Adjuvant Therapy for Pancreatic Cancer

Ahmed Badheeb, M.D.Prof. Of Oncology / Internal Med.

SummaryGITSG (1985)EORTC (1999)ESPAC 1 (2004)CONKO-001 (2007)RTOG 97-04 (2008) Conclusion: no clear evidence for XRT, and good evidence for chemo (5FU and/or Gem). R1 benefit more. 

Jemal A, et al. CA Cancer J Clin. 2007;57:43-66.

Peak incidence in 7th and 8th decades of lifeAverage age at diagnosis: 60-65 yearsSlightly higher incidence in men.

Epidemiology

Pancreatic CA in Jordan 2004

33 cases.0.9 % of all CA.Males> females

1. Jemal A, et al. CA Cancer J Clin. 2007;57:43-66.

Incidence and death rates due to pancreatic cancer remain stableMortality rates parallel incidenceFew long-term survivorsPoor responses to combined modality

treatmentHigh risk of recurrence following surgery

Pancreatic Cancer: Scope of the Clinical Problem

survival5-year survival: < 2%

Disease Stage

Percent of Patients at Diagnosis

Median Survival, mos

Metastatic 60 6

Locally advanced 25 9

Resectable 15 15

1. Geer RJ, Brennan MF. Am J Surg 1993; 165:68-72.2. Willett CG, et al. J Clin Oncol. 2005;23:4538-4544.

Environmental exposure1

Smoking (main risk factor)Risk increases with dose and exposureOther tobacco carcinogens likely involved2

Organic and nickel-containing solvents Chlorinated compounds

High BMI3

Risk higher in obese individuals Decreases with weight loss and exercise

1. Lowenfels AB, et al. Pancreatology. 2003;3:1-7.2. Ojarvani IA, et al. Occup Environ Med. 2000;57:316-324.3. Michaud DS. JAMA. 2001;286:921-929.

Risk Factors

Comorbid conditions Chronic pancreatitis Diabetes mellitus, type II1

Risk doubles with > 5-year history of diabetes mellitus, type II

Familial syndromes Account for 15% to 20% of cases2

1 family member affected: 18 times risk3

3 family members affected: 57 times risk

Risk Factors

1. Yeo TP, et al. Principles and Practice of Oncology, 7th ed. 2006;26:176-275. 2. Klein AP, et al. Cancer J. 2001;7:266-273.3. Harrison’s Principles of Internal Medicine. 16th ed.

Syndrome Molecular/Genetic Defect

Hereditary pancreatitis 7q35

Hereditary nonpolyposis colorectal cancer (Lynch syndrome II)

hMSH2, hMLH1

Hereditary breast and ovarian cancer BRCA2

Familial atypical multiple mole melanoma (FAMM)

p16 (9p21)

Peutz-Jeghers syndrome STK11/LKB1 (19p13)

Ataxia-telangiectasia (ATM) syndrome 11q22-23

Familial Syndromes

Klein AP, et al. Cancer J. 2001;7:266-273.

AJCC Staging

TUMORTis: in situ carcinomaT1: < 2 cmT2: > 2 cmT3: beyond pancreasT4: involves celiac axis or superior mesenteric artery (unresectable)

NODEN0: no lymph node metastasesN1: regional lymph node metastases

METASTASESM0: no distant metastasesM1: distant metastases present

Stage 0 Tis, N0, M0Stage IA T1, N0, M0Stage IB T2, N0, M0Stage IIA T3, N0, M0Stage IIB T1-3, N1, M0Stage III T4, any N,

M0Stage IV Any T, any N,

M1

unresectable

AJCC Cancer Staging Manual, 6th ed. www.cancerstaging.net.

Quality of surgery: “R”

Verify Quality of Surgery: R0 / R1 vs R2

R Designation Gross Resection Microscopic MarginR0 complete negativeR1 complete positiveR2 incomplete positive

Identify patients (25%) who develop metastatic disease after CT restaging

Adjuvant Strategies

Why Adjuvant Therapy?

Surgical failure (ie, disease recurrence) is common80% of patients will develop

progressive disease within 12 months of surgery1,2

Disease progression occurs both locally and in distant sites

1. Mu DQ, et al. World J Gastroenterol. 2004;10:906-909.2. Shibata K, et al. Pancreas. 2005;31:69-73.

Adjuvant TherapyNo clear consensus on adjuvant therapy Difference in philosophy between Europe & North AmericaEuropeans have moved to adjuvant chemotherapy alone

What is the standard approach?

