TRIALS IN OBS &GYN

CHIPS TRIAL

( CONTROL OF HYPERTENSION INPREGNANCY )
Difference clinical outcome of severe
hypertension by adjusting of interventions of
“less tight “ ( DBP 100 mmHg ) Vs “ tight “
( target DBP 85 mmHg ).

• Randomised controlled open multicentre trial.
• Inclusion criteria : Women at 14+0 – 33+6 weeks gestation with non proteinuric
  preexisting or gestational hypertension DBP 90-105 mmHg (/ 85 – 105 mmHg if on
  antihypertensives) with live fetus were randomised.
• Exclusion criteria : Women on Atenolol, ACEIs, ARBs > 14 weeks.
• Composite primary outcome : Pregnancy loss or high level neonatal care for > 48
  hrs in first 28 days of life .
• Secondary outcome : Maternal death or serious maternal complications < 6 weeks ppm, severe hypertension,preeclampsia, delivery at < 37 or < 34 weeks, plt<100000, increased ALT/ AST with symptoms, maternal length of stay > 10 days
  or readmission < 6 weeks ppm.
• Sample size : 981 women randomised in primary CHIPS analysis. Severe
  hypertension (N-334, 33.9%) and preeclampsia (N-464, 47.3%) were common.
  Most women with severe hypertension had preeclampsia (248/334, 74.5%). > Half
  of women with preeclampsia had severe hypertension (248/464, 53.4%).
• Conclusion : Women who developed severe hypertension were more likely to
  have been randomised to less-tight control. Severe hypertension is a risk marker
  for adverse maternal and perinatal outcomes and these risks associated with
  severe hypertension are over and above those associated with co-occurrence of
  preeclampsia.
  CLASP TRIAL
  Low dose Aspirin for the prevention and treatment of
  preeclampsia. ( Collaborative Low-dose Aspirin Study in
  Pregnancy )
• Multicentrerandomised controlled trial.
• Sample size : 9364 women were randomly assigned 60 mg
  Aspirin daily or matching placebo. 74% entered for
  prophylaxis of preeclampsia, 12% for prophylaxis of IUGR,
  12% for treatment of preeclampsia, and 3% for treatment
  of IUGR.
  Overall use of Aspirin was associated with reduction in
  only 12% of incidence of proteinuric preeclampsia which
  was not significant. There was no significant effect on
  incidence of IUGR or stillbirth or neonatal death.
  Aspirin however significantly reduce likely hood of preterm
  delivery (19.7% Aspirin vs 22.2% control); absolute
  reduction of 2.5/100 women treated. There was a
  significant trend towards progressive greater reduction in
  proteinuric preeclampsia, the more preterm the delivery.
  Aspirin was not associated with significant increase in
  placental haemorrhages or bleeding during preparation of
  epidural anaesthesia, but slight increase in blood tx after
  delivery.
• Conclusion :
• Routine prophylactic or therapeutic
  administration of anti-platelet therapy in pregnancy to all
  women at increased risk of preeclampsia or IUGR. Low
  dose Aspirin may be justified in women judged to be
  especially liable to early onset preeclampsia severe
  enough to cause very preterm delivery. In such women it is
  appropriate to start low-dose Aspirin prophylactically early
  in the second trimester.
  ASPRE TRIAL
  Objective : To screen and compare for preterm and term pre-eclampsia (PE) in the
  study population.
  Method : Prospective first-trimester multi-center study on screening
  for preterm PE.
  Population : 26941 singleton pregnancies in 2017. Combine maternal factors,
  MAP, uterine artery PI and maternal serum PAPP-A and PGF at 11–13weeks’
  gestation. Eligible women with high risk for preterm PE of >1/100 participate in
  double-blind trial of aspirin (150mg per day) vs placebo from 11–14 until
  36weeks’ gestation,
  Results : First-trimester screening for preterm PE with a risk cut-off of 1/ 100,
  detection of 76.7% for preterm PE and 43.1% for term PE.
