LAD Pancreatic Cancer

Caio Max S. Rocha Lima, M.D. P f Professor off M Medicine di i University y of Miami & Silvester Comprehensive Cancer Center

Conflicts • Research Grant: – Newlink Genetics – Celgene – Roche – Spectrum S t – Lilly Oncology

Pancreas Cancer Prognosis • 5 year survival i l – Overall is 3% – After a successful pancreaticoduodenectomy approaches 20% • Tumor 180o U Unreconstructible t tibl SMV/portal SMV/ t l vein i occlusion l i Any celiac abutment (head) or celiac encasement > 180o (body/tail) ( y ) Aortic invasion or encasement Lymph node metastases beyond field of resection Borderline resectable: SMA encasement < 180o SMV/portal impingement Short segment SMV occlusion Celiac encasement < 180o (tail) ( ) Abutment/encasement of hepatic artery

Questions • XRT or no XRT? – Up-front U f t vs. delayed d l d radiation di ti

• How often are we missing occult micrometastatic disease at the time of initial diagnosis? – Role of PET, staging laparoscopy?

• Wh Whatt systemic t i agents t should h ld be b usedd (before/during/ after radiation)?

Role of Laparoscopy

Occult Mets in Locally Advanced Disease Upstage by laparoscopy: Author/ A th / year Shoup/ 2004 Liu/ 2005 White/2001

n LAD radiology di l 100 70 55

Laparoscopy: + Mets L M t 37% 34% 24%

Aboutt 30% off pts Ab t di diagnosed d with ith LAD hhave mets t by laparoscopy M. Shoup M Shoup. J Gastrointest Surg 8(8):1068-71, 8(8):1068-71 2004 R. Liu. Surg Endosc 19:638-642, 2005 R. White. J Gastrointest Surg 6: 626-633, 2001

RT Alone vs. vs Chemo-RT Chemo RT Median S Survival (Mo)

1Y survival (%)

Radiation (Gy)

Chemo

No. off Patients

Moertel et al1.

35-40 35-40

5-FU Placebo

32 32

10.4 6.3

22 6

GITSG 92732

60 40 0 60

5-FU 5-FU X

111 11 117 25

11.4 8 8.4 5.3

46 3 35 10

Study

Conclusion: Chemo-RT superior to radiation alone. 1. Moertel CG. et al. Lancet. 1969;25:865-867. 2. Moertel CG et al. Cancer 1981;48:1705-1710.

Chemo Alone vs vs. Chemo-RT Chemo RT Chemo

No. of Patients

Median Survival (Mo)

1 Y survival (%)

40

5-FU 5-FU

47 44

8.3 8.2

28 31

GITSG 92832

54

5-FU 5 FU & SMF* SMF*

22 21

9.7 9 7 7.4

41 19

FFCD-SSRO3

60

5-FU & Cis* Gemcitabine

59 60

8.6 13

32 53

ECOG 42014

50.4

Gemcitabine Gemcitabine

34 37

11.0 92 9.2

50 32

Radiation (Gy)

Study ECOG1

1. Klaassen DJ, et al. J Clin Oncol. 1985;3:373-378. 2. GITSG. J Natl Cancer Inst. 1988;80:751-755. 3 Chauffert B 3. B, et al al. Ann Oncol. Oncol 2008;19:1592-1599. 2008;19:1592 1599 4. Loehrer PJ, et al. J Clin Oncol. 2011;29:4105-4112.

Induction CT followed by CRT in LAPC CRT ft 2 5 3 CRT after 2.5‐3 months of chemotherapy th f h th

Huguet F et al, al J Clin Oncol 2007

Krishnan S et al al, Cancer 2007

Induction chemotherapy : promising option

Flow Chart LP-07 Assessed for eligibility (n= 449) Excluded (n= 7) 1st Randomization I t t t t t principle Intent-to-treat i i l (n= 442) Excluded (n= 173, 39%) Gemcitabine (n= 223)

Gemcitabine + erlotinib (n= 219)

Progressive disease 114 Toxicity 16 Delay 14 Patients' decision 11

2nd Randomization Intent-to-treat principle (n= 269, 61%) (n

Investigators’ decision 11 SD1

Chemotherapy py (n= 136)

Chemoradiotherapy py (n= 133)

Hammel P. et al: LBA 4003, ASCO 2013

Intercurrent disease 4 Surgery 3

Slide 14 SD1

PXN- please make one of these lines dotted. Shari Dermer; 26/11/2013

Overall Survival by Random 1 Status 1.0 –

Ove erall Surviv val Probab bility

Total Event Cens Median 0.8 –

Gemcitabine (ref)

