Rectal Cancer Flashcards
What is the definition of a rectal cancer?
Cancer within 15cm of anal verge by rigid proctoscopy - 5cm or less = Low - 5.1-10cm = Mid - 10.1 to 15cm = High At or below the peritoneal reflection Below the 1st or 2nd sacral vertebrae
What is the main histology for rectal cancer?
Adenocarcinomas 95-98%
What is T4?
(A) Perforation into visceral peritoneum
Or
(B) invasion to other organs
What is N1
1-3 regional LN involved
What is N2
4 or more regional LN involved
What is the sub classification in M1 disease?
M1a = one distant organ or set of LN
M1b = More than one organ or to the peritoneum
What are the layers of the GI tract
(M.S. M.S.)
Muscularis mucosae
Submucosae
Muscularis propria
Subserosal connective tissue
What is the Haggitt classification
This represents the histological classification of the extent of invasion of pedunculated malignant colorectal polyps
What is T2 and T3?
T2 = invasion into Muscularis propria T3 = invasion into Subserosa/perirectal tissue
What is T1?
Invasion into Submucosae
Why is pre-op treatment preferred?
More effective
Less toxic
What is Total mesorectal excision (TME)?
Total mesorectal excision = TME
Excision of all the mesorectal fat, including all lymph nodes.
If an abdominoperineal excision is planned, what must the dissection encompass?
Dissection from above must be stopped at the tip of the coccyx,
Be continued from below (to get a cylindrical specimen)
Without a waist effect towards the tumor carrying a risk of cram+ or an R1/2 resection
Is postop CRT encouraged?
Not anymore. However, this can be used in :
- positive crm
- perforation in the tumor area
- defects in the mesorectum
- in cases with high risk of local recurrence if preop RT was not given.
What are the risks of short-course RT?
Increases:
- risk of poor anal and sphincter sexual function
- small bowel toxic effect with obstruction
- secondary malignancies
What are considered high-risk features on transanal excision ?
Positive margins
LVI+
Poorly differentiated tumor
Sm3 invasion
What are the options available if a pt has symptomatic rectal cancer but Unresectable synchronous mets?
1) Combination systemic chemo
2) Infusional 5FU/RT or Bolus 5-FU/RT or Cape/RT
3) Resection of involved rectal segment
4) Laser recanalization
5) Diverting ostomy
6) Stenting
After above then proceed to chemo for advanced/met disease
What are the ways that recurrence in rectal cancer can occur?
1) Serial CEA elevation
2) Isolated pelvic/anastomotic recurrence
3) Documented metachronous mets by CT/MRI/biopsy
What is considered as a negative circumferential resection margin?
> 1mm
What is the no. Of LN retrieved dependent on?
Age
Gender
Tumor grade
Tumor site
What are considered tumor clusters?
These are
What are the criteria to render a rectal cancer amenable for transanal excision?
3mm)
Mobile, not fixed
Within 8cm of anal verge
T1 only (i.e. Does not invade beyond Submucosae)
Endoscopic ally removed polyp with cancer/indeterminate pathology
No LVI
No PNI
Well-to moderately differentiated
No evidence of LN on pretreatment imaging
What are the ways in which concurrent ChemoRT can be given for 5FU?
1) RT + CI5FU
- 5FU (225) over 24 hours
- 5-7 days a week during RT
2) RT + Cape
- Cape (825) BD, 5 days a week
- RT for 5 weeks
3) RT + 5FU/Leucovorin
- Bolus 5FU (400) + Bolus Leucovorin (20)
- 4 days, Week 1 and Week 5 of RT
What should RT in Rectal Ca encompass ?
- Tumor/Tumor Bed with a 2-5cm margin
- Presacral nodes
- Internal iliac LN
- External Iliac LN if T4 tumors which involved anterior structures.
- Perineal wound if APR done
How is MMR deficiency detected?
As changes in the length of repetitive DNA elements in tumor tissue caused by the insertion deletion of repeated units
How is Lynch syndrome detectable by?
