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ROLE OF CHEMOTHERAPY IN IMPROVING
DYSPHAGIA FREE SURVIVAL IN PATIENTS WITH
ADVANCED ESOPHAGEAL CANCER TREATED
WITH HIGH DOSE RATE BRACHYTHERAPY
ROLE OF CHEMOTHERAPY
IN
IMPROVING DYSPHAGIA FREE SURVIVAL
IN PATIENTS WITH ADVANCED ESOPHAGEAL
CANCER
TREATED WITH HIGH DOSE RATE
BRACHYTHERAPY
By
EMILIA OLIMPIA TIMOTIN, BSc
A Thesis
Submitted to the School of Graduate Studies
in Partial Fulfillment of the Requirements for the Degree of
Master of Science
McMaster University
II
Master of Science
(Medical Physics and
Applied Biology)
McMaster University
Hamilton, Ontario
Title
Role of Chemotherapy in
Improving Dysphagia Free
Survival in Patients with
Advanced Esophageal Cancer
Treated with High Dose Rate
Brachytherapy
Author
Emilia Olimpia Timotin
Supervisor
Dr. Ranjan K Sur
Dr. Thomas Farrell
Number of Pages
104
III
ABSTRACT
BACKGROUND
High dose rate Intraluminal Brachytherapy (HDRILBT) is one of the most used palliative
treatment options for advanced esophageal cancer. The present study evaluates the role of
additional chemotherapy in improving dysphagia free survival (DFS) and overall survival
(OS) in patients with inoperable advanced esophageal cancer treated with brachytherapy.
MATERIAL and METHODS
132 patients with advanced metastatic esophageal cancer with total or near total
dysphagia were given HDRILBT to a dose of 18 Gray (Gy) in 3 fractions on alternate
days. Intraluminal brachytherapy alone was performed on 98 patients. 34 patients
received Epirubicin, 5-Fluorouracil, and Cisplatin (ECF) chemotherapy regimen after
HDRILBT. The mean age of the whole group was 65 years (HDRILBT-71.41,
HDRILBT+ECF-59.98; p<0.0001). Male: Female was 101:31 (HDRILBT 72:26;
HDRILBT +ECF 29:5; p>0.05). The location incidence was GEJ: Lower Esophagus: Mid
Esophagus: Cervical Esophagus 24:81:17:5 respectively; for the whole group HDRILBT17:57:16:4; HDRILBT+ECF-7:24:1:1; p>0.05. 78 patients presented with co-morbidities
(cardiac) (HDRILBT- 59; HDRILBT+ECF- 19; p>0.05). 74 patients presented with
distant metastasis (54 with HDRILBT and 20 with HDRILBT+ECF; p>0.05). The ECOG
scores were as follows 0:1:2:3:4 15:52:51:12:2 (HDRILBT- 10:35:41:10:2;
HDRILBT+ECF- 5:17:10:2:0; p=0.0014). All patients completed 3 fractions of
HDRILBT. 34 patients received additional chemotherapy with ECF regimen. Selection of
patients was done by the medical oncologist. Statistical analysis of data was done using
the SAS statistical analysis software system. Univariate and multivariate analysis was
done using the log rang test.
IV
RESULTS
Patients who received additional ECF were younger (p< 0.001) and with a better
performance status than those who received HDRILBT alone (p=0.0014). Mean DFS was
higher for patients who had further chemotherapy treatment (232 days) vs. patients who
had HDRILBT only (155 days) (p>0.05). The mean OS for HDRILBT + ECF was 266
days (p = 0.0010) compare with HDRILBT alone which was 155 days, when the effect of
10 prognostic factors was analyzed for DFS and OS. Only additional ECF after
brachytherapy impacted on DFS while age (p<0.001) and performance status (p=0.0014)
impacted on overall survival on univariate analysis. On multivariate analysis tumor length
and nodal presentation (p<0.000) impacted on OS. The incidence of stricture and fistulae
were similar. Chemotherapy related side effects: gastrointestinal tract (25 patients),
neurotoxicities (2) and nephrotoxicities (2) were seen as a result of 5-FU and Cisplatin
respectively. 18 patients completed at least 3 cycles of ECF.
CONCLUSION
Additional chemotherapy with ECF after HDRILBT improves the DFS and OS in
selected patients with advanced esophageal cancer. These patients tend to be younger
with better performance status, small tumor length and nodal metastasis. The incidence of
complications is similar with more than 50% patients completing at least 3 cycles of
chemotherapy.
V
ACKNOWLEDGEMENTS
I would never have been able to finish my thesis without the guidance of my committee members, help
from friends, and support from my family.
First and foremost I would like to express my deepest gratitude to my advisor, Dr. Ranjan K. Sur. Without
his vision and initiative, this research would have not been done. I am thankful for his aspiring guidance,
invaluably constructive criticism and friendly advice during the project work. Many thanks for offering me
the opportunity to conduct this study, for his excellent guidance, for mentoring me throughout this
endeavor, for his enthusiasm.
Nonetheless my gratitude goes to my supervisor Dr. Thomas Farrell for sharing his truthful and
illuminating views on a number of issues related to the project. I am grateful that he provided the necessary
support for me to gain confidence in myself. I am sincerely grateful to him for patiently corrected my
writing, for his motivation, insightful comments, support and immense knowledge.
As always, for believing in me and for her support, my sincere appreciation goes to my manager Marcia
Smoke.
I would also like to thank Bernard Donde for his help and guidance in data analysis.
Special thanks go to Dr. Colin Seymour who was willing to participate in my final defense committee at
the last moment.
I would like to thank Christine Pinho, who as a good friend was always willing to help and give her best
suggestions. It would have been a lonely work without her.
Many thanks to my colleagues and friends at work especially Michele Cardoso and Lilian DoerwaldMunoz who contributed with encouraging words and comforting words and kept me going. My research
would not have been possible without their help.
Last but not least, I would like to offer my deeply thanks to my husband and two children Antonia and Titus
for their patience and tremendous help during this time. They were always supporting me and encouraging
me with their best wishes. Thank you for being there for me throughout my life and supporting my every
decision.
VI
TABLE OF CONTENTS
Abstract
iv
Acknowledgments
vi
Table of Contents
vii
List of Illustrations, Chart, and Diagrams
ix
List of Abbreviations, and Symbols
xii
1.0 Introduction
1.1 Esophageal cancer
1
1.1.1 Incidence and Mortality in North America and Worldwide
3
1.1.2 Risk Factors
6
1.1.3 Pathology
10
1.1.4 Presentation
11
1.1.5 Factors Affecting Prognosis
12
1.1.6 Diagnostic Work-up
13
1.1.7 Assessment and Staging
15
1.2 Treatment Options
19
1.3 Objectives and Aims
22
1.4 Hypotheses of the Study
23
1.5 Review of Literature
24
VII
1.5.1 The role of brachytherapy in palliation of dysphagia
25
1.5.2 The role of chemotherapy in metastatic esophageal cancer
33
2.0 Patients and Methods
52
3.0 Results
62
4.0 Discussion
77
5.0 Conclusion
81
6.0 Reference List
82
VIII
LIST OF FIGURES AND TABLES
Figure 1.1
Anatomy of the esophagus
Figure 1.1.6.1
Advanced esophageal cancer: A, Near total obstruction;
B, Barium swallow x-ray
14
Figure 1.1.7.1
Esophageal Cancer Staging
15
Figure 2.8
Remote Afterloader Brachytherapy Unit
55
Figure 2.9
Barium swallow examination of an complete tumor
obstracted esophagus
55
Figure 2.10
Localization of Intra-oral tube/Catheter in situ
56
Figure 2.11
Marker wire used to measure the tumor length.
57
Figure 2.12
Diagram showing definition of the target volume
57
Figure 2.13
Treatment Plan Distributions
58
Figure 3.1
Pie graph showing age distribution of patients
65
Figure 3.2
Pie graph showing gender distribution of patients
66
Figure 3.3
Pie graphs showing male and female distribution of
patients studied for each treatment strategy
66
Figure 3.4
Pie graph showing tumor location
67
Figure 3.6
Pie graph showing tumor pathology
68
Figure 3.7
Distribution of Nodal Metastasis for patient receiving
HDRILBT only
69
Figure 3.8
Distribution of Nodal Metastasis for patient receiving
HDRILBT plus Chemotherapy
69
IX
1
Figure 3.9
Distant Metastases
70
Figure 3.10
Distribution of treatment given and number of patients
71
Figure 3.12
Dysphagia Free Survival DFS
72
Figure 3.13
Overall Survival OS
74
Table 1.1.2.1
Esophageal cancer risk factors
Table 1.1.4.1
Dysphagia Grading
11
Table 1.1.7.2
TNM 7th Edition of the AJCC Cancer Staging Manual:
17
6
Esophagus and Esophagogastric Junction
Table 1.1.7.3A
7th Edition of the AJCC Cancer Staging Manual;
Adenocarcinoma stage grouping
18
Table 1.1.7.3B
7th Edition of the AJCC Cancer Staging Manual;
Squamous-cell carcinoma stage groupings
18
Table 1.2.1
Palliative Treatment Methods for Advanced Esophageal
Cancer
19
Table 1.2.2
Methods of Palliation and Median Survival
21
Table 1.2.3
Comparison between treatment modalities for dysphagia
relief
21
Table 1.5.1.1
High Dose Rate Brachytherapy – Palliative Results
26
X
Table 1.5.2.1
Old single chemotherapy agents
34
Table 1.5.2.2
New single chemotherapy agents
37
Table 1.5.2.3
Combination of two chemotherapy agents
45
Table 2.1
EORTC-QLQ
53
Table 2.2
Dysphagia algorithm
54
Table 2.3
Clinical Patient Characteristics
62
Table 2.4
Tumor Characteristics and Treatment Features
63
Table 2.6
WHO/ECOG
64
Table 2.7
Study Patients’ Performance Status
64
Table 3.5
Tumor Pathology
68
Table 3.11
Dysphagia free survival for both treatment modalities
72
Table 3.14
Overall survival for both treatment modalities
74
Table 3.15
Complications for both treatment modalities
76
Table 3.16
Total numbers of toxicities for both treatment modalities
together
76
Review HDRILBT with literature
77
Table 4.1
XI
LIST OF ABREVIATIONS
HDRILBT
High Dose Rate Intraluminal Brachytherapy
ECF
Epirubicin, Cisplatin, 5- Fluorouracil
EORTC-QLQ
European Organization for Research and Treatment of Cancer
Quality of Life Questionnaire
WHO
World Health Organization
ECOG
Eastern Cooperative Oncology Group
DFS
Dysphagia Free Survival
OS
Overall Survival
SCC
Squamous Cell Carcinoma
AC
Adenocarcinoma
CT
Computed Tomography
PET
Positron Emission Tomography
EUS
Endoscopic Ultrasound
HRQoL
Health Related Quality of Life
GEJ
Gastro-esophageal Junction
XII
1.0 INTRODUCTION
1.1
ESOPHAGEAL CANCER
The esophagus is a long hollow tubed organ that is lined with stratified squamous
epithelium and has the main function of passing food from the mouth to the stomach.
Several layers of tissue make up the wall: the mucosal layer, submucosal layer, muscular
layer and the adventitia layer (Figure 1.1).
The uncontrolled division of abnormal cells leads to cancer. This cell growth and
development remains unregulated and will develop into a tumor. The cells can enter the
blood stream or lymphatic system and as a result can spread to other organs. This process
is known as metastasis.
Figure 1.1 - Anatomy of the esophagus [3]
1
Esophageal cancer is a gastrointestinal malignant tumor that forms in esophagus tissue. It
has an insidious onset and a poor prognosis. On average, for tumors under 5cm long, 30%
are localized, 40% are locally advanced and 30% have undergone metastasis [19]. For
tumors longer than 5cm, 10% remain localized, 25% become locally advanced and 70%
undergone distant metastasis [19]. The spread occurs from the inside of the esophagus,
outwards through several layers of tissue. Among many presenting symptoms
experienced by patients, dysphagia is the most predominant. Dysphagia is defined as
difficulty in swallowing caused by a lesion or a stricture, leading to an obstruction of the
esophagus by a tumor. When dysphagia to solid food occurs, the esophagus is almost
completely obstructed with 90% of the lumen compromised and the muscularis mucosa
has been penetrated by the tumor into the adventitia.
One of the major concerns with esophageal cancer is the poor prognosis in the majority of
cases. Almost all patients have advanced disease at the time of initial consultation [19].
2
1.1.1 INCIDENCE AND MORTALITY IN ESOPHAGEAL CANCER IN NORTH
AMERICA AND WORLDWIDE
INCIDENCE AND MORTALITY IN NORTH AMERICA
The incidence of esophageal cancer has been steadily increasing over the past decades
worldwide [19]. In North America in 2013 the incidence of new cases of esophageal
cancer was estimated to be around 2000 from all Canadians [22]. The number of
Canadians with esophageal cancer who will die from the disease has been approximated
to be around 1900 [22]. Annually this number has been increasing at a steady rate with a
change in histologic type of esophageal cancer and the location of the primary tumor [19].
Esophageal cancer is amongst the 10 most common causes of cancer death in men with
an estimated percentage of 5-7%. A five-year relative survival rate is approximately 38%
when the disease is localized, 20% for regional and 3% for metastasis. These survival
rates for esophageal cancer pertain to squamous cell carcinomas and adenocarcinomas
together [142].
