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

3. Pancreatic cancer Invasive Aggressive Poor prognosis

4. 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

5. Stereotactic Radiotherapy
High intensity focused beams
Many different angles
Tumor gets high dose
Surrounding tissue gets low dose

6. Cyberknife® Virtually any angle Can target soft tissue
X-ray tracks metal particles inserted into tumor
Works for soft tissue that cannot be immobilized

7. 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

8. 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

9. 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.

10. 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’

11. 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:
Cheung Y, Chappell R. (2000). Sequential designs for phase I clinical trials with late onset toxicities. Biometrics;56: