THE ROLE OF RADIATION THERAPY IN MANAGEMENT OF PANCREATIC ADENOCARCINOMA. TIMUR MITIN, MD, PhD

Transcription

1 THE ROLE OF RADIATION THERAPY IN MANAGEMENT OF PANCREATIC ADENOCARCINOMA TIMUR MITIN, MD, PhD

2 RESECTABLE DISEASE

3 MANAGEMENT: RESECTABLE DISEASE Resection offers the only possibility of long term survival This possibility is not high: 5 yr survival after R0 resection is ~20% Median survival for resectable disease is ~20 months

4 A TALE OF TWO CONTINENTS United States (support for CRT) GITSG RTOG Europe (support for chemo alone) EORTC ESCPAC-1 CONKO-1 (chemo alone study) ESPAC-3 (chemo alone study)

5 RTOG SECONDARY ANALYSIS

6 RTOG SECONDARY ANALYSIS

7 RTOG SECONDARY ANALYSIS

8 RTOG 0848 Accrual: 347/950

9 SEER REGISTRY ANALYSIS National Propensity-Adjusted Analysis of Adjuvant RT McDade et al., Cancer , 5676 patients, 40% received adjuvant RT Predictors of improved OS on MVA: white race, married status, earlier stage, tumors < 2 cm, well-differentiated path, LN-, recent diagnosis (within 6 years) and receipt of adjuvant RT. RT: HR of ( , p<0.0001) Benefit remained significant after propensity adjustment for the likelihood of receiving RT (HR 0.774; ). Median survival: 10 months no RT vs 18 months with RT (p<0.0001) Sugawara et al., Journal of Surgical Oncology , 2532 patients, 40% received adjuvant RT On MVA RT associated with improved cause-specific survival (HR 0.654) and OS (HR 0.647) Median survival: 16 months no RT vs 20 months with RT (p<0.0001)

10 LOCAL VS SYSTEMIC DISEASE Most, but not all, pancreatic cancers are metastatic 12% of patients with no metastatic disease at autopsy 18% of patients with limited metastatic burden, not deemed directly contributing to their cause of death Genetic markers may help distinguish pancreatic cancer with predilection for local progression vs systemic spread SMAD4 (Dpc4) tumor suppressor gene Lost in up to 80% of pancreatic cancers Immunohistochemical assessment of SMAD4 protein is a reliable predictor of gene status Loss in a surgically resectable carcinoma corresponds to a relative risk of 3.3 of development of widespread mets compared to those with intact Dpc4 labeling. Iacobuzio-Donahue et al., JCO 2009

11 SMAD4 GENE STATUS Iacobuzio-Donahue et al., JCO 2009

12 SMAD4 GENE STATUS Boone et al., J of Surg Onc, Univ of Pittsburgh Retrospective review of 117 patients undergoing resection SMAD4 loss in 70% Metastatic disease: 13.3% vs 51.4% at 1 year 36.8% vs 78.5% at 2 years On logistic regression analysis: SMAD4 loss was associated with 6 times odds ratio of developing metastatic disease Neoadjuvant treatment did not affect the predictive value of preoperative SMAD4

13 THE ROLE OF SBRT IN ADJUVANT SETTING , 24 patients at Univ of Pittsburgh 8 patients with close margins of mm 16 patients with positive margins Single fraction SBRT Gy Median target volume 11 cc ( cc) Results: Median followup 12.5 months Median OS 26.7 months OS1: 80%, OS2: 57% Freedom from Local Progression: at 6 mos: 95%, at 1 year 66%, at 2 years 44% 19/24 patients resumed or started a 6-month course of gemcitabine at a median interval of 18 days (range, 9-31 days) post-sbrt Toxicity: No grade 3-5 toxicity 3 patients (12.5%) grade 1-2 acute GI toxicity 2 patients (8.3%) grade 1-2 late toxicities Rwigema, et al., Am J Clin Oncol 2011

14 THE ROLE OF SBRT IN ADJUVANT SETTING BIDMC, Boston 8 patients with pt3n0-1, positive margins 7 head and 1 tail lesions 10 Gy SBRT boost to positive margins, followed by Gy of fractionated RT to pancreatic bed with concurrent capecitabine With a median followup of 8.8 months: PFS 75% (2 patients progressed systemically and died) Remaining 6 patients were free of disease 100% local control at death or last follow -up. ASTRO 2007 abstract, IJROBP 2007; 69:S307

15 LOCALLY ADVANCED DISEASE

16 LOCALLY ADVANCED Median survival 7-12 months Ideally enroll on protocol

17 GERCOR H U G U E T e t a l. J C O Rationale: Management of locally advanced disease was controversial. Retrospective analysis of 181 pts from 4 prospective Phase II and III GERCOR studies Compared chemotherapy to chemoradiation (decision was investigator s choice) Gem based chemo x 3 months Chemo Gem based x 3 months chemoradiation (55 Gy + 10 Gy boost + 5-FU)

18 GERCOR H U G U E T e t a l. J C O % developed metastatic disease within 3 months of chemo 70% (128) eligible

19 GERCOR H U G U E T e t a l. J C O Conclusions: Chemo CRT PFS 7.4 mon 10.8 mon OS 11.7 mon 15 mon 1 yr survival 47.5% 65.3% Chemotherapy should be first line treatment for LAPC. If no progression of disease after three months, CRT could increase survival.

20 LOCALLY ADVANCED Median survival 7-12 months Ideally enroll on protocol Otherwise, FOLFIRINOX based chemo x 2-4 months 5FU based chemoradiation Begin chemoradiation if: Radiographic local progression CA 19-9 increase Symptoms Chemo poorly tolerated

21 RTOG 1201 Gem/abraxane x 3 Gem/abraxane x 3 Gem/abraxane x 1 + IMRT 63 Gy Gem/abraxane x 1 + RT 50.4 Gy Stratify by: Ca19-9 < 90 SMAD4 status

22 SBRT IN LOCALLY ADVANCED Representative pancreatic SBRT plan: (A) axial view showing pancreatic tumor (GTV: green), a typical PTV (red), and the duodenum (magenta); (B) coronal view demonstrating tumor relationship with the duodenum; (C) dose distribution for a plan treating to 33 Gy in 5 fractions. Isodose lines: green = 45 Gy; magenta = 40 Gy; cyan = 33 Gy; blue = 30 Gy; light green = 20 Gy; and brown = 10 Gy.

23 Trakul et al., Seminars in Radiation Oncology, 2014

24 THE ROLE OF RADIATION THERAPY IN MANAGEMENT OF PANCREATIC ADENOCARCINOMA THANK YOU!