastrooesophageal reflux disease (GORD), high BMI, thoracic radiation, low
fruit/vegetable intake and family history of upper gastro-intestinal cancers
(Pennathur et al., 2013). The best measures, in order to prevent OC is
avoiding smoking and alcohol consumption (American Cancer Society,
2016b).
Pathogenesis and Pathophysiology
During mitosis, the parent cell starts to grow (G1 Stage), duplicates
its chromosomes (Synthesis Stage), continues to grow (G2 Stage) and
forms two identical daughter cells (Mitosis Stage) (Genetics Home
Reference, 2016). Cancerous cells usually have a number of
defects/changes in their genes, that cause the cell to make an excess of
certain proteins which influence the cells growth and reproduction. Factors
such as nutrient limitations, lack of growth factors or cell damage
normally get detected by the cells checkpoints, giving it time to repair or
causing the cell to die. However, when the cell systems fail to detect
abnormalities during the cell DNA synthesis, the damaged cell continues
to divide with the mutation in metabolic enzyme called the isocitrate
dehydrogenase (Yen & Schenkein, 2012). This disrupts the structure of
cells DNA and as these damaged cells continue to multiply they form
masses/tumours. Malignant tumours tend to grow faster than benign and
over time can rapidly metastasise via blood supply to other organs (Kruth
& Tew, 2012). There are many types of cancer cells and they have
different genetic changes, therefore, treatments differ depending on the
type of cancerous cell is being targeted.
Pre-treatment OC staging is based on the Tumour Node Metastases
(TNM) system. The TNM system is designed to identify the subtype, depth
of the primary tumour and identification of the mediastinal organs/lymph
nodes. The staging is a prime indicator if the patient will be considered for
a surgery (Napier & Scheerer, 2014).

It is believed that chronic inflammation of the oesophageal mucosa

due to carcinogenic influences of aetiological factors causes/contributes to
the damage of cells genetic makeup, resulting in cancerous cell formation.
Due to the lack of the serous membrane in the anatomy of the
oesophagus, OC often has a mediastinal spread at the time of detection
invading submucosal/muscular layers and nearby organs such as
tracheobronchial tree, the aorta and the recurrent laryngeal nerve. Distant
metastasis usually occurs in the early stage to the peri-oesophageal
lymph nodes, lungs and liver (DeMeester, 2009). The formed tumour may
partially or fully occlude the lumen of the oesophagus and contribute to
the presenting symptoms such as dysphagia, regurgitation, leading to
pain caused by oesophageal spasms, fatigue, loss of appetite resulting in
weight loss (Moxon, 2011). Squamous-cell carcinoma tends to develop
along the oesophagus, while ACA generally develops in the lower part of
the oesophagus and may involve the gastric cardia (American Cancer
Society, 2016b).
Diagnostic Tools
Typically, OC has a late presentation explaining the often poor
prognosis. Screening is advisable for patients with a family history of OC,
long-standing reflux or achalasia. The four most common diagnostic
factors of OC are: reflux, dysphagia, odynophagia and weight loss. Up to
40% of patients diagnosed with Barretts with dysplasia tend to have
carcinoma in situ or invasive cancer. One of the firsts tests in patients with
the presence of dysphagia is a barium swallow with double contrast
(Layke & Lopez, 2006). However, BPACNZ (2014) writes that patients with
red flags of GORD (dysphagia, odynophagia, hematemesis, weight loss
and >55 years of age) are more likely to develop OC and should
immediately be referred to endoscopy for biopsies.
If OC is identified CT/MRI/PET scans are considered in order to
establish the size of primary tumour, invasion and/or presence of
metastases. Endoscopic ultrasound is also a very accurate test to help

