Recent Advances in the Treatment of Gastric and Esophageal Cancers

Jeffrey S. Rose, MDThe Ohio State UniversityOctober 8, 2010

Esophageal and Gastric Cancer Incidence (US) Esophageal Cancer 2010

– 16,640 new cases, 14,500 deaths– 89% fatality rate– Over 70% adenocarcinoma

Gastric Cancer 2009– 21,130 new cases, 10,620 deaths– 50% fatality rate– Increasing incidence of cardia

tumorsAmerican Cancer Society

Incidence (cont)

SEER database: 1975-2004

White males– 463% increase in

incidence of adenocarcinoma

– 1.01-5.69/100,000– 50% decrease in SCC

White females– 335% increase in

incidence of adenocarcinoma

– 0.17-0.74/100,000– 29% decrease in SCC

Brown. JNCI 2008

What’s New: Gastroesophageal Junction Cancer Staging AJCC 6 staging guideline has been

criticized as a poor predictor of survival Emphasizes the importance of depth of

invasion (T) and the involvement of lymph nodes based on anatomic location

Multiple studies demonstrate the number of involved lymph nodes may better predict survival

What’s New: Gastroesophageal Junction Cancer Staging Retrospective

review of 336 patients with resected ACA and SCC at MSKCC compared AJCC 6 staging with # of involved lymph nodes

Rizk N, et al. J Thorac Cardiovasc Surg. 2006.

Nodal Status Matters

Rizk N, et al. J Thorac Cardiovasc Surg. 2006.

Survival Improves if >18 Lymph Nodes Removed

Rizk N, et al. J Thorac Cardiovasc Surg. 2006.

Staging: WECC/AJCC 7

Essential changes: – Inclusion of tumor grade– Addition of N1, N2 and N3 based on

# of LN involved (1-3, 4-6 or >6)– M1 changed to nonregional lymph

node involvement or distant metastasis

Staging: WECC/AJCC 7

Stage 0: T0N0M0, Any Grade; TisN0M0, Any Grade

Stage IA:T1N0M0, Grade 1-2 Stage IB: T1N0M0, Grade 3-4; T2N0M0,

Grade 1-2 Stage IIA: T2N0M0, Grade 3-4 Stage IIB: T3N0M0/T0-2N1M0, Any Grade Stage IIIA: T0-2N2M0, Any Grade; T3N1M0,

Any Grade; T4aN0M0, Any Grade Stage IIIB: T3N2M0, Any Grade Stage IIIC: T4aN1-2M0, Any Grade;

T4bAnyNM0, Any Grade; Any TN3M0, Any Grade

Stage IV: AnyTAnyNM1, Any Grade

Staging: WECC/AJCC 7 Validation for GEJ ACA Single institution cohort at MDACC comparing

WECC/AJCC 7 to both gastric and esophageal AJCC 6 staging systems

449 GEJ ACA patients (Siewert I-III) treated with neoadjuvant therapy followed by surgery or surgery alone

All staging systems predictive– For GEJ ACA: WECC/AJCC 7 > AJCC 6 Esoph > AJCC

6 Gastric CONCLUSION: Incorporating the number of

positive lymph nodes within the staging system appears to better predict survival

Gaur P, et al. Ann Thorac Surg. 2010.

Assessment of Response Following Neoadjuvant Therapy-Biopsy Endoscopic biopsy after CRT has been used to

determine response 156 patients at MSKCC received CRT for local-

regionally advanced esophageal cancer -> biopsy -> resection

118 patients had no tumor identified on endoscopic biopsy:– 69% had local disease at time of surgery– Negative biopsy better predicted a pCR for squamous

cell carcinoma versus adenocarcinoma (54.3% vs 13.6% P< 0.001).

– Nodal status of surgical specimens did not correlate – Survival was equivalent

CONCLUSION: A negative endoscopic biopsy is not a useful predictor of a pCR after CRT, final nodal status, or overall survival

Sarkaria IS, et al. Ann Surg. 2009.

