Gynae Landmark Trials Flashcards
What is the PLCO trial and aim
The effect of screening on ovarian cancer mortality - the prostate, lung, colorectal and ovarian cancer screening randomised control trial, 2011
RCT - 78,000 women
Aim: to assess effect of ovarian cancer screening on mortality
PLCO trial
PICO
The effect of screening on ovarian cancer mortality - the prostate, lung, colorectal and ovarian cancer screening randomised control trial
Population: 55-74 yr olds, nil previous lung/ovarian/CRC cancer
Intervention: Annual Ca-125 screening, abnormal >35 + TVUSS
Comparison: usual care
Outcomes: mortality from ovarian cancer
PLCO trial results
The effect of screening on ovarian cancer mortality - the prostate, lung, colorectal and ovarian cancer screening randomised control trial 2011
- No difference in ovarian cancer mortality, diagnosis or stage
- Increased harm from screening, 5% false + each –> OT –> 15% serious complication rate
- PPV of ca-125 + TVUSS only 23%, only 60% of cancer screen detected
- All cause mortality unchanged
Strengths/limitations of PLCO trial
The effect of screening on ovarian cancer mortality - the prostate, lung, colorectal and ovarian cancer screening randomised control trial 2011
Strengths
- large numbers
minimal screening outside protocol
limits
- not blinded
- no information re. which systemic therapy or surgeon both affect survival
- screening usually invasive test (TVUSS)
Summary of PLCO trial
The effect of screening on ovarian cancer mortality - the prostate, lung, colorectal and ovarian cancer screening randomised control trial 2011
screening intervention is not effective at reducing mortality from ovarian cancer in average risk women AND increases harm from intervention
What is the SPIN trial and aim
SPIN (Scottish Pregnancy Intervention) study: a multi centre, RCT of LMWH and LDA for recurrent miscarriage. Blood 2010
RCT - multi-country - 294 women
Aim: to assess whether aspirin + LMWH + monitoring is better than monitoring alone in those with unexplained recurrent miscarriage
SPIN
PICO
SPIN (Scottish Pregnancy Intervention) study: a multi centre, RCT of LMWH and LDA for recurrent miscarriage. Blood 2010
Population: at ANC <7/40 with history of 2+ consecutive pregnancy loss <24/40, no cause identified for recurrent MC
Intervention: aspirin 75 mg + LMWH 40 mg SC + monitoring
Comparison: monitoring alone
Outcome: loss of index pregnancy
SPIN trial results
SPIN (Scottish Pregnancy Intervention) study: a multi centre, RCT of LMWH and LDA for recurrent miscarriage. Blood 2010
- No difference in outcomes
- loss of about 20% in both groups
Strengths and limitations of SPIN trial
SPIN (Scottish Pregnancy Intervention) study: a multi centre, RCT of LMWH and LDA for recurrent miscarriage. Blood 2010
Strengths
- RCT
Limitations
- Design not robust enough to examine subgroups
- Small Numbers
- Looked at 2 rather than 3 consecutive miscarriages
- already 7 weeks along - further research into starting preconception
SPIN trial summary
SPIN (Scottish Pregnancy Intervention) study: a multi centre, RCT of LMWH and LDA for recurrent miscarriage. Blood 2010
LMWH + Aspirin DOES NOT reduce unexplained recurrent pregnancy loss
What is the LACE trial and aim
Effect of Total Laparoscopic Hysterectomy vs Total Abdominal Hysterectomy on Disease-Free survival among women with stage I endometrial Cancer. Janda et al 2017
Multinational randomised trial - 760 women
Aim: to investigate whether TLH is equivalent to TAH in women with treatment naive endometrial Ca
LACE
PICO
Effect of Total Laparoscopic Hysterectomy vs Total Abdominal Hysterectomy on Disease-Free survival among women with stage I endometrial Cancer. Janda et al 2017
Population: 760 women with stage 1 endometrioid endometrial Ca
Intervention: TLH
Comparison: TAH
Outcomes: disease-free survival assessed at 4.5 years after randomisation, secondary outcomes: recurrence of endometrial Ca and overall survival
LACE trial results
