Controversies in adjuvant therapy for pancreatic cancer
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Controversies in Adjuvant Therapy for Pancreatic Cancer. Parag Sanghvi M.D. Tasha McDonald M.D. Department of Radiation Medicine OHSU. Median Survival of Patients With Pancreatic Cancer. Localized/ Resectable15-19 months 10% Locally Advanced 6-10 months 30%

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Controversies in Adjuvant Therapy for Pancreatic Cancer

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Controversies in adjuvant therapy for pancreatic cancer

Controversies in Adjuvant Therapy for Pancreatic Cancer

Parag Sanghvi M.D.

Tasha McDonald M.D.

Department of Radiation Medicine

OHSU


Median survival of patients with pancreatic cancer

Median Survival of Patients With Pancreatic Cancer

  • Localized/ Resectable15-19 months 10%

  • Locally Advanced 6-10 months 30%

  • Metastatic/ Advanced 3-6 months 60%


Adjuvant therapy

Adjuvant Therapy

  • No clear consensus on adjuvant therapy for pancreatic cancer

    • Difference in philosophy between Europe & North America

  • Europeans have moved to adjuvant chemotherapy alone


Adjuvant chemort

Adjuvant ChemoRT


Gitsg 1985

GITSG (1985)

  • 43 pts randomized into two groups

  • XRT/bolus 5-FU  5FU X 2 years vs. Observation

  • Split course radiation – total dose 40 Gy

  • Median survival – 20 vs. 11 months

  • 2 y OS – 43% vs. 18%


Eortc 1999

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 19991

EORTC (1999)


Eortc 19992

EORTC (1999)

  • Criticism is that this study included patients with ampullary tumors

  • Improved benefit of adjuvant therapy seen in patients with pancreatic head tumors

    • 2 y OS 34 % vs. 26% (p = 0.099)

    • MS 17.1 months vs. 12.6 months


Espac 1 2001

ESPAC 1 (2001)

  • Randomized trial with 2 X 2 factorial design

  • Patients 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 20011

ESPAC 1 (2001)


Espac 1 2001 chemort vs no chemort

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

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

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

Newer Trials

  • CONKO -001 (2007)

    • Adjuvant chemotherapy vs. observation

  • RTOG 9704 (ASCO 2006)


Conko 001 2007 oettle et al jama

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

CONKO-001 (2007)

  • Results

    • Median DFS 13.4 months vs. 6.9 months (p < 0.001)

      • R0 13.1 months vs. 7.3 months

      • R1 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 20071

CONKO-001 (2007)


Rtog 9704 asco 2006

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 9704 treatment paradigm

RTOG 9704Treatment Paradigm


Rtog 9704 results

RTOG 9704 Results

  • No statistically significant difference in OS between the two arms when all patients analyzed

  • However, patients with pancreatic head lesions showed significantly improved survival in the Gemcitabine arm

    • MS 36.9 months vs. 20.6 months

    • 3 y OS 32% vs. 21%


Rtog 9704 results1

RTOG 9704Results


Rtog 9704 results2

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

Adjuvant Radiation Therapy in Surgically Resected Pancreatic Cancer: SEER Database

  • 1973 - 2003

  • 2636 patients with resectable pancreatic cancer

    • 1123 received adjuvant RT

    • 1513 did not receive any adjuvant therapy

  • Median F/U 19 months


Adjuvant radiation therapy in surgically resected pancreatic cancer seer database1

Adjuvant Radiation Therapy in Surgically Resected Pancreatic Cancer: SEER Database

  • Median 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

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 experience results

Mayo Clinic ExperienceResults


Mayo clinic experience results1

Mayo Clinic ExperienceResults


Future trials espac 3

Future Trials – ESPAC 3


Conclusions

Conclusions

  • Obvious controversies in management of pancreatic cancer

  • All randomized trials have significant flaws

  • What 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)


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