Post on 11-Jan-2016
Colon Cancer
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COLORECTAL CANCER
>140,000 new cases each yr in the US
3rd leading cause of death
It is curable if detected early
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HNPCC (Lynch syndrome)
Lynch I: No associated other cancers
Lynch II: Associated with ovarian, uterine cancers
+ ve Genetic test : Consider colectomy/TAH/BSO
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Familial adenomatous polyposis (FAP)
Autosomal-dominant 50% of pts will develop adenomas by age 15 and
95% by age 35. Left untreated, 100% of pts will develop
colorectal cancer. Invasive cancer occurs at ~ 42Y. The familial adenomatous polyposis coli (APC)
gene localized to chromosome 5q21.
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Genetic Tests
HNPCC COLARIS
FAP/AFAP COLARIS AP
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Work-up
Laboratory: CBC, Iron profile LFTs CEA
Preoperative CT scan Colon cancer: Adjacent organ invasion/Liver met
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PET Scan
Staging Restaging
91% sensitivity, ~ 100% specificity for pelvic disease (CT: 52%, 80%)
95% sensitivity for liver disease (CT 74%)
PET scan
NCCN: PET only as a pre-op baseline if CT/US
indicates potentially surgically curable M1. Characterization of extent of potentially
resectable disease
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Staging
Smooth metastatic nodules in pericolic or perirectal fat are considered LN mets (N1)
Irregular met nodules in peritumoral fat are considered vascular invasion
Minimum of 12 LN to accurately identify stage II
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TNM Stage I: T1 (invade submucosa) A
T2 (invade muscul propria) B1 Stage II: T3 (invade through musc propria B2
into subserosa or nonperit. Tissue)
T4 (perforate ves perit or B3 invade adjacent structure)
Stage III: N1 (1-3 pericolic/rectal) N2 (> 4) C
N3 (along vascular trunk)
Stage IV: M1
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5-Year Survival in CRC
Stage 5-Yr Survival rate (%)
I (A) 97
I (B1) 90
IIA (B2) 80
IIB (B3) 60
III (1-4 LN) 56
III (>4 LN) 26
IV 8
Polyps Pedunculted polyp with invasive cancer (pT1):
single specimen + favorable features + clear margins Observe
Fragmented, unfavorable features, unclear margins Colectomy
Sessile polyp with invasive cancer (pT1): single specimen + favorable features + clear margin
Observe or colectomy Fragmented, unfavorable features, unclear margin
Colectomy
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Laparoscopic vs Conventional Colectomy
Barcelona trial (small trial): Modest survival advantage of laparoscopic
COLOR trial (1248 pts): 3Y DFS favor conventional
CLASSIC study (794 pt): No difference in DFS or OS
COST study (872 pt): No difference in 5Y recurrence, OS
Meta-analysis: No difference in local recurrence or OS
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Laparoscopic Colectomy: NOT RECOMMENDED in case of:
Tumor in lower and mid rectum Tumor acutely obstructed or
perforated T4 Adhesions
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Regional LN
Need at least 12 LN to accurately identify stage II colorectal cancer (AJCC and College of American Pathologists)
The number of +ve lymph nodes correlates with survival
At the present time the use of sentinel LN and detection of cancer cells by IHC alone should be considered investigational
SLN Results are promising
No uniformity in the detection of true clinically relevant positive LN
It is investigational at the present time
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Positive margin
Presence of tumor within 1-2 mm from transected margin or within the diathermy margin
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Stage II-IIIAdj Therapy
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5-FU Thymidylate synthase inhibitors
Fluoropyrimidines
5 days IVP regimen: Mucositis, diarrhea, neutropenia
Wkly IVP regimen: Diarrhea
CI regimen: Hand-foot syndrome, mucositis Diarrhea or neutropenia
High dose regimen 24-48hrs Altered MS, angina-like chest pain
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New Drugs and Survival !!!
Capecitabine (Xeloda) Oxaliplatin Bevacizumab Cetuximab Panitumumab (Vectibix)
Oxaliplatin-based Adj Therapy
MOSAIC trial (FOLFOX vs 5-FU/LV): 2246 pts with stage II and III 3, 4, and 6 yrs F/U
Stage III: 5Y DFS 66.4% vs 58.9% (P 0.005) Stage II: 5Y DFS not sig.
Analysis of individual pt data from 20,898 pts on 18 randomized colon adj trials:
OS of stage III treated with FOLFOX sig increased at 6Y f/u (78.5% vs 76%) hazard ratio=0.80; 95% CI, 0.65-0.97; P=0.023
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NSABP C-07 (bolus FLOX vs bolus FU/LV):
2407 pts with stage II, III 4Y DFS 73.6% vs 67% (P=0.0034)
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IRINOTECAN-based Adj therapy CALGB C89803:
Stage III colon ca IFL vs 5-FU/LV
No improvement in DFS or OS IFL: more neutropenia, fever, death
FOLFIRI: not superior to 5-FL/LV
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Oral Fluoropyrimidine (5-FU) derivatives
Capecitabine (Xeloda).