Esophageal cancer can be either squamous cell carcinoma or adenocarcinoma. The most
common histological form of cancer in the esophagus has long been the squamous cell
carcinoma type. For the last ten years, reports have shown a rising incidence of
esophageal adenocarcinoma in most of the western world, and an unchanged percentage
in Asia and South America [122]. It had been largely thought that esophageal
adenocarcinoma, for the most part, did not exist until the 1950's. Lately it has been one of
the fastest growing cancers in America [116, 97, 2]. For different types of esophageal
cancer, squamous cell carcinoma has been seen commonly in blacks and white women
while adenocarcinoma among white men.
The primary tumor location was more frequently in the distal esophagus. Squamous cell
carcinoma occurred mostly in the upper third or middle of the esophagus.
Adenocarcinomas were predominant in lower third of the esophagus and gastroesophageal junction [24, 50].
3
The incidence rates have increased from 1996 to 2009 by 0.5% in all races. This has
happened because of an increased incidence in men. In woman, the incidence actually had
dropped by 0.4% [99]. The incidence of blacks have been shown to be twice that of
whites (8.63/100000 vs. 4.39/100000, p<0.05) [35].
Esophageal cancer has occurred 3-4 times more often in males than females [24, 50].
Keighley study showed the same result with male to female ratio of 3 to 1 [74].
In Asia men and women ratio had been almost equal [75].
As per Canadian Cancer Society statistics, in Canada it was estimated that 1,550 men and
460 women were diagnosed with esophageal cancer in 2013 [22].
The risk of esophageal carcinoma, for both squamous cell carcinomas and
adenocarcinomas, has increased with age. The mean age at diagnostic was seen to be 67
years [35].
Esophageal cancer is seen all around the world. The geographic difference in cancer of
the esophagus suggests that the environmental exposure plays an important role.
Blot et al showed that squamous cell carcinoma is the most frequent histological type of
esophageal cancer. Additionally, they concluded that the incidence of adenocarcinoma of
the esophagus and esophagogastric junction has been rising especially in US and Europe
among white men [12].
The same conclusion was confirmed by studies of Pera et al. They reported a shift in the
histology of esophageal cancer in the western countries and the location of the tumor
being more frequent in the distal esophagus [105]. In contrary, it was seen an unchanged
incidence in this matter in Asia [47] and South America [44]. In 90% of cases of
esophageal cancer in central Asia to North - Central China, squamous cell carcinomas had
been predominant [54, 134]. Furthermore, it was observed an incidence pattern change
because of immigrants that are adjusting correspondingly to where they live [135].
4
INCIDENCE AND MORTALITY WORLDWIDE
The top five cancers that kill are lung, colon, breast, prostate and pancreas. Cancer related
deaths are liver cancer at 3%, ovarian cancer with 2.7%, esophageal cancer having 2.4%,
bladder cancer 2.4% and brain cancer with 2.3% incidence rates. In combination, these
account for 69.1% of all deaths related to cancer [122].
Esophageal cancer is detected in approximately half a million people every year
worldwide and the incidence is increasing unfortunately very fast [103]. It is the eighth
most common cancer and the sixth most common cause of cancer death [101]. Surgical
removal is no longer a viable treatment strategy for more than half of patients diagnosed
with an advanced stage of esophageal cancer [116].
It also has been reported that the majority of esophageal cancer cases (80-85%) are
diagnosed in developing countries; the predominant type is squamous cell carcinoma and
it is the fourth most common cancer in men [18].
Incidence rates vary worldwide by about 16-fold where South and East Africa and East
Asia are at the highest and Western and Middle Africa and Central America is the lowest
[24, 50].
Worldwide, the survival rate of the esophageal cancer patient is poor because of advanced
or inoperable disease at presentation. The disease has very aggressive nature and less than
15% of patients survive 5 years after initial diagnosis [74].
5
1.1.2 RISK FACTORS
The recognized main risk factors for esophageal cancer in general are smoking, excessive
alcohol consumption, dietary factors mostly red meat consumption, gastro-esophageal
reflux disease (GERD) and Barett’s esophagus [136] (Table 1.1.2.1). Lifestyle factors are
associated with a risk of mucosal irritation and could promote tumor formation [34].
Table 1.1.2.1 - Esophageal cancer risk factors [42]
RISK FACTOR
SQUAMOUS CELL
ADENOCARCINOMA
CARCINOMA
Smoking
+++
++
Alcohol consumption
+++
Red meat consumption
+
+
Barnett’s esophagus
++++
Reflux symptoms
+++
Being overweight
++
Poverty
++
Caustic injury to the esophagus
++++
History of head and neck cancer
++++
History of radiotherapy
+++
+++
Hot drinks consumption
+
-: No effect; +: Suspicious effect; ++: Positive effect; +++, ++++: Strong positive effect.
SMOKING AND ALCOHOL
Cigarette smoking had been long correlated with squamous cell carcinoma of the
esophagus. A study reported that smoking and alcohol if consumed alone, it accounted for
87% of squamous cancers but if they were mixed they accounted for 50% of
adenocarcinomas [138]. Lately, there were studies that correlated smoking with gastroesophageal adenocarcinomas [125]. Sung et al. reported that the combination of cigarette
and alcohol was associated with both squamous cell carcinoma and adenocarcinoma of
esophagus, cardia, and proximal and distal gastric cancers. Engel and co-workers stated
6
that low risk areas like U.S.A and other western countries had alcohol and smoking
contributing to 90% of the cases [41].
Another risk factor noted, was chewing betel nut and betel leaf. It had been very common
in India. Nayar et al., conducted a study and noticed that this tradition would increase the
chance of getting esophageal cancer by 3.16 times [100].
INFECTIOUS FACTORS
Viral Agents:
The risk of Human Papilloma Virus (HPV) infection was not clear, but it was believed
that it was linked with the development of squamous cell carcinoma [39, 73].
Fungal Agents:
There had been studies, which showed a potential association between fungi, most
common candida albicans and esophageal cancer incidence [11].
Another factor taken in consideration by many studies was Helicobacter pylori [25, 148].
It has been noted that H. Pylori has actually a protective effect to adenocarcinoma but
plays an opposite role, as a risk factor for squamous cell carcinoma.
GENETIC FACTORS
The researchers were questioning if genetic factors were linked with the development of
esophageal cancer. There were not too many studies to prove the link. Akbari and his
colleagues showed that familial and genetic factors play an important role as a risk factor
for first-degree relatives of patients with esophageal cancer [5]. No particular genetic
factors were recognized.
7
DIETARY FACTORS/ LOW SOCIO-ECONOMIC STATUS
Nutrition plays a role as a risk factor. Although it is largely investigated, the role of diet is
inconclusive.
Populations that were at higher risk for squamous cell carcinoma were those with diets of
corn, wheat, and millet, with minimal fruits, vegetables and animal products. The risk
factors for adenocarcinoma of the esophagus are not well understood. Wu and co-workers
did a study on the impact of dietary factors in developing esophageal and gastric cancer
[149]. The study was done on 206 esophageal, 257 gastric and 366 distal gastric
adenocarcinoma patients and 1,308 control subjects in Los Angeles. The conclusion of
the study showed that high fiber intake is associated with a significant reduction in cancer
risk [149].
Cook-Mozaffari and co-workers did a study in 1979 on esophageal cancer patients in Iran
[31]. They wanted it to see if there was a strong association between a low intake of fruits
and vegetables and the low-socio-economic class. The study showed that low-socioeconomic class, which had predominantly low protein diet, associated with low
vegetables and fruits intake and excessive drinking of hot water increased the chances of
developing esophageal cancer [31]. Although the exact cause is still unknown, another
study showed the same conclusion: it was believed that poor nutrition and drinking
beverages at high temperatures were associated with the onset of esophageal cancer
[67,150].
The other risk factor appears to be obesity, especially for adenocarcinomas not so for
squamous cell carcinomas [83]. Overweight, Barrett’s esophagus, gastroesophageal reflux
disease (GERD) and dysplasia were known risk factors especially for adenocarcinoma.
Kubo and Coorley did a review of observational studies, which included body mass index
(BMI) and esophageal and cardia cancers [78]. It showed a direct relation between BMI
and the risk of developing esophageal adenocarcinoma. An increase in BMI, increased the
risk of cancer. The study showed that it was more relevant for men than women, for
esophagus than cardia and no clear association with regards to China population.
8
The causative agent is not known, however, changes in life style, diets, deficient in Zn,
Ca, etc. had all been shown to be contributing to esophageal cancer [122]. Selenium,
dietary fiber, fruits and vegetables and antioxidants were seen as protective factors [13].
In review, it seems that a healthy lifestyle maintaining a good intake of proteins, fruits
and vegetables with avoiding smoking, excess of alcohol consumption reduces the risk of
esophageal carcinomas.
9
1.1.3 PATHOLOGY
Histologically, esophageal cancer is classified into squamous cell carcinoma (SCC) and
adenocarcinoma (AC) due to the variation in pathogenesis and cancer biology. This
malignancy can occur within a) the gland cells known as adenocarcinoma, located usually
in the distal third of the esophagus and gastroesophageal junction, or b) the squamous
cells known as squamous cell carcinoma, which can be found anywhere along the
esophagus, mostly upper two-thirds [139]. The squamous cell carcinoma has remained
histologically the most common worldwide. However, adenocarcinoma of the esophagus
has seen an increase in the proportions of epidemics in other Western countries and the
United States. Both histologies have been documented to carry a poor prognosis [66].
Esophageal cancer is also classified according with the Japanese Research Society
Committee. Based on the degree of differentiation there can be papillary/well
differentiated, tubular/moderately differentiated and poorly differentiated tumors. This is
related to the depth of invasion. If submucosal invasion exists, cancer is considered
advanced and poorly differentiated [46].
10
1.1.4 PRESENTATION
Treatment of esophageal cancer is based on the assessment and diagnosis. The common
signs are difficulty and/or painful in swallowing and weight loss. Many patients ignore
the first signs of not being able to swallow. They change their food to puree or liquids,
denying the severity of the problem. For the patient with advanced esophageal cancer,
relief of dysphagia is the goal of therapy. Because of the tumor progressing rapidly,
patients reach the stage when they cannot swallow liquids or their own saliva [37]. The
severity of dysphagia can be quantified by using the scale proposed by Mellow and
Pinkas [95] (Table 1.1.4.1).
Table 1.1.4.1- Dysphagia Grading
Grade
0
1
2
3
4
Symptom
Able to eat normal diet
Able to eat some solid food
Able to eat semisolids only
Able to swallow liquids only
Unable to swallow anything, including saliva
Because of the advanced stage at the initial presentation, it is recognized that an
appropriate palliation for dysphagia, it is important for re-expanding the lumen of the
esophagus and providing adequate nutrition support. The dysphagia grading can be used
to quantify if a palliation method improves the symptom and if the approached method is
effective for the patient (e.g. being able now to tolerate a liquid diet).
Associated with dysphagia, is the finding of weight loss in about 42 to 46 percent of
patients at diagnostic [111]. Pain in the back or retrosternal, occurs less often in about 20
percent of patients and suggests the existence of extensive disease in the surrounding
areas or dilation of the proximal part of the esophagus with food [111].
Other problems may include the following: cough with eating or drinking, hoarseness,
indigestion and heartburn, iron deficiency anemia, blood in the stool. Part of the
assessment amongst the other symptoms can include drooling after swallowing, poor
vocal quality after swallowing, head or neck adjustment to ease the swallowing [72].
11
1.1.5 FACTORS AFFECTING PROGNOSIS
One of the major concerns with esophageal cancer is the poor prognosis [116]. Of the
symptoms experienced by esophageal carcinoma patients, dysphagia and weight loss are
seen in more than 90% [19].
The onset of dysphagia is generally late, which prevents patients from seeking in depth
diagnosis. The prognosis depends on the size of the tumor, the stage of cancer, the length
of the tumor and the tumor pathology.
Besides the extent of the disease and amount of weight loss, prognosis depends on the
patient’s age and general condition. The patients are often elderly with severe comorbidities limiting the ideal treatment.
Many patients will have locally advanced esophageal cancer where it is unresectable or it
is considered metastatic [122]. In this case the diameter of the lumen of the esophagus is
less than 13 mm and a significant weight loss will occur [45]. If the weight loss at
presentation is more than 10-percent body mass this indicates a poor prognosis [45].
The understanding of esophageal adenocarcinoma is becoming far clearer in terms of
biology. It was previously believed that it was systemic when it is diagnosed, but it is now
clear that the esophageal cancer is similar with gastrointestinal cancers in that lymphatic
metastasis arises earlier than systemic disease in most cases [101, 108, 123].
Since esophageal cancer is diagnosed late, it has a poor prognosis with a high local
recurrence and metastasis [6]. Ilson in his study reinforced that patients with advanced
esophageal cancer have poor prognosis due to the early systemic spread of the disease and
a high incidence of failure with the local-regional treatment given [66].
Once the cancerous cells have reached the lymph nodes through the lymphatic system
they can spread to any organ in the body. The common metastatic sites for esophageal
cancer are: liver, lungs, bones and adrenal glands. The survival rate will therefore depend
strongly on the stage of esophageal cancer, and it will decrease as the stage increases.
12
1.1.6 DIAGNOSTIC WORK-UP
An accurate staging of the disease is essential, and several investigations are
recommended.

Physical Examination and History of the patient

Barium Swallow

Upper GI endoscopy and biopsy

Chest/abdominal/Pelvic computed tomography (CT) scans

Positron emission tomography (PET) evaluation preferred if no evidence of M1
disease (PET_CT preferred over PET scan)

CBC and chemistry profile

Endoscopic ultrasound (EUS) if no evidence of M1 disease, with FNA if indicated

Bronchoscopy, if tumor is at or above carina with no evidence of M1 disease

Laparoscopy (optional) if no evidence of M1 disease and tumor is at GE junction

Biopsy confirmation of suspected metastatic disease

HER-2 neu testing if metastatic disease is documented/suspected
Diagnosis of esophageal cancer starts with a physical exam and history of the patient
followed by chest-x-ray and barium swallow test.