Assessment of Response Following Neoadjuvant Therapy-PET/CT PET is useful in restaging after CRT to

exclude distant metastasis Multiple studies are looking at

prognostic value after CRT or chemotherapy

Preliminary results suggest that PET/CT can potentially be a prognosticator for OS, but data on meaningful prediction of response are lacking

Assessment of Response Following Neoadjuvant Therapy-PET/CT Retrospective analysis of 152 patients

with Esoph/GEJ ACA treated with CRT and surgery

>52% SUV decrease was associated with improved OS (43% vs 72% at 3 y)

Pathologic response with <50% residual cancer associated with longer OS – % SUV decrease not associated

In multivariate analysis, SUV decrease only prognostic factor of OS

Javeri H et al. Cancer. 2009

Assessment of Response Following Neoadjuvant Therapy-PET/CT

Javeri H et al. Cancer. 2009

Assessment of Response Following Neoadjuvant Therapy CONCLUSIONS: No role for repeat endoscopy with

biopsy PET/CT useful for excluding

distant disease, but not ready as a prognostic test

Definitive Therapies:

CROSS Study: Effect of preoperative concurrent chemoradiotherapy on survival of patients with resectable esophageal or esophagogastric junction cancer: Results from a multicenter randomized phase III study

A. V. Gaast, P. van Hagen, M. Hulshof, D. Richel, M. I. van Berge Henegouwen, G.

A. Nieuwenhuijzen, J. T. Plukker, J. J. Bonenkamp, E. W. Steyerberg, H. W.

Tilanus, CROSS Study Group

Phase III study comparing preoperative chemoradiotherapy (CRT) followed by surgery versus surgery in patients with esophageal or GE junction cancer (T2-3/N0-1)

Preoperative CRT with weekly paclitaxel 50 mg/m2 and carboplatin AUC = 2 for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery versus surgery

363 pts were enrolled with adeno/squamous/other carcinoma 273/86/4

CROSS Study

CROSS Study

CRT+Surgery Surgery

Resection Rate 90% 86%

RO Resection Rate 92.3% 64.9%

pCR 32.6% NR

In-hospital Mortality

3.8% 3.7%

Median Overall Survival

49 months 26 months

One, 2 and 3 year survival rates

82%/67%/59% 70%/52%/48%

Overall Survival

Preoperative CRT-ACA

Trial Therapy Patients %ACA %R0 pCR Survival

Stahl Surgery 94 100 66 -- 28% 3y

CRT-S 72 16 47%

Walsh Surgery 110 100 NS -- 6% 3y

CRT-S NS 25 32%

Urba Surgery 100 75 90 -- 16% 3y

CRT-S 88 28 32%

Tepper Surgery 56 67 -- -- 16% 5 y

CRT-S -- 16 39%

Gaast Surgery 363 73 67 -- 48% 3y

CRT-S 92 32.6 59%

Preoperative CRT-SCC

Trial Therapy

Patients

%SCC %R0 pCR Survival

Le Prise Surgery

86 100 NS -- 14% 3y

CRT-S NS 25 19%

Bossett Surgery

282 100 90 -- 36% 3y

CRT-S 88 28 34%

Bedenne

CRT-S 259 100 75 23 34% 2y

CRT 40%

Stahl CRT-S 172 100 82 35 31% 3y

CRT 24%

Neo-adjuvant CRT: Conclusion Neo-adjuvant CRT/trimodality

therapy is the standard of care for resectable ACA of the esophagus

CRT alone may be sufficient for certain patients with SCC

Surgery aids in decrease of local recurrence, but does not improve survival

Herskovic A et al. N Engl J Med 1992;26:1593-98, Tepper JE et al. ASCO 2006, Gaast AV et al. ASCO 2010

Advanced Disease

Last Year, We Were “On Target”. One Year Later?

Yes, with Herceptin Probably, with Cetuximab No, with Avastin

CALGB 80403 / ECOG 1206: Randomized Phase II Study of Standard Chemotherapy + Cetuximab for Metastatic Esophageal Cancer

PC Enzinger, BA Burtness, DR Hollis, D Niedzwiecki, DH Ilson, AB Benson 3rd,

RJ Mayer, RM Goldberg

Background

Cetuximab: a chimeric (mouse/human) monoclonal antibody against epidermal growth factor receptor (EGFR)

EGFR expression in ~80% (30-90%) esophageal cancer, ~40% gastric cancer

EGFR expression correlates with prognosis in esophagogastric ACA and SCC

KRAS mutations occur in ~2% (0-9%) of esophageal cancers

Mukaida. Cancer 1991; Itakura. Cancer 1994; Yacoub. Mod Pathol 1997; Torzewski. Anticancer Res 1997; Koyama. J Cancer Res Clin Oncol 1999; Lea. Carcinogenesis 2006

