cyberknife®: can we cure pancreatic cancer? A Phase I dose-finding study Medical physics and statistical science Tim Ramsay, phd April 4, 2017

www.ohri.ca/ottawamethodscentre/

Pancreatic cancer Invasive Aggressive Poor prognosis http://www.medscape.com/viewarticle/875099

cancer treatment options Ablative radiation High dose Targeted at tumor Kills everything: cancer AND healthy cells Intentionally causes lots of damage Low dose radiation therapy Preferentially kills cancer cells Healthy cells recover (hopefully) Tumor cells don’t (hopefully) Chemoradiation therapy Chemotherapy + low dose radiation Chemo sensitizes cancer cells to radiation Chemotherapy Targets whole body Kills distant cancer cells (hopefully) Prevent metastases after tumor is killed Unresectable: surgery is not an option

Stereotactic Radiotherapy High intensity focused beams Many different angles Tumor gets high dose Surrounding tissue gets low dose http://large.stanford.edu/courses/2014/ph241/zhang2/

Cyberknife® Virtually any angle Can target soft tissue X-ray tracks metal particles inserted into tumor Works for soft tissue that cannot be immobilized http://www.neurosurgery.pitt.edu/sites/default/files/cyberknife.jpg

The dream! First, hit it hard with cyberknife Second, chemoradiation Three step process First, hit it hard with cyberknife Weaken tumor cells Second, chemoradiation Kill the tumor completely Third, chemotherapy Prevent metastases We want to cure locally advanced, unresectable pancreatic cancer

Phase I trial maximum tolerated dose? Dose Level Dose per fraction Total dose Level 3 10 Gy X 3 Fr 30 Gy Level 2 9 Gy X 3 Fr 27 Gy Level 1 8 Gy X 3 Fr 24 Gy Level 0 7 Gy X 3 Fr 21 Gy Level -1 6 Gy X 3 Fr 18 Gy Accept 20% probability of dose limiting toxicity Toxicity can appear early (2 months) Toxicity can occur late (up to 12 months) Critical Organ Dose- Volume Constraint for SBRT Duodenum Dmax (0.3 cc) < 10 Gy Small intestine Dmax (0.3 cc) 10 Gy, Stomach Dmax (0.3 cc) 19 Gy, Spinal cord Dmax (0.3 cc) ≤15 Gy Colon Dmax (0.3 cc) 19 Gy Liver 700cm3 of healthy liver shall receive less than 15 Gy. [Including conventional radiation] Mean total liver dose <31 Gy Heart/ Pericardium <15 cc should receive 6.4 Gy/ fraction; Dmax≤105% of PTV prescription. Great vessels <10 cc should receive <9.4Gy/ fraction; Dmax ≤ 105% of PTV prescription

CRM design Continual reassessment method Cumulative experience informs next allocation Probability of toxicity: 𝑝 𝑑 𝑘 = 𝑒 3+ ∝𝑑 𝑘 1+ 𝑒 3+𝛼 𝑑 𝑘 Prior distribution on α: N(1,0.32) nth patient’s dose: Compute posterior distribution for α (based on patients 1,….,n-1) Estimate highest dose associated with 𝑝 𝑑 ≤0.2 Subject to two rules: First three patients receive 𝑑 0 At most one step above highest dose so far PROBLEM: need to wait 1 year between patients! Start with ‘safe’ dose (expect suboptimal) Dose response model Prior distribution Sunsequent doses based on experience of all previous patients.

TITE-CRM weighted posterior Time-to-event Continual reassessment method Weighted posterior distribution Let f = months of follow-up (0<f≤12) f=12: weight = 1 2 ≤ f < 12: toxicity: weight = 1 no toxicity: weight = 𝑓−2 10 0<f≤2: weight = 0 Patients can contribute ‘partial information’

thank you Collaborators: Jason R. Pantarotto, MD Wayne Kendall, MD PhD Avijit Chaterjee, MD William Petrcich, MSc O’Quigley J, Pepe M, Fisher L. (1990). Continual reassessment method: a practical design for phase I clinical trials in cancer. Biometrics;46:33- 48. Cheung Y, Chappell R. (2000). Sequential designs for phase I clinical trials with late onset toxicities. Biometrics;56:1177-1182.