CLINICAL TRIALS IN 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 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

p = Cancer 20, 5, , 1967 No: / %CR

CISPLATIN IN CERVICALCANCER

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 IRT ONLY IIRT + BLM + CDDP (BP) III RT + BLM + CDDP + Iphosphamide (BIP) IVRT + 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 1I cycle CT / Placebo Week 2 Whole pelvic 6 MV x-ray therapy started Day 21 II cycle CT (No RT during this period) At 40 Gy Evaluation + ICA / EBRT to 65 Gy 8 weeks after ET First FU evaluation

4-arm trial – arm - II BLM30 mg IV 24 h infusionDay 1 CDDP50 mg / m 2 IV 24 h infusion (in 2 divided doses) Days 2 & 3

4-arm trial – arm - III BLM30 mg IV 24 h infusionDay 1 CDDP50 mg / m 2 IV 24 h infusion (in 2 divided doses) Days 2 & 3 Iphos5 gm IV 24 h infusion Mesna 3 gm / m 2 Day 4 Day 4 & 5

4-arm trial – arm - IV BLM30 mg IV 24 h infusionDay 1 CDDP50 mg / m 2 IV 24 h infusion (in 2 divided doses) Days 2 & 3 CTX2.5 gm over 5 days IV bolus (500 mg / day) Day 1 - 5

p = N.S. % 5 YR NED

Trials world wide Randomized trials GOG trial Keys et al – 1999 Pearcey et al – 2002 More effective regimens

CLINICAL TRIAL OF ORAL ETOPOSIDE & BLM WITH RT IN 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 trial Oral 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 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

For CR, p <0.045 (Mantel Haenszel corrected) No: / %CR/ %NED

Toxicities Upper GI – all patients - 74 Alopecia – all patients – 74 Pigmentation – 55 – 77% Dermatitis -32 – 46% Skin reaction – 12 – 16% Neutropenia – Gr – II – 18%

HYDROXYUREA AS 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

p = NS No: / %CR/ %NED

REGIONAL HYPERTHERMIA COMBINED WITH RADIATION IN 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) 42 0 C C Maintained for one hour BP & pulse rate monitored

Int.J.Radiation Oncology Biol.physics 2005;61 No: / %CR/ %NED

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 B 2 arm trial Arm – 1 – ext radiation + LDR 23Gy Dose rate at Point A cGy / Hr Arm – 2 – ext radiation + 3 HDR 15Gy Dose rate at Point A Gy / Hr

3-yr survival NED Stage NED rate LDRHDR II B 64 / 94 (68.1%) 60 / 88 (68.2%) III B 44 / 82 (53.7%) 44 / 73 (60.3%) Total 108 / 176 (61.4%) 104 / 161 (64.6%) * Patients lost to FU taken as failures

% 3 YR NED p= NS

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

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