Standards of care vary depending on which side of the Atlantic you are on:North America: chemo-radiotherapy

followed by chemotherapy (GITSG study )Europe (ESPAC-1 &CONKO studies):

chemotherapy alone

[6] Cancer 1987; 59:2006-10. [Link][7] Neoptolemos JP, et al. Lancet 2001; 358:1576-85. [Link][8] Oettle H, et al. JAMA 2007; 297:267-77. [Link]

Adjuvant ChemoRT

GITSG (1985) The first trial. Was initiated in US by the GastrointestinalTumor Study Group (GITSG) in 1974.

Observation

Split course RT (20Gy on 2w =total 40 Gy) +bolus 5-FU 500/m2/dX 3d2w off the same repeated 5FU same dose X weekly X2 years

43 pts resected

Tx # Pts MS (mo) 2 Yr. S40 Gy/5-FU 21 20 (P = .035) 43%

Observation 22 11 18%

GITSG (1985)

Small size (43 pts). Individual role of each ( CTX vs. Chemo RT)Long protocol ( ? Compliance).Early termination, after the first 43 patients due to a statistically significant survival advantage to adjuvant chemoradiation and maintenance CTX

Slow accrual (43 patients in 8 years)

Kaiser MH, et al. Arch Surg. 1985;120:899-903.

GITSG : weakness

Survival advantage for chemoradiation followed by

5-FU for 2 year.

Kaiser MH, et al. Arch Surg. 1985;120:899-903.

GITSG : conclusion

GITSG Trial

This study started the use of combined chemoradiation as an American standard for adjuvant therapy.

(EORTC) 40891 Klinkenbijl et al .

Phase III randomized trial designed to validate the result of the smaller GITSG trial.This trial was the second prospective randomized multicenter trial

Designed to evaluate the potential benefit of adjuvant CRT (vs. observation)

RT (40 Gy-SC) + infusional 5-FU 25mg/kg/d no following CTxResected

Pancreas/Periampullary Ca

EORTC (1999)

Median S (mo) 5 Yr. S (%)Pancreatic CaRT/5-FU (n=60) 17.1 20 Observe (n=54) 12.6 10

P=0.099

Klinkenbijl JH. Ann Surg. 1999;230:776-782.

Observation

EORTC (1999) : overall results

MS Two year survival

“5” year survival

XRT/5 FU 24.5 months

41% 20%

Observation 19 months 51% 10%

P value 0.21 0.21 0.99%

EORTC (1999) :Pancreatic head only results(114/207)

MS Two year survival

“5” year survival

XRT/5 FU 17.1 months

37% 20%

Observation 12.6 months

23% 10%

trend

EORTC (1999)

Criticisms of EORTC:* Allowed enrollment of non-pancreatic

peri-ampullary CA( e better survival) when compared with pancreatic head.

No Maintenance CTx20% of “Tx Patients”: No TxUnderpowered Study

EORTC (1999): Conclusions

Overall Negative trial.Chemo-RT: Trend to Improved survivalPancreatic > periampullary (4.5 months).

No survival benefit for chemoradiation, but no maintenance chemotherapy

Klinkenbijl JH. Ann Surg. 1999;230:776-782.

EORTC : Conclusions No statistically significant survival benefit to adjuvant chemoradiation

Adjuvant Chemotherapy: 2004-2007

Two recent randomized clinical trials demonstrated benefit

ESPAC-1: European Adjuvant Trial

541 Pts. With “Macroscopically Resected” Pancreatic Cancer Eleven Countries: Austria, Belgium, France, Germany, Greece, Hungary, Italy, Spain, Sweden, Switzerland, UK61 Centers

Neoptolemos et al, Lancet 358: 1576-85, 2001

ESPAC-1: European Adjuvant Trial

Two Main Tx Questions:

ChemoRT vs. No ChemoRT

ChT vs. No ChTNeoptolemos et al, Lancet 358: 1576-85, 2001

After potentially

curative resection

(N = 289)

Observation(n = 69)

Chemoradiotherapy same as GISTG 20 Gy to tumor over 2 weeks plus

5-FU 500 mg/m2 on Days 1-3 of radiotherapy x 2 cycles(n = 73)

ChemotherapyLeucovorin 20 mg/m2 plus 5-FU 425 mg/m2,

Days 1-5 of 28 x 6 cycles(MAYO) (n = 75)

Combination ChemoradiotherapyChemoradiotherapy followed by chemotherapy,

administered as above(n = 72)

Neoptolemos JP, et al. NEJM. 2004;350:1200-1210.

ESPAC-1 Study

4-arm study

ESPAC-1 Study

MS Two year survival

“5” year survival

XRT/5 FU 15.9 months

29% 21%

CTx alone 19.7% 34.3% 23.3%

None 17.9% 28.7% 9.9%P = 0.001

Neoptolemos et al, Lancet 358: 1576-85, 2001

CRT worse !!