  In Aspirin group, incidence of preterm PE reduced by 62%.
  Conclusion : Combined screening detected 76.6% of cases of preterm PE and
  38.3% of term PE.
  HYPITAT 1 TRIAL
  Induction of labour versus expectant
  monitoring for gestational hypertension or
  mild pre-eclampsia after 36 weeks POA
• Multi centre open- label RCT
• Population : 6 Academic & 32 Non-academic hospitals inNetherlands.
• Period : Oct 2005 – March 2008.
• Inclusion criteria : Singleton pregnancy at 36 – 41weeks gestation ,
  who had gestational hypertension ormild preeclampsia.
• Primary outcome : Composite measure of poor maternaloutcome –
  maternal mortality , maternal morbidity (eclampsia, HELLP syndrome,
  pulmonary oedema,thromboembolism, placental absorption ),
  Progression to severe hypertension or proteinuria, andmajor PPH (
• 1000 ml blood loss ).

• Sample size : 756 patients allocated to receive IOL orexpectant
  monitoring. 117 women (31%) allocated to IOLdeveloped poor
  maternal outcome compared with 166women (44%) allocated to
  expectant monitoring. ( RR0.71 ). No cases of maternal or neonatal
  death oreclampsia were recorded.
• Conclusion: Induction of labour is associated withimproved maternal
  outcome and should be advised forwomen with mild hypertensive
  disease beyond 37 weeksof gestation.
  HYPITAT-11 TRIAL
  Immediate delivery versus expectant monitoring for
  hypertensive disorders of pregnancy between 34 and 37
  weeks of gestation
• Multicentre, open- label randomised controlled trial.
• Population : 7 Academic and 44 non-academic hospitals in Netherlands.
• Period : 1.3.2009 and 21.2.2013.
• Inclusion criteria : Women with non- severe hypertensive disorders of pregnancy
  between 34
  and 37 weeks of gestation randomly allocated to either IOL / LSCS within 24 hours (
  immediate
  delivery) or strategy aimed at prolonging pregnancy till 37 weeks of gestation (expectant
  monitoring).
• Primary outcomes : Composite of adverse maternal outcomes ( Thromboembolism,
  pulmonary oedema, eclampsia, HELLP syndrome,placental abruption, or maternal
  death) and
  neonatal respiratory distress syndrome.
• Sample size: 703 were allocated for trial, 352 for immediate delivery vs 351 for
  expectant
  monitoring. Composite adverse maternal outcome occurred in 4 (1.1%) of 352 women
  vs
  11( 3.1%) of 351 women allocated for expectantmonitoring ( RR 0.36 ). RDS diagnosed in
  20 (
  5.7%) of 352 neonates in immediate delivery group vs 6 ( 1.7%) of 351 neonates in
  expectant
  monitoring group ( RR 3.3 ).No maternal or perinatal deaths occurred.
• Conclusion : For women with non- severe hypertensive disorders at 34–37 weeks of
  gestation, immediate delivery might reduce already small risk of adverse maternal
  outcomes.
  However it significantly increases the risk of neonatal RDS. Therefore routine immediate
  delivery does not seem justified and a strategy of expectant monitoring till clinical
  situation deteriorates can be considered.
  MAGENTA TRIAL
  Magnesium sulphate at 30 to 34 weeks ‘ of gestational age:
  neuroprotection trial – study protocol.
  • Randomised, multi centre, placebo controlled trial.
• Inclusion criteria: Women at risk of preterm birth between 30
  to 34 weeks ‘ of gestation where birth is planned or definitely
  expected within 24 hours, with a singleton or twin pregnancy
  and no contraindications for using magnesium sulphate.
  Women in magnesium sulphate group, 50ml of 100ml infusion
  bag containing 8g MgSO4 heptahydrate (16 mmol magnesium
  ions), and in placebo group 50ml of 100ml infusion bag
  containing isotonic NaCl
  solution (0.9%) were administered with infusion line for over 30
  minutes.
• Primary outcome : Death or cerebral palsy measured in
  children at 2 years corrected age.
