Disclosure Nothing to Disclose Will not be discussing off label use of

any of the medications

Where’s Cranbrook?

Follow Up of Colorectal Cancer

Stage 0 (in-situ disease) and Stage I (T1-2 N0)

Follow up completion colonoscopy within the first year of diagnosis

Colonoscopy at the discretion of the endoscopist

No routine imaging or CEA testing is indicated

Follow Up of Colorectal Cancer

Stage II T3/T4, N0, M0

Stage III

Any T, N1-2, M0

Stage IV Any T, Any N, M1 with no evidence of

disease (NED)

Patient ED 65 y/o F 2012 Cecal cancer

Open Right Hemicolectomy and primary ileocolic anastomosis

pT3 pN2b (7/15) M0 with LVI and PNI Adjuvant CAPOX, switched to FOLFOX due

to side effects Completed 6 months of therapy Completion CT scan negative CEA 1 What do we do next?

Intensive Surveillance of CRC Survivors Why?

80% recurrences occur within 3 years 95% recurrences occur within 5 years

Who? Asymptomatic CRC patients treated with

curative intent Good functional status Would tolerate further treatment

Stage II, III, and IV (NED) Clinical Review

Hx and P/E q 3-6 months x 3 yrs, then q 6 months x 2 yrs

Recurrences Liver, lung Less common to bone, brain, spleen,

adrenals, peritoneum, retroperitoneal nodes Anastomotic site Metachronous cancer

Symptomatic patients should be seen promptly

Stage II, III, and IV (NED) CEA

At each visit for examination as above CEA < 15 mcg/L may be false positive

○ Repeat within 28 days Positive CEA

CT scan, Colonoscopy, consider PET/CT Investigations negative:

○ Repeat CEA and imaging until disease is identified or CEA stabilizes or declines

CEA may be normal in up to 40% of recurrences More sensitive in liver and peritoneal mets, less

in lung and retroperitoneal

Stage II, III, and IV (NED) Imaging

Stage II/III: CT chest/abdomen/pelvis annually for 5 years

Stage IV with NED: CT chest/abdo/pelvis q 3-6 months for 2 years, then q 6-12 months for 3 years

Colonoscopy Completion colonoscopy within the first year

of diagnosis At the discretion of the endoscopist based

on findings

Stage II, III, and IV (NED) Lifestyle modifications

Eat more like grandma did Exercise: 150 minutes per week of moderate

intensity, or 75 minutes per week of high aerobic intensity

ASA? ○ Still insufficient evidence to recommend ASA

for CRC prevention Screening of other family members Transfer of Care

Detailed, specific, and clear

Patient ED: pT3 pN2b (7/15) M0 with LVI and PNI Apr/13: Treatment completion

CEA 1, CT negative Q 3/12: CEA 1 and exam normal Dec/13: Colonoscopy

Anastomosis neg. Sessile polyp in sigmoid, tubular adenoma, no high grade dysplasia

Repeat colonoscopy 2 years Jan/14: CEA 1 and exam normal Apr/14: CT negative, exam normal, CEA 1

Asymptomatic/stable for another year Apr/15: CEA 1 CT shows 2 enhancing

lesions consistent with metastasis 3.3 cm and 2.1 cm in right hepatic lobe No other evidence of metastatic disease Biopsy proven. Contrast enhanced MRI

confirms only 2 mets Can show more metastases, particularly in

the presence of fatty liver. PET scan shows disease localized only

to the liver

Liver Anatomy

Limited Hepatic Metastases

Multidisciplinary Conference Resectability:

Hepatic lesions that can be completely resected (<10 mm margin may be ok with ablation therapy as well)

