Nazmul thesis about carcinoma rectum.

Effect of Neoadjuvant Concurrent Three Dimensional
Conformal Chemoradiotherapy with Conventional Two
Dimensional Chemoradiotherapy in Locally Advanced
Rectal Cancer
Submitted by :
Dr. S. M. Nazmul Alam
Resident, Phase-B
Course : MD(Oncology)
Exam. Session – January, 2021
Thesis Guide :
Dr. Md. Abdul Bari
Associate Professor
Department of Oncology
BSMMU

ACKNOWLEDGEMENT
• I am deeply indebted to my respected teacher and guide Dr. Md.
Abdul Bari, Associate Professor, Department of Oncology,
BSMMU for his supervision, continuous guidance and needful
support from the beginning of the proposal till completion of this
thesis

ACKNOWLEDGEMENT
• I am earnestly grateful to my honorable teacher Professor Dr.
Sarwar Alam, Chairman, Department of Oncology, BSMMU for his
valuable and inspiring advice, direction and suggestion which has
made this possible

ACKNOWLEDGEMENT
I express my gratitude to all my respected teachers - the Associate and
Assistant Professors of the Department of Oncology, BSMMU for their
extended co-operation
I am greatly indebted to my parents and wife for their blessings, guidance
and support.

• Colorectal cancer is the third most common cancer and the second leading
cause of cancer-related death worldwide, with rectal cancer representing
about 40% of cases (GLOBOCAN, 2018)
• In Bangladesh, it is the 8th most common cancer and also the 6th leading
cause of incidence in male and 9th in female (Hospital-Based Cancer
Registry Report, NICRH, 2014)
• Most of the rectal cancer patients are within an age limit of 35-54 years
(Hospital-Based Cancer Registry Report, NICRH, 2014)
INTRODUCTION

• Environmental and genetic factors have been established as contributing to
colorectal cancer
• The choices of therapeutic approach for rectal cancer are surgery,
radiotherapy, and chemotherapy depends greatly on tumor stage and the
location of the tumor in the rectum
• Clinical staging is divided into three categories for treatment purpose: a)
Early stage --- Stage I, b) Locally advanced stage --- Stage II and III, c)
Advanced stage --- Stage IV
INTRODUCTION

• Preoperative chemoradiotherapy has been established as the standard of care
and is clearly preferred when tumor shrinkage is required before surgery,
that is, in locally advanced disease and low-lying tumors when sphincter
preservation is attempted (Gerard et al., 2006)
• Now neoadjuvant three dimensional (3D) conformal chemoradiation is well
accepted treatment protocol worldwide
• As well as neoadjuvant concurrent conventional two dimensional (2D)
chemoradiotherapy is another option.
INTRODUCTION

• Cancer incidence and mortality rapidly increasing worldwide.
• In Bangladesh, the incidence of colorectal cancer is in 8th leading place and
most of the colorectal patients come to tertiary level hospital in advanced
stages. (Hospital-Based Cancer Registry Report, NICRH, 2014)
• At present, the standard care of locally advanced rectal cancer is neoadjuvant
chemoradiotherapy followed by definitive surgery
• Multiple randomized trials showed a decreased local recurrence rate, cancer
mortality rate and increased sphincter preservation, complete response rate
comparison to adjuvant chemoradiotherapy (Sauer R et al., 2004)
RATIONALE OF STUDY

• Capecitabine is an oral prodrug of 5FU acts as a radiation sensitizer in the
neoadjuvant treatment setting
• Several randomized trial (kunheri et al. 2016, yoney and Isikli 2014 and
Hofheinz et al. 2012) were done in world wide and capecitabine was proven
beneficial than infusional 5 FU
• The standard preoperative radiotherapy regimen is currently pelvic
radiotherapy to a dose of 45-50.4 Gy in 25-28 fractions in 5 weeks with
concurrent capecetabine based chemotherapy agent (Shin et al., 2016)
RATIONALE OF STUDY

• Since last 50 years, radiotherapy technique has developed much. There is a
shift from two dimensional radiotherapy technique to modern three
dimensional conformal radiotherapy (International Atomic Energy Agency,
2008)
• Two dimensional (conventional ) RT is based on bony landmarks using X-
ray which is associated with a degree of uncertainty
• Normal tissue around the field gets more unnecessary radiation, so increase
risk of acute and late toxicities(Joye et al., 2014)
• Mahmoud et al., (2011) reported that by using 3DCRT technique, where
more normal tissue can be spared compared to two dimensional
(conventional) radiotherapy technique
RATIONALE OF STUDY