• Sample size : 1676 children were required to detect a
  decrease in combined outcome from 9.6% in placebo to 5.4% in
  magnesium sulphate group.
• Conclusion : A trial of magnesium sulphate for women at risk
  of preterm birth between 30 to 34 weeks’ gestation is both
  important and relevant for clinical practice globally.
  But there was uncertainty about benefits at later gestational
  ages.
  MagNET Trial
• In 1997, the MagNET trial, the first RCT, published
  interim safety data because an unexpectedly high
  number of adverse outcomes were found in fetuses
  exposed to MgSO4.
• Sample size & gestational age :Four-arm study of
  149 women in preterm labour between 24 and 34 weeks
  of gestation.
• Study Method :In the two unblindedtocolytic arms,
  women in preterm labour were randomised to receive
  MgSO4 or an alternative tocolytic.
  In the other two double-blinded arms MgSO4 was given
  to mothers in one group purely as a neuroprotective
  agent (and compared with normal saline).
• Primary outcome : Number of intrauterine deaths.
• Results : The study found ten intrauterine deaths in
  those receiving MgSO4, compared with one death in
  those given saline; a significant difference.
  On further analysis, other causes of death such as
  congenital abnormality in one case and twin-to-twin
  transfusion in two cases were found in fetuses exposed
  to MgSO4, leaving seven unexplained.
  The Magpie Trial
  A randomised trial comparing magnesium
  sulphate with placebo for preeclampsia.
  Outcome for women at 2 years.
• Multi centrerandomised controlled trial.
• Objective : To assess long term effects for women following use of magnesium sulphate for
  preeclampsia.
• Population : Follow up after discharge from hospital at 125 centres in 19 countries.
• Sample size : 4782 women were selected for follow up, of whom 3375 (71%) were traced.
• Primary outcome : Death or serious morbidity potentially related to preeclampsia at follow
  up, Other morbidity and use of health service resources.
  Neonatal outcome of mothers who received MgSO4 in labour.
• Follow-up :Medium time of delivery to follow up was 26 months.
• Results : 58 of 1650 ( 3.5%) women allocated magnesium sulphate, died or had serious
  morbidity potentially related to preeclampsia compared with 72 of 1725 (4.2%) women
  allocated placebo. Lower risk of death or CP in children at 18 months of age, however this was
  not statistically significant ; RR 0.83 .
• The main criticism of this study was the inconsistency of the paediatric follow-up.
• Conclusion : The reduction in risk of eclampsia following prophylaxis with magnesium
  sulphate was not associated with an excess of death or disability for women after 2
  years.
  PREMAG Trial
• Sample size and location :573mothers ; 688 infants. France.
• Gestational age : <33 weeks.
• Follow-up period :6years .
• Dosage of MgSO4 :Single loading dose 4g
• Primary outcomes :
  Overall neonatal mortality before hospital discharge.
  Detection of neonatal cranial ultrasound abnormalities
  evocative of severe white matter injury (WMI) Combination
  of severe WMI and / or neonatal mortality.
  • Results ( MgSO4 versus placebo ) :
    Severe white matter injury and /or death : 16.5% versus 17.9% ; OR 0.86.
    Death : 9.4% versus 10.4% ; OR 0.79.
    Severe white matter injury : 10.0% versus 11.7% ; OR:0.78.
• PREMAG follow-up
  Results : Death and CP : OR 0.65 ;
  CP alone : OR 0.63 ;
  Gross motor dysfunction : OR 0.65 ;
  Death and / or gross motor dysfunction : OR 0.62 ;
• Conclusion : Total mortality, severe white matter injury, and combination of
  these outcomes, were less frequent in babies exposed to MgSO4, but these
  differences were not statistically significant. The complete 2-year followup data
  did not show a significant difference in rates of CP, gross motor dysfunction or
  combined death and CP between the control and treatment groups. However , a
  significant reduction was noted in the combined outcomes of death and gross
  motor dysfunction, as well as the composite outcomes of death , CP and cognitive
  dysfunction.