Tegafur (under investigated in Europe and US).
•IV 5FU is the standard adjuvant therapy for CRC.
•Oral xeloda is at least as effective as IV 5FU in mCRC.
•Can Oral xeloda replace IV 5FU in adjuvant setting?
Adjuvant Oral Adjuvant Oral
FluoropyrimidineFluoropyrimidine
Capecitabine (Xeloda) Capecitabine (Xeloda)
= =
IV 5-FU/LIV 5-FU/L
Conve
nient
ANOTHER REASONANOTHER REASON
Tota
l Cos
t
XELOX significantly improves DFS and RFS compared with 5-FU/LV
Trend to superior overall survival XELOX shows similar DFS benefit to
FOLFOX4 in a cross-trial comparison
With proven efficacy and a favourable safety profile, XELOX is a new standard
of care in the adjuvant treatment of early colon cancer
XELOX: a new standard of care
in the adjuvant setting
Adj chemo for Stage II colon cancer Meta-analysis of 5 trials and practice-based
studies: Stage II and III treated with surgery +/- FU/LV
Most of benefits in stage III
Pooled data from 7 randomized trials: FU/LV sig improves OS in N+, Not in N0 colon ca
SEER databases: Stage II: Adj vs No Adj chemo 5Y OS 78% vs 75% not sig
QUASAR adj FU/LV: 3-4% OS benefit (small but sig)
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High Risk Stage II
G3-4 except MSI-H Lymphatic/vascular invasion Bowel obstruction Localized perforation Intermediate or positive margins < 12 LN examined Perineural invasion Oncotype DX (recurrence score >41)
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MicroSatellite Instability (MSI)
High MSI = deficient mismatch-repair phenotype (dMMR) = pood prognosis.
May not benefit from 5-FU, even could be harmful.
MMR testing for all pts < 50
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Following surgery NCCN panel recommends
6 month of adj chemo for stage III (T1-4, N1-2, M0)
Options: FU/LV/Oxal (standard) or Capecitabine or FU/LV
No Irinotecan-based adj regimen 5-FU-based chemo for high risk stage II:
T4, G3-4, lymphovasc inv, BO, localized perforation, close or +ve margins, <12LN Subset from MOSAIC: No sig DFS benefit of FOLFOX
over FU/LV in stage II (but trend for improved DFS in high risk stage II receiving FOLFOX)
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Adj RT for colon cancer
Consider concurrent RT with 5-FU for:
T4 tumor penetrating into a fixed structure Locally recurrent disease
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Targeted therapies in
adjuvant setting.
CONCLUSION Adjuvant Bevacizumab:
Did not prolong DFS Failed to improve the cure rate of patients
with resected colon cancer Did not reach the goal of eradicating
occult metastases
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SURVEILLANCE
H/P q 3 m for 2 y, then q 6 m for 3 y CEA q 3 m for 2 y, then q 6 m for 3 y Annual CT chest/abd/pelvis for high risk pts Colonoscopy in 1 y:
repeat in 1 y if abnormal
Then q 2-3 y If no preoperative colonoscopy:
colonoscopy in 3-6 mo.
METASTATIC METASTATIC COLON COLON CANCERCANCER
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Oral Fluoropyrimidine for mCRC.
ConclusionsXELOX
XELOX is non-inferior to FOLFOX
XELOX and FOLFOX safety profiles are balanced
XELOX offers the advantage of oral fluoropyrimidine administration
XELOX is a good alternative to FOLFOX
Oral Fluoropyrimidine for Oral Fluoropyrimidine for
mCRC.mCRC.
