A STUDY OF HIGH-DOSE-RATE BRACHYTHERAPY

IN THE TREATMENT OF

CARCINOMA OF THE UTERINE

BEING DISSERTATION SUBMITTED BY

DR. A.R. OYESEGUN

AS PART OF THE PRE-REQUISITES

FOR PART II OF THE M.MED PROGRAMME IN

RADIOTHERAPY AND ONCOLOGY

University of Zimbabwe Library


TABLE OF CONTENTS

SUMMARY

i

1 INTRODUCTION ........................................ 1

1.1 IMPORTANCE OF CARCINOMA OF THE CERVIX IN




ZIMBABWE .......................................... 1

1.2 USE OF RADIOTHERAPY IN THE TREATMENT OF




CARCINOMA OF THE CERVIX.......................... 2

1.3 USE OF INTRACAVITARY IRRADIATION IN THE




TREATMENT OF CARCINOMA OF THE CERVIX.............. 3

1.4 ADVANTAGES OF HIGH-DOSE-RATE REMOTE AFTERLOADING




INTRACAVITARY BRACHYTHERAPY ........................ 4

1.5 DISADVANTAGES OF HDR BRACHYTHERAPY .......... 6


1.6 FRACTIONATION - NUMBER, TIMING, SIZE ........ 8


1.7 DOSE OF HDR EQUIVALENT TO LDR................ 10


1.8 AIM OF THE STUDY............................ 12




2 MATERIALS AND METHODS .............................. 13

2.1 PATIENTS' CHARACTERISTICS.................... 14


2.2 TREATMENT TECHNIQUES........................ 15




2.2.1 EXTERNAL BEAM THERAPY....................15


2.2.2 INTRACAVITARY BRACHYTHERAPY..............16


2.3 DOSAGE CALCULATION ............................ 17


2.4 LDR INTRACAVITARY BRACHYTHERAPY IN HARARE PATIENTS 18


2.5 CLINICAL PROCEDURE USED FOR INTRACAVITARY




BRACHYTHERAPY FOR MPILO PATIENTS .................. 19

2.6 ACUTE SIDE EFFECT SCORING ......................20


2.7 FOLLOW-UP STUDIES ............................ 21




5.3 TIME SCHEDULE FOR HDR INTRACAVITARY TREATMENT .

22

23

25

28

30

30


31




6 CONCLUSION ..........................................

37

7 ACKNOWLEDGEMENTS ....................................

38

8 REFERENCES




39


SUMMARY

AIM:

To study the acute side effects associated with HDR brachytherapy 
and compare it with those of LDR.

MATERIALS AND METHODS:

Sixty two (62) patients treated with HDR studied. Seven (7) had 
had previous surgery. Thirty one (31) had HDR intracavitary 
insertion concomitant with EBT and twenty four (24) after. A 
total of 104 patients treated with LDR evaluated for comparison.

RESULTS:

Diarrhoea was the most frequent acute side effect noticed, mostly 
of low Grade - I & II - recorded in 18/31 (58%) of concomitant arm 
and 10/ 24 ( 42%) of after-EBT arm. Dysuria was uncommon in HDR

patients. Diarrhoea was less frequent in LDR patients - 28/104 
(26%) - while dysuria was more frequent - 30/104 ( 29%) - than in 
HDR patients. These symptoms in LDR patients were mostly of low- 
grade nature. Previous surgery was associated with a higher 
incidence of acute side effects - 6/7 (85%) patients had low

grade diarrhoea and 2/7 (28%) patients had dysuria.

CONCLUSION:

Acute side effects associated with two insertions of 7 Gy HDR 
were low grade and tolerable. Literature review showed that 
larger numbers of insertions are better tolerated with reduced 
late complications comparable to those of LDR. Most late 
complications were associated with fraction sizes greater than 
7 or 8 Gy. It is recommended that HDR afterloading treatment 
continues in Bulawayo using three fractions each of 6 Gy given 
at weekly intervals, the first two during the course of EBT and 
the third following completion of EBT, keeping overall time under 
seven weeks. Further work is indicated to assess the frequency 
of late complications.

i


1

INTRODUCTION

1.1 IMPORTANCE OF CARCINOMA OF THE CERVIX IN ZIMBABWE




Carcinoma of the cervix is the commonest cancer in females in 
Zimbabwe. According to the Cancer Registry in Harare, between 
January and December 1991, 600 cases of cancer of the cervix were 
recorded. This formed 25% of all cancers reported in females 
during same period. A breakdown of this figure showed that:

44 cases (7%) occurred in the 20 - 30 year age group;

134 cases (22%) occurred in the 30 - 40 year age group;

151 cases (25%) occurred in the 40 - 50 year age group;

149 cases (25%) occurred in the 50 - 60 year age group; and 
74 cases (12%) occurred in the 60 - 70 year age group, as 
shown below in Figure I:

Age in Years

FIGURE I:

HISTOGRAM SHOWING THE DISTRIBUTION BY AGE GROUP

For 1992, cervical cancer formed 24% of the total cases of cancer 
recorded in females; it formed 38% in 1990, 33% in 1989, 28% in 
1988 and 35% in 1987.

1


1.2 USE OF RADIOTHERAPY IN THE TREATMENT OF CARCINOMA OF THE 
CERVIX




Radiotherapy plays a major role in the treatment of Carcinoma of 
the uterine cervix. Most patients with this disease will require 
radiotherapy, either as definitive treatment or as an adjuvant. 
Over 90 percent of our patients in Zimbabwe fall in the former 
category, i.e. over 90 percent will require radiotherapy as the 
definitive form of treatment, because most of them present with 
advanced disease not amenable to surgery. There are two 
modalities of administering radiotherapy, the external beam 
therapy, involving the use of megavoltage machines such as 60Co 
machines and the linear accelerator - treatment given in 
fractionated doses over a period of several weeks. The second 
involves the use of intracavitary brachytherapy (see 1.3 below).

2


1.3 USE OF INTRACAVITARY IRRADIATION IN THE TREATMENT OF 
CARCINOMA OF THE CERVIX




Intracavitary brachytherapy is an essential component in the 
treatment of cervical cancer. It involves the insertion of 
radioactive sources through applicators into the uterus and 
vagina to deliver high doses of irradiation to the immediately 
surrounding tissues. According to the International Commission 
on Radiation Units (ICRU) Report 38 on dose and dose 
specification for reporting intracavitary brachytherapy in 
gynaecology,

- Dose Rates in the range of 0.4 - 2.0 Gy/hour are referred 
to as low dose rates.