  BEAM Trial
  • Sample size and location :2241.
    USA.
• Gestational age :< 32 weeks.
• Follow-up period :2 years.
• Dosage of MgSO4 :6g loading dose then 2g/h for 12h.
• Primary outcomes :
  Composite of stillbirth or infant death by 1year of age or
  moderate or severe CP , as assessed at or beyond 2years of
  age ( with ages corrected for prematurity ).
• Results ( MgSO4 versus placebo ) :
  Composite outcome (combined death or CP) :
  11.3% versus 11.7%; RR0.97.
  CP*: [moderate to severe] 1.9% versus 3.5%; RR 0.55.
  Gross motor dysfunction : Not considered.
• Conclusion :
  It found a significant difference in outcome between placebo
  and MgSO4 for the occurrence of severe CP ;
  but not for milder forms of CP.
  ACTOMgSO4 Trial
• Sample size and location : 1062 .
  Australia & New Zealand.
• Gestational age : <30weeks.
• Follow-up period : 2 years.
• Dosage of MgSO4 : 4g loading dose then 1g/h.
• Primary outcomes :
  Total paediatric mortality up to a corrected age of 2 years.
  CP at corrected age of 2years.
  Combined adverse outcome of death or CP at 2 years of age.
• Results (MgSO4 versus placebo) :
  Composite outcome (combined death or CP ) : 19.8% versus 24.0% ;
  RR 0.83
  Death : 13.8% versus 17.1% ; RR 0.83
  CP : 6.8% versus 8.2% ; RR 0.83
  Gross motor dysfunction : 17.0% versus 22.7% ; RR 0.75
• Conclusion :
  Non significant reduction in CP and death;
  However, a significant reduction in the prevalence of gross motor
  dysfunction was noted.
  ORACLE I STUDY
  4826 of women with PPROM
  04 arms. Erythromycin 250mg
  Co-amoxiclav 375mg
  Combination
  Placebo
  4 times a day for 10 days or until established PTL(whichever early)
  prophylactic erythromycin: improves neonatal morbidity
  reduces the risk of sepsis
  longer latency period
  Prophylactic co‐amoxiclav: increases necrotizingenterocolitis(AVOID)
  Prophylactic antibiotics of any type:(DO NOT) reduce the incidence of perinatal death
  neonatal encephalopathy
  rates of maternal sepsis
  maternal death.
  These findings have been confirmed by meta‐analysis of subsequent studies.
  A Cochrane review(Prophylactic antibiotics for PPROM)
  reduction in chorioamnionitis
  reduction in the numbers of babies born( 48 hours-07days)
  Reduction Neonatal infections
  Reduction of use of surfactant,
  Reduction of oxygen therapy
  Reduction of abnormal cerebral ultrasound prior to discharge from hospital
  NO reduction in perinatal mortality
  health of the children at 7 years of age.
  ORACLE II STUDY:
  The ORACLE II study
  In 2001 (6295 women)
  Inclusion criteria :spontaneous preterm labour with intact
  membranes and without evidence of clinical infection)
  04 arms. Erythromycin 250mg
  Co-amoxiclav 375mg
  Combination
  Placebo
  4 times a day for 10 days or until established PTL(whichever
  early)
  The primary outcome measure: composite of neonatal death,
  chronic lung disease, or major cerebral abnormality on
  ultrasonography before discharge from hospital.
  NO change of primary outcomes.
  Only reduce maternal infections
  Increase risk of CP in 07 years follow up
  (Erythromycin+Augmenting>Erythromycin)
  Conclusion:antibiotics should not be routinely prescribed for
  women in spontaneous preterm labour (without evidence of
  clinical infection)
  PPROMT trial
  (Immediate delivery compared with expectant management after
  preterm pre-labour rupture of the membranes close to term)
  Multi center RCT (65 centers across 11 countries) in 2016
  Selection criteria:>16 years with singleton pregnancies, ruptured
  membranes before the onset of labour between 34 weeks and 36
  weeks and 6 days weeks who had no signs of infection were included.
