Trials Flashcards
POISE 3
PeriOperative ISchaemic Evaluation trial series
TXA vs placebo for non-cardiac surgery, and comparison of hypotension avoidance vs hypertension avoidance
Outcome: composite of death, MI and cardiac arrest
The primary objective of the study is to determine; if TXA is superior to placebo for the occurrence of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic event; and to determine the impact of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of vascular death and major vascular events in patients who are followed for 30 days after noncardiac surgery.
ALACART
Stevenson et al JAMA
RCT to see whether lap rectal surgery noninferior to open
475 patients
Lap surgery was not shown to be non-inferior – so potentially may be worse, though not proven using this methodology
No sig diff in DFS or OS
Take away: overall lap and open are probably comparable (according to the literature)
TAILORx
Breast cancer
- Randomised patients to chemo+endocrine rx vs endocrine rx only for mid range risk score (11-25) on Oncotype DX
- 10273 women with hormone+ her2- node neg breast ca
Did not show any benefit to chemo in addition to endocrine therapy in these patients
Oncotype DX
- Score from 0 - 100
- High risk score = >26
POSNOC
UK & Australasian trial
- Broader inclusion criteria than Z11 – includes mastectomy and neoadj
- Women with 1 or 2 +ve sentinel nodes
- Comparing systemic treatment alone to systemic rx + axillary rx (clearance OR radiotx)
- Clearance or radiotx is according to local guidelines
- Basically to answer question over whether any axillary rx is needed
Leopard-1 and 2
LEOPARD 1
Lap vs open distal pancreatectomy
Earlier recovery, longer op times, 15% conversion rate, less blood loss with lap
Dutch onc group
LEOPARD 2
Lap vs open pancreatoduodenectomy
Stopped early due to 10% mortality in lap group vs 2% in open
50% vs 39% clavien-dindo 3 or higher complications
FLOT
Gastric cancer
Al-Batran - Lancet 2019 – FLOT-4-AIO
Docetaxel, Oxaliplatin, Leucovorin and FU
4 cycles before and 4 cycles after surgery
Improved survival compared to MAGIC protocol; further support for use of pre/periop chemo for gastric ca
CROSS
Oesophageal cancer
BMC Surg 2008
Neoadjuvant chemo (carboplatin and paclitaxel) and radiotherapy followed by surgery, vs surgery alone 366 patients randomised Overall survival twice as long (48 vs 24 mo)
CROSS compared to MAGIC in Neo-AEGIS trial 2014
MAGIC
NEJM 2006 (before CROSS)
MAGIC trial (Cunningham, UK)
Pre and post-op chemo vs surgery alone for lower oesoph, GOJ and gastric ca
Epirubicin, cisplatin and 5-FU
Downstaged disease, improved OS, DFS, local recurrence, distant mets
Also criticised for inadequate lymph node dissection (but most had D2, 15% got D1)
CRASH-2
TXA for bleeding trauma patients
Multicentre RCT (a lot in developing countries)
1 g TXA stat then 1g 8h infusion
Reduced overall mortality
Increased thromboembolic complications if started >3h post-injury
SNAC
Breast cancer
Gill et al Annals of Surgical Oncology 2009
>1000 women randomised to SNB followed by ALND, or SNB with clearance only if positive
Outcome = increase in arm volume (lymphoedema)
Sentinel node based management causes less lymphoedema
Z-011
Guiliano JAMA 2017
- T1/2 breast ca with no clinical nodes, and 1-2 positive sentinel nodes at surgery
- Showed that ALND can be avoided for this group – no difference in survival or local control
Criticisms:
- Whole breast irradiation postop included wide fields and encompassed much of axilla, so patients were really getting some axillary treatment
- Most patients received systemic chemo postop
- Doesn’t apply to mastectomy (didn’t include these pts in trial)
- Didn’t include neoadjuvant patients
- Included micromets as positive node (a lot of people would not treat these as positive nodes)
NSABP P-1
Tamoxifen vs placebo for 5 years for prevention of breast cancer in higher risk women (age over 60 or Gail model risk >1.6%% or history of LCIS)
- Reduced risk of breast ca by half
- Increased risk of PEs and endometrial cancer
HERA trial
HER2 for 1 year, 2 years or placebo for HER2 positive breast ca, given after adjuvant chemo (adj/neoadj)
Significant survival benefit for 1 year
No additional benefit (and more cardiotoxicity) if given for 2 y
Dutch Trial
Dutch TME Trial
- Multinational RCT of neoadj SHORT course radiation for rectal ca
- 1861 patients enrolled
Fixed cancers excluded
- 2 yr local recurrence better with RTx (2.4% vs 8.2%)
No difference in OS
German Trial
October 21, 2004 N Engl J Med 2004; 351:1731-1740 5 weeks of radiotherapy + IV fluorouracil during 1st and 5th weeks = LONG course 823 patients randomised No difference in OS Improved local recurrence (6 vs 13%)
Swedish Trial
N Engl J Med. 1997 Apr 3;336(14):980-7.
