pancreatic cancer: highlights from the 42 nd annual meeting of the american society of clinical...

Pancreatic Cancer: Highlights from the 42nd Annual Meeting of the American Society of Clinical

Oncology, 2006

Muhammad Wasif Saif, M.D.Associate Professor

Yale University School of MedicineNew Haven, CT, USA

AbstractDespite advances in our understanding of the molecular and genetic basis of pancreatic cancer, the disease remains a clinical challenge. Gemcitabine, the standard chemotherapy for pancreatic cancer, offers modest improvement of tumor-related symptoms and marginal advantage of survival. New approaches, alone and in combination with gemcitabine, are being developed to combat this cancer. Combination chemotherapy trials incorporating gemcitabine, cisplatin, 5-fluorouracil, oxaliplatin, or irinotecan generally show improved outcomes in objective response rates but with little or no improvement in survival in phase III trials. In this article, the author describes the key studies presented at the Annual Meeting of ASCO, held in Atlanta, GA from June 2nd to 6th. The studies discussed here include the following: RTOG 9704 (#4007), FFCD-SFRO study (#4008), meta-analysis of gemcitabine plus cisplatin and gemcitabine plus oxaliplatin vs. gemcitabine alone (GERCOR #4003), and ECOG 6201 (Late Breaking Abstract #4004). Based on the results presented at the annual meeting, it comes to us that patients with locally advanced vs. metastatic pancreatic cancer should be studied separately, better understanding of the biology of pancreatic cancer is mandatory and evaluation of novel agents is crucial. We as oncologist have to change our attitudes towards clinical trials and need to think beyond a trial design such as gemcitabine vs. drug of our choice. Environment within which research is being conducted also has to be changed and last but not the least, access to trials for patients with pancreatic cancer is the key step in the fight against pancreatic cancer.

What did we know already?

What we learn?

What we miss?

What we do next?

Lessons from ASCO 2006



What we learn?

What we miss?

What we do next?

Median Survival of Patients with Pancreatic Cancer

(Staley’s Classification, 1996) [1]

Localized/Resectable 15-19 months 10%

Locally Advanced6-10 months 30%

Metastatic/Advanced 3-6 months 60%

[1] Staley CA, et al. Pancreas 1996; 12:373-80.

Adjuvant Chemo and Chemo-XRT

No clear consensus on adjuvant therapy for pancreas cancerGITSG [2]:

43 pts randomized into two groups:XRT/bolus 5-FU weekly 5-FU x 2 years vs. Observation

Median survival 20 and 11 months, respectively favoring Chemo-XRT arm

ESPAC – 1 [3]: No benefit for Chemo-XRT (P=0.24)Significant overall benefit for Chemotherapy

(P<0.001)CONKO-001 [4]:

Randomize to: Gemcitabinevs.ObservationDisease free survival:14.2 mvs. 7.5 m

(P<0.001)

GITSG: Cancer 1987 ESPAC-1: Lancet 2003

[2] Cancer 1987; 59:2006-10. [3] Neoptolemos JP, et al. Lancet 2001; 358:1576-85.[4] Neuhaus P, et al. J Clin Oncol 2005, 23(16S):4013.

Locally Advanced Disease

Chemo-XRT may improve survival compared to XRT alone

Chemotherapy is equivalent to the combination of Chemo-XRTin randomized trials

No randomized trials comparing gemcitabine to Chemo-XRTwas available till FFCD-SFRO study presented at ASCO 2006

GITSG [5] # Pts

Median

survival

Localfailure

rate

1-year

1.5-yearXRT (60 Gy/10 weeks) only

25 5.3 monts

24% 10% 5%

XRT (40 Gy/6 weeks) + 5-FU

83 8.4 monts

26% 35% 20%

XRT (60 Gy/10 weeks) + 5-FU

86 11.4 monts

27% 46% 20%

Survival

[5] Moertel CG, et al. Cancer 1981; 48:1705-10.

Gemcitabine Pivotal Studies: Results

[6] Rothenberg ML, et al. Ann Oncol 1996; 7:347-53.[7] Burris HA 3rd, et al. J Clin Oncol 1997; 15:2403-13.