  Expectant Mxvs IOL
  expectant management:
  Does not increase the risk of neonatal sepsis
  Evidence of more maternal sepsis at delivery
  No increase risk of LSCS
  IOL: More respiratory morbidity
  Conclusion:
  in the absence of signs of infection or fetal compromise, a policy of
  expectant management with appropriate surveillance of maternal and
  fetal well‐being should be followed in pregnant women who present
  with PPROM up to 37 weeks.
  PRROMEXIL trial
  (PPROM Expectant Management versus Induction of Labor)
  Large trial in Netherland in 2012
  compared immediate induction of labour or expectant
  management in women with PPROM between 34 and 37
  weeks’ gestation
  risk of chorioamnionitis was slightly reduced in IOL
  NO differences in rates of neonatal sepsis, RDS or LSCS.
  (Subsequent meta analysis with 8 studies confirmed above
  findings)
  1.GRIT.
  Growth restriction intervention trial is a multicenter trial
  Objective- to compare the effect of delivering early to pre terminal
  hypoxia with delaying for as long as possible to increase the maturity
  early to pre empt terminal hypoxemia with delaying for as long as
  possible to increase maturity
  Inclusion criteria-548 women or 587 babies pregnant women with fetal
  compromise between 24 to 36 weeks
  Compared- immediate delivery versus delayed until the obstetrician no
  longer Uncertain
  Outcome measures-1.survival to hospital discharge

1. development Quotient at 2 years of age that was the follow-up
   study
   interpretation- insufficient evidence
   but the follow-up study after 2 years no overall difference in the rate of
   death or severe disability and not support early delivery as useful
   measure to prevent hypoxemia improve long-term brain development
   2.Truffle study 1
   is a multicenter trial included 503 women at POA of 26 to 32 weeks.
   FGR definition was used here is abdominal circumference less than 10 Centile+
   umbilical artery PI value 95 ppercentile.
   Three arms with total 503 women
   One arm is reduced STV that again divided into two less than 3.5 ms in UPTO 28 + 6
   weeks or less than 4ms in upto 31 + 6
   Second arm- early change in DV wave form. DV PI >95th centile
   Third arm-late changes in ductusvenosus waveform
   safety net used for delivery regardless of arm with show time STV criteria and UADF
   criteria.
   If umbilical artery Doppler reversed more than or equal to 32 weeks and if absent and
   diastolic velocity more than or equal 34 weeks or if persistent unimproved deceleration,
   immediate delivery done
   primary outcome measures –
   1.survival without cerebral palsy -similar in all three groups
2. Bayley III developmental score less than 85 at 2 years
   overall 81% delivered for the fetal condition and 97% delivered by cesarean section
   at two year follow up –
   better functional outcome in those delivered based on waiting for late DV changes
   rather than CTG abnormality
   3.Truffle 2 study
   which was started on January 2020 and its plan to include the women from 34 to 37
   weeks of period of gestation
3. DIGITAT study
   Disproportionate intrauterine growth intervention trial is also a multicentre trial
   included the women with the POA between 36 + 0 to 41 + 0
   totally 325 women were included per arm
   inclusion criteria was used is suspected fetal growth restriction less than 10
   centile
   Objective.to compare as expectentmanagemnt versus deliver within 48 hours.
   web-basedrandomisation was used
   primary outcome measures were
   1.death before hospital discharge
   2.5 minutes APGAR less than seven
4. umbilical artery pH less than 7.05
5. admission to NICU
   secondary outcome measures were operative delivery
   maternal morbidity
   NICU stay
   conclusions- no important differences in adverse outcomes between induction of
   labour versus expectant management.
   but increase in ICU admission in the induction of labour group.
   it overlapped with HYPITAT study but if hypertension with suspected FGR ,they
   were included in the DIGITAT trial
   trial had selection bias and induction was not associated with any increase in
   operative or instrumental delivery rates
   5.PORTO study
   a prospective observational study to optimise pediatrics health in
   IUGR.
   evaluatedsonographic findings associated with perinatal morbidity
   and mortality.
   multivesseldoppler used in 1116 women aassessed with regard to
   fetal surveillance and delivery
   conclusion- abnormal umbilical artery Doppler flow or estimated
   fetal weight less than third Centile is strongly and more
   consistently associated with adverse perinatal outcome .
   umbilical artery and MCA Doppler remainmost useful in predicting
   88 percentage of all adverse outcomes.
