Dr. Blackstock and colleagues are to be commended for their concise review broadly outlining current advances in the management of pancreatic cancer and future avenues of development.
As noted by the authors, a significant obstacle to improving survival remains the large percentage of patients presenting with advanced disease at diagnosis. However, even patients with localized, resectable disease have a 5-year survival rate of only 20% [1,2].
Locoregional failure remains the predominant mode of failure in patients with localized tumors undergoing resection, as well as in those with locally advanced disease. In 1990, Griffin et al [2] reported the failure patterns of 36 patients who underwent curative resection. Disease recurred in 72% of these patients at a median of 8 months after surgery. Of patients who suffered a failure, all had a component of intra-abdominal failure, 73% failed locally, and 62% failed in the liver. Local control was unaffected by more extensive surgical resection (Whipple resection vs total pancreatectomy) but was improved in patients who received adjuvant external- beam treatment more than 55 Gy (50% vs 25%).
Although external-beam irradiation given in conjunction with 5-fluorouracil (5-FU) has improved median survival in patients with both resectable [3] and locally advanced [4] disease, locoregional control remains problematic. Other techniques discussed in the article (intraoperative radiation therapy [5], interstitial brachytherapy [6]) have improved local control but not survival. These approaches, however, did not address other potential sites of intra-abdominal failure.
Recent Efforts to Improve Locoregional Control
In an attempt to improve locoregional control, recent efforts not mentioned by the authors have focused on prophylactic hepatic irradiation given in conjunction with localized chemoradiation. The Medical College of Wisconsin [7] reported a trial of prophylactic hepatic radiation (2,340 cGy) and localized pancreatic radiation (6,120 cGy) plus bolus 5-FU (500 mg/m²/d given the first 3 days of weeks 1 and 5) in 16 patients with locally advanced disease. Only two patients developed clinical recurrences in the liver.
This finding prompted the Radiation Therapy Oncology Group [8] to initiate a phase I/II trial in patients with unresectable pancreatic carcinoma. Treatment consisted of continuous pancreatic radiation (6,120 cGy) and simultaneous prophylactic hepatic irradiation (2,340 cGy) given during the last 2½ weeks, combined with continuous-infusion 5-FU (1,000 mg/m²/d for 5 days beginning on days 1 and 30). Of the 79 patients evaluated, 2 died from treatment complications while 9 developed life-threatening toxicity. Overall, liver metastases were documented in 32% of patients and abdominal dissemination in 27%. However, 73% developed persistent or progressive tumor in the pancreas. The median survival of patients entered into the trial was 8.4 months.
Evans et al [9] recently recounted their experience at M.D. Anderson Cancer Center using a similar approach to treat 11 patients with potentially resectable carcinoma of the pancreas. Patients received external-beam radiation to the pancreas (5,040 cGy) and liver (2,340 cGy) with continuous-infusion 5-FU (300 mg/m²/d). Seven of nine patients who were restaged were taken to surgery. Four underwent pancreaticoduodenectomy and received 10 Gy of intraoperative electron-beam irradiation to the tumor bed, half of whom have no evidence of disease 18 and 25 months after surgery. Five of seven patients dying of disease had metastases to the liver. Two patients died of treatment-related complications, prompting termination of the study.
Improvements in Median Survival for Resected Patients
Although the outlook remains poor for the majority of patients diagnosed with pancreatic carcinoma, improvements in median survival have been reported for patients with localized tumors undergoing resection. As reviewed by Blackstock et al, the Johns Hopkins experience [1] of 201 patients undergoing pancreaticoduodenectomy for carcinoma of the head of the pancreas between 1970 and 1994 showed significant improvements in median survival over the past 3 decades attributable to decreased operative mortality and increased use of adjuvant chemoradiation. Of note, patients with negative lymph nodes and negative resection margins had a median survival of 32 months and a 5-year survival rate of 40%. Other reported predictors of long-term survival included diploid tumor DNA content and tumor diameter less than 3 cm.
Summary
In summary, advances in diagnostic technology have not appreciably changed the percentage of patients diagnosed with localized, potentially resectable disease. Although localized chemoradiation has improved median survival in localized and advanced disease, local control and intra-abdominal metastases remain significant impediments to long-term survival. Recent trials of prophylactic hepatic irradiation given with pancreatic chemoradiation for localized and advanced disease have been disappointing to date. Methods to improve detection of disease while resectable are needed. Until such methods are available, we must continue clinical trials utilizing both current and newer modalities.
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