Rothenberg [6] Burris [7] Burris [7]Gemcitabine 5-FU

Partial response6 (9.5%) 3 (5.4%) 0Stable disease17 (27%) 22 (39.3%) 11 (19.3%)Progressive disease 20 (31.7%) 19 (33.9%)

34 (59.6%)

Survival: median3.9 months5.7 months 4.4 months6-month 31% 46% 31%9-month 15% 24% 6%12-month 4% 18% 2%

Time to progression 2.5 months 2.1 months0.9 months

Clinical benefitResponse 17 (27%) 15 (23.8%) 3 (4.8%)

(P=0.0025)

(P=0.0002)

(P=0.0022)

Developmental Strategies of Gemcitabine-Based Therapies in Pancreas Cancer: 4 Approaches

In doublets/Triplets of cytotoxics

With radiation

By fixed dose rateinfusion

With targeted therapies

GemcitabGemcitabineine

II

I

III

IV

Fixed Dose-Rate Gemcitabine

Gemcitabine is a pro-drug that must be phosphorylated to its active metabolites, gemcitabine diphosphate and triphosphate

Conversion of gemcitabine to the active triphosphate form is saturable with standard rates of infusion

Gemcitabine infused at a fixed dose rate of10 mg/m2/min optimizes triphosphate accumulation

Gemcitabine MetabolismGemcitabine

(dFdC) Cell membrane

dFdC-DNA

dFdCDeoxycytidine

deaminase

Deoxycytidine kinase

dF-dCMP

dF-dCTP

dFdU

dF-dCDP

What Did We Know Before?Advanced Pancreatic Cancer

Gemcitabine used Media

n1-year

Author

30-min infusion 5.7 month

s

18% Burris [7]

Fixed dose rate (FDR)

7.8 month

s

24% Tempero [8]

GemOx 9.2 month

s

36% Louvet [9]

[7] Burris HA 3rd, et al. J Clin Oncol 1997; 15:2403-13.[8] Tempero M, et al. J Clin Oncol 2003; 21:3402-8. [9] Louvet C, et al. J Clin Oncol 2005; 23:3509-16.

Survival



What we learn?

What we miss?

What we do next?

Pancreatic Cancer UpdateAdjuvant

I. RTOG 9704 (Abstract #4007) [10]

Locally advancedI. FFCD-SFRO study (Abstract #4008)

[11]

MetastaticI. GERCOR: Gem/cisplatin vs. GemOx vs.

Gem alone (Abstract #4003) [12]

II.ECOG 6201: 30-min vs. FDR vs. GemOx (Late Breaking Abstract #4004) [13]

[10] Regine WF, et al. J Clin Oncol 2006; 24(18S, Part I):4007.[11] Chauffert B, et al. J Clin Oncol 2006; 24(18S, Part I):4008.[12] Louvet C, et al. J Clin Oncol 2006; 24(18S, Part I):4003.[13] Poplin E, et al. J Clin Oncol 2006; 24(18S, Part I):LBA4004.

Pancreatic adenocarcinoma, status-post resection:T1-4, N0/N1

July 1998 – July 2002538 patients in the trial(pancreatic head carcinoma: 381)

442 patients eligible and analyzable(22 no CA19-9, >8 weeks post op.)

More T3/4 disease in the Gem arm (P=0.013)

Regine WF, et al. J Clin Oncol 2006; 24(18S, Part I):4007. [10]

RTOG 9704: Adjuvant Trial in Pancreatic Ca

Random

5-FU 250 mg/m2/day

for 3 weeks

Gemcitabine1,000 mg/m2 weekly

for 3 weeks

XRT 50.4 Gy + 5-FU (250 mg/m2/day)

5-FU 250 mg/m2/dayfor 12 weeks

Gemcitabine1,000 mg/m2 weekly

for 12 weeks

RTOG 9704: Treatment

AA BB


RTOG 9704: Toxicity

Arm A Arm B> Grade 3 Hem 2% 14%*> Grade 3 non-Hem

58% 58%

Ability to complete Chemo

88% 90%

Ability to complete XRT

86% 88%* No difference in febrile neutropenia


Regimen Arm A(n=18

7)

Arm B(n=194

)

Median survival(months)

20.6 36.9

P=0.047HR=0.79

(95% CI=0.63-0.99)

3-yearr survival

21% 32%When analysis was inclusive of patients with body/tail tumors (n=442) no significant difference in survival was found (P=0.20).