Adequate functional reserve (> 20%) No involvement of hepatic artery, bile ducts,

main portal vein, para-aortic or celiac lymph nodes

Conventional vs Aggressive

Khatri et al, J Clinical Oncology 2005; 23:8490

Copyright 2005 ASCO

< 4, unilobar Size < 5 cm Margin > 1 cm No extrahepatic mets Adequate liver remnant No mets at confluence

of vena cava/hepatic vein

No hepatic pedicle LN

No limits. Chemo/staged No limits Cryo or RF ablation of margins Resectable Pulmonary mets Portal vein embolization Resection and reconstruction

can be performed

No celiac axis metastases

Hepatic Metastases Resection benefit

five-year survival rates after resection range from 24 to 58 percent, averaging 40 percent

surgical mortality rates are generally < 5 % five-year survival rates with the most active

systemic chemotherapy regimens are only 10 to 11 %

Induction Chemotherapy for Surgery

Patient ED did not require induction therapy

If potentially resectable (larger size, number, location, no other mets except lung) Chemotherapy for 4-6 cycles Imaging 6-8 weeks prior to surgical date to

assess response Pseudoadjuvant chemo after resection to

complete 12 cycles?

Induction Chemotherapy FOLFOX

Disease appeared after 12 months Oxaliplatin sinusoidal obstructive syndrome

FOLFIRI Recent Oxaliplatin Irinotecan induced steatohepatitis

+/- Bevacizumab Still considered investigational for benefit Needs to be stopped at least 4-6 weeks

prior to surgery

“Adjuvant” therapy after metastasectomy

Generally done EORTC 40983: RCT FOLFOX 6 cycles vs

surgery alone

Consider 5FU/capecitabine alone for older patients or residual neuropathy

Nordlinger, Lancet Oncology 2013; Primrose, Lancet Onc 2014

Peri-op chemo Surgery alone p - value PFS 20.9 mos 12.5 mos p = 0.04 OS (all pts) 63.7 mos 55.0 mos p = 0.30 OS (resected) 77.5 mos 73.3 mos p = 0.35

Non-Surgical Options Ablative therapy

Less than 3 cm and less than 3 tumours Radiofrequency or cryoablation Also used when margin is < 10 mm

Stereotactic Body Radiotherapy SBRT Less than 6 cm and less than 3 tumours Child Pugh A or very early B

Embolic therapy Radioembolization Y90 not funded ○ Hepatic artery vs portal circulation

Chemoembolization investigational

Patient ED

Jun/15: Partial right hepatectomy Follow up: Stage IV NED

Same as Stage II/III except CT chest/abdo/pelvis q 3-6 months for 2 years, then q 6-12 months for 3 years

Follow up CEA 1-2 and CT’s negative at 3 and 6 months

Patient ED

Jan/16: CEA 1 and presented with abdominal cramps and change in bowel function, no blood in stool or wt loss

CT shows pulmonary, hepatic, pelvic mets with RPLNs and thickening at anastomosis.

Patient ED Unresectable mCRC Colonoscopy: narrowing of lumen, high

risk of obstruction Biopsy positive for mCRC

GI conference No down staging with chemo, Proceed to surgery

Laparotomy, excised anastomotic recurrence and biopsied pelvic mass, anastomosis ileum to transverse colon

Navigating the Terrain

Chemotherapy for mCRC

Irinotecan

5FU, Capecitabine

Pembrolizumab?

Regorafenib?

Oxaliplatin

Cetuximab

Bevacizumab

Raltitrexed Panitumumab

Chemotherapy for mCRC Multiple combinations, important that a

patient receive as many drugs as tolerated. Supportive Care Median Overall Survival of

< 6 months Chemotherapy MOS 24-28 months Some have prolonged response measured

in years Choice based on disease related factors,

patient factors and patient preferences

Does Side Matter?

OS (months) Overall Cetuximab Bevacizumab Left 33 36 31

Right 19 17 24

p < 0.0001 p < 0.0001 p < 0.0001

mCRC by left (distal/rectal) vs. right (proximal) colon site

Replicated by large SEER population based analysis

Likely driven by different molecular profiles No difference with age, gender, race, synch/metachronous, MSI, BRAF, RAS, CMS