ESPAC-1 : results

chemoRT 15.1 mos chemo 19.7 mos

vs. p = 0.24 vs.

no chemoRT 16.1 mos no chemo 14.0 mos

P = 0.0005

median survival median survival

Neoptolemos et al, Lancet 358: 1576-85, 2001

Neoptolemos JP, et al. NEJM. 2004;350:1200-1210.

Median SurvivalNo chemoradiotherapy: 17.9 monthsChemoradiotherapy: 15.9 months

5-year survival: 8% vs 21% (P = .009)

ESPAC-1- : results CRT worse !!

Median SurvivalNo chemoradiotherapy: 17.9 monthsChemoradiotherapy: 15.9 months

HR: 1.28 (95% CI: 0.99-.66); P = .05

Neoptolemos JP, et al. NEJM. 2004;350:1200-1210.

ESPAC-1 : Median Survival

0

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Months

Surv

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Chemoradiotherapy

No chemoradiotherapy

Overall Survival by CT

Survival rates 2-year 5-yearNo CT: 28.7% 9.9%CT: 43.3% 23.3%HR=0.64 (0.52, 0.78), p<0.001

Neoptolemos, NEJM, 2004

ESPAC 1 : median survivalChemotherapy vs. No Chemotherapy

MS 20.1 vs. 15.5 months (p = 0.009)2 y OS 40% vs. 30%

ESPAC 1 : median survivalChemoRT vs. No ChemoRT

MS 15.9 months vs. 17.9 months2 y OS 29% vs. 41% (p = 0.05)

ESPAC 1 :CriticismsSplit course RT; No central review of RTDoses ranged from 40-60 Gy; treatment not uniform or not delivered in 30% patientsSignificant protocol violations in all arms; cross-over allowed

ESCPAC-1 : conclusionAdjuvant chemoradiotherapy: lower median survival vs. no

chemoradiotherapy

Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial.Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, et al.Lancet 2001; 358:1576-85. [Full text] (PMID 11716884) BACKGROUND: The role of adjuvant treatment in pancreatic cancer remains uncertain. The European Study Group for Pancreatic Cancer (ESPAC) assessed the roles of chemoradiotherapy and chemotherapy in a randomised study. METHODS: After resection, patients were randomly assigned to adjuvant chemoradiotherapy (20 Gy in ten daily fractions over 2 weeks with 500 mg/m(2) fluorouracil intravenously on days 1-3, repeated after 2 weeks) or chemotherapy (intravenous fluorouracil 425 mg/m(2) and folinic acid 20 mg/m(2) daily for 5 days, monthly for 6 months). Clinicians could randomise patients into a two-by-two factorial design (observation, chemoradiotherapy alone, chemotherapy alone, or both) or into one of the main treatment comparisons (chemoradiotherapy versus no chemoradiotherapy or chemotherapy versus no chemotherapy). The primary endpoint was death, and all analyses were by intention to treat.Findings 541 eligible patients with pancreatic ductal adenocarcinoma were randomised: 285 in the two-by-two factorial design (70 chemoradiotherapy, 74 chemotherapy, 72 both, 69 observation); a further 68 patients were randomly assigned chemoradiotherapy or no chemoradiotherapy and 188 chemotherapy or no chemotherapy. Median follow-up of the 227 (42%) patients still alive was 10 months (range 0-62). Overall results showed no benefit for adjuvant chemoradiotherapy (median survival 15.5 months in 175 patients with chemoradiotherapy vs 16.1 months in 178 patients without; hazard ratio 1.18 [95% CI 0.90-1.55], p=0.24). There was evidence of a survival benefit for adjuvant chemotherapy (median survival 19.7 months in 238 patients with chemotherapy vs 14.0 months in 235 patients without; hazard ratio 0.66 [0.52-0.83], p=0.0005).Interpretation This study showed no survival benefit for adjuvant chemoradiotherapy but revealed a potential benefit for adjuvant chemotherapy, justifying further randomised controlled trials of adjuvant chemotherapy in pancreatic cancer.

ESPAC-1While the EORTC trial studied only combined chemoradiation, the GITSG trial included both chemoradiation and subsequent chemotherapy but could not differentiate the effect of these two modalities. The European Study Group for Pancreatic Cancer (ESPAC) group attempted to address adjuvant therapy with chemotherapy, radiation, and chemoradiation. In the ESPAC-1 trial the investigators began with a 2X2 factorial design with one randomization to chemoradiation or no chemoradiation and the other to chemotherapy vs no chemotherapy.[4] This resulted in four treatment groups: observation, concurrent chemoradiation, chemotherapy alone, and chemoradiation followed by chemotherapy (Figure 1). The study was powered to compare chemoradiation vs no chemoradiation and chemotherapy vs no chemotherapy.

