Colon cancer

Colon cancer

Adjuvant and Neoadjuvant Therapy

CHO SANG-HEE

DEPARTMENT OF HEMATO-ONCOLOGY

CHONNAM NATIONAL UNIVERSITY MEDICAL SCHOOL

Medical oncologist’s role in

multidisciplinary team – colon cancer

Whom? For Optimal regimen

Duration, Time to

start

Toxicity

Agenda

 Stage II :For whom

 stage III : For elderly

 stage IV : Perioperative chemotherapy

Case 1

M/71Y

hematochezia ECOG PS 1

Preserved organ function

S/P of Left hemicolectomy

Case 1 : postop. Bx

Histologic grade : moderate differentiated invades into pericolic tissue

No of examined : 35, N of involved : 0 Venous/lymphatic invasion : absent Perineural invasion : absent

Number of tumor deposit : absent EGFR (+), KRAS wild

Microsatellite stability : stable

Case 1 - Prognosis

이 환자의 5년 생존율은?

1. 10%

2. 20%

3. 40%

4. 60%

5. 80%

Case 1 - Treatment

이 환자에게 적절한 보조요법은?

1. observation 2. capecitabine

3. concurrent chemoradiothearpy 4. FOLFOX

5. FOLFIRI

Case 2

– postoperative biopsy result

Histologic grade : moderate differentiated invades into pericolic tissue

No of examined : 35, N of involved : 0 Venous/lymphatic invasion : absent Perineural invasion : absent

Number of tumor deposit : present EGFR (+), KRAS wild

Microsatellite stability : stable

Case 1 - Prognosis

이 환자의 5년 생존율은?

1. 10%

2. 20%

3. 40%

4. 60%

5. 80%

Case 2 - Treatment

이 환자에게 적절한 보조요법은?

1. observation 2. capecitabine

3. concurrent chemoradiothearpy 4. FOLFOX

5. FOLFIRI

Stage II vs. Stage III

Histologic grade : moderate diff invades into pericolic tissue

No of examined : 35, N of involved : 0 Venous/lymphatic invasion : absent Perineural invasion : absent

Number of tumor deposit : absent

LVI -, PNI -, MSS

Histologic grade : moderate diff invades into pericolic tissue

No of examined : 35, N of involved : 0 Venous/lymphatic invasion : absent Perineural invasion : absent

Number of tumor deposit : present

LVI -, PNI -, MSS

T3N0M0, AJCC Stage II

MSS T3N1cM0, AJCC Stage IIIb

MSS

Prognosis depends on stage AJCC 6 ^th vs 7 ^th (T stage)

Stage TNM 5Y-OS (AJCC 6^th) 5Y-OS (AJCC 7^th)

I T1/T2 ; N0 93.2%

IIA T3N0 84.7%

IIB T4N0 72.2% IIB : T4aN0 60.6%

IIC : T4bN0 45.7%

IIIA T1-2 ; N1 83.4%

IIIB T3-4 ; N1 64.1%

IIIC Any T ; N2 44.3%

IV Any T ; Any N; M1 8.1%

AJCC 6^th O’Connell JB et al. J Natl Cancer Inst. 2004 AJCC 7^th Edge SB et al. Springer, NY 2010, J Clin Oncol 2009; 28: 264

T4a : penetrates to the visceral peritoneum

T4b : directly invades or in adherent to other organ (≈ perforation)

Prognosis depends on stage AJCC 6 ^th vs 7 ^th (N stage)

6

7

N0 No LN met No LN met

N1 regional mets :

1~3 1a : 1 regional met

1b : 2-3 regional mets

1c : tumor deposit in the subserosa, mesentery, or non-peritonealized pericolic or perirectal ts. w/o

regional LN mets N2 Regional mets ≥ 4 N2a : 4-6 regional mets

N2b : ≥ 7 reginal mets

AJCC 6^th O’Connell JB et al. J Natl Cancer Inst. 2004 AJCC 7^th Edge SB et al. Springer, NY 2010