Importance has to be given what patient can swallow: liquids, semi-solids or solids.
Questions to be asked which will be significant for a near or total esophagus obstruction
include: if there is drooling after swallowing, if presence of a frothy sputum after
swallowing, hoarse voice, regurgitation of the mucus.
If the barium swallow test shows irregular filling defect or a stricture it can be a sign of
presence of esophageal cancer and usually an endoscopy with multiple endoscopic
biopsies is followed (Figure 1.1.6.1). This procedure verifies the diagnosis: the location,
size and appearance of the cancer.
13
Figure 1.1.6.1- Advanced esophageal cancer: A, Near total obstruction; B, Barium
swallow X-ray [51]
For the early cancers, the tumor may appear as plaques, nodules or ulcers, but advanced
cancer shows as strictures, mass ulcers, circumferential masses or very large ulcers. At
this point histology of the tumor is confirmed.
After diagnosis, staging is achieved by a combination of procedures. The initial
recommended technique should include the computed tomography (CT) scans of chest,
abdomen and pelvis with intravenous contrast. Recently positron emission tomography
(PET) is used to evaluate the staging and presence of metastatic disease. Metastasis can
be detected using integrated PET/CT scans. For T- and N stage endoscopic
ultrasonography (EUS) is used that can estimate in 80- 90% of cases the depth of tumor
invasion and also the involvement of lymph node metastasis (in 70-80% of cases) [143,
132]. Bronchoscopy is another procedure used for work-up for patients with an advanced
esophageal tumor that is localized at or above the level of carina. The procedure rules out
the possibility of an airway tumor invasion.
Endoscopies with a biopsy, computerized tomography, endoscopic ultrasound
examination, PET scan, all are part of the staging procedure and great importance in
deciding the exact length of the tumor, how invasive the disease is and localization of the
tumor.
14
1.1.7 ASSESMENT AND STAGING
Esophageal cancer develops consecutively along a series of four stages.
It is classified according to the 2010 American Joint Committee on Cancer (AJCC)
(Table. 1.1.7.2 and 1.1.7.3) – tumor node metastasis (TNM) Classification system and the
International Union Against Cancer (UICC) [109a]. In Canada the most common staging
system used is the TNM classification. Furthermore the AJCC and UICC group the TNM
data into stages.
Both esophageal and gastric cancers are diagnosed and staged based on the results from
several investigations. At stage 0 the cancerous cells are confined to the inner lining of
the esophagus and are known as in situ (Figure 1.1.7.1).
Figure 1.1.7.1- Esophageal Cancer Staging [133]
Once the cancer is at Stage I, the malignant cells have penetrated the inner layer. Stage II
is broken down into Stage IIA and Stage IIB. The cells have either entered the lymph
nodes (Stage IIB), invaded the muscle layer (Stage IIA) and have grown through the outer
layer of the esophagus. Most patients seek diagnosis by Stage II that is already late,
15
leaving the patient at risk for cancer spreading. By Stage III the cancer has invaded the
lymph nodes and has began to spread to the trachea, the neighboring air canal organ [94].
Esophageal cancer is referred to as advanced esophageal cancer once it has reached Stage
IV. During Stage IV, the cancer has spread to other parts of the body such as bones, liver
or even brain, through a process known as metastasis. Metastasis is seen in over 50% of
esophageal cancer patients at presentation [3].
16
Table 1.1.7.2 - TNM 7th Edition of the AJCC Cancer Staging Manual: Esophagus and
Esophagogastric Junction
T classification
Tis
High-grade dysplasia
T4a
Resectable cancer invades adjacent structures such as
pleura, pericardium, diaphragm
Unresectable cancer invades adjacent structures such as
aorta, vertebral body, trachea
Regional lymph node- Any periesophageal lymph node
from cervical nodes to celiac nodes
No regional lymph node metastases
1 to 2 positive regional lymph nodes
3 to 6 positive regional lymph nodes
C7 positive regional lymph nodes
T4b
N classification
N0
N1
N2
N3
M classification
M0
M1
Histopathologic
No distant metastases
Distant metastases
Adenocarcinoma
Squamous-cell carcinoma
Histologic grade
G1
G2
G3
G4
Cancer location
Well differentiated
Moderately differentiated
Poorly differentiated
Undifferentiated
Upper thoracic
Middle thoracic
Lower thoracic
Esophagogastric junction
20–25 cm from incisors
25 to 30 cm from incisors
30 to 40 cm from incisors
Includes cancers whose epicenter is in the distal thoracic
esophagus, esophagogastric junction, or within the
proximal 5 cm of the stomach (cardia) that extends into
the esophagogastric junction or distal thoracic esophagus
(Siewert III). These stomach cancers are stage grouped
similarly to adenocarcinoma of the esophagus
17
Table 1.1.7.3A- 7th Edition of the AJCC Cancer Staging Manual; Adenocarcinoma stage
groupings
STAGE
0
1A
1B
11A
11B
111A
111B
111C
1V
T
is(HGD)
1
1
2
2
3
1-2
1-2
43
4a
3
4a
4b
Any
Any
N
0
0
0
0
0
0
1
2
1
0
2
1-2
Any
N3
Any
M
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
G
1
1-2
3
1-2
3
Any
Any
Any
Any
Any
Any
Any
Any
Any
Any
Table 1.1.7.3B- 7th Edition of the AJCC Cancer Staging Manual; Squamous-cell
carcinoma stage groupings
STAGE
0
1A
1B
11A
11B
111A
111B
111C
1V
T
is(HGD)
1
1
2-3
2-3
2-3
2-3
1-2
1-2
3
4a
3
4a
4b
Any
Any
N
0
0
0
0
0
0
0
1
2
1
0
2
1-2
Any
N3
Any
M
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
18
G
1
1
2-3
1
1
2-3
2-3
Any
Any
Any
Any
Any
Any
Any
Any
Any
LOCATION
Any
Any
Any
Lower
Upper, Middle
Lower
Upper, Middle
Any
Any
Any
Any
Any
Any
Any
Any
Any
1.2 TREATMENT OPTIONS FOR PALLIATION OF ADVANCED
ESOPHAGEAL CANCER
Dysphagia is the most common symptom for advanced esophageal cancer patients.
Esophageal cancer symptoms are worrying and devastating. An effective palliation for
dysphagia it is important for re-expanding the lumen of the esophagus or providing a
source of nutrition at any point in the disease course. The stricture or obstruction occurs
in more than 70% of patients with esophageal cancer. The normal diameter of esophagus
lumen is 2.5cm in diameter and if a decrease to 1.3cm occurs, dysphagia appears
affecting solid and regular food diet [45]. It implies the necessity of immediate attention
with proper evaluation to define the cause and commence treatment. The treatment is
used for the relief of symptoms, mostly dysphagia. The intent is palliative and remains a
main focus because dysphagia impairs the patient’s nutrition and therefore the quality of
life. Over the years many palliative options are available for palliation of esophageal
cancer. A variety of palliative treatment methods have been promoted (Table 1.2.1).
Table 1.2.1- Palliative Treatment Methods for Advanced Esophageal Cancer
NON-ENDOSCOPIC TECHNIQUES
Surgery
Resection
Excision Bypass
Chemotherapy
Radiation Therapy
External Beam Radiation Therapy
Brachytherapy
ENDOSCOPIC TECHNIQUES
Dilation
Laser Therapy
Stent Placement
Photodynamic Therapy
Argon Plasma Coagulation
Chemical Injection Therapy
Feeding Gastostromy
COMBINED MODALITIES
19
Surgery is no longer an option for the patients with advanced esophageal cancer.
Palliative radiotherapy with or without chemotherapy becomes the most common
treatment modality. Other methods of palliation are endoscopic techniques.
Not all patients can tolerate all the methods. The choice of palliation will depend upon
three strong criteria: tumor characteristics, patient preference and patient performance
status. When the treatment is mostly palliative, the aspect of the patient’s quality of life
may be considered. The optimal approach is though controversial.
A review of the various methods of palliation is beyond the scope of this thesis. A brief
summary of the available methods and overall dysphagia improvement is presented in
Table 1.2.2 and Table 1.2.3.
20
Table 1.2.2- Methods of Palliation and Median Survival
Methods Brachy
of
therapy
palliation
By-pass
Surgery
EBRT
Laser
Chemo
therapy
Stent
(Intubation)
Author
Mannell
et al,
1991
[92]
Sur 1994
Segalin et
al 1989
[116]
Kelsen
et al,
1986
[77]
Mannell
et al, 1989
5months
4months
4months
2.5months
Median
Survival
Sur,
1991
[127]
6-9
months
Bown,
1991 [16]
4months
5-6months
Madhusudan
et al., 2009
2months
Table 1.2.3- Comparison between treatment modalities for dysphagia relief [72]
Treatment
Modality
Dysphagia relief
Duration of relief
Mortality
Dilation
92%
1 week
<1%
Laser
80-90%
4-6 weeks
1%-2%
Stent
95-100%
Up to 20 weeks
0%-8%
Photodynamic
Therapy
85-90%
7-9 weeks
1%-2%
Brachytherapy
50-80%
28 weeks
No data
Argon coagulation
80-85%
3-4 weeks
NA
Electrochemical
80-90%
4weeks
NA
NA – not applicable
21
1.3 OBJECTIVES AND AIMS
The data in Table 1.2.3 show that brachytherapy is the best treatment option for the
palliation of dysphagia. The objectives and aims of this thesis are to investigate the
addition of chemotherapy to brachytherapy. In particular:
1. To evaluate the role of additional chemotherapy with brachytherapy in patients
with advanced esophageal cancer with the following endpoints
a) Dysphagia free survival
b) Overall survival
2. To evaluate the incidence of complications in patients treated with brachytherapy
alone or brachytherapy with additional chemotherapy
22
1.4 HYPOTHESES OF THE STUDY
It is hypothesized that the combination of intra-luminal brachytherapy with chemotherapy
will improve the survival of patients with esophageal cancer and that the patients will
have a better control of dysphagia for a longer period of time. This will contribute to the
current understanding of chemotherapy as additional treatment to brachytherapy for
symptom management in the palliative setting.
Alternative hypotheses
There is an increased overall survival in esophageal cancer patients receiving High Dose
Intraluminal Brachytherapy followed by Chemotherapy compared with those receiving
High Dose Rate Intra-luminal Brachytherapy alone.
There is an improved dysphagia free survival of esophageal cancer patients receiving
High Dose Intraluminal Brachytherapy followed by Chemotherapy compared with those
receiving High Dose Rate Intraluminal Brachytherapy alone.
Null hypotheses
There is no increment in the survival in esophageal cancer patients receiving High Dose
Intraluminal Brachytherapy followed by Chemotherapy compared with those receiving
High Dose Rate Intraluminal Brachytherapy alone.
There is no improvement in the dysphagia free survival of esophageal cancer patients
receiving High Dose Intraluminal Brachytherapy followed by Chemotherapy compared
with those receiving High Dose Rate Intraluminal Brachytherapy alone. The addition of
Chemotherapy to High Dose Rate Intraluminal Brachytherapy may not improve posttreatment complications.
23
1.5 REVIEW OF LITERATURE
Many studies have shown that locally advanced esophageal cancer patients have a poor
prognosis if treated only with a single treatment modality. The failure is due to early
metastasis of the disease and the high incident of local recurrence. The need to improve
dysphagia has made HDR brachytherapy an important treatment. The need to minimize
the spread of esophageal cancer and to further improve dysphagia free survival and
quality of life has led to the question if an additional chemotherapy treatment is an
advantage.
There are no studies done to report the effect of chemotherapy following HDRILBT in
palliation of dysphagia and the difference in the overall survival rate for patients with
esophageal cancer receiving either HDRILBT or HDRILBT with additional
chemotherapy.
24
1.5.1 The role of brachytherapy in palliation of dysphagia
Esophageal cancer often leads to death due to its severity. Although radical surgery has
proven to be the most successful treatment of this severe disease, the majority of the
patients are not operable at the time of diagnosis.
In advanced esophageal carcinomas with or without distant metastases surgical palliation
plays a minimal role mainly due to short life expectancy. Although there are some studies
showing benefit from surgery palliation treatment, the procedure is rarely adopted. It may
interfere with the opportunity for other alternatives such as definitive chemotherapy and
radiation to have positive benefit.
In esophageal cancer with advanced disease, nonsurgical modalities should be
recommended in the majority of patients. A choice for palliation is provided by the
external beam radiotherapy without or with concurrent chemotherapy [151]. Intraluminal
brachytherapy has been reported as a method of palliation of advanced esophageal cancer
and increase local control by many authors (Table 1.5.1.1).
25
Table1.5.1.1- High Dose Rate Brachytherapy – Palliative Results
#
Author
1
BHATT
, 2012
2
#
Pts.