determine the extent of local tumour invasion and spread to the nearby
lymph nodes (American Cancer Society, 2016b).
Treatment Options
The treatment options for OC has undergone major revaluation and
advancement in the last decade (Siegel, Miller, & Jemal, 2016). Treatment
of OC depends on a number of factors such as TNM and the overall
physiological state of the patient. Regardless of improvements with OC
staging, patient selections and new surgical techniques, the overall
/pulmonary complications rates continue to stay high (Mariette, Piessen, &
Triboulet, 2007). Oesophagectomy (removal of some/most of the
oesophagus, +/- gastroesophageal junction) used to be the only
treatment for OC and despite new surgical improvements, the median
survival post-surgery alone remained between 12-18 months, with a 5yearly survival of just 20% (Society for Surgery of the Alimentary Tract,
2007). Oesophagectomy can be done by open, minimally invasive
(laparoscopic/thoracoscopic) or in some cases a hybrid combination of
both depending on the overall fitness of the patient, size/extent of the
tumour (Briez et al., 2011). Post-surgical complications and risk factors
include pneumonia, cardiac complications, other organ failure, severe
infections, anastomotic leakage and bleeding. Complication rates are
extremely high and seem to develop in up to 75% of patients (Viklund et
al., 2006).
In order to increase cure rate/prolong life and reduce
micrometastasis, the size of the tumour and to increase the chances of
curative resection, co-treatments such as NCT and/or radiotherapy were
introduced for patients with advanced disease process (Society for
Surgery of the Alimentary Tract, 2007). Many cytotoxic anticancer drugs
target specific cell cycle division processes causing cancer cell mutation
aiming to achieve cell apoptosis by inhibiting the synthesis of cells DNA
and subsequently reducing the number of cancerous cell per administered
cycle (Skipper, Schabel, & Wilcox, 1964). The most common regime for OC
patient is cisplatin with 5-fluorouracil. Definitive chemotherapy has shown

up to 30% long-term survival for patients with SSC undergoing surgery

(Karran et al., 2014). Neoadjuvant chemo/radio therapy followed by
surgery is now considered to be the standard of care for advanced OC
(Miyata et al., 2016).
In the treatment of OC post chemotherapy and post-surgery
complications still remain high. Cytotoxic chemotherapy drugs have the
ability to break rapidly growing and reproducing tumour cancer cells.
However, as the drug travelling through the body, it also damages the
normal body cells that are undergoing cell division leading to serious sideeffects. Cytostatic cancer therapy works but attacking specific types and
parts of the of cells, such a specific protein in the cell or boosting the way
the body fights against these cells (American Cancer Society, 2016a).
Often chemotherapeutic agents have a toxic effect even if
administered at the normal doses. In cases where the extent of the
disease is severe, treatment is often regarded as palliative. In this case,
the expected toxicity/side effects from chemotherapy must be weighed
against the possibility of positive results and discussed with the client
(Plenderleith, 1990). Common cytotoxic chemotherapy side effects are:
fatigue, nausea/vomiting, diarrhoea/constipation, thrombocytopenia, loss
of appetite, lymphedema, alopecia, infection/neutropenia, peripheral
neuropathy, mouth/throat problems, infertility, urinary problems and skin
problems. It has also been reported to have a very high
haematological/non-haematological toxicity such as mucositis, diarrhoea
and cardiac and bone marrow toxicity (Matsusaka & Lenz, 2015). The
common side effects of cytostatic are: skin problems, gastrointestinal
perforation, negative effect on clotting factors and wound healing
(National Cancer Institute, 2015). Due to the high mortality and morbidity
rates, quality of life post/during cancer treatment is of high importance
(Viklund et al., 2006).
Malignant oesophageal dysphagia is one of the most common
symptoms in OC, caused by a tumour obstruction of the oesophageal
lumen. Oesophageal stenting is a common treatment for symptom relief in