RATIONALE OF STUDY
• However, 3D-CRT requires more skill man power, sophisticated machine as
well as it is expensive, which is associated with high cost and also difficulty
to get facility of 3D-CRT in every instituition
• So, 2D-RT is another good alternative for the treatment of rectal cancer where
the cancer patient load is very high with suboptimal number of RT machine
• This study compares the outcome of three dimensional conformal
chemoradiotherapy with two dimensional conventional chemoradiotherapy in
terms of tumor response and acute toxicity.

HYPOTHESIS
• Neoadjuvant concurrent three dimensional conformal chemoradiotherapy is
more effective than concurrent two dimensional chemoradiotherapy for
better locoregional control with less normal tissue toxicity in locally
advanced rectal cancer

OBJECTIVES OF THE STUDY
• General objective:
To assess the clinical response and toxicity of neo adjuvant three
dimensional conformal chemoradiotherapy with conventional two
dimensional chemoradiotherapy in locally advanced rectal cancer

• Specific objectives:
 Assessment of the treatment response in terms of
reduction of tumor size.
 Assessment of the acute toxicity in terms of gradation.
 Assessment of the rate of sphincter sparing surgery after neoadjuvant
chemoradiotherapy.
 To measure the basic demographic characteristics of the patients.
OBJECTIVES OF THE STUDY

MATERIALS AND METHODS
Study design:
• Quasi experimental study
Duration of study:
• January 2019 to June 2020 (One and half year)
Sampling technique:
• Convenient and purposive sampling
Research instrument:
•Structured Data Collection form

•Place of study
This study was conducted in following oncology and radiotherapy center in
Bangladesh.
1. Department of oncology, BSMMU, Dhaka.
2. Department of Radiation Oncology, NICRH, Dhaka.
3. Department of oncology, AMC&GH, Dhaka.

• Study population
 Patients with clinically and histologically proven locally advanced
adenocarcinoma of rectum (stage II – stage III) were enrolled in this
study
 They were convinced to participate in the study after giving their
written consent
 The study population satisfied the inclusion and exclusion criteria.

• For determination of sample size following formula was applied: -
P1 = Proportion of patients developing outcome in one arm
P2 = Proportion of patients developing outcome in another arm
Z=Z-value (two tail) at a definite level of significance e.g 1.28 at 20% level
of significance
Z=Z-value at a definite power e.g 0.52 at 70% power.
( Haque et al.,2009)

• A. Inclusion criteria:
 All patients were diagnosed as locally advanced adenocarcinoma of
rectum, clinical TNM staging, stage II (T3-4N0) or stage III (T1-4N1-2) by
CT scanning or MRI
 Distal margin of the tumor located within 10 cm from the anal verge
on colonoscopy

• B. Exclusion criteria:
Patients with distant metastases
Age below 18 years and above 70 years
Initial surgery (excluding diagnostic biopsy) of the primary site
Patients with double primaries
Poor performance status (ECOG score >2)
Family history of rectal cancer when it was diagnosed as hereditary
nonpolyposis colorectal cancer

• C. Criteria for discontinuation of treatment:
Patients refusal to continue study participation
Occurrence of unacceptable toxicity necessitating major
modification of treatment

• Treatment of enrolled patients
Total 60 patients with locally advanced rectal cancer were selected by
described patient selection criteria.
Patients were divided into two arms
• Arm A - Treated by concurrent three dimensional conformal (3D-CRT)
chemoradiotherapy
• Arm B - Treated by concurrent two dimensional (Conventional)
chemoradiotherapy

• Treatment by Radiotherapy
• Position: supine position, arm above the chest using a head rest and knee rest
used for lower leg immobilization
• Bladder preparation: comfortably full bladder protocol was used for planning.
• Bowel preparation: low residual food diet with bowel clearance was ensured
for simulation.
• Anal marker: A radiopaque marker was placed on the anus.