21
Dose/fractio
n
12Gy/1fract
HDR
Dysphagia
relief
53%
Survival
HARVE 12
Y, 1993
12.5Gy/1fra
ct
HDR
4.5mo mean
(11)
5.8mo
mean
3-esophagitis
9-esophagitis
3
HOMS,
2002
149
6-20Gy/12fract
HDR
51%
160days
median
12% major
complication
8%minor
complication
4
HOMS
2006
95
12Gy/1fract
HDR
74%
155 days
median
12% major
complication
8%minor
complication
5
JAGER,
1992
37
15Gy/1fract
HDR
5mo median
20%12mo
5-fistulae
1hematemesis
2-ulceration
6
KULH
AVY,
SUR
LEVIN
1995
12
14
14
11
10Gy/1fract
12Gy/1fract
15Gy/1fract
18Gy/1fract
HDR
5mo mean
5mo mean
6mo mean
8mo mean
NR
2-failures
2-failures
1-stricture
3-stricture
1-fistula
8
LOW,
1992
12
15Gy/1fract
83%
NR
33%esophag
itis
17%pain
17%pyrexia
8%bleeding
9
SUR,
1991
9
12Gy/2fract
HDR
3/9 pts-9mo
9mo
4-stricture
2-failure
3-esophgitis
1
SUR,
36
12Gy/2fract
HDR
NR
10%,
14%stricture,
HDR
26
5mo
median
Complicatio
ns
NR
0
1996
68
68
16Gy/2fract
18Gy/2fract
1
1
SUR,
2002
112
120
16Gy/2fract
18Gy/3fract
1
2
1
3
SKOW 91
RONEK
,
2004
WEI203
BOYIN,
1989
NR
20%fistula
25%stricture,
3%fistula
42%stricture,
11%fistula
207days
median
243days
median
11%stricture
10%fistula
22.5Gy/3fra
ct
HDR
NR
8.2mo
11-fistula
65-pain
15-30Gy/24fract
HDR
NR
34.5%,
12mo
66%
esophagitis
49.3% back
pain
11.8%
strictures
15Gy/2fract- HDR 13weeks
NR
1-stricture
7
mean
1-fistula
15Gy/1fract6
#-Number; Pts.-Patients; Mo-Months; HDR-High Dose Rate; NR-Not Reported; GyGray; Fract-Fractions
1
4
WEE,
1994
HDR
1year
22%,
1year
35%,
1year
15
High dose rate Intraluminal Brachytherapy, in combination with chemotherapy and
radiation or simply radiation, improves the outcome of the treatment because of the
biological response. Due to the rapid dose fall off and the ability to deliver a high dose
directly to the tumor site, brachytherapy is used for local boost [10]. Due to the limited
time of treatment, ease of administration and better compliance by patients, high dose rate
brachytherapy is most commonly preferred.
Skowronek, Protrowski and Zweirzchowski conducted a study to analyse the outcomes
from HDR brachytherapy of palliation for patients of advanced esophageal cancer [121].
27
Most patients showed improvement in dysphagia. Both complete and partial remissions
were seen for elderly patients. After the first month of treatment, dysphagia of a lower
grade with longer survival was observed. An increase in pain was reported in sixty-five
out of ninety-one patients during treatment and up to 3weeks later. In conclusion, there
was a smaller size of tumour, a higher rate of Karnofsky Performance Status and clinical
stage with a lower level were the important factors of prolonged survival.
Harvey et al., used two different dose schedules for local advanced as well as metastatic
esophageal carcinoma [59]. The medium dose rate Cesium-137 and high dose rate
Iridium-192 was given to patients. In this study two types of brachytherapy were
compared. The HDR-treated patients had a longer dysphagia relief (5.8 months) compare
with MDR-treated patients (4months).
Homs et al., studied the impact of HDR brachytherapy for palliation of the malignant
dysphagia [61]. Dysphagia scores improved for HDR brachytherapy of 6 weeks at a
median of 3 to 2 months but did improve the dysphagia in 49% patients. It was found
that HDR brachytherapy was a moderate and effective treatment with a low occurrence of
earlier complications. Homs et al., in another study, examined the use of a single dose of
brachytherapy as a palliative treatment modality for the treatment of oesophageal
carcinoma [62]. They found that a single dose of brachytherapy was not favourable for
those patients who already underwent the chemotherapy treatment. A higher or
fractionated dose may be a good options treatment for these patients. Other patients who
did not receive already chemotherapy needed a single dose of brachytherapy.
Jager et al., determined the efficacy of palliation by applying the single session of the
intraluminal irradiation [71]. A dose of 15 Gray (Gy) prescribed at 1cm from the central
axis was given to all patients. Fifty-one patients received Medium Dose Rate (MDR)
treatment with Cesium 137 and thirty-seven patients received High Dose Rate (HDR)
brachytherapy with Iridium 192. Dysphagia improved in fifty-five patients. There was a
complete relief of swallowing for thirty-five out of fifty-five patients. A second treatment
was applied to those patients who met with re-obstruction. Administration of intraluminal
28
irradiation was easier and safe, which formed a useful addition for therapeutic
possibilities.
Bhatt, Tirmazy and Sothi studied the symptoms of dysphagia, and reported the usage of
HDRILBT at their centre for a number of years since 2006 [10]. Both survival and
dysphagia were used as endpoints. The local database of radiotherapy was used to
identify the patients and their details of treatment. A single fraction of 12 Gy was given to
all patients in their study from a period of 2006 to 2010. The patients with
adenocarcinoma were 62% and 38% patients were with squamous cell carcinoma.
Patients with severe conditions of tumours received first line treatment of brachytherapy
before chemotherapy. None of the patients showed the toxicity of acute esophagitis. This
treatment was well tolerated and efficient and was considered the palliative treatment a
choice for oesophageal cancer in the future.
Sur et al., determined that fractionated brachytherapy was a significant modality for the
process of palliation in the advanced esophageal cancer [129]. As compared with all
available modalities, fractionated brachytherapy presented the best palliation. An optimal
dose of brachytherapy ranged from 12 Gy to 18 Gy given in two fractions for a week. In a
third study, Sur et al., worked on applications of fractionated HDR brachytherapy and
found it as an effective way for palliation of advanced esophageal cancers [130]. They
used two different dose fractions of 8 Gy x 2 and 6 Gy x 3, which gave similar results for
survival, strictures, overall survival and equal effectiveness of palliation from dysphagia.
Wee, Theobald and Chua found that the esophagus cancer was the most common in male
population of Singapore [146]. Palliation treatment was given to all patients with
advanced esophageal cancer. Patients were treated with a high dose of HDR
brachytherapy of (Ir192) in a single or two fractions of 7.5 Gy per fraction. 63% of patients
had an improvement in dysphagia lasting over 11 weeks.
Sharma et al., included another factor of swallowing status in addition to overall survival
and complication rate [119]. Patients included in the study were thirty-seven with no
previous treatment and twenty-one with post-treatment recurrent tumours. The rate of
29
swallowing in 22 patients reduced and 24 patients had the same rate of swallowing, as it
was pre-treatment. The untreated group had a low rate of complication as compared to the
treated group of patients and higher median survival rate, but not significantly. The
results indicated that use of HDRILBT was supported in achieving acceptable
complications. Patients with an advanced stage of oesophageal cancer did not qualify for
the surgery and constituted the poor prognosis. Applications of HDR brachytherapy for
patients having the advanced esophagus cancer were analysed by Skowronek et al. [121].
For HDR brachytherapy, a dose of 22.5 Gy was given in three fractions at the exact sites
of tumours. Results from the complete treatment were assessed after the 1st, 3rd and 6th
month. Partial remission, total remission, and no remission were the important factors of
study. In some cases, total remission was lasted for more than 6 months with good
tolerance. However, complications were same as other authors reported in their studies.
Gasper et al., worked on a prospective and multi-institutional study in order to find the
tolerance, the feasibility of the external beam irradiation, in addition to esophageal
brachytherapy and concurrent chemotherapy [52]. The results of this multi-institutional
study were not optimistic as life-threatening toxicity occurred in 26% patients, which
resulted into deaths of patients. The survival rate did not differ greatly from the
application of external beam radiation, concurrent chemotherapy and esophagus
brachytherapy as compared to only esophageal brachytherapy and chemotherapy. The
concerning point of this study was the development of fistulas in a large number of cases.
Therefore, an extreme need was required to combine these three techniques for patients
with esophageal cancer. Another study, Gaspar et al., focused on the establishment of
guidelines for brachytherapy for treatment of esophagus cancer [53]. For the development
of recommendation in brachytherapy in the palliative and definitive treatment, some
standards were established. Definitive treatment was based on the adenocarcinoma or
squamous cell carcinoma =<10 cm length. As indicated in the earlier study of Gasper et
al., the concurrent use of the external beam of radiation with chemotherapy and
brachytherapy was more damaging as compared to alone treatment with brachytherapy
30
with chemotherapy, the concurrent use of three techniques was not used [52]. The use of
external beam radiation was only plausible on the identification of a controversial 3
months of life expectancy. In such circumstances, the use of 25-40Gy as LDR (0.41Gy/hr.) and 15-20Gy in two to four fractions was set and considered beneficial. The use
of a single dose brachytherapy and metal stent for palliation of the esophagus required the
selection of the best option between two techniques.
The work of Homs et al., was based on the comparison of stent placement and
brachytherapy outcomes [64]. This study covered a large area of the Netherlands with the
participation of nine hospitals. The total number of patients was 209 regrouped into two
groups of patients for evaluation of two different techniques. Stent placement was applied
for 108 patients and brachytherapy of a single dose (12 Gy) for 101 patients. The result of
this study showed the fast improvement with stent in dysphagia as compared to
brachytherapy. Stent placement produced many complications for the patient than
brachytherapy such as late haemorrhage. Brachytherapy had a high score of quality of life
than stent placement. The cost for brachytherapy as well as stent placement remained
same. Instead of initial fast dysphagia improvement, the slow improvement from a single
dose brachytherapy produced long-term relief for the patients. Homs et al., in other study
on the same factors of single dose chemotherapy and stent placement, further explored the
comparison between two techniques based on the quality of life related generically health
specific and diseases [65]. In a similar statistics, the stent placement was carried in 108
patients and single dose brachytherapy (12 Gy) was carried in 101 patients. Change in
health related quality of life, (HRQoL) were observed and analysed after treatment for
both groups of patients. Similarly, the dysphagia development was fast in stent placement
group as compared to the brachytherapy group of patients. On generic bases, the
improvement in HRQoL was more favourable for brachytherapy as compared to stent
placement. Deterioration in general HRQoL in the role and physical functioning became
more common in stent placement group than brachytherapy group. However, stable
improvements were seen in eating scales and dysphagia. Both groups showed the same
31
level of abdominal and chest pain. There was a need of generic HRQoL scales for future
studies for palliative care of esophageal cancer in patients.
The efficacy of brachytherapy depends on many treatment factors, brachytherapy
fractionation, dose rate and dose, active length. The aim of the treatment is to relief
dysphagia. The improvement in swallowing occurred in 51% of patients [62].
Tumour treated with MDR in Rowland and Pagliero study showed a 70% improvement
for squamous cell carcinoma and 60% for adenocarcinoma [114]. MDR treatment was
used in several studies: Harvey et al. and Jager et al., which reported the same, mean
dysphagia relief of 5.1 months [59, 71]. High percentage of the dysphagia score between
80-95% was showed in Kaul et al, Low et al., study [79, 88].
The fractionation is important in quick relief of swallowing as shown in different studies.
In 172 patients Sur et al. compared 18 Gy/3fractions with 16 Gy/2fractions and 12
Gy/2fractions, and concluded that the first fractionation reported better dysphagia free
survival (38.9% vs. 25.4% vs. 11% at 12 months) [129]. The arm with 12 Gy over 2
fractions was stopped. Harvey et al. in his study compared two arms: 12 patients treated
with HDR-ILRT 12.5 Gy/1fraction and 10 patients treated with MDR-ILRT 20
Gy/3fraction [59]. The first arm showed better improvement of dysphagia (5.1 vs.
4.5months). Kulhavy et al. reported a comparison of different doses delivered in a single
fraction 10, 12, 15 and18 Gy [81]. The higher doses used for treatment, 15 Gy and 18 Gy,
the better dysphagia relief.
One of the complications reported by most of the authors is post treatment stricture
ranging from 11.8-44%. Esophagitis is an early major complication and it was reported in
Low et al. study in 33% of patients and Wei-Bo-Yin et al. study in 66% of patients
[88,145]. Jager et al. reported 8% ulceration [71].
Comparing the different series, overall survival (mean or median) using intraluminal
brachytherapy for advanced esophageal cancer ranges from 4.5 months to 9.9 months.
32
1.5.2 The role of chemotherapy in metastatic esophageal cancer - drugs used
Esophageal cancer is often diagnosed late and has particularly a poor prognosis with high
local recurrence and metastasis. The poor prognosis arises because most of the
esophageal cancer patients are diagnosed late when the cancer has already spread [6]. In
addition, not more than half of all the esophageal cancer patients are curative treatment
candidates. In fact, even if the cure is attempted, esophageal cancer can still recur. In this
regard, chemotherapy is very valuable in improving the chance in improving dysphagia
and subsequently quality of life in patients with advanced esophageal cancer.
Since 1970 chemotherapy was tested for esophageal carcinomas. Many single agents and
combination regimens have been studied. First regimen adopted was the combination of
5-Fluorouracil plus Cisplatin. The two drugs served as a base for other studies then added
a third or fourth agent to them. Just a few studies reported on AC of the esophagus. They
indicated the same chemosensitivity for AC and SCC.
Over the years the epidemiologic changes had occurred in the histological aspect of
esophageal cancer, squamous cell carcinomas representing a minority of patients. The
clinical trials conducted since 1980 showed that histologic subtype does not have a great
role in survival rate and response rate in patients treated with different chemotherapy
regimens.
SINGLE OLD AGENTS
Since 1990 single agents were used for chemotherapy treatment (Table 1.5.2.1). The
agents were Bleomycin, Cisplatin, Methotrexate, Mitomycin, 5-Fluorouracil,
Doxorubicin, and their response rate were low, varying between 10% and 20%, which
approximates to a short duration less than six months. Another agent was Carboplatin but
was infrequent used because appears to be less active.