RTOG 9704: Survival

Pancreatic head Ca (n=381)


RTOG 9704: Conclusions

Addition of gemcitabine to 5-FU/XRT improves survival in head pancreatic cancer

Addition of gemcitabine increases hematologic toxicity, but manageable

? New standard to be consideredESPAC-3 [14]:Randomize to Gemcitabine vs.

5-FU vs. ObservationOngoing

[14] National Cancer Research Network Trials Portfolio, 2004. (ISRCTN 37494643)

ESPAC–3: Trial Design

Patients with adenocarcinoma of the pancreashaving ‘curative’ resection

Randomizationstratified by resection margins

Gemcitabine5-FU/FA ObservationFA (20 mg/m2 iv bolus),

5-FU (425 mg/m2 iv bolus)5 days every 28 days,

x6 cycles

1,000 mg/m2 iv infusiononce weekly x3 wks,

1 wk rest,x6 cycles

National Cancer Research Network Trials Portfolio, 2004. (ISRCTN 37494643) [14]

FFCD-SFRO study

Rationale: The GITSG studies have shown a greater

survival after 5 FU-based Chemo-XRT than XRT radiotherapy [5] or polychemotherapy alone [15] in patients with locally advanced non metastatic pancreatic cancer

Gemcitabine is more active than 5-FU in advanced pancreatic cancer [7]

This randomized trial evaluated whether initial Chemo-XRT adds to modern gemcitabine in term of overall survival. Chauffert B, et al. J Clin Oncol 2006; 24(18S, Part I):4008. [11]

Phase III trial comparing Chemo-XRT (cisplatin and 5-FU) followed by

gemcitabine vs. gemcitabine alone in patients with locally advanced pancreatic

cancer

[5] Moertel CG, et al. Cancer 1981; 48:1705-10.[7] Burris HA 3rd, et al. J Clin Oncol 1997; 15:2403-13.[15] J Natl Cancer Inst 1988; 80:751-5.

FFCD-SFRO: Study Design

Stratification:• PS (WHO)• Center• Exp surgery or not

Patients with

locally advance

d nonmeta

tstaic pancreat

ic cancer

Ran

dom

izati

on 5-FU

+ cisplatin+ XRT

Gemcitabine

Gemcitabine

InductionMaintenan

ce

Randomized Phase III Study

Chauffert B, et al. J Clin Oncol 2006; 24(18S, Part I):4008. [11]

FFCD-SFRO Study: G 3-4 Toxicities

5-FU + cisplatin

+ XRT

Gemcitabine

Neutropenia 60% 23%Febrile neutropenia

0 2%

Anemia 3.4% 1.7%Thrombocytopenia

8.5% 0

Nausea/Vomiting

20% 10%

Diarrhea 7% 0Cutaneous 0 3%


FFCD-SFRO Study: Survival

Survival 5-FU +

cisplatin+ XRT

Gemcitabine

Median (months)

8.4 14.3 P=0.014

6 months 78% 82%12 months 24% 51.4%


FFCD-SFRO Study: Conclusions

Gemcitabine alone allowed a significant overall survival in locally advanced nonmetatstatic pancreatic cancer

Increased toxicity and decreased maintenance gemcitabine in patients with initial Chemo-XRT may explain this difference

Study was stopped before the planned inclusion due to lower survival with initial Chemo-XRT when compared to Gem alone

Pooled Analysis of 2 Randomized Trials

GERCOR/GISCAD Intergroup Study and a German Multicenter Study

Gem + platinumcompoun

d

Gemalone

Patients (n=503) n=252 n=251ECOG PS = 0 40% 35%Distant metastases

72% 73%

Pathological grading = 3

34% 38%

Louvet C, et al. J Clin Oncol 2006; 24(18S, Part I):4003. [12]

Meta-Analysis: Results GERCOR/GISCAD Intergroup Study and a German

Multicenter Study

Gem + platinu

mcompou

nd

Gemalone

P value; HR

Progression-free survival

5.5months

3.5months

P=0.003

HR: 0.66

Overall survival8.3

months6.7

months

P=0.031

HR: 0.77


Meta-Analysis: Results in Stratified Patients

GERCOR/GISCAD Intergroup Study and a German Multicenter Study


Progression-free survival

Overall survival

MonthsHR (95% CI)

MonthsHR (95% CI)

Stage ofdiseaseLocally advanced vs.