patients with unresectable/resectable/potentially resectable cancers. The

process of stent placement often requires endoscopy under fluoroscopic
guidance. Oesophageal stent placement complications include
perforation, bleeding, tumour overgrowths and stent migration (Adler,
2013).
Evidence from Three Selected RCT
RCT 1
Allum, Stenning, Bancewicz, Clark, and Langley (2009) from United
Kingdom, in the early 1990s, designed a randomized control trial (RCT)
with 802 participants. The purpose was to determine if neoadjuvant
chemotherapy followed by surgery would decrease the mortality rate
compared to immediate surgery alone (S-group). The eligible patients for
the RCT had to have oesophageal carcinoma for which they have not
previously had treatment and that could be considered for surgery. The
tumour had to be located in the oesophagus including the cardia, but
excluding postcricoid cancer and not suitable for surgery oesophageal
tumours. The article did not indicate any other exclusions for the trial.
Participants were aged between 30 and 84 years (median age was 63),
605 males, all of them were diagnosed with oesophageal cancer. Of the
recruited patients, 400 were randomly assigned on CS group and 402 on S
group. Patients were followed up at 3, 6, 9 and 12 months, from the date
of treatment then every 6 months until death. The median follow-up of the
analysis was 6 years. The primary measurable outcome of the trial was
the survival rate between two groups and the secondary were survival
without further disease, dysphagia and overall performance. However, for
the purpose of this assignment I will be concentrating only on the primary
measurable outcome of survival rate.
During the term of the trial 655 people died, 355 in the S-group and
320 in the CS group. The hazard ratio of 0.84 means that the CS group
had 16% survival benefit when compared to group S over the whole time
of the trial, with 95% CI (0.72 to 0.98), P=0.03 (strong evidence to

suggest that NCT improves the survival rate). At 5 years, 23% of

participants from the CS group and 17.1% from the S group had survived,
giving almost 6% improved survival rate. Consequently, according to the
results of this trial, NCT in operative OC prolongs survival and as
recommended by researchers, should be considered to be a standard of
care.
RCT 2
Kelsen et al. (1998) performed a multi-institutional RCT in the US,
that compared the survival rates of patients (n=440) with localized
oesophageal cancer undergoing NCT followed by surgery to patients
undergoing surgical treatment alone. The median duration of study was
55.4 months. The process of randomization included <10% of total body
weight loss and histologically included ACA and epidermoid cancer (EC).
Patients were randomly assigned to undergo 3 cycles of chemotherapy. All
patients had to be stable and able to respond to chemotherapy. Of the
total patients 213 where assigned to CS group and 227 to S group. In SC
group 83% of patients completed 2 cycles of chemotherapy, due to death
or disease progression. Following chemotherapy 133 patients had surgery.
The median time to surgery in group S was 9 days and 93 days in group
CS. Postoperatively 10 patients died in group CS and 13 in group S. The
median survival was 14.9 months in SC group and 16.1 in S group, the
P=0.53, without significant difference between the groups. Similar results
were seen in 1-year with 59% survival rate in group SC and 60% in group
S, at 2-years the survival rate in group SC was 35% and 37% in group S.
No significant difference in survival was noted from a histological
perspective of this trial and weight loss was the main predictor of poor
outcome (P=0.03). The follow-up was up to 5 years. This study concluded
that surgery alone continues to be the standard of care for locoregional
OC patients.
RCT 3

This prospective RCT by Law, Fok, Chow, Chu, and Wong (1997) was
done in Hong Kong in order to determine the role of NCT compared to
surgery alone in regards to survival of patients with SSC of the
oesophagus. The trial consisted of 147 patients, 74 were in CS group and
73 in the S group. In the CS group, 13 people did not adhere to the trial
protocol, one had a complete response to chemotherapy and refused
surgery. Twelve patients did not complete 2 cycles of chemotherapy and 6
did not have surgery. Five out of the 6 refused treatment and 1 died due to
transient ischemic attack. Out of 6 patients in the SC group 2 patients had
to stop chemotherapy due to tuberculosis and one due to pancytopenia.
Sixty-six patients in the CS and 69 in the S groups underwent resection,
P=not significant (NS). Out of 60 patients who completed chemotherapy
and underwent a resection, 35 had a significant response and 4 had a
pathologic response. Post-surgery mortality was 8.3% in SC and 8.7% in S
group, P=NS. R0 successful resections 67% in CS group and 35% in S
group, P=0.0003. The response to treatment was higher in the
interventional group who responded to chemotherapy as oppose to
controlled group, with median survival of 42.2 months in SC group and
13.8 months in the S group, over 2-year difference (P)=0.003. Patients
who did not respond to treatment had significantly lower median survival
of 8.3 months, P=0.03. Therefore, patients who responded to
chemotherapy had a higher survival rate compared to patients who
underwent surgery alone.