33
Table 1.5.2.1- Old single chemotherapy agents
OLD SINGLE
AGENT (group)
CELL
TYPE
HOW THEY
WORK
5-Fluorouracil
(Antimetabolites)
SCC+
AC
Irreversible
inhibition of
thymidylate
synthase
Methotrexate
(Antimetabolites)
SCC
Cisplatin
(Heavy metals)
SCC+
AC
Carboplatin
(Heavy metals)
SCC+
AC
Mitomycin C
(Anthracycline)
SCC
DOSE
AUTHOR
N
RR
%
Ezdinli, E;
1980[43]
23
17
Ezdinli, E;
1980[43]
24
13
100 mg/m2
repeated every
3 weeks
Bleiberg, H;
1997[14]
37
19
450 mg/m2
was given as a
I-hour
intravenous
infusion
Mannell and 11
Winters;
1998[92]
9
Whittington, 31
R;
1970[147]
Bonadonna, 10
1972[15]
35
By bolus or
continous
infusion:
500 mg/M2
I.V. x 5 days q
five weeks
Inhibiting the 40 mg/M2 I. V.
metabolism
q one week
of folic acid
(in vivo)
Crosslinking
of DNA,
which
ultimately
triggers
apoptosis
15 mg/m2 x
20
2/week for 4
weeks
SCC-Squamous Cell Carcinoma; AC-Adenocarcinoma; N-Number of patients; RRResponse Rate
Bleomycin
(Anthracycline)
SCC
34
MAIN SIDE EFFECTS:
5-FLUOROURACIL
Mouth and throat inflammation
Low blood counts
Severe allergic reactions
Visual impairment
Liver damage
Fever
Nosebleeds
Weakness
Confusion
Headache
Heart pain (angina)
Diarrhea
Stomach ulcers
Dermatitis
Discoloration of skin
Alopecia
Hand-foot syndrome,
Stomatitis
Neurotoxicities
Cardiotoxicities
Nausea and vomiting
Diarrhea
Alopecia
METHOTREXATE
Ulcerative stomatitis
Low white blood cell count
Nausea
Abdominal pain
Fatigue
Fever
Dizziness
Acute pneumonitis and rarely pulmonary fibrosis
CISPLATIN, CARBOPLATIN
Nephrotoxicity
Neurotoxicity
Nausea, vomiting
Ototoxicity
Electrolyte disturbance
Myelotoxicity
Hemolytic Anemia
35
MITOMYCIN C
Low blood counts (most common and severe)
Rashes
Hair loss
Injection site inflammation
Kidney damage
Lung damage
Fever
Nausea
Vomiting
The response rate range varies for each agent, 19% has been observed for patients
receiving Cisplatin [14]; 50% for Bleomycin [26]; 35% for patients receiving Mitomycin
C [147]
In a study, Ezdinli et al., 72 patients received randomly Adriamycin (ADR) 60 mg/m2 for
three weeks intravenously or Methotrexate (MTX) for one week or 5-Fluorouracil (5-FU)
over five weeks period [43]. The response rate for 72 patients remained as 5% for ADR,
13% for MTX and 17% for 5-FU. No complete response was observed. Patients were not
benefited from ADR treatment for the advanced squamous cells carcinoma of the
esophagus.
Mannell and Winters worked on the Cisplatin’s role for squamous cell cancer of
esophagus and found that substantial activity of Cisplatin reduced the benefits because of
significant toxicity [92]. Carboplatin was used to keep and continue the antitumor
activities and decrease the toxicity of Cisplatin. Carboplatin was given to eleven patients
and found that it tolerated well in patients and showed reduced toxicity. It was a good
alternative to Cisplatin.
36
SINGLE NEW AGENTS
Table 1.5.2.2- New single chemotherapy agents
NEW SINGLE
AGENT
(group)
Paclitaxel
(Taxane)
-24 hour
infusion
TYPE
HOW THEY
WORK
DOSE
AUTHOR
N
R
R
SCC+
AC
Stabilizing
microtubules,
interferes with
the normal
breakdown of
microtubules
during cell
division
250mg/m2
repeated every
21 days (Q3w)
Ajani, J;
1994[4]
50
32
80 mg/m2
weekly over a
1-h infusion
Ilson, D;
2007[66]
10
2
15
70mg/m2 i.v.,
over 1–2 h,
every 21
days(Q3w)
Muro, K;
2004[98]
50
20
3 mg/m2 as a
continuous
infusion over
48 hours
followed by 3
mg/m2 iv
weekly for 4
weeks and then
by monthly
Bezwoda,
WR;
1984[8]
52
27
25mg/m2 short
i.v. infusion
weekly
Conroy, T;
1996[33]
46
15
Kulke, M;
2006[82]
Ezdinli,
1980[43]
29
7
20
5
Weekly short
infusion
Docetaxel
(Taxane)
SCC+
AC
Vindesine
(Alkaloids)
SCC
Vinorelbine
(Alkaloids)
SCC
Inhibiting
mitosis
through
interaction
with tubulin
AC
Doxorubicine
(Anthracycline)
SCC
Interposing
DNA strands
Triggers DNA
cleavage by
topoisomerae
II resulting in
37
mechanisms
that lead to
cell death
Generating
free-radicals cause cell and
DNA damage.
Etoposide
(Topoisomerase
inhibitor I)
SCC
AC
Irinotecan
(Topoisomerase
inhibitor II)
AC
Forming a
ternary
complex with
DNA and the
topoisomerase
II enzyme
prevents
religation of
the DNA
strands,
causing DNA
strands to
break
prevents DNA
from
unwinding by
inhibition of
topoisomerase
I
200 mg/m2 on 3 Harstrick A; 26
consecutive
1992[57]
days every 3
weeks (Q3w)
19
Weekly
125 mg/m2
15
Enzinger P;
2000[42]
38
1250 mg/m2
Sandler,
21 4
over 30–60
AB;
minutes on days 2000[114]
1, 8, and 15
followed by 1
week of rest
SCC-Squamous Cell Carcinoma; AC-Adenocarcinoma; N-Number of patients; RRResponse Rate;
Gemcitabine
(Deoxycytidine
nucleoside
analog)
SCC
AC
Inhibit
processes
required for
DNA
synthesis
38
MAIN SIDE EFFECTS:
TAXANES
Life-threatening allergic reactions
Low blood pressure
Heart damage (slowing of the heart rate)
Low blood counts
Nerve damage
Nausea
Vomiting
Diarrhea
Unusual infections
Edema (swelling)
VINORELBINE
Bone marrow damage
Nerve damage
Headache
Face pain
Nausea, vomiting, diarrhea, constipation
Liver damage
Inflammation of the mouth
Fever
Hair loss
Rashes
Muscle damage
ETOPOSIDE
Low blood pressure
Hair loss
Pain and or burning at the IV site
Constipation or diarrhea
Metallic food taste
Bone marrow suppression, leading to:
Decreased white blood cell counts (leading to increased susceptibility to infections)
Low red blood cell counts (anemia)
Low platelet counts (leading to easy bruising and bleeding)
IRINOTECAN
Low blood counts
Nausea, vomiting, diarrhea, constipation, abdominal pain
Liver damage
Blood clots
Low blood pressure
Breathing problems
Inflammation of the mouth
Lightheadedness
39
Sleepiness
Insomnia
Fever
Headache
Hair loss
Rashes
GEMCITABINE
Flu-like symptoms such as muscle pain, fever, headache, chills, and fatigue
Fever (within 6–12 hours of first dose)
Fatigue
Nausea (mild)
Vomiting
Poor appetite
Skin rash
Allergic reaction
Diarrhea
Weakness
Hair loss
Mouth sores
Difficulty sleeping
Shortness of breath
The main new agents confirmed for advanced esophageal cancer include: Taxanes
(Paclitaxel and Docetaxel), Vinorelbine, Irinotecan, Oral 5-FU prodrugs, Capecitabine
(Table 1.5.2.2). The response rate range varied for each agent, 26-34% for the patients
treated with Capecitabine [89];15-20% for Vindesine and Vinorelbine [76]; 15-32% in
the patients treated with Paclitaxel [4,66]; 20-25% response rate in case of Docetaxel
treatment [42, 98]; 0-19% response rate for patients with Etoposide and 15% for
Irinotecan [90].
Ilson et al., applied the weekly Paclitaxel (Taxol) for one hundred and two patients with
advanced oesophageal cancer and found limited activity of Taxol [66]. One cycle was 1
week of treatment with Paclitaxel 80mg/m2 weekly over a 1-hour infusion. They showed
172 days being the median duration of response. They concluded that Taxol might be a
good option for those patients who could not tolerate the combined chemotherapy.
40
In another work of Muro et al., the author evaluated the toxicity and activity of Docetaxel
for the patient with metastatic esophageal cancer [98]. Dose of Docetaxel used was 70
mg/m2 given intravenously for 1 to 2 hours for 21 days. Total of 52 patients were
enrolled and 3 of them did not take Docetaxel because their conditions worsened very
early of treatment. Ten patients showed a partial response with a grade 3 or 4 neutropenia,
and febrile neutropenia. Survival time at median level was 8.1 months. Although,
Docetaxel as a single agent produced good results but the complication of neutropenia
was complex and needed a careful management.
From the study of Heath et al., it was determined that Docetaxel as a single agent did not
provide improvement in chemotherapy efficacy [60]. No complete response was seen and
the median survival time remained as 3.4 months.
In an open study Bezwoda et al., applied the Vindesine at the dose of 3 mg/m2 on 52
patients for advanced esophageal cancer [8]. The treatment was given for 4 weeks
followed by monthly maintenance therapy with the same dose. Only 27% patients
responded positively with prolong survival. It was found that Vindesine had a definite
impact but with limited influence against oesophageal cancer. Kulke et al., found the
same conclusion in a phase II study regarding Vinorelbine used as a single agent; twentynine patients treated or untreated with the metastatic gastroesophageal adenocarcinoma
disease were entered and they received a weekly dose of 25 mg/m2 Vinorelbine [82].
High overall response rate with respect to Capecitabine was shown in the study done by
Lee et al., in a range of 57.8% [84].
Bonadonna et al. studied the application of intravenous Bleomycin (BLM) from phase I
and phase II in 176 patients [15]. Different doses based on varying schedule were
employed. The main side effect seen with BLM was pulmonary toxicities. The most
important and less toxic regimen was with 15 mg/m2 x 2/week for 4 weeks. A lower dose
of BLM resulted into a lesser incident of the lung toxicity.
Enzinger et al., reported findings on 46 patients who were previously untreated with
metastatic esophago-gastric adenocarcinoma [42]. An intravenous dose of the Irinotecan
was applied for 90 minutes and continued for 4 consecutive weeks. After 4 weeks of
41
treatment patients were given rest for two weeks. The response rate was 14% as only one
complete and five partial responses were seen. It was found that Irinotecan as a single
active agent had moderate toxicity at the schedule. They also suggested that a single agent
used three times within a week was more preferred for the same population. In later work
of Burkart et al. it was found that Irinotecan as a single agent had moderate activity for
esophageal cancer in a Cisplatin-refractory [20].
COMBINATION OF CHEMOTHERAPY DRUGS
Several single agents demonstrated modest activity as anti-tumour agents. However,
combined agents also provided effective results in several studies for the solid tumours of
oesophageal cancer.
Most used combinations for adenocarcinoma of the esophagus are: Cisplatin and
Fluorouracil (CF) or Cisplatin and Capecitabine (CX), Epirubicin, Cisplatin and
Fluorouracil (ECF), Epirubicin, Oxaliplatin and Capecitabine (EOX).
For squamous cell carcinoma of the esophagus the most common combinations are:
Cisplatin and Fluorouracil (CF) or Cisplatin and Capecitabine (CX).
The other different combinations may include Taxol, Vinorelbine, Irinotecan.
Cisplatin/5-fluorouracil (5-FU)
Cisplatin and 5-FU are two drugs that are widely used for esophageal cancer patients,
either as a combination of the two of them or one of them as a backbone with other agents
(Taxane or Irinotecan). Positive responses to Cisplatin and 5-FU were seen for locaregional disease. For advanced metastatic or unreseactable disease, most studies reported
low response rates between 35% and 40% [14]. Cisplatin (CDDP) 100 mg/m2 was
combined with the 5-Fluorouracil and applied for 1 to 5 days at a dose of 1000 mg/m2
(Arm A) or it was given alone CDDP (Arm B). There was a repetition of cycles for 3
weeks. Out of 92 patients, 88 were found eligible. The response rate was found to be
35% in Arms A and in Arm B was 19%. The survival duration at a medium level was 33
42
weeks and 28 weeks for A and B arm respectively. In Arm A, the toxicities of
haematological and non- haematological were found severe. In Arm A, about 16% deaths
related with treatment were observed, and no death was found in Arm B. Hence, no
standard chemotherapy was suggested and recommended for the patients with esophageal
cancer [14].
Iizuka et al., designed a study for the evaluation of the 5-Fluorouracil (days 1-5) and
Cisplatin (day1) effectiveness for thirty-nine patients with advanced squamous cell
oesophageal carcinoma [70]. The patients who had positive response to the chemo regime
showed a survival rate of 9.5 months compared with 5.6months for patients who did not
responded to treatment. They found that combination of the drugs used, had reasonable
effects and may be used for the postoperative chemotherapy as demonstrated mild side
effects.
Cisplatin and 5-FU chemotherapy regimen was considered standard therapy when given
pre-operative for esophageal and gastro-esophageal junction adenocarcinoma. For
squamous cell carcinoma and adenocarcinoma of esophagus, the combined chemotherapy
was given concurrent with radiation therapy. No surgery was offered. Lately, the two
drugs were combined with a third agent, usually epirubicin on ECF regimen or docetaxel
in DCF regimen.
