BY SARAH E. HOFFE, MD
Department of Radiation Oncology
Moffitt Cancer Center
Pancreatic cancer remains a difficult oncologic challenge, with the majority of patients presenting with locally advanced or metastatic tumors. A minority of patients present with tumors amenable to either upfront surgical resection or potential resection following neoadjuvant therapy. Although no universal criteria for borderline resectable pancreatic cancer (BRPC) exist, many institutions, like ours, follow the NCCN criteria.
When patients present to our multidisciplinary pancreatic team with a pancreatic mass, we advise endoscopic ultrasound to further characterize the lesion and perform fine needle aspiration (FNA) for diagnosis. Our workup includes a thin cut pancreatic protocol CT scan with both arterial and venous phases to assess the degree of vascular abutment and length of involvement.
PET/CT imaging ensures no evidence of occult metastasis, which we note can change management 11 to 22 percent of the time.1,2 All our patients are presented to our weekly multidisciplinary tumor board run by Dr. Mokenge Malafa, vice chair of the NCCN pancreas group.
Once the tumor board has agreed that the patient has a BRPC, we proceed with our institutional neoadjuvant approach. Nationally, there is no uniform standard of care approach in this setting.3 Our approach to facilitate margin negative resection was designed by medical oncologist Dr. Gregory Springett and begins with three cycles of GTX (gemcitabine, docetaxel, and capecitabine) chemotherapy.
When I joined the faculty at Moffitt in 2006, I instituted intensity-modulated radiation therapy (IMRT) delivery concurrently with infusional fluorouracil (5-FU). Initially, I delivered 45 Gy in 25 fractions to the gross tumor volume (GTV) delineated by 4D CT scan and a clinical target volume (CTV) including the regional nodes at risk. A cone down boost to 5.4 Gy in three fractions to the GTV ensured a total dose of 50.4 Gy. he IMRT strategy then expanded to a dose painted simultaneous integrated boost (SIB) technique over five weeks to deliver 45 Gy to the CTV and 50 Gy to the GTV.
During this time, the Stanford series reported by Koong et al was available and discussed delivery of a single fraction of stereotactic body radiation therapy (SBRT) for patients with locally advanced tumors.4 At our tumor board, my surgical colleagues were intrigued by this concept and wanted to know if we could do the same but focus more dose on the tumor/vessel abutment.
This collaboration led to an investigator-initiated prospective protocol with GTX and five-fraction SBRT to 25 Gy. Our experience with this early trial showed good toleration with an acceptably low toxicity profile and encouraged us that the five-fraction SBRT technique was feasible.
By 2009, we recruited Ravi Shridhar, MD, PhD, to our practice. Together, we have continued our work in the five-fraction SBRT model for BRPC. Our institution has now been employing this approach for more than five years with the support of our GI surgical oncology colleagues on our agreed-upon institutional pathway.
Our typical practice is to consult with the patient at initial diagnosis as part of the multidisciplinary team. We then arrange to see the patient again during the third cycle of GTX to coordinate endoscopic ultrasound evaluation and implantation of two to three fiducial markers into the pancreatic primary tumor.
Following implantation, the patient undergoes a conventional simulation so we can assess the degree of respiratory-associated tumor motion. If the motion is more than 5 mm, we assess the patient for a technique to decrease such motion. Our preferred techniques are either respiratory gating or abdominal compression.
The patient next undergoes 4D CT simulation. A full-body immobilization device is customized to patients with their arms over their head. An initial scan is done to visualize the fiducial markers and place isocenter. A second scan is done using 4D technique with IV/oral contrast.
We time image acquisition to start 60 to 90 seconds after contrast injection to capture the venous phase. After the images are processed, we review the 4D data. If we are gating, we determine the phase at which the tumor is at maximum expiration. We then choose that scan as the primary data set and fuse the phases at which the patient begins and exits exhalation. If available, we will fuse a 3D PET using soft tissue deformation or fuse a 4D PET to the appropriate phase.
If we are not gating, we would simulate the patient with abdominal compression and delineate the GTV in all phases as our internal target volume (ITV).
The radiotherapy technique varies depending on the clinical situation. We often use a 3D conformal multileaf collimator (MLC) delivery technique for our gated SBRT patients. For set up, we have patients fast three hours prior to treatment, and we do a cone beam CT (CBCT) on the day of preports to ensure no changes in the patient’s weight or fiducial marker position since the time of simulation.
We then proceed using kilovoltage (kv) imaging in the ap and lateral directions, matching the position of the fiducial marker in maximum exhalation phase on the machine to the position on the digitally reconstructed radiograph (DRR) from simulation. If there are significant shifts of more than 1 cm, we re-4D CT the patient. We fuse the dosimetry and contours from the initial plan to the updated CT to ensure that we do not need to adjust the plan.
In the setting where we choose an IMRT technique for SBRT delivery, we often use VMAT. Initially, we were concerned about potential dose degradation with a moving target and sliding MLC leaves; however, our physics colleagues have reported no such dose degradation up to 3 cm of motion.5
SBRT dosing is dependent on normal tissue constraints. Our philosophy is to deliver 30 Gy in 5 fractions to the planning volume encompassing the GTV and up to 40 Gy in 5 fractions to the GTV/vessel abutment. We have published our results and note a nearly 10% complete pathologic response (pCR) rate with this approach.6 In our report of 32 patients with BRPC, 31 (96.9%) underwent R0 resection with a median overall survival of 16.4 months and a 1 year overall survival of 72.2%, encouraging results in such a difficult disease.
Coronal view of planning CT showing radiation doses for stereotactic treatment plan.
1. Farma JM, Santillan AA, Melis M, et al. PET/CT fusion scan enhances CT staging in patients with pancreatic neoplasms. Ann Surg Oncol 2008;15:2465-2471.
2. Yao J, Gan G, Farlow D, et al. Impact of F18-fluorodeoxyglycose positron emission tomography/computed tomography on the management of resectable pancreatic tumours. ANZ J Surg 2012;82:140-144.
3. Katz MH, Crane CH, Varadhachary G. Management of Borderline Resectable Pancreatic Cancer. Semin Radiat Oncol 2014;24:105-112.
4. Koong AC, Le QT, Ho A, et al. Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2004;58:1017-1021.
5. Stambaugh C, Nelms BE, Dilling T, et al. Experimentally studied dynamic dose interplay does not meaningfully affect target dose in VMAT SBRT lung treatments. Med Phys 2013;40:091710.
6. Chuong MD, Springett GM, Freilich JM, et al. Stereotactic body radiation therapy for locally advanced and borderline resectable pancreatic cancer is effective and well tolerated. Int J Radiat Oncol Biol Phys 2013;86:516-522.