- Dose Rates in the range of 2 - 12 Gy/hour are referred to 
as medium dose rates.


- Dose Rates greater than 12 Gy/hour are high dose rates.




The method of delivery could also be manual afterloading or by 
remote control afterloading technique, which is the method being 
studied.

3


1.4 ADVANTAGES OF HIGH-DOSE-RATE REMOTE AFTERLOADING 
INTRACAVITARY BRACHYTHERAPY




Recently, there has been increased interest in HDR remote—control 
afterloading intracavitary brachytherapy for carcinoma of the 
cervix. This emanated from certain advantages of this mode of 
treatment over the LDR which include:

1) Low personnel exposure;


2) Short treatment time, therefore, a greater number of 
patients per week could be treated;


3) More convenient and more comfortable treatment given on 
an out-patient basis, thus minimizing cost in terms of stay 
in the hospital, avoidance of catheter complications, 
reduced chance of thrombophlebitis and pulmonary emboli and 
skin breakdown in buttock crease;


4) Greater stability of the applicators during treatment 
because of short treatment time.


5) Constant and reproducible geometry of source 
positioning, therefore treatment planning and dosimetry are 
more exact (Speiser).




Besides these advantages, HDR and LDR have been found by 
different authors to have comparable local control rates and 
five-year survival rates. For example, in the series by Akine 
et al (1990) local control rate was 71% in the HDR group and 83% 
in the LDR group for stage II8 disease and 64% and 61% 
respectively for stage III8 diseases. The 5-year survival rate 
for both methods according to the FIGO annual report 1987(2) is 
as shown below:

4


HDR VS LDR INTRACAVITARY BRACHYTHERAPY FOR CARCINOMA OF THE

CERVIX

(1979-1981) - FIGO ANNUAL REPORT 1987(2)

Stage

No of Patients 
HDR/LDR

5—year Survival 
(%)

HDR

LDR

I

160/422

76.9

71.6

II

358/796

58.1

54.4

III

386/588

38.1

38.4

IV

66/50

15.2

10.1



5


1.5 DISADVANTAGES OF HDR BRACHYTHERAPY




The history of brachytherapy evolved empirically to dose rates 
of +/- 10 Gy/day. Many efforts at high-dose teletherapy all 
revealed severe delayed complications and daily doses of 150 - 
300 cGy are generally accepted for radical courses of treatment 
(although higher doses may be used in the treatment of pain and 
bleeding in palliative situations). HDR is very similar to a 
large external-beam-therapy fraction, however desirable it is 
to treat with few fractions, from a logistic point of view, 
brachytherapy is still under the same constraints biologically 
as teletherapy. Chen et al, 1991, compare the late complication 
rates in stage II8 and III8 diseases treated with LDR and HDR 
after external beam therapy. Analysis of their result showed 
slightly higher late-complication rates for HDR, though not 
statistically significant as shown in the table below.

TABLE I

II8

III8

HDR

LDR

HDR

LDR

Late

Complications

Rectal

34%

20%

31%

26%

Bleeding

Rectal

2%

0%

4%

4%

Stenosis

Haematuria

9%

5%

3%

4%

Fistula

2%

0%

3%

4%



Choi et al, 1992, showed an unexpectedly high complication rate 
in patients treated with HDR brachytherapy which they found 
significant and unacceptable. In their study, late complications 
developed in 47% (65/137) of their patients. Grade 3 or above 

6


complications occurred in the bladder, small bowel and sigmoid 
colon/rectum. Apart from Choi et al, most other studies showed 
slightly higher late complication rates with HDR, but were not 
statistically significant. Certain issues also remained 
unresolved for now regarding the use of HDR brachytherapy. For 
example:

1) What dose of HDR is equivalent to the standard dose of 
LDR?


2) Optimal treatment regimen schedule, including dose 
prescriptions, number of insertions and the interval 
between them and pelvic irradiation doses - these are all 
as yet unresolved.




Most of the studies that have examined these problems to date are 
largely retrospective and are all non-randomized. Broad-based 
prospective randomized studies will be required to resolve these 
issues and this will take some time.

In the meantime, however, what are the guidelines to be used as 
regards HDR brachytherapy in our situation for now?

7


1.6 FRACTIONATION - NUMBER, TIMING, SIZE




There is as yet no consensus of opinion on the optimal 
fractionation schedules to be used in HDR brachytherapy. Several 
authors have used different fraction numbers and sizes and have 
achieved fairly comparable results. Orton (1991) prefers 
conventional Low—Dose—Rate brachytherapy and multiple 
fractionation to allow for repair of normal tissues. He likened 
HDR to teletherapy with fewer big fractions and associated more 
late complications. Therefore, he feels it is important to use 
increased number of fractions in order to reduce late 
complications. He used 3.8 Gy per fraction and gave a total of 
12 fractions. In his view, this fractionation will keep the dose 
to the bladder and rectum per fraction to 2 Gy — 2.5 Gy and that, 
with good application, rectum and bladder dose will be about 60% 
of the point A dose. His intracavitary fraction size of 3.8 Gy 
HDR is much less than that used by most other authors.

Chen et al, 1991, treated 365 patients with HDR. They gave 
external beam therapy with 10 MeV Linac Anterior and Posterior 
fields using field size 16 x 18 cm3 at isocentre initially giving 
44 Gy/22 fractions/4h weeks, then 14 Gy/7 fractions side-wall 
boost for some IIs and III8. This was followed by intracavitary 
insertion in three fractions. EBT for 2 weeks, 1st intracavitary 
(IC), then 2 weeks later 2nd IC, and 3rd IC 2 weeks after, 
totalling 11 weeks of treatment time. The intracavitary dose was 
770 - 850 cGy per fraction initially and was later reduced to 
720 cGy per fraction to minimize dose to the rectum. Their 
complication rate in 20 cases of IIs and 23 cases of III8 who 
completed 3 insertions after follow-up period of 2 - 9 years was 
13%, which was slightly above the usual LDR figures, but their 
local recurrence rate was 12% for stage II8 and 17% for stage 
III8 cancer.

8


Roman et al, 1991, in their treatment of 87 patients with stages 
IIA , IIB and III8 after a median follow-up of 40 months, used 
external beam therapy with 4-10 MeV Linac and 4 fields (Box) 
technique to 46 Gy at 2 Gy/fraction, and then intracavitary 
insertion giving 800 cGy - 1000 cGy to point A per insertion. 
They gave IC once weekly, with the number of insertions varying 
from 1-3. Six patients had one insertion only (either because 
of inability to find the cervical canal at the time of insertion 
or bulky residual disease), 51 had two insertions and 30 patients 
had three insertions performed. They obtained a survival rate of:

- 88% for stage IIA patients


- 64% for stage IIs patients


- 32% for stage III8patients.