Cisplatin/Paclitaxel
Ilson et al., treated 38 patients with advanced esophageal cancer with Cisplatin (CDDP)
75 mg/m2 iv d2 in combination with Paclitaxel (Taxol) 200 mg/m2 civi over 24hrs d1
Q3w [66]. Overall dysphagia relief was 80 percent with a complete dysphagia relief of 72
percent.
Polee et al., applied the combination of paclitaxel and Cisplatin for patients at a dose of
180 mg/m2 Paclitaxel and Cisplatin 60 mg/m2 every two weeks for three times. After
43
receiving this dosage patients were referred to surgery [106]. Nearly 71% patients
suffered from haematological toxicity. The overall response rate was measured 59% and
pathological examination resulted into a tumour free margin for 38 patients. The
treatment was well tolerated with a median overall survival (OS) of 20 months.
Van der Gaast et al., (1056) worked on Paclitaxel advantages given either as a single
agent or combined with Cisplatin. Because of a brief period of neutropenia, a high dose
for a shorter period was possible [137]. An increase of dose up to 200 mg/m2 of Paclitaxel
combined with Cisplatin at a dose of 60 mg/m2 became possible. There was not toxicity
related with haematological dose-limiting. A higher dose of paclitaxel delayed the
treatment percentage because granulocytopenia could not increase substantially. This
suggested that treatment was safe as the granulocyte count was >0.75 x109 I-j.
Carboplatin/Paclitaxel
Paclitaxel in combination with Carboplatin is a regimen that produces complete disease
regression in about 25% of the patient with advanced esophageal cancer. In a phase I
study, Polee et al., treated the patients with Paclitaxel at a dose of 100 mg/m2 with a
combination of Carboplatin to follow on specific days such as “1, 8, 15, 29, 36 and 43”
[107]. The study showed a recommended dose level for Carboplatin for other studies and
trials. About 77% patients suffered from neutropenia of grade 3 and grade 4. There was
shown well tolerance of treatment in all patients. The acceptable level of toxicity was
achieved. Other toxicities were either mild or absent. The response rate observed during
this Phase I study was noted as 54% that seemed to be high as most patients were with
liver metastasis. This study concluded that Carboplatin combined with Paclitaxel could be
useful if patients were untreated advanced oesophageal cancer.
44
Cisplatin/Irinotecan
A phase II study done by Ilson and colleagues reported results about a chemotherapy
regimen of Cisplatin (CDDP) 30 mg/m2 iv
with Irinotecan (Camptosar, CPT-11) 65
mg/m2 iv given weekly on day 1,8,15, 22 followed by 2 weeks of rest in advanced
metastatic esophageal cancer. Complete dysphagia relief was seen in 14 of 20 patients
(70%) [66].
Cisplatin/Bleomycin (DB)
Coonley et al., studied the effects of two combined drugs such as Bleomycin (DB) and
Cisplatin [32]. Patients having locoregional disease (LRD), the Bleomycin was given
before radiation therapy or surgery. In the case of extensive disease (ED), about 27
patients were primary treated with DB. The response rate was observed as 14% in LRD
and 17% in extensive disease (ED). Minimum follow-up for the LRD group of patients
was continued for 42 months and resulted that 10% patients remained alive with no
disease. On the other hand, the follow-up for the ED group continued for 6 months.
Other phase II studies that combine two chemotherapy agents and reported dysphagia
relief are shown in the table 1.5.2.3.
Table 1.5.2.3- Combination of two chemotherapy agents
Author
N
Treatment
Overall
dysphagia
relief (%)
89
Spiridon 27 Etoposide +
idis et al
cisplatin
[126]
Tebbutt 12 5-FU +
64
et al
9
mitomycin
[131]
N-Number of Patients; NS-Not Significant
45
Complete
dysphagia
relief (%)
89
Duration of
relief
(months)
93
Survival
(months)
NS
NS
5.3
9.8
Cisplatin/5-FU/Paclitaxel
Petrasch et al., found that Paclitaxel as a single agent was effective for both types of
adenocarcinoma and squamous cell carcinoma of the esophagus. In a setting, patients
were treated by Paclitaxel at dose of 90 mg/m2 for 3 hours and followed by Cisplatin 50
mg/m2 [103]. This treatment was repeated each 14 days. The remission rate was found as
40% with complete responses. Only 10% patients suffered from neutropenia of grade 3
and no grade 4 neutropenia was observed. Patients with a poor prognosis showed
improvement after Cisplatin and Paclitaxel treatment given for 14 days with an accepted
level of toxicity. Kok and associates studied the same regimen but different doses of
Cisplatin and Paclitaxel. 52% of patients had objective response and grade 3 and 4
granulocytopenia was the main toxicity seen [80].
Epirubicin/Cisplatin/5-FU (ECF) vs. Epirubicin/Ciplatin/Capecitabine (ECX);
Epirubicin/Oxaliplatin/Fluorouracil (EOF) vs. Epirubicin/Oxaliplatin/Capecitabine
(EOX) Phase II and phase III studies were conducted with agents, which potentially can
substitute Cisplatin and 5-FU. Cunningham and associates compared in two-by-two study
design Epirubicin/Cisplatin/5-FU (ECF) vs. Epirubicin/Ciplatin/Capecitabine (ECX);
Epirubicin/Oxaliplatin/Fluorouracil (EOF) vs. Epirubicin/Oxaliplatin/Capecitabine
(EOX) for patients with advanced esophageal and gastric cancer [36].
Epirubicin + Cisplatin + Capecitabine (ECX) Epirubicin 50 mg/m2 iv bolus d1 q3w x 8
cycles
Cisplatin (CDDP) 60 mg/m2 iv d1 q3w x 8 cycles Capecitabine (Xeloda) 625
mg/m2 po bid x 6 months
Epirubicin + Oxaliplatin + 5-FU (EOF) Epirubicin 50 mg/m2iv bolus d1 q3w x 8 cycles
Oxaliplatin (Eloxatin) 130 mg/m2 iv over 2 hours d1 q3w x 8 cycles 5-FU 200 mg/m2/d
civi x 6 months
Epirubicin + Oxaliplatin + Capecitabine (EOX) Epirubicin 50 mg/m2 iv bolus d1 q3w
x 8 cycles Oxaliplatin (Eloxatin) 130 mg/m2 iv over 2 hours d1 q3w x 8 cycles
Capecitabine (Xeloda) 625 mg/m2 po bid x 6 months
46
Cisplatin + 5-FU + Epirubicin (ECF) Epirubicin 50 mg/m2 iv bolus d1 q3w x 8 cycles
Cisplatin (CDDP) 60 mg/m2 iv d1 q3w x 8 cycles
5-FU 200 mg/m2/d civi for 6 months
All regimes showed comparable results, the response rate being 31% to 48% across
treatment arms. Median survival times for ECF, ECX, EOF, and EOX were 9.9 months,
9.9 months, 9.3 months, and 11.2 months, respectively.
Findlay et al., in a study found that ECF showed a high level anti-tumour activity with a
low level toxicity [48].
A recent trial done by Ross and associates involved almost 600 patients with advanced
esophageal cancer with histology, squamous cell carcinoma and adenocarcinoma. The
study compared Epirubicin, Cisplatin and 5-FU (ECF) regimen to Mitomicyn, Cisplatin,
5-FU [112]. Both regimens had similar the response rate and median survival (42%, 9.4
months for ECF compared with 44%, 8.7 months for Mitomycin regimen.
Cisplatin/5-FU/Adriamycin
Gisselbrecht et al. used the combination of Adriamycin, Cisplatin, and 5-Fluorouracil
(FAP) with hydration and mannitol-induced diuresis [55]. This combined course of
medicine was given for four weeks for all 21 patients. The results from this study reported
that seven out of 21 patients (33%) showed objective response, two with complete
responses and five responses remained partial. All patients had metastasis before the
treatment. The survival at the median level was found to be 8 months for 21 patients.
There was no sever nephrotoxicity or myelosuppression observed as side effects.
5-FU/Cisplatin/Folinic acid/Etoposide
In order to test the efficacy and toxicity of four combined drugs such as 5-FU, Cisplatin,
Folinic acid and Etoposide, Polee et al., conducted a phase II study for patients with
oesophagus carcinoma cancer [107]. A dose of combined drugs was given 6 times per day
for 4 weeks. Evaluation of response from patients was taken after every two courses.
Patients suffered from haematological toxicities such as leukocytopenia 16%,
47
thrombocytopenia in 7% patients, and non-haematological toxicity was seen as vomiting,
diarrhoea and mucositis in patients. The response rate was observed as 34% (30% partial
and 4% complete). The median time for progression was as seven months for 17 patients
without any additional treatment. The median survival time was noted as 9.5 months, and
the survival rate of one year. It was concluded that combination of these four drugs was
an active and safe treatment for patients with advanced squamous cell carcinoma.
Mostly phase II clinical trials have a higher response rate for combination of two or three
chemotherapy agents in advanced esophageal cancer compare with single agent
chemotherapy. Despite higher response rate, survival rate stays unclear.
Non- cisplatin/5-FU based combinations
Paclitaxel/Etoposide/Cisplatin
Combination of three drugs such as Paclitaxel (T), Etoposide (E) and Cisplatin (P) also
known as (TEP) were active alone as well as combined for the gastro- esophageal
carcinoma. All 25 patients, eighteen with local disease and seven with liver metastases at
presentation received the drug TPE. All patients had experienced neutropenia and grade
3anaemia. Out of 25 patients, 22 were evaluable, and 3 patients showed complete
response while 19 presented partial response. The study showed a positive outcome with
twenty-three patients alive. It was also suggested that the introduction of 5-Fluorouracil
could be beneficial due to its role for the same disease [91].
Cisplatin/Vindesine/Mitoguazone (DVM)
Kelsen et al., studied a combination of three drugs such as Cisplatin, Vindesine and
Mitoguazone (DVM) [77]. DVM produced the toxic effects of leucopoenia but no
evidence of pulmonary toxicity was observed. The level of toxicity was acceptable for the
esophagus cancer cells. Even though, there was a reduction in the pulmonary damaging
48
risks, but the substitution of mitoguazone for bleomycin could not increase the capability
for dose limiting toxicity for myelosuppression.
Docetaxel/Irinotecan
Burtness et al., enrolled in his study 29 patients with advanced esophagogastric cancer
and no previous treatment and 15 patients with chemotherapy-exposed [21]. A
combination of Irinotecan 50mg/m2 and Docetaxel 35 mg/m2 was given on day 1 and day
8 of a 21-day schedule for the. Patients with no previous treatment had a partial response
of 26.9% and one a complete response. Just two chemotherapy-exposed patients had a
partial response. The study showed that a weekly schedule with a safety regimen
Docetaxel-Irinotecan was established for patients who did not receive prior
chemotherapy.
Epirubicin/Cisplatin/Oral UFT/Leucovin
In spite of benefit of the treatment of 5-FU with protracted venous infusion (PVI), Choi et
al., applied the new regimen with Leucovorin and oral UFT (Tegafur, a prodrug that is
converted by the liver to 5-FU, and Uracil, a competitive inhibitor of dihydropyrimidine
dehydrogenase (DPD), the enzyme responsible for Fluorouracil catabolism) in order to
improve the complication related with catheter and convenience [27]. The schedule was a
combination of: Epirubicin, Cisplatin, oral UFT and Leucovin. The response rate was
highly optimal 45.9% and one of the patients showed a complete response. There was 13
months median survival. Adenocarcinoma was observed in four patients and the response
rate went up to 75%. The most important toxicity found was myelosuppression while
other toxicities were at an acceptable level. Therefore, the combination of Epirubicin,
Cisplatin, UFT and Leucovin was found an alternative of ECF for patients of advanced
oesophageal cancer.
Chau et al., conducted a study on a large population; 2110 patients with adenocarcinoma
of esophagus, gastro-esophageal junction (GEJ) and stomach were enrolled in four
49
randomized control trials [28]. The regimes assessed were Fluoropyrimidine +/platinum-based chemotherapy:
1) ECF or FAMTX (Fluorouracil, Doxorubicin, Methotrexate) (Waters et al., 1999)
(Webb A et al., 1997);
2) ECF or MCF (Mitomicyn, Cisplatin, 5-FU) (Ross et al., 2002);
3) 5-FU or 5-FU plus Mitomycin (Tebbutt NC et al., 2002);
4) ECF, ECX, EOF and EOX (Cunningham D et al., 2008)
The median overall survival was 9.5 months in esopageal, 9.3 months in GEJ and 8.7
months in patients with gastric cancer. There was no difference at a large level on the
multivariate analysis for response rate, overall survival and toxic effects for patients with
esophagus and gastric cancers.
The next chemotherapy regimens demonstrated to be a small efficacy for a long-term
management of advanced esophageal cancer.
Dinwoodie et al., conducted their study on a combination of Vindesine, Bleomycin and
Cisplatin [40]. The trial was conducted for 27 patients and 7 patients showed partial
response within early therapy. Out of 27 patients, 13 patients received greater than two
cycles. Out of thirteen patients, five patients finished the intended 5 cycles of the
treatment. They did not show any progress while they received more three cycles. A
major side effect was seen as the granulocytopenia in 52% patients. Bleomycin lung
toxicity was also observed in 2 patients. It was concluded that the same treatment could
not be continued for more than 3 cycles for patients with advanced oesophageal cancer.
