CLINICAL TRIALS IN CERVICAL CANCER Cancer Institute (WIA) experience

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CLINICAL TRIALSINCERVICAL CANCERCancer
Institute (WIA) experience
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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

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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)

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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

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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

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SPI TRIAL
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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

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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

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No / CR
p 0.0005 Cancer 20, 5, 822-825, 1967
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CISPLATIN INCERVICALCANCER
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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

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4-arm trial
I RT ONLY
II RT BLM CDDP (BP)
III RT BLM CDDP Iphosphamide (BIP)
IV RT BLM CDDP CTX (BCP)
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4-arm trial

• Histologically confirmed sq. cell carcinoma
• Stages II B III B
• No previous treatment
• Satisfacory PS
• Age lt 60 years

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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

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4-arm trial
Week 1 I 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
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4-arm trial arm - II
BLM 30 mg IV 24 h infusion Day 1
CDDP 50 mg / m2 IV 24 h infusion (in 2 divided doses) Days 2 3


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4-arm trial arm - III
BLM 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

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4-arm trial arm - IV
BLM 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

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Trials world wide

• Randomized trials
• GOG trial
• Keys et al 1999
• Pearcey et al 2002
• More effective regimens

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CLINICAL TRIAL OFORAL ETOPOSIDE BLM WITH RTIN
LOCALLY ADVANCEDCARCINOMA OF THE UTERINE CERVIX
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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

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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

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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

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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

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No / CR/ NED
For CR, p lt0.045 (Mantel Haenszel corrected)
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Toxicities

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

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HYDROXYUREAASRADIATION SENSITIZER
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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

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No / CR/ NED
p NS
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REGIONAL HYPERTHERMIACOMBINED WITH RADIATIONIN
LOCALLY ADVANCED CERVICAL CANCERS
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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

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HT trial

• HT immediately following RT
• Once a week (Tues)
• 420 C - 430C
• Maintained for one hour
• BP pulse rate monitored

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No / CR/ NED
Int.J.Radiation Oncology Biol.physics 200561
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RANDOMISED TRIAL ON COMPARISON OF LDR AND HDR ICA
IN CARCINOMA CERVIX
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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

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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 160-180cGy / Hr
• Arm 2 ext radiation 3 HDR 15Gy
• Dose rate at Point A 36-48 Gy / Hr

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3-yr survival NED
Stage NED rate NED rate
Stage LDR HDR
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
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3 YR NED
p NS
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Nos
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Future trials

• More effective chemotherapy regimens.
• Omit cisplatin.

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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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THANK YOU