These results are comparable with other results in the 
literature. Their acute complications are similar to those 
obtained with LDR, and their total complication rate was 11.5%. 
Some of the late complications they reported included proctitis -

2%; fistula - 3.5%; and small bowel obstruction - 6%.

9


1.7 DOSE OF HDR EQUIVALENT TO LDR




To estimate what dose of HDR is equivalent to LDR, Akine et al 
(1990) in a non-randomized retrospective study treated 370 
patients with external beam therapy (EBT), then with either LDR 
or HDR brachytherapy. EBT was with 6 MeV Linac using anterior and 
posterior fields and field size 16 x 16 - 17.5 x 17.5 cm3. They 
gave 50 Gy in 25 fractions over five weeks. This was followed by 
intracavitary insertions two weeks later, either as one or two 
applications of LDR doses, or four applications of 5 Gy HDR. 
Their local control rates and survival rates revealed no 
statistically significant difference.

Complication rates - they compared major complications only in 
stages IIs (69 patients) and III8 (184 patients) who had 
conventional LDR, with those who had HDR (16 stage II8 and 31 
stage III8; excluded were 46 patients who had less than 48 Gy or 
more than 52 Gy EBT, and 23 patients not treated according to the 
HDR protocol). Since both groups had the same external beam dose, 
it was the comparison of :

HDR — 2000 cGy/4 fractions with

LDR - 20 - 30 Gy, or 30 - 40 Gy to point A.

Then they plotted the incidence of major radiation injury as a 
function of the point A dose, as shown below in Figure II:

10


V - .

X.tVSMA'i

3;c 55 4c

o

~^0%£.To /s QC,^

'\nC.\\<L^CQ. o^- fAf*\O>r 'CcA'\a\\<™ \'A'^?C'^ ^Xp-V^M 
U>M\ Scf'A c£ Ahl Xo\v\V A. Xoso.. %cv« 
CjO'T-c^^vA \o %Su Q-'CTOV'- VA'AvrSQ.fS

\<A va^^Q-SVS Q_0 'T'AS'^O'oX \$) A'A*t\\3£LC' <S^5

^oA.\<Lma\S <y\<x\0^c \ 'A’^A'C'A

Q's^-r \s>\^X <\A YtxV/L'T <£) ^xA\<bn?tS


By curve—fitting the data with a linear function, a dose—response 
equation was obtained: the incidence of radiation injury (Y%) = - 
13.9 + 0.6 Dose (Gy). From this equation, the 4.3% incidence of 
injury using 2000 cGy HDR was equivalent to 30 Gy LDR.

4.3 = -13.9 + 0.6D

18.2 = 0.6D . ,

By taking a ratio of doses from HDR over LDR irradiation (20/30 
Gy), it was concluded that the clinically equivalent dose for HDR 
irradiation was approximately 2/3 of the dose used in LDR therapy 
in their protocol. Others have made similar conclusions — Orton, 
1991. Based on the desirability (the advantages) of HDR 
brachytherapy, the World Health Organization (WHO) in its report 
of a WHO Meeting of Investigators, 1980, advocated the use of HDR 
intracavitary irradiation in the treatment of cervical cancer in 
developing countries when feasible.

11


1.8 AIM OF THE STUDY




Study aimed basically at identifying acute side effects 
associated with HDR brachytherapy and compare it with those of 
LDR. Also the study was to define the dose of intracavitary 
insertions, intervals of insertions, overall treatment times in 
weeks, to be used at Mpilo Hospital as standard therapy. The 
study was designed such that all the patients started with 
external beam therapy, then some to have their 2 intracavitary 
insertions during external beam therapy and others to have one 
insertion during and one after EBT. Then comparing them stage for 
stage, the acute side effects of each arm were to be studied to 
determine which regimen was better tolerated in the patient. The 
number of insertions was deliberately kept low initially until 
the outcome of this study was known, since when introducing a new 
treatment modality, one does not want to have an unacceptable 
initial complication rate.

12


2 MATERIALS AND METHODS

The Curietron - which is a high-dose-rate remote after—loading 
machine became functional at Mpilo Hospital in Bulawayo in July 
1992. Since then, to date, most patients with carcinoma of the 
cervix seen at the centre were treated with a combination of 
External Beam Therapy (EBT) and two intracavitary insertions. 
Between July 1992 and March 1993, 70 patients had one or two 
intracavitary insertions with the Curietron. As of March 1993, 
62 patients had completed external beam treatment and two 
intracavitary insertions. It is these 62 patients that were 
studied in this non-randomized prospective exploratory study.

In all, 198 patients were studied:

BULAWAYO — 62 patients comprising of

GROUP A - 31 patients had EBT and first insertion 3rd week 
of EBT and 2nd insertion one or two days after n of EBT.

GROUP B - 24 patients had EBT and first insertion 3rd week 
of EBT and the 2nd insertion within two weeks of completion 
of EBT.

GROUP C - 7 patients had previous surgery, then EBT and 2 
insertions of HDR intracavitary brachytherapy (dose: 7 
Gy/fraction in 20 minutes to 0.5cm depth).

HARARE - 104 patients

GROUP D - had EBT and one insertion of LDR intracavitary 
brachytherapy (dose: 25-28 Gy over 60—65 hours to point A). 
GROUP E - palliated cases - 32 patients.

Of the 62 patients at Mpilo Hospital, Bulawayo, seven had 
previous surgery and subsequent vault caesium. Therefore, 55 
patients had two courses of intracavitary insertions — 31 of them 
during EBT, i.e. first insertion in third week of EBT and second 
insertion one or two days after (GROUP A) and therefore completed 
their treatment within five weeks of commencement. Twenty four 
had first insertion during EBT and the second within two weeks 
of completion of EBT (GROUP B), thus completing within six to 
seven weeks after commencement of EBT.

13


2.1 PATIENTS' CHARACTERISTICS




All patients included in the study had histologically proven 
carcinoma of the cervix. All the patients were staged clinically 
by gynaecologists and radiotherapists, 2 patients had intravenous 
urogram done as part of the staging procedure. Patients studied 
included those with stages Is to IIIs carcinoma of the cervix. 
Excluded from the study were patients treated palliatively and 
were as such offered only EBT. Reasons for exclusion, number of 
patients and treatment outcome were as shown in Table II. They 
were reviewed at the completion of treatment to monitor response 
to treatment.