   Term Breech Trial (TBT)
   2088
   RCT – planned LSCS vsPlanned vaginal breech delivery 26 Countries
   LSCS – Reduced perinatal mortality 0.3% ( vs 1.3%) & reduced neonatal morbidity
   2y follow up – no deaths & no neurodevelopment delay
   Criticism – 31% no uss.FGRIncluded. Randomation problems. EFM not used in
   some
   PREMODA
   2526 vs 5579
   Planned vaginal breech delivery vs planned LSCS
   Radiological pelvimetry 82% in planned Vaginal breech delivery – Also EFM. USS
   IOL & Augmentation allowed
   Planned vaginal breech – 79% Delivered.0.08% deaths.Increased low
   APGAR.Increaed fracture
   Planned LSCS – 0.16% Delivered vaginally .deaths 0.12%
   Neonatal outcome not differe significantly
   NICU admission =
   Mortality =
   Morbidity =
   HAPO study
   Multinational RCT, 9 countries, 15 centers
   Sample size 25505
   All non-diabetic pregnant women
   Used test 75 g OGTT from 24-32 weeks.
   Primary outcome measures
   FBS 1
   st hour 2
   nd hour
   Delivery via LSCS 1.11 1.10 1.08
   Large for Gestational
   age
   1.38 1.46
   Significant association
   1.38
   Neonatal hypoglycemia 1,08 1.08 1.13
   Significant association
   Cord blood C- peptide
   more than 90th centile
   1.55
   More significant
   1.46 1.37
   PTD 1.05 1.18
   Significant association
   1.16
   Significant association
   MIG trial
   Sample size 751 female
   All are DMWomen( GDM,Type II DM)
   Two arm
   1
   st arm -Metformin with supplementary insulin as required
   Maximummetformin dose
   2
   nd arm – Insulin only arm
   Primary outcome measure
   Metformin Insulin
   comparison of neonatal complication.
   (Due to hypoglycemia)
   31% 34%
   Admission to NICU 17.5% 18.3%
   No difference
   Admission _ more than 24 hours 11.7 % 11.6%
   No difference
   Primary and secondary outcomes are not significantly differ in both arm.
   One European study compare Body composing of fat in neonate – no difference
   Ovarian CA Trials
6. Screening
   PLCO (prostrate, lung, colon, ovarian)
   USA study
   Population 78000
   Age 55-74
   Two arm
    Screening arm -28000
   Interventionuss for yearly for 4 years, CA 125 yearly 6 years
    Non screening arm
   Out come
   More cases detected on screening arm
   No improvement in short or long term mortality
   Drawbacks
   Detected cases are not in early stage
   High false positive- which lead to more surgical intervention and more surgical
   complication
   UKCTOCS
   50-74 years
   Sample size >200 000
   Three arms
   i) CA 125 annually then USS
   ii) USS only
   iii) Third arm no intervention
   Mortality at 7 years
   Other psychological and economical
   Result:
   Multimodal screening arm detect more early stage ovarian /peritoneal CA
   Mortality reduced by 15%
   No difference in survival
   UK FOCSS
   Screening for familial CA history
   Study Population 3563
   Age more than 35years with the strong FHx ofbreast and/or ovarian
   Annual CA125 and TV- USS
   Result:
   Insufficient sensitivity to detect early stage disease
   2
   nd part of this study
   4531 study population
   CA 125 four monthly
   Same result as previous study
   Conclusion
   CA125 has limited sensitive to detect early stage disease in women with family
   history of Cancer.
