Download Colon Cancer

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
 3rd leading cause of death
 It is curable if detected early
5/23/2017
2
HNPCC (Lynch syndrome)
 Lynch I:
 No associated other cancers
 Lynch II:
 Associated with ovarian, uterine cancers
 + ve Genetic test : Consider colectomy/TAH/BSO
5/23/2017
3
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.
5/23/2017
4
Genetic Tests
 HNPCC
 COLARIS
 FAP/AFAP
 COLARIS AP
5/23/2017
5
SCREENING
5/23/2017
6
Work-up
 Laboratory:
 CBC, Iron profile
 LFTs
 CEA
 Preoperative CT scan
 Colon cancer: Adjacent organ invasion/Liver met
5/23/2017
7
PET Scan
 Staging
 Restaging
 91% sensitivity, ~ 100% specificity for pelvic disease
(CT: 52%, 80%)
 95% sensitivity for liver disease (CT 74%)
5/23/2017
8
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
5/23/2017
9
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
5/23/2017
10
TNM
 Stage I:
T1 (invade submucosa)
T2 (invade muscul propria)
A
B1
B2
 Stage II: T3 (invade through musc propria
into subserosa or nonperit. Tissue)
T4 (perforate ves perit or
B3
invade adjacent structure)
 Stage III:
 Stage IV:
N1 (1-3 pericolic/rectal) N2 (> 4) C
N3 (along vascular trunk)
M1
5/23/2017
11
5-Year Survival in CRC
Stage
I (A)
I (B1)
IIA (B2)
IIB (B3)
III (1-4 LN)
III (>4 LN)
IV
5-Yr Survival rate (%)
97
90
80
60
56
26
8
5/23/2017
12
ADVANCES IN THE MANAGEMENT
OF COLORECTAL CANCER
SURGICAL TREATMENT
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
5/23/2017
15
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
5/23/2017
16
Laparoscopic Colectomy:
NOT RECOMMENDED in case of:
 Tumor in lower and mid rectum
 Tumor acutely obstructed or perforated
 T4
 Adhesions
5/23/2017
17
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
5/23/2017
18
SLN
 Results are promising
 No uniformity in the detection of true
clinically relevant positive LN
 It is investigational at the present time
5/23/2017
19
Positive margin
 Presence of tumor within 1-2 mm
from transected margin or within
the diathermy margin
5/23/2017
20
Stage II-III
Adj Therapy
5/23/2017
21
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
5/23/2017
22
New Drugs and Survival !!!





Capecitabine (Xeloda)
Oxaliplatin
Bevacizumab
Cetuximab
Panitumumab (Vectibix)
5/23/2017
23
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
5/23/2017
24
 NSABP C-07 (bolus FLOX vs bolus FU/LV):
 2407 pts with stage II, III
 4Y DFS 73.6% vs 67% (P=0.0034)
5/23/2017
25
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
5/23/2017
26
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?
XELOX: a new standard of care
in 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
 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)
5/23/2017
32
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)
5/23/2017
33
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
5/23/2017
34
Stage II
MMR status
T3 & MMR-D
(low risk)
T3 & MMR-P
(Standard risk)
Consider
observation
Oncotype DX
T4 & MMR-P
(High risk)
Consider chemo
5/23/2017
35
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)
5/23/2017
36
Adj RT for colon cancer
 Consider concurrent RT with 5-FU for:
 T4 tumor penetrating into a fixed structure
 Locally recurrent disease
5/23/2017
37
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
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.
5/23/2017
40
METASTATIC
COLON CANCER
5/23/2017
41
Oral Fluoropyrimidine
for mCRC.
Conclusions
XELOX
 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
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
ANTI-EGFR THERAPY
Cetuximab (Erbitux)
Panitumumab (Vectibix)
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.
5/23/2017
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
5/23/2017
50
Anti-EGFR + Anti-VEGF agents
 PACCE trial (chemo/Avastin+/-Panitumumab)
 CAIRO2 trial (cape/Oxali/Avastin+/-Erbitux)
 Decreased DFS
 Increases Toxicity
5/23/2017
51
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
5/23/2017
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
5/23/2017
53
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.
5/23/2017
54
DOES SURGERY HAS A ROLE?
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
5/23/2017
56
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%
5/23/2017
57
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
5/23/2017
58
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
5/23/2017
59
Liver mets
Surgical 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
5/23/2017
60
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
5/23/2017
61
 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.
5/23/2017
62
Preoperative chemo
 Neoadjuvant:
 For resectable metastatic disease
 Conversion chemo (downstaging):
 Liver-limited unresectable disease
5/23/2017
63
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
5/23/2017
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
5/23/2017
65
Preoperative chemo
What 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
5/23/2017
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)
NCCN recommends:
*at least 6 wks from last dose of Avastin before elective
surgery.
*6-8 wks post-op before resuming Avastin
5/23/2017
67
Preop chemo and hepatotoxicity
 Irinotecan:
 Steatohepatitis
 Oxaliplatin:
 Sinusoidal liver injury
 Surgery should be berformed ASAP after the
pt becomes resectable
5/23/2017
68
Extra-hepatic mets
 Lung:
 Most of treatment recommendations for hepatic
mets applicable for pulmonary mets
 Abdominal/peritoneal mets:
 Treatment is palliative
5/23/2017
69
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
NCCN:
Recommends active chemo for total of 6 months of
perioperative time
5/23/2017
70
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
5/23/2017
71
Liver-directed therapy
 Arterial radioembolization with yttrium-90
microspheres
 Arterial chemoembolization
 Conformal RT
5/23/2017
72
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
5/23/2017
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
5/23/2017
74
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)
5/23/2017
75
How to
Predict and
Avoid Toxicity
?
5/23/2017
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)
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
5/23/2017
77
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

5/23/2017
78
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
5/23/2017
79