5.80.66 (0.54-0.81)

10.10.68 (0.55-0.82)

Metastatic 3.5 P<0.001 6.9 P<0.001

PerformancestatusECOG 0 vs. 5.80.49 (0.15-

0.77)10.60.59 (0.49-0.72)

ECOG 1-2 3.5 P<0.001 6.4 P<0.001

Meta-Analysis: Conclusions GERCOR/GISCAD Intergroup Study and a German

Multicenter Study PS 0 pts may achieve a greater benefit in

progression-free survival (5.8 vs. 3.5 months; HR 0.49, P<0.001) and overall survival (10.6 vs. 6.4 months; HR 0.59, P<0.001) from treatment with a gemcitabine/platinum doublet

This is similar to data reported by Hermann [16] with gemcitabine + capecitabine

Stage of disease and PS remain important prognostic factors

Careful PS evaluation and stratification is important

Specific studies according to stage: locally advanced vs. advanced should be done

[16] Herrmann R, et al. J Clin Oncol 2005; 23(16S Part I):LBA4010.


Meta-Analysis: Comparison to Other Gemcitabine-Based Combinations

Evidence from Randomized Trials

Regimen No. of

cases

Survival

(months)

HR P valu

e

Gem + platinum-analog vs. Gem alone (meta-analysis)

5038.36.7

0.77

0.031

Gem + capecitabine vs.Gem alone [16]

5337.46.0

0.80

0.026

Gem + erlotinib vs.Gem alone [17]

5306.45.9

0.81

0.034

[16] Herrmann R, et al. J Clin Oncol 2005; 23(16S Part I):LBA4010.[17] Moore MJ, et al. J Clin Oncol 2005; 23(16S):1.

Gemcitabine administration: 30-min vs. FDR

Gemcitabine dose intensity across single agent and combined arms

Platinum analogs (oxaliplatin is not cisplatin)

It is not know how many pts received XRT prior

Impact of these differencescannot be implicated

Meta-Analysis: Differences in Groups

Meta-Analysis: Pitfalls

ObviousExtent of diseasePerformance statusIt will take a lot of patients to show a

differenceOxaliplatin is not cisplatin30-min gemcitabine is not FDR

gemcitabine Pharmacologic basis Toxicity Cost (time of infusion)

ECOG 6201: Advanced Pancreatic Cancer

Poplin E, et al. J Clin Oncol 2006; 24(18S, Part I):LBA4004. [13]

Random

Gemcitabine 1,000 mg/m2 30 min i.v.weekly x7 on 1 off , then x3 on 1 off

Gemcitabine 1,500 mg/m2

150 min i.v. (10 mg/m2/min FDR) weekly x3 on 1 off

Gem 1,000 mg/m2, FDR, day 1Oxaliplatin 100 mg/m2, day 2every 14 days

AAn=280

BBn=277

CCn=276

March 2003 – March 2005: 833 patientsMedian follow-up: 5.7 months

Males: 53% - PS 0-1: 88% - Metastases: 88%

Primary:To determine whether either FDR gemcitabine or GemOx increases survival compared with standard 30-min infusion

Secondary:Progression-free survivalToxicityQuality of life

ECOG 6201: Objectives


Adenocarcinoma or poorly differentiated

No > grade 2 peripheral neuropathy

Prior adjuvant Chemo-XRT allowed

No prior gemcitabine or oxaliplatin

ECOG PS > 2

ECOG 6201: Inclusion Criteria


ECOG 6201: Worst Toxicity

Arm A Arm B Arm CGrade 3 4 3 4 3 4Neutrophils 19%15%29%31%10%14%

Platelets 12% 0 29% 0 10%<1%

Hemoglobin 8% 2% 15% 3% 4% 1%

Nausea 7% 0 8%<1%

14%<1%

Vomiting 5% 0 5% 1% 10% 1%

Infection 2% 1% 5%<1%

1% 0

Peripheral neuropathy

0 0<1%

0 9% 0


ECOG 6201: Response rate (RECIST)

