Management of Liver Management of Liver Metastases of CRC Metastases of CRC

originorigin

Mohamed Abdulla (M.D.)Mohamed Abdulla (M.D.)Professor of Clinical OncologyProfessor of Clinical OncologyKasr El-Aini School of MedicineKasr El-Aini School of Medicine

Cairo UniversityCairo University12/200812/2008

Challenges

MagnitudeResection

or not?Neoadjuvant

ChemotherapyTargeted Therapies

Toxicity Of Therapy

Duration of Therapey

1. Jemal A, et al. CA Cancer J Clin. 2007;57:43-66. 2. Leonard GD, et al. J Clin Oncol. 2005;23:2038-2048. 3. Pawlik TM, et al. J Gastrointest Surg. 2007;11:1057-1077.

CRC annual US incidence[1]

~ 150,000 patients

Hepatic metastases (~ 50%)[2]

75,000 patients

Mets confined to liver (~ 30%)22,500 patients

Historical hepatic resection,rate (10% to 25%)[2]

2250-5625 patients

Hepatic resection, with expanded indications[3]

10,000-15,000 patients

Hepatic Metastases From Colorectal Carcinoma

Liver Metastases

Resectable20% to 25%

Survival Benefit30% to 50% at 5 years

15% at 10 years

Resectable10% to 20%

Downsizing

Size

Location

Number

Leonard GD, et al. J Clin Oncol. 2005;23:2038-2048.

Hepatic Metastases From Colorectal Carcinoma

Nonresectable75% to 80%

Hepatic Resection: A Cure for mCRC?

Disease Status

Treatment Intent

5-Year Survival

Unresectable

Palliation Uncommon

Resectable Cure 30% to 40% historically;

approaching 60% in recent series

Unresectable to

resectableCure

Pawlik TM, et al. J Gastrointest Surg. 2007;11:1057-1077.

StudyStudy Last Year Last Year IncludedIncluded

Span, Span, YearsYears Patients, NPatients, N 5-Year OS, %5-Year OS, %

AdsonAdson 19821982 3434 141141 2525Registry*Registry* 19851985 3737 859859 3333JamisonJamison 19871987 2727 280280 2727Nordlinger*Nordlinger* 19901990 2222 15681568 2828GayowskiGayowski 19911991 1010 204204 3232ScheeleScheele 19921992 3232 434434 3333JenkinsJenkins 19931993 1818 131131 2525Kato*Kato* 19961996 44 585585 3333FongFong 19981998 1313 10011001 3737ChotiChoti 19991999 1616 226226 4040BramhallBramhall 20012001 1212 212212 2828WeiWei 20022002 1010 395395 4747AbdallaAbdalla 20022002 1010 358358 5858FernandezFernandez 20022002 77 100100 5858Pawlik*Pawlik* 20042004 1414 557557 5858Adam*Adam* 20042004 3030 21222122 4242FiguerasFigueras 20042004 1414 501501 4545*Patients included from multiple institutions (vs single-institution series).

Resection of CRLM: 5-Year Survival,Selected Reports (≥ 100 Pts) Over Time

Survival After Hepatic Resection Has Improved Over Time Lower operative mortality

– ~ 1% with experienced hepatobiliary surgeons

Improved patient selection– CT, MRI, PET, PET/CT

Improved surgical techniques– Intraoperative US, portal vein embolism, radiofrequency

ablation

Increased rates of repeat hepatectomy after recurrence

More frequent and better perioperative chemotherapy– Irinotecan, oxaliplatin, biologics

Factors Advanced age > 3 or 4 liver metastases Tumor size > 5 cm Inability to resect to 1-cm margins Bilobar disease Hilar lymphadenopathy Extrahepatic disease

Abdalla EK, et al. Ann Surg Oncol. 2006;13:1271-1280.Pawlik TM, et al. J Gastrointest Surg. 2007;11:1057-1077.

Historical Contraindications For Resection of Liver Limited mCRC:

1Macroscopic and microscopic (R0) treatment is feasible with either resection alone or resection combined with radiofrequency ablation*

2 2 adjacent liver segments can be spared

3Vascular inflow, outflow, and biliary drainage can be

preserved

4Sufficient future liver remnant (> 20% of the total estimated liver volume)†

5Ability to tolerate the surgery (eg, no excessive risk due to comorbidities)

*1-cm margins not required.†Portal vein embolization may be used to preoperatively increase the size of the future liver remnant by inducing hypertrophy.

Abdalla EK, et al. Ann Surg Oncol. 2006;13:1271-1280.Pawlik TM, et al. J Gastrointest Surg. 2007;11:1057-1077.

