III SESSIONE Decidere la chemioterapia adiuvante

e della malattia metastatica

Evidenze nella scelta della chemioterapia adiuvante

Evaristo Maiello UOC Oncologia

IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo (FG)

Milano, 28 novembre 2017

Criteria for Resectability: Intergroup/NCCN

Potentially

Resectable

Katz MH, et al. Ann Surg Oncol. 2013;20(8):2787-2795.

Borderline

Resectable

Locally

Advanced

Portal vein/SMV TVI<180º

TVI<180º and/or

reconstructable

occlusion

Unable to

reconstruct

Hepatic artery No TVI

Reconstructable

short-segment TVI

of any degree

Unable to

reconstruct

Superior mesenteric No TVI TVI<180º TVI≥180º

Celiac trunk No TVI TVI<180º TVI≥180º

NCCN, National Comprehensive Cancer Network; SMV, superior mesenteric vein; TVI, tumor-vein circumferential interface

Percent of Cases and 5-Year Survival By Stage at Diagnosis

Regional

52%

Metastatic

Stage

Unknown 9%

35

30

25

20

15

10

5

0

Column1

Perc

en

t

31.5%

11.5%

2.7% 5.1%

Dx, diagnosis

SEER 18 2007-2013, published April 2017. https://seer.cancer.gov/statfacts/html/pancreas.html. Accessed on: 25 Sep 2017

Stage at Dx

29%

10% Localized

5-Year OS

Patterns of recurrence after resection

Katz MH et al, Ann Surg 2009

Frequency, location, and timing of disease recurrence after resection for patients with resectable and borderline resectable pancreatic adenocarcinoma

Outcome for Resectable Pancreatic Cancer

%5y OS: 20-25%

but………

Pts with intra-op. M+ (>10%) Post-op M+ (>10%) Slow/no post-op recovery (>10%)

Poor prognostic factors that suggest that a

cancer is more likely to recur after surgery

• Large tumor size (high T stage)

• Poorly differentiated tumors

• Positive resection margin (?)

• Starting time of adjuvant therapy (?)

• Ca 19-9: High pre- or post-operative level ; no decrease after surgery

• Positive lymph node involvement

When is Appropiate to Start Adjuvant Treatment?

• Start adjuvant chemotherapy until up to 12 weeks post-surgery does not affect prognosis

• Completion of 6 cycles of adjuvant CRT is prognostic

Valle JW, et al. J Clin Oncol. 2014;32(6):504-512.

OS According to Time Between Surgery and Start of Treatment in the ESPAC-3 Trial

Surgical Mortality & Volume Center

Surgical Mortality & Volume Center

Linee Guida AIOM 2017

High volume Institutions with high volume surgeons have: - Longer OS - Fewer surgical complications (morbidity) and fewer deaths (mortality)

Perioperative mortality: - Low volume MD, low volume hospital: 10-15% - High volume MD, high volume hospital: 3-4%

Adjuvant Trials in Pancreatic Adenocarcinoma

Slide 7

Resectable PCA: Adjuvant Therapy CONKO-001

Gemcitabine vs Observation ESPAC-1

5-FU vs Observation

OS:

50%, 2-Year

20-25%, 5-Year

Cu

mu

lati

ve

Su

rviv

al

Months

CT, chemotherapy; 5-FU, fluorouracil

Oettle H, et al. JAMA. 2013;310(14):1473-1481. Neoptolemos JP, et al. N Engl J Med. 2004;350(12):1200-1210.

Adjuvant – Single Agent FU > Obs

Is Adjuvant Gemcitabine Alone An Option?

CONKO-001 Trial: Disease-Free Survival and Overall Survival

Follow-up time: 136 months DFS, disease-free survival; m, months; OS, overall survival

Oettle H, et al. JAMA. 2013;310(14):1473-1481.

DFS: 13.4 m vs 6.7 m HR 0.55, P<.001

OS: 5-year OS: 10-year OS:

HR 0.76, P = .01 20.7% vs 10.4% 12.2% vs 7.7%

Is Adjuvant Gemcitabine Alone An Option?

Oettle H, et al. JAMA. 2013;310(14):1473-1481.

CONKO-001: Conclusions

• Adjuvant GEM significantly improves both disease-free and overall survival compared to observation

• Adjuvant GEM is associated with more than twice the rate of 5-year survival

• The OS benefit from GEM holds for R0 and R1 resections, node +/- disease, and all T stages

• This study supports adjuvant GEM as a community standard

2y OS 48% vs 48%; HR 0.93

Adjuvant – Single Agent FU = GEM

ESPAC-3 study

Dose intensity: 11% did not receive 5-FU/LV

10% no GEM

55% all cycles 5-FU/LV

60% all cycles of GEM

Neoptolemos JP, et al. J Clin Oncol 2009; 27(18 Suppl.):Abstract LBA4505.

