Current status and future perspectives of adjuvant

therapy

Maria Chiara Banzi

U.O. Oncologia MedicaASMN-IRCCSReggio Emilia

Area Valutazione del FarmacoAgenzia Sanitaria e Sociale

Regionale, RER

COLORECTAL CANCER: ITALY, CHANGES IN 18 Yrs

- NEW CASES / Yr

30.000 1995 55.000 2013

- DEATHS / Yr

18.000 1995 20.000 2013

Prevalenza 300.000 pazienti

con pregressa diagnosi di tumore colonrettale (51% uomini)

0

50

100

150

200

250

300

350

400

450

500

0-4

5-9

10-1

4

15-1

9

20-2

4

25-2

9

30-3

4

35-3

9

40-4

4

45-4

9

50-5

4

55-5

9

60-6

4

65-6

9

70-7

4

75-7

9

80-8

4

85+

Age 15-44 45-54 55-64 65-74 75+

5 ys Survival 65% 62% 62% 59% 49%

Gender

INCIDENCE and SURVIVAL

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50

DISEASE-FREE SURVIVAL STAGE III PATIENTS

DFS (months)

FOLFOX 72%LV5FU2 65%

3-year

FUFA 63%CH 44%

ANALYSIS OF 6 ADJUVANT TRIALS

MOSAIC MOSAIC FOLFOXFOLFOX

NSABP C-07 NSABP C-07 FLOXFLOX

NO16968 NO16968 XELOX XELOX stage IIIstage III

CALGB 89903 CALGB 89903 IFLIFL

ACCORD 02 ACCORD 02 FOLFIRIFOLFIRI HR stage IIIHR stage III

PETACC-3   PETACC-3   FOLFIRIFOLFIRI

CONCLUSION

MOSAIC MOSAIC FOLFOXFOLFOX

NSABP C-07 NSABP C-07 FLOXFLOX

NO16968 NO16968 XELOXXELOX

CALGB 89903 CALGB 89903 IFLIFL

ACCORD 02 ACCORD 02 FOLFIRIFOLFIRI

PETACC-3   PETACC-3   FOLFIRIFOLFIRI

3

0

249 patients2246 patients

André, New England Journal of Medicine 2004; 350: 2343-2351

DFS: ITT

Data cut-off: June 2006Disease-free survival (months)

FOLFOX4

LV5FU2

Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54

Events

FOLFOX4 304/1123 (27.1%)

LV5FU2 360/1123 (32.1%)

HR : 0.80 [95% CI, 0.68–0.93]

5.9%

p=0.003

5.3%

DFS: STAGE II AND STAGE III PATIENTS

Data cut-off: June 2006

HR [95% CI] p-value

Stage II* 0.84 [0.62–1.14] 0.258

Stage III 0.78 [0.65–0.93] 0.005

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

Months

Pro

bab

ility

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 72

3.8%

7.5%

p=0.258

p=0.005

*Not powered for stage II

DFS: HIGH-RISK STAGE II PATIENTS

Disease-free survival (months)

FOLFOX4 n=286

LV5FU2 n=290

Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 72

3-year 5-year

FOLFOX4 85.4% 82.1%

LV5FU2 80.4% 74.9%

HR 0.74 [95% CI: 0.52–1.06]

High-risk stage II- at least one : T4, tumor perforation, bowel obstruction, G3, venous invasion , <10 lymph nodes

7.2%

Data cut-off: June 2006

5.0%

OVERALL SURVIVAL (ITT)

FOLFOX4(N=1123)

LV5FU2(N=1123)

Number of deaths (%) 245 (21.8) 283 (25.2)

Probability of surviving (%): § 3 years§ 4 years§ 6 years

88.284.9

78.5 *

86.682.8

76.0 *

Patients alive with recurrence (%) 67 (6.0) 96 (8.5)

Hazard ratio [95% CI] 0.91 [0.75 –1.11]

* HR 0.80, CI 0.68-0.93, p = .003 cut-off data 16 Jan 2007

Δ

1.62.12.5

USA CHANGES IN 5 Yrs ( 2004 – 2008 ): FU + OXA

- Stage III

39% 91%

- Stage II

23% 79%

Abrams. JCO 2011

FU B Rest

LV 500

FU 500

RestLV 500

ELOX 8585 2hr2hr

500

Week 1 2 3 4 5 6 7 8

2hr

X3

NSABP C-07NSABP C-07

R

N=1207

N=1200

5yrs DFS 69.4 vs 64.2

HR 0.82 p 0.002

JCO, Oct 2011

5yrs OS 80.3 vs 78.4

HR 0.88 p 0.08

JCO, Oct 2011

NSABP C 07

mFOLLOW UP 8 ys

ST II 29%

G 3 NEUROTOXICITY 8 %

OXALIPLATIN 760 mg/mq ( MOSAIC 1020 mg/mq )

