CK RS for non-resectable pancreatic tumors Laura Fariselli Besta-Milano CDI- Milano Cristina Baiocchi San Bortolo Hospital - Vicenza European Protocol Development Committee Meeting (EPDC) MILANO 10.10.2009

PANCREATIC Cancer Tenth cause of cancer mortality in Europe In 2000: 74,000 new cases in Europa Survival: at 1 year: 15.9 % at 3 years: 5.4% at 3 years: 4.1% Average survival for patients in stage I: 13-20 months

PANCREATIC Cancer 5-25% of the patients with pancreatic cancer is resectable at the time of the diagnose. Most of pancreatic patients receive chemotherapy, alone or in conjunction with radiation theraphy

LOCAL ADVANCED PANCREATIC Cancer Randomized chemotherapy studies have shown a significant improvement of the average survival in those patients treated with external radiotherapy combined with 5-FU bolus, in comparison to the bypass surgical resection alone, to chemotherapy alone or radiotherapy alone

LOCAL ADVANCED PANCREATIC Cancer In USA and in Europa the combined treatment Chemotherapy – Radiotherapy is the therapeutic gold standard: 50.4 Gy in 28 stages + 5-FU or Gemcitabine

LOCAL ADVANCED PANCREATIC Cancer Chemotherapy: New cytotoxic agents Radiotherapy: dose escalation / conformational RT

LOCAL ADVANCED PANCREATIC Cancer Terjanian et al ASCO in 2000 a non-invasive stereotactic technique to irradiate a ipofractionated, high dose to the pancreas Koong et al., 2004 Phase I study: CyberKnife stereotactic radiation therapy in single stage Koong et al., 2005 Phase II study: CyberKnife stereotactic radiation therapy as a boost after ERT + CT Chang et al, 2007 SBRT is effective for local control with acceptable toxicity. Distant metastases account for the vast majority of disease-related mortality. Schellenberg et al, 2008 Evaluation of the efficacy od stereotactic radiation therapy with CyberKnife single session

Koong et al, 2005

Schellenberg et al, 2008

CyberKnife radiosurgery for the treatment of non resectable pancreatic tumor Dr. Laura Fariselli, MD, Chief Director, U.O. Radioterapia, I. Besta, Milano and Project Director, CyberKnife Program, Milano Dr. Rosabianca Guglielmi, Chief Director, U.O. Radioterapia, USSL 6 - San Bortolo H. Vicenza  Dr. Cristina Baiocchi, MD, U.O. Radioterapia USSL 6 - San Bortolo H. Vicenza Dr. Giancarlo Beltramo, MD, Cyberknife Center- Centro Diagnostico Italiano Milano Dr. Lorenzo Brait PhD, Cyberknife Center- Centro Diagnostico Italiano Milano Dr. Livia Corinna Bianchi, MD, U.P. CyberKnife, Centro Diagnostico Italiano, Milano Dr. Francesca Brovelli, MD, U.P. Imaging, Centro Diagnostico Italiano, Milano Dr. Maurizio Meregalli, MD, U.O. Oncologia Medica, S. Carlo H., Milano Dr. Marco Possanzini, MD, U.P. CyberKnife, Centro Diagnostico Italiano, Milano Dr. Paolo Scalchi, PhD, U.O. Fisica sanitaria, USSL 6 - San Bortolo H. Vicenza

Cyberknife radiosurgery for the treatment of non resectable pancreatic tumor Eligibility Gender: male and female patients with primary non operable pancreatic tumor or with locally advanced pancreatic tumor without metastatic lesion. Histology will be performed for all patients to confirm diagnosis and stage of pancreatic cancer Age: ≥ 18 years old Patient deemed not operable for clinical or surgical reasons or who refused surgery Stage: stage I pancreatic tumor (T1 and T2 N0) stage II (T3 N0) without duodenum and/or biliary tree involvement stage III (only T4 N0) with minimal peri-pancreatic blood vessel infiltration Maximum diameter of tumor ≤ 6 cm measured on CT-Scan Local recurrence after radical surgery KPS ≥ 70 Life expectancy > 3 months Minimal peri-pancreatic blood vessel infiltration Written informed consent

Cyberknife radiosurgery for the treatment of non resectable pancreatic tumor Required Sample Size Four patients for each step of dose escalation will be enrolled. The patients will be assessed within one month of treatment for acute toxicity. Escalation to the next dose level will be performed 1 month after delivery of the last treatment regimen at the earliest. Late toxicity will also be assessed.

Cyberknife radiosurgery for the treatment of non resectable pancreatic tumor Primary Objectives of this protocol are: to assess acute radiation toxicity. Acute toxicity is the toxicity observed during treatment and up to 1 month after treatment to provide local control in patients with primary pancreatic tumor or locally advanced pancreatic tumors with no-metastatic lesions

Cyberknife radiosurgery for the treatment of non resectable pancreatic tumor Secondary Objective of this protocol are: to increase the overall survival rate to increase quality of life in this population of patients to assess early delayed (1 month to 6 month) and late radiation toxicity (after 6 months)

Prescription doses (dose escalation): Curative effect (Ø ≥3 cm) Cyberknife radiosurgery for the treatment of non resectable pancreatic tumor Prescription doses (dose escalation): Curative effect (Ø ≥3 cm) 24 Gy in 3 fractions 32 Gy in 4 fractions 40 Gy in 4 fractions

Maximum acceptable dose for OARs Cyberknife radiosurgery for the treatment of non resectable pancreatic tumor Maximum acceptable dose for OARs Spinal cord: 6 Gy per fraction (Max 18 Gy) Liver: 12 Gy (in 30% of volume), 7,5 Gy (in 50% of volume), less than 700 cc ≤ 15 Gy Kidneys: ≤ 15 Gy ( in 35% of volume) Duodenum: 9-10 Gy per fraction (Max 27-30 Gy in 5% of volume) Stomach: 9 Gy per fraction (Max 27 Gy in 5% of volume)

Pancreatic cancer

Pancreatic cancer

CK RS for non-resectable pancreatic tumors SRS is an alternative method of treating patients not suitable for surgery It’s necessary to have data about toxicity and acceptable dose for OARs in controlled protocol In Milan the CK protocol has been approved by Ethic Committee; in Vicenza we are waiting the consent.