RCT of preop SHORT course RTx vs straight to surgery
Gave radiotx over 1 week, followed by surgery within a week
Reduced local recurrence (11 vs 27%) at 5yr
Improved overall survival (74 vs 65%)
COST
Clinical Outcomes of Surgical Therapy Study Group. “A comparison of laparoscopically assisted and open colectomy for colon cancer”.NEJM 2004
Multicentre North American RCT, 872 pts
No difference in recurrence rates at 3 years, OS, DFS
Shorter LOS and duration of iv analgesia
Criticisms: no rectal ca
CLASSIC
Long-term follow-up of the Medical Research Council CLASSIC trial of conventional versus laparoscopically assisted resection in colorectal cancer. Br J Surg 2013 (original study reported in 2005)
Multicentre UK RCT
No difference in OS or DFS for lap vs open at longterm f/u
Conversion assoc with worse outcomes
Original study didn’t recommend lap for rectal ca as had more +ve margins in rectal group
COLOR
COLOR: a randomized clinical trial comparing laparoscopic and open resection for colon cancer. Lancet Oncol 2008
Lap vs open colon ca, European Multicentre RCT
NB: COLOR II showed similar results for lap vs open rectal surgery
COLOR III: transanal vs lap TME – ongoing, started 2016
Meta-analysis of lap vs open colorectal surg - J Clin Med Res. 2015
Lower LOS and complication rate with lap surgery
Comparable DFS, OS, surgical outcomes (nodes harvested etc)
TROG
TROG trial - Lancet 2012 - Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy
Randomised patients as above
Reduces risk of lymph node field relapse
No difference in relapse-free- or overall survival
High rate of complications
Recommended avoiding radiotherapy outside of trial setting
STOMAMESH
Randomized controlled double-blinded multicenter trial
A lightweight polypropylene mesh was placed around the colostomy in the sublay position. 232 patients randomised to mesh or no mesh.
The use of reinforcing mesh does not alter the rate of PSH. No difference in complication rate was seen between the 2 arms. Based on these results, the prophylactic use of mesh to prevent PSH cannot be recommended.