Very predictive toxicity : Stomatitis (10% vs. 0), diarrhea (13% vs. 2%)

more with 5-FU/LV

Thrombocytopenia more with GEM

Treatment-related hospitalizations (10% vs. 3.5%):

more with 5-FU/LV

No difference between the two regimens:

Equal overall survival with both arms

GEM not superior to 5-FU/LV

Safety, compliance, dose intensity, and severe adverse event better with GEM

Important study because there has been a tendency to reject 5-FU/LV in pancreatic cancer and now it is very much back on the stage

Conclusions

Espac-3

Phase III adjuvant therapy trials: what regimen?

ESPAC-4: Survival By Treatment

Gemcitabine

Gemcitabine-

Capecitabine

mOS

5-Year OS (estimate)

SAEs

Grade 3-4 ANC

Grade 3-4 HFS

25.5 months

16%

26%

24%

-

28.0 months

29%

24%

38%

7%

ANC, absolute neutrophil count; HFS, hand foot syndrome; mOS, median overall survival; SAE, serious adverse event

HR for death 0.82 (95% CI,0.68-0.98)

P = .032

Neoptolemos JP, et al. Lancet. 2017;389(10073):1011-1024.

Can We Consider Gem + CPC a Standard Adjuvant Therapy?

Gem, gemcitabine; CPC, capecitabine

Neoptolemos JP, et al. Lancet Oncol. 2017;389(10073):1011-1024.

Overall Survival in ESPAC-4 Trial

Median OS: 28.0 m vs 25.5 m (HR 0.82 [95% CI 0.68-0.98], P = .032)

Median follow-up time: 43.2 months

Overall Survival in ESPAC-4 Trial By Resection Margin Status and Treatment Group

Neoptolemos JP, et al. Lancet Oncol. 2017;389(10073):1011-1024.

Can We Consider Gem + CPC a Standard Adjuvant Therapy in R0 Patients?

X2(1) trend = 14.83, P = .0001

Median OS in R0 patients was 27.9 m (gem arm) vs 39.5 m (gem-CPC arm)

Median OS in R1 patients was 23.0 m (gem arm) vs 23.7 m (gem-CPC arm)

Adjuvant – CAPEGEM > GEM (?)

• Post-op CT scan NOT MANDATORY • Elevated post-op CA19-9 was not an exclusion criterium

Adjuvant – CAPEGEM > GEM (?)

• 29% of pts had post-operative CA 19-9 level > 1.0 ULN • 15% of pts had post-operative CA 19-9 level > 2.5 ULN (and up to 8112 U/mL) • 9% had no measurement available • OS in this subset of pts was only 13.1 months

• Some important issues in the ESPAC-4 trial:

–No clear benefit with gem + CPC in mPC

–Follow-up only 43.2 months

–No CA 19.9 restrictions, no recent CT scan before randomization

–Poor prognostic population: 60% R1, 80% N+, with promising OS…why?

Can We Consider Gem + CPC a Standard Adjuvant Therapy?

CONKO-005: Gemcitabine ± Erlotinib Efficacy By Treatment

mOS gemcitabine = 26.5 months

mOS gem + erlotinib = 24.5 months

Dis

ea

se-F

ree

Su

rviv

al

Pro

ba

bil

ity,

%

Time, Months O

ve

rall

Su

rviv

al

Pro

ba

bil

ity,

%

Time, Months

Sinn M, et al. J Clin Oncol. 2017 Aug 17. [Epub ahead of print].

NRG Oncology/RTOG 0848 Trial of Adjuvant Gemcitabine

± Erlotinib in Resected Pancreatic Head Carcinoma

55% (47%, 63%)

55% (47%, 63%)

83% (78%, 89%)

83% (77%, 89%)

39% (31%, 47%)

38% (30%, 45%)

mOS gemcitabine = 30 months

mOS gem + erlotinib = 28 months

Overall Survival By Treatment

Log-rank P value = .62

Ove

rall

Su

rviv

al,

%

Months From Randomization

Safran H, et al. J Clin Oncol. 2017;35(Suppl 4): Abstract 4007

Linee Guida AIOM 2017

Clinical trials address unanswered question regarding adjuvant chemotherapy and

radiation fro resectable PC

Radiation • Is it beneficial? Is it necessary?

Adjuvant ChemoRT Role

Radiotherapy: Any Opportunity in Adjuvant PC Treatment?

Median OS: 15.9 m vs 17.9 m (HR 1.28, P = .05)

CRT, chemoradiotherapy

Neoptolemus JP, et al. N Engl J Med. 2004;350((12):1200-1210.

ESPAC-1 Trial: OS According to Whether or not Patients Received CRT

• No role for RT in our patient; however,...

