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Colon Cancer. Elshami Elamin, MD Medical oncologist central care cancer center www.cccaner.com wichita , ks - usa. COLORECTAL CANCER. >140,000 new cases each yr in the US 3 rd leading cause of death It is curable if detected early. HNPCC (Lynch syndrome). Lynch I:

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colorectal cancer
COLORECTAL CANCER
  • >140,000 new cases each yr in the US
  • 3rd leading cause of death
  • It is curable if detected early
hnpcc lynch syndrome
HNPCC (Lynch syndrome)
  • Lynch I:
    • No associated other cancers
  • Lynch II:
    • Associated with ovarian, uterine cancers
  • + ve Genetic test : Consider colectomy/TAH/BSO
familial adenomatous polyposis fap
Familial adenomatouspolyposis (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.
genetic tests
Genetic Tests
  • HNPCC
      • COLARIS
  • FAP/AFAP
      • COLARIS AP
work up
Work-up
  • Laboratory:
    • CBC, Iron profile
    • LFTs
    • CEA
  • Preoperative CT scan
    • Colon cancer: Adjacent organ invasion/Liver met
pet scan
PET Scan
  • Staging
  • Restaging
    • 91% sensitivity, ~ 100% specificity for pelvic disease (CT: 52%, 80%)
    • 95% sensitivity for liver disease (CT 74%)
pet scan1
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
staging
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
slide11
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
polyps
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
laparoscopic vs conventional colectomy
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
laparoscopic colectomy not recommended in case of
Laparoscopic Colectomy: NOT RECOMMENDED in case of:
  • Tumor in lower and mid rectum
  • Tumor acutely obstructed or perforated
  • T4
  • Adhesions
regional ln
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
slide19
SLN
  • Results are promising
  • No uniformity in the detection of true clinically relevant positive LN
  • It is investigational at the present time
positive margin
Positive margin
  • Presence of tumor within 1-2 mm from transected margin or within the diathermy margin
slide22
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
new drugs and survival
New Drugs and Survival !!!
  • Capecitabine (Xeloda)
  • Oxaliplatin
  • Bevacizumab
  • Cetuximab
  • Panitumumab (Vectibix)
oxaliplatin based adj therapy
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
slide25

NSABP C-07 (bolus FLOX vs bolus FU/LV):

      • 2407 pts with stage II, III
      • 4Y DFS 73.6% vs 67% (P=0.0034)
irinotecan based adj therapy
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
oral fluoropyrimidine 5 fu derivatives
Oral Fluoropyrimidine (5-FU) derivatives
  • Capecitabine (Xeloda).
  • Tegafur (under investigated in Europe and US).
x act

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?

X-ACT

slide29

Adjuvant Oral Fluoropyrimidine

Capecitabine (Xeloda)

=

IV 5-FU/L

Convenient

slide30

ANOTHER REASON

Total Cost

xelox a new standard of care in the adjuvant setting
XELOX: a new standard of carein the adjuvant setting
  • 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

adj chemo for stage ii colon cancer
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: Adjvs No Adj chemo
      • 5Y OS 78% vs 75% not sig
  • QUASAR adj FU/LV:
      • 3-4% OS benefit (small but sig)
high risk stage ii
High Risk Stage II
  • G3-4 except MSI-H
  • Lymphatic/vascular invasion
  • Bowel obstruction
  • Localized perforation
  • Intermediate or positive margins
  • < 12 LNexamined
  • Perineural invasion
  • OncotypeDX (recurrence score >41)
microsatellite instability msi
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
slide35

Stage II

MMR status

T3 & MMR-D

(low risk)

T3 & MMR-P

(Standard risk)

T4 & MMR-P

(High risk)

Consider observation

OncotypeDX

Consider chemo

following surgery nccn panel recommends
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)
adj rt for colon cancer
Adj RT for colon cancer
  • Consider concurrent RT with 5-FU for:
      • T4 tumor penetrating into a fixed structure
      • Locally recurrent disease
conclusion
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
surveillance
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.
conclusions xelox
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
slide44

Oral Fluoropyrimidine for mCRC.

Capecitabine (Xeloda)

=

IV 5-FU/L

Convenient

conclusions bevacizumab
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
opus crystal meta analysis
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.

k ras braf
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
anti egfr anti vegf agents
Anti-EGFR + Anti-VEGF agents
  • PACCE trial (chemo/Avastin+/-Panitumumab)
  • CAIRO2 trial (cape/Oxali/Avastin+/-Erbitux)
    • Decreased DFS
    • Increases Toxicity
chemotherapy for advanced disease
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
chemotherapy for advanced disease1
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
metastatic crc which chemotherapy first
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.

metastatic colon cancer
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
liver mets
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%
resection of liver mets
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
independent predictors of survival after resection
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
liver mets surgical approach
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
radiofrequency ablation rfa
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
slide62

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.
preoperative chemo
Preoperative chemo
  • Neoadjuvant:
      • For resectable metastatic disease
  • Conversion chemo (downstaging):
      • Liver-limited unresectable disease
preoperative chemo1
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 2m
preoperative chemo2
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
preoperative chemo what are the choices
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/Panitumumab
is bevacizumab safe in the perioperative setting
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)
  • 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
Preop chemo and hepatotoxicity
  • Irinotecan:
      • Steatohepatitis
  • Oxaliplatin:
      • Sinusoidal liver injury
  • Surgery should be berformed ASAP after the pt becomes resectable
extra hepatic mets
Extra-hepatic mets
  • Lung:
      • Most of treatment recommendations for hepatic mets applicable for pulmonary mets
  • Abdominal/peritoneal mets:
      • Treatment is palliative
adj chemo following curative resection of liver or lung mets
Adjchemo 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

NCCN:

Recommends active chemo for total of 6 months of perioperative time

hepatic artery implantable pump hai
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
liver directed therapy
Liver-directed therapy
  • Arterial radioembolization with yttrium-90 microspheres
  • Arterial chemoembolization
  • Conformal RT
synchronous unresectable liver and lung mets
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 Avastin
synchronous abd peritoneal mets
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
metachronous mets
Metachronousmets
  • 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)
oxaliplatin neurotoxicity
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)
  • 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
slide78
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
irinotecan
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