Expanded Indications: New Criteria Defining Resectability

Is there an “optimal” cytotoxic regimen?– FOLFOX– FOLFIRI– FOLFOXIRI

Neoadjuvant Cytotoxic Chemotherapy

Nordlinger B, et al. ASCO 2007. Abstract LBA5.

Phase III study: patients with CRC

and resectable liver metastases; WHO/ECOG performance

score 0-2

(N = 364)

FOLFOX4 for 6 cycles (12 wks)

(n = 182)

Surgery(n = 182)

SurgeryFOLFOX4

for 6 cycles (12 wks)

EORTC 40983: FOLFOX4 in mCRC With Resectable Liver Metastases

Nordlinger B, et al. ASCO 2007. Abstract LBA5.

EORTC 40983: PFS in Resected Patients

42.433.2

0

20

40

60

80

100

Surgery OnlyPeri-Op CT

HR: 0.73; 95% CI: 0.55-0.97; P = .025

Pat

ien

ts (

%)

PFS at 3 Years

Summary: Initially Resectable Little clinical trial data to guide Little clinical trial data to guide

treatment decisionstreatment decisions– EORTC 40983: EORTC 40983: benefit less than less than

expectedexpected– Current EORTC 40051 trial assessing Current EORTC 40051 trial assessing

addition of targeted agentsaddition of targeted agents– Cetuximab plus bevacizumab vs Cetuximab plus bevacizumab vs

cetuximab alone when administered cetuximab alone when administered preoperatively and perioperativelypreoperatively and perioperatively

Authors Year Patients, n

Chemotherapy Type

No Resection

, n(%)

5-Year Survival,

%

Levi 1992 98 Fu-Fol-Ox 18 (19) --

Fowler 1992 -- Fu-Fol 11 --

Bismuth 1996 330 Fu-Fol-Ox 53 (16) 40

Giacchetti 1999 389 Fu-Fol-Ox* 77 (20) 50

Adam 2001 701 Fu-Fol-Ox 95 (14) 39

Wein 2001 53 Fu-Fol 6 (11) --

Rivoire 2002 98 Fu-Fol-Ox 18 (19) --

Resection of Initially Unresectable Liver Metastases After Systemic Chemo

Lévi F, et al. Cancer. 1992;69:893-900. Fowler WC, et al. J Surg Oncol.1992;51:122-125. Bismuth H, et al. Annals of Surgery. 1996;224:509-522. Giacchetti S, et al. Ann Oncol. 1999;10:663-669. Adam R, et al. Ann Surg Oncol. 2001;8:347-353. Wein A, et al. Ann Oncol. 2001;12:1721-1727. Rivoire M, et al. Cancer. 2002;95:2283-2292.

0

20

40

60

80

100

OS

(%

)

95

88

92

1 Year 3 Years 5 Years

63

55

44

12

3730

8

Progression (n = 34)

Stabilization (n = 39)

Partial response (n = 58)

P < .0001

Adam R, et al. Ann Surg. 2004;240:1052-1064.

Outcome Based on Initial Response to Chemotherapy131 patients with colorectal metastases received preoperative Cth.

Chemotherapy (N = 1512) Resection (N = 740)

535 (72%) Initially resectable

205 (28%) Initially unresectable

1307 (86%)

205 (14%)

Adam R et al. Ann Surg Oncol. 2001;4:347-353.(Updated at ASCO GI Cancer Symposium 2007)

Neoadjuvant Oxaliplatin Before SurgeryPaul Brousse hospital study: 2047 patients with colorectal liver

metastases treated from April 1988 to December 200314% of 1512 patients treated with chemotherapy achieved a response,

permitting resection

Adam R. Ann Oncol. 2003;14(suppl 2):ii13-iii16.

Survival After Primary or SecondaryResection of Liver Metastases

Initially nonresectable (n = 95)

Resectable (n = 425)

Survival Time (Years)

100

80

60

40

20

0

Pro

po

rtio

n S

urv

ivin

g

0 1 2 3 4 5 6 7 8 9 10

54%

34%27%

19%29%

34%

50%

Adam R, et al. Chemotherapy and surgery: new perspectives on the treatment of unresectable liver metastases, Annals of Oncology, 2003, Vol. 14, supplement 2, pp.ii13-ii16, by permission of Oxford University Press.

*FOLFOX4: biweekly oxaliplatin 85 mg/m2 followed sequentially by leucovorin 200 mg/m2, bolus FU 400 mg/m2 and continuous FU infusion 600 mg/m2 over 22 hours on Day 1.