OS : 5~13%

OS : 5~19%

N0

N1

N2

Tumor deposit is a

independent prognostic factor in stage II, III colon cancer less than 4 LN mets

Nagayoshi K et al, Dis Colon Rectum 2014;57:467-74

Survival according to stage (from SEER study)

Hari DM et al, Am Coll Surg 2013;217:181-90

Adjuvant chemotherapy (FU) or not : from QUASAR trial

• Chemotherapy with FU/LV improve small benefit of survival in stage II colon cancer

• Only 66% of overall cohort had both colon cancer and stage II 5Y OS, RR 0.86 (95% CI, 0.66-21.12, NS)

• 64% had less than 12 LN sampled

QUASAR group, Lancet Oncol 2007;37:2020-29

2Y relative risk of recurrence in first 2 years after randomization

International Clinical Trial about Adjuvant Chemotherapy in CRC

Study Stage Standard arm Experimental

arm Benefit

X-ACT III Bolus 5FU Capecitabine equivalent

MOSAIC* II/III Infusional 5FU FOLFOX

NSABP C-07** II/III Bolus 5FU FLOX

XELOXA*** III Bolus 5FU CapeOx

CALGB89803 III Bolus 5FU IFL

PETACC-03 II/III Infusional/ Bolus 5FU FOLFIRI/FUFIRI ACCORD III/II (high) Infusional 5FU FOLFIRI

*Andre T, J Clin Oncol 2009:27;3109-16, ** Yothers G, J Clin Oncol 2011;29:3768-74,

*** Haller DG, J Clin 2011;10:1465-71

More than 5-FU/LV chemotherapy for Stage II ? : from MOSAIC study

Andre T, J Clin Oncol 2009:27;3109-16

High risk stage II

from MOSAIC study

Subgroup 5Y DFS P 6Y-OS P

Stage II 0.84

(0.62-1.14) 0.258 1.00

(0.7-1.41) 0.986 High risk 0.72

(0.51-1.01) 0.062 0.91

(0.61-1.36) 0.648 Low risk 1.36

(0.76-2.45) 0.305 1.36

(0.67-2.5) 0.399

High risk : T4, tumor perforation, bowel obstruction, poorly diff, venous invasion, ≤ 10 LNs examined,

Tournigand C , J Clin Oncol 2012;30:3353-60

High risk stage II

from SEER database

Stage II, no poor px factor Stage II, any poor px factor

Stage III

P=0.20 P=0.65

P < 0.001

O’Connonr ES et al , J Clin Oncol 2012;29:3381-88

Poor px factor

obstruction, perforation, emergent admission, T4 stage, resection of fewer than 12 lymph nodes, and poor histology

Consensus guideline definition of high risk stage II colon cancer

Guideline Definition

ASCO pT4, perforation, poorly diff, inadequately sampled nodes ESMO pT4, LVI or PNI, perforation or obstruction, poorly diff, LN

sampling < 12 nodes

NCCN pT4, LVI or PNI, perforation, obstruction, close or

indeterminate or positive margin, poorly diff (exclusive of those that are MSI-H), LN sampling < 12 nodes

건강보험심 사평가원 (2013.9.1)

T4, poor diff, LVI, PNI, bowel obstruction, T3 with perforation or close/positive margin

LVI : lymphovascular invasion, PNI : perineural invasion

Biomarker as a prognostic role

• MMR (MSI status)

• KRAS

• BRAF

…..

Mismatch Repair Deficiency (dMMR)

PCR on tumor DNA for MSI

IHC for MMR protein

Sinicrope FA et al, 2012: Feb dMMR (MSI-H), pMMR (MSS or MSI-L)

MLH1 MSH2

N

N

T

T

T

T

Defective MMR as A Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in Colon Cancer

- Tested on 5 completed, randomized clinical trial

Sargent DJ et al, J Clin Oncol 2010;28:3219-3226

Stage II - dMMR

Stage II - pMMR

Stage III - dMMR

Stage III - pMMR

Colorectal cancer grade

incorporated with MSI status

MSS, high grade MSI, high grade

Rosty C et al, Hum Pathol 2014;45:2077-84

Colorectal cancer grade

incorporated with MSI status

Diff. Histologic

grade MSI

status New grade

PD High MSS High

PD High MSI Low

WD/MD Low MSS Low WD/MD Low MSI Low

Rosty C et al, Hum Pathol 2014;45:2077-84

Stage III :

Which regimen ?