• Issues with ESPAC-1 Trial:

–Complicated factorial design

– Limited quality control for radiotherapy

• Any role of RT in adjuvant treatment in PC?

Trial Objective Treatment N

• Role of new RT approaches has to be tested…

RTOG 8048

NCT01013649 OS

Gemcitabine +/- adjuvant CRT

Erlotinib randomization removed 952

Radiotherapy: Any Opportunity in Adjuvant PC Treatment?

RT, radiotherapy

Adjuvant – Single Agent FU = GEM

Adjuvant – ChemoRT Quality

Adjuvant - ChemoRT RM status

Linee Guida AIOM 2017

Clinical trials address unanswered question regarding adjuvant chemotherapy and

radiation fro resectable PC

Radiation • Is it beneficial? Is it necessary?

Chemotherapy • Are the newer regimens for advanced disease also better in the post-operative (adjuvant) setting?

How Do We Expect to Treat Patients Who Are Resectable After Surgery in the Near Future?

APACT Trial

Resected PC

nab-paclitaxel + gemcitabine

for 6 cycles

Gemcitabine for 6 cycles

Accrural completed

Results 2018

National Institutes of Health. http://clinicaltrials.gov/ct2/show/NCT01964430. Accessed: 20 September 2017.

N = 800

DFS

FOLFOXIRI for 6 cycles

Italy GIP-22

Gemcitabine for 6 cycles

N = 310

DFS Resected PC

How Do We Expect to Treat Patients Who Are Resectable After Surgery in The Near Future?

National Institutes of Health. 1. http://clinicaltrials.gov/ct2/show/ NCT01526135.

2. http://clinicaltrials.gov/ct2/show/NCT01526135. Accessed: 20 September 2017.

PRODIGE A-241

mFOLFIRINOX for 6 cycles

Gemcitabine for 6 cycles

N = 490

RFS Resected PC

Clinical trials address unanswered question regarding adjuvant chemotherapy and

radiation fro resectable PC

Radiation • Is it beneficial? Is it necessary?

Chemotherapy • Are the newer regimens for advanced disease also better in the post-operative (adjuvant) setting?

Timing • Is it better to give chemotherapy before surgery?

Adjuvant Therapy is Standard, but…

• Recurrence rates after surgery are 50% to 90%

• 25% to 40% of upfront resected patients fail to complete adjuvant therapy due to surgical complications and disease progression

• …it is possible that neoadjuvant therapy might treat systemic disease sooner and more patients will be able to receive it

Neoadjuvant Therapy in Resectable PCA

Surg Oncol. 2017;43(9):1711-1717.

O’Reilly 2014 38 GemOx

+ Adjuvant Gem 27 (71%) 27.2

NR

(3-year 60%)

Golcher 2015

Randomized

Prospective

33

33

Gem/Cis + RT

+ Adjuvant Gem

vs

Adjuvant Gem

19 (57%)

23 (70%)

17.4 vs 14.4

P = .96

25.0 vs 18.9

P = .79

Itching 2017

Cohort Retrospective

87

133

Nab-Paclitaxel/Gem or

FOLFIRINOX

+ Adjuvant Gem

Adjuvant Gem

69 (79%) 25.9 vs 26.9

P = .58 29.2 vs 26.9

Evans DB, et al. J Clin Oncol. 2008;26(21):3496-3502. Varadhachary GR, et al. J Clin Oncol. 2008 Jul 20;26(21):3487-3495.

O’Reilly EM, et al. Ann Surg. 2014;260(1):142-148. Golcher H, et al. Strahlenther Onkol. 2015;191(1):7-16. Itchins M, et al. Eur J

Resected OS OS Resected

Reference N Neoadjuvant (%) (months) (months)

Evans 2008 86 Gem-RT 64 (74%) 22.7 34

Varadhachary 2008 90 Gem/Cis + GemRT 52 (66%) 17.4 31

Reference Adjuvant Neoadjuvant/Adjuvant

NEOPAC (R)

NEPAFOX (R and BR)

NEONAX (R)

Gemcitabine

Gemcitabine

nab-Paclitaxel/Gem

GemOx/Gem

FOLFIRINOX/FOLFIRINOX

nab-P/Gem/nab-P/Gem

Retrospective Analysis National Cancer Database 2006-2012

mOS 26 months

vs 21 months

P<.01

Mokdad AA, et al. J Clin Oncol. 2016;35(5):515-522.

The role of primary chemotherapy

PACT-15 RESULTS

TAKE HOME MESSAGE

• Outcome of surgery followed by adjuvant chemo: overstimated (?)

• Adjuvant Gemcitabine or fluoropyrimidine: standard

• Evidence in favor of adjuvant combination chemo: not convincing (?)

• Chemoradiation after adjuvant chemo: may be indicated in (RT) large volumes centers

• Preoperative chemo trials are eagerly waited