Response Arm A

Arm B

Arm C

Complete/partial

5% 10% 9%

Stable disease

29% 29% 29%

Progressive disease

26% 24% 24%

Unknown 41% 37% 38%Poplin E, et al. J Clin Oncol 2006; 24(18S, Part I):LBA4004. [13]

ECOG 6201: Survival and HR

Survival Arm A Arm B Arm CMedian (months)

5.0 (4.5-5.6)

6.0 (5.4-6.9)

6.5 (6.1-6.8)

1-year 17% 21% 21%HR 95% CI

30 min vs. FDR (A vs. B)

1.21 1.00-1.45

P=0.053

30 min vs. GemOx (A vs. C)

1.22 0.73-1.05

P=0.045Survival by

disease extentLocally advance

d

Advanced

Median (months) 9.1 5.4 P=0.001Poplin E, et al. J Clin Oncol 2006; 24(18S, Part I):LBA4004. [13]

ECOG 6201: Conclusions

Both FDR and GemOx had approximately 1 month longer median overall survival than standard Gem, but not statistically significant

Survival outcome with 30 min gemcitabine is persistent

Median overall survival: slightly less than other trials:

Study design, such as locally advanced and metastatic patients, need to be studied separately

FDR and GemOx with increased toxicity: Hematologic, nausea and vomiting with

FDR Neuropathy with GemOx

ECOG 6201 adds to multiple studies that showed adding another cytotoxic to gemcitabine does not add any benefit to the modest survival by gemcitabine alone

Progression-free survival and quality of life not given at the meeting



What we learn?

What we miss?

What we do next?

Promising New Regimens inthe Cooperative Groups

Gemcitabine + bevacizumab [18]Median survival of 8.8 monthsNow in randomized trial vs.

gemcitabine aloneGemcitabine + cetuximab [19]Promise in this regimen was a 1-year

survival rate of 32%Erlotinib data adds encouragement to

this trialNow in randomized trial vs.

gemcitabine aloneIrinotecan + docetaxel [20] Ignored largely, but phase II trial had

a 9-month median survivalBeing tested in a multi-institutional

trial with or without cetuximab to confirm this data

[18] Kindler HL, et al. J Clin Oncol 2005; 23:8033-40.[19] Xiong HQ, et al. J Clin Oncol 2004; 22:2610-6.[20] Kurtz JE, et al. Hepatogastroenterology 2003; 50:567-70.



What we learn?

What we miss?

What we do next?

Promise from Non-Clinical Trials

Better understanding of the biology of pancreatic cancer is emerging

New mouse models show promise as potentially more predictive than the old models

Newer imaging techniques may help to gauge disease better

Palliative care is improvingWe can’t underestimate this as

data suggest that improved pain control alone impacts on survival in this disease

GemcitabineAlone

Can Oncologists Change?

RANDOMIZE

Gemcitabine + Your Drug

Here

What Really Needs to Change?

Oncologist attitudes towards clinical trials

Environment within which research is being conducted

Access to trials for patients

What Actions Need to Be Taken to Change?

Study design:Locally advanced and metastatic patients

need to be studied separatelyAppropriate trial size:Gemcitabine + cisplatin may have been

underpoweredGemcitabine + erlotinib may have been

overpoweredAdvocacy input needs to be sought

early:How much benefit is enough to a patient?How much toxicity is too much for a

patient?Regulatory environment: Gemcitabine vs. drugs X + Y wins no

FDA approval and may never be able to happen

Conclusions

30-min Gem vs. FDR? Revisit platinum compounds probably not

FFCD another study negating benefit of platinum compounds

Need to identify surrogates for survival Accelerate testing new drugs, including

targeted agents Move more quickly to adjuvant setting Focus on 2nd Line Rx as most 1st Line regimens

failed in the last decade Standardize our approach: design, analysis,

reporting Move away from “ONE SIZE FITS ALL”