1) IHC analysis for MMR protein expression
- often diminished because of mutation
2) Analysis for micro satellite instability
- This results from MMR deficiency
- detected as changes in the length of repetitive DNA elements in tumor tissue, which is caused by the insertion/deletion of repeated units
When MLH1 expression is absent, what does BRAF gene mutation indicate?
BRAF mutation indicates that MLH1 expression is down regulated through somatic methylation of the promote region of the gene, and NOT through a Germline mutation
What does an Abdominoperineal resection (APR) include?
En Bloc resection of the recto sigmoid, Rectum, anus \+ Surrounding mesentery, mesorectum (TME) \+ Perianal soft tissue \+ Creation of a colostomy
Any evidence for preop CRT?
Large prospective RCT from the German Rectal Ca Study group compared preop vs postop CRT in Stage II/III rectal Ca.
RESULTS: preop Therapy a/w: - reduction in LR 6% v 13% >>10y LR 7% vs 10% - reduction in tx-associated toxicity 30% vs 40% - ~OS
What are the advantages of pre-op RT?
Reducing tumor volume may facilitate resection, increase likelihood of sphincter-sparing procedure
Surgery-naiive tissue is better oxygenated. Irradiating preop may result in increased sensitivity to RT
Preop RT can avoid the occurrence of radiation-induced injury to small bowel rapped in the pelvis. By post-surgical adhesions
Anastomosis remains unaffected by effects of RT as irradiated tissues resected
What are the disadvantage of using preopRT?
Possibility over over-treating early-stage tumors that do not require adjuvant radiation
What is the advantage of concurrent CRT?
Local RT sensitization
Systemic control of disease (eradication of micromet)
Preop CRT can also increase pCR rate
What is the NSABP R-04 trial?
Cape = 5FU in periop CRT therapy.
N=1600, stage II/III rectal cancer
2x2 factorial:
10) Infusional 5FU +/- Ox
2) Cape +/- Ox
RESULTS:
- no differences in local-regional events, DFS, OS, complete pCR, SSS, or surgical down staging
- However, toxicity increased with inclusion of Ox.
Cape = 5FU for CRT. True?
Yes
1) NSABP R-04
- O’connell et al
- n=1600; 2x2 factorial design
- 5FU+/-Ox vs Cape +/-Ox
- no difference in Local-regional events/DFS/OS/pCR/SSS/surgical down stating.
- Tox worse with Ox.
2) Hofheinz et al Lancet Onco 2012 N=400 2arms: 2#Cape-->CRT-->3#Cape vs 2#bolus 5FU-->CRT-->2#bolus 5FU RESULTS: - 5yOS in Cape non-inferior - Cape with fewer distant met 20% vs 30%
How is short-course radiation therapy administered?
25Gy in 5 fractions
Surgery within 1-2 weeks of completion of therapy
Not combined with chemotherapy
What is the advantages of short-course RT and in which group of patients do we use this?
Gives effective local control and the same OS
T3N0 or T1-2N1-2 rectal Cancer
NOT recommended for T4 disease
What evidence do you know for short-course RT?
1) Dutch TME trial
Peeters Ann Surg 2007
Aim: To invx efficacy of Short-course RT + Total mesorectal excision in resectable rectal CA
2 arms:
1) RT–>TME
- 5x5Gy
2) TME alone
* No chemo allowed in both arms.
RESULTS: F/u 6 years 5y Local recurrence risk 6% vs 11% (RT) 5y OS ~60% ESP useful for: lesions 5-10cm from anal verge and for pts with uninvolved CRM
What does a good response to neoadjuvant in rectal cancer tell us?
50-60% are down staged with neoadjuvant.
20% showing pCR
It predicts for:
- OS
- DFS
- distant mets
- response to neoadjuvant treatment response
MERCURY prospective cohort trial:
- 100 patients assessed by MRI and pathologic staging
- poor tumor regression grade had 5y OS 30% vs 70% in those with good regression grade.