G 3- 4 DIARRHEA !!! 38%

BOWEL WALL INJURY 4.5%

TOXIC DEATHS 1.3 % (FLOX all ages, 3.6% 70+)

Bolus 5-FU/LVRoswell or Mayo regimen

XELOX capecitabine 1000mg/m2 bid d1–

14 oxaliplatin 130mg/m2 d1

q3w 8 cycles

n=944

n=942

Schmoll et al. JCO 2007Haller et al. JCO 2011

RANDO MISATION

NO16968: XELOX ADJUVANT THERAPY IN STAGE III DISEASE

• Primary endpoint: superior 3-year DFS• Secondary endpoints include: OS, tolerability and

convenience

Stage III chemo/radiotherapy-naive CC

Potentially curative resection ≤8 weeks

n=1886

XELOX: 5 Yrs DFS

1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6

XELOX (n=944) 70.9% 68.4%

Absolute difference at 3 years: 4.5%

p=0.0045

3-yearDFS

ITT population

5-FU/LV (n=942) 66.5% 62.3%

4-yearDFS

HR=0.80 (95% CI: 0.69–0.93)

Absolute difference at 4 years: 6.1%

Estimated probability

5-yearDFS

59.8%

66.1%

Absolute difference at 5 years: 6.3%

Haller et al. JCO 2011

5Yrs OS 77.6% vs 74.2% p 0.148

ADJUVANT CHEMOTHERAPY: RECENT STUDIES WITH BIOLOGICS

THE RESULTS OF BIOLOGICS

BEVACIZUMAB

- C-08 Negative

- AVANT Negative

- Quasar 2 Closed

CETUXIMAB

- NO 147 Negative

- PETACC 8 Negative

ADJUVANT THERAPY: OPEN QUESTIONS

• Stage II

• Elderly

• Predictive and prognostic markers

• DPD

ADJUVANT THERAPYOPEN QUESTIONS

• Stage II

• Elderly

• Predictive and prognostic markers

• DPD

AJCC CANCER STAGING 2002. COLORECTAL CANCER

81% 77%53- 68% 46- 61%

27- 64% 21- 59%

LOW vs HIGH

LOW vs HIGH

LOW vs HIGH

T1-2,N1

T3-4,N1

any T,N2

IIIA

IIIB

IIIC

82% 79%

74% 70%LOW vs HIGH

LOW vs HIGH

T3,No

T4,No

IIA

IIB

5yrs DFS

(Surgery +CT)

GradingAJCC

2002 Stage

TNM Stage

MOERTEL 1990 , 929 STAGE III pts : 7 Yrs OS

SURGERY SURGERY + 5 FU-Lev

44%

ALIVE

56%

DEAD

39%

DEAD

61%

ALIVE

17 Pazients saved out of 100 treated ( RR death - 40%)

Stage II : DFS 79% vs 71% ( NS )

QUASAR : A RANDOMIZED STUDY OF ADJUVANT 5FU VS OBSERVATION IN 3239 STAGE II COLON PTS

OBS CT HR p

PTS 1617 1622

5 YRS DFS 73.8% 77.8%* 0.78 0.001

5 YRS OS 77.1% 80.8%* 0. 82 0.008

+ 3.6%

Lancet 2007

+ 4.0%

1.0

0.8

0.6

0.4

0.2

0.0

Stage II Stage III

Follow-up (years)

Surgery alone: 66.8%

Surgery + FU-based chemotherapy: 72.2%

Surgery alone: 42.7%

Surgery + FU-based chemotherapy: 53.0%

0 1 2 3 4 5 6 7 8

1.0

0.8

0.6

0.4

0.2

0.0

Sargent et al. JCO 2009

∆=5.4%p=0.026

0 1 2 3 4 5 6 7 8

∆=10.3%p=<0.0001

8-year OS 8-year OS

ADJUVANT THERAPY :EVIDENCE FROM 20,898 PATIENTS

DISEASE-FREE SURVIVAL: STAGE II AND STAGE III

Data cut-off: June 2006

HR [95% CI] p-value

Stage II* 0.84 [0.62–1.14] 0.258

Stage III 0.78 [0.65–0.93] 0.005

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

Months

Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 72

3.8%

7.5%

p=0.258

p=0.005

*Not powered for stage II !

