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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