De Besi et al., used tri-combination of drugs such as Cisplatin, Bleomycin and
Methotrexate for the treatment of esophageal cancer from 1981 to 1982 [38]. Thirty-one
patients with local advanced oesophageal carcinoma were applied the combination of
three drugs as mentioned above. Out of 31 patients 16 showed improvement. However,
only 8 patients (26%) had given the major responses. The responses were obtained within
the initial two courses. The most prominent side effects of mild myelosuppression and
gastrointestinal toxicity were reported.
50
More than 50% of patients with esophageal cancer are unresectable at presentation.
Chemotherapy is a palliative treatment, which alone shows to improve dysphagia and
quality of life in 60 to 80% of patients [66, 103].
THE ROLE OF CISPLATIN/5-FLUOROURACIL
Cisplatin and 5-FU are two drugs that were widely used either alone or as a combination
chemotherapy regime or one of them as a backbone with other agents. Lately, the two
drugs are combined with a third agent, usually Epirubicin on ECF regimen or Docetaxel
in DCF regimen.
In the literature there are several studies done to evaluate Cisplatin as single agent
chemotherapy. The majority of them were looking only at squamous cell carcinoma of
esophageal cancer. With an increased in adenocarcinoma incidence more trials are
evaluating both types of histology. Cisplatin and 5-FU chemotherapy regimen became the
standard therapy and the most effective regimen for advanced metastatic esophageal
cancer in squamous cell carcinoma and adenocarcinoma because of their drug interaction
[120]. There are several studies that are evaluating the regime, Cisplatin and 5-FU, in
different doses. One study done by Bleiberg et al. used Cisplatin 100mg/m2 on day 1 and
5-FU 1,000mg/m2/d by continuous infusion. The results showed that the combination of
Cisplatin with 5-Fluorouracil had a better response rate (35%) than Cisplatin alone. The
survival rate was similar. Comparable overall response rate was seen in other studies done
by Hayashi et al. (33.3%) or Caroli-Bosc et al. (33%) [56, 23]. Webb and colleagues (73)
in a prospective study evaluated the survival rate for the ECF regime [144]. The trial
compared ECF with a regimen: 5-Fluorouracil, Doxorubicin, Methotrexate (FAMTX).
256 eligible patients were entered in the study. The results concluded that ECF survival
rate of 8.9 months is more superior to 5.7 months for FAMTX.
51
2.0. PATIENTS AND METHODS
The study is a retrospective study of a prospective non-randomized data base of 132
patients.
Patients diagnosed with stage III/IV advanced esophageal cancer and metastatic disease
were treated with High Dose Rate Intraluminal Brachytherapy alone or with additional
chemotherapy at the Juravinski Cancer Centre (JCC), Hamilton Health Sciences
Corporation.
All patients were treated initially with palliative HDR Intraluminal Brachytherapy
(HDRILBT). Two or three weeks after the completion of HDRILBT, chemotherapy was
given to selected patients. Patients suitable for the additional chemotherapy received
Epirubicin, Cisplatin and 5-Fluorouracil (ECF) regimen prescribed by the medical
oncologist.
All patients included in the study had total or near total dysphagia at presentation. None
of patients received adjuvant external radiation therapy.
The primary end point was dysphagia free survival. The secondary end point was overall
survival.
Brachytherapy was intended to treat disease in the luminal aspect of the esophagus to
maintain swallowing while chemotherapy was meant to treat systemic disease.
All patients were seen in a GI Multidisciplinary Clinic and reviewed by a Thoracic
Surgeon, Radiation Oncologist, Medical Oncologist, Radiologist, and Pathologist together
after all investigations were completed.
52
Dysphagia scoring was done on a 5 point scoring system: 0, no dysphagia; 1, dysphagia
for solids; 2, dysphagia for semisolids; 3, dysphagia for liquids; and 4, total dysphagia.
An improvement of dysphagia was recorded if there was an improvement by at least one
grade. The EORTC-QLQ was used for recording dysphagia (Table 2.1).
Table 2.1- EORTC-QLQ, European Organization for Research and Treatment of Cancer
Quality of Life Questionnaire
QUESTION:
Not at all
A little
Quite a bit
1. Could you eat solid food?
1
2
3
Very
much
4
2. Could you eat liquidized or
soft food?
3. Could you drink liquids?
1
2
3
4
1
2
3
4
4. Have you had trouble with
swallowing your saliva?
1
2
3
4
Dysphagia-free survival was defined based on the 4 question scores from the table above.
The dysphagia scoring algorithm is illustrated in Table 2.2.
~~ If the sum of the first two questions was adding up to 6, 7, 8 dysphagia score was
classified as “0” (no dysphagia),
~~ If the sum of the first 2 questions was equal to 5 dysphagia score was “1” (dysphagia
to solids),
~~ If the sum of the first 2 questions was equal to 4 dysphagia score was “2” (dysphagia
to semisolids)
~~ If the sum of the first 2 questions was equal to 2 or 3 and the 3rd question was 3 or less
dysphagia score was classified as a “3” (dysphagia to liquids)
~~ If the sum of the first 3 questions was equal to 3 and the 4th question was 3 or 4
dysphagia score was classified as “4” (total dysphagia)
53
Table 2.2- Dysphagia algorithm
Q1 score
Q2 score
4
3
3
2
1
2
1
1
1
1
1
1
1
4
4
3
3
4
2
3
2
2
1
1
1
1
SUM of
Q1+Q2 scores
8
7
6
5
5
4
4
3
3
2
2
2
2
54
Q3 score
Q4 score
3
2
3
2
1
1
3
4
DYSPHAGIA
score
0
0
0
1
1
2
2
3
3
3
3
4
4
HIGH DOSE RATE BRACHYTHERAPY
Brachytherapy is a form of radiation treatment where radioactive sources are placed in or
near the treatment site. High dose rate brachytherapy is brachytherapy delivered with a
dose rate of >12 Gy/hr. Typically, the radioactive source used is Iridium-192 (Ir192), with
an activity of up to 10 Ci. At JCC the radiation is delivered using a VariSource HDR
Remote Afterloader Unit (Figure 2.8) using a single source with a diameter of 0.34 mm
and length of 5 mm.
Figure 2.8- Remote Afterloader Brachytherapy Unit
Figure 2.9- Barium swallow examination of an complete tumor obstracted esophagus
55
Figure 2.10- Localization of Intra-oral tube/Catheter in situ
The treatment was performed as an outpatient procedure under conscious sedation. A preHDRILBT treatment barium swallow examination was carried out for each patient to
fluoroscopically visualize the area where the tumor obstructed the esophagus (Figure 2.9).
After premedication, the radiation oncologist performed an endoscopy, which is the most
convenient, safe assessment of the tumor. The procedure was assisted using fluoroscopy.
Either a 7mm esophageal applicator, which contains the 1.7mm esophageal catheter or the
catheter alone, was temporally placed intraluminal in the esophagus with the aid of a
flexible tip wire (Figure 2.10). After the placement of the applicator with a marker wire
inside (Figure 2.11), an X-ray image was taken to define the tumor length.
56
Figure 2.11- Marker wire used to measure the tumor length
The active length (tumor volume) of the treatment was visualized/identified and
documented by gastro-esophagoscope and then marked fluoroscopically.
The marker wire was removed from the catheter and the catheter was attached to the high
dose rate brachytherapy afterloader. The dose was delivered to the entire tumor length
plus an additional 2cm margin in the craniocaudal direction (Figure 2.12).
Figure 2.12- Diagram showing definition of the target volume
57
For all patients the dose was prescribed at 1cm from the central axis. Based on the dose
and tumor length a treatment plan was generated using Brachyvision planning software.
The Treatment plan showed a high conformity of isodose lines to the tumor volume with
good sparing of normal tissues from vicinity (Figure 2.13). The treatment prescription
was a dose of 18 Gy divided in 3 fractions with 6 Gy per fraction, given over two week’s
period. All patients finished all 3 fractions.
Figure 2.13- Treatment Plan Distribution.
58
CHEMOTHERAPY
Chemotherapy was given after 2-3 weeks after completion of the last fraction of the
HDRBT. The chemotherapy regime, ECF was given as a day patient and included:
Epirubicin 50mg/m2 IV day 1(1 cycle) 3-weekly was given as an injection along with a
drip of saline
Cisplatin 60-100mg/m2 IV day 1(1cycle) 3-weekly - given as an infusion
5-Fluorouracil (5FU) infusion 750-1000mg/m2 day IV 1-5) every 28 days for 3 cycles
Dose calculation of all chemotherapy drugs was based on body surface area. The body
surface area was calculated by using the actual body weight.
Laboratory investigation was done for each patient before the treatment started
a.
Complete blood work
b.
Coagulation profile
c.
Base line renal function serum creatinine, electrolyte, urine routine.
For chemotherapy to maintain the same weight during the course of treatment was very
important. In case of a weight change, around 10% or more, treatment doses had to be
recalculated.
TIMING OF BRACHYTHERAPY with CHEMOTHERAPY
Chemotherapy when given in addition to brachytherapy the sequencing was important.
59
FOLLOW-UP
All patients were booked for a 6 weeks follow-up after the last HDR treatment. After that,
follow-up was booked with the radiation oncologist every 3 months up to 24 months.
Even though the patients were booked to see the doctor every 3 months they were asked
to call any time if swallowing problems occurred: difficulty swallowing or pain during
swallowing.
Before each appointment the patients were booked to have a CT scan of the chest and
abdomen to check for any metastasis or local recurrence plus blood test including
baseline renal function creatinine. Dysphagia together with other symptoms was
evaluated at each visit and a thorough physical examination was done.
At every appointment the new investigation findings were compared with the first post
treatment scans.
At each appointment the degree of dysphagia plus radiologic and clinical factors were
assessed. The patients’ survival was linked with the following factors: gender, disease
site, tumor location, pathology, stage and size, ECOG status, and grade of dysphagia,
treatment received, and treatment length. Clinical examination was done for all patients
every time plus CT scans comparison.
60
STATISTICAL ANALYSIS
Analysis was performed using the SAS statistical analysis software system (SAS Institute,
Cary, NC, USA).
Overall survival and dysphagia relief score were estimated based on a univariatecategorized analysis. These numbers were plotted and the Kaplan-Meier graph method
was used for the description of survival analyses. In order to compare the two treatment
strategies a log-rank test was used for survival analyses of variables as predictors.
Univariate analysis for age, gender, pathology, tumor location, length, performance score,
weight and treatment given on dysphagia free and overall survival was performed.
Because of the large number of covariates observed only those that were significant on
univariate analysis were included in the multivariate analysis. If the variables were too
unevenly balanced or had a high percentage of missing data theywere not included into
the multivariable procedure. The percentage of missing data was not recorded.
The performance status was measured using the Eastern Cooperative Oncology Group
(ECOG) Performance Status Scale Performance.
To test the hypotheses regarding the effect of treatments: HDRILBT alone and HDRILBT
followed by Chemotherapy on overall survival, a Cox regression model was used for
multivariate survival analyses.
Pearson Chi-Square Tests were used and categorical prognostic data was evaluated based
on chi-squared distribution where the expected cell counts were less than 5.
ETHICS
The study was approved by the Research Ethics Committee, McMaster University,
Hamilton.
61
3.0 RESULTS
In this study 132 patients with advanced esophageal cancer treated at Juravinski Cancer
Centre, Hamilton Health Sciences Corporation from 2005-2008 were included.
The demographic variables plus clinical variables which includes gender, disease site and
length, dysphagia, ECOG status, weight loss, co-morbidities (heart problems) were
analyzed. Table 2.3 shows a summary of the patient population characteristics.
Table 2.3- Clinical Patient Characteristics
Characteristics
Number of patients,
percentage (%)
HDRILBT alone
Number of patients,
percentage (%)
HDRILBT +ECF
p- value
Age at Diagnoses
Mean Age: 71.41
Mean Age: 59.98
<0.0001
Gender
Male n=101
Female n=31
72 (54.5%)
26 (19.7%)
29 (21.96%)
5 (3.7%)
Disease Site
GE junction n=24
Lower esophagus n=81
Mid esophagus n=17
Cervical esophagus n=5
Unspecified n=5
<0.0001
NS
17 (12%)
57 (43.1%)
16 (12.12%)
4 (3.03%)
4 (3.03%)
7 (5.3%)
24 (18.2%)
1 (0.75%)
1 (0.75%)
1 (0.75%)
NS
Co-morbidities
None n=54
39 (29.54%)
15 (11.36%)
Present n=78
59 (44.59%)
19 (14.39%)
NS-Not Significant
Pathological variables included tumor stage, pathology type, and treatment modalities.
Histologically, the type of cancer was proven either squamous cell carcinomas (37
62
patients, 28%) or adenocarcinoma esophageal cancer (90 patients, 68.18%). Most patients
had poorly differentiated carcinoma (77 patients, 58.3%). Tumor location on the
esophagus included the upper esophagus, the middle esophagus, the lower esophagus, and
the gastro-esophageal junction and any anastomosis place. At presentation some patients
already had distant metastasis (74 patients, 56%) and nodal metastasis were present in 87
patients (65.9%) (Table 2.4)
Table 2.4- Tumor Characteristics and Treatment Features
Characteristics
Treatment given
Number of
patients,
percentage (%)
HDRILBT alone
98 (74.25%)
Number of
patients,
percentage (%)
HDRILBT +ECF
34 (25.75%)
Tumour pathology
Adenocarcinoma n=90
Squamous n=37
63 (47.73%)
32 (24.24%)
27 (20.45%)
5 (3.70%)
Adeno-squamous n=3
Unspecified n=2
2 (1.5%)
1 (0.75%)
1 (0.75%)
1 (0.75%)
Grade
Well n= 5
Moderate n=33
4 (3.03%)
26 (19.7%)
1 (0.75%)
7 (5.30%)
Poorly differentiated n=77
60 (45.45%)
17 (12%)
Unspecified n=51
42 (31%)
9 (6%)
Distant Metastatic at
presentation
Absent n=58
Present n=74
Nodal Metastasis at
presentation
Absent n=45
Present n=87
NS-Not Significant
p-values
NS
NS
NS
44 (33.3%)
54 (40.9%)
14 (10.6%)
20 (15.15%)
p<0.000
42 (31%)
56 (42.42%)
63
3 (2.3%)
31 (23.4%)
The selection of patients receiving additional chemotherapy was based on performance
status and age. The WHO (World Health Organization)/ECOG (Eastern Cooperative
Oncology Group) score was an observer-rate scale that measured the patient performance
status and ranges from 0 to 4 (Table 2.6).
