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CLINICAL TRIALSIN
CERVICAL CANCER
Cancer Institute (WIA) experience
Incidence
• Incidence is 24.8 per 100,000 female population - MMTR data
• Frequency at the Institute is 37.9%
• Majority of these patients (71.4%) present with advanced stages of disease
Treatment
• Surgery & radiation therapy provide excellent 5-year & 10-year survival rates for early cancers
• 5-year survival rate for locally advanced carcinoma ranges from 65% (FIGO stage II B) to 5% (FIGO stage IV A)
Radiotherapy
• Radiation fails to control 35-90% of disease with 66% of the failures occurring in the pelvis
• Failures attributed to metastatic disease outside the radiation field & large central tumor volumes resistant to local therapies
Clinical trials
• The limitation of radiotherapy led us on the long trail of prospective concurrent randomized placebo-controlled clinical trials, since 1960, using a variety of chemical sensitizers, cytotoxic drugs & physical agent like hyperthermia to potentiate the radiotherapeutic effect
• Randomization & evaluation were blind in these trials
SPI TRIAL
SPI trial
• Histologically confirmed squamous cell carcinoma
• Stage III cervical cancers
• Satisfactory general health
• Patients with gross anemia, cardiac decompensation, or renal or hepatic dysfunction were excluded
SPI trial• SPI & SPG are podophyllin derivatives• Dose of SPI was 400 mg in 25 ml of
distilled water, injected IV slowly over 1-2 min 25-30 min before RT
• Controls received 25 ml of distilled water• CBT was administered to a total tumor
dose of 65 Gy in about 6-7 weeks on a 5 days a week schedule
• Study patients received SPG capsules 400 mg per day orally for eight weeks after the end of RT
SPI TRIAL
63 61.974
31
0
25
50
75
100
No: of Patients %CR
Study
Controls
p = 0.0005
Cancer 20, 5, 822-825, 1967
No
: / %
CR
CISPLATIN INCERVICALCANCER
4-arm trial
• The objectives of the trial were to study the differential response and survival in the different arms and also to study the cost benefit in relation to the different arms
4-arm trial
I RT ONLY
II RT + BLM + CDDP (BP)
IIIRT + BLM + CDDP + Iphosphamide (BIP)
IV RT + BLM + CDDP + CTX (BCP)
4-arm trial
• Histologically confirmed sq. cell carcinoma
• Stages II B & III B
• No previous treatment
• Satisfacory PS
• Age < 60 years
4-arm trial
• No hydronephrosis / nonfunctioning kidney
• Compensated IHD, Controlled DM & HT – No bar
• Satisfactory renal, hepatic & pul. functions
• Br. Asthma & emphysema – relative contraindications
• Informed consent - Mandatory
4-arm trial
Week 1 I cycle CT / Placebo
Week 2Whole pelvic 6 MV x-ray therapy started
Day 21II cycle CT (No RT during this period)
At 40 GyEvaluation + ICA / EBRT to 65 Gy
8 weeks after ET
First FU evaluation
4-arm trial – arm - IIBLM 30 mg IV 24 h infusion Day 1
CDDP 50 mg / m2 IV 24 h infusion (in 2 divided doses)
Days 2 & 3
4-arm trial – arm - IIIBLM 30 mg IV 24 h infusion Day 1
CDDP 50 mg / m2 IV 24 h infusion (in 2 divided doses)
Days 2 & 3
Iphos 5 gm IV 24 h infusion Mesna 3 gm / m2
Day 4
Day 4 & 5
4-arm trial – arm - IVBLM 30 mg IV 24 h infusion Day 1
CDDP 50 mg / m2 IV 24 h infusion (in 2 divided doses)
Days 2 & 3
CTX 2.5 gm over 5 days IV bolus (500 mg / day)
Day 1 - 5
4 ARM TRIAL - 5 YEAR NED
64.676 70.5 78.6
41.354.3 46.555
0
20
40
60
80
100
RT ONLY RT+ BP RT + BIP RT + BEP
II B III B
p = N.S.
