Papers Flashcards
GOG33
Precis:
GOG 33 was a study of the likelihood of LN+ in women with clinically presumed stage I Endometrial Can. Published in Cancer 1987 by Creaseman et al., Between 1977 and 1983 it collected 1180 women of whom 621 were suitable for inclusion. These women had clinical stage I and TAHBSO + selective pelvic and para-aortic lymphadenectomy and procurement of peritoneal cytology. Representative slides were centrally reviewed. The method of nodal disease examination was not indicated.
GOG 33 identified:
- Washings do not identify node +ve
- Age and size of uterus are not relevant to LN+ve status
- In general the deeper the tumour invaded the less differentiated the tumour became.
- e.g. 78% of Gr 1 had endometrial or superficial muscle involvement only
- 58% of Gr 3 lesions had mild or deep muscle invasion.
- 70 patients (11%) had mets to either pelvic and/or paraaortic nodes
- 22 pts (3%) had mets to both the pelvic and paraaortic nodes
- 12 pts (2%) had metastases to the paraaortic nodes only
- Other category which includes papillary and clear cell had more paraaortic node Mets (18%) than adenosquamous carcinoma (9%)
- Grade of tumor was correlated with the freq of nodal mets.
○ Only 3% of well differentiated tumours had pelvic nodes mets
○ This increased to 18% in poorly differentiated cancers. The same correlation is noted with regard to paraaortic node mets
- An excellent correlation exists between depth of invasion and nodal metastases
- Only 1% of pts with endometrial only had mets to either pelvic or paraaortic nodes
- In Deep myometrial invasion 25% had pelvic and 17% had paraaortic nodal disease
- Lower segment lesions were twice as likely as fundal lesions to have both pelvic and paraaortic meds
- 51% of women with gross peritoneal disease had LN +
- Capillary space involvement was present in 15% and pelvic LN were +ve 4 x and paraaortic 6x more often in that group.
- Depth of invasion and Grade were astd with LN +ve
- Using these low, moderate and high risk groups were formed
- Low risk - Gr 1 endometrium only with no intraperitoneal disease.
○ 0 (none) of these had lymph node disease
- Mod
○ Inner of mid muscle invasion and /or grade 2 or 3 lesions with no intraperitoneal metastasis
○ Depending on whether one or both were present, the risk for nodal mets was 3% and 6 % respectively
- High risk category
○ 2 pertinent factors:
§ Deep invasion and intraperitoneal metastasis
§ Pelvic Lymph nodes metastasis was found in 18% on pts with deep MMI only
§ 33% of pts with intraperitoneal mets had pelvic lymph nodes
§ When both present 61% had nodal mets
- Age and menopausal status had no effect on nodal metastasis
- Nodal palpation - NOT SENSITIVE
- <10% of pt with +ve LN had grossly enlarged nodes
PORTEC 1
PORTEC -1 (Post-Operative Radiation Therapy in Endometrial Cancer (PORTEC)) was an RCT aiming to identify whether post-operative pelvic radiotherapy improve locoregional control and survival for pts with stage 1 EC. Published in the Lancet in 2000.
Women were enrolled with Stage 1 EC (Gr 1, >50% MMI, Gr 2 with any invasion or grade 3 with <50%) after TAHBSO without lymphadenectomy from 19 centres in the Netherlands to received 46 Gy with 2 Gy daily fractions, 5 days a week or follow up. Reviewed 3mth for 3 yrs. Excluded if >8 weeks from OT or had other Ca in the past Primary endpoint were locoregional recurrence and death. Secondary treatment related morbidity and survival after relapse. 714 women were evaluated with a median duration of f/up of 52 months.
Overall EBRT had complications in 25%, whilst most were grade 1 2% had grade 3 or 4 and 20% had long term issues that whilst mild affect QOL.
EBRT lead to a decrease in locoregional recurrence from 14% to 4%. 76% of these recurrences were in the vault and
This was NOT associated with a survival benefit. In fact more women diet in the EBRT than control (81 v 85% p0.31).