5FU vs CONTROL + 4.0 %

FOLFOX vs 5FU + 3.8 %

FOLFOX vs CONTROL + 7.8 %

Mod. da Grothey and Sargent, JCO 2005

DATA EXTRAPOLATION FROM QUASAR and MOSAIC STUDIES : DFS STAGE II

NB Stage II not selected for high risk

DISEASE-FREE SURVIVAL: HIGH-RISK STAGE II

Disease-free survival (months)

FOLFOX4 n=286

LV5FU2 n=290

Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 72

3-year 5-year

FOLFOX4 85.4% 82.1%

LV5FU2 80.4% 74.9%

HR [95% CI]: 0.74 [0.52–1.06]

High-risk stage II- defined as at least one of the following: T4, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion , <10 lymph nodes examined; Data cut-off: June 2006

7.2%

Exploratory analysis

5.0%

The addition of Oxaliplatin did not improve either DFS or OS in

patients age 70-75 years with either Stage II or Stage III cancer.

Adjuvant Treatment for Stage II of Colon Cancer

The updated results of the MOSAIC and C-07 trials reveal a consistent pattern showing that the addition of Oxaliplatin to 5Fu-LV enhances OS by 3% to 5% in patients with stage III disease but has no effect on the likelihood of cure in patients with stage II disease.

CONCLUSION: STAGE II

Benefit of Monotherapy

3-4 % in 5 yr DFS/OS

Clinically meaningful?

Additional benefit of Oxaliplatin

No benefit in Overall Survival

+5% DFS in high risk stage II

Stage II should be considered for adjuvant CT, but need tools to inform decision

02

04

06

08

01

00

0 2 4 6 8

Rx

No Rx

Age<=70

Years from Randomization

02

04

06

08

01

00

0 2 4 6 8

Rx

No Rx

Age>70

Years from Randomization

Time to RecurrenceAdjuvant: in Elderly

Sargent, NEJM 2001

“Postoperative 5FU improves survival in elderly patients, however data are conflicting whether Oxaliplatin added to 5FU provides survival benefits.In the absence of clinical evidence and with no ongoing prospective studies in this patient group, physicians are also guided by data from observational studies”.

ASCO 2012, Daily News, McCleary, Dana Farber Cancer Institute

CONCLUSION: ELDERLY

CONCLUSION : STAGE III

Patients < 70 years old :

12 cycles of FOLFOX 4 or mFOLFOX 6 or

8 cycles of XELOX

Patients ≥70 years old :

12 cycles of LV5FU2 or

8 cycles of Capecitabine

XELOX ?Andrè T, N Engl J Med,2004

Allegra CA, J Clin Oncol,2010

Haller D, J Clin Oncol,2011

Twelves C et al, N Engl J Med,2005

TRIAL “ 3 vs 6”

Adjuvant Therapy of Stage II and III colon carcinoma : 3 vs 6 months

FOLFOX / XELOX

GISCAD

and Italian Intergroup

ADJUVANT THERAPY: OPEN QUESTIONS

• Stage II

• Elderly

• Predictive and prognostic markers

• DPD

MAIN RISK FACTORS

T4

G3

N < 10-13

OCCLUSION-PERFORATION

VENOUS-LYMPHATIC-PERINEURAL INVASION

TS

MSS

GENE EXPRESSION PROFILE

18q LOH

…………….

39

Schmoll, Ann Oncol, Oct 2012%

40

Schmoll, Ann Oncol, Oct 2012

Defective MMR - Colon cancerDefective MMR - Colon cancer

Characterized by presence of MSI & loss of MLH1, MSH2, MSH6 or PMS2 expression

~15% of Sporadic CC, >90% loss of MLH1

Clinical Correlations: Right sided, Female, Early stage,

Better prognosis

Tumors: Poorly differentiated, Signet-ring-cell,

dMMR cells resistant to 5-FU1,2 ( ???? )

1Carethers, 1999; 2Arnold 2003

MSI prognostic for RFS stage II

HR 0.27 (0.11-0.37)

