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Safiya Karim, MD, FRCPC CAGPO Annual Meeting October 1, 2017 RIGHT VS LEFT SIDED COLON CANCER - SHOULD THE TREATMENT BE DIFFERENT?
Safiya Karim, MD, FRCPC
CAGPO Annual Meeting
October 1, 2017
RIGHT VS LEFT SIDED COLON CANCER -
SHOULD THE TREATMENT BE
DIFFERENT?
Objectives By the end of this presentation, you will be able to:
• Describe the biological, molecular and clinical differences between RCC and LCC
• Understand the prognostic value of primary tumour location in metastatic colon cancer
• Describe the predictive value of primary tumour location in the treatment of metastatic colon cancer
• Discuss the current guidelines that incorporate the primary tumour location in the treatment of metastatic colon cancer
Overview
■ Case
■ Background
■ Individual Trial Data
■ Meta-analyses
■ Limitations
■ Guidelines/ Consensus Statements
Faculty/Presenter Disclosure• Relationships with commercial
interests:
– Grants/Research Support: None – Speakers Bureau/Honoraria: None – Consulting Fees: None – Other: None
Disclosure of Commercial Support
• No Disclosures
• Potential for conflict(s) of interest: None
Mitigating Potential Bias
■ Not applicable
Case – Mrs. K■ 63 yo F presented to the ER with a history of a 2
month change in bowel pattern and recent history of obstructive-like symptoms
■ CT scan revealed a 5 cm obstructing ascending colon mass
■ Numerous liver lesions were also visualized and were suspicious for metastatic disease
■ Query peritoneal deposits
Case – Mrs. K
■ Pre-op CEA = 52
■ R hemicolectomy:
– Low-grade adenocarcinoma– Extension into the visceral peritoneum – 1/23 lymph nodes positive – Evidence of metastatic disease in omentum,
appendix, mesentary and 1 peritoneal nodule
– All RAS wild-type
Questions to Consider
What is the estimated prognosis of this patient? Is it better or worse than a patient with left-sided metastatic colon cancer?
What is the best upfront treatment for this
patient a) Chemotherapy alone (FOLFIRI or
FOLFOX) b) Chemotherapy +
Bevacizumab c)
Chemotherapy + Anti-EGFR (cetuxiumab or
panitumumab)
Review: Prognostic vs. Predictive Factors
Prognostic MarkerIndicates the likelihood of an outcome
regardless of the specific treatment
Predictive MarkerIndicates the likelihood of response
to a given therapy
Background
■ Colorectal cancer is the 2nd most common cause of cancer death in the western world
– Despite improvements in screening, 10-15% of patients present with synchronous metastatic disease
■ Several molecular and clinical characteristics have been identified that are prognostic or predictive of outcomes
– i.e. MSI, KRAS, BRAF
Sidedness as a Prognostic Marker
■ Several studies in the 80s/90s studied sidedness as a prognostic factor in colon cancer
– Showed that RCC inferior OS compared to LCC
– Limited by small sample sizes
■ Renewed interest in sidedness ASCO 2016
ASCO 2016
Left vs Right? What are the differences?
28%Range (19-38%)
72%Range (63-81%)
Left vs Right? What are the differences?1) Embryology 2) Blood supply 3) Molecular Characteristics 4) Clinical Characteristics
RCC associated with: Older age Female gender T3/T4 Higher grade Mucinous Multiple vs single sites of metastatic
disease
R Colon
L Colon
Ghazi S et al. J Gastroenterol. 2012 Jun;47(6):619–34
INDIVIDUAL TRIAL DATA
Studies with EGFR mAbs vs. chemo alone or BSC
NCIC CO.17
Third line + mCRC
Phase III
Cetux
BSC
3rd line + mCRC
CRYSTAL First line mCRC
Phase III
FOLFIRI + Cetux
FOLFIRI
PRIMEFirst line mCRC
Phase III
FOLFOX + Pmab
FOLFOX
1st line mCRC
2nd line mCRC 20050181
Second line mCRC
Phase III
FOLFIRI+Pmab
FOLFIRI
CRYSTAL Trial – Prognostic impact In both arms, LCCs had better OS compared to RCCs
< <
Tejpar, S. et al. JAMA Oncol. 2017;3(2):194-201.
Tejpar, S. et al. JAMA Oncol. 2017;3(2):194-201.
CRYSTAL Trial – Predictive Impact Only LCCs did better with the addition of Cetuximab
PRIME – OS – 1st line
HR, hazard ratio; OS, overall survival; Pmab, panitumumab
Overall survival (months)
Median OS (95% CI), months
Pmab + FOLFOX FOLFOX HR (95% CI)
Left 30.3 (25.8–36.1) 23.6 (18.2–26.9) 0.73 (0.57–0.93)
Right 11.1 (8.1–25.2) 15.4 (9.1–21.7) 0.87 (0.55–1.37)
100
80
60
40
20
0
Kap
lan-
Mei
er e
stim
ate
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68
169
159
39
49
164
151
36
42
147
137
26
34
136
120
18
28
124
103
17
23
107
86
15
20
97
76
13
14
86
64
11
11
77
56
8
9
66
44
6
8
56
32
5
7
46
24
4
6
39
21
4
5
30
19
4
4
16
11
3
1
11
6
1
1
3
1
1
0
0
1
0
No. of subjects:
1:
2:
3:
4:
Censor indicated by vertical bar
1: Pmab + FOLFOX left
2: FOLFOX left
3: Pmab + FOLFOX right
4: FOLFOX right
PRIME Trial – Predictive impact Only LCC had improved OS with addition of Pmab
Douillard and Pignon. ESMO 2016.