Effect of Total Laparoscopic Hysterectomy vs Total Abdominal Hysterectomy on Disease-Free survival among women with stage I endometrial Cancer. Janda et al 2017
no statistically significant difference in recurrence of endometrial Ca or overall survival between TLH or TAH
LACE trial strengths and limitations
Effect of Total Laparoscopic Hysterectomy vs Total Abdominal Hysterectomy on Disease-Free survival among women with stage I endometrial Cancer. Janda et al 2017
Strengths
- Randomised equivalence trial
- Nz population - generalisable
- Surgeons were accredited to perform in the study
Limitations
- Not blinded
- Randomisation was performed prior to the patient being scheduled for surgery
- Funding constraints - 2 phase design first focusing on QoL
- Inconsistency of pelvic and aortic retroperitoneal lymph node dissection
LACE trial Summary
Effect of Total Laparoscopic Hysterectomy vs Total Abdominal Hysterectomy on Disease-Free survival among women with stage I endometrial Cancer. Janda et al 2017
Women with early stage endometrial Ca - TLH is appropriate approach for treatment of stage 1 endometrial Ca
What is ALIFE trial and aim
Aspirin + Heparin or Aspirin alone in women with recurrent miscarriage. Kaandorp (NEJM2010)
RCT 364 women
Aim: does aspirin + heparin vs. aspirin alone improve live births rates vs. placebo
ALIFE trial
PICO
Aspirin + Heparin or Aspirin alone in women with recurrent miscarriage. Kaandorp (NEJM2010)
Population: 18-42y, 2 or more unexplained MC <20/40 attempting conception or <6/40
Intervention/comparison
- 80 mg aspirin to 36/40 + LMWH from 6/40 till labour
- 80 mg aspirin alone
- Placebo
Outcomes: rate of live birth
ALIFE trial results
Aspirin + Heparin or Aspirin alone in women with recurrent miscarriage. Kaandorp (NEJM2010)
no difference in live birth rates between groups ~ 55%
Those receiving combo therapy delivered 1 weeks earlier than placebo
No difference in the subgroup analysis of women with thrombophilia
ALIFE trial strengths/limitations
Aspirin + Heparin or Aspirin alone in women with recurrent miscarriage. Kaandorp (NEJM2010)
Strengths
- RCT
Limitations
- 2 or more MC rather than 3
- only 85% adherence to treatment
- Use of LMWH not blinded
- Not powered to assess effect of treatment on thrombophilia (prevalence was 16%)
ALIFE trial summary
Aspirin + Heparin or Aspirin alone in women with recurrent miscarriage. Kaandorp (NEJM2010)
LDA +/- heparin does not improve life birth rate for unexplained recurrent MC
Million women study and aim
Breast Cancer and hormone replacement therapy in the Million women study, Million woman study group, Lancet 2003
Aim: Effects of HRT on breast cancer incidence and mortality
Million women study
PICO
Aspirin + Heparin or Aspirin alone in women with recurrent miscarriage. Kaandorp (NEJM2010)
Population: cohort study on million UK women 50-65 y gave info on HRT use and personal details, FU for cancer incidence and death
- 9364 Br Ca, 637 deaths
Inclusion: women recruited at time of triennial breast screening
Intervention: split according to use and type of HRT, menopausal status and baseline factors
Million women study results
Aspirin + Heparin or Aspirin alone in women with recurrent miscarriage. Kaandorp (NEJM2010)
HRT - half had used at some time
Breast Ca
- current users at recruitment more likely to develop than never uses RR 1.66 (ss)
– E only RR 1.3 (ss)
– E+P RR 2 (ss)
also more likely to die from Br Ca RR 1.22
- Past users of HRT were not at increased risk of Br Ca/death RR 1.01 and 1.05
- Tibolone increased risk of Br Ca incidence 1.45 (ss) - less effect than E/P
- In current users, Br Ca increased with total duration of use
- Little variation in the RR between specific Es and Ps and their doses or between continuous or sequential regimens
- After 10 years of HRT = 5 additional breast Ca per 1000 users E only and 19 for E+P
- Effect of HRT or tibolone for increased Br Ca risk wears off by about 5 years
Million Women Study strengths and limitations