Patients with unresectable liver-only metastases received

FOLFOX4*(N = 42)

Clinical response to chemotherapy

(n = 25)

No response to chemotherapy†

(n = 17)

Surgery not possible(n = 8)

Surgery(n = 17)

Alberts SR, et al. J Clin Oncol. 2005;23:9243-9249.

Prospective, multi-institutional study

NCCTG Study 97-46-51: FOLFOX4 in Unresectable Colon Cancer

Parameter Outcome

Clinical response (N = 42), % Complete 2 Partial 50 Regression 10 SD 26 Progression 12

Surgical response (n = 17), n Complete resection 14 Partial resection 1 Unresectable 2OS (N = 42), mos 26 Resected patients 35

Time to recurrence/progression Median time to recurrence in resection patients (n = 15) 19

Overall time to disease progression (N = 42) 12

NCCTG Study 97-46-51: Response and OS

Alberts SR, et al. J Clin Oncol. 2005;23:9243-9249.

1. Barone C, et al. Br J Cancer. 2007;97:1035-1039.2. Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.

Parameter

Neoadjuvant FOLFIRI Therapy Followed by Surgical Resection of

Liver Metastases[1]

Gruppo Oncologico Nord Ovest Study of FOLFIRI in First-Line Treatment of

mCRC[2]

Patients 40 122

Median follow-up, mos

56 18.4

Response rate, %

48 41

Resection rate, %

33 12

FOLFIRI for Unresectable Liver Metastases

Regimen, % Response Rate Resection Rate

FOLFOX 45-52 33

FOLFIRI 48 33

FOLFOXIRI 55-64 10-50

Alberts SR, et al. J Clin Oncol. 2005;23:9243-9249.Barone C, et al. Br J Cancer. 2007;97:1035-1039.De La Cámara R, et al. ASCO 2004. Abstract 3593.Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.Abad A, et al. ASCO 2005. Abstract 3618.Ho WM, et al. Med Oncol. 2005;22:303-312.

Summary of Cytotoxic Regimens

Role of Biologic, Targeted Therapy

Role of Targeted Therapy: EGFR Inhibitors

Tabernero J, et al. J Clin Oncol. 2007;25:5225-5232. Folprecht, et al. Ann Oncol. 2006;17:450-456. Cervantes, et al. ECCO 2005. Abstract 642. Peeters, et al. ECCO 2005. Abstract 664.

First-line therapy with FOLFOX + cetuximab for metastatic colorectal cancer– Response rate: 72%– 10 of 43 (23%) patients underwent potentially

curative resection

Regimen nRR (%)

Resectability (%) Author

AIO/IRI + cetuximab

21

67 24 Folprecht

FOLFOX + cetuximab

42

79 23 Cervantes

FOLFIRI + cetuximab

42

45 24 Peeters

Evaluation

FOLFOX6 + Cetuximab

Clinical Trials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT00056030. Accessed January 10, 2008.

N014A: Resection of Unresectable CRC Limited to Liver

Endpoints: resectability, response rate, survivalEndpoints: resectability, response rate, survival Initial assessment: surgical response rate 25%Initial assessment: surgical response rate 25%

CR/PR resectable OR CT x 2

PR, unresectable Rx to prog/tolerability

Prog off study, Rx per MD

CRYSTAL Trial: Surgery With Curative Intent

In cetuximab arm, significantly more patients undergoing surgery with curative intent had successful resection

Van Cutsem, et al. ASCO 2007. Abstract 4000.

Outcome, % FOLFIRI + Cetuximab(n = 599)

FOLFIRI(n = 599)

Surgery with curative intent 6.0 2.5

No residual tumor after resection

4.3* 1.5

No residual tumor in patientswith liver metastases only

9.8 4.5

*P = .0034

Summary: Current Experience With Cetuximab

Compared with chemotherapy alone– Consistently increased RR in all trials– Evidence of improved resectability

Initially unresectable metastatic colorectal cancer

First-line and refractory Nonselected and selected (liver-limited)

patients

Role of Bevacizumab

Gruenberger B, et al. ASCO 2007. Abstract 4060.

Phase II trial: XELOX + bevacizumab– 54 patients with potentially resectable

liver metastases– 6 cycles of neoadjuvant therapy (1 week

on, 1 week off)– Clinical response: 74%– pCR: 11%– No long-term follow-up reported

*P =.0034 for cetuximab + FOLFIRI vs FOLFIRI alone, all patients.