- DFS 30% vs 60%
CAO/ARO/AIO094 showed that pCR patients had:
- 10y incidence of distant met 10% vs 40%
- 10y DFS 90% vs 60%
EORTC 22921
- patients down staged to ypT0-2 were more likely to benefit from chemo cf to ypT3-4
How is OS affected by the delay in adjuvant therapy?
2011 systematic review and meta-Analysis, n=15000
Each 4-week delay results in a 14% decrease in OS
What do you know about recurrence scores in CLR CA?
Oncotype Dx colon cancer assay
quantifies the expression of 7 recurrence-risk genes and 5 reference genes as a prognostic classifier of low, intermediate, or high likelihood of recurrence.
Clinical validation done in QUASAR and NSABPC-07 trials
Recurrence scores are prognostic for recurrence, DFS and OS in stage II/III
Low risk = 3y recurrence 12%
Intermediate risk = 3y recurrence 18%
High risk = 3y recurrence 22%
What are the options for T3-4 lesions/nodal involvement/locally Unresectable disease/medically inoperable patients?
T3-4/N0
Tany/N1-2
Locally Unresectable disease
Medically inoperable:
1) Chemo+Long-course RT–>resect if possible –> chemo
2) Short-course RT (not for T4) –> Resect if possible–>Chemo
3) Chemo–> CRT –> Resect if possible
Radiation dose to small bowel should be limited to how much?
45Gy
What is intraop RT (IORT) and when do we consider it?
IORT involves direct exposure of tumors to RT during surgery, while removing normal structures from the field of treatment.
Considered as an additional boost to facilitate resection.
Considered when:
T4 tumors
Recurrent cancers
Very close/positive margins
What is an alternative to IORT?
10to 20Gy and/or brachytherapy to a limited volume
How often do CLR CA patients p/w synchronous liver mets?
20-30%
What are some of the liver-directed therapies that you know of?
Hepatic arterial Infusion TACE (TransArterial ChemoEmbolization) Liver-directed radiation - Radioembolization with microspheres - Conformal (Stereotactic) EBRT Tumor Ablation - RFA - Microwave ablation - Cryoablation - Percutaneous ethanol injection - electro-coagulation
What is Hepatic Arterial Infusion?
Placement of a hepatic arterial port or implantable pump during surgical intervention for liver resection
With subsequent infusion of chemotherapy directed to the liver mets through the hepatic artery.
What is TACE?
TransArterial ChemoEmbolization involves hepatic artery catheterization to cause vessel occlusion with locally delivered chemotherapy
How common is peritoneal Carcinomatosis in CLR CA?
20% of met CLR CA
2% having the peritoneum as the only site of disease
What is the evidence for HIPEC?
What are the criticisms of this trial?
Verwaal JCO 2003
Aim: Confirm that aggressive CRS+HIPEC > palliative chemo +/- surgery
N=100
2 arms:
- systemic chemo (5FU based) +/- palliative surgery
- aggressive CRS+HIPEC–> same systemic chemo
RESULTS
2y f/u
Median survival 22m vs 13m
Criticisms:
- No Oxaliplatin/Irinotecan/molecular targets used
- peritoneal carcinomatosis origin from appendiceal, which is known to have better prognosis.
» retrospective study: peritoneal carcinomatosis from Colon median OS 30m vs 77m (appendiceal)
What is the survival for stage I rectal CA?
80-90%
What is the 5y survival for stage II Rectal CA?
What is the LR rate after surgery alone in the following situations:
1) T1-2N0
2) T3N0
3) T3-4N1-2
1) T1-2N0 =
What were the 3 trial that formed the basis on adjuvant therapy for rectal cancer in 1990s?
1) NSABP -R01
2) GITSG 7175
3) NCCTG-Mayo 794751
Came about because postop RT alone does not confer a survival advantage.
Tell me about NSABP-R01
N=550
Dukes B and C rectal CA s/p curative resection.
3 arms:
1) observation
2) postop adjuvant chemo with MOF
- Semustine, Vincristine, 5FU
3) post-op RT
RESULTS:
1) Chemo>observation
- improvement in DFS and OS
2) Men>Female get the benefit from postop chemo
3) Younger>older
4) Postop RT reduced Loco-regional recurrence it failed to affect DFS and OS
How did we prove CRT >RT?
