clinical trials in cervical cancer cancer institute (wia) experience

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

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Grade

1 C

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Grade

2 C

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Grade

1 P

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Grade

2 P

rocti

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Grade

3 P

rocti

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Inte

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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