• Treatment Planning of Arm A
• Simulation : CT simulation (with IV and oral contrast)
• Target volume definition : GTV, CTV, PTV , OAR volumes were defined
• Dose prescription : 50.40 Gy in 1.8 Gy per fraction in 28 Fractions, single
fraction per day, 5 fraction per week over a period of 5.3 week along with
chemotherapy.

• Treatment Planning of Arm B
• Simulation: X-ray simulation
• Fields: Two (AP – PA) fields box technique used
• Boundary: Bony land marks are used to define field borders
• Dose prescription: 50 Gy in 2 Gy per fraction in 25 Fractions, single fraction per
day, 5 fraction per week over a period of 5 week along with chemotherapy.

Chemotherapy along with RT(CCRT):
• For both the arms, tablet capecitabine 825mg/m2 (Day 1-5/wk) twice daily, was
used throughout the course of EBRT.
• Vitamin B6 was supplemented (pyridoxine, 50 mg per oral twice daily) to prevent
and/or reduce the incidence and severity of hand-foot syndrome.
• Anti-emetics were prescribed routinely for the prevention of nausea and vomiting.

Patients assessment
Pre-treatment:
History, physical examination and relevant investigations
During treatment:
• Patients were assessed weekly during treatment
After treatment:
• Toxicity and response evaluation was done after 6 weeks of completion of
chemoradiotherapy.
• After surgery, patients were re-assessed to evaluate the pathological treatment
response (pTNM status), sphincter sparing surgery, type of surgical resection and
positive surgical margin.

• Response criteria:
• Tumor response was evaluated according to the WHO guideline of
responses (RECIST criteria)
• Toxicity reporting:
• To assess toxicity, RTOG and CTCAE guideline was used
• If any toxicity developed during treatment, it was managed appropriately

• Analysis and Interpretation of Data
• Information obtained were tabulated on master chart.
• Difference between two means was assessed by T-test.
• Statistical software SPSS version 25.0 for Windows was used.
• All outcomes were compared by chi-square test and Fisher's exact test .
• A p-value of less than 0.05 considered as statistically significant.

Figure 1 – X ray simulation at NICR&H

Figure 2 – X ray simulation at NICR&H

Figure 3 – 3D-CRT contouring at NICR&H

Figure 4 – 3D-CRT contouring at NICR&H.

OBSERVATION & RESULTS
DISCUSSION

Discussion:
Column diagram shows that the
peak age incidence of rectal cancer
in patients were 31-40 years and
41-50 years in arm A and 41 to 50
years in arm B. The mean age of
patient was 45.20 years for arm A
and 42.43 for arm B. This is
consistent with cancer registry
report (2014) that showed the peak
incidence occurs at 41-50 years.
Figure 5: Distribution of patients in relation to
age group in both arms

Discussion:
This figure shows that male
patient was dominant in both arm.
The percentage of male patient in
arm-A and arm-B were 56.66%
and 63.33% respectively. But in
female 43.33% and 36.67% were
in arm-A and arm-B respectively.
Male and female ratio in total was
1.5:1 which is relevant to cancer
registry report (2014) that showed
male and female ratio 1.4:1.
Figure 6: Percentage distribution of patients by
sex

Discussion:
Majority of patients in this study
belongs to middle class economic
condition.
Figure 7: Distribution according to economic condition
of patients

Smoking
habit
Arm-A
No. of the
patients(%wit
hin arm)
Arm-B
No. of the
patients(
%within
arm)
Total
No. of the
patients(
%within
arm)
Chi-
square
value
P-
value
Smoker 15
(50.0%)
16
(53.3%)
31
(51.7%)
.067 .796Non-
smoker
15 (50.0%) 14
(46.7%)
29
(48.3%)
Discussion:
In this study the table
shows that 51.7% patients
were smoker and 48.3%
were non smoker in total
in which 50.0% and 53.3%
were smoker in arm-A and
arm-B respectively. which
is supported by Nyrén et
al., 1996.
Table 1: Distribution of patients in relation to smoking habit

Discussion:
Majority of patients
were housewife in Arm-
A 33.33% and farmer &
housewife in Arm-B
23.33%. Service holders
were 18.3%, business
person were 11.7% and
student were 8.3% in
both Arm A and Arm B.
Figure 8: Distribution of patients according to Occupation in
both arm