BackgroundRegimen Phase Tumor

SitesResponse Survival Reference

ECF III Esoph GEJ Stomach

45% 8.9 mos Webb.J Clin Oncol 1997

ECF III Esoph GEJ Stomach

42.4% 9.4 mos Ross.J Clin Oncol 2002

ECF III Esoph GEJ Stomach

40.7% 9.9 mos Cunningham. N Engl J Med 2008

IC II EsophGEJ

57% 14.6 mos Ilson. J Clin Oncol 1999

IC II GEJ Gastric

58% 9 mos Ajani. Cancer 2002

FOLFOX II Esoph GEJ Cardia

40% 7.1 mos Mauer. Ann Oncol 2005

FLO III GEJ Gastric

41.3% 10.7 mos Al-Batran. J Clin Oncol 2008

Stratification:ECOG 0-1 vs 2ADC vs. SCC

ARM A: (ECF + cetuximab); 1 cycle = 21 days

Cetuximab 400 250mg/m2 IV, weeklyEpirubicin 50 mg/m2 IV, day 1Cisplatin 60mg/m2 IV, day 1Fluorouracil 200mg/m2/day, days 1-21

ARM B: (IC + cetuximab); 1 cycle = 21 days

Cetuximab 400 250mg/m2 IV, weeklyCisplatin 30 mg/m2 IV, days 1 and 8Irinotecan 65 mg/m2 IV, days 1 and 8

ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days

Cetuximab 400 250mg/m2 IV, weeklyOxaliplatin 85 mg/m2 IV, day 1Leucovorin 400 mg/m2, day 1Fluorouracil 400 mg/m2 IV bolus, day 1Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)

Treatment Schema

Primary endpoint RR

0 5 10 15 20 25

Months from Study Entry

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n P

rog

res

sio

n-F

ree

ECF-C (n=67)IC-C (n=71)FOLFOX-C (n=72)

Progression-Free Survival

Median PFS: ECF-C 5.9IC-C 5.0FOLFOX-C 6.7

0 5 10 15 20 25

Months from Study Entry

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n S

urv

ivin

g

ECF-C (n=67)IC-C (n=71)FOLFOX-C (n=72)

Overall Survival

Median OS: ECF-C 11.5IC-C 8.9FOLFOX-C 12.4

* Includes 4 deaths** Includes 2 deaths† Indicates a death

ECF-CECF-C IC-CIC-C FOLFOX-CFOLFOX-CNon-HematologicNon-Hematologic 66%*66%* 77%**77%** 65%65%

Constitutional symptomsConstitutional symptoms 13%13% 18%18% 17%17%DermatologicDermatologic 16%16% 11%11% 19%19%GastrointestinalGastrointestinal 28%28% 42%†42%† 22%22%InfectionInfection 13%13% 8%8% 7%7%MetabolicMetabolic 16%16% 34%34% 22%22%NeurologicNeurologic 12%12% 4%4% 17%17%PainPain 9%9% 1%1% 3%3%PulmonaryPulmonary 4%4% 1%†1%† 0%0%VascularVascular 6%6% 7%7% 4%4%Death; no CTCAE definedDeath; no CTCAE defined 6%6% 0%0% 0%0%

Total (Heme + Non-Heme)Total (Heme + Non-Heme) 75%75% 86%86% 79%79%

p=0.05

p=0.03

p=0.06

p=0.01

P-value

p=0.05

p=0.03

p=0.06

p=0.01

P-value

Toxicity

Response Survival Response Survival

ECF 41-45% 8.9-9.9 mos

ECF-C57.8% 11.5 mos

IC (Phase II)57-58% 9-14.6 mos

IC-C45.6% 8.9 mos

FOLFOX40-41% 7.1-10.7 mos

FOLFOX-C 53.6% 12.4 mos

Random Phase II* Regimen Pts Response PFS OS

1st line therapy for esophageal SCC

Cis/5-FU 30 13% 3.6 5.5

CF + Cetux 32 19% 5.9 9.5

*Lorenzen. Ann Oncol 2009

15%

2.5mo

-10%

-2mo

Vs.

Discussion: Is there a signal for cetuximab in esophageal cancer?