In addition to this 2X2 factorial design, an additional 256 patients were allocated to one of two randomizations, chemoradiation vs observation, or chemotherapy vs observation. According to the authors, this option was allowed because some study centers may not have had access to both modalities. The treating physician was allowed to choose the randomization for each patient, although it was not intended for these patients to be part of the planned primary analysis.In the first ESPAC-1 report, all three randomization methods were combined in the data analysis. The 175 patients receiving chemoradiation in the 2X2 factorial and the chemoradiation randomization were compared to the 178 patients who did not receive chemoradiation (ie, the observation and chemotherapy-only groups). There was no difference in 2-year survival between the two groups—15.5 vs 16.1 months, respectively. Similarly, in the 2X2 design and the chemotherapy randomization groups, the 238 patients who received chemotherapy alone were compared to the 235 patients who did not (observation and chemoradiation). This comparison did show a statistically significant improvement in 2-year survival—19.7 months (95% CI = 16.4-22.4) vs 14 months (95% CI = 11.9-6.5).[5]After a median follow-up of 47 months, data were reported for the 289 patients from the primary analysis group involved in the 2X2 randomization design. The 2-year survival for patients who received "chemotherapy alone" (both the chemotherapy and chemoradiation-followed-by-chemotherapy groups) was 40%, whereas the survival for those who did not receive chemotherapy alone (observation and chemoradiation groups) was 30%.[6] Five-year survival also improved at 21% vs 8%, respectively (no P value given). Conversely, chemoradiation appeared to be detrimental, as the 2-year survival in those patients who received chemoradiation was 29% compared to 41% in those who did not receive any radiation, with a hazard ratio for death of 1.28 (CI = 0.99-1.66, P = .05).The authors of the ESPAC-1 trial concluded that all patients should receive adjuvant chemotherapy. However, several issues must be considered in interpreting these results. The statistical design was written originally to evaluate a primary endpoint of 2-year survival for margin-negative patients.[4] The final results for this endpoint were never reported. Appropriately, no comparison was made for each of the four individual treatment groups, as ESPAC-1 was not powered for this. Although the addition of the other randomizations adds complexity to the interpretation of the results, the data from the single randomization groups were appropriately not included in the final analysis and paper.The ESPAC-1 authors also suggested that chemoradiation is ineffective. However, these results are relevant to the split-course radiation used in this trial and cannot be extrapolated to more modern chemoradiation regimens. Use of infusional 5-FU regimens and single-course radiation without breaks may provide benefit, and these strategies have not yet been compared to non-radiation-containing arms in prospective, randomized trials. Additional concerns for the chemoradiation question in ESPAC-1 have been raised. First, the doses of radiation varied between sites despite a recommendation for 40 Gy. Second, the lack of central review for radiation ports is of significant importance.[7]

Meta-analysisRecently, investigators (including the authors of ESPAC-1) performed a meta-analysis to address the issues of adjuvant chemoradiation and adjuvant chemotherapy for pancreatic cancer separately.[8] This analysis showed a benefit for chemotherapy with a pooled hazard ratio of 0.75 (CI = 0.64-0.90), and no effect for chemoradiation (HR = 1.09, CI = 0.89-1.32). Analysis of prognostic subgroups showed a potential benefit for chemoradiation in patients with positive margins, with a hazard ratio of 0.62 (but the confidence interval was wide).The majority of patients in the meta-analysis were from the ESPAC-1 trial, including those randomized in the 2X2 design as well as those in the separate randomization groups. In addition, subgroups of three other trials were used in this analysis. ESPAC-1 weighed significantly in determining the results, and the use of subgroups may not be valid for meta-analysis. A meta-analysis is designed only as a tool for hypothesis generation, and based on the limitations of this report, the results should be interpreted with caution.

Newer TrialsCONKO -001 (2007)Adjuvant chemotherapy vs. observation

RTOG 9704 (ASCO 2006)

CONKO-001Between July 1998 and December 2004, 368 pts were randomized .Observation vs. gemcitabine 1g/m² (Days 1, 8, and 15 of 4-week cycle x 6 months)

Oettle H, et al. J Am Med Assoc. 2007;297:267-277

Methods: CONKO-001

A prospective, open, multicenter, controlled phase III studyTo evaluate the efficacy and toxicity of gemcitabine in PC pts after complete (R0 or R1) resection.

CONKO-001: endpoints:Primary : (DFS)Secondary: OS & toxicity.

CONKO-001: Results:By December 1, 2007, 303 events (85.6%) have occurred for DFS and 293 events (82.8%) for OS. The analyses confirm the significant improvement for G in median DFS [G:13.4 months (m), O: 6.9m, p< 0.001].