Discussion:
The pie chart shows that
17% of total patients had
family history and 83%
had no previous family
history. (p=0.488)
Figure 9: Percentage of total patients according to
family history
17%
83%
Family history
Present
Absent

Discussion:
Majority of patients were
presented with per rectal
bleeding (78.33%) followed
by Alteration of bowel habit
(53.33%). Some patients
presented with loss of
appetite, urinary problems,
pelvic pain and rectal
discomfort (23.33%) which
is supported by Hamilton et
al., 2005.
Table 2: Distribution of the patients according to sign
and symptoms
Clinical presentation Number of complain (%)
Per Rectal Bleeding 47 (78.33)
Alteration of bowel habit 32 (53.33)
Tenesmus 21 (35)
Mucus discharge 9 (15)
Others 14 (23.33)

Discussion:
The table shows that
total 61.7% patient
performance status
was "0" and only 5%
of total patient
performance status
was "2". p-value was
not significant.
Table 3: Percentage of performance status of patients
Performance
status
(ECOG)
Arm A Arm B Total Chi square
value
p-
value(Fisher' s
Exact Test)
0 20(66.7%) 17(56.7%) 37(61.7%)
1.377 0.502
1 8(26.7%) 12(40%) 20(33.3%)
2 2(6.7%) 1(3.3%) 3(5%)

Discussion:
The table shows that lower
end of the most of the tumors
was 4 cm from anal verge in
arm-A and 3 cm in arm-B.
The highest distance was in
both arm was 10 cm. Mean
distance was 5.93 cm in arm-
A and 4.96 cm in arm-B and
average was 5.45 cm
(p=0.852, Fisher's Exact Test)
Table 4: Distribution of patients according to Tumor
distance in both arm
Tumor
distance (cm)
Arm A no. of
the patients
(%within
Arm)
Arm B no. of
the patients
(%within
Arm)
Total no. of
the patients
(%within
Arm)
p-value
(Fisher's
Exact Test)
2 2 (6.7%) 2(6.7%) 4(6.7%)
0.852
3 4 (13.3%) 7(23.3%) 11(18.3%)
4 5 (16.7%) 6(20%) 11(18.3%)
5 2 (6.7%) 4(13.3%) 6(10%)
6 4 (13.3%) 4 (13.3%) 8(13.3%)
7 4 (13.3%) 3(10%) 7(11.7%)
8 3 (10%) 2(6.7%) 5(8.3%)
9 4 (13.3%) 1(3.3%) 5(8.3%)
10 2 (6.7%) 1(3.3%) 3(5%)

Discussion:
Most of the tumor
grade was moderately
differentiated 53.3%
and 60% in arm-A and
arm-B, respectively
which is comparable to
Yoney and Isikli.,
2014.(p=0.871)
Figure 10: Distribution of patients by grading of
tumor

Discussion:
The table shows that
most of the patients were
T3N1 in arm-A (26.7%)
and T3N0 & T3N1 in
arm-B (23.3%). (p=
0.957, Fisher's Exact
Test)
Table 5: Pre-treatment TNM stage of the patients
TNM
stage
Number of
patient (%)
Arm A Arm B Total P value
T2N1 Number 1 3 4
0.957
% within Arm 3.3% 10% 6.7%
T2N2 Number 1 1 2
% within Arm 3.3% 3.3% 3.3%
T3N0 Number 5 7 12
% within Arm 16.7% 23.3% 20%
T3N1 Number 8 7 15
% within Arm 26.7% 23.3% 25%
T3N2 Number 5 3 8
% within Arm 16.7% 10% 13.3%
T4N0 Number 2 2 4
% within Arm 6.7% 6.7% 6.7%
T4N1 Number 4 4 8
% within Arm 13.3% 13.3% 13.3%
T4N2 Number 4 3 7
% within Arm 13.3% 10% 11.7%
Total Number 30 30 60
% within Arm 100.0% 100.0% 100.0%

Discussion:
76.7% and 70% patients of arm-
A and arm-B were stage-III,
respectively in pre-treatment
state.73.3% patients were stage-
III. Though P value was not
significant.
Table 6: Pre-treatment clinical stage of the patients
Stage of the
disease
Arm A Arm B Total Chi-
square
value
p value
Stage II 7(23.3%) 9(30%) 16(26.7%)
0.341 0.559
Stage III 23(76.7%) 21(70%) 44(73.3%)