Study
Sample
Intervention
Results
Allum et
Oesophageal
Intervention CS:
CS group prolonged
al (OEO2
disease-free survival
N=400
Cancer
o Chemotherapy (two cycles compered to S group
Study)
HR 0.82; 95% CI,
2009, UK, 802 participants
of cisplatin and
with
OC
0.71 to 0.95;
RCT 1
fluorouracil) completed by
SSC 124
P=0.003
N=350 (90%)
ACA 268
CS N=345
The overall survival:
Undifferentiate Chemotherapy Only N=26
CS: HR 0.84;
d 10
two cycles of cisplatin
95%CI, 0.72 to
80mg/m2 IV (over 4hrs
0.98; P=0.03
Mean age 63
on day 1) and fluorouracil In absolute terms, the

Male 605

Kelsen at
el 1998,
US Multiinstitutio
nal
Study,
RCT 2

1000mg/m2 (daily over

96hrs and repeated
every 3 weeks), followed
by surgery in 3 to 5
weeks
Refused Chemotherapy, had
surgery only N=12
Neither chemotherapy or
surgery refused/death N=5
Missing details N=12
Deaths total N=320
Alive at time of analysis n=80
Control Group S:
n=402
Had Surgery n=386
Death/refused surgery n=13
Missing details n=3
Deaths total n=335
Alive at time of analysis n=67

above equates to 5year survival for:

CS-23%
compared to
17.1% S group
Cause-specific analysis
of survival by OC
death confirming the
CS group advantage
HR 0.83; 95% CI, 0.70
to 0.98; P=0.04
Due to poor accrual,
the study was stopped,
with 17% complete
pathologic responses
17% compared to
2.5% after
Chemotherapy

Median Follow up 6.1 years

9% of patients in both groups
also received radiation
therapy
38 new deaths in both groups
post analysis from OC
6 other cancers
7 other known causes
8 unknown causes
In 30 deaths occurring over
5years
11 in S group due to OC
19 in CS group due to OC
Oesophageal
Intervention CS:
CS group median
Cancer
survival:
N=233
440 participants
14.9 months
Chemotherapy received S group median
with OC
CS N=204
EC 213/eligible
survival:
cisplatin 100mg/m2 IV
16.1 months
204
on day 1 and
ACA 244/eligible
P=0.53 by long-rank
fluorouracil
236
test
1000mg/m2 from day
P=0.49 by Cox
1 to 5, 120 hrs, cycles
Mean age 61
proportional-hazards
repeated on week 4
Male 370
analysis
and 8, followed by
RR of death 1.07 in CS
surgery 2 to 4 weeks
group
after chemotherapy
95% CI, 0.87 to 1.32
1 cycle N=32
Out of CS N=233, 180

died
Out of S n=234, 173
died
At 1 year
Less than 3 cycles received due
SC survival 59%
to:
S alone survival
Patient/Dr choice N=25
60%
Disease progression
At 2 years
N=14
SC 35%
Death N=12
S
37%
Toxicity N=3
At 3 years
Other N=6
CS 23%
S
26%
Out of Eligible Patients N=213:
surgery performed on N=171 Long-rank test P=0.74
Cox proportional Resection achieved:
hazards RR of death
R0 N=133
CS 1.04, 95% CI, 0.84
R1 N=8
to 1.29
R2 N=21
Analysis of evaluated
None N=51
patients only P=0.50
Postoperative Death
(disease free
N=10
survival)
Major complications
N=53
Minor complications
N=49
None N=59
2 cycles N=26
3rd cycle N=144
None N=2