More women died from EC in the EBRT group than control 9 v 6%. As per other studies significant changes in grading. ~ 25% of times pathologists will disagree on grade of tumour. There was no difference in outcome depending on which pathologist (i.e. local or central) reported grade. Rate of distant mets was similar 8 & 7%. Suggesting that these were probably present before therapy and that local recurrences do not lead to metastatic disease. Higher rate of GI Ca in both group - same - which is inline with previous evidence of an increased risk of GI Ca in EC patients.
Salvage therapy in vagina with EBRT, Vault or OT was often successful with 2yr survival of 79% vs 21% in distant mets. (3yr 69% and 13%). >60 more likely to die and have recurrence, Gr 3 with <50% MMI as likely to recur ad Gr 1 or 2 with > 50% MMI. But Gr 3 astd with increased rate of distant mets. No Rx 3 x rate of regional recurrence > 60 y.o. Survival after relapse better for control group.
Overal
• Reduced locoregional recurrence but did not impact overall survival and is astd with increased morbidity.
“Post op radiotherapy is not indicated in pts with Stage 1 EC <60 y.o. and Grade 2 tumours with superficial invasion”
SOLO 1
SOLO1 was a placebo-controlled double-blind RCT of olaparib v placebo in maintenance treatment of Stage III or IV Ovarian cancer that had a complete or partial response after platinum-based chemotherapy. All women had germline (388) or somatic (2) BRCA 1 /2 mutations. Published in the NEJM in Dec 2018
The primary outcome was PFS. Secondary - Second PFS, OS, Time from second subsequent therapy or death. Health related QOL. 391 women in 15 countries with HGSC Or Endometriod. 260 olaparib and 131 placebo. Women were randomised to olaparib 300mg BD at 2:1 and placebo. Stage III could have up front or IDS. Continued meds up until 2 years and then stopped if they had no evidence of disease. Partial response could continue in a blinded manner past 2 years.
After discontinuation pt could receive any Rx at the Investigators discretion. Baseline majority had NED and normal CA125.
Median duration of F/up was 40.7 months in olaparib and 41.2 months in THE PLACEBO GROUP.
47% of olaparib and 27% of placebo continued trial intervention at 2 yrs and 10% and 2% continued beyond 2 years.
Free from disease or progression at 3 year was 60% in olaparib and 27% in placebo. Medium PFS in placebo was 13.8% ( consistent with other platinum PARP trials)
Blinded independent review
Rate of progression and death at 3 yrs was 69% in olaparib group, as compared with 35% in the placebo group. HR for progression 0.28 (95% CI 0.20 - 0.39)
Median PFS was approx. 36 months longer in the Olaparib group than in the placebo group.
○ Median Time to 1st subsequent therapy or death was 51.8 months in olaparib and 15.1 months in placebo.
○ Freedom from use of subsequent therapy and death at 3 yrs was 74% in the olaparib group and 56% in the placebo group
- Safety
○ No significant difference between groups.
○ No AE during the trial or up to 30 days post that resulted in death.
○ AML occurred in 3 of 260 patients (1%) in olaparib group and 0 of the placebo - consistent with other PARP trials.
○ New Primary Ca in 2% in both group
○ Pneumonitis or interstitial ling disease in 2% and 0% respectively
- QOL
○ No statistically signif difference ID’d
Pipelle Meta- Analysis
In a Metanalysis from Cancer in 2000 studies from 1966 – 98 were identified that looked at the diagnosis of Endometrial Cancer and hyperplasia from Pipelle vs HD&C or D&C alone. 39 studies with 7914 women.
The sensitivity for diagnosing endometrial cancer in pre and post menopausal women with pipelle was 99.6% and 91%. The sensitivity for the Dx of endometrial hyperplasia was 81%.
The Specificity for the Dx of endometrial Cancer was ~98%. In this meta-analysis only 5% did not have a sample. This is up to 15-20% in other studies.
From another Meta-analysis in BJOG in 2002:
• The post-test probability of Endometrial Ca with an abnormal Pipelle was 82% (HR 66)
• The post-test probability in a –ve test was 0.9% (HR 0.14)
A higher grade may be assigned in up to 30% of cases of endometrial biopsy. This can be important in women not suitable for surgery.
