""""'~~~~~~~~~~~ ; .JK SCIE 'CEr lJ',

IORIGINAL ARTICLE IComparative Evaluation of Concurrent Chemotherapy &

Hyperfractionated radiotherapy Versus ConventionalRadiotherapy alone in the Treatment of Locally Advanced

Carcinoma Cervix-A Prospective Randomised StudyChander Mohan Sehgal, Firuza D. Patel, Sushmita Ghoshal, Than S. Kehwar,

Rakesh Raman Sharma, Rakesh Kapoor', Suresh C. Sharma.

Abstract

The aim of this study was to determine whether the addition of concurrent cisplalin andhyperfractionation in external pelvic radiotherapy improves local control and survival in paticntswith locally advanced carcinoma cervix as compared to treatment with conventional radiolherap.Jalonc. The morbidity oftwo treatment protocols was also compared. Sixty patients of ne" I) diagnosedsquamous cell carcinoma cervix, FIGO stage 118 and III were randomised into the following twotreatment protocols: Group A (study group): Cisplatin30 mg/m2 "eekly x 5 courses and e"lernalbeam pelvic radiotherapy 50 Gy/33#4.5 weeks with hyperfractionation in first and f01ll1h weel,s.Group B (control group) : External beam pelvic radiotherapy 46 Gy/23#/4.5 weeks. Patients inboth the groups\vere then treated with intracavitary brachytherapy by LDR/MDR Selectron and adose of28 Gy was delivered to point A. The patienls who were not suitable for intracavitary trcatmell1were treated by supplementary external beam pelvic radiotherapy 20 Gy/ 10#/2" ceks. The actuariallocal control at 4 years was 60% in group A and 42% in Group 8 9p<0.05). The aCluarial diseasefree survival at 4 years was 52% in Group A and 35% in Group 8 (p<0.05). Only gl'ade I acute anddelayed haematological toxicity and grade I nausea and vomiting as acute toxicity "ere significantl)higher for Group A patients as compared to Group 8. Concomitant chemotherapy withhyperfraclionated radiotherapy is well tolerated and seems to offer potential benefit for imprOl ingthe locoregional control in locally advanced carcinoma of cervix.

Key Words

Carcinoma Cervix: Ilyperfractionated Radiotherapy plus Concurrent Chemotherapy: ConvcntionalRadiotherapy.

Introduction

Carcinoma cervix constitutes about 40% ofall female

malignancies and 85% of all gynaecological

mal ignancies (I). The most common histological type is

the squamous cell carcinoma which comprises about 95%

of all cases (2). The local spread of the disease is the

1110St common and important, although para-aortic and

distant metastases are not unknown. At Qurcentre.l11ore

than 70% of cases present in FIGO slage liB. III. The

From the DCllttS. of Radiotherapy and Oncology, Postgraduate Institute of Medical Education and Research. Chandigarh. India.

Correspondence to: Dr. Rak~sh Kapoor. Assistant Professor. Department or RadiOlherapy PGIMER. Chandigarh - 160012. Indi"

32 Vol. -I No. I. JanU<lr~-rvlarch 10{j~

... ~.-JK SCIENCE

33

These patients were randomised into two groups A

and B.

Our clinical trial is an attempt to exploit the potential

i5'eWeft\'()(6'6\',1'e6\\"6lW,itil\\\l.s,\I51'~iS\\\151'Jl91 ,\V,i,\I! ,so';'?",,1&,t,i,'!and intermittent hyperfractionation in patients with

locally advanced carcinoma cervix.

Materials and Methods

2. Methodology

With hyperfractionated external radiotherapy. it is

possible to increase the total tumour dose and thus

improve the locoregional control but with reduced acute

toxicity and similar late complications.