7. Lymphadenectomy
   Two arms
   One arm: Only removing bulk LN only
   Other arm: removing systemic LN
   Result:
   At 5 years more progression free interval in systemic Lymphadenectomy
   group
   No difference in overall survival
   LION trial
   Study populations 650 women with Stage II B- IV after complete debulking
   surgery but no bulky lymphadenectomy
   Intervention
   One group underwent para aortic and pelvislymphadenetomy
   Others no lymphadenectomy
   Result:
   No difference in overall or PFI(progression free interval)
8. Primary Surgery vs Delayed PrimarySx
   EORT,CHORUS trial
   Two arms
   One arm- primarycytoreduction
   Second arm – Neo Chemo followed by Delayed primary cytoreduction
   Result:
   Long term survival superior in Neo Chemo followed by delayed primary
   cytoreductive group.
9. Chemotheraphy
   GOG 111 and OV10
   Cisplatin + paclitaxel VS Cisplatin+ cyclophosphamide
   First regime is better than second
   GOG132
   On arm Cisplatin alone
   Second arm Cisplatin + paclitaxel
   No diferecnce in survival
   ICON 3
   One arm- carboplatin + paclitaxel
   Other arm- Carboplatin alone/CAD
   ( cyclophospamide/doxorubincin,cisplatin)
   Out come
   No diference in PFS and overall survival
   GOG 218
   One arm -Combine front line CT+VEGF ab(bevacizumab)
   Other arm- CT only
   Result:
   PFS 3.8 months morewith First arm
   But no difference in overall survival
   ICON 7
   European study
   Same as GOG 218
   Result
   Overall survivalincreased by 5 months in addition to PFI 3.8 months
   JGOG(Japanese)
   One arm 3 weekly carboplatin + paclitaxel
   Other arm weekly dose dense therapy of paclitaxel + 3 weekly carboplatin
   Outcome:
   Second arm PFS increase by 11 months
   Overall survival also improved
   ICON 8
   3 arms
   1
   st arm- 3 weekly Carboplatin + paclitaxel
   2
   nd arm- weeklypaclitaxel + 3 weekly carboplatin
   3
   rd arm- weekly paclitaxel and carboplatin
   Result:
   Pending
   GOG 0262
   Small study
   Lack of benefit of the dose dense Japanese regimen over standard regimen
   Prospective study
   Four arms
   One arm 3 weekly carboplatin + paclitaxel
   One arm 3 weekly carboplatin + paclitaxel +bevacizumab
   Other arm weekly dose dense therapy of paclitaxel + 3 weekly carboplatin
   Other arm weekly dose dense therapy of paclitaxel + 3 weekly carboplatin+
   bevacizumab
   Result :
   Japanese arm alone more PFS
   Japanese arm + bevacizumab – similar PFS but worse QoL due to side effect
   of bevacizumab- neurophathy,anemia,neutropenia
   Fractionated paclitaxel has anti angiogenic effect like bevacizumab.
