Important Studies in Colorectal Surgery Flashcards
Which study highlighted the utility of adjuvant chemotherapy in Colon cancer?
The NSABP (National Surgical Audit Breast and Bowel Project) C-03 Trial of 1993; Compared LV+5FU with Lomustine and Vincristine. 3 year follow up data.
Treatment with LV + 5-FU significantly prolongs disease-free survival and results in a significant benefit relative to overall survival (30% AR in 3-year mortality). These findings, when considered together with results from a recent meta-analysis demonstrating a benefit from LV + 5-FU in advanced disease, provide evidence to support the concept of metabolic modulation of 5-FU.
Which study supports the addition of Oxaliplatin in stage III colon cancer patients?
Which subsequent meta-analysis confirmed this finding?
The MOSAIC trial of 2004; compared FL alone with FL+Ox.
Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant treatment of colon cancer. Approximately a 5-10% AR in 5-year mortality and corresponding improvement in DFS.
The ACCENT analysis confirmed that stage III patients get improved DFS and lower mortality. Stage II patients have reduced LR but not risk of death.
Summarise the evidence base around neoadjuvant chemotherapy in colon cancer.
Describe the two underlying seminal trials from the last 3 years.
- Neoadjuvant chemotherapy has no clear advantage over adjuvant chemotherapy and over-treatment is a barrier to large-scale adoption.
PRODIGE-22 (Ann. Surg. 2020): “Perioperative FOLFOX for locally advanced resectable CC is feasible with an acceptable tolerability but is not associated with an increased major pathological response rate as expected. However, perioperative FOLFOX induces pathological regression and downstaging. Better preoperative staging tools are needed to decrease the risk of over-treating patients.”
FOXTROT (Ann. Onc. abstr 2019): “Six weeks NAC for operable primary colon cancer can be delivered safely, with improved perioperative morbidity and marked pathological downstaging including some pCRs. There is a trend toward better disease control at 2 years.”
Describe the trials that established the role of EGFR and VEGFR inhibitors in metastatic colorectal cancers.
What were the findings in patients with KRAS/NRAS mutations?
EGFR (Cetuximab):
CRYSTAL trial (2015): Randomized patients between FOLFIRI + Cetuximab versus FOLFIRI alone. In RAS-wt patients the addition of cetuximab improved median overall survival by 8 months.
EGFR (Panitumumab):
PRIME trial (2010): Randomized patients between FOLFOX + Pani versus FOLFOX alone. The addition of panitumumab improved median overall survival by 5.8 months
VEGFR vs EGFR:
FIRE-3 trial (2014): Randomized patients to either bevacizumab or cetuximab, in combined regimens with FOLFIRI. FOLFIRI plus cetuximab group had a longer overall survival (~3 months), suggesting that EGFR inhibition should be the preferred first-line regimen.
Note: In these same trials, patients with KRAS/NRAS mutations did not benefit from these monoclonal ABs.
Describe the trial that established the role of immune-checkpoint inhibitors in metastatic colorectal cancers.
What was the improvement in survival with Pembrolizumab?
KEYNOTE-177 trial (2020). This phase III trial randomized patients with untreated MSI-H/MMR-D metastatic CRC to the immune checkpoint inhibitor pembrolizumab or investigators’ choice of FOLFOX or FOLFIRI with or without bevacizumab or cetuximab.
The median progression-free survival was 16.5 months with pembrolizumab and 8.2 months without (P .002).
However, overall survival was challenging to interpret because patients who progressed in the chemotherapy group crossed over to the pembrolizumab group.
Describe the seminal study assessing neoadjuvant chemoradiotherapy versus radiotherapy alone in rectal cancer.
What do subsequent meta-analyses show?
The largest trial, European Organisation for Research and Treatment of Cancer (EORTC) 22921 (2005), examined long-course (five-day bolus FU and LV regimen during weeks 1 and 5 of RT) versus short-course RT alone (45 Gy over five weeks) Compared with RT alone, patients undergoing preoperative chemoradiotherapy had a significantly higher pCR rate (14 versus 5 percent), significantly less advanced pT and pN stages, and fewer cases with venous, perineural, or lymphatic invasion.
In a subsequent meta-analysis of this trial and five others the addition of concomitant chemotherapy to neoadjuvant RT improved local control (McCarthy et al 2012). However, there was also a higher rate of acute treatment-related toxicity with chemoradiotherapy.
Describe the seminal trial assessing targeted therapy in patients with BRAF V600E mutations.
What is Binimetinib?
BEACON trial (2019):
This phase III trial randomized patients with BRAFV600E mutations to either triplet Cetuximab + Encorafenib + Binimetinib versus doublet regimens of either Cetuximab + Encorafenib or Cetuximab + FOLFIRI/irinotecan in patients with disease progression.
The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group.
Binimetinib is a selective inhibitor of the enzyme MEK, a central kinase in the tumour-promoting MAPK pathway.
Which two recent trials address TNT?
What were the respective regimen’s used and what were the outcomes?
The 2021 RAPIDO trial compared short-course radiotherapy + consolidation chemotherapy (FOLFOX/CAPOX) versus long-course chemoradiation + adjuvant FOLFOX/CAPOX. Both groups underwent TME after neoadjuvant treatment.
Patients in the experimental group had significantly higher rates of pCR (28% v 14%, p <0.001). Regarding survival, RAPIDO demonstrated an improvement in disease-related treatment failure (23.7 vs 30.4% p = 0.019).