Study N Regimen

Metastasis, %

ORR

Resectability(Liver Limited), %Liver

Limited

Liver

> 1 Site

R0 All

Van Cutsem 2007(CRYSTAL)

599 IR/FU/Cet21 NR 85

47 4.3 (9.8)* 6.0

599 IR/FU 39 1.5 (4.5) 2.5

Bokemeyer 2007(OPUS)

169 OX/FU/Cet38 88 40

46 4.7 6.5

168 OX/FU 36 2.4 3.6

Cassidy 2007(NO16966)

700 OX/FU/Bev25 NR NR

38NR

8.4 (19.2)

700 OX/FU 38 6.1 (12.9)

Downstaging of Unresectable mCRC:Randomized Studies

Van Cutsem E, et al. ASCO 2007. Abstract 4000.Bokemeyer C, et al. ASCO 2007. Abstract 4035.Cassidy J, et al. ASCO 2007. Abstract 4030.Hecht JR, et al. World GI Congress 2007.

Liver Toxicity of Neoadjuvant Therapy

A Combined Study of Liver Toxicity of Neoadjuvant Therapy

No chemotherapy

n = 63

n = 158

5-FU/LV

5-FU/LV + Irinotecan

5-FU/LV + Oxaliplatin

Other Therapy

n = 94

n = 79

n = 12

Patients aged 18-86 years divided on basis of preoperative

chemotherapy regimen*

(N = 406)

*Primary colon carcinoma: 76.3%; node-positive disease: 60.3%

Vauthey JN, et al. J Clin Oncol 2006;24:2065-2072.

Patients from M. D. Anderson Cancer Center and Istituto per la Ricera e la Cura del Cancro Candiolo (Torino, Italy) who underwent hepatic surgery for colorectal metastases with curative intent between (June 1992 - June 1999)

Primary endpoint: toxicity

Liver Toxicity of Neoadjuvant Therapy

Patients with steatohepatitis had an increased 90-day mortality compared with patients who did not develop steatohepatitis (P = .001)

Patients, n (%) No CTx 5-FU/LV 5-FU/LV + Irinotecan

5-FU/LV + Oxaliplatin

Other

Sinusoidal dilation Yes 3 (1.9) 0 4 (4.3) 15 (18.9) 0 No 155 (98.1) 63 (100) 90 (95.7) 64 (81.1)* 12 (100)

Steatosis > 30%

Yes 14 (8.9) 9 (16.6) 9 (10.6) 3 (3.8) 1 (8.3) No 144 (91.1) 54 (83.3) 85 (89.4) 76 (96.2) 11 (91.7)

Steatohepatitis

Yes 7 (4.4) 3 (4.8) 19 (20.2) 5 (6.3) 0 No 151 (95.6) 60 (95.2) 75 (79.8)* 74 (93.6) 12 (100)

*P = .0001 compared with no treatment arm.

Vauthey JN, et al. J Clin Oncol. 2006;24:2065-2072.

Complications Following Neoadjuvant Bevacizumab

Kesmodel S, et al. ASCO 2007. Abstract 234.

Retrospective study of preoperative bevacizumab therapy and postoperative complications in patients with colorectal cancer who underwent hepatic surgery for liver metastases (N = 1186)– No increase in hepatobiliary, wound, or other

postoperative complications– Optimal timing of surgery in patients receiving

bevacizumab not known

Patient Selection??

Treatment-Associated Liver Toxicity

Irinotecan: steatohepatitis (80%) Oxaliplatin: sinusoidal/vascular injury Bevacizumab

– Impaired liver regeneration– Wound healing complications– Need to wait 6-8 weeks before surgical resection

Cetuximab: no acute or chronic effects to date

Morbidity increased with prolonged use

1. Taylor RA, et al. ASCO 2007. Abstract 4058.2. Wicherts, DA et al. ASCO 2007. Abstract 4063.

Does a Clinical CR or Pathologic CR Lead to Survival Benefit?

Clinical series from MSKCC[1]

– 435 patients treated with neoadjuvant therapy 39 (9%) of patients had 117 lesions disappear on CT

scan 43 pathological CR in lesions Durable CR in 26 patients (> 40 months)

791 consecutive patients receiving neoadjuvant therapy[2]

– Pathological CR: 4% (31 patients)– “Strongly impacted” OS

Issues to Consider

Increased duration of therapy raises risk of hepatic toxicity– Duration of therapy must be balanced with

limiting liver toxicity CR may inhibit ability to resect and/or

ablate

Summary

Neoadjuvant chemotherapy appears to enhance long-term outcomes

Multiagent chemotherapy regimens provide similar clinical benefit with resection rates in the 20% to 30+% range

pCR appears to be 5% to 10% with current regimens

Role of targeted therapy appears promising– Cetuximab may offer advantages in clinical efficacy

and safety over bevacizumab Active area of clinical investigation Multidisciplinary team approach required