Study Group A

Between September 1996 and Febrauary 1998. 60

patients of newly diagnosed carcinoma cervix v.ere

enrolled in th is study. EI igi bi! ity criteria included biopsy

proven squamous cell carcinoma of cervix, FIGO stage

liB or III, age less than 70 years, Karnofsky performance

score is more than 70, no history ofuncontrolled chronic

disease e.g. ischaemic heart disease, hypertension,

diabetes mellitus. A complete blood count, liver and renal

chemistries, blood sugar test, a chest X-ray. intravenous

pyelogram and cystoscopy 'were mandatory for all

patients whereas ultrasonography and computed

tomography were optional investigations.

I. rretreatrpent Evaluatiou

Chemotherapy: The patients in study group were

planned for treatment with concurrent chemoradiation.

Cisplatin "as administered weekly before radiotherapy

in a dose oDO mg/m2. starting on first day of treatment

and total of 5 courses were planned. All patients had

repeat complete blood counts. blood urea and serum

creatinine before every course of chemotherapy.

Radiation: External radial ion therapy in study group

included intermittent hyperfractionation in first and

fourth weeks:

~ \0. I. Januar) -~larch 2002

e'lmeni of Ihese cases is radiotherapy administered to

""" wleranee levcl. Despite all advances in the

manag.ement of cervica\ carcinoma. results of treatment

w\>l1ced stages remain sub-optimal. With radical

dial ion Iherapy alone. 5 year survival rates for locally

lanced ca{i/lovm.~ ...en.i. :v.ary .ill .r1\I.'2-e pf 50 to 76%

;.1\. The siles of failure in these pat ients are pelvis only

n12-18%. pelvis and distant metastases in 11-27% and

IIlanl metastases in 15-20% (5). Various alternate

erapeutic modalilies evolved to improve local control

re h) perbaric O\y gen. neutron beam teletherapy

rach~lherap: and post-radiation surgical extirpation.

Although Ihese mcthods may improve local control, they

!>'either impractical in a typical clinical setting or have a

igh rate of morbid ity (6- 7).

ClSplniin is one of the most active drugs in carcinoma

en i\ and is a documented radiation potentiator (8).

Furthermore. if cisplatin could be administered in

h"apeutic doses. it is hypothesised that micrometastases

nd CIrculating tumour cells could also be eliminated

thus potentially cOlltrolling distant disease as well.

Recently, concomitant chemotherapy and

radit'lherapy has become the focus of interest in locally

advanced carcinoma cervix. Concurrent chemotherapy

nhioits the repair of sublethal damage from radiation.

)nchroniscs cells to a particularly radiosensitive phase

flhecell eyclc and is cytotoxic in vitro (9). Concurrent

crapy produces no delay in the start of definitive

rradiation. The entirc treatment Course is not prolonged

nd the effects of tumour prol iferation are therefore

inimised. The pOlential interaction of concurrent

hemolherapy \\ ith radiation treatment may lead to

ncreased tumour cell kill.

The COI1\ en' ional fractionation for radiation therapy

becadsc ofempiricism and con veil ience, has evolved into

fi,e fractions per week. However, with the aim of

ncreasing the therapcutic differential between the

tumour and the late respond ing normal tissues, a nlim bel'

f olher fractionation schedules have been proposed.

~ ,JK SCIE CE------------'Ih-<

These patients received conventional external

radiation therapy:

Radiotherapy techniq ue

All patients received external radiation to whole pelvis

on a Cobalt-60 tcletherapy unit or a 6-MV linear

accelerator lIsing anterior and posterior opposing fields

with superior bordcr at LS-S I vertebral junction and

inferior bordcr at lower margin of obturator foramina.

This was followcd by a single intracavitary treatment on

the LORIMOR Selectronmachine to a dose of28 Gy to

point A at dose ratc of 180± I0 cGy/houL The patients

\\ho were ullsuitable for intracavitary application were

treated by supplementary external radiation to whole

pelvis to a dose of20 Gy/lO#/2 weeks.

Evaluatioll oftoxicity

Treatment induced toxicity if any was documented

throughout treatment and follow up using WHO grading

system for haematological. renal toxicities and nausea!

vomiting. Franco-Italian complication repOlting glossary

way used for rectal, urologic and vaginal complications( 10).