Capecitabine (Xeloda) Capecitabine (Xeloda)
= =
IV 5-FU/LIV 5-FU/L
Conve
nient
Targeted therapies in mCRC
Bevacizumab (Avastin) (anti-VEGF)46
Conclusions “Bevacizumab”
1st evidence from 1st line CRC phase III trial that bevacizumab adds
clinically meaningful statistically superior benefit to oxaliplatin-based chemotherapy
Safety profile overall in line with previous trial experience in colorectal cancer
The outcome of this trial adds to the large body of evidence supporting the use of bevacizumab in combination with standard 1st line chemotherapy
Cetuximab (Cetuximab (ErbituxErbitux))
Panitumumab Panitumumab ((VectibixVectibix))
OPUS-CRYSTAL Meta-Analysis
Addition of cetuximab to chemotherapy showed PFS benefit in patients with wild-type KRAS
With > 90% of samples collected, addition of cetuximab reduced risk of disease progression by 34% (HR: 0.66; P < .001)
OS results showed an advantage for patients with
wild‑type KRAS who received chemotherapy + cetuximab (HR: 0.81; P = .0062)
Van Cutsem E, et al. ECCO/ESMO 2009. Abstract P-6077. 04/21/23 49
K-RAS, BRAF
K-RAS mutations in codon 12 or 13 in exon 2 predict lack of response to anti-EGFR drugs
Wild type K-RAS respond
Consider doing BRAF when K-RAS is non-mutated Wild type K-RAS and mutated BRAF
unlikely respond to ant-EGFR therapy
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Anti-EGFR + Anti-VEGF agents PACCE trial (chemo/Avastin+/-
Panitumumab) CAIRO2 trial (cape/Oxali/Avastin+/-
Erbitux) Decreased DFS Increases Toxicity
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Chemotherapy for advanced disease FULV +/- Avastin
MS 17.9 vs 14.6 m IFL +/- Avastin:
MS 20.3 vs 16.6 m (P<0.001) Phase III randomized N016966:
CapeOX vs FOLFOX CapeOX is not inferior to FOLFOX
Avastin only add 1.4 m to PFS and MS BICC-C study (phase III):
FOLFIRI is superior to mIFL or CapeIRI in efficacy and safety
FOLFIRI + Avastin vs mIFL + Avastin: MS 28 vs 19m
FOLFOX vs FOLFIRI: No diff in RR, PFS, OS FOLFOXIRI vs FOLFIRI:
One of 2 phase II showed improvement of DFS. FOLFOXIRI is more toxic 04/21/23 52
Chemotherapy for advanced disease
CRYSTAL trial (FOLFIRI +/- Erbitux): Subset analysis for KRAS tumor status:
Sig improvement in M PFS (9.9 vs 8.7m ) if wild type gene
OPUS trial (FOLFOX +/- Erbitux): Improved RR
FOLFIRI, FOLFOX, CapeOX +/- Bevacizumab
FOLFIRI, FOLFOX +/-Cetuximab/Panitumumab
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Metastatic CRC Which Chemotherapy
First?
FOLFOX = FOLFIRI[1]
CapeOx = FOLFOX[2]
1. Tournigand C, et al. J Clin Oncol. 2004;22:229-237.2. Cassidy J, et al. J Clin Oncol. 2008;26:2006-2012.
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Metastatic colon cancer
50-60% CRC pts will develop mets Synchronous liver mets: 15-25%
80-90% unresectable Intact tumor + synchronous mets:
Palliative resection is rarely indicated (acute obstruction and or significant bleeding)
Metachronous met is most common Mainly liver
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Liver mets
>50% of pts died of CRC have liver mets at autopsy
Liver met is cause of death in the majority In 30% liver as the only site of disease
Without surgery 5Y survival is very low In selected pts resection of liver mets could
lead to cure 5Y survival about 50%
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Resection of liver mets
Liver resection currently represents the only potentially curative therapeutic option for hepatic colorectal metastasis
5Y survival rates of 25% to 58% have been reported
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independent predictors of survival after
resection primary tumor stage Preoperative CEA hepatic tumor size number of hepatic metastases time from primary tumor treatment to
diagnosis of hepatic metastases presence of extrahepatic disease Status of surgical resection margin
Negative margins + maintaining adequate liver reserve
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Liver metsSurgical approach
Simultaneous resections of primary and synchronous liver mets
Preop portal vein embolization to increase the volume and function of remaining liver
Two stages of liver resection for bilobular disease
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Radiofrequency Ablation (RFA)
RFA is an option if surgery is not feasible
RFA is NOT a substitute to resection
RFA is inferior to resection with respect to rates of local recurrence and 5Y OS
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The goal of resection and or RFA is cure
Resection, RFA or combination “debulking” with goal less than complete resection/ablation of all known met sites is NOT RECOMMENDED.
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Preoperative chemo
Neoadjuvant: For resectable metastatic disease
Conversion chemo (downstaging): Liver-limited unresectable disease
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Preoperative chemo
Advantages: Treat micromets Chemo response Avoidance of local therapy
Disadvantages: Chemo-induced liver injury Missing the window of opportunity
Disease progression Achievement of complete response (difficult
to identify areas for resection) NCCN: Surgical eval 2 month after neoad and q
2m04/21/23 64
Preoperative chemo
Study by Pozzo et al: Preop IFL in unresectable liver mets:
32.5% able to undergo rescetion Median time to progression: 14.3 months
NCCTG phase II: FOLFOX in 44 pts with unresectable liver mets
40% able to undergo resection
1439 pts with unresectable liver mets: 335 pts underwent primary liver resection 1104 pts received preop chemo:
138 good responders underwent resection 5Y OS = 33%
Intergroup N9741 phase III (retrospective): 795 pts underwent preop mostly Oxal-based chemo
24 pt able to undergo curative resection OS = 42.4 months
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Preoperative chemoWhat are the choices?