TABLE II

Patients Treated Palliatively with only EBT - E

(NED = No Evidence of Disease)

REASON

NUMBER

OUTCOME

Fistula - WF,

RVF

7

No treatment

IA - Referral 
for Surgery

1

Stage II Bulky

2

1 NED after 
treatment; 1 
persistent 
disease

III A+s

11

3 NED; 8 
persistent 
disease

IVA

3

1 NED; 2 
persistent 
disease

IIIs Bulky

8

1 NED; 7 
persistent 
disease

TOTAL

32



14


2.2

TREATMENT TECHNIQUES

2.2.1 EXTERNAL BEAM THERAPY




All the Patients who received external beam radiotherapy were 
treated on 60Co machine, using 80 cm SSD. They were treated in 
two phases. In phase I, they received parallel opposed 
anteroposterior field to 40 Gy/20 fractions in four weeks. In 
phase II, they received two lateral fields to treat the 
parametrium taking the dose to the pelvis to 50 Gy. The rectum 
was shielded posteriorly at 46 Gy in all patients to reduce dose 
to the rectum except when the posterior vaginal walls were 
involved in IIIA or IIIA+B cases. When using anteroposterior 
fields, the treatment volumes were as follows:

1) Superior border at the junction of L4/L5 level


2) Lateral border 1 - 2 cm clear of the pelvic brim


3) Lower border usually at the lower margin of the 
obturator foramen, except where lower 1 /3 of the vagina 
is involved, when the inferior margin was extended to 
the level of the ischial tuberosity using an anal 
marker.




Check films were taken in all cases and corrections made on the 
fields where necessary. The dose delivered ranged from 42 - 50 
Gy at 2 Gy per fraction, using 5 fractions per week. All fields 
were treated each day. The patients were treated in both prone 
and supine positions to prevent buttock crease ulcerations.

15


2.2.2 INTRACAVITARY BRACHYTHERAPY




The Curietron remote after—loading machine in use in Bulawayo 
consists of 4 sources. These include:

1) 6 cm long with source strength of 2466 mCi—137Cs; 
active length is 6 cm, labelled TU08.


2) 8 cm active length with source strength of 3315 mCi- 
137Cs.




Appropriate uterine tandems were used depending on the length of 
the uterine cavity as determined by uterine sound. Either of the 
two uterine sources was used such that not more than 1 cm of the 
active length lay within the vagina.

The other two sources are the vaginal colpostats:

1) 2 cm active length of 830 mCi- labelled TA65.


2) 2 cm active length of 835 mCi- labelled TA64.




With the uterine tandem in place and the two vaginal colpostats 
in the lateral fornices and with adequate packing (anteriorly and 
posteriorly to separate the anterior rectal wall and posterior 
bladder wall from the sources as much as possible) the most 
superior edge of the 2 colpostats lies at the lowest active point 
of the uterine tandem. The point A dose was taken as 2 cm lateral 
to and superior to the lateral fornix along the long axis of the 
uterus. The arrangement of the sources was as shown below in 
Figure III:

16


2.3 DOSAGE CALCULATION




Clipping the colpostats together after insertion leaves a 
distance of about 4 cm between them. Considering the two 
colpostats as point sources and each centimetre of the 6 cm 
long tandem as six separate point sources, the contribution from 
all the three sources to point A was calculated. The K-factor of 
137Cs was taken as 3.28 R-hr mCi-1 at 1 cm. The Roentgen to Rads 
conversion factor as 0.957. Using the inverse square law, the 
summation of each point sources to point a was approximately:

Zli®.(_L_+_JL^+A + _l_^+_L+—l_^+_J^+_l_)+{830xAM835x-l-}=487.6x3.28x0.957 =1531Rhr_1

6 4.62 3.82 32 2.92 22 2.42 2.42 2.92 52 32

The same distribution* of sources and calculations using both the 
anteroposterior and lateral films entered into the computer gave 
1750 R hr-1 which was within 15% range of the manual calculation. 
With the lateral anteroposterior films taken after insertion of 
the applicators, dose to point A was calculated and the time to 
deliver 7 Gy to point A was calculated, which was about 21 
minutes on our Curietron.

17


2.4 LDR INTRACAVITARY BRACHYTHERAPY IN HARARE PATIENTS




The 104 Harare patients all had EBT on 6 MeV linear accelerator 
in two phases, and the total dose ranged from 42 - 50 Gy at 2 
Gy/fraction, five days a week. Following the completion of EBT, 
intracavitary insertions were done within two weeks. These 
patients were treated with the conventional low-dose-rate manual 
afterloading 137Cs sources. Patients were admitted on the day of 
the procedure, shaved and catheterised on the ward. Premedication 
was given 30 minutes before the procedure — IM 
Pethidine 100 mg and IM Valium 10 mg stat. They were cleaned and 
draped in the theatre, vaginal examination done to assess disease 
status and uterus sounded with the uterine sound to determine the 
depth. Amersham applicators - one uterine tandem and two vaginal 
colpostats of appropriate size were then inserted and packed 
adequately anteriorly and posteriorly. Manual afterloading done 
in a separate room on the ward designed for the purpose. Doses 
from IC insertion ranged from 25 - 28 Gy to point A in single 
insertions of between 60 - 67 hours, during which the patients 
were cautioned against active movements that could displace the 
source positioning.

18


2.5 CLINICAL PROCEDURE USED FOR INTRACAVITARY BRACHYTHERAPY FOR 
MPILO PATIENTS




Patients who had intracavitary insertions were admitted on the 
morning of the procedure. The external beam treatments were 
omitted that day. They were pre-medicated with Tabs Diazepam 10 
mg and IM Pethidine 100 mg 30 minutes before the procedure. After 
cleaning and draping the patient, pelvic examination was done on 
all of them to assess the degree of tumour regression. Uterus was 
then sounded using uterine sound to determine the appropriate 
length of uterine tandem to be used. The appropriate length of 
the tandem and the two vaginal colpostats were then inserted and 
clipped together. This was followed by packing anterior and 
posteriorly as much as possible. The applicators were then 
connected to the source.