Elderly

International Clinical Trial about Adjuvant Chemotherapy in CRC

Study Stage Standard arm Experimental

arm Benefit DFS OS

X-ACT III Bolus 5FU Capecitabine equivalent

MOSAIC* II/III Infusional 5FU FOLFOX 7.5%↑ 4.2%↑*

NSABP C-07** II/III Bolus 5FU FLOX 6.6%↑ 2.7%↑

XELOXA*** III Bolus 5FU CapeOx 6.3%↑ 6%↑

CALGB89803 III Bolus 5FU IFL

PETACC-03 II/III Infusion/ Bolus 5FU FOLFIRI/FUFIRI ACCORD III/II (high) Infusional 5FU FOLFIRI

*Andre T, J Clin Oncol 2009:27;3109-16, ** Yothers G, J Clin Oncol 2011;29:3768-74,

*** Haller DG, J Clin 2011;10:1465-71

* Not a statitistically significance

In stage III

Adjuvant Trials with Biologic Targeted Agents

Trial Stage Treatment 3Y- DFS (%)

NSABP C-08 High II/III FOLFOX

FOLFOX+Bevacizumab 75.5

77.4 (NS) AVANT High II/III FOLFOX

FOLFOX+Bevacizumab XELOX+Bevacizumab

76% 73%

75% (NS) NCCTG N-0147 III

(KRAS wild) FOLFOX

FOLFOX+cetuximab 75.8

72.3(NS)

III FOLFIRI

FOLFIRI+cetuximab 66.7%

86.6% (P=0.04) PETACC-8 III

(KRAS wild) pT4N2b

FOLFOX

FOLFOX+cetuximab 78.0

75.1% (NS) 56.9 vs 40.8 (*)

Elderly : Add oxaliplatin or not

 Benefit

 Toxicity

Role of oxaliplatin in elderly : from ACCENT data base

McCleary NJ, et al. J Clin Oncol 2013;31:2066-06

Trials (Total n)

(≥ 70Y %, III %) DFS P* OS P TTR P

MOSAIC (2,246) (14, 60)

< 70Y

≥ 70Y 0.78

0.94 0.09 0.83

1.04 0.05 0.77

0.86 0.36 NSABP C-07 (2,434)

(16, 71)

XELOXA (1,862) (22, 100)

Irinotecan

CALGB89803 PETACC-3 Oral FU

NSABP-C06 X-ACT

No DFS or OS benefit, may delay recurrence Patients ≥ 70Y seems to reduced benefit from

adding to FU in adjuvant setting

: (whereas oral FU retained their efficacy)

* : P interaction

Role of oxaliplatin in elderly

: from pooled analysis from RCT

Pooled individual Pt data from RCT

• X-ACT (Cap/5FU)

• XELOXA (CapeOx)

• AVANT (FOLFOX)

• NSABP C-08 (FOLFOX)

Age < 70 N=3,915 Age ≥ 70

N=904

Haller DG, et al. Ann Oncol 2015;26:715-24

*Incorporating of medical comorbidity

Role of oxaliplatin in elderly

: benefit from RCT pooled analysis

DFS HR, 95% CI OS HR, 95 CI

≥ 70 Years 0.77, 0.62-0.95 0.78, 0.61-0.99

< 70 Years 0.68, 0.61-0.76 0.62, 0.54-0.72

Haller DG, et al. Ann Oncol 2015;26:715-24

MOSAIC (1998-2001)* NSABP C-07 (2000-2002)**

Treatment schedule

Infusional 5FU

400mg/m² bolus and then 600mg/m² civ

Oxaliplatin (85mg/m²) biweekly

Bolus 5-FU 500mg/m²

weekly for 6wks and 2 wks rest Oxaliplatin 85mg/m²

at D1, 15, 29/8wks schedule

Median cumulative dose received

FOLFOX FL FLOX FULV

5-FU 21,759mg/m² 24,000/m² 7,003mg/m² 7,800mg/m²

Oxaliplatin 810mg/m² NA 667mg/m² NA

* Planned dose 5-FU

Oxaliplatin 24,000mg/m²

1,020mg/m² 9,000mg/m²

765mg/m²

Toxicity according to regimen

*Andre T, J Clin Oncol 2009:27;3109-16, ** Yothers G, J Clin Oncol 2011;29:3768-74,