Follow-up and Asscssmcnt

After the completion of treatment, the patients were

examined e\ eJ) six to eight" eeks for one year and every

threc months thereafter. Follow up period ranged from

10-42 months. At each follow up, patients were clinically

evaluated for locoregional control ofdisease. The tumour

control or complete response was defined as the complete

disappearancc of visible and palpable disease. Local

100 cGy/fraction. 1 fraclion/da)

(5 dnys/wcek)

120 cGy/fraction. 2 fractions/day

(5 daysh\t:ek) \\ ith 6 hours gap

be{wt:en 2 fractions

Where,

BED ~ md[ I + (~)d { I+H(8)} ]

. (2) [ 8 I (1-8")\]H (8) = ~n 1=8 \m - i=ii J

Calculation ofBiological Effective Dose (BED)

Since intracavitary pan of treatment \\as similar for

both groups with respect to dose ratc as well a; tOial

dose to point A. BED for only the external radiotherapl

pa,1s of the treatment in both Ihe groups was calculated

using incompletc repair L.Q. model (II) :

rai lure was recorded in the event of a recurrent tumour

or if the primary tumour never completcl) disappeared.

On the suspicion ofall) local recurrence. cen,ical smear

was taken for cytology and correlated clinicall). Palicl1h

were also evaluated for distant failurc which included

para-aortic node failures. To evaluate the distant

metastasis, relevant investigation were done as indicated.

8 = c-Il'

X = time interval between closely spaced fractions11 = repair constant of sublethal damage (1.4 h-I 1<"

acute effects 0.46 h-I lor late effects)111 = number of fractions per da)d = dose per fraction

a/~ = tissue specific parameter (a!b values for varioustissues were chosen as commonl) used in Iheliterature: for acute effects and cervi:\. tulllOur.

a/~ - lOGy and for late effects, a/~ = 3 G)).

Then, the expected difference bctween the tllO groups

was calculated using simple Chi-square mcthod:

Statistical Analysis

The primary end points II ere pelvic disease control.

distant failure, disease free survival and treatment relatcd

morbidity. Survival was ca Iculated from the date ofcntlj

into the study to the date of death or the last folloll up.

The actuarial values of local control and disease frce

survival were evaluatcdusing the life table method. The

p value estimated are those of a two-tailed test and Ihe

significance level was chosen to be 50/0.

4.5 weeks

(5 days/week)

4.5 '\ceks

J fraction/day

Duration

Duration

2nd. 3rt! &

5th \\ceks

COlllrol GrollP B

rota! dose

Fractionation 200 c

Gy/lractioll.

Fractionation 1st & 4th

Total dose

Vol. 4 No. I. Januar) ·Man.:h 2()()2

\'~JK SCIENCE----------~-......................._---------Observations and Results

C!utrflclerislics ,,(patienls : The majority of patients

lIere in the fourth and fifth decades. The stage wise

distribution in both the groups was also comparable. In

,roup A. 6 patients were in stage 11-8 and 24 patients in

tage 1118. In group 13.4 patients were in stage 118 and

:6 patients in stage 1118.

Survival: Most of the failures took place in first t\\O

years in both the groups. The four years actuarial local

control rate was 60% for the study group compared to

42% for the control group with p-value <0.05 (Fig. I).

The actuarial four years disease free survival \\as 520/0

for the study group compared to 35% for the control

group with p-value <0.05 (Fig. 2).

Fig. 1: Actuarial pelvic disease control rateTreillmenl delays/misses: Four patients in study

~rollp had delay in completing external radiotherapy

calise of acute toxicities in form of diarrhoea (I

tienl). grade III vomiting (2 patients) and skin reactions

'. patient). Ilowever. the delay was never more than 10%

,ftheoverall scheduled duration. In the study group 33%

010) patients could not receive all the five courses of

emotherap) as planned because of haematological

\icit). (Table I).

ecoU

~o--' .