Table 2.6- WHO/ECOG
SCORE
0
1
2
3
4
DESCRIPTION
Full active
Ambulatory, capable of light work
In bed <50% of time, capable of self-care but not work
In bed >50% of time, capable of only limited self care
Completely bed ridden
Out of 132 patients entered in the study, 52 were evaluated to have performance status 1
and 51 score of 2 (table 2.7).
Table 2.7- Study Patients’ Performance Status
ECOG Total number of
patients, percentage (%)
score
Number of patients,
HDRILBT alone
Number of patients,
HDRILBT +ECF
0
15 (11.36%)
10
5
1
52 (39.4%)
35
17
2
51 (38.6)
41
10
3
12 (9.1%)
10
2
4
2 (1.5%)
2
0
64
3.1) AGE
Patients eligible for chemotherapy in addition to brachytherapy were younger than those
who received brachytherapy alone. On analysis, age was a statistically significant factor
(p<0.0001) (Figure 3.1).
Figure 3.1- Pie graph showing age distribution of patients
65
3.2) GENDER
The majority of the patients in the study were men i.e. 76.5% (101 cases out of 132)
(Figure 3.2)
Figure 3.2- Pie graph showing gender distribution of patients
More male patients than female went on to have additional chemotherapy 21.96% vs.
3.7%. (Figure3.3)
Figure 3.3- Pie graphs showing male and female distribution of patients studied for each
treatment strategy
66
3. 3) TUMOUR LOCATION
The tumor location and the influence on the survival rate were analyzed but it was not
statistically significant. Most often the tumor was located mainly in the lower third of
esophagus and GE junction (Figure 3.4)
Figure 3.4- Pie graph showing tumor location
.
67
3. 4) PATHOLOGY
Histopathology was mainly adenocarcinoma (90/132) (68.2%)(Table 3.5). In the
univariate analysis there was no correlation between survival rate and histology of the
tumor. Histopathological reports were done in all cases based on endoscopic biopsy and
gross specimen.
Table 3.5- Tumor Pathology
Tumour pathology
Adenocarcinoma n=90
Squamous n=37
Other n=5
Percentage
68.2%
28.0%
3.8%
Figure 3.6- Pie graph showing tumor pathology
3. 5) TUMOR LENGTH
The length treated for patients included in the study had a median of 11 cm regardless of
the treatment strategy. The tumor length was not a statistically significant factor.
68
3. 6) NODAL METASTASIS
Nodal metastasis was present in 55.8% (87/132) of esophageal cancer patients. The
patients’ charts were reviewed to identify patient with existing nodal metastasis (Figure
3.7 and 3.8). The data were analyzed and showed it to be strongly statistically significant
(p<0.000).
Figure 3.7- Distribution of Nodal Metastasis for patient receiving HDRILBT only
Figure 3.8: Distribution of Nodal Metastasis for patient receiving HDRILBT plus
Chemotherapy
69
3. 7) Esophagus cancer patients were divided in two categories: with or without distant
metastasis (Figure 3.9). Even though the expectation was that patients with no distant
metastasis 43.9% (58/132 would do better compared with the ones with metastasis this
was not strongly significant.
Figure 3.9- Distant Metastases
70
3. 8) TREATMENT GIVEN
98 (74.25%) patients underwent HDR brachytherapy alone and 34 (25.75%) patients
underwent HDR brachytherapy followed by chemotherapy (Figure 3.10).
Figure 3.10- Distribution of treatment given and number of patients
3. 9) ECOG SCORE
The ECOG performance status was higher for HDRILBT plus chemotherapy group of
patients. This reached statistically significance, a p-value of 0.0014.
Patients treated with HDRILBT and received additional ECF were in better condition
status than those who received HDRILBT alone.
71
INFLUENCE OF DYSPHAGIA ON SURVIVAL
All patients (n=132, 100%) had near total or total dysphagia at presentation. Relief of
dysphagia was seen in more than 90% of patients. The improvement of dysphagia was at
least by 2 grades within 6 weeks of brachytherapy.
DFS improved in patients who received ECF chemotherapy (mean 232 days) when
compared with those who received HDRILBT alone (mean 182 days). However, this
difference was not statistically significant (p=0.2954)
Table 3.11- Dysphagia free survival for both treatment modalities
Mean DFS (by 2 grades)
182 days
232 days
HDRILBT alone
HDRILBT + ECF Chemotherapy
Figure 3.12- Dysphagia Free Survival DFS
Percent
Figure 1- Dysphagia Free Survival
100%
80%
60%
40%
20%
0%
0
60
Days Survived
Brachytherapy
120 180 240 300 360
Days Survived
Brachytherapy+Chemotherapy
--------------Brachytherapy; ----------------Brachytherapy plus Chemotherapy
72
On univariate analysis there was no impact of any prognostic marker on dysphagia free
survival. On multivariate analysis the HDRILBT treatment with additional ECF
chemotherapy had a significant impact on DFS (p= 0.0462).
73
OVERALL SURVIVAL
Overall survival improved in patients who received additional ECF chemotherapy (p=
0.0010) than HDRILBT alone.
OS for HDRILBT + ECF was 266 days compared to HDRILBT alone 155 days (p =
0.0010). An important observation, additional ECF chemotherapy had a considerably
impact on OS (p=0.0007). On multivariate analysis tumor length (p=0.02003) and nodal
metastases at presentation (p=0.000) were impacted on overall survival.
Table 3.14- Overall survival for both treatment modalities
Overall Survival
155 days
266 days
HDRILBT alone
HDRILBT + ECF Chemotherapy
Figure 3.13- Overall Survival
OS
Figure
2- Overall Survival
100%
Percent
80%
60%
40%
20%
0%
0
60
Days Survived
Brachytherapy
120 180 240 300 360
Days Survived
Brachytherapy+Chemotherapy
--------------Brachytherapy; ----------------Brachytherapy plus Chemotherapy
74
On univariate analysis patients undergoing brachytherapy with additional ECF
chemotherapy were younger age (p<0.001) and with a better performance status
(p=0.0041) compared to those patients receiving brachytherapy alone.
75
COMPLICATIONS
Complications of treatment occurred in both treatment strategies. There were 11 cases of
stricture, with 11 after brachytherapy alone and 4 after the addition of chemotherapy after
brachytherapy. None was life threatening and they were successfully treated.
Table 3.15- Complications for both treatment modalities
HDRILBT alone
Stricture
Median Time to occur
7
106 days
HDRILBT alone
Fistulae
Median Time to occur
4
0
HDRILBT+ECF
CHEMOTHERAPY
4
110 days
HDRILBT+ECF
CHEMOTHERAPY
0
-
TOXICITIES
Table 3.16- Total number of toxicities for both treatment modalities together
Toxicities
Number of
occurrences
GI
25
Neurotoxicity
2
Nephrotoxicity
2
All patients finished all 3 fractions of high dose rate brachytherapy. ECF chemotherapy
was delivered in a range from 1-10 cycles. 18 patients completed at least 3 cycles. Most
of the toxicities were caused by the 5 Fluorouracil induced mucositis. The side effects
were related mostly to gastro-intestinal tract. Complications because of Cisplatin were
rare and mostly neuro- and nephro- toxicities. Epirubicin did not give any cardio side
effect to any patient.
76
4.0 DISCUSSION
Many studies have shown brachytherapy to be widely used for palliation of dysphagia
due to advanced esophageal cancer (Table 4.1).
Table 4.1- Review HDRILBT with literature
AUTHOR
CONCLUSION
BHATT, 2012
Older patients with increased dysphagia
tolerated HDRILBT well and treatment was
effective.
BERGQUIST 2005
HDRILBT compared with stent: rapid
improvement of dysphagia with the stent but
after 1 month both treatment modalities have the
same improvement rate. Better QOL with
brachytherapy than stent
FONTANESSI, 1989
HDRILBT decreased dysphagia, no further
treatment for obstruction needed.
HARVEY, 1993
Comparison between HDRILBT and EBRT:
brachytherapy is an effective modality for older
patient, with poor physical condition
HOMS, 2002, 2006
HDRILBT is effective, no major complications
but recurrent and persistent dysphagia occurs
that requires further treatment (e.g. stent)
HOMS, 2005
HDRILBT compared with stent: rapid
improvement of dysphagia with the stent but
after 1 month both treatment modalities have the
same improvement rate
JAGER, 1992
Single HDRILBT of 15Gy dose was appropriate
for dysphagia relief
KAUL, 1990
Single HDRILBT of 12Gy dose was effective in
dysphagia relief for elderly patients
77
KULHAVY, SUR and LEVIN,
1995
HDRILBT dose between 12-15Gy gives least
morbidity
LOW, 1992
Similar results between HDRILBT and laser
treatment but retreatments were 3 times higher
for laser group
SUR, 1991
HDRILBT with 12Gy given in 2 fractions had a
high survival rate and more effective than
intubation in dysphagia relief
SUR, 1996
HDRILBT best palliative modality, optimal
dose 16Gy/2 fractions or 18Gy/3 fractions
SUR, 2001
Patient received either HDRILBT or HDRILBT
with EBRT-no difference in survival between
the 2 treatment strategies
SKOWRONEK, 2004
HDRILBT dose 22.5Gy in 3 fractions effective
in improvement of dysphagia
WEI-BO-YIN, 1989
Combination of HDRILBT +EBRT better
survival results than EBRT alone
WEE, 1994
HDRILBT dose of 15Gy in 1 or 2 treatment.
Same dysphagia improvement
FLEISHMAN, 2006
HDRILBT can be used instead of EBRT with
same palliative effect
ROWLAND, 1985
HDRILBT more effective than intubation in
dysphagia relief
The role of additional chemotherapy to high dose rate intraluminal brachytherapy in
improving DFS has not been reported before. Sur et al. [128] have previously examined
the role of chemosensitization with brachytherapy in advanced esophageal cancer. The
incidence of toxicities in form of stricture and fistulae significantly increased when
78
chemotherapy with 5 Fluorouracil was used with brachytherapy. Also strictures occurred
earlier and were more recalcitrant and difficult to dilate when chemotherapy was used as
a sensitizer. The study recommended that the two not to be used together.
Patients with metastatic esophageal cancer present with dysphagia and weight loss. In
these patients the first aim of treatment is to restore swallowing. Brachytherapy is an
effective method of palliation to relief dysphagia [127-130]. Dysphagia relief is sustained
in more than 70% cases for many months after treatment. HDRILBT can be done in all
patients regardless of their performance status. Unlike brachytherapy chemotherapy alone
can only be offered to selected patients who are in good general condition. A RCT is
therefore not feasible that can compare chemotherapy (CCT) alone to HDRILBT alone as
majority of patients would not be in a condition to receive palliative CCT due to their
poor performance status.
Patients with metastatic esophageal cancer present with dysphagia and weight loss. In
these patients the first aim of treatment is to restore swallowing. Brachytherapy is an
effective method of palliation to relief dysphagia [127-130]. Dysphagia relief is sustained
in more than 70% cases for many months after treatment. HDRILBT can be done in all
patients regardless of their performance status. Unlike brachytherapy chemotherapy alone
can only be offered to selected patients who are in good general condition. A RCT is
therefore not feasible that can compare CCT alone to HDRILBT alone as majority of
patients would not be in a condition to receive palliative CCT due to their poor
performance status.
79
For some patients with esophageal cancer who have metastatic cancer and are in good
general condition, chemotherapy is often used after brachytherapy especially if the patient
is young (as was seen in this series). In these patients the value of additional multiagent
chemotherapy (ECF in this series) was never examined. This study shows that additional
ECF chemotherapy in selected patients improves DFS and significantly improves OS.
The incidence of complication and toxicity related to chemotherapy is reasonable and the
treatment is well tolerated in the majority of patients. A break of 3-4 weeks between
brachytherapy and chemotherapy is needed to improve the outcomes. This interval allows
tissue healing and recovery post brachytherapy, improves nutrition and the general
condition of the patient. As a result patients tolerate treatment a lot better. The incidence
of complications related to radiation i.e., strictures and fistulae does not increase by the
additional chemotherapy especially if the break is given allowing tissue recovery.
Chemotherapy after brachytherapy should therefore offered to all patients with
esophageal cancer who are in good general condition.
This study is a retrospective analysis of a prospective database. Being retrospective this
study has limitations in selection bias and outcome measures. A well designed RCT is
indicated.
80
5.0 CONCLUSION
High Dose Rate Intraluminal Brachytherapy is an effective modality of palliation in
advanced esophageal cancer patients. Additional chemotherapy with ECF after
HDRILBT improves dysphagia free survival and overall survival significantly in selected
patients with advanced esophageal cancer. These patients tend to be younger with better
performance status, small tumor length and nodal metastasis. The incidence of
complications is similar with more than 50% patients completing at least 3 cycles of
chemotherapy.
81
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