In the first few patients, AP and lateral films were taken after 
insertion of the applicators to ensure the positioning of the 
applicators and to assist the physicist in calculating the dose 
to point A. This was however discontinued due to poor quality 
picture obtainable from the old machine available in the 
Curietron room. Since the treatment time was quite short and 
patients' movement minimal (all patients were advised to stay 
still during treatment and were also monitored outside the 
Curietron room through the remote television camera installed in 
the room) . It was assumed that position of the applicators if 
placed properly in the first instance, would not have changed 
enough to affect the dosimetry significantly during the short 
treatment time. Most of the patients had 7 Gy delivered to point 
A on two occasions this way. Thirty one had their two doses while 
on EBT, twenty four had one during and one after EBT, and seven 
had vault caesium, also during EBT. Two had 8 Gy at the initial 
stage and some patients with vaginal stenosis had their dose 
reduced to 5 - 6 Gy to prevent overdosing the rectum. Those who 
had had previous surgery had only the vaginal colpostat inserted 
and packed adequately. A dose of 20 Gy to 0.5 cm depth was 
delivered to the vaginal mucosa in this way. After the procedure, 
applicators were removed and patients moved to the ward attached 
to the Curietron room to rest for the day.

19


2.6 ACUTE SIDE EFFECT SCORING




Since the study was aimed at monitoring the acute side effects 
the patients suffer from during treatment, they were all seen at 
least once weekly in the on-treatment clinic to assess their 
progress, elicit any complaints and treat as appropriate. Similar 
information was retrospectively analyzed from the case files of 
the Harare patients treated with LDR. The main symptoms sought 
for were diarrhoea, dysuria, nausea and vomiting, skin reaction, 
any vault narrowing or vagina stenosis during examination, and 
haematuria. Acute side effect was defined as side effects noticed 
or treated within 90 days after the commencement of treatment. 
Late side effect was regarded as those noticed 90 days or more 
after completion of treatment - though late side effect was not 
assessed in this study. The side effects were graded according 
to RTOG/EORTC acute radiation morbidity scoring criteria for 
bladder and small/large bowel since these were the major symptoms 
most patients complained of. This is shown in Table III.

TABLE III - RTOG/EORTC ACUTE RADIATION MORBIDITY SCORING 
CRITERIA

Grade

1 -

Minor symptoms requiring no treatment.

Grade

2 -

Symptoms responding to simple out-patient 
management. Life style (performance status) not 
affected.

Grade

3 -

Distressing symptoms altering life style 
(performance status). Requiring stoppage of 
treatment, hospitalization for diagnosis, or 
requiring minor surgical intervention.

Grade

4 -

Major surgical intervention or prolonged 
hospitalization or prolonged stoppage of treatment 
required.

Grade

5 -

Fatal complications.



20


2.7 FOLLOW-UP STUDIES




Following completion of treatment, patients were seen six weekly for three months, two 
monthly for six months and thereafter two to three monthly for two years. Patients were 
questioned for complaints and were examined for tumour status, skin reactions, vaginal or 
vault stenosis or rectal problems. Follow-up period in this study ranged from six months for 
those treated early in the study to a few weeks for those treated only recently.

21


3

STATISTICAL ANALYSIS

Using a statistical package called NANOSTAT (developed by 
Professor Healy of the then London School of Tropical Medicine 
and Hygiene) the Chi—squared (X2) values were used to find out 
whether there were any associations between the treatment and the 
side effects observed.

22


4

RESULTS

The Tumour characteristics are shown in Tables IV and V.

TABLE IV

Stage

N9 of Patients

. TOTAL

62



TABLE V

Histology

Ne of Patients

Squamous Cell Carcinoma

59

Adenocarcinoma

2

Clear Cell Carcinoma

1

TOTAL

62



The radiation doses are shown in Tables VI and VII.

TABLE VI

EBT Dose to the Pelvis (Gy)

Ns of Patients

50

51

48

3

42

2

40

4

46

2

TOTAL

62



23


TABLE VII

Dose per Fraction to

Point A (Gy)

N2 of Patients

1st Insertion

2nd Insertion

4-5

3

3

5-6

1

2

6-65

5

4

7

42

41

7 - 7.5

3

4

8

1

1

TOTAL

55

55



24


4.1 ACUTE SIDE EFFECTS

Diarrhoea

As shown in Table VIII, 18/31 patients in group A (those had two 
IC during EBT) and 10/24 in group B (those who had one IC 
insertion during EBT and the other after) had grades I and II 
diarrhoea. P=0.35 and X2 = 0.87- no statistically significant 
difference observed. In the LDR-Group-D, 28/104 patients had

diarrhoea Grades 1 and 2.

Comparing the incidence of diarrhoea in HDR (groups A and B) and 
LDR Group D - Table IX - P = 0.0048 and X2 (with two degree of 
freedom) = 10.67 showed a highly statistically significant;

difference. Comparing the different arms of HDR with LDR (A vs 
D), P = 0.003 and X2 = 8.97 - the difference is highly 
statistically significant, in contrast comparing B vs D, P= 0.24 
and X2 = 1.39 - no statistically significant difference 
observed.

Dysuria and Frequency

As shown in Table IX, 30/104 (29%) patients in the LDR group had 
dysuria and frequency during treatment, as compared to 3/55 
(5.5%) patients (Table VIII) in the HDR group (P = 0.0011 and X2 
=10.59, which is a highly statistically significant difference).

25


TABLE VIII

ACUTE SIDE EFFECTS IN HDR-TREATED PATIENTS ACCORDING TO STAGE:

DIARRHOEA GRADES I & II

A -

31

B -

24

Stage

Diarrhoea 
Grades I & II

Stage

Diarrhoea 
Grades I & II

I

2/6

I

1/2

II

12/16

II

7/12

III8

Unilateral

2/4

III8

Unilateral

2/4

III8 Bilateral

1/3

III8

0/3

IIIA+B

1/2

IIIA+B

0/3

TOTAL

18/31 (58%)

TOTAL

10/24 (42%)

A - DURING EBT

B - AFTER EBT

No grade III and above 
diarrhoea seen in either 
group

Skin - 6 patients: 3 Stage 
III, 1 Stage II, 2 Stage I 
Nausea & Vomiting - 4 
patients

Dysuria - 2 patients

Skin - 4 patients

Vomiting - 3 patients 
Dysuria - 1 patient



26


TABLE IX

ACUTE SIDE EFFECTS IN LDR-TREATED PATIENTS—ACCORDING TO STAGE—D— 
LDR—Total—104.