EORTC phase III: Initially resectable liver mets periop FOLFOX 6 cycles before and after
surgery vs surgery alone) Absolute improvement in 3Y PFS of 8.1%
(P=0.041) and 9.2% (p=0.025) for all eligible and all resected pts repectively.
Chemo options: FOLFIRI, FOLFOX, CapeOX +/- Bevacizumab FOLFIRI, FOLFOX
+/-Cetuximab/Panitumumab04/21/23 66
Is Bevacizumab safe in the perioperative
setting? Two retrospective randomized trials (1,132 pts): Increased wound healing complications for pts
undergoing major surgery while receiving Avastin 13 vs 3.4% P=0.28
Preop chemo +/- Avastin: Wound healing complications in either group was
low (1.3% vs 0.5% P=0.63)
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NCCN recommends: *at least 6 wks from last dose of Avastin before elective surgery.*6-8 wks post-op before resuming Avastin
Preop chemo and hepatotoxicity
Irinotecan: Steatohepatitis
Oxaliplatin: Sinusoidal liver injury
Surgery should be berformed ASAP after the pt becomes resectable
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Extra-hepatic mets
Lung: Most of treatment recommendations for
hepatic mets applicable for pulmonary mets
Abdominal/peritoneal mets: Treatment is palliative
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Adj chemo following curative resection of liver
or lung mets Not enough data Pooled analysis from 2 randomized trials:
FU/LV vs observation: Median PFS: 27.9m vs 18.8m (P=0.058) No diff in OS
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NCCN: Recommends active chemo for total of 6 months of perioperative time
Hepatic Artery implantable pump (HAI)
Done during hepatic resection Adj floxuridine + dexam by HAI +/-
systemic chemo: 2Y survival and time to progression favor
HAI No diff in OS
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Liver-directed therapy
Arterial radioembolization with yttrium-90 microspheres
Arterial chemoembolization Conformal RT
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Synchronous unresectable Liver and lung mets
Palliative resection of primary: acute obstruction significant bleeding
Chemo options: FOLFIRI, FOLFOX, CapeOX +/- Bevacizumab
or Cetuximab Intact tumor is NOT a contra-indication to
Avastin Debulking surgery may be a risk factor for
bowel perforation when treat with Avastin04/21/23 73
Synchronous Abd/Peritoneal mets
If Obstructive: Colon resection, diverting colostomy,
bypass, stenting Then chemotherapy
Carcinomatosis Cytoreductive (peritoneal stripping) – in
clinical trial Perioperative hyperthermic IP chemo - in
clinical trial
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Metachronous mets
Resectable: Resection followed by chemo X 6 m or Neoadj chemo x 2-3 m resection
chemo for total of 6 m peri-op chemo Unresectable:
Chemo based on prior chemo E.g.; Progression on FOLFOX within 12m,
switch to FOLFIRI)
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How to Predict and
Avoid Toxicity
?04/21/23 76
Oxaliplatin Neurotoxicity OPTIMOX1 (Stop-and-Go approach) :
FOLFOX x6 FULV reintroduce Oxali upon progression
Decreased toxicity, did not affect survival
OPTIMOX2: OPTIMOX1 vs FOLFOX x6 Stop reintroduce FOLFOX
upon progression
MOS 26 vs 19 m (P=0.0549)
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NCCN:*Consider D/C Oxali from FOLFOX/CapeOx after 3m or sooner for unacceptable neurotoxicity, with other drugs maintaned until progression.*Oxali should not be reintroduced unless near-total resolution of neurotoxicity*Infusion of Ca and Mg may limit neurotoxicity
5-FU DihydroPyrimidine Dehydrogenase deficincy (DPD) Thymidylate Synthase (TYMS/TS) mutation
associated with reduced TS production and subsequent 5-FU toxicity
TheraGuide 5-FU: TYMS and DPYD genes mutation
25% of pts have them 60% risk of severe or life threatening toxicity
OnDose (target range AUC of 20-24mg.hr/L) To optimize dosing of 5-FU To reduce 5-FU toxicity do test at any time after 2 hr of C. I. 5FU
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Irinotecan
Due to accumulation of active metabolite (SN-38) in the intestine
SN-38 metabolized by UGT1A1 UGT1A1 *28 allele associated with
reduced UGT1A1 expression
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