Neo-AEGIS
CROSS (chemorads) vs MAGIC or FLOT (periop chemo) for oesophageal and GOJ tumours
Suggests no difference in OS, both options equal
Some suggestion of greater tumour response in chemorads arm
ALMANAC
SNB vs routine ALND for clinically node neg cancers
SNB management equivalent outcomes and less morbidity
CAPP and CAPP 2
Aspirin for prevention of colorectal cancer
RAPIDO
Trial of total neoadjuvant therapy in rectal ca
Enrolled 920 patients with MRI-diagnosed locally advanced rectal cancer with either: - T4a/b - extramural vascular invasion - cN2 disease - involved mesorectal fascia - enlarged lateral lymph nodes (Basically, bad cancers)
Gave short course RT, followed by 18 week course of chemo (FOLFOX or CAPOX), compared to long course CRT with adjuvant chemo
Reduced distant mets and treatment failure
No difference in locoregional recurrence or overall survival
MOSAIC
Addition of oxalplatin to 5-FU and leucovorin for adjuvant colorectal cancer
Benefit for stage 3, not for stage 2
IBIS - 1
Role of tamoxifen for prevention of breast cancer in high risk patients
- 20mg tamoxifen daily for 5 years
Significant risk reduction, mainly in hormone+ cancers
IBIS - 2
Role of anastrazole for prevention of breast ca in high risk postmenopausal women
1mg anastrazole daily for 5 years or placebo
Significant risk reduction, mainly in hormone+ cancers
MSLT-1
2000 patients, 10 year followup
Inclusion
- Breslow 1mm or more
- Localised melanomas
Randomised patients to:
- SNB with clearance if sentinel node positive
- Observation, with clearance for clinical positive disease
Results
- Improved disease-free survival
- Patients who underwent SNB have fewer recurrences than patients who are observed only
- Sentinel node positivity was strongest predictor for disease recurrence or death
Conclusions and criticism
- Sentinel node is useful for prognostication
- Showed the efficacy of sentinel node-based management
- Can’t truly compare groups as sentinel node status only known for SNB group - thus biasing survival toward biopsy group. Provides rationale for MSLT-2
MSLT - 2
Randomised 1939 patients with a positive SNB to clearance, or observation with clearance if node basin positive
Results
- No difference in overall survival
- Improved disease control with early dissection
Summarise the trials that guide sentinel node management in breast cancer
Sentinel node based management of breast cancer has become the norm internationally, though the most appropriate management of the results continues to be controversial and is evolving.
Trials demonstrating the efficacy of sentinel-node based management rather than routine axillary dissection are numerous, but include the ALMANAC and SNAC trials from Australasia. In the SNAC trial, routine axillary dissection was compared to sentinel node-based management, whereby a positive sentinel node would prompt ALND, with a negative avoiding further axillary surgery. There was considerably reduced morbidity in the sentinel-node arm without a difference in oncological outcomes. ALMANAC and NSABP-B32 had similar findings.
Micrometases in the sentinel node do not require further axillary treatment as suggested by the IBCSG 23-01 trial.
More recently the policy of mandatory ALND for a positive sentinel node has been questioned. The Z011 trial in the US enrolled early stage breast cancers undergoing breast conserving surgery with adjuvant whole breast irradiation, with 1 or 2 positive sentinel nodes. They compared routine ALND to no further surgery and found no difference in oncological outcomes, though there was more morbidity in the ALND group. They concluded that ALND could be avoided in this subset of patients with 1-2 positive SLNs. Criticisms include that patients undergoing mastectomy were excluded; most patients received some form of adjuvant systemic therapy; and the breast radiation fields were wide and encompassed much of the axilla. This counts as axillary treatment.
The AMAROS trial compared similar patients with positive sentinel nodes and randomised them to axillary radiotherapy or surgery. Oncological outcomes were similar between groups, with less morbidity in the radiotherapy group.
The POSNOC trial in the UK and Australasia aims to clarify whether any axillary treatment (radiotherapy or surgery) is necessary in patients with early breast cancer. Inclusion criteria are broader than Z011, with patients undergoing mastectomy included, as well as those who had had neoadjuvant chemotherapy. Patients are randomised to no axillary treatment for 1-2 positive SLNs, vs radiotherapy OR surgery according to local protocols. Results are anticipated.
Summarise neoadjuvant treatment for rectal cancer including the trials that inform this
Indications for neoadj:
- absolute = locally advanced disease
- relative = clinical nodal disease, CRM threatened
Dutch
- Short course radiation
- Reduced local recurrence, no difference in OS
German
- Long course chemorads
- Reduced LR, no difference in OS
Swedish
- Short course rads
- Reduced LR, improved OS (unlike the others)
TROG 0104
- No difference between short course and long course
Surgery is best performed after a longer interval post neoadj - 8 weeks or more
Discuss the evidence for laparoscopy in colorectal surgery
Laparoscopic surgery was developed in the 1980s and has seen an explosion in popularity and indications. Initial experience in the colorectal setting was tempered by concerns about achieving comparable oncological outcomes, prompting a number of trials to address the question.