Stage

Diarrhoea

Dysuria & 
Frequency

I

2/5

2/5

II

11/29

6/29

IIIB Unilateral

3/17

5/17

IIIB Bilateral

8/24

6/24

IIIA+B

4/25

9/25

IVA

0/4

2/4

TOTAL

28/104 (26%)

30/104 (29%)



TABLE X

PATIENTS WHO RECEIVED HDR RADIOTHERAPY FOLLOWING SURGERY—C

27


5

DISCUSSION

5.1 ACUTE SIDE EFFECTS

Diarrhoea was the most common acute side effect that was noticed 
in the patients treated with EBT plus two intracavitary 
insertions (C - 58%, A - 42%) and most were grades I and II. 
Only two of the patients had grade III diarrhoea. In one of them 
the diarrhoea persisted for the whole duration of the treatment 
time. One had persistent diarrhoea over 3 months after the 
completion of treatment and this patient turned out to be HIV 
positive, which explained the persistent nature of her diarrhoea. 
Fifty eight percent of those who had their insertion during EBT 
had grades I - II diarrhoea, as compared with 42% of those who 
had it after. Diarrhoea in LDR patients occurred also in 26% of 
patients.

That diarrhoea was more common in those who had their IC 
insertions during EbT than in those who had it after is not 
unexpected, since they had their irradiation to the large and 
small bowel within a shorter overall treatment time. Dysuria is 
generally a less common complaint amongst patients treated with 
HDR brachytherapy and occurred in only three patients. That 
dysuria was less common in these groups of patients compared to 
29% in LDR patients may be explained. Since they did not require 
hospital admission, bed rest with catheterization, their chances 
of developing urinary tract infection was smaller.

Other side effects were less common. Six patients in group A had 
minor skin exfoliation/ulceration and four patients in group B.

28


Buttock crease ulceration was rare since most of the patients 
were treated in prone and supine positions, which reduce the 
chance of gluteal ulceration. Nausea and vomiting were also not 
common in both groups.

When the acute side effects in patients with HDR were compared 
with those treated with LDR in Harare, it was also observed that 
diarrhoea was commoner in HDR patients (A - 58%, B — 42%) as 
compared to 26% in LDR patients (P = 0.0048 and X2 = 0.67). By 
contrast, LDR patients had a higher incidence of dysuria and 
frequency - 29%, as compared to three patients (5%) in the HDR— 
treated group (P = 0.001 and X2 = 10.59. The incidence of 
diarrhoea was considerably lower in LDR patients, perhaps because 
these patients were apparently getting much lower dose rate to 
their bowel but the incidence of dysuria and frequency was 
greater , perhaps because all of them required catheterisation 
for their treatment with increased urinary-tract trauma and 
infection (while HDR patients were not catheterized and had their 
treatment completed within 30 minutes).

Six of seven patients who had had previous surgery had diarrhoea 
grade I and II, and 2/7 had dysuria. This was in keeping with 
the known fact that previous abdominal surgery is associated with 
higher complication rates in pelvic irradiation (Perez and 
Brady).

Post treatment, over 90% of the patient were without evidence of 
residual disease at first review and non of the patient has had 
recurrence following subsequent review.

29


5.2 PATJ.IATED CASES




Table II shows the breakdown of 32 patients not included in HDR 
group in Bulawayo during the same period. Twelve of them had no 
radiotherapy treatment, nine because they had had fistula 
already, their pain was controllable with morphine and they were 
bleeding actively. Those with bulky IIB disease, IIIA+B disease and 
IIIs bulky disease treated palliatively had a poor response to 
treatment despite high dose of palliation given - 3750 Gy/10 
fractions, 40 Gy/15 fractions and 50Gy/20 fractions. 18/32 (56%) 
of these patients had persistent disease n follow up. They 
probably would not have done better on intracavitary insertions, 
because they were all assessed midway and towards the completion 
of EBT for fitness for intracavitary insertions. With residual 
disease on cervix ranging from 3-6 centimetres in diameter and 
parametrial residual disease, it was preferable not to give 
intracavitary treatment.

30


5.3 TIME SCHEDULE FOR HDR INTRACAVITARY TREATMENT

Overall treatment time is quite important in radiotherapy of 
carcinoma of the cervix, as in head and neck cancer. This was 
one of the reasons why some of the patients treated had their 
first IC insertion given before completion of EBT. The overall 
treatment time in most of these patients was less than 6 weeks. 
This was in keeping with the current Pattern of Care study in 
patients with carcinoma of the cervix (Lanciano et al, 1992) . 
They evaluated 837 patients in a multivariate analysis of overall 
time, stage, Karnofsky status and dose of irradiation.

TABLE XI

OVERALL TREATMENT TIME (O.T.)

< 6 weeks

22%

6-8 weeks

41%

8-10 weeks

22%

> 10 weeks

15%



TABLE XII

RESULT AT 4 YEARS - LANCIANO ET AL

<6/52

6 - 8/52

8 - 10/52

>10/52

Pelvic 
recurrence

6

12

15

20

Survival (%)

81

74

73

76

Major 
complications

15

11

12

17



31


They also showed that in field recurrence and survival were 
independent prognostic factors and paracentral doses > 75 Gy have 
greater complication rates as compared to doses less than 75 Gy. 
This study supported our practice of keeping our overall 
treatment time as reasonably low as possible, since the shorter 
the overall treatment time, the lower the pelvic recurrence rate 
the better the survival and complications are not significantly 
worse than for those treated with longer overall treatment time. 
Review of the literature showed that treating patients with EBT 
and concomitant IC is quite a common practice worldwide, as shown 
in Table XIII. External beam doses ranging from 29 to 67 Gy 
additional to intracavitary insertions, as many as 6, utilizing 
6-7 Gy/fraction had been utilized by many authors

32


TABLE XIII

HDR BRACHYTHERAPY FOR CARCINOMA OF THE CERVIX: DOSE 
FRACTIONATION SCHEDULE

A x After. B = Before; C «= Concurrent with brachytherapy

• Dose - maximum on the A-line (or A-plane) 2 cm lateral from the central axil of the applicator

+ Dose it the surface of the target volume

1st Author (Country)

Dose/Fx at Pt A (Gy)

No of Fx

No of FxAVeek

Dose (Gy)

Timing

Glaser (Germany)

6 - 7

5-6

1

40 - 50

A

Vahrson (Germany)

6 - 14*

3 - 7

.5 - 1

43 - 46

C

Cikaric (Yugoslavia)

9 • 10

4

1

35 - 46

C

Akine (Japan)

3 - 5

5 - 6

2 - 3

29 - 67

B

Himmelman

*

8.5

5

1

40 - 50

A

Kuplers (Netherlands)

8.5

2

2

46

B

Sato (Japan)

6.1

5

1

50 - 60

B

Shigemalsu (Japan)

8 - 10

3

I

40

C

Tuna (Finland)

7.5 - 10

3 - 5

1

50

A

.Ara! (Japan)

3 - 7

4 - 13

1 - 3

45 - 65

A

Joslin (UK)