223

188

35

13.6

Gemcitabine + Erlotinib

219

191

28

11.9

Gemcitabine (ref) Gemcitabine + Erlotinib

0.6 –

HR – 95%Cl = 1 1.19 19 – [0.97; [0 97 1.45] 1 45]

0.4 –

Log rank p = 0.0930 0.2 –

0–

| 0

| 3

| 6

| 9

| 12

| | 15 18

| 21

| | | 24 27 30

| | 33 36

| 39

| 42

7 5

6 4

Time Since the First Randomizations (Months) Number at risk 223 219

215 209

191 180

157 140

123 104

91 76

66 56

Hammel P. et al: LBA 4003, ASCO 2013

45 38

33 24

25 14

20 10

12 7

8 6

Overall Survival byy Random 2 Status Overall Su urvival Probability

1.0 –

Total Event Cens Median Chemotherapy (ref)

136

112

24

16.4

Chemoradiotherapy

133

109

24

15.2

0.8 – 0.6 –

Chemotherapy (ref) Chemoradiotherapy

04– 0.4

HR – 95%Cl = 1 1.03 03 – [0.79; [0 79 1.34] 1 34] Log rank p = 0.8295

0.2 – 0 –| 0

| 3

| 6

| 9

| | | | | | | | | | | 12 15 18 21 24 27 30 33 36 39 42

Time Since the First Randomizations (Months) Number at risk 136 133

136 133 117 133 131 113

94 87

70 66

55 45

Hammel P. et al: LBA 4003, ASCO 2013

39 34

24 26

14 18

12 12

8 9

4 9

4 8

4 6

Overall Survival Combining R d Random 1&R Random d 2 St Status t

Overa all Surviva al Probabiliity

T t l Event Total E t

1.0 –

Gemcitabine/Chemotherapy

08– 0.8

Gemcitabine/Chemoradiotherap y Gemicatabine + Erlotinib/Chemotherapy Gemcitabine + Erlotinib/Chemoradiotherapy

0.6 –

C Cens

M di Median HR 95%CI

68

56

12

18.0

1

67

52

15

16.7

1.0 [0.7;1.5] 0.9

68

56

12

14 5 14.5

1 3 [0.9;1.9] 1.3 [0 9;1 9] 0.2 02

66

57

9

14.7

1.3 [0.9;2.0] 0.1

Gemcitabine/Chemotherapy Gemcitabine/Chemoradiotherapy Gemicatabine + Erlotinib/Chemotherapy Gemcitabine + Erlotinib/Chemoradiotherapy

0.4 –

Log rank P=0.2391

0.2 – 0 –| 0

Number at risk 68 67 68 66

P

| 4

| 6

68 67 68 66

67 67 66 64

| | | | | | | | | | 9 12 15 18 21 24 27 30 33 36 Time Since the First Randomization (Months) 61 59 56 54

50 47 44 40

40 36 30 30

30 25 25 20

Hammel P et al: LBA 4003 ASCO 2013

21 19 16 15

15 15 9 11

11 11 3 7

9 8 3 4

6 6 2 3

2 6 2 3

| 39

| 42

2 5 2 3

2 5 2 2

Conclusions • Lack of superiority of CRT vs continuing chemotherapy in LAPC patients with tumor controlled after 4 months of chemotherapy • Erlotinib: not beneficial in LAPC, increased the toxicity

Hammel P. et al: LBA 4003, ASCO 2013

Recent Chemotherapy Regimens g in LAD

FOLFIRINOX experience p in LAPC

Hosein P et al: BMC Cancer. 2012 May 29;12:199

FOLFIRINOX toxicityy

Hosein P et al: BMC Cancer. 2012 May 29;12:199

FOLFIRINOX Outcomes in LAPC

Hosein P et al: BMC Cancer. 2012 May 29;12:199

Locally Advanced Disease Conclusions • XRT + Chemotherapy better survival to XRT alone • Gemcitabine + XRT is potentially superior to G Gemcitabine it bi alone. l – The ECOG study had poor accrual and closed early.

• Retrospective data: chemo chemoXRT p to chemoXRT upfront. p superior • LP07, the largest randomized trial performed to date showed no benefit to XRT or Erlotinib date, Erlotinib.

Locally Advanced Disease Conclusions • Novel Chemotherapy Regimens and Novel Strategies (IRE) are Promising and may lead to higher resectability rates particularly in borderline resectable pancreas cancer. cancer

AACR CDA proposal (not funded)

LAPC IRE study schema (Lustgarten grant application submitted)

Ongoing UM Protocol No response B Still But S ill LAP Folrinox F li x6

Response ChemoXRT Progression Distant

ChemoXRT + N k if Nanoknife Surgery

Surgery ?

Chemotherapy?

Alternative Palliative chemotherapy

+/ Algenpantucel L Subcutaneous QOW +/-Algenpantucel

Obrigado!