Evidence based approach to cases presented with liver only metastases of colorectal cancer emphasizing the current theme of management in 2017

1. Liver Limited mCRC
“Real Life Problems & Solutions”
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
NEMROCK 20TH Annual Meeting
Ritz Carlton Hotel – Cairo
29/03/2017

2. Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Pfizer, Mundipharma, MSD, Eli Lilly.
• The content of this presentation does not relate to any product of a
commercial interest
Speaker Disclosures:

3. Colon Cancer:
Basic Facts & Figures:
• 2nd & 3rd most common cancers in females and males.
• 9% of cancer related deaths.
• 90% occurring around the age of 40 – 50 years.
• OAS for entire patients = 65%.
• Metastatic disease: 5-year OAS = 10%.
• Organ limited metastatic disease (Metastatectomy):
5-year OAS > 40%
• Median survival of metastatic disease > 35 months.
• Improved OAS with exposure to all available drugs
guided by predictive markers to improve outcome
through drug sequencing.
• Unified global treatment algorhytm is still controversial.

4. Met. CRC: Different Presentations, Aims &
Outcomes
Potentially
resectable
LLD of mCRC
Resectable 15-
20%
Unresectable 80-
85%
Resection
Cure 30-40%
Potentially
Resectable 10-
30%
Unresectable 70-
90%
Cth +/-
Others
OAS
Q0L

5. mCRC with LLD: Key Players
Systemic
Therapies Alone
Cures 1 – 2%
of Patients
Surgery
Alone
Cures > 30%
of Patients
Don’t Miss Surgical Intervention
The Race Toward More Responses

6. Results of Hepatic Resection for Patients
with mCRC:
Survival (%)
Author (year) No. Patients Mortality,% Median Survival 1-year 5-year
Hughes et al (86) 607 --- --- --- 33
Gayowski et al (94) 204 0 33 mo 91 32
Scheele et al (95) 469 4 40 mo 83 39
Fong et al (95) 577 4 40 mo 85 35
Jamison et al (97) 280 4 33 mo 84 27
Fong et al (99)
Choti et al (02)
Pawlik et al (05)
1001
226
557
3
1
1
42 mo
46 mo
74 mo
---
96
97
36
40
58
Hughes KS, et al. Surgery. 1986;100(2):278-284. Gayowski TJ, et al. Surgery. 1994;116(4):703-710. Scheele J, et al. World J Surg. 1995;19(1):59-71. Fong Y, et
al. Ann Surg. 1995;222(4):426-434.; Jamison RL, et al. Arch Surg. 1997;132:505–510. Fong Y, et al. Ann Surg 1999;230:309-318; Choti MA, et al. Ann Surg.
2002;235(6):759-766; Pawlik TM, et al. Ann Surg. 2005;241(5):715-722.

7. LLD mCRC:
Key-players:
Resectability
Chemotherapy Backbone
Doublets or Triplets
Predictive Markers & Adding Biologics
Role of Interventional Radiologist
Hepatologist
> 50% of Patients Cannot be Saved & Cured

8. 1. Perioperative in upfront resectable disease.
2. Preoperative Treatment in potentially
convertible disease.
3. Oxaliplatin or Irinotecan?
4. Adding Biologics?
5. 3 – 4 months of treatment; “Don’t seek
complete radiologic response”
6. Surgery +/- Ablative Procedures.
7. Postoperative therapy.
LLD mCRC:
Classic Theme:

9. Systemic Therapy Induced Liver Injury:
•STEATOSIS
➨ 5FU
•STEATOHEPATITIS
➨ Irinotecan
•SINUSOIDAL OBSTRUCTION
➨ Oxaliplatin

10. 1. Role of MDT.
2. Molecular Classification.
3. Sidedness.
LLD mCRC:
Theme in 2017:

11. MDT: Definition
Individual Specialties Together Either Physically or Virtually
Discussing Therapeutic Strategy of a Given Patient

12. It’s MANDATORY!
 Greater accuracy of staging
 Fewer treatment delays
 Better outcome!
Fleissing A, et al. Lancet Oncol. 2006; 7(11): 935 – 943; Du CZ, et al. Worl J Gastroenterol. 2011;17(15):2013-2018;
MacDermid E, et al. Colorectal Dis. 2009;11(3):291-295; Viganò L, et al. Ann Surg Oncol. 2013 Mar;20(3):938-45
MDT: Benefits

14. Impact of Molecular Subtyping:
Nature Medicine, October, 2015

15. Molecular Subtypes & Treatment
Tailoring:
Critical Reviews in Oncology/Hematology 109 (2017) 9–19

16. ~30% of patients
Sidedness
~70% of patients
Median OS
>38 months!
• Over 10 months more than bev + CT
(FIRE-3)
• 7 months more than bev + CT (CALGB
80405)
• 7 month more than CT (crystal)
Bad prognosis
regardless of
therapy
Small sample size ,
premature data
LEFT RIGHT