8.5

2 - 5

1

24 - 45

C. B

Mizae (Japan)

5.0

6 - 7

2

40 - 50

B

Hie (Yugoslavia)

9 - 10.5

4

1

27

C

Teshima (Japan

7.5

3 - 6

1

14 - 40

C

Utley (USA)

5 - 6.6

6 - 10

2

20 - 50

C

Newman (UK)

7 - 8.5

2.5

1

22 - 63

C

Choi (Hong Kong)

7 - 8

3

I

40 - 58

C



33


The majority of centres worldwide utilize a schedule of three to 
six insertions of 7 - 8 Gy per week. The external beam dose was 
variable worldwide and dependent on the stage of disease. In 
most countries, the intracavitary brachytherapy was carried out 
concurrently with or after external beam irradiation. In three 
centres, it was given before external beam irradiation. 
Significantly better survival for HDR group, local control rate 
comparable, and in some cases, better than LDR group were 
recorded by most authors,. Most individual institutions also 
showed comparable late complication rates between LDR and HDR, 
except a few. Cikaric et al 1988 in their series showed a higher 
complication rate with the LDR technique. The rectal 
complication was significantly higher in the LDR group, in this 
series - 7.1% for HDR and 16.6% for LDR, with a p < 0.01. They 
also showed that the bladder complication rate was lower in the 
HDR group - 5.0% - than the LDR group - 9.6% with p< 0.01, which 
was quite significant; the reason for this unusual finding was 
not stated. ¦,

(Choi et al 1992) in Hong Kong in their studies showed an 
unexpectedly high and unacceptable high complication rate with 
their HDR technique. In their study, they gave EBT to the whole 
pelvis - 46 Gy/23 fractions and 3 weekly applications of HDR 
intracavitary brachytherapy of 7 or 8 Gy per fraction to point 
A. Their results showed good local control rate and survival 
rate comparable with other studies, but late complications 
developed in 47% (65/137) of their patients. Grade III or above 
complications occurred in the bladder, small bowel and sigmoid 
colon/rectum in 5%, 3% and 7% of patients respectively.

34


They found that patients aged above 60 years and stage III 
disease were adverse determinants for survival by multivariate 
analysis. The most significant determinants of severe rectal 
complications in this study were:

1) Addition of a lower vaginal tandem (p < 0.01) which




increased the volume of the rectum receiving high dose;

2) Uterine source length greater than 5 cm;


3) A total biological effective dose to the rectum of more than 
120 Gy;


4) Stage III disease.




Literature review showed that 7 Gy to point A in 2 doses is not 
only tolerable for most patients, but more on the side of being 
too little. This study did not show any higher acute side effect 
with this dose, neither did any study show this. Also, late 
effect from 7 Gy/fraction in 3 insertions did not show worse 
complication rates. It is however important to examine factors 
associated with higher complication rates in Choi et al’s study:

1) They used lower vaginal tandem we feel the vault ovoids are 
adequate to prevent vault recurrence.


2) Our uterine sources length are both longer than 5 cm. A 4 
cm source would be desirable.


3) Most of our patients come with stage III disease and we do 
not have influence over this, as early presentation might still 
take some time to be the norm in our environment.


4) We do not know or estimate the biologically effective dose 
to the rectum in our practice, because of lack of diagnostic 
equipment, e.g. TLD.




35


In order to minimise late complication rates, one option is to 
reduce our dose per fraction to 6 Gy and give at least three 
insertions. This may be difficult given the number of D & C sets 
at our disposal and the staff establishment, but these are 
surmountable problems.

In view of the fact that 7 Gy per fraction given to most of our 
patients now is tolerable in terms of acute side effect and most 
centres giving such doses reported acceptable late effects, it 
is my recommendation that we continue to give 6 Gy/ fraction and 
give three insertions at weekly intervals, preferably two 
insertions during EBT and one after, reducing our overall 
treatment time 6 to 7 weeks maximum.

This is an exploratory study with the aim of studying the acute 
side effects in HDR brachytherapy patients. While it was found 
that the acute side effects were tolerable and not significantly 
higher than LDR, it must be borne in mind that the disadvantage 
of HDR does not really lie in the acute side effects but in the 
late complications. This could not be studied at this time in 
our centre with our less than one—year experience in the sue of 
HDR brachytherapy. Most late complications in patients treated 
with HDR appear from one to four years after the completion of 
treatment. Further work is therefore suggested to analyze late 
complications that develop in our HDR patients and compare these 
with those of patients treated with LDR.

36


6

CONCLUSION

Acute side effects of HDR as given in our centre in Bulawayo - 
7 Gy/fraction and two insertions (either both during EBT and one 
during and one after EBT) - are of low grade and tolerable. An 
increased number of insertions to three insertions (two during 
EBT — second and third week - and one immediately after 
completion of EBT) and dose reduction to 6 Gy/fraction is 
suggested. This however is a higher dose of irradiation which 
may require slight reduction in the EBT dose to 45 Gy or 46 gy 
maximum. It is therefore recommended that HDR remote control 
afterloading treating continue in Bulawayo using three insertions 
each of 6 Gy given at weekly intervals, the first two during the 
course of EBT dose, keeping overall treatment time under seven 
weeks. Further work is indicated to assess the frequency of late 
complications of HDR and compare these with those of LDR.

37


7

ACKNOWLEDGEMENTS

I wish to acknowledge the invaluable assistant I got from the 
following people in conducting this study:

1) Dr C. J. Powel-Smith for supervising this study and 
providing me with valuable information which 
contributed significantly to the success of the study.


2) Prof W M C Martin for significantly necessary 
guidelines from the beginning to the end of the study, 
and going through the entire dissertation after 
completion, making useful suggestions.


3) Dr D Otim-Oyet for providing me with useful literature 
review.


4) Mr Siziya of the Department of Community Medicine of 
the University of Zimbabwe for his assistance in the 
statistical analysis of the results.


5) Mrs Swellingubo (the Nursing Sister at Mpilo Hospital 
Radiotherapy Centre) for the marvellous and cheerful 
manner with which she treated these patients.


6) Mrs Ndiweni (Bulawayo) and Mr Remission Marecha for 
their assistance in retrieving most of the data I 
gathered for the study.


7) Last, but not least, Mr Akinyemi 0. Adegbola who 
undertook the computer typing, setting, correction and 
final print out of the dissertion.




38


8) REFERENCES ' S




1. Akine et al Dose Equivalence for High-Dose-Rate to Low-




Dose-Rate Intracavitary Irradiation in the Treatment of 
Cancer of the Uterine Cervix, International Journal of 
Radiation Oncology/Biologv/Physics,Volume 19, No 6,

December 1990, 1511 - 1514.

