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Controversy surrounds treatment of hepatopancreatobiliary malignancies

Monday, October 20 2008 | Comments
Evidence Grade 0 What's This?
By David MacDougall

The prognosis of patients with pancreatic adenocarcinoma treated with surgical resection alone is poor, but the use of adjuvant chemotherapy and radiation in such patients remains controversial, said Dr. Andrew Lowy.

Speaking at a general session, Dr. Lowy noted that few studies have examined the role of adjuvant treatment in patients with pancreatic adenocarcinoma and that these studies have many significant methodological differences. Dr. Lowy said a small randomized study performed in the 1980s by the Gastrointestinal Tumor Study Group (GITSG) showed encouraging results with fluorouracil (5-FU)-based, split-course chemoradiotherapy, but these findings were not confirmed in a randomized study several years later by the European Organisation for Research and Treatment of Cancer (EORTC).

Meanwhile, in a landmark trial, the European Study Group for Pancreatic Cancer randomized 289 patients with resected pancreatic ductal adenocarcinoma to treatment with chemoradiotherapy alone, chemotherapy alone, chemotherapy plus chemoradiotherapy, or observation. The estimated 5-year survival rate was 10% among patients assigned to receive chemoradiotherapy and 20% among patients who did not receive chemoradiotherapy (P=0.05). The 5-year survival rate was 21% among patients who received chemotherapy and 8% among patients who did not receive chemotherapy. "Adjuvant chemotherapy had a significant survival benefit, whereas adjuvant chemoradiotherapy was detrimental," Dr. Lowy said.

According to Dr. Lowy, the role of adjuvant chemotherapy in patients with resectable pancreatic cancer was clarified in a study of 368 patients with complete resection of pancreatic cancer who were randomized to receive postoperative gemcitabine or observation. Median disease-free survival was 13.4 months in the gemcitabine group and 6.9 months in the control group (P<.001). Estimated disease-free survival at 3 and 5 years was 23.5% and 16.5% in the gemcitabine group, and 7.5% and 5.5% in the control group, respectively. The findings provide support for the use of postoperative adjuvant chemotherapy in this patient population, Dr. Lowy noted.

Support for the addition of gemcitabine to postoperative chemoradiotherapy with 5-FU in patients with resected pancreatic head adenocarcinoma emerged in RTOG 9704, Dr. Lowy said. RTOG 9704 was a randomized Phase III study in which 422 patients with resected pancreatic adenocarcinoma were randomized to receive pre-and post-chemoradiotherapy with 5-FU with or without gemcitabine. The addition of gemcitabine provided a significant survival advantage in patients with pancreatic head tumors but not in those with body/tail tumors.

Preoperative gemcitabine-based chemoradiation followed by restaging and evaluation for surgery is useful for the identification of patients with pancreatic adenocarcinoma in whom surgery would be unlikely to provide clinical benefit, Dr. Lowy said. This observation is based on the findings of a Phase II trial in which 86 patients with potentially resectable pancreatic adenocarcinoma received preoperative chemoradiation with gemcitabine. Patients underwent restaging 4 to 6 weeks after completion of chemoradiation and, in the absence of disease progression, underwent surgery. Overall, 64 patients underwent successful surgery. Median survival was 34 months for the 64 patients who underwent successful surgery and 7 months for the 22 unresected patients (P<.001).

"Systemic chemotherapy approximately doubles survival time over surgery alone, but median survival remains poor," Dr. Lowy said. "The role of radiation therapy remains unclear."

Management options for patients with early stage hepatocellular carcinoma (HCC) include surgical resection, hepatic transplantation, and radiofrequency ablation (RFA), and the roles of these interventions in individual patients are uncertain, said Dr. Kenneth Tanabe. According to Dr. Tanabe, criteria for the diagnosis of early stage HCC are not well established, and clinical and histologic characteristics are important determinants of the choice of therapy and prognosis.

"Vascular invasion is more important than tumor size in determining the outcome of resection," he said.

RFA has largely replaced percutaneous ethanol injection (PEI) in the treatment of early stage HCC, Dr. Tanabe noted. RFA provides better outcomes than PEI, he said, primarily due to lower rates of tumor recurrence. Survival rates are similar in patients with early stage HCC treated with surgery or RFA, he said, but the outcomes of surgical treatment are superior in patients with larger tumors.

Liver transplantation is a useful option in patients with early stage HCC, Dr. Tanabe commented, but the widespread utilization of this approach is limited by the availability of donor organs. Hepatitis C virus infection decreases survival following liver transplantation, and early antiviral therapy may delay or prevent hepatic reinfection in transplant recipients.

RFA is widely used for local control of small unresectable HCC, Dr. Tanabe said, but its pretransplant role remains unclear. Dr. Tanabe further noted that RFA is an effective bridge to transplantation in patients with compensated liver function and safely accessible tumors. The favorable post-transplant outcomes of patients treated with RFA can be attributed to the efficacy of RFA in producing local cure or curbing tumor progression during the transplant waiting period.

Hepatic resection is a reasonable first-line treatment in patients with early stage HCC and preserved liver function with favorable 5-year survival rates, Dr. Tanabe said. Many patients with early stage HCC treated with surgical resection survive without recurrence for up to 10 years, he noted, and many of those with recurrence may be eligible for salvage transplantation.

"The potential for the combined use of surgical resection, RFA, and transplantation should be considered," Dr. Tanabe said. "Treatment recommendations for early stage HCC should not be dependent upon which specialty manages the patient."

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