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

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Disclosures

• Clinical trial support from:

– Augmenix – Oncosil

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Trial Arms N mOS 1-year OS P-value

ECOG (1985) 1) 40 Gy + 5FU → 5-FU until progression 2) 5-FU until progression 44 47 8.2 mos 8.3 mos

• NS

GITSG (1988) 1) 54 Gy + 5FU → SMF for 2 years or until progression 2) SMF for 2 years or until progression 22 21 42 weeks 32 weeks 41% 19% Significant but not specified FFCD/SFRO (2008) 1) 60 Gy + 5FU/cisplatin → gemcitabine maintenance 2) Gemcitabine x 7 weeks → gemcitabine maintenance 59 69 8.6 mos 13.0 mos 32% 53% p = 0.006 ECOG 4201 (2011) 1) 50.4 Gy + gemcitabine → gemcitabine x 5 cycles 2) Gemcitabine x 6 cycles 34 35 11.2 mos 9.2 mos 50% 32% P = 0.017 2/12/19 3

***Antiquated regimens with high toxicity*** ***Poor outcomes across all arms***

Historical LAPC trials

LAP 07

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Hammel et al., JAMA, 2016

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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?

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Multi-agent chemotherapy

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Von Hoff et al., NEJM, 2013 Conroy et al., NEJM, 2011

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

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JHH experience

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• 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

JHH experience

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• 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

Radiation for LAPC

• Margin sterilization prior to exploration
• Reduction in local recurrence
• Local progression-free survival in unresectable

patients

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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) BED10 59 Gy

• Stereotactic body radiation therapy

– 6.6 Gy x 5 (33 Gy) BED10 55 Gy

• Lung SBRT

BED10 >100 Gy

• Pancreas RT is far from ablative at current doses

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Dose escalation of RT

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• Improved OS with dose-escalation for rare tumors

>1cm from duodenum

Krishnan et al., IJROBP, 2016

Dose escalation of RT

• Strategies to increase RT dose:

– Intra-operative radiation – Brachytherapy – Hydrogel spacing – MRI-guidance – Particle therapy

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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

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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

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