CONKO-001: DFS :DFS

Gemzar Observation

3y 23.5% 8.5%

5y 16% 6.5%

CONKO-001: Subgroup analyses

Significant ↑ DFS for G in all subgroups of stratification.

G significantly ↑ median OS [G:22.8m, O: 20.2m, p=0.005].

CONKO-001: OS :DFS Gemzar Observation

3y 36.5% 19.5%

5y 21% 9%

CONKO-001: Conclusions: Treatment with G for 6 months for pts after complete resection of PC significantly increases DFS and OS compared with O alone.

Tolerability for Gemzarpostoperative G is well tolerated and significantly delays the development of recurrent disease after complete resection of PC.

CONKO-001 (2007)Oettle et al. (JAMA)

Randomized Phase III European trial; 368 patientsT1-4 N0-1 M0 pancreatic cancerR0 or R1 resectionChemotherapy Started 10-42 d after surgery 6 cycles of Gemcitabine q 4 weeks Each cycle – 3 weekly infusions 1000mg/m2

CONKO-001: Disease-Free Survival

Oettle H, et al. HAMA. 2007;297:267-277.

Months

Cum

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Dis

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Fre

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rviv

al

100%

75%

50%

25%

0%847260483624120

observation

gemcitabine

ESPAC-1: SurvivalCONKO-001: Disease-Free Survival

Oettle H, et al. J Am Med Assoc. 2007;297:267-277.

Adjuvant Chemotherapy:Outcomes

Neoptolemos JP, et al. NEJM. 2004;350:1200-1210.Oettle H, et al. J Am Med Assoc. 2007;297:267-277.

Months

Cum

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Dis

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Fre

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100%

75%

50%

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0%0

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25%

0%12 24 36 48 60 72

Chemotherapy

No chemotherapy

Months

Surv

ival

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847260483624120

observation

gemcitabine

CONKO-001 (2007)Results Median DFS 13.4 months vs. 6.9 months

(p < 0.001)R0 13.1 months vs. 7.3 monthsR1 15.8 months vs. 5.5 months

OS MS 22.1 vs. 20.2 months (p = 0.06)Overall, 83% of all patients had relapses

DFS: 6.9 vs. 13.4 months5-year DFS: 5.5% vs. 16.5%

CONKO-001 (2007)

CONKO-001 (2007)Oettle et al. (JAMA)

Randomized Phase III European trial; 368 patientsT1-4 N0-1 M0 pancreatic cancerR0 or R1 resectionChemotherapy Started 10-42 d after surgery 6 cycles of Gemcitabine q 4 weeks Each cycle – 3 weekly infusions 1000mg/m2

CONKO-001 (2007)Results Median DFS 13.4 months vs. 6.9 months

(p < 0.001)R0 13.1 months vs. 7.3 monthsR1 15.8 months vs. 5.5 months

OS MS 22.1 vs. 20.2 months (p = 0.06)Overall, 83% of all patients had relapses

CONKO-001 (2007)

CONKO-001More recently, the Charité Onkologie (CONKO)-001 trial published promising data regarding disease-free and overall survival for patients receiving adjuvant gemcitabine vs observation.[10] This was a large multicenter trial that randomly assigned 368 patients with pancreatic cancer to adjuvant gemcitabine, 1,000 mg/m2 weekly for 3 weeks of a 4-week cycle, or to observation. Margin-positive and node-positive patients were included. The primary endpoint of disease-free survival was reached with a median follow-up of 53 months.Disease-free survival in the gemcitabine arm was 13.4 months (CI = 11.4-15.3) vs 6.9 months (CI = 6.1-7.8) in the control arm (P < .001), and this benefit was maintained in both the margin-negative and margin-positive subgroups. Overall survival in this intent-to-treat analysis was not statistically significant, but the data demonstrated a trend in favor of the gemcitabine arm. Median survival was 22.1 months for the gemcitabine arm (CI = 18.4-25.8) and 20.2 months in the control arm (CI = 17-23.4), with a P value of .06.In addition to an intent-to-treat analysis, the investigators also performed a preplanned "qualified" analysis excluding patients in the treatment arm who did not receive at least one cycle of treatment, patients in the control arm who received adjuvant radiation or chemotherapy, or patients with protocol violations in either arm. Improvement in disease-free survival was also seen in this qualified analysis—13.7 vs 6.9 months for the control group (P < .001). Overall survival was statistically significant in this analysis, with a median survival of 24.2 months in the gemcitabine group vs 20.5 months in the control group (P = .02). The benefit in overall survival seen in the qualified analysis was small, but the authors concluded that this is likely due to most of the patients in the control arm receiving gemcitabine-based therapy at relapse.Thus, this well-designed study showed a significant benefit for adjuvant gemcitabine for both margin-negative and -positive resections, and this will likely become a standard of care for treatment of resected pancreatic cancer.[10]