18. Personal History
• Mrs. MAN 34 years old Female
• Married with 2 children
• No special Habits of Medical History
• No Past history of Medical Importance
• Family History:
– Grandmother: Colon Cancer
– Aunt: Breast Cancer

19. Initial Presentation
• Right Hypochondria pain of 3 months duration
(intermittent, dull aching)
• Associated Change in Bowel Habits (Diarrhea)
• No other System symptoms
• Sought medical advice with her family doctor,
received medical treatment with no improvement
of the symptoms
• Abdominal U/S: Hepatomegaly with hepatic
focal lesion.

20. Baseline Multi-slice CT of Abdomen & Pelvis
+ Panel of Tumor Markers
• Liver is enlarged in size & shows a large hypodense mass with
lobular margin measuring 15.7 x 13.8 x 12.5 cm seen within right
lobe of liver.
– The mass shows heterogeneous enhancement with peripheral to
central filling seen in delayed scan taken up to 20 minutes suggest
possibility of benign mass possibly hemangioma.
• The rest of the study is unremarkable.
CA 19-9 452
CEA 143.7
AFP 2.44
CA 125 24.37

21. Baseline MRI Abdomen & Pelvis
• Large heterogeneous soft tissue signal intensity lesion noted in the
right liver lobe
– Mainly segment VI and VII
– Measuring 11 x 11.1 x 14.2 cm
– Low signal intensity on T1 and relatively heterogeneous high signal
intensity at T2 weighted images with central necrosis
– Compressing the right portal vein and causing expansion of the
inferior liver capsule indenting the upper pole of the right kidney.
• Post contrast images showed early capsular enhancement with
heterogeneous enhancement on delayed images.
• Multiple adjacent peripheral satellite nodules.

22. Whole body PET/CT
Review of PET, CT and fused images
• Metabolically active FDG avid circumferential mural thickening of
the splenic flexure of the colon measures about 5 cm in its
maximum diameter with SUV max 22.7
• Large hepatic focal lesion is involving the right lobe (mainly at
segments V, VI, VII and VIII) it shows peripheral active FDG uptake
with central breaking down, the mass measures about 15.6 x 12.7 x
10.3 cm in its maximum dimensions with SUV max 21.5
• Other 2 small sized metabolically active hepatic focal lesions are
seen at segments II & VII, the larger measures about 1.4 cm with
SUV max 3.7
• No other metabolically active lesions.

23. Colonoscopy
• Cauliflower mass at 40cm from the anal verge at the
sigmoid descending colon junction causing
complete obstruction of the lumen extending for 5
cm , biopsies are taken for histopathology.
• Passage with extreme difficulty to the rest of the
colon revealed no other abnormality to the cecum
Adenocarcinoma grade II possibly arise on top of high villous
adenoma
Somatic mutation in codon 12 of the KRAS
oncogene was detected in the assayed sample.

24. Baseline Physical Examination
• PS: 1
• Within Normal Vital Signs & Lab Values
• Unremarkable General Examination
• Right lobe Hepatomegaly of 2 fingers below Costal
margin, extremely tender.
• Weight: 61 Kgs
• Height: 165 cm
• BSA: 1.67 m2

25. Q1: Intention of Treatment?
1. Cure?
2. Palliation?
• Young age with perfect PS & adequate organ
functions.
• Neither extra-hepatic visceral nor nodal disease.
• Left sided lesion.
• Neither hepatic nor associated systemic comorbid
disease.
• No life threatening warning signs  Not obstructed.

26. Q2: Scenario of Therapeutic Strategy:
1. Upfront Surgery? 1 - Stage
2. Upfront Surgery? 2 – Stage
3. Upfront Systemic Therapy?
4. Upfront Ablative Approach?
1. Complexity of Resection?
2. Future Liver Remnants?
3. Overestimating outcome & Prognosis?

27. Initial Management
• Curative Intent: aiming for possible
resectability
• Started CapeOX
• Bevacizumab added later after RAS analysis
• Good Tolerance

28. BEVACIZUMAB & Liver Mets …
 IT IS SAFE … but wait al least 5 weeks
• D’Angelica ASO 2007, Reddy JACS 2008, Gruenberger JCO
2008, Kesmodel JCO 2008, Wicherts BJS 2011, …
 PROTECTS AGAINST SINUSOIDAL OBSTR.
• Ribero Cancer 2007, Klinger EJSO 2009
 IMPROVES PATHOLOGIC RESPONSE
• Ribero Cancer 2007, Blazer JCO 2008, Klinger ASO 2010,
Wicherts BJS 2011