Conclusions

All 3 regimens > 40% RR IC-C: appeared to have lowest

response and survival & most adverse events

ECF-C: appeared to have highest response, but highest treatment-related mortality and most treatment-related modifications

FOLFOX-C: good response and survival and best tolerated

* http://clinicaltrials.gov/ct2/show/NCT00824785

**http://clinicaltrials.gov/ct2/show/NCT00678535

REAL 3*

EXPAND**

EOX

EOX + Panitumumab

Cape / Cis

Cape / Cis + Cetuximab

Studies on the Horizon

AVAGAST: a randomized, double-blind placebo- controlled, phase III study of first-line capecitabine and cisplatin + bevacizumab or placebo in patients with advanced gastric cancer (AGC)Y-K Kang, A Ohtsu, E Van Cutsem, SY Rha, A Sawaki, SR Park, H-Y Lim, J Wu, B Langer,

MA Shah on behalf of AVAGAST investigators

Rationale for Bevacizumab in AGC Angiogenesis important for tumor

growth, progression and metastases

Bevacizumab:– Humanized monoclonal antibody to

VEGF– Promising results in Phase II studies

in AGC

Shah et al. 2006

R

AVAGAST: A Randomized Double-Blind, Placebo- Controlled Phase III Study

Capecitabine*/Cisplatin (XP)

+ Placebo q3w

Capecitabine*/Cisplatin (XP)

+ Bevacizumab q3w

Locally advanced or metastatic gastric cancer

Cape 1000 mg/m2 oral bid, d1–14, 1-week rest

Cisplatin 80 mg/m2 d1

Bevacizumab 7.5 mg/kg d1

Maximum of 6 cycles of cisplatin

Cape and bevacizumab/placebo until PD

Primary endpoint OS

Overall Response

XP + PlaceboN=387

XP + BevN=387

Patients with measurable disease 297 311

Overall response 111 (37%) 143 (46%)

95% CI 0.6–16.6

P value (2) 0.0315

Complete response 3 (1%) 5 (2%)

Partial response 108 (36%) 138 (44%)

Stable disease 90 (30%) 93 (30%)

Progression-Free Survival

387387

279306

145201

86123

5571

3238

33

1511

00

XP + PlaceboXP + Bev

XP + Placebo

XP + Bev

HR = 0.80

95% CI 0.68–0.93

p = 0.0037

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

3 9 15 18 21 240 6 12

5.3

6.7

Study month

Overall Survival

387387

343355

271291

204232

146178

98104

1519

XP + PlaceboXP + Bev

5450

00

XP + Placebo

XP + Bev

HR = 0.87

95% CI 0.73–1.03

p = 0.1002

3 9 15 18 21 240

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

6 12

Study month

10.1

12.1

Regional Differences in Efficacy

RegionXP + PlaceboMedian, mo

XP + BevMedian, mo

Delta, mo

Hzrd Ratio 95% CI

OS Asia 12.1 13.9 1.8 0.97 0.75–1.25

Europe 8.6 11.1 2.5 0.85 0.63–1.14

America 6.8 11.5 4.7 0.63 0.43–0.94

PFS Asia 5.6 6.7 1.1 0.92 0.74–1.14

Europe 4.4 6.9 2.5 0.71 0.54–0.93

America 4.4 5.9 1.5 0.65 0.46–0.93

Patients enteredPatients receiving second-line

treatment (%)

Asia 376 66

Europe 249 31

Pan-America 149 21

Conclusions Primary endpoint of OS not met

Secondary efficacy endpoints (PFS, best ORR) significantly improved, indicating clinical activity of bev + chemo in AGC

Apparent greater benefit in America>Europe>Asia

No unexpected / new safety signals for bev

Further analysis ongoing, including preplanned biomarker analysis

Other Therapeutic Options in Advanced Disease GE junction:

– FLO vs FLOT (abs 4013) Improved PFS, RR, not

OS Increased, but

expected, toxicity– DCF vs Modified DCF

(abs 4014) Improved PFS, RR and

OS 53% vs 30%

hospitalized for toxicity Gastric:

– Granite-1 study looking at Everolimus. 56% DCR in phase II study.

– TOGA: QoL not affected

Conclusions

Cetuximab looks promising, not ready for clinical practice (REAL-3/EXPAND)

No role for Bevacizumab in gastric cancer

All patients with gastric and GEJ ACA should have her2neu status assessed

DCF active but still toxic, even when modified and administered with GCSF

Thank You and GO BIG RED!