Aspirin + Heparin or Aspirin alone in women with recurrent miscarriage. Kaandorp (NEJM2010)
Strengths
- Large numbers and long f/up
Limits
- Poor design
- Previous estradiol use - used then stopped had been included in never used group
- Endometrial Ca risk persists after stopping HRT
- Average age women 55.9 so higher risk group that women taking HRT in 40s and early 50s
- Only assessed the 75% of women who show up for screening
Million women study summary
Aspirin + Heparin or Aspirin alone in women with recurrent miscarriage. Kaandorp (NEJM2010)
Increased invasive Br Ca with HRT use
- Combined use @5 yrs 6/1000 @10 years 19/1000, 2 less endometrial Ca
- E alone @ 10 years 5/1000 + 4 extra endometrial Ca
Current/recent HRT increases BCa, E+P significantly more than E only
Ovarian Conservation at the time of hysterectomy for benign disease
Ovarian Conservation at the time of hysterectomy for benign disease. Parker (obstetrics and Gynaecology 2005)
Aim: to establish an average age at which prophylactic oophorectomy could be recommended/beneficial for women at average risk of ovarian Ca
Ovarian Conservation at the time of hysterectomy for benign disease
PICO
Ovarian Conservation at the time of hysterectomy for benign disease. Parker (obstetrics and Gynaecology 2005)
Methods: Retrospective analysis of published data for absolute and relative risks after oophorectomy vs conservation. Using Markov decision analysis model to estimate optimal survival strategy per 5 years.
Population: 40-80yo in published data from 1990
Intervention/comparison
4 strategies compared:
Oophorectomy (with or without E)
Conservation (with or without E)
Outcomes:
- Survival to 80 years
- Ovarian ca, Coronary heart disease, Hip fracture, Breast ca, Stroke
Ovarian Conservation at the time of hysterectomy for benign disease. Parker
Results
Ovarian Conservation at the time of hysterectomy for benign disease. Parker (obstetrics and Gynaecology 2005)
Conservation until age 65 benefits long term survival
- oophorectomy < 55 - 8.5% excess mortality by 80
- oophorectomy <59 - 4% excess mortality by 80
- increased mortality mostly from extra CHD/Hip#, replacing E reduced this
- At no age is there a clear benefit from oophorectomy
Ovarian Conservation at the time of hysterectomy for benign disease. Parker limitations and strengths
Ovarian Conservation at the time of hysterectomy for benign disease. Parker (obstetrics and Gynaecology 2005)
Strengths
- large numbers
Limits
- probability estimates mostly from case control studies - selection bias, reporting bias, chance
- Predominantly white Caucasian not necessarily generalisable
- Other morbidities not includes
- A definition for average risk was not provided
Ovarian Conservation at the time of hysterectomy for benign disease. Parker (obstetrics and Gynaecology 2005)
Summary
ovarian conservation should be performed until 65yo for long term survival benefit in women at average risk for ovarian Ca
WHI RCT aim
Women’s health Initiative: Risks and benefits of estrogen + progesterone in healthy postmenopausal women - principal results from WHI RCT, WHI (JAMA 2002)
Aim: to assess risk and benefits of E+P in healthy PM women. Aims to prevent CHD, breast and colon Ca and improve #/osteoporosis
RCT - 16608 women (average age 63) recruited by mail or media
WHI E+P
PICO
Women’s health Initiative: Risks and benefits of estrogen + progesterone in healthy postmenopausal women - principal results from WHI RCT, WHI (JAMA 2002)
Population: 50-79y post menopausal, intact uterus, likely to stay in same area for >3 years
Intervention: CEE (conjugated equine estrogen) 0.625mg + MPA 2.5mg
Comparison: placebo
Outcomes: CHD, breast cancer
Secondary outcomes: global index of risks and benefits, primary outcomes + stroke, PE, Colorectal Ca and other Ca, Hip fracture, death from other causes
WHI E+P
Results
Women’s health Initiative: Risks and benefits of estrogen + progesterone in healthy postmenopausal women - principal results from WHI RCT, WHI (JAMA 2002)
Primary: Increased!
