Pancreatic and Stomach Malignancies

Pancreatic cancer is a morbid disease with a high mortality rate, and patients are often diagnosed with metastatic disease at presentation. Approximately 53,000 patients were diagnosed with pancreatic cancer in 2016, and only 7.7% of them will be alive in 5 years [1, 2]. Despite the high rate of distant dissemination, up to 30% of patients die of local disease progression [3]. While the treatment paradigm for pancreatic cancer may change with the development of prognostic and predictive biomarkers to help determine who may benefit from local treatment versus systemic treatment, we currently utilize surgical resection when patients have resectable disease followed by adjuvant chemotherapy, with or without adjuvant chemoradiation. Patients with borderline or unresectable disease are treated with chemotherapy, and we often utilize chemoradiation for local disease control with some patients who had borderline resectable disease subsequently able to undergo surgical resection. Local failure occurs in about 50 percent of patients following resection and results in considerable morbidity and mortality. The use of postoperative radiation is supported by the GITSG 91-73 study, which showed an increased median survival from 11 to 20 months with chemoradiation following surgery compared to observation alone [4]. RTOG 9704 also reported on adjuvant chemoradiation, with a median survival of 20.5 months in the concurrent gemcitabine and radiation arm [5]. However, the use of adjuvant radiation has been controversial, since the CONKO-001 study of chemotherapy versus observation showed gemcitabine alone conferred a median survival of 22.8 months [6], EORTC 40891 showed no difference between chemoradiation and observation [7], and ESPAC-1 showed a benefit to chemotherapy over chemoradiation [8]. It is important to note that in the EORTC study, 45% of patients had ampullary cancer (with a better prognosis), so it was likely underpowered to detect a survival advantage in the pancreatic cancer patients, and 20% of the chemoradiation arm did not receive the prescribed regimen. There is also very strong evidence for adjuvant chemoradiation in large retrospective case series from Johns Hopkins and the Mayo Clinic showing the median survival extended from 11 to 20 months with adjuvant chemoradiation [9]. A National Cancer Database study using propensity score analysis in 11,526 patients revealed that chemoradiation was associated with improved overall survival, compared to adjuvant chemotherapy alone, when each was matched to surgery alone with a hazard ratio of 0.7–1.04, respectively [10]. The phase III RTOG 0848 trial of resected pancreatic head tumors treated with five cycles of adjuvant gemcitabine ± erlotinib and then, if free from progression, randomized to an additional cycle of chemotherapy or an additional cycle followed by chemoradiation is currently open to accrual and will help determine the optimal adjuvant regimen. There is evidence that for borderline resectable disease, local radiation treatment with concurrent high-dose chemotherapy offers a survival advantage, improved disease control, and the potential for a high rate of an R0 resection. A multi-institutional phase II trial of systemic dosing gemcitabine and oxaliplatin with radiation (30 Gy in 15 fractions) resulted in a 63% resection rate, 84% of which had negative margins, and a median survival of 18 months [11]. The benefit of chemoradiation compared to chemotherapy alone in unresectable disease has been controversial. The limitations in the intact setting have been toxicity to the upper abdominal structures as a result of the large radiation fields needed to cover the gross tumor volume in the 3D conformal era. The ECOG 4201 randomized phase II study of gemcitabine alone versus gemcitabine with concurrent conventional radiation (IMRT not allowed) showed an improved median survival and decreased local recurrence with radiation but with substantial grade 3 and 4 toxicities [12]. A phase I/II study from the University of Michigan evaluated high-dose conformal IMRT with concurrent gemcitabine and showed an increased median survival of 14.8 months and an increased freedom from local progression of 60% compared to historical controls [13]. More recently, the Lap 07 trial randomized unresectable patients to gemcitabine versus gemcitabine + erlotinib, and then patients without progression were additionally randomized to chemoradiation, 54 Gy with concurrent capecitabine, versus additional chemotherapy [14]. The results showed no significant difference in overall survival between chemoradiation and chemotherapy alone but did show decreased locoregional progression in patients receiving chemoradiation. There are many patients for whom local progression results in significant morbidity and mortality. Autopsy series have reported that up to 30 percent of patients die of local disease progression which was correlated with the expression of SMAD4, indicating there are patients for whom local disease control is very important [3]. Local progression of unresected pancreatic cancer can also result in significant morbidity with obstructive symptoms, bleeding, bowel perforation, and pain necessitating palliation even in the patient with metastatic disease. With little improvement in survival seen in studies of chemoradiation using modest radiation doses (~50–54 Gy in 1.8–2 Gy fractions), dose escalation has been attempted with 3D conformal radiation, resulting in significant gastrointestinal toxicities [15]. Studies utilizing IMRT have reported lower rates of acute grade 3 nausea and vomiting, diarrhea, and late gastrointestinal toxicities such as duodenal ulceration compared to studies using 3D conformal radiation [16]. However, IMRT dose escalation with concurrent gemcitabine also resulted in significant toxicities, with 24% of patients experiencing grade 3 or 4 dose-limiting toxicities [13]. SBRT has been evaluated for unresectable disease with comparable median survival to conventional fractionation and with increased concern for acute gastrointestinal toxicity when the disease is in close proximity to or invading the duodenum [17]. In theory, proton radiation with its characteristic Bragg peak and rapid falloff at the distal end of the proton beam could be superior to IMRT or SBRT in sparing normal tissues. In practice, however, range uncertainties related to CT calibration, organ motion, and patient setup have necessitated an increase in margins in proton therapy. As double-scattered (DS) and uniform scanning (US) proton therapy cannot modify beam portal along their beam path, conformality is increased with pencil beam scanning (PBS) compared to DS and US.