Discussion:
This table shows that most
patients suffered from
grade-1 toxicity, 80% and
86.7% for arm-A and arm-
B respectively.10% of arm
A and13.3% of arm-B had
grade-2 toxicity. (p-
value=0.20, Fisher's Exact
Test)
Table 7: Distribution of patients on the basis of
treatment related Anemia in both arm
Anemia Number of
patient (%)
No toxicity Number 3 0 3
0.20
% within
Arm
10% 0% 5%
Grade 1 Number 24 26 50
% within
Arm
80% 86.7% 83.3%
% within
Arm
10% 13.3% 11.7%
% within
Arm
100.0% 100.0% 100.0%

Discussion:
23.3% and 33.3% patients
were suffered from Grade-
1 toxicity and 13.3% and
20% suffered from Grade-
2 toxicity respectively
from arm-A and arm-B
during treatment.
(p-value=0.4302, Fisher's
Exact Test)
Figure11: Treatment related toxicity grading of leukopenia
in both arm

Discussion:
The table is showing no
significant difference by
Fisher's Exact Test (p =
0.571).
Table 8: Treatment related neutrophil toxicity grading
of patients in both arm
Neutrophil
count decrease
Number of
patient (%)
0.571
% within Arm 60% 46.7% 53.35%
% within Arm 26.7% 33.3% 30.0%
% within Arm 13.3% 20.0% 16.7%
% within Arm 100.0% 100.0% 100.0%

Discussion:
The table shows overall
chemoradiotherapy related
gastrointestinal toxicities.
All the toxicities were
managed by conservative
treatment. Treatment
discontinuation or
hospitalization for toxicity
management was not
needed during treatment
and follow-up period.
Table 9: Distribution of patients according to treatment
related gastrointestinal toxicities in both arm
Variables Group Chi square p value
(Total=60)
Arm A [n (%)] Arm B [n (%)] value
Nausea
No toxicity 24 (80.0) 18 (60.0)
2.857a
0.091
Grade 1 6(20.0) 12(40.0) (Chi square test)
Vomiting
No toxicity 24(80.0) 19(63.3)
2.052 0.152
Grade 1 6(20.0) 11(36.7) (Chi square test)
Diarrhea
No toxicity 10(33.3) 3(10.0)
Grade-1 17(56.7) 22(73.3) 4.910 0.086
Grade-2 3(10.0) 5(16.7)
(Fisher's Exact
Test)

Discussion:
The bar diagram shows that
grade-1 oral mucositis toxicity
was more common in both
arm (56.7% and 60% in arm-A
and arm-B respectively).
Grade-2 toxicity occurred
only 3.3% in both arm. (P =
0.965, Fisher's Exact Test)
Figure 12: Distribution of patients according to oral
mucositis in both arm

Discussion:
In arm-A, 33.3% patients had
grade-1 hand-foot syndrome
where in arm-B, it was 40.0%
and was not significant (p =
0.592). No patient needed any
intervention.
Table 10: Distribution of patients by gradation of hand-foot
syndrome
Hand-foot
syndrome
Number of
patient (%)
0.592
% within
Arm
66.7% 60.0% 63.3%
% within
Arm
33.3% 40.0% 36.7%
% within
Arm
100.0% 100.0% 100.0%

Discussion:
Radiotherapy during treatment
caused grade-2 toxicity 13.3%
and 40% patients in arm-A
and arm-B, respectively
supported by Gunnlaugsson et
al., 2007. Mostly grade-1
toxicity occurred in arm-A
(43.3%) and arm-B (46.7%).
Fisher's Exact Test: p value
0.012 was significant.
Figure 13: Column diagram distribution of patients
by radiation induced proctitis

Discussion:
In arm-A and arm-B, 76.7%
and 80% suffered from grade-1
dermatitis respectively. Only 1
patients in arm-A and 3 patients
in arm-B had grade -2
dermatitis. But none was
admitted in hospital or needed
interruption of treatment. (p =
0.364)
Table 11: Gradation of radiation dermatitis
Radiation
dermatitis
Number of
patient (%)
0.364
% within
Arm
20.0% 10.0% 15.0%
% within
Arm
76.7% 80.0% 78.3%
% within
Arm
3.3% 10.0% 6.7%
% within
Arm
100.0% 100.0% 100.0%