% 5
YR
NE
D
Trials world wide
• Randomized trials
• GOG trial
• Keys et al – 1999
• Pearcey et al – 2002
• More effective regimens
CLINICAL TRIAL OFORAL ETOPOSIDE & BLM
WITH RTIN LOCALLY ADVANCED
CARCINOMA OF THE UTERINE CERVIX
Objectives
• To determine response rates, duration of response & survival following twice daily, long term, low dose oral Etoposide and 5-week, low dose BLM with concomitant RT for patients with locally advanced carcinoma of the uterine cervix
• To observe the toxicity following this
BLM - Eto trial
• The eligibility criteria was the same as the previous trial
• Stage – III.B• 2-arm trial• 75 patients in each arm• Study arm - RT with BLM &
Etoposide• Control arm - RT with placebo
BLM-Eto trialOral etoposide• 25 mg twice a day • Days 1-14 of a 21-day cycle• 6 cycles
Inj. Bleomycin • 5 mg / IV daily • Days 1-5 / week• 5 weeks
BLM-Eto trial
• 6 MV X-ray therapy - 180 cGy / #, 5 # / week to a dose of 50.4 Gy / 5½ weeks
• Followed by ICA, delivering a dose of 5 Gy each, 5 applications, twice weekly
BLM-ETOPOSIDE TRIAL
74 73 76.7
56.746.6
89.2
0
20
40
60
80
100
RT+BLM+ETO RT ONLY
No: of Patients % CR %5 Year NED
For CR, p <0.045 (Mantel Haenszel corrected)
No
: / %
CR
/ %N
ED
Toxicities
• Upper GI – all patients - 74
• Alopecia – all patients – 74
• Pigmentation – 55 – 77%
• Dermatitis -32 – 46%
• Skin reaction – 12 – 16%
• Neutropenia – Gr – II – 18%
HYDROXYUREAAS
RADIATION SENSITIZER
HU trial
• 2-arm study
• Only stage III B
• Study arm - HU 80 mg / kg body weight per oral two hours prior to RT every Monday & Thursday
• Control arm - Placebo tablets at the same time
• 50 Gy to whole pelvis followed by ICA 23 Gy
HYDROXY UREA TRIAL
100 100
74 75
48 46
0
20
40
60
80
100
RT + HU RT ONLY
No: of Patients % CR %5 Year NED
p = NS
No
: / %
CR
/ %N
ED
REGIONAL HYPERTHERMIACOMBINED WITH
RADIATIONIN
LOCALLY ADVANCED CERVICAL CANCERS
HT trial• 2 arm trial, • 50 patients in each arm• Obese patients with more than 3cm
anterior abdominal wall fat thickness were excluded
• Patients with pacemakers and metal objects within the treatment area were also excluded
HT trial
• HT immediately following RT
• Once a week (Tues)
• 420 C - 430C
• Maintained for one hour
• BP & pulse rate monitored
HYPERTHERMIA TRIAL
50 50
827474
66
0
20
40
60
80
100
RT + HT RT ONLY
No: of Patients % CR % 3 Year NED
Int.J.Radiation Oncology Biol.physics 2005;61
No:
/ %
CR
/ %N
ED
RANDOMISED TRIAL ON COMPARISON OF LDR AND
HDR ICA IN CARCINOMA CERVIX
LDR-HDR trial
• To compare the efficacy of HDR vs. LDR intracavitary brachytherapy
• to know the number of #s and dose / # that should be given at HDR, to produce the same biological effects as LDR
LDR-HDR trial
• Criteria of eligibility was the same as other trials
• Stages II B & III B2 arm trial• Arm – 1 – ext radiation + LDR 23GyDose rate at Point A 160-180cGy / Hr• Arm – 2 – ext radiation + 3 HDR
15Gy Dose rate at Point A 36-48 Gy / Hr
3-yr survival NED
StageNED rate
LDR HDR
II B64 / 94 (68.1%)
60 / 88 (68.2%)
III B44 / 82 (53.7%)
44 / 73 (60.3%)
Total108 / 176 (61.4%)
104 / 161 (64.6%)
* Patients lost to FU taken as failures
LDR VS HDR TRIAL
68.1
53.7
68.260.3
0
20
40
60
80
100
II B III B
LDR
HDR
% 3
YR
NE
D
p= NS
HDR VS LDR - MORBIDITY
02468
101214
Grade
1 C
ystiti
s
Grade
2 C
ystiti
s
Grade
1 P
rocti
tis
Grade
2 P
rocti
tis
Grade
3 P
rocti
tis
Inte
stina
l Obs
truct
ion
LDR
HDR
Nos
:
Future trials
• More effective chemotherapy regimens.
• Omit cisplatin.
Future Trials
• Non-myelosuppressive biologic response modifiers
• Epidermal growth factor modulators
• Vascular endothelial growth factor modulators
• Cyclooxygenase 2 inhibitors
• Targeting hypoxic cells
THANK YOU