- CHD + 7
- Br Ca +8 (significant after 5 years)
Secondary outcomes total of 19 extra risk events/10,000 woman years
- More: stroke +8, PE +8
Less: colorectal Ca -6, Hip fracture -5
No significant effect on total mortality
WHI E+P
Strengths and limitations
Women’s health Initiative: Risks and benefits of estrogen + progesterone in healthy postmenopausal women - principal results from WHI RCT, WHI (JAMA 2002)
strengths
- large numbers
- 6y f/up
Limits
- Trial stopped when overall finding of harm for breast Ca and GIS (5.2 yrs)
- only one dose and formulation tested (CEE and MPA) - results don’t apply to lower dose MHT regimes or other forms of E or P e.g. transdermal
- doesn’t differentiate effect from E vs, P - results don’t apply to E only
- average age 63 - higher than those using HRT for sx (50% past/present smokers)
- Nil appropriate screening for significant comorbidities and were included
WHI E+P
summary
Trial demonstrates increased risk of harm in older women using HRT (stoke, VTE, CHD, Breast Ca)
Did not demonstrate increased CVD risk in younger women ie. <10 years after menopause
Overall risks>benefits at 5 yrs. No effect on mortality, don’t use E+P for primary prevention of CHD
The CHOICE contraceptive project and aim
Provision of no-cost, long acting contraception and teenage pregnancy. Secure et al 2014
Large prospective cohort study - 1404 teenage girls and women
Aim: designed to promote the use of LARCs to reduce unintended pregnancy in the St. Louis region
CHOICE
PICO
Provision of no-cost, long acting contraception and teenage pregnancy. Secure et al 2014
Population: 9256 girls and women aged 14-45
Intervention: participants were educated about reversible contraception, with an emphasis on the benefits of LARC methods, were provided with their choice of contraception at no cost and followed for 2-3 years
Comparison: National US data
Outcomes
- pregnancy, birth and induced abortion rates among teenage girls and women 15-19 of age in this cohort
CHOICE results
Provision of no-cost, long acting contraception and teenage pregnancy. Secure et al 2014
-72% chose IUD or implant
- remaining 28% chose another method
- Lower rates of pregnancies, births and abortions in CHOICE participants (substantially lower)
- Continued to use LARC methods for longer than shorter-acting methods
CHOICE strengths and limitations
Provision of no-cost, long acting contraception and teenage pregnancy. Secure et al 2014
strengths
- Large numbers
Limitations
- Information about pregnancy was self-reported could be underestimated in CHOICE cohort
- Regular surveys may contribute to adherence to their contraception
- Generalisability is uncertain
CHOICE summary
Provision of no-cost, long acting contraception and teenage pregnancy. Secure et al 2014
When barriers to contraception (lack of knowledge, limited access and cost) are removed and the use of the most effective contraceptive methods are encouraged a large percentage opted for a LARC
Rates of pregnancy, birth and abortion in CHOICE cohort were below the most recent corresponding national rates and below the CDC 2015 goal
WHI E alone
Aim
Effects of conjugated equine estrogen in postmenopausal women with hysterectomy - the women’s health initiative RCT 2004
Double blind RCT - 10,739 women
Aim: to assess effects of MHT on major disease incidence in healthy postmenopausal women
WHI E alone
PICO
Effects of conjugated equine estrogen in postmenopausal women with hysterectomy - the women’s health initiative RCT 2004
Population: 50-79y (avg 63) post menopausal, previous hysterectomy, likely to stay in same area >3y. No breast Ca
Intervention: CEE 0.625 mg
Comparison: placebo
Outcomes: CHD, Breast Ca