Tejpar, ASCO 2009

CONSENSUS

MMR status is prognostic: 515 untreated stage II colon cancer in 13 RCT

0102030405060708090

100

0 1 2 3 4 5

% D

ise

as

e F

ree

Years

HR: 0.51 p=0.009

deficient

proficient

Sinicrope F. ASCO 2010, 3519

In MSI pts higher incidence of local and abdominal relapses after adjuvant chemotherapy with 5FU. No

difference in control

DFS in dMMR pts, Pooled data*

0102030405060708090

100

0 1 2 3 4 5Years

% D

isea

se F

ree

HR: 2.80 (0.98-8.97)

p=0.05

HR: 1.08 (0.44-2.68)

p=0.86

Stage II (N=102) Stage III (N=63)

Untreated 87%

Treated 72%

Untreated 62%

Treated 67%

5 yr DFS 5 yr DFS

Sargent D. ASCO 2008

*not confirmed by recent analysis from PETACC3 and QUASAR: Schmoll , Ann Oncol Oct 2012

PROPOSED STAGE II ALGORITHM

MMR

Clinical

Risk

No Adjuvant

MSI MSS

Not HighHigh

No Adjuvant

Or

Adjuvant

Adjuvant

*all decisions require discussion with patient

Meropol NJ Ed Session ASCO 2010

E5202: STAGE II COLON CANCER

Tumour block risk assessment based on biology (18q/MSI)

High-risk(MSS and18q LOH)

Arm A mFOLFOX6

ObservationLow-risk

(MSI or no loss of 18q )

Arm B mFOLFOX6 + Bevacizumab 5mg/kg

SURGERY

Accrual goal= 3,125 patients

Validation of a 18 gene expression classifier (ColoPrint) for predicting outcome in the T3-MSS subgroup of Stage II colon cancer patients.Abstract No: 3510

T3–MMS : 61% Low Risk

3-years RFS : Low Risk 91% High Risk 74% (HR 2,9; p 0.001).

Validation of the 12-gene colon cancer Recurrence Score (RS) in NSABP C07 as a predictor of recurrence in 264 Stage II and 628 Stage III pts treated with 5FU/LV or FLOX

Abstract No: 3512

12-gene RS predicted recurrence (p= .001)indipendent of T, N, MMR, G

39% LRS, 35% IRS, 26% HRS

5FU treated 5 Yrs RS:

St.II: 9, 13, 18%St.III: 21, 29, 38%St.IIIC: 40, 51, 64%

ADJUVANT THERAPY: OPEN QUESTIONS

• Stage II

• Elderly

• Predictive and prognostic markers

• DPD

DPD : DIIDROPIRIMIDINA DEIDROGENASI CATABOLISMO 5FU

80% inattivato a livello epatico mediante DPD

15% eliminatocon le urine senza essere trasformato

5% della dose resta disponibile per esercitare

la sua azione tossica

5fluorodiidrouracile

52

ENZYMATIC ACTIVITY OF DPD and 5-FU TOXICITY

DPD

5-FdUMP

TS

Tolerabletoxicity

5-FDHU

5-FdUMP

TS

Tossicitàgrave

5-FU

Deficiency

5-FDHU

5-FU

Normal

Danesi R et al. Trends Pharmacol Sci 2001Di Paolo A et al. Clin Pharmacol Ther 2002

DPD guidelines of the Royal Dutch Association for the Advancement of Pharmacy

DPD mutations ( 0.3 – 1.5% ) :

HOMOZYGOUS carriers ALTERNATIVE DRUG

HETEROZYGOUS carriers DOSE REDUCTION OF 50% FOR

5-FLUOROURACILE AND

CAPECITABINE

Swen J et al, Clinical Pharmacology & Therapeutics, 2011

CONCLUSIONS

The screening test of DPD mutation can prevent severe adverse reactions and fatal toxicity to 5FU,(especially relevant in adjuvant setting)

Recommended dose reduction of 50% seems insufficient to avoid toxicity

Intern Emerg Med. 2013 Aug;8(5):417-23.Fluoropyrimidine toxicity in patients with dihydropyrimidine dehydrogenase splice site variant: the need for further revision of dose and schedule.Magnani E, Farnetti E, Nicoli D, Casali B, Savoldi L, Focaccetti C, Boni C, Albini A, Banzi M.

CONCLUSIONS: WHAT IS THE STANDARD ADJUVANT THERAPY IN COLON CANCER ?

FOLFOX/XELOX remains standard adjuvant therapy in stage III and high-risk stage II colon cancer (NNT 17)

Capecitabine for those patients who are not considered candidates for Oxaliplatin

Bevacizumab and Cetuximab are not recommended

High risk Stage II elderly patients should be considered for therapy

Emerging markers may allow personalization of therapy

Dan Sargent