RTOG R9704In the RTOG R9704 trial, Regine et al randomized patients with potentially resectable pancreatic cancer to either pre- and postchemoradiation 5-FU or pre- and postchemoradiation gemcitabine, with both groups receiving concurrent chemoradiation using infusional 5-FU.[9] Tumors of the pancreatic body and tail were included, but because of rapid accrual, an additional primary endpoint of survival in patients with pancreatic head tumors was added. Patients were also stratified by nodal status, tumor size, and surgical margin status.For the group with tumors of the head of the pancreas, a statistically significant improvement in 3-year survival was seen in the arm that received gemcitabine compared to the arm that received 5-FU—32% vs 21% respectively (P = .033), with a hazard ratio of 0.76 (CI = 0.61-0.97). When all tumor locations were analyzed, no significant improvement in survival was revealed. Although more hematologic toxicity was seen, neutropenic fever and infection rates were similar, and more than 85% of patients completed therapy in both arms.

RTOG 9704 (ASCO 2006)538 patients enrolled; 442 eligible & analyzableT1-T4 N0-1 M0381 pancreatic head lesionsPatients randomized to pre and post chemoRT 5FU vs. pre and post chemoRT gemcitabine

RTOG 9704Treatment Paradigm

RTOG 9704 Results

No statistically significant difference in OS between the two arms when all patients analyzedHowever, patients with pancreatic head lesions showed significantly improved survival in the Gemcitabine armMS 36.9 months vs. 20.6 months 3 y OS 32% vs. 21%

RTOG 9704Results

RTOG 9704Results

No real gains in survival seen in this 1st RCT with modern doses / treatment technique compared to historical RCT with split course lower dose RT

RTOG 9704 / US INTERGROUP Phase III Study (Schema)Resected Adenocarcinoma of the Pancreas

Nodal StatusNeg. vs. Pos.

Tumor Diameter< 3cm vs. >3 cm

Surgical MarginsNeg. vs. Pos.

Vs. Unknown

ARM 1: Pre-CRT 5 – FU + CHEMORADIATION (CRT)

+ Post – CRT 5 – FU

ARM 2: Pre-CRT GEMCITABINE +

CHEMORADIATION (CRT) +

Post – CRT GEMCITABINE

% A

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YEARS FROM RANDOMIZATION0 1 2 3 4

/ // /// /

//

/ // / // / // ///// // // / / / ///// ///// / / ////// / / //

RTOG 9704 / US INTERGROUP Phase III Adjuvant Study Overall Survival – ‘Pancreatic Head’ Patients Only

134132

7763

4631

2419

187194

Patients at RiskRT + GEMRT + 5FU

Total Dead MST CRT + Gemcitabine 187 134 1.72 CRT+ 5-FU 194 156 1.41

p = 0.033

Median: 20.6 vs 16.9mos 3-Year: 32% vs 21%

Both ESPAC1 and CONKO-001 demonstrate comparable outcomes with chemotherapy alone compared to gemcitabine and chemoradiation

in RTOG 9704.

Adjuvant Radiation Therapy in Surgically Resected Pancreatic

Cancer: SEER Database 1973 - 20032636 patients with resectable pancreatic cancer1123 received adjuvant RT1513 did not receive any adjuvant therapy

Median F/U 19 months

Adjuvant Radiation Therapy in Surgically Resected Pancreatic

Cancer: SEER DatabaseMedian Survival Adjuvant RT vs. No RT – 18 months vs. 11

months (p <0.001)Cox regression showed HR 0.57 (0.52,0.63; p<0.01)Independent statistically significant factors linked to decreased survival African Americans Moderate & Poorly diff. adenoCA Age <60 Stage

Mayo Clinic ExperienceRetrospective review of 472 consecutively treated patients with R0 resectionT1-3 N0-1 M01975-2005If adjuvant chemoRT given Median dose 50.4 Gy 98% received concurrent 5FU based

chemotherapy

Mayo Clinic ExperienceResults

Mayo Clinic ExperienceResults

Future Trials – ESPAC 3

ESPAC 3

Surgery

5FU & leucovorin

gemcitabine

Without chemoradiation, it’s a simple platform.