Venoook, ASCO 2016 and 2017, Schrag ASCO 2017

Chemotherapy for mCRC Patient ED

Didn’t tolerate 5FU/oxliplatin very well as adjuvant, refused more oxaliplatin

Mar/16: Started GIFFIRB KRAS testing requested CT at 3 and 6 months showed stability

of disease by RECIST criteria CEA 1

Bevacizumab Anti – VEGF monoclonal antibody Benefit if added to FOLFOX or FOLFIRI for

first line in mCRC Some centers will continue it as 2nd line increased risk of post-operative bleeding

and wound healing ,osteonecrosis of the jaw has been reported, uncontrolled HTN, VTE, arterial thromboembolic events, serious hypersensitivity reactions

Caution with age > 65 years, congenital bleeding diatheses, acquired coagulopathy, full dose anticoagulants

KRAS and Oncopanel RAS mutations predict for lack of benefit

from anti-EGFR therapy (cetuximab and panitumumab) 7-10 days, less tissue Wild type 45% 15-17% wild type for KRAS on exon 2 are found

to have a different RAS mutation Oncopanel 14 – 21 days, more tissue

KRAS, NRAS, BRAF and a host of other genetic markers of varying significance

Rapid gene sequencing technology designed to be expandable

Obtain consent for Predictive Genetic Panel ○ Unexpected answers to questions you weren’t

asking

Hot Off the Press UGIFFOXPAN

1st line therapy if not suitable for bevacizumab Patient becomes ineligible for 2nd line

bevacizumab ○ Includes those with resection of mets and were

not considered suitble for 1st line bev Also ineligible for 3rd line panitumumab

Optimal timing of Oncopanel or KRAS testing? Anytime for fit patient with mCRC

Anti – EGFR Therapy Patient ED: Clinical and CT progression

after 28 cycles GIFFIRB KRAS negative for the mutation

When EGF binds to EGFR WT this signals cell proliferation

Mutated KRAS is continuously active. Proliferation occurs regardless of EGF-EGFR binding

Panitumumab Human MAb Cetuximab Mouse/human chimeric MAb Median Overall Survival Benefit 10 mos.

What about the responders? Maintenance/de-escalation

OPTIMOX: RCT to de-escalating to 5FU vs. continuous FOLFOX

PFS, OS similar Less toxicity Other studies similar with FFOXB

Treatment holiday OPTIMOX2: RCT chemo free interval vs.

5FU maintenance Disease control and PFS worse on holiday

Back to our patient Apr/17: Started Panitumumab

Had not tolerated Irinotecan well after dose reductions

Rash ○ Moisturizers/sunscreen ○ Clindamycin2%/Hydrocortisone1% ○ Minocyline 100 mg bid

Hypomagnesemia ○ IV supplementation when oral failed

Much improved quality of life Unfortunately, CT Sept/17 showed definite

progression. CEA 1

Is it all downhill from here?

Other Options? Best supportive care

But ECOG 1, age 65, and not ready to quit Regorafenib (Stivarga ®)

Oral multi-kinase inhibitor, 160 mg full dose CORRECT: RCT 2:1 to regorafenib vs

placebo 53% grade 3/4 toxicity ○ HFS, fatigue, rash, GI, HTN, RPLS

OS: 6.4 vs 5.0 mos p = 0.005 PFS: 1.9 vs 1.7 mos p < 0.0001

Patient support program available

And because every cancer talk now includes Immunotherapy

Anti – PD1 therapy in MSI high KEYNOTE trials of pembrolizumab in mCRC

and other cancers Response: MSI high (dMMR) much greater

than MSI low (pMMR) Somatic MSI > germline (Lynch) 5-10% mCRC somatic MSI (sporadic) Objective Response Rate 36% The median duration of response was not yet

reached (range, 1.6+ months to 22.7+ months) Among patients who responded to

pembrolizumab, 78% had responses that lasted for at least 6 months

Immune therapy in MSI high Pembrolizumab FDA approved May/17 Nivolumab FDA approved Aug/17 Should every mCRC be tested for

MSI/dMMR? Histology comments on MSI in path report

Tailoring to Biomarkers Something to watch for in the future BRAF, HER2, ERCCI, CIMP, NTRK, ALK

Stemness High-Cancer cell Inhibitor

Advance Care Planning Have the Discussion

Thank-you and Questions