2nd and 3rd line + Studies
■ 20050181 Study – No significant difference in OS or PFS
between treatments for either LCC or RCC
■ NCIC CO.17 Study– Patients with LCC had a 6 months
improvement in OS with cetuximab (10 mos vs 4.1 months, HR 0.49).
– OS also improved in patients with RCC by 3 months but not statistically significant. Brule et al. Eur J Cancer. 2015;51(11):1405-14.
Studies comparing EGFRmAbs vs Bevacizumab
CALGB/ SWOG 80405
First line mCRCPhase III
Chemo + Cetux
Chemo + Bev
FIRE-3First line mCRC
Phase III
FOLFIRI + Cetux
FOLFIRI + Bev
FOLFIRI or FOLFOX (MD
choice)
PEAK First line mCRCPhase II
FOLFOX + Pmab
FOLFOX + Bev
CALGB/ SWOG 80405 – Prognostic Impact
CALGB/ SWOG 80405 – Predictive Impact
FIRE-3 – Prognostic Impact
Tejpar, S. et al. JAMA Oncol. 2017;3(2):194-201.
FIRE-3 - Predictive Impact
Tejpar, S. et al. JAMA Oncol. 2017;3(2):194-201.
PEAK Study– Predictive Impact
Douillard and Pignon. ESMO 2016.
META-ANALYSES
Arnold. D et al. Ann Oncol. 2017;28():1713-29.
CT +/- Bev CT + EGFR inhibitor
Prognostic Value – Pooled Analysis
HR= 1.38 (1.17-1.63), p<0.001
HR= 2.03 (1.69-2.42), p<0.001
Arnold. D et al. Ann Oncol. 2017;28():1713-29.
Predictive Value – Pooled Analysis
Arnold. D et al. Ann Oncol. 2017;28():1713-29.
Holch, JW et al. Eur J Cancer. 2017;70:87-98.
■ 13 first-line RCTs and 1 prospective pharmocogenic trial
■ Prognostic and predictive impact of primary tumour location
■ Predictive impact grouped into trials comparing anti-EGFR to chemo alone vs. anti-EGFR to Bevacizumab
Holch meta-analysis – Prognosis
Holch, JW et al. Eur J Cancer. 2017;70:87-98.
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Overall Survival -
Chemo+/-EGFR
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Overall Survival`
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Overall Survival -
EGFR vs Bev
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Limitations
■ Retrospective analyses
– Selection, systematic and random bias
■ Heterogeneity in line of treatment, comparator arm, RAS/ BRAF status
■ Definition of RCC vs LCC
– Most studies have included transverse colon into RCC
– Substantial heterogeneity within RCC and LCC?
■ No data on triplet therapy (i.e. FOLFOXIRI)
GUIDELINES/ CONSENSUS STATEMENTS
Guidelines – NCCN
Canadian Consensus Statement
Pending publication (October 2017)
Recommendations – 1st line
Patients with RAS-wild-type LCC should receive chemotherapy with an EGFR mAb (cetuximab or panitumumab)
In patients with RAS wild-type RCC, the combination of bevacizumab with standard chemotherapy remains the standard of care
Extended RAS testing should be available in a timely manner to allow the appropriate selection of a biologic for first line treatment decisions.
Recommendations – 2nd and 3rd line
At this time, there is no evidence to recommend the selective use of EGFR mAbsin the second line setting based on tumour location
In the second line, patients who have not been treated with bevacizumab in the first line should be offered bevacizumab in combination with standard chemotherapy.
In the third line or beyond, all RAS wild type patients who have not previously been treated with an EGFR mAb should be offered one.
Case Questions Revisited What is the estimated prognosis of this
patient? Is it better or worse than a patient with left-sided metastatic colon cancer?
OS is worse for patients with mRCC mOS 15-23 months
What is the best upfront treatment for this patient: a) Chemotherapy alone (FOLFIRI or FOLFOX) b) Chemotherapy + Bevacizumab c) Chemotherapy + Anti-EGFR (cetuxiumab or panitumumab)
Summary and Conclusions
■ RCC and LCC represent different entities and primary tumour location has a prognostic and predictive impact in mCRC
■ Patients with metastatic RCC have inferior survival compared to LCC
■ Having a LCC is predictive of response anti-EGFR mAb combined with chemotherapy in the 1st line setting
■ Current treatment strategies should take into account the PTL to determine the best upfront targeted agent
– Application to pCODR for funding of panitumuab in combination with chemo for patients with LCC
■ Future clinical trials should stratify patients based on PTL
■ Further research should focus on understanding the patient and tumour related factors that underlie the differential benefits of biologics that have been observed based on PTL
Summary and Conclusions
Questions?