ConclusionsObvious controversies in management of pancreatic cancerAll randomized trials have significant flawsWhat we need (but will not get) is a well designed RCT Our design: 3 arms, no cross-over

Observation Adjuvant chemotherapy (gemcitabine) Adjuvant chemoRT (5-FU with RT to 50.4 Gy followed by

gemcitabine)

Combination Chemotherapy

Despite the improvement in progression-free and median survival shown in the ESPAC-1 and CONKO-001 trials, most patients with resected pancreatic cancer still recur and die of their disease. Therefore investigations of other adjuvant treatment regimens need to be investigated.A trial from the Norwegian group compared no adjuvant therapy to adjuvant chemotherapy alone.[11] This study used AMF (doxorubicin, mitomycin, and 5-FU) for six cycles after surgery. In 61 patients, median survival was 23 months in the AMF arm vs 11 months in the control arm (P = .02), and 2-year survival was 43% vs 32%, respectively (P = .04). This study did include carcinoma of the ampulla of Vater and cancer of the body and tail (in a total of 18 patients). This was the first major trial to suggest a potential survival advantage of adjuvant chemotherapy without the addition of radiation. However, this survival advantage was not maintained after 3 years.The American College of Surgeons Oncology Group (ACOSOG) recently stopped accrual on a multi-institutional trial (Z05031) using radiation combined with an aggressive chemotherapy regimen after surgical resection. This trial used a protocol combining radiation with continuous infusion 5-FU, cisplatin, and interferon-alpha, followed by 4 months of infusional 5-FU. This regimen showed promising survival data when it was first evaluated at the Virginia Mason Cancer Center in a 43-patient, single-institution trial. In this study, Picozzi et al demonstrated 2- and 5-year survival rates of 64% and 55% respectively, but this was associated with significant morbidity.[12] As there were no treatment-related deaths and the survival data were encouraging, ACOSOG went on to perform the larger Z05031 trial to better clarify the efficacy and toxicity of this aggressive regimen, and results are currently pending.Another small, single-institution trial using interferon-based therapy was recently reported. Based on the data showing gemcitabine's superiority over 5-FU, this trial used a similar interferon-and-chemoradiation induction regimen, albeit with smaller doses, but followed by two cycles of consolidative gemcitabine rather than 5-FU. Like the Picozzi trial, toxicity was high, with 35% of patients requiring hospitalization. Nonetheless, survival data were promising, with actuarial survival rates of 53% at 2 years and 44% at 4 years.[13]

Ongoing TrialsMultiple studies have suggested the benefit of adjuvant therapy in resected pancreatic cancer, both with and without positive margins. The most beneficial regimen remains uncertain. Many studies have used 5-FU therapy, but evidence suggests that gemcitabine is superior in the metastatic setting. More recent studies have used gemcitabine therapy, but with the exception of R9704, gemcitabine has not been directly compared to 5-FU. ESPAC-3 is attempting to answer this question by comparing adjuvant 5-FU to adjuvant gemcitabine. This trial has completed accrual, and results are currently pending.Significant controversy surrounds the role of radiation in the adjuvant setting, as many argue that local recurrence rates suggest the need for this modality. However, no randomized phase III trial directly addresses the effect of chemoradiation vs chemotherapy alone, and regardless of the issues addressed, the only trial that studied the value of chemoradiation, ESPAC-1, suggested that chemoradiation may be detrimental in this setting. A randomized phase II trial, EORTC 40013-22012, hopes to address this issue by comparing adjuvant gemcitabine vs gemcitabine followed by chemoradiation. Accrual is complete, but there are plans to expand this important trial to a phase III study.Future Directions in Adjuvant TherapyAs the poor prognosis of pancreatic cancer is due to the systemic nature of the disease, further improvements on local control, surgery, and radiation may have only a modest impact. Significant improvements in prognosis will likely rely upon improvements in systemic therapies and multimodality therapy. The role of newer chemotherapy agents such as oxaliplatin (Eloxatin) and irinotecan (Camptosar) is currently being evaluated in the metastatic setting. However, results of phase III trials have not suggested a significant benefit when these agents are combined with gemcitabine.[14,15] The combination of targeted therapies with gemcitabine has shown more promising results in the metastatic setting. In a large randomized, controlled trial, erlotinib (Tarceva) combined with gemcitabine showed an improved hazard ratio for death compared to gemcitabine alone.[16] Phase II trials had shown promising data combining cetuximab (Erbitux) and bevacizumab (Avastin) with gemcitabine.[17,18] Phase III trials are now complete for these regimens, and while bevacizumab did not add significantly to the effects of gemcitabine in the metastatic setting, the cetuximab trial has not yet reported results.[19]Given the therapeutic action of these targeted agents, tolerability in the metastatic setting may not correlate with safety postoperatively. To address this issue, an ongoing intergroup trial, Eastern Cooperative Oncology Group (ECOG) 2204, is evaluating the safety of both bevacizumab and cetuximab in combination with gemcitabine in the adjuvant setting. This randomized phase II trial will evaluate bevacizumab compared to cetuximab when given with both adjuvant chemotherapy (gemcitabine) and chemoradiation (capecitabine [Xeloda]). This study will also provide safety data for the use of capecitabine, rather than infusional 5-FU, in combination with concurrent radiation. As the adjuvant setting is much different from metastatic disease, the bevacizumab arm remains part of the study despite the results reported for the phase III metastatic trial.Neoadjuvant TreatmentWhile adjuvant therapy has been the most widely studied approach to pancreatic cancer, neoadjuvant treatment has multiple theoretical benefits. First, as many as 20% to 30% of patients do not receive their planned adjuvant chemotherapy and/or radiation due to factors such as delayed recovery from surgery.[3,20] Neoadjuvant treatment may allow all eligible patients to receive the entire planned treatment course, and thus benefit from the full effect of combined-modality treatment.