LION Lymphadenectomy Ovarian Ca
International RCT of the effect on OS and PFS in women who after resection to R0 had preoperatively and intraoperatively negative node status to either
No lymphadenectomy
Systematic pelvic and para aortic lymphadenectomy
Published in the NEJM in Feb 2019
Women were assigned pre operatively and operating surgeons only told of their assignment after they had confirmed that they were suitable for the trial. That is they were R0 and did not have any pre-operative and no intraoperative nodes on concern.
Between Dec 08 and jan 12 – 1895 women gave consent and 650 met intraoperative criteria for randomisation.
323 in lymphadenectomy and 324 in no lymphadenectomy group.
More than 90% had partial peritonectomy and 50% GIT resection in both groups. 99.1% had the assigned intervention undertaken in the lymphadenectomy group and 96.6% in the non-lymphadenectomy group. Median of 57 resected nodes was reported inc 22 paraaortic and 35 pelvic. Microscopic metastases in 55.7% of the patients in the lymphadenectomy group.
Median PFS and OS were overall 25.5. months and 67.2 months
Overall Survival: Lymphadenectomy group median OS 65.5 months and 69.2 months in the no lymphadenectomy group. HR 1.06
PFS: 25.5 months in both groups. HR 1.11
WOL – No meaningful differences in global health status and subdomains of QOL were not found.
OT – took longer (340 vs 280 mins)
More blood loss (650 v 500 mL)
More transfusions
More admissions to ICU - 77.6% vs 69.0%
More infections Rx with Abx 25.8% vs 18.6%
+ lymph cysts at discharge, symptomatic and asymptomatic cysts and repeat laparotomies for complications 12.4% vs 6.5%
Higher 60 day mortality 3.1% vs 0.9% - main indication for repeat laparotomy in both groups was bowel leakage or fistula 22 in nodes and 8 in non-nodes group.
80.5% of patients in lymphadenectomy and 83.9% of those in the no-lymphadenectomy group were treiated with platinum and taxane with or without bev
Overally – pts with ovarian Ca Rx with macroscopically complete resection did not benefit from systematic lymphadenectomy. This resulted in treatment burden and harm to patients.
GOG 99
GOG99 was a phase III RCT of surgery +/- adjuvant EBRT in intermediate risk EAC and was published in Gyn Oncology in 2004. It aimed to ID if adjunctive EBRT lowers the risk of recurrence or death in women with EC stages IB, IB and II. 458 women with intermediate risk EAC were randomised after OT to either no additional therapy (NAT) or EBRT with 50.4 Gy in 28 fractions. Intermediate risk based on GOG 33 with any degree of MMI and no LN involvement. Women were eligible if they Endometroid type, had surgical staging with Pelvic and para Aortic LN sampling with their TAHBSO. All nodes -ve. Normal CXR, no previous Ca Rx. Path, surgery and treatments centrally reviewed.
The primary outcome was recurrence (time from study entrance to clinical, histologic or radiographic evidence of recurrence) Secondary were all-cause survival and recurrenve free survival.
Groups change due to low risk of reucrrence into HIR - High intermediate and LIR - Low intermeidate.
HIR - 70+ with 1 RF or 50+ with 2 RF, any age with all 3.
RF - Gr2/3, LVSI, Outer 1/3 MMI
Results
Most recurrences occurred within 18 months. Median follow up was 69 months. Estimated recurrence in 24 months was 3% for RT and 12% for the NAT group.
Major difference was in the vaginal vault recurrences 1.6% for RT and 7.4% for NAT ( in RT the recurrences did not get RT but were included on the intention to treat) Improved survival in RT but not statistically significant. Overall 1/2 of the deaths in the study were not due to EAC.
The HIR group accounted for 2/3 of the recurrence and 2/3 of the Ca deaths.
Absolute decrease in recurrence of 4% in LIR group from 5 - 2%.
Absolute terms RT patients showed a 19% improvement in cumulative incidence of recurrence at 24 months compared to the NAT group
LIR at low risk of recurrence and allows a clearer decision re the need for adjuvant radiotherapy.