approach to TAILORED patient management

References1. Staley CA, et al. Pancreas 1996; 12:373-80.2. Cancer 1987; 59:2006-10.3. Neoptolemos JP, et al. Lancet 2001; 358:1576-85.4. Neuhaus P, et al. J Clin Oncol 2005, 23(16S):4013.5. Moertel CG, et al. Cancer 1981; 48:1705-10.6. Rothenberg ML, et al. Ann Oncol 1996; 7:347-53.7. Burris HA 3rd, et al. J Clin Oncol 1997; 15:2403-13.8. Tempero M, et al. J Clin Oncol 2003; 21:3402-8. 9. Louvet C, et al. J Clin Oncol 2005; 23:3509-16.10.Regine WF, et al. J Clin Oncol 2006; 24(18S, Part I):4007.11.Chauffert B, et al. J Clin Oncol 2006; 24(18S, Part I):4008.12.Louvet C, et al. J Clin Oncol 2006; 24(18S, Part I):4003.13.Poplin E, et al. J Clin Oncol 2006; 24(18S, Part I):LBA4004.14.National Cancer Research Network Trials Portfolio, 2004.

(ISRCTN 37494643)15.J Natl Cancer Inst 1988; 80:751-5.16.Herrmann R, et al. J Clin Oncol 2005; 23(16S Part

I):LBA4010.17.Moore MJ, et al. J Clin Oncol 2005; 23(16S):1.18.Kindler HL, et al. J Clin Oncol 2005; 23:8033-40.19.Xiong HQ, et al. J Clin Oncol 2004; 22:2610-6.20.Kurtz JE, et al. Hepatogastroenterology 2003; 50:567-70.

Keywords bevacizumab; capecitabine; cetuximab; Cisplatin; Chemotherapy, Adjuvant; gemcitabine; Epidermal Growth Factor; erlotinib; Fluorouracil; oxaliplatin; Pancreatic Neoplasms; Radiation; Radiotherapy, Adjuvant; Receptor, Epidermal Growth Factor; Review; Vascular Endothelial Growth Factor AAbbreviations ASCO: American Society of Clinical Oncology; CONKO: Charité Onkologie - clinical studies in GI cancers; ECOG: Eastern Cooperative Oncology Group; EGFR: epidermal growth factor receptor; ESPAC: European Study Group of Pancreatic Cancer; FA: folinic acid; FDR: fixed dose rate; FFCD-SFRO: Federation Francophone de Cancerologie Digestive and Societe Francaise de Radiotherapie Oncologique; Gem: gemcitabine; GemOx: gemcitabine plus oxaliplatin; GERCOR: Groupe d'Etude et de Recherche en Cancreologie Onco-Radiotherapic; GISCAD: Italian Group for the Study of Gastrointestinal Tract Carcinomas; GITSG: Gastro-Intestinal Study Group; HR: hazard ratio; LBA: late breaking abstract; PS: performance status; RECIST: Response Evaluation Criteria in Solid Tumors; RTOG: Radiation Therapy Oncology Group; XRT: radiation/radiotherapy

The author is grateful to the authors/presentors of the major studies discussed in this review article:Chauffert B. Unite INSERM 517, Faculty of Medicine, 7, Boulevard Jeanne d'Arc, BP 87900, 21079, Dijon, France. [email protected] (FCCD-SFRO).Louvet C. Institut National de la Sante et de la Recherche Medicale (INSERM), Unit 643 and Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes, France. [email protected] (meta-analysis: GERCOR/GISCAD).Poplin EA. Cancer Center of New Jersey, New Brunswick, New Jersey 08901, USA. [email protected] (ECOG 6201)Regine WF. University of Maryland School of Medicine, Radiation Oncology Clinical, Gudelsky Tower; Room GGK-17E, Baltimore, MD 21201, USA. [email protected] (RTOG 9704)CorrespondenceMuhammad Wasif SaifSection of Medical Oncology - Yale University School of Medicine333 Cedar Street; FMP 116New Haven, CT 06520 - USAPhone: +1-203.737.1569Fax: +1-203.785.3788E-mail: [email protected]

Acknowledgement

pancreatic cancer: highlights from the 42 nd annual meeting of the american society of clinical...

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