•

•

•

•

~ Study group... Control group

•• •

Table 1

Treatment Delays and/or Misses

Study group

(n~30)

Conlrol group

(n=30)

.l--.. ~

• ., II U • M q _

\lolllhs :InCl' diagllosi~

• )1:1;1\ III complcllllg c\lernalradl:lllOIl

4 (13.3%) rig. 2: Actu:lI'ial discllse-free sUI'vival rale

•• 'I( "' l\(l\ Pl)~Slhk 0 3 (10%)

• \ llhcr 01 SiS courses 20 (67%) .. A

on olhcrap\ courses 4,:; courses~ ) (33~'o)

1't\:CI\o:d 3'5 courses

, " \ - Inlrlll;:l\ liar)' application

.. K\· Not arrlicabk

TllmOllr COillrol : In the study group 70% (21/30) of

Ilents and 47% (14 /30) in control group were clinically

.ease free at last follo\\-up. (Table 2).

Table 2

Disease Control and Patterns of Failure

m N

>2~

~ "'"~'" N~

rn

'"~u •<f'm •.~~

13« "

--+- Study group.A Control group

•

lanuary-~larch 2002

Months after diagnOSIs

35

Adverse Effects: There were no trealmenl related

deaths in the study group. The types and frequencies of

adverse effects are shown in Table 3.

Stud) Control (n~30)

23(76',) 18(60',)

5 9

2 3

2 4

21 (70%) 14(47%)

:a..~ status

I Pthic + distant rajlun:

• <am failure alone

t ;;rail control

• ,. (Control

,______________J::JK SCIENCE

Table 3

ADVERSE AFFECTS

Concomitant Chemmherap) and lIyperfractionated Radiotherap) (n-3D) Con\entional Radiothcrap) alone (n -30)

Grade I Grade II Grade III (jrad~ IV IOlalGrade I Grade II Grade III Grade IV Total

ACUTE TOXICITYIlematological 10 4 3 0 17(56.6~")

Renlal 2 0 0 0 2{6.6%}

NauseaIVomiting 8 6 2 0 16(53%)

Bowel 5 2 0 0 7(23%)

Skin 0 3 I 0 4( 13%)

TOlal ~\ents 46

DELAYED TOXICITY

Ilcmatological 7 3 I I 12{42%)

Rt.:l1al 2 0 0 0 2(6.6%)

Rectal 2 2 I 0 5(16.6"0)

Urinal) Bladder 0 0 I 0 1(3.3%)

Vaginal complicalions 2 0 0 0 2(6.6%)

Total c..-cnts 22

oo

2

3

5

·4

62

2

3

2

oI

o

ooo

o

o

6(20".)

6(20%)

3( IO~ol

15 p<O.1l5

2(6.6%)

6(20"")

16 p>0.05

Biological Effective Dose (Bed)-Comparison withObserved Results

(_) ·MlllUS sign denotes lesser incidence of the particular eftcct in the studygroup compared to the control group

BED COlllparison : In Table 4, we have compared

the effect of hyperfractionation schedule versus

convenlional external radiotherapy schedule.

Tabke 4

Discussion

Hislorically. locally advanced carcinoma ofcervix hasbeen Heated \\ ith radiotherapy alone. Despite

improvements in radiation equipment and techniques,

in approximately two thirds of the cases, relapse andprogression occurs within the area that was irradiated

(3, 4). So. it is logical 10 combine radiotherapy with

another antineoplastic modality i.e. chemotherapy in an

attempt to increase tumour control. This would enhanceIhe effect of radiotherapy by additive cell kill.

radiosensitisation or both. Cisplatin is believed 10

augment the effects of radiation by inhibiting the repairof radiation-induced sublelhal damage and by sensitising

the hypoxic cells to radiation and because of its cytoloxic

effects, the drug reduces the bulk oflumours. \\ hich leads

to the reoxygenation of the lumour and entry ofthe cells

inlo a radiation sensilive phase of the cell cycle. Brillen

et al found that radiotherapy and concomitant cisplalinchemotherapy increased the rates of death of these

tumour cells (12).