Discussion:
The table showing that
43.3% patients in arm-A and
56.6% patients in arm-B
developed radiation induced
grade-1 urinary toxicity.
They were managed
conservatively. Result are
compareable with Corner et
al.,2011.
Table 12: Distribution of patients having urinary
toxicity
Urinary
toxicity
Number of
patient (%)
0.145
% within Arm 46.7% 23.3% 35.0%
% within Arm 43.3% 56.67% 50.0%
% within Arm 10.0% 20.0% 15.0%
% within Arm 100.0% 100.0% 100.0%

Discussion:
The table shows that 5 patients
(16.7%) showed complete
response in arm-A whereas 3
patients (10%) in arm-B. Both
arm had partial response 51.2%
and 48.8% respectively ,stable
disease was 10% and 20% in
arm-A and arm-B, respectively.
P value was non-significant
(0.467) supported by Wei et
al.,2007.
Table 13: Distribution of patients according to post CCRT
treatment response after 6 week in both arm
Post CCRT
treatment
response
(after 6
weeks)
Number of
patient (%)
Complete
response
Number 5 3 8
0.467
% within Arm 16.7% 10.0% 13.3%
Partial
response
Number 22 21 43
% within Arm 51.2% 48.8% 71.7%
Stable disease Number 3 6 9
% within Arm 10.0% 20.0% 15.0%
% within Arm 100.0% 100.0% 100.0%

Discussion:
This table is showing
that 3 (10%) patient in
arm-A and 1 (3.3%) in
arm-B had complete
pathological response.
Pathological
complete
response
Number of
patient (%)
Yes Number 3 1 4
0.301
% within Arm 10.0% 3.3% 6.7%
No Number 27 29 56
% within Arm 90.0% 96.7% 93.3%
% within Arm 100.0% 100.0% 100.0%
Table 14: Distribution of patients by pathological complete
response

Discussion
Sphincter sparing surgery was
possible in 73.3% patients in
arm-A and 56.7% patients in
arm-B among them 52% and
43% was achieved with a
tumour located 6 cm or less
from anal verge respectively. P-
value was non-significant
(0.176). The study result is also
supported by Wagman et al.,
1998 (77% in 3D-CRT); P Das
et al., 2005(78% in 3D-CRT)
Yoney and Isikli, 2014(51.4 in
2D-RT)
Sphincter
preservation
Number of
patient (%)
Yes Number 22 17 39
0.176
% within Arm 73.3% 56.7% 65.0%
No Number 8 13 21
% within Arm 26.7% 43.3% 35.0%
% within Arm 100.0% 100.0% 100.0%
Table 15: Distribution of patients according to sphincter
preservation

DISCUSSION
• After careful analysis of the above data, it is very much evident that the present
study could not demonstrate any significant differences about short-term tumor
responses, tumor size reduction and sphincter sparing surgery between 3D-CRT
and 2D-RT.
• Though arithmetically 3D-CRT was more effective than 2D-RT. Lower
gastrointestinal toxicity(proctitis) was more common in 2D-RT patients and was
significant (<0.05).

LIMITATIONS OF STUDY
• The time period was short.
• Small sample size was major limitation to have an accurate clinical
outcome.
• The study was non-randomized quasi experimental study, it failed to
prevent selection bias.
• Short time follow up, late toxicities and survival data could not measured.

CONCLUSION
• Tumour response was not statistically significant between the patients of
concurrent 3D-CRT and 2D-RT Arms. But the patients of 3D-CRT arm
showed better response arithmetically. Also, there was an observable
significant reduction of toxicity (lower gastrointestinal) in the 3D-CRT arm.

RECOMMENDATIONS OF STUDY
• Further randomized controlled study of longer duration should be done to
explore late toxicities, long term locoregional control rate, progression free
survival and 5-year overall survival.
• Head to head study comparing more advanced radiotherapy technique like
intensity modulated radiotherapy (IMRT) with 3D-CRT should be done to
find better ways to reduce late toxicities.
• Conventional radiotherapy technique is still an effective method and should
not be underestimated, particularly in low resource setting.

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