The 2021 PRODIGE 23 trial compared TNT using long-course radiotherapy preceded by induction FOLFIRINOX versus standard long-course chemoradiation. Both groups received adjuvant FOLFOX (3 months in the intervention group, 6 months in the control group). Both groups underwent TME after preoperative treatment.
Patients in the experimental group again had significantly higher pCR rates (28 vs 12%, p<0.001 and 3-year disease free survival (76 vs 69%, p = 0.034).
Both trials used slightly unconventional approaches; RAPIDO choosing SCRT instead of long course in one arm, and PRODIGE-23 using Irinotecan triplet chemo and giving everyone adjuvant FOLFOX.
Which landmark trial established the use of Neoadjuvant Radiotherapy?
The 1997 Swedish Rectal Cancer Trial:
Compared NASCRT to surgery alone. LR was halved from 27% to 11%. OS and DFS were improved in the NASCRT group by about 10% each.
Which landmark paper consolidated pre-operative as opposed to post-operative radiotherapy?
The German Rectal Cancer Study Group trial in 2004.
Randomly assigned patients with T3-T4 tumours or node-positive disease to pre-operative or post-operative chemoradiation.
5-year OS was similar between the groups (76% vs. 74%) but LR was lower in the patients who received pre-operative chemoradiotherapy (6% vs. 13%, p=0.006). This group also experienced less strictures and lower toxicity.
Which trial addressed the optimal fractionation of pre-operative radiotherapy and timing to surgery?
What were the results?
The STOCKHOLM-III trial of 2017.
840 patients randomized to short-course-short-wait (within one week), short-course-long-wait (4-8 weeks), or long-course-long-wait (4-8 weks).
“Delaying surgery after short-course radiotherapy gives similar oncological results compared with short- course radiotherapy with immediate surgery. Long-course radiotherapy with delay is similar to both short-course radiotherapy regimens, but prolongs the treatment time substantially… Based on these findings, we suggest that short-course radiotherapy with delay to surgery is a useful alternative to conventional short-course radiotherapy with immediate surgery.”
Provide a summary of the long-term results from the International Watch and Wait database.
(Rates of re-growth, subsequent salvage, metastatic disease, and OS/DFS)
880 patients were identified who had a cCR and were offered W&W on the database. Median follow up time was 3 years.
Two-year regrowth rates were 25.2%, ~90% of which was diagnosed in the first two years, and 97% of which was located in the bowel wall.
~80% of patients with re-growths underwent subsequent TME, while ~20% underwent local excision only.
The rate of distant metastases was 8%, but only a small percentage of these (11%) were found in the first year.
5-year OS was 85% and 5-year DFS was 94% for all patients in the IWWD
“Local regrowth occurs mostly in the first 2 years and in the bowel wall, emphasising the importance of endoscopic surveillance to ensure the option of deferred curative surgery. Local unsalvageable disease after W&W was rare”
What was the purpose of the OPRA study?
What was the design and what were the findings?
The Organ Preservation in Patients with Rectal Adenocarcinoma Treated with TNT trial (2022) was designed to assess the outcomes of rectal cancer patients treated with either TNT induction versus TNT consolidation regimens. Both arms received long-course CRT and CAPOX/FOLFOX chemotherapy for their TNT.
Median follow-up was 3 years. Three-year DFS was 76% for both induction and consolidation groups.
Three-year TME-free survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 62) in the CRT-CNCT group. This lead the authors to conclude that
“Organ preservation is achievable in half of the patients with rectal cancer treated with (consolidation) total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, TME, and postoperative chemotherapy.”
Provide an overview of the seminal trials assessing the role of antibiotics in uncomplicated diverticulitis.
- The AVOD (Antibiotika Vid Okomplicerad Divertikulit – Swedish for ‘antibiotics in uncomplicated diverticulitis’) trial of 2012:
- ~600 patients with uncomplicated left sided disease
- Randomised to IV ABx versus Supportive care only
- No differences between study groups for complications, subsequent diverticulitis, need for surgery, or hospital stay
- The DIABLO trial (DIverticulitis: AntiBiotics Or cLose Observation?) was undertaken in 22 centres from the Netherlands and was published in the British Journal of Surgery in 2017
- 528 patients with a first episode of left sided, uncomplicated, acute diverticulitis, confirmed within 25 hours by CT
- Randomised to no antibiotics or 48 hours of intravenous amoxicillin–clavulanic acid antibiotic
- No difference between study groups for the primary outcome of time to full recovery. In addition, the duration of hospital stay was shorter in the no antibiotic group.
- The STAND study (Selective Treatment with Antibiotics for Non-complicated Diverticulitis) was the most recent randomised controlled trial on this topic published in Clinical Gastroenterology and Hepatology 2021.
- This was undertaken in 4 centres in Australia and New Zealand and randomised 180 patients with CT proven Hinchey 1a acute left sided diverticulitis to either antibiotics (intravenous or oral) or placebo.
- There were no significant differences identified between groups for the primary outcome of length of hospital admission. There were also no significant differences for adverse events or hospital readmission.
What are the major criticisms of the PRODIGE-7 trial assessing the role of HIPEC with CRS?
- The study included patients with CC-1 (i.e. incomplete CRS)
- The study population included patients pre-treated with Oxaliplatin-based systemic chemotherapy, who may have developed resistance
- The study included patients with PCI scores of up to 25
- The adjuvant therapy was restricted to 5-FU only
- Mortality rates were above average for major centres (3% cf 1%).
Proponents of CRS and HIPEC therefore assert that the findings of PRODIGE-7 are not generalisable, particularly to the US population.