NCCTG-Mayo 794751
NEJM 1991
Trial study evolved from GITSG group.
N=200
2 arms:
1) Post op RT
2) Post op CRT (Semustine+5FU)
RESULTS:
CRT had lower LR (50% reduction) and lower chance of death (30% reduction)
What are the trials looking at CRT?
GITSG
NCCTG-Mayo 794751
Norwegian Adjuvant Rectal Cancer Project
NSABP-R02
Tell me about the Norwegian Adjuvant Rectal Cancer Project Group
n=136
2 arms:
1) observation
2) postop 5FU+RT
RESULTS: LR 10% vs 30% (Obs) Better DFS 60%vs 50% Better OS 60% vs 50% No difference in distant mets
Tell me about the NSABP-R02
N=700
2 arms:
1) Postop CRT (RT + either MOF or 5FU/LV)
2) Postop chemo (either MOF or 5FU/LV)
RESULTS:
5FU/LV had a longer DFS compared to MOF
Addition of RT to adjuvant chemo improved local control 8% vs 13% but not survival 60%
What are the trials that talked about optimizing postop CRT?
(G.I.I.N.K)
1) GITSG 7180
2) INT 0114
3) INT 0144
4) NCCTG 864751
5) Korean study
What is the GITSG 7180 about?
N=200
2arms:
1) Postop 5FU/RT -> 5FU/Semustine
2) Postop5FU/RT->5FU
RESULTS
N difference in OS, Semustine is not an essential component
Tell me about NCCTG 864751 in rectal cancer
N=660
Stage II/III rectal cancer
All received 2# post-op chemo before and after CRT
2 arms:
1) Bolus 5FU
2) prolonged venous infusion
RESULTS:
Infusional 5FU/RT was a/w longer OS, RFS, and few distant mets wen compared to Bolus 5FU, no difference in LRC
No need for Semustine
What is INT 0114 about?
JCO 2002
N=1700
Locally advanced rectal cancer
4 arms:
1) Postop 5FU + RT
2) Postop 5FU/LV + RT
3) Postop 5FU/LEV + RT
4) Postop 5FU/LV/LEV + RT
No difference in LR, RFS and OS
3-drug with more toxicity
Tell me about INT 0144
JCO 2006
N=2000
3 arms:
1) 2# Bolus 5FU before and after PIV 5FU/RT
2) CI 5FU before after and during RT
3) 2# Bolus 5FU/LV/LEV before and after Bolus 5FU/RT
No difference in LR, RFS and OS
But toxicity lower past in PVI only arm
What about the Korean study?
JCO 2002
N=300 resected stage II/III rectal CA
Randomized to t2 arms:
1) Early CRT (RT started with 1st cycle of chemo)
2) Late CRT (RT started with 3rd Cycle of chemo)
RESULTS:
10y f/u no difference in DFS/OS
But in subgroup requiring APR, early CRT had better DFS cf late CRT
What is the evidence for using Capecitabine in rectal CA
German Phase III Cap/RT study in Lancet 2012
N=400
Stage II/III rectal CA s/p TME surgery
2x2 factorial design
Asking 2 questions:
1) Cape vs Bolus 5FU
2) Preop vs postop CRT
In the neoadjuvant arm:
- Cap/RT –> Surgery –> CapeQ21d x5#
- 5FU/RT –> Surgery –> 5FUQ28d X4#
In the adjuvant arm:
- Surgery –> Cape 2# –> Cap/RT –> Cape 3#
- Surgery –> 5FU 2# –> 5FU/RT –> 5FU 2#
RESULTS:
1) Capecitabine non-inferior to 5FU for OS
- 5y OS 76% vs 67%
- Similar DFS and LR
>3yDFS 75%vs 67%
>LR 6% vs 7%
- Fewer patients developed distant mets in Cape group 20% vs 30%
- Cape a/w more HFS, fatigue and proctitis but less leukopenia
2) In the neoadjuvant arm, ape a/w higher rate of down-staging
