Controversies in Adjuvant Therapy for

Pancreatic Cancer

Parag Sanghvi M.D.Tasha McDonald M.D.

Department of Radiation MedicineOHSU

Median Survival of Patients With Pancreatic Cancer

Localized/ Resectable 15-19 months 10%10%

Locally Advanced 6-10 months 30%

Metastatic/ Advanced 3-6 months 60%

Adjuvant Therapy

No clear consensus on adjuvant therapy for pancreatic cancerDifference in philosophy between Europe &

North America

Europeans have moved to adjuvant chemotherapy alone

Adjuvant ChemoRT

GITSG (1985)

43 pts randomized into two groupsXRT/bolus 5-FU 5FU X 2 years

vs. ObservationSplit course radiation – total dose

40 GyMedian survival – 20 vs. 11 months2 y OS – 43% vs. 18%

EORTC (1999)

Phase III randomized trial

Adjuvant chemoRT vs. observation

Split course RT (40 Gy) with concurrent 5 FU vs. Observation

Median survival 24.5 months vs. 19.0 months (p = 0.21)

2 y OS 41% vs. 51% (p = 0.21)

EORTC (1999)

EORTC (1999)

Criticism is that this study included patients with ampullary tumors

Improved benefit of adjuvant therapy seen in patients with pancreatic head tumors2 y OS 34 % vs. 26% (p = 0.099) MS 17.1 months vs. 12.6 months

ESPAC 1 (2001)

Randomized trial with 2 X 2 factorial designPatients randomized to Chemoradiation Chemoradiation followed by Chemotherapy Chemotherapy alone Observation

Radiation was split course RT (total dose 40Gy; 2 week course)Chemotherapy was 5FU + Leucovorin

ESPAC 1 (2001)

ESPAC 1 (2001)ChemoRT vs. No ChemoRT

MS 15.9 months vs. 17.9 months

2 y OS 29% vs. 41% (p = 0.05)

ESPAC 1 (2001)Chemotherapy vs. No Chemotherapy

MS 20.1 vs. 15.5 months (p = 0.009)

2 y OS 40% vs. 30%

ESPAC 1 (2001)Criticisms

Split course RT; No central review of RT

Doses ranged from 40-60 Gy; treatment not uniform or not delivered in 30% patients

Significant protocol violations in all arms; cross-over allowed

Newer Trials

CONKO -001 (2007)Adjuvant chemotherapy vs. observation

RTOG 9704 (ASCO 2006)

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

Randomized Phase III European trial; 368 patients

T1-4 N0-1 M0 pancreatic cancer

R0 or R1 resection

Chemotherapy 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)

RTOG 9704 (ASCO 2006)

538 patients enrolled; 442 eligible & analyzable

T1-T4 N0-1 M0

381 pancreatic head lesions

Patients 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

Adjuvant Radiation Therapy in Surgically Resected Pancreatic

Cancer: SEER Database 1973 - 2003

2636 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 Experience

Retrospective review of 472 consecutively treated patients with R0 resection

T1-3 N0-1 M0

1975-2005

If adjuvant chemoRT given Median dose 50.4 Gy 98% received concurrent 5FU based

chemotherapy

Mayo Clinic ExperienceResults

Mayo Clinic ExperienceResults

Future Trials – ESPAC 3

Conclusions

Obvious 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)