Second, patients who develop early metastases are unlikely to benefit from surgical resection, and identifying this population prior to surgery would be ideal. Delaying surgery while administering chemoradiation may spare these patients from a complicated surgery. Finally, incomplete resections are common, and the incidence of positive margins can be as high as 51%.[21,22] Moutardie et al demonstrated improved margin-negative resections (91% vs 65%) in patients treated with neoadjuvant chemoradiation, and other centers have also found improved fibrosis, increased negative margins, and decreased lymph node involvement.[22,23]Most studies addressing neoadjuvant therapy are small, use a variety of regimens, and use different criteria to define resectability. Most include either bolus or infusional 5-FU, and radiation doses vary from 30 to 50 Gy with continuous irradiation or up to 60 Gy for split-course therapy. Moutardier et al conducted a review of patients with localized pancreatic head carcinomas, comparing patients who received neoadjuvant 5-FU and cisplatin with radiation to those who went directly to surgery. This was not a randomized trial, and the reasons for patients going directly to surgery included inability to obtain a biopsy, inability to endoscopically drain the biliary system, and patient refusal of chemoradiation. In patients who went on to resection, they found improvements in median survival from 13.7 to 26.6 months and in 2-year survival from 31% to 51% in the no neoadjuvant therapy and neoadjuvant therapy groups, respectively. Of the 39 patients thought to be initially resectable who received neoadjuvant therapy, 15 developed unresectable disease and did not go on to resection. In addition,

there were more margin-negative resections in the neoadjuvant group.[22]Nakamori et al recently reported data from a randomized phase II trial using gemcitabine and radiation. Patients who went directly to surgery and achieved negative margins did not receive adjuvant therapy. Of 19 patients receiving neoadjuvant chemoradiation, 83% went on to resection. The rate of margin-negative resections in this group was 70% in the treatment group vs 89% in the control group (no P value given). Despite the apparent adverse effect on margin status, among those patients who did achieve negative margins, 1-year survival was 81.2% in the treatment group vs 70.6% in the control group; however, this difference was not statistically significant. As gemcitabine has been shown to be effective in metastatic pancreatic cancer, it will be important to follow the results of further trials using this agent.[24]Whether neoadjuvant therapy can downstage a tumor from unresectable to resectable status is even less clear. The Moutardier study showed no downstaging of the initially unresectable tumors after concurrent chemoradiation. Other studies have shown 0% to 40% downstaging to resectable disease.[25-27] The wide disparity in benefit between studies is likely due to small population size, selection bias, treatment regimen, and variation in the definition of resectability.Although there is good rationale for neoadjuvant approaches and some promising preliminary data, randomized controlled trials with standardization of inclusion criteria, resectability, radiation modality, and surgical technique are necessary to better understand this option. Ideally, trials comparing neoadjuvant therapy to adjuvant therapy will be required to truly define the role of neoadjuvant therapy in the treatment of pancreatic cancer.

ConclusionsPancreatic cancer, even when resectable, remains a deadly disease. Older small, randomized trials did not definitively establish adjuvant therapy with either chemotherapy or chemoradiation. While two recent trials (CONKO-01 and ESPAC-1) demonstrated benefit for adjuvant chemotherapy with either gemcitabine or 5-FU, respectively, the majority of patients still have recurrences with either of these regimens. Therefore, more active agents and/or combinations need to be found and evaluated in the adjuvant setting.Retrospective analyses and the GITSG study have been used in the United States to justify the establishment of chemoradiation as a standard of care. However, with regard to chemoradiation, the only study that ESPAC-1 fully refutes is the GITSG study. While no data have proven that modern chemoradiation is ineffective as part of adjuvant therapy for pancreatic cancer, lack of proof against a regimen does not justify its routine use. Without an adequately powered randomized trial proving the benefit of adjuvant chemoradiation in pancreatic cancer, its role should appropriately be limited to clinical trials. One intriguing area of investigation for chemoradiation is the neoadjuvant setting.