29. CT Abdomen & Pelvis “1st Interval Assessment”
• It showed Regressive Course (but was still
beyond resectability)
• Patent homogeneously enhancing portal vein as
well as its main branches.
• Unremarkable Rest of the study
• After Discussions with the surgeon: We decided
to continue further

30. CT Abdomen & Pelvis “2nd Interval Assessment”
• Compared to the last CT study dated 16/06/2016 the
current study shows no appreciable changes of the
size.
• Enlarged liver showing diffuse homogeneous reduction
of its parenchymal CT attenuation denoting fatty
infiltration.
• Patent homogeneously enhancing portal vein as well as its main branches.
No biliary radicle dilatation.
• Unremarkable Rest of the study
• A PET CT was requested to better estimate the
situation

31. Pre-operative PET Assessment
• Marked regression in size and metabolic activity in the previously
described neoplastic lesion in the splenic flexure, currently
measures 2cm with SUVmax~3.3. (previously 22)
• Moderate regression in size and marked regression in metabolic
activity of the old right hepatic lobe deposit that currently
measures 11 Cm in its maximum diameter with SUVmax~5.9. (was
21)
• Similar regression of the other two FDG avid HFLs with current
SUVmax~4.8.
• The rest of the body is free with no newly developed FDG avid
metastasis.

32. Q3: Further Steps of Management?
1. Continue on more treatment sessions to
increase response rate?
2. Surgical Resection of both primary and
Secondaries?
3. Surgical resection of liver disease only?

33. Trial Resection
Dead / Total
No resection
Dead / Total
Hazard Ratio HR [95% CI]
Favors resection Favors no resection
Overall effect P<.0001
… what about RESECTION of PRIMARY ?
Faron M, et al. J Clin Oncol. 2012;30(15S): Abstract 3507.
FFCD 9601 130 / 146 60 / 60 0.5 [ 0.4 , 0.7 ]
FFCD 2000-05 138 / 168 123 / 140 0.6 [ 0.4 , 0.7 ]
ACCORD 13 24 / 59 24 / 37 0.6 [ 0.3 , 1.1 ]
ML16987 58 / 105 74 / 95 0.6 [ 0.4 , 0.8 ]
Total 350 / 478 281 / 332 0.6 [ 0.5 , 0.7 ]
Heterogeneity P = .87
0 0.5 1 1.5

34. Underwent Operation
• Segmental colectomy
– INFILTRATING ADENOCARCINOMA, GRADE II, ON TOP OF TUBULO-VILLOUS
ADENOMA WITH HIGH GRADE DYSPLASIA, No lymphovascular invasion. No
Necosis.
– WITH POSITIVE LYMPH NODE METASTASIS [L.N 1/9],
– STAGE B1, T2 N1, FREE COLONIC SURGICAL MARGINS.
• Right hepatic lobectomy
– METASTATIC ADENOCARCINOMA, GRADE II, LIKELY OF COLONIC ORIGIN, FREE
SURGICAL MARGINS. Extensive Necrosis.
• Left hepatic lobe lesion Excision biopsy
– CAVERNOUS HEMANGIOMA, MARKED STEATOSIS.
Smooth postoperative period and discharged on day 8 P.O.

35. Multivariate analysis revealed
that independent predictors of
pathologic response* were:
• CEA <5 ng/mL
• tumor size <3 cm,
• FP + OXA + BEVACIZUMAB
*assessed by the proportion of
residual cancer cells
Blazer DG III, et al. J Clin Oncol. 2008;26(33):5344-5351.

36. During Follow Up:
• Asymptomatic, infrequent abdominal cramps.
• Dropping liver enzyme profile (3 folds P.O.)
• Improving appetite & regain of normal activity.
• Follow up US:
– Status post-operative showing 3 focal metastatic
lesions implicating the residual left lobe.
– Minimal residual abdominal and pelvic ascetic
peritoneal fluid smearing (Reactionary).

37. MRI Abdomen
• 2 focal hepatic lesions at segments IV and
junction between II & III measuring 11 x 9 mm &
31 x 20 mm.
• Both appear of low T1 signal intensity that
become brighter in T2 images.
• They show no contrast enhancement with the
larger exhibiting some marginal enhancement.

38. Q: Further Actions to Be Taken:
1. Start salvage systemic treatment?
2. Re-operate?
3. Closed ablative procedures?

39. The Need for Second Hepatectomy:
Adam R, et al. The Oncologist. 2012;17:1225-1239

40. Re-operation & Follow up Descision
• 9 Focal Lesions
– RFA
– Excision of the largest (Same pathology)
• Shifted to FOLFIRI + Bevacizumab

41. 3 months later:

42. Complementary PET CT Scan:

43. Further Management?
1. Continue another 3 months?
2. Continue on FOLFIRI only?
3. Active Surveillance?

44. Thank You