Hyperfractionated external radiotherapy offers

potential benefit of improving locoregional conlrol while

keeping same late morbidity. There are two main

concepts regarding the repopulation oflhe tumour cells

while on radiotherapy. According to Withers et al. the

tumour cells proliferation accelerates around Ihe fourthweeks after beginning radiotherapy (13). Other including

Fowler assume that proliferation speeds up as soon astumour shrinks which can be "' soon as two to ·three

fraclions have been delivered (14). Taking into account

both the above said concepls, an inlermittenl

hyperfractionation external radiotherapy schedule fOrlhe

a b BED Expected Obsened(G») (btemal R l.) difference difference

1Il results in resultsStud) (Gy) Study (Gy)

10 58,08 55.20 5,22% 16%

-J..!' (R)

3 7754 76.67 1.13% 3.3% (8)·20%· (V)

Tissue

rlllllour(Cervi,)Lntel:OcetsRectum (R)Bladdt.;r (B)

Vagina (V)

Vol. 4 No. I. January-March 2(Ml2

)'~JK SCIENCE[-----------Q,

37

radiation schedule in four patients because of the acute

toxicities in the combined modality group. Grade I-II

haematological toxicity "as the main toxicity in our

chemoradiation group but overall the toxicity as

acceptable and well tolerated by the patients.

This study differed from previous chemoradiation

studies in that the external radiotherapy schedule was

also modified with an intermittent hyperfractionation.

The experience with hyperfractionated external

radiotherapy in carcinoma cervix is limited. Cherian

Varghese ef. al. used a continuous hyperfractionation

programme delivering a total dose of60 Gy/50 fractions!

5 weeks to the whole pelvis. followed by single

intracavitary treatment and reported enhanced acute

normal tissue reactions whereas no significantdilTerence

"as noted in llImour control (23). In another study b)

Sergio ef. al. 'A here only external pelvic radiotherapy 72

Gy/60 fractions/6 weeks was used, a statistically higher

incidence of acute bowel toxicity was noticed \\ ithout

any advantage in tumour control (24). The onl} previous

chemoradiation study with hyperfractionation in external

radiotherapy is b) Heaton ct al "ho used cisplatin, 5-1 Uand hyperfractionated week-on/\Veck-off external

radiotherapy in 29 patients and in this study. pelvic

control rate was 58% and five years disease free sUrl'i\ al

\\as 34% with an acceptable complication rate (25).

Various randomised trials of chemoradiation in

cerl' ical cancer have been reported which strengthen the

body ofevidence supp0l1ing the use ofcombined therapy

in women with advanced cervical cancer. Rose ct al

performed a randomised trial in patients \Vith locally

advanced cervical cancer \\ ith chcll1oradiation lIsing

three different concurrent chemotherapy rcgimcns - (I)

cisplatin alone, (2) cisplatin, fluorouracil and

hydroxyurea, (3) hydroxyurea alone. The rclative risks

of progression ofdisease or death were 0.57 in group I

and 0.55 in group 2 as compared with group 3 (p<O.OO I

for both comparisons) (26).

In a phase 3 study by Morris ef. al. among patients

with stage IB to IVA, the cumulative rates of survival at

five years were 73% among patients treated with

I ~ \10. l. January-March 2002

ud) group was designed. This intended to increase the

olaltulllour dose while expecting same late effects as

ith conventional radiotherapy. No compromise was

made on the dose of intracavitary part oftreatmenl.

Despite the critic ism of in itia Ichemoradiation stud ies

carcinoma cervix with hydroxyurea (15), the results

fthese studies and those of trials assessing concurrent

.hemorndialion for other tumours stimulated further

udies inlocall} advanced cervical cancer with various

rugs such as fluorouracil, cisplatill , mitomycin.