COLOR 1, 2, 3
- COLOR 1: Laparoscopic surgery for non-metastatic colon cancer is associated with similar rates of disease-free survival, overall survival and recurrences as open surgery at 10-year follow-up.
- COLOR 2: similar for rectal surgery
COST
- No difference in DFS or OS
- Shorter LOS and fewer complications
- Only colon ca
CLASSIC
- No difference in DFS or OS
- Shorter LOS and fewer complications
- Included colon and rectal ca
ALACART
- A more recent study in Australasia comparing total mesorectal excision performed laparoscopically vs open for rectal cancers
- Could not demonstrate non-inferiority of lap TME compared to open
Discuss the role of “ watch and wait” strategies for rectal cancer with reference to the evidence
Complete clinical response may be seen in around 15% after neoadj for rectal ca
Studies conducted using International Watch and Wait database
- Suggest that this is safe approach, with 25% rate of recurrence (and recurrences are salvageable)
- OS is the same for WnW vs surgery
- But very intense surveillance required
Discuss the role of total neoadjuvant treatment in rectal cancer with reference to the evidence
- Instead of just giving 5-FU, give FOLFOX or FOLFIRI (as would be done for mets or adjuvant rx) as well as Radiotx
- PRODIGE 23 trial suggests increased pCR but no effect on OS
- RAPIDO trial showed no difference in LR or OS
Benefit of TNT is higher rates of pathologic complete response
So far no trial has shown any benefit for OS compared to conventional treatment
Discuss the evidence for perioperative treatments in oesophageal cancer
Oesophageal cancer is a highly deadly malignancy and high recurrence rates with surgery alone, prompting the search for more effective multimodal treatments. Initial trials identified a benefit for chemotherapy and radiotherapy in the adjuvant setting, and more recently neoadjuvant or perioperative chemotherapy has been investigated. It is indicated for stage II or above oesophageal carcinoma - that is, locally advanced (T3 or T4) tumours or clinical nodal disease.
The MAGIC trial from the UK investigated pre- and post-operative chemotherapy with Epirubicin, Cisplatin and 5-fluorouracil for gastrooesophageal junction and gastric cancers, demonstrating a significant survival advantage compared to surgery alone. Subsequently the FLOT protocol of 5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel, 4 cycles pre- and 4 cycles post-op, has been shown to have superior oncological outcomes to MAGIC for gastric and junctional cancers and is frequently used for oesophageal adenocarcinomas too.
More recently, neoadjuvant chemoradiotherapy has been demonstrated to offer greater survival benefits to surgery alone. The CROSS trial showed neoadjuvant carboplatin and paclitaxel plus radiotherapy doubled overall survival compared to surgery alone.
The Neo-AEGIS trial compared preoperative chemoradiotherapy (CROSS protocol) to perioperative chemotherapy (FLOT protocol) and found no difference in overall survival or local control.
Discuss the evidence for perioperative treatments in gastric cancer
MAGIC
MacDonald
FLOT
TOPGEAR
TOPGEAR
Australasian RCT for gastric ca
Comparing MAGIC protocol periop chemo to pre-op chemoradio and postop chemo
Results awaited
MacDonald protocol
Indications: Adjuvant Stage IB to IV (M0) adenocarcinoma of the stomach following curative resection.
Protocol: postoperative chemo radio with leucovorin and fluorouracil
Generally superseded by MAGIC or FLOT as very toxic
Also criticised as in original study, lots of patients had D0 or D1 resection only and so survival benefit with chemorads may only be due to compensating for suboptimal surgery
CRASH-2
.
MATTERS
..
PROPPR
- RCT of 12 north American trauma centres
- Randomised patients to 1:1:1 Plt:FFP:RBC vs 1:1:2
- No difference in survival at 24h or 30d
- Death by exsanguination better in intervention group, with no difference in complications
- Time to achieve haemostasis was less
- Total products transfused was less
- Underpowered