Toxicities (FOLFOX vs. FLOX)

Yothers G, et al. J Clin Oncol 2011;29:3768-3774 Sharif S, et al. Cancer Invest 2008;26:956-963

0 10 20 30 40 50 60

0 1 2 3 4

FOLFOX (during Tx)

FLOX (during Tx)

0 10 20 30 40 50 60 70 80 90

0 1 2 3 4

FOLFOX (6M) FLOX (6M) FOLFOX (4Y)

0 5 10 15 20 25 30 35 40

FOLFOX FL FLOX FULV

Diarrhea Nausea Vomiting

Comparison of peripheral sensory neuropathy

GI toxicities NCI-CTC ≥ Grade 3

NSABP-C07, Age related toxicities

Yothers G, et al. J Clin Oncol 2011;29:3768-3774

0 10 20 30 40 50 60

FULV

Age <70 Age≥70

0 10 20 30 40 50 60

FLOX

Age <70 Age≥70

Elderly

 The addition of oxaliplatin in elderly III colon cancer had only a small, non-significant benefit

 GI toxicities (esp, diarrhea) are more common in

oxaliplatin containing regimen than 5-FU monotherapy

 The addition of oxaliplatin to 5-FU/LV in patients aged

more than 70 years has not been proven in stage II or

stage III colon cancer

Optimal time

for starting adjuvant therapy

• If a patient fit to initiate 4 weeks after surgery

• If adjuvant therapy is delayed

- at 8 weeks, 12% increased mortality - at 12 weeks, 25% increased mortality

Biagi JJ et al. 2011 ASCO GI Syposium

Flow chart for adjuvant therapy in early stage colon cancer

J Clin Oncol. 2015 Jun 1;33(16):1787-1796.

Clinical trial/observation/FL or capecitabine

: not consider FOLFOX Consider oxaliplatin based Relative benefit of indirect evidence for stage II,

especially for those with high risk feature (NCCN V3,2015)

Case 3

해당 환자는 수술 후 보조요법으로 6개월의 FOLFOX 항암치료를 시

행받았고, 추적검사 중 1년 만에 다음과 같은 CT 소견을 보였다.

Grade 2의 신경병증으로 인해 산책하는데 불편감이 있는 것 이외

특이 증상을 호소하지는 않았다.

Treatment I

이 환자에게 적절한 치료는?

1. chemotherapy 2. hepatectomy

3. radiofrequency ablation 4. hepatic artery infusion 5. palliative care

Liver metastases

80% non-resectable 20% resectable

10–30% initially non-resectable might become resectable

70–90% remain non-resectable

Resection

Potential for cure!

:20-30% (5YSR: ~50%) Relapse : 70-80% whithin 2Y 2nd line?

Active therapy

Location Number Size

EPOC - EORTC 40983

perioperative FOLFOX vs. surgery alone in resectable liver mets from CRC

Lancet Oncol. 2013 14(12):1208-15

Treatment II

우선적으로 고려할 수 있는 항암요법은?

