Pancreatic cancer is the fourth most common cause for cancer related mortality in the U.S. . Incidence in 2009 was 10.9 /105 for men and 7.5/105  for women and peaks between the seventh and eighth decade of life . Consumption of nicotine and more than 45 grams of alcohol per day [41,42], diabetes and a history of pancreatitis are among the accredited risk factors [43-46]. Neither incidence, nor the mortality rate has changed substantially over the past 20 years . In 2011 approximately 44,030 new patients were diagnosed, while 37,660 people died of pancreatic cancer in the U.S. . Prognosis remains poor and overall 5-year survival rate is below 4% . Only 20% of tumours are small (<3cm) and localized to the pancreas without extra-capsular spread or metastases. Complete surgical resection could yield 5-year survival rates between 18 to 24% for limited disease . As for all other stages chemotherapy and or radiation, as well as palliative operation and best supportive care mark the standards of therapy. It is in the opinion of several panels that patients with any stage of pancreatic cancer should be considered for clinical trials since response to either conventionally used treatment modality is poor [50,51]
Treatment strategy of conventional radiotherapy
Adjuvant therapy strategy for resectable stage I and II tumour is controversial and may consider either chemoradiation with 5-FU and/or gemcitabine [52,53], or gemcitabine alone [54-56]. Locoregional advanced stage III tumours are mostly unresectable due to vascular impingement or infiltration. Neoadjuvant chemoradiation for borderline resectable tumour may improve operability [57-59]. For unresectable tumour chemoradiation [60-63] or intraoperative radiotherapy (IORT) [64,65] can be considered for elected patients. Prescribed dose for percutaneous radiotherapy (EBRT) varies institutionally and ranges depending on treatment intent from 30 to 60 Gy in 1.8 – 3.0 Gy fractions. Commonly prescribed dose for unresectable disease is 45-46 Gy for CTV and 50-54 Gy for gross tumour volume in 1.8-2.0 Gy fractions. IORT is commonly prescribed as single fraction of 15-20 Gy alone, or 10-20 Gy in combination with EBRT [64-68].Planning should be performed based on a contrast enhanced 3D – CT dataset and can be assisted by MRI or PET . GTV encompasses macroscopic tumour. In case of biliary obstruction stent placement before radiotherapy should be considered . PTV dose should follow ICRU-62 guidelines . For adjuvant EBRT the CTV includes tumour bed derived from preoperative imaging or anastomoses/strategically set clips and peripancreatic lymph nodes. CTV margins for PTV consider organ motion/breathing and set-up errors and range from 0.5-2.0 cm. Breath holding/gating techniques in combination with IMRT or stereotactic body radiotherapy (SBRT) may be used to reduce margins and increase dose conformity [71-73]. Recommended dose constraints for liver is Dmean < 30 Gy, bilateral kidney Dmean < 15-18 Gy, only one working kidney V18Gy < 10%, stomach D100 < 45 Gy, small bowel V45Gy < 195cc and spinal cord Dmax < 45-50 Gy [9,51].
Treatment outcome of conventional radiotherapy
Several trials showed that median survival after adjuvant chemoradiation was mostly superior to operation alone for locally advanced stages, ranging 15-22.7 months (mos) vs. 10.9-15 mos [49,52,74,75]. Survival after IORT for locally advanced pancreatic cancer ranged 8 -16.5 mos, being similar to combined IORT and EBRT with 7.3 -16.5 mos. As for resectable tumours IORT yielded a median survival of 5-19 mos (one trial with low patient numbers reported 39 mos ) .
Therapeutical gap between conventional radiotherapy and ion beam therapy
Results for photon therapy for pancreatic cancer are jeopardized by radiosensitive organs at risk and resistance of tumour against irradiation. Both handicaps might hint to a potential benefit for treatment with protons. Developments in photon beam application like breath holding techniques and IMRT improved therapy related morbidity within the last years [71-73]. However, first results of planning studies reported improvements with PBT. In a preparation for a phase I trial Kozak et al.  evaluated a planning study that compared 5 fractions of 5 GyE PBT with conventionally fractionated IMRT (50.4 / 1.8 Gy). They learned that the Dose Volume Histograms showed improvements for organs at risk (kidney, liver, small bowel) in favor of the PBT-plan. Also another similar study demonstrated the superior dose distribution in PBT-plans compared to conventional 3D plans with photons . In January 2011 Massachusetts general hospital reported a phase I study on the feasibility of neoadjuvant hypofractionated proton beam chemoradiation with Capecitabine for resectable adenocarcinoma of the head pancreatic . Fifteen patients were enrolled and grouped into four dose levels with either 10 x 3 GyE (level 1) or 5 x 5 GyE with progressively shortened total treatment time schedules (level 2-4). All patients had the same dose of capecitabine over 10 days and were scheduled for operation within 4 to 6 weeks after chemotherapy. Grade 3 toxicity was seen in 4 patients (pain, stent obstruction, infection). 11 out of 15 patients were operated (3 had metastases, 1 patient remained inoperable). No unexpected 30 day post-operative complications were seen. A phase II study is in progress. The lower integral dose of PBT may offer options like reduced treatment time using hypofractionated protocols as well as the possibility to escalate tumour dose . However, until today there is little experience and further surveys are needed to increase level of evidence.
author: Dr. David Kuczer
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