   ICON 8B
   Stage III or IV EOC
   3arms
   1
   st arm- 3 weekly carboplastin+ paclitaxel +bevacizumab
   2
   nd arm- Japanese regime (weeklypaclitaxel and 3 weekly carboplastin) only
   3
   rd arm – Japanese regime + bevacizumab
   Result- Pending
10. Intraperitonial Chemo
    GOG 172
    Two arms
    1
    st arm- IV paclitaxel D1 + IP Cisplatin D2+ IP paclitaxel D8 of 21 day cycle
    for 6 cycles
    2
    nd arm- IV drugsonly
    Result :
    Largest difference in RCT boz improvement over 17.4 months
    But toxicity is high in IP arm such as Neuropathy, Myelotoxicity,GI toxicity
    PETROC / OV21
    Stage IIb/ III or IV who underwent suboptimal Sx
    Population 275
    3 arms
    1
    st arm IP carboplatin + IV paclitaxel + IP paclitaxel
    2
    nd arm IP cisplatin + IV,IPpaclitaxel
    3
    rd arm IV carboplatin + IV paclitaxel
    Result
    1
    st arm super disease free interval, well tolerated
    GOG 252
    Stat II or III disease
    Population 1560
    3 arms
    Arm 1- IV carbo + IV paclitaxel + IV bevacizumab
    Arm 2- IP carbo+ IV paclitaxel + IV bevacizumab
    Arm 3- IP carbo + IV carbo +IP paclitaxel + IV bevacizumab
    Result – no advantage ( againstGOG 172 result)
    IP Chemo has highmorbidity and costly
    bevacizumab- not approved for routine use
    Weeklypaclitaxel only little advantage
11. Platinum sensitive CT
    MRC ICON 4
    Relapse more than 6 months of Chemo
    paclitaxel and carboplatin was given
    MRC ICON 3
    No improvement of survival in Carbo+ paclitaxel in advance cancer
    ICON 4
    By adding paclitaxel improve the survival in platinum sensitive recurrence cancer
    CALYPSO
    Two arms
    Arm 1- Carboplatin + PLDH (Pegylated liposomal doxorubicin HCL)
    Arm 2- Carboplatin + paclitaxel
    IF platinum sensitive or platinum partial sensitive add PLDH to platinum
    If allergic to platinum
    Option1 PLDH
    Option 2 topotecan+paclitaxel
    Option 3 tapectadine (DNA mcrobinding inhibitor) + PLDH
    Platinum sensitive study
    OCEANS study
    Carbo + bevasizumab +gemcitabine
    Outcome:
    PFS improved but no overall survival.
    Platinum resistance recurrence
    AURELIA
    PLDH+ topotecan + oral etoposite
    Compare with weekly paclitaxel
    Weekly paclitaxel arm shows more improvement
    Adding bevacizumab improve additional benefit
12. Secondary Sx the recurrence
    DEXTOP 1 Trial
    267 population
    Retrospective study
    Result :
    Benefit from secondary surgery derived only when total macroscopic
    clearance is achieved.
    So select only or possible optimal debulking disease for surgery
    Selection depend on AGO score
    AGO score1. good performance status
13. complete resection at primary surgery or early FIGO stage,
14. Absence of ascites at relapse.
    DEXTOP 2 trial
    Prospective study
    Surgical principle
    Prospective AGO score useful to predict complete tumor resection in
    platinum sensitive relapse.
    DEXTOP 3 trial
    Prospective study
    Impact of surgery with AGO score positive
    Outcome- good PFS ,
    Overall survival result waiting
    TCS 406 (tetiarycytorerecdctivesurgry)
    Participants t 406
    At tertiary stage,
    Tumor stage, age ,histo-subtype are not a predictive value
    3
    rd line postop CT improves overall survival
15. Future
    KEYNOTE -028 study
    Immunotherapy + chemotheraphy
    Study done in 26 patients
    Disease control rate of 54.7% observed
    OCTOPUS
    mTORinhibitor with weekly paclitaxel to patients with platinum resistant and refractory cases
    Ongoing ……….
    LAP 2
    RCT
    2616
    Stage 1/ 2a Endo CA
    TAH BSO / TAH BSO LND
    Results:
    Complications =
    Hospital stay reduced in Lapaposcopy
    Operation time high in Laparoscopy
    Laparoscopy – 23% converted to laparotomy
    QOL 30d =
    No difference in stage
    NO DIFFERENCE IN SURVIVAL
    ASTEC
    RCT
    Early Endo CA
    1st Randomization
    Standard Sx / Standard Sx + LND
    2nd randomization
    RT / no further Rx
    Results:
    Survival = ( primary end point)
    Recurrence free survival =(2ry end point)
    LND – High lympoedema
    PORTEC
    RCT
    715 pt
    Early endo CA
    After TAH
    Pelvic RT vs no treatment
    5 year survival equal 81 vs 85%
    Recurrence lower in RT group.
    PORTECE 3
    RCT
    Ongoing
    standard RT vs combination treatment
    

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