1. capecitabine 2. FOLFOX

3. FOLFOX + bevacizumab 4. FOLFIRI

5. FOLFIRI + cetuximab

Tumor shrinkage is a primary treatment goal for CRC

Group Clinical presentation Treatment goal Treatment intensity GROUP 0 Clearly R0-resectable liver and/or lung metastases Cure, decrease

risk of relapse Nothing or moderate GROUP 1 Not R0-resectable liver and/or

lung metastases only, may become resectable after induction CT

Maximum

tumor shrinkage Upfront most active combination

GROUP 2 Multiple metastases/sites, with rapid progression and/or tumor-related symptoms

Clinically relevant tumor shrinkage as soon as possible,

control PD

Upfront active combination:

at least doublet

GROUP 3 Multiple metastases/sites, no option for resection and/or initially asympt omatic, less aggressive disease

Prevent further progression, low

toxicity

Watchful waiting or sequenti al approach (triplet regimen

s only in selected patients)

Schmoll H-J, et al. Ann Oncol 2012;23:2479–2516

Neoadjuvant chemotherapy

 Which Regimen?

 How long?

Resection of metastases depends on the tumor response rate

△ Studies including non-selected patients with mCRC (r=0.74;

p<0.001)

■ Studies including selected

patients (liver metastases only, no extrahepatic disease)

(r=0.96; p=0.002)

▲ Phase III studies including non- selected patients with mCRC (r=0.67; p=0.024)

Folprecht G, et al. Ann Oncol 2005;16:1311–1319

Best active regimen

for R0 resection

Response rate:

Targeted therapies in 1 ^st line CRC

Response rate (%)

0 10 20 30 40 50 60 70

*Significant vs CT control

p=0.004

45

BEV + CT (n=402)

AVF2107g*

(ITT)

35

CT (n=411)

p=0.99

38

BEV + CT (n=699)

NO16966 (ITT)

38

CT (n=701)

p=0.018 57

Pani + CT (n=325)

PRIME*

(KRAS wt)

48

CT (n=331)

COIN*

(KRAS wt)

Cetuximab + CT (n=362)

64 p=0.049 57

CT (n=367)

CRYSTAL*

(KRAS wt)

Cetuximab + CT (n=316)

57 p<0.001

40

CT (n=350)

Cetuximab + CT (n=82)

57 p=0.0027

OPUS*

(KRAS wt)

34

CT (n=97)

Role of cetuximab in

perioperative setting : New EPOC

Primrose J et al. Lancet Oncol. 2014 May;15(6):601-11.

Primrose J et al. Lancet Oncol. 2014 May;15(6):601-11.

How long?

: Concerns about hepatotoxicities

Normal

Clearly JM et al. Oncologist. 2009;14(11):1095-105

Before Oxaliplatin After Oxaliplatin

The longer the chemotherapy…

the higher the postoperative morbidity…

13.6

19

45.4

61.5

No CT ≤5 cycles 6–9 cycles ≥10 cycles

Adam R, et al. Ann Surg 2004;240:644–658;

Ellis LM, et al. J Clin Oncol 2005;23:4853–4855; Karoui M, et al. Ann Surg 2006;243:1–7

70 60 50 40 30 20 10 0

Morbidity (%)

치료 : #4 FOLFIRI with cetuximab

전 후

환자는 대장암 다학제 회의 결과 대장암과 간종괴에 대해 수술을

시행하도록 결정하였다. 수술은 마지막 항암치료 후 언제 시행하

는 것이 좋을까?

1. 2주 후 2. 4주 후 3. 8주 후 4. 12주 후

5. anytime possible

Interval between surgery and chemotherapy

4 weeks after chemotherapy : 11% rate of complications 5–8 weeks after chemotherapy : 5.5%

9–12 weeks after chemotherapy : 2.6%

At least 6 weeks between the last dose of bevacizumab and elective surgery

Clearly JM et al. Oncologist. 2009;14(11):1095-105

NCCN ver 3. 2015

환자는 특별한 합병증 없이 수술을 시행받았고, 수술 후 조직소견에서 전체 병소는 R0 resection을 보였고, TRG (tumor regression grade) 3 (Dworak grade)이었다.

이 환자의 다음 치료로 알맞는 것은?

1. observation 2. FOLFOX

3. FOLFIRI with cetuximab 4. FOLFIRI

5. FOLFIRI with avastin

Tumor regression grade

Becker K et al. Cancer 2003;98:1521–30

Dworak O et al. Int J Colorectal Dis 1997;12(1):19–23

Adjuvant chemotherapy after

operation in neoadjuvant setting

감사합니다.