Liver Limited mCRC“Real Life Problems & Solutions”

Mohamed Abdulla M.D.Prof. of Clinical Oncology

Cairo UniversityNEMROCK 20TH Annual MeetingRitz Carlton Hotel – Cairo29/03/2017

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:

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.

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

OASQ0L

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

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)

1001226557

311

42 mo46 mo74 mo

--- 9697

364058

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.

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

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:

Systemic Therapy Induced Liver Injury:

•STEATOSIS

➨ 5FU

•STEATOHEPATITIS

➨ Irinotecan

•SINUSOIDAL OBSTRUCTION

➨ Oxaliplatin

1. Role of MDT.2. Molecular Classification.3. Sidedness.

LLD mCRC: Theme in 2017:

MDT: Definition

Individual Specialties Together Either Physically or Virtually Discussing Therapeutic Strategy of a Given Patient

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

Impact of Molecular Subtyping:

Nature Medicine, October, 2015

Molecular Subtypes & Treatment Tailoring:

Critical Reviews in Oncology/Hematology 109 (2017) 9–19

~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

therapySmall sample size ,

premature data

LEFT RIGHT

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

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.

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 452CEA 143.7AFP 2.44

CA 125 24.37

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.

Whole body PET/CTReview 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.

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.

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

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.

Q2: Scenario of Therapeutic Strategy:

1. Upfront Surgery? 1 - Stage2. Upfront Surgery? 2 – Stage3. Upfront Systemic Therapy?4. Upfront Ablative Approach?

1. Complexity of Resection?2. Future Liver Remnants?3. Overestimating outcome & Prognosis?

Initial Management

• Curative Intent: aiming for possible resectability

• Started CapeOX

• Bevacizumab added later after RAS analysis

• Good Tolerance

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

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

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

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.

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?

Trial Resection Dead / Total

No resection Dead / Total

Hazard Ratio HR [95% CI]

Favors resection Favors no resectionOverall 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

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.

Multivariate analysis revealed that independent predictors ofpathologic 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.

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).

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.

Q: Further Actions to Be Taken:

1. Start salvage systemic treatment?2. Re-operate?3. Closed ablative procedures?

The Need for Second Hepatectomy:

Adam R, et al. The Oncologist. 2012;17:1225-1239

Re-operation & Follow up Descision

• 9 Focal Lesions

– RFA

– Excision of the largest (Same pathology)

• Shifted to FOLFIRI + Bevacizumab

3 months later:

Complementary PET CT Scan:

Further Management?

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

Thank You