(Jrboplatin and pacl itaxe I( 16-1 9). Out ofall these drugs,

. splatin is the most active as a single agent with response

te as high as 50% (20). The effect of radiotherapy with

,ollcomitanl treatment with cisplatin alone has been

'udied in several phase 2 trials (21 ,22). In a small study

.45 patients with cervical cancer by Choo ef. al.

diotherapy and chemotherapy with cisplatin (25 mg/

2 per week) increased the rate of local control by 35

,rcenl «<0.025) for comparison with radiotherapy

,lone) but there" as no long term improvement in

>Urli"al (21).

The results in the present study sho\\ that concomitant

,lSplatin chemotherapy with hyperfractionation in the

\ternal radiotherapy was more effective for locally

d\anced ccnical cancer than conventional radical

"diotherapy alone and reduced both local and distant

ecurrenees leading to significantly higher actuarial local

ntfol and disease free survival rates (Figs. I and 2).

\Ithough chemotherapy increased the hematologic

0\icit). this effect was reversible and the incidence of

• tal urologic late side effects was similar in the t\\O

~atment groups.

The toxicity of various chemoradiation studies has

aIsobeen rep0l1ed in detail and the most common adverse

effect encountered is grade !-II haematological toxicity

or nausea/vomiting (20). In a series by Fields ef. at.edian of four cisplatin cycles (out of planned five

~ urses) were administered with a range of two to five

courses (22). In our series, 67% (20/30) patients received

lithe five courses, with a range of three to five courses.

\Iso.there "as a minimal delay in completing external

j ~JK SCIENCE

------------~-combination ofchemotherapy and pelvic radiation versus

58% among patiellls treated with pelvic and paraaortic

radiation (p=0.004). The cumulative rates ofdisease free

survival a1 five years wcre 67% in the combined therapy

group compared to 40% among patients in the

radiotherapy alone groups (p<O.OO I). The seriousness

ofside enecls \\as similar in the two groups. with a higher

rate of reversible hematologic FFects in the

chel11oradiation group (27).

References }

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3. Ilorlot Jc. Pigll~U' J. POllrquicr H ef. 01. RadiOlherap)alon~ in carcinoma or intact ut~rine cervix according 10

GI [ Fktcher guidelines: A Fr~nch co-operative stud) of1383 cases. Inl J !?adiol Oneol Bioi Phys 1988: 14 : 605-11.

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13. Withers IIR. Ta) lor JMG. Maciejewski B. The hazard ofacceleralcd tUl1lour colongen repopulation duringradiolhcrap). Aela Oneologica 1988 : 276 : 131-46.

38

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potentiator in carcinoma or the uterine cervix. A randomiSL'ddouble blind study. AmerJ Obslel GYI/aeco/1983 : 174 803418

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.Im J Clin Oneol Cancer ('fin 7i-tals 1989: 12 (6) 461-466

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in advanced cervical cancer. Gynaf'!col Neol 1989 : 35159-163.

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G",'naecoIOncol 1996 : 61 : 416-22.

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advanced carcinoma or the utefille cervi\: A prdiminaf)report. III/ J Nadia, Oneol Bioi Phys 1992 ; 23 : 393-96.

24. Faria SL. Ferrigno F. II) pcrfractionalcd c\tcrnal radiation

thcrapy in stage 11113 carcinoma of uterine ccni\ aprospective pilot stud~. 1m J Radial Oneol Bioi Phys 1997

38: 137·142.

25. Ikaton O. Yordan E. Reddy S. el al. Treatment of 19patients with bulky squamous cell carcinoma of the em i\

with simultaneous cisplatin. 5·fiuorouraeil. and split·

course hyperfractionatecl radiotherapy. GYlfoec:olDl/col1990: 38 : 323-327.

26. Rose PG. Oundy B . Watkins EB el. 01. Concum:nt cl~platin"

based radiotherap) and chemotherapy for locall} ad\anccrlcervical cancer. X Engl J .\Ied 19<;9 : 340: 11-14-53.

27. Morris M. Eifel PL Lu J el. 01. Pelvic radiation \\lthconcurrent chemotherapy compared with pelvic andparaaonic radiation for high-risk cervical cancer. \ Eng JMed 1999: 340: 1137-43.

Vol. 4 No. I. JaouaT) -March 2002