Authors: T. S. Hong, D. P. Ryan, L. S. Blaszkowsky, H. J. Mamon, R. C. Wadlow, E. L. Kwak, C. R. Ferrone, J. Adams, B. Yeap, B. Winrich Institution: Massachusetts General Hospital, Boston, MA; Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, MA
Pancreatic cancer is overwhelmingly adenocarcinomatous in origin (PDAC, pancreatic ductal adenocarcinoma) and is the fourth leading cause of cancer death in the United States. Most patients present with unresectable disease. The five-year survival is poor even in patients who can be resected (5-year survival 10-20%) and is even worse in patients who are unresectable (2-year survival 15%).
In the treatment of pancreatic cancer, local failure occurs following surgery alone.
Early randomized data demonstrated a benefit with chemoradiation although there is one notable and controversial trial that did not demonstrate efficacy with chemoradiation (ESPAC, Neoptolemos et al. 2001, 2004).
No Level I evidence supporting neoadjuvant therapy for pancreatic cancer exists at this time. One potential concern regarding such therapy is that a protracted 6-week course of chemoradiation may delay full dose systemic therapy, and therefore, compromise treatment.
Data exists in gastrointestinal primary sites that neoadjuvant radiation delivered in a 5 Gy x 5 fashion is safe and efficacious (Dutch and Swedish rectal cancer trials).
Hypofractionation in the neoadjuvant setting is complicated by concerns regarding high acute toxicities. One such strategy to mitigate these toxicities would be to employ highly conformal radiation therapy such as proton beam radiotherapy (PBT).
Protons interact more densely with tissue, resulting in a greater degree of ionization per unit volume and have a higher radiobiological effect (RBE) than photons.
Charged particle beam therapy with protons allows the delivery of higher doses of conformal radiation due to the dose characteristics of proton beam radiotherapy, including finite range and steep dose fall off beyond the Bragg peak.
Because of its superior conformality and higher radiobiological effectiveness, charged-particle radiation therapy is expected to deliver biologically equivalent doses with superior precision and with less radiation-induced morbidity than conventional photon radiation therapy.
In this study, the authors explore the safety and efficacy of a one-week course of pre-op CRT with proton beam therapy and concurrent capecitabine (cape) followed by early pancreaticoduodenectomy (PD).
Materials and Methods
This was a phase I/II trial enrolling patients with radiographically resectable, biopsy proven PDAC of the head of the pancreas. Patients were enrolled from May 2007- March 2010 on this IRB-approved, NCI-sponsored clinical trial.
Phase I: standard 3+3 design with 6 patients treated at the MTD
Phase II: 25 patients at the MTD provided 81% probability of ruling out grade 3 toxicity rates higher than 20% at a one sided significance level of 10%
Eligibility included lack of CT involvement of SMA or celiac artery, adequate renal, hepatic and hematopoietic function, and an ECOG performance status of 0/1.
Dose level 1 consisted of PBT delivered 3 Gy x 10 Monday to Friday. Patients in subsequent dose levels received 5 Gy x 5 in progressively shortened schedules: level 2 (wk 1 M/W/F, wk 2 T/Th), level 3 (wk 1 M/T/Th/F, wk 2 M), and level 4 (wk 1 M-F).
Proton beam therapy was targeted at pancreatic mass with elective nodal coverage:
A 1-2 cm margin was placed around the primary tumor.
Elective coverage consisted of the porta hepatis at the level of station 8A, the celiac axis, SMA, pancreaticoduodenal nodes, and the aortocaval nodes through the duodenal sweep.
Patients received prophylactic proton pump inhibitors and ondansetron 8 mg 30 minutes prior to radiation.
Patients received capecitabine (cape) 825 mg/m2 BID wk 1 and 2 M-F.
Surgery was performed 1-6 wks after completion of chemotherapy.
Patients were recommended to receive 6 months of gemcitabine after surgery.
Follow-up was performed every 3 months with CA 19-9 levels and CT of the chest, abdomen and pelvis performed every 6 months.
53 patients were screened for eligibility for this study of which 46 were enrolled and 38 (29 at MTD) eligible for analysis.
8 patients were excluded from analysis because they lacked 30 day postoperative follow-up
Median age was 65 (range 50-80)
Gender breakdown: 20 female, 18 males
Median pretreatment CA 19-9: 459 (range 0-3398)
Median pretreatment tumor size: 2.8 cm (range 1.1-4.3 cm)
7 patients (13%) were found to have positive laparoscopy (gross metastases or positive cytology)
No dose limiting toxicities were observed. Grade 3 toxicity was noted in 5 patients (biliary/cholangitis in 2 patients, the remainder were: nausea, gastroparesis, colitis, hyperglycemia, elevated alkaline phosphatase, constipation, and hyponatremia).
Median hospital length of stay following resection was consistent with historical averages for PD for the patients that underwent resection.
Reasons for patients not undergoing resection included metastases on imaging in 2 patients,
Operative pathology: 5 of 30 resected patients had positive margins, 24 of 21 had positive nodes, mean tumor size was 2.7 cm.
Median follow-up was 7.1 months.
There have been 2 local failures, both with synchronous metastatic disease (at 10 months and 17 months). Metastatic failure occurred in 16 patients: liver in 10 patients, lung in 5 patients, carcinomatosis in1 patient and distant abdominal lymphadenopathy in 1 patient.
Neoadjuvant CRT with 1 wk of PBT and capecitabine followed by early surgery is feasible and associated with satisfactory local control.
Short course proton-based chemoradiation therapy followed by early surgery appears feasible and safe.
Follow-up is too short to draw conclusions regarding efficacy.
Even with a shortened platform of treatment, there is a substantial rate of early metastases.
In this study, the authors report on the use of hypofractionated chemoradiation delivered in a neoadjuvant fashion in an attempt to shorten the definitive treatment package time such that patients can begin full dose adjuvant therapy as soon as is feasible, which has been shown to confer a disease-free survival advantage (CONKO-OO1, Oettle et al. 2007).
The presented data reveal that this regimen is reasonably well-tolerated, utilizing PBT to deliver the external beam radiation. However, the overwhelming cause of progression in this patient population is the development of distant metastatic disease, consistent with historical controls.
Overall, the data presented here appear promising, with interesting results; however, the small sample size and relatively short follow-up time presented preclude our making statements regarding effectiveness. It would be interesting to include data regarding the percentage of patients able to receive full dose gemcitabine in the adjuvant setting after this type of neoadjuvant regimen.
If longer-term follow-up demonstrates outcomes comparable to historical controls, the authors can consider a randomized phase III study comparing standard fractionation neoadjuvant photon-based chemoradiation against hypofractionated proton-based chemoradiation.
Sep 27, 2012 - There are no statistically significant differences in the rates of local recurrence, distant recurrence, relapse-free survival, overall survival, or late toxicity in patients treated with short-course radiotherapy or long-course chemoradiation, according to research published online Sept. 24 in the Journal of Clinical Oncology.