Secondary outcomes: globe index of risks and benefits, primary outcomes + stroke, PE, colorectal Ca, Hip fracture, death from other causes
WHI E alone
Reulsts
Effects of conjugated equine estrogen in postmenopausal women with hysterectomy - the women’s health initiative RCT 2004
Primary: no difference
- No significant diff CHD RR 0.91
- No sig diff Breast Ca RR 0.77 (CI 0.59-1.01)
Secondly outcomes: no difference in overall global index (+2 events, NS)
+ significant increase stroke +12/10,000 women years (39% increase)
+sig increase DVT HR 1.47
- sig decrease hip fracture HR 0.6 lower (6 less)
No sig difference on overall mortality, colorectal Ca, PE
WHI E alone
strengths and limitations
Effects of conjugated equine estrogen in postmenopausal women with hysterectomy - the women’s health initiative RCT 2004
strengths
- large numbers
Limitations
-Terminated early - similar results with E+P- deemed unacceptable risk, a longer intervention may have provided stat sig evidence esp CHD and BCa
- Lower than anticipated rates for CHD and hip# reduce the power
-Adherence to protocol 53%- high discontinue of meds (dilute CEE effect)
-Only one dose and formulation tested
-Average age 63yo- higher than those using HRT for Sx
-Nil appropriate screening for significant comorbidities and were included
WHI E alone
summary
Effects of conjugated equine estrogen in postmenopausal women with hysterectomy - the women’s health initiative RCT 2004
CEE did not change risk of CHD or Br Ca or mortality but did reduce fracture and increase risk of stroke/DVT
Medical vs surgical for EP failure
A comparison of medical management with misoprostol and surgical management for early pregnancy failure, Zhang NEJM 2005
RCT - 652 women
Aim: Evaluate safety, efficacy and acceptability of medical vs surgical management of miscarriage
Medical vs surgical for EP failure
PICO
A comparison of medical management with misoprostol and surgical management for early pregnancy failure, Zhang NEJM 2005
Population:
- Anembyronic gesetation (35%) MSD 16-45mm
- Embryonic death (60%) CRL 5-40mm no FH
- Sac <2mm over 5d, <3mm over 7d
- Rise in hcg <15% over 2 d with YS seen
- Incomplete mc with >30mm RPOC
- Inevitable mc <45mm sac, <40mm crl
Intervention
- Misoprostol 800 mag pv D1, repeated D3 if USS incomplete, ERPOC D8 if incomplete
Comparison: surgical management
Outcome: treatment failure: surgical treatment within 30 days
medical vx surgical for EP failure
Results
A comparison of medical management with misoprostol and surgical management for early pregnancy failure, Zhang NEJM 2005
- misoprostol = 16% treatment failure vs 3% surgical
- 70% expulsion by D3, 84% success by D8
- 80% would use again and recommend to others
- more pain/nausea/vomiting/diarrhoea
- lower success in anembryonic gestation
- Sig more Hb drop >30
surgical - 97% success
No sig difference in complications: pelvic infection, haemorrhage same <1%
no sig diff in frequency of ED visits <24 hours
Medical vs surgical for EP failure
Strength/limitations
A comparison of medical management with misoprostol and surgical management for early pregnancy failure, Zhang NEJM 2005
Strengths
- strict inclusion criteria and well defined end points
- minimal loss to FU
Limitations
- unblinded
- small numbers incomplete miscarriages (as RPOC >3 cm)
- Included varying different types of MC - heterogenous
- One dose regime only
Medical vs surgical for EP failure
summary
A comparison of medical management with misoprostol and surgical management for early pregnancy failure, Zhang NEJM 2005
treatment of early MC with 800 msg OV is safe and acceptable with 85% success at D8 with no difference in infection or haemorrhage