2. Arai et al Radiation Treatment of Cervix Cancer Using High- 
Dose-Rate Remote Afterloading Intracavitary Irradiation, 
Japan Journal of Clinical Oncology Volume 25, pp 605 - 612, 
1979.


3. Arai T et al. Relationship Between Total Iso-effect Dose 
and Number of Fractions for the Treatment of Uterine 
Cervical Carcinoma by High-Dose-Rate Intracavitary 
Irradiation, in Bate,T. et al, High-Dose—Rate Afterloading 
in the Treatment of Cancer of the Uterus, London, British 
Journal Special Report 17, 1980, pp 89 - 92.


4. Bethesda, M.D, ICRU Report No. 38, Dose and Volume 
Specifications for Reporting Intracavitary Therapy in 
Gynaecology, International Commission on Radiation Units, 
1985, 4-5.




5 Burton, S. , Advantages of High-Dose-Rate Remote




Afterloading systems: Physics or Biology, Editorial,

International Journal of Radiation Oncology, Volume 20, pp 
1133 - 1135, 1990.

6 Choi et al, High-Dose—Rate Remote Afterloading of Carcinoma 
of the Cervix in Hong Kong: Unexpectedly High Complication 
Rate, Journal of Clinical Oncology (1992) 4: pp 186 - 191.




39


7 Cikaric, S., Radiation Therapy of Cervical Carcinoma Using 
Either HDR or LDR Afterloading: Comparison of 5-year 
Results and Complications, Strahlenther Oncology 82 
(Supplementary), 1988, pp 119 - 122.


8 Glaser, F.H, Comparison of HDR Afterloading with 1921 Ir 
versus Conventional Radium Therapy in Cervix Cancer: 5—year 
Results and Complications, Stahlenther Oncology 
82(Supplementary), 1988, pp 106 -113.


9 Himmerlmann, A. et al. Intracavitary Irradiation of 
Carcinoma of the Cervix stage IB and IIA: A Clinical 
Comparison between a Remote High-Dose—Rate Afterloading 
System and a Low-Dose-Rate Manual System, Acta Radiology 
Oncology 24, 1985, pp 139 - 144.


10 Ilic, S. et al, 5 - year with HDR Afterloading Cervix




Cancer: Dependence on Fractionation and Dose, Strahlenther 
Oncology 82 (Supplementary), 1988, pp 139 - 146).

11 Joslin, C.A.F., High Activity Source Afterloading in 
Gynaecologic Cancer and its Future Prospects, Endocuriether 
Hyperrtherapy,, Oncology 5, 1989, pp 69 - 82.


12 Kuplers, T. , High-Dose-Rate Intracavitary Irradiation — 
Results of Treatment, The Netherlands Nucleatron Trading 
BV, 1984, pp 169 - 175.


13 Lanciano et al. Astro Meeting Lecture on "Influence of 
Overall Time Carcinoma of the Cervix Radiotherapy - A 
Pattern of Care Study", International Journal of Radiation 
Oncology/biology/Physics, November 1992, Volume 25, pp 391 
- 397.




40


14 Ming Shai Chen M.D. et al High Dose Rate Afterloading




technique in the Radiation Treatment of Uterine Cervical 
Cancer: 339 Cases and 9 years Experience in Taiwan,

International Journal of Radiation Oncology, Biology and 
Physics, Volume 20, No 5 (May 1 1991) 915 — 919.

15 Mizae, J et al. Five-year Results and Complications with 
HDR Afterloading in Cervix Cancer Using a Linear 
Arrangement of Source, Strahlenther Oncology 82 
(Supplementary), 1988, pp 114 -126


16 Newman, H. et al. Treatment of Cancer of the Cervix with a 
High-Dose-Rate Afterloading Machine (the Cathetron), 
International Journal of Radiation Oncology/Biology/Physics 
9, 1983, 931 - 937.


17 Orton, C.G. HDR: Forget not "Time" and "Distance",




Editorial, International Journal of Radiation Oncology — 
Biology - Physics, Volume 20, No 5, May 1 1991 - pages 1131 
- 1132.

18 Perez and Brady, Principles and Practice of Radiation 
Oncology -Sequelae of Treatment in Carcinoma of Uterine 
Cervix, pp 946 - 949.


19 Roman et al, High-Dose-Rate Afterloading Intracavitary 
Therapy in Carcinoma of the Cervix, International of 
Radiation Oncology/Biology/Physics, Volume 20, No. 5 May 1 
1991, pp 921 - 926.


20 Sato, S. et al. Therapeutic Results Using High-Dose-Rate 
Intracavitary Irradiation in Cases of Cervical Cancer, 
Gynaecological Oncology 19, 1984, pp 143 - 147.




41


21 Shiqematsu et al. Treatment of Carcinoma of the Uterine 
Cervix by Remotely Controlled AfterloAding itracavitary 
Radiotherapy with High Dose Rate: A comparative Study with 
a Low—Dose—Rate System, International Journal of Radiation 
Oncology/Biology/Physics 9, 1983, pp 351 - 356.


22 Taina, E. , Complications Following High and Low-Dose-Rate 
Intracavitary Radiotherapy for I-II Cervical Carcinoma: A 
Comparison of Remotely Afterloading 60Co(Catherton and 
Conventional Radium Therapy), Acta Obstetrics and 
Gynaecology, Scandinavia 103, 1981, pp 39 - 49.


23 Teshima, T. et al, High-Dose-Rate Intracavitary Therapy for 
Carcinoma of the Uterine Cervix: 1 General Figures of 
Survival and Complication, International Journal of 
Radiation Oncology/Biology/Physics 13, 1987, pp 1035 -1041.


24 Utley, J.F et al, High-Dose-Rate Afterloading Brachytherapy




in Carcinoma of the Uterine Cervix, International Journal 
of Radiation Oncology/Biology/Physics 10, 1984, pp 2259 -

2263.

25 Vahrson, G et al, 5-year Results in HDR Afterloading in




Cervix Cancer: Dependence on Fractionation and Dose,

Stahlenther Oncology 82 (Supplementary), 1988, pp 139 - 
146.

2 6 Varhson, G. et al. History of HDR Afterloading

Brachytherapy, Stahlenther Oncology 82 (Supplementary), 
1988, pp 2-6.

27 World Health Organization, Optimization of Radiotherapy, 
report of a WHO meeting of Investigators, Technical Report 
Series NO 644, WHO, Geneva, 1980, pp 24 - 29.

42