Role of local/regional therapy in locally advanced disease Amol - PowerPoint PPT Presentation

Role of local/regional therapy in locally advanced disease Amol Narang, MD Department of Radiation Oncology & Molecular Sciences Johns Hopkins Hospital 2/12/19 1

Disclosures • Clinical trial support from: – Augmenix – Oncosil 2/12/19 2

Historical LAPC trials Trial Arms N mOS 1-year OS P-value ECOG (1985) 1) 40 Gy + 5FU → 5-FU until progression 44 8.2 mos --- NS 2) 5-FU until progression 47 8.3 mos --- GITSG (1988) 1) 54 Gy + 5FU → SMF for 2 years or until 22 42 weeks 41% Significant progression but not 2) SMF for 2 years or until progression 21 32 weeks 19% specified FFCD/SFRO (2008) 1) 60 Gy + 5FU/cisplatin → gemcitabine 59 8.6 mos 32% p = 0.006 maintenance 2) Gemcitabine x 7 weeks → gemcitabine 69 13.0 mos 53% maintenance ECOG 4201 (2011) 1) 50.4 Gy + gemcitabine → gemcitabine x 5 cycles 34 11.2 mos 50% P = 0.017 2) Gemcitabine x 6 cycles 35 9.2 mos 32% ***Antiquated regimens with high toxicity*** ***Poor outcomes across all arms*** 2/12/19 3

LAP 07 Hammel et al., JAMA, 2016 2/12/19 4

LAP 07 • Only 60% of pts w/o progression after 4 mos gemcitabine – Did poor systemic control undermine the value of local therapy? • Local progression decreased with RT (32% vs. 46%) but local progression rate still high in RT arm – Can higher doses of RT be safely administered? – Can higher doses lead to improvements in local control and perhaps survival? • <5% of patients were resected (mOS 30.9 mos) – Can more patients be successfully resected after upfront therapy? – What are the survival outcomes of these patients? 2/12/19 5

Multi-agent chemotherapy Conroy et al., NEJM, 2011 Von Hoff et al., NEJM, 2013 2/12/19 6

Surgical exploration in LAPC • Ferrone et al., Ann Surg, 2015; Hackert et al., Ann Surg, 2016; Michelakos, Ann Surg, 2017 – Multi-agent chemotherapy can downstage disease – Radiographic response after multi-agent chemotherapy may not be consistent with pathologic response or operative findings – Higher rates of R0 resection can be achieved after intensive neo- adjuvant therapy (multi-agent chemotherapy +/- RT) – OS outcomes may be similar to upfront resected patients – Difficult to predict resectability pre-operatively – Difficult to predict OS after resection 2/12/19 7

JHH experience • 28% (116/415) explored • 72% (84/116) resected – 17% metastatic disease – 10% local extent prohibitive • 89% (75/84) R0 resection • Resection associated with: – Age – KPS – Tumor size – CA19-9 level – Multi-agent chemotherapy administration – Duration of chemotherapy – RT administration He et al., Ann Surg, 2018 2/12/19 8

JHH experience • mOS – Resected: 35.3 mos – Non-resected: 16.2 mos • 19.0 mos if >5 mos chemo • 25.5 mos if >5 mos chemo + RT • Local recurrence common pattern of failure He et al., Ann Surg, 2018 2/12/19 9

Radiation for LAPC • Margin sterilization prior to exploration • Reduction in local recurrence • Local progression-free survival in unresectable patients 2/12/19 10

Dose escalation of RT • RT dose limited by radio-sensitivity of neighboring bowel and stomach • “Standard” or “conventional” radiation – 1.8 Gy x 30 fxs (50.4-54 Gy) BED 10 59 Gy • Stereotactic body radiation therapy – 6.6 Gy x 5 (33 Gy) BED 10 55 Gy • Lung SBRT BED 10 >100 Gy • Pancreas RT is far from ablative at current doses 2/12/19 11

Dose escalation of RT • Improved OS with dose-escalation for rare tumors >1cm from duodenum Krishnan et al., IJROBP, 2016 2/12/19 12

Dose escalation of RT • Strategies to increase RT dose: – Intra-operative radiation – Brachytherapy – Hydrogel spacing – MRI-guidance – Particle therapy 2/12/19 13

Hopkins autopsy study • Iacobuzio-Donahue et al., JCO, 2009 – Rapid autopsies of 76 pts who died of pancreatic cancer – Divergent extent of disease at autopsy • 30% w/ primarily locally destructive disease • 70% w/ widespread metastasis • Potentially correlation with DPC4 status 2/12/19 14

Conclusions • Available RCT data insufficient for addressing role of local therapy for LAPC • Local disease can contribute to mortality • Institutional series show encouraging survival outcomes after resection in well- selected patients in the setting of multi-agent-chemotherapy • RT for margin sterilization, prevention of local recurrence, or local control – Strategies to increase RT dose are needed • Role of local therapy for locally advanced disease is individualized decision – Better models to predict resectability and outcomes after local therapy are needed 2/12/19 15