Control Group S:

n=277
Had Surgery n=217
Resection achieved:

R0 n=135
R1 n=35
R2 n=33

None n=24

Postoperative Death
n=13
Major complications
n=57
Minor complications
n=67
None n=80
Median Follow-up CS/S 5

Law et al
(1997)
Hong
Kong,
RCT 3

Oesophageal
Cancer
147 participants
with SSC OC
Mean age 64
Male 125

years
No significant difference in
Out of N=60 in CS
tumour differentiation, level or
group 35 or 58% had
stage at the enrolment of the
significant response
trial.
and 4 or 6.7% had
complete pathologic
Intervention CS:
response
Post-op mortality rates
N=74
CS 8.3%
Chemotherapy
S 8.7%
Two cycles of cisplatin
P=NS
and fluorouracil)
Curative resection
completed by N=60
67% CS
One cycle completed by 35% S
N=6
P=0.0003
Bypass N=1
T3 and T4 tumours
found in CS=67%
Refused Surgery, had
and S=91%,
chemo
P=0.0002
N=1
N1 disease
One cycle, stopped
CS=70%,
treatment N=6
S=88%,
P=0.17
Control Group S:
Analysis of Intend
N=69
to treat P=NS.
Bypass n=4
Median survival
Follow up: monthly for a year,
CS=16.8
followed by every 3 months
months,
S=13 months
Analysis of survival
CS who responded
to Chemotherapy
Vs S
42.2 months
13.8 months
P=0.003
Non responders
survival
CS 8.3 months

N (CS)/ n (S)=number. R0 -complete resection /complete remission. R1 resected margins

show the microscopic residual tumour. R2 resected margins show the macroscopic
residual tumour. T=Tumour, T1, T2 (the higher the number is the more the tumour grown
into close by tissues). N-nodes (the higher the number is the more cancer has spread into
nearby lymph nodes). CS-chemotherapy and surgery, S-surgery only.

Summary
Two out of 3 RTC analysed in this assignment supported the
evidence that NCT improves the survival rates for patients with OC. Allum
et al. (2009) RCT1 had a better design, longer follow-up time and had
twice the amount of the participants as the RCT2 by Kelsen et al. (1998)
and 5.5 times more as the RCT3 by Law et al. (1997). In RCT2 by Kelsen et
al. (1998) only 2/3 of the patients completed 3 cycles of chemotherapy,
and the analysis was limited to patients who only had a successful
curative resection. In RCT3, Law et al. (1997) concluded that participants
who responded to the chemotherapy had 2 years higher survival rates.
Since the late 90s surgical methods for oesophagectomy have
moved away from open surgery to minimally invasive laparoscopic
surgery. Careful patient selection and modern anaesthetic assessment
along with improved postoperative care have also contributed to improved
morbidity/mortality rates (Zingg et al., 2011). The design and
randomization in RCT has also improved (Knlo, Groenwold, & Grobbee,
2012).
Conclusion
In the last decade, NCT has become a more prevalent therapeutic
procedure for approved patients with OC in order to increase survival
rates and improve the rates of successful resections. Neoadjuvant
chemotherapy treatment is considered for patients who are fit enough to
receive the treatment and help with symptoms of dysphagia as well as
reducing the tumour size prior to resection. Ideally, a careful patienttailored approach with consideration of all factors by a multidisciplinary
team including surgeons, oncologists, radiologists, endoscopists and
pathologists is necessary to provide optimum treatment for this complex
disease process. Healthcare providers must stay vigilant and investigate
high-risk patients early.

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