Adjuvant chemotherapy dosages
Surgery for biliary tract cancer, including pancreatoduodenectomy and major hepatectomy, is very aggressive and does not allow postoperative chemotherapy to be administered in the usual dosage due to adverse events, which may be caused by insufficient liver function.
Fujiwara et al performed a study of dose finding of adjuvant gemcitabine in patients with biliary tract cancer who underwent a surgical resection with major hepatectomy. These authors evaluated the pharmacokinetics and pharmacodynamics of gemcitabine in these patients after administration at a dose of 800–1,000 mg/m2. The authors concluded that major hepatectomy did not affect the pharmacokinetics of gemcitabine.42
Other authors determined the recommended dose for gemcitabine and S-1 after major hepatectomy in patients with biliary tract cancers, concluding that the recommended dose is 1,000 mg/m2 of gemcitabine every two weeks and 80 mg/m2/day of S-1 on days 1–28 every six weeks.43
Yamanaka et al studied the benefit of adjuvant gemcitabine with different dosages depending on the aggressiveness of the surgery. In those who underwent major hepatectomy, gemcitabine was administered at a dose of 800 mg/m2biweekly. Otherwise 1,000 mg/m2 for three weeks every month. These authors concluded that adjuvant gemcitabine may be effective, especially for patients with stage III and ICC.44
Kobayashi et al hypothesized that the feasibility of three-weekly protocol (days 1 and 8, every three weeks) of adjuvant gemcitabine may be superior to the four-weekly treatment (days 1, 8, and 15 for every four weeks). Their study enrolled 27 patients, and the authors concluded that the three-weekly protocol did not yield superior completion as the rate of adverse events or recurrence-free survival was similar to the four-week regimen.45
The study by Kainuma et al assessed the feasibility and the efficacy of gemcitabine plus cisplatin (CDDP) for biliary tract cancer in the adjuvant setting. Gemcitabine at 1,000 and 25 mg/m2 of CDDP on days 1 and 8 was repeated for every three weeks. They concluded that this treatment is tolerable in patients who underwent curative resection with or without major hepatectomy.46
Toyoda et al studied a phase I study to determine the maximum tolerated dose and recommended dose of a combination with gemcitabine and cisplatin in the adjuvant setting for this cancer. The starting dose was the standard: gemcitabine (1,000 mg/m2) and cisplatin (25 mg/m2) on days 1 and 8, every three weeks. These authors defined the standard dose as the recommended dose for adjuvant chemotherapy for biliary tract cancer treated by curative resection without major hepatectomy, but they recommended further study to clarify the safety and efficacy of this regimen for all patients.47
Radiotherapy and chemoradiotherapy
Retrospective studies suggest that adjuvant radiotherapy following resection had a survival benefit in ICC patients with regional lymph node metastasis.48
Gwak et al carried out a study with adjuvant radiotherapy compared to surgery alone in extrahepatic bile duct carcinomas. The study showed a benefit in five-year survival following adjuvant radiotherapy (21 vs. 11.6%).49
However, Gonzalez et al used combinations of pre- and postoperative external beam radiotherapy, and no impact on survival was observed.50
Newer radiation therapy techniques, such as intraluminal transcatheter brachytherapy, intraoperative, or intensity-modulated radiation therapy, and three- and four-dimensional treatment planning, permit radiation dose escalation without significant increment in normal tissue toxicity, thereby increasing the effective radiation dose. Preliminary results of studies with hepatic transplantation and radiation therapy are encouraging, but prospective trials are needed in order to get solid evidence.51
Further prospective studies are needed at this moment as there are no data supporting the use of adjuvant radiotherapy in patients with negative resection margins.
Horgan et al in their meta-analysis conclude that radiation therapy seems to benefit only patients with R1 resections, with possible harm in R0 disease.37
Their meta-analysis included Takada et al’s trial, two SEER registry analyses, and 17 retrospective series. This includes 6,712 patients, of whom 1,797 received some form of adjuvant therapy.
There were eight studies of radiotherapy plus chemotherapy, three of chemotherapy alone, and nine of RT alone. Only one study included ICC.
The authors conclude an improvement in five-year survival with any adjuvant therapy. Although not statistically significant compared with surgery alone, the benefit became significant if data from the two large series were excluded.37
A combined analysis of gallbladder and bile duct cancers showed a significant survival benefit for chemotherapy and chemoradiotherapy but not for radiation alone.
In patients with nodal positivity, this meta-analysis showed a benefit in OS for any adjuvant therapy. Most of these patients had received chemotherapy alone (77%), and the remainder received chemoradiotherapy.
In patients with margin positivity, adjuvant therapy showed also a benefit.