HAMBURGA 10-center phase III trial from the Netherlands has revealed that adjuvant vaccine therapy not only reduces the risk of recurrence but also prolongs relapse-free survival in patients with Dukes B2, B3, or C colon cancer, Dr. J.B. Vermorken reported at the Ninth European Cancer Conference (ECCO 9).
The 254 enrollees in the Dutch trial were randomized after radical resection to either observation or active specific immunotherapy with irradiated autologous tumor cells.
Unlike US studies, which have employed only three vaccine doses, this trial protocol called for three doses on postoperative days 30, 37, and 44, as well as a booster dose at 6 months. The first two vaccine doses contained 107 irradiated tumor cells and 107 BCG organisms while the third and fourth doses contained only irradiated tumor cells.
The recurrence-free interval was significantly longer in patients who received active immunotherapy, reported Dr. Vermorken, of the Comprehensive Cancer Center, Amsterdam. After a median follow-up period of 52 months, vaccine-treated patients showed a 43% proportional reduction in recurrence and a 32% reduction in mortality. The benefit was especially striking for vaccinated Dukes B patients, who had 61% fewer recurrences and 48% lesser mortality.
Dr. Vermorken pointed out, however, that while the vaccines-related gains in the recurrence-free interval and recurrence-free survival were significant, the difference in overall survival has not yet reached statistical significance.
The interesting aspect of this trial is that, in contrast to chemotherapy trials in the adjuvant setting, the side effects here were minimal, Dr. Vermorken said. Local ulceration at the injection site developed in more than 90% of patients after the first or second BCG-containing dose, but occurred in fewer than 5% of patients after subsequent doses.
Additional side effects included lymphadenopathy in two-thirds of patients, and transient fever or chills in 40%. All study participants were able to receive their vaccine doses as outpatients.
The addition of the 6-month booster dose was vindicated by the finding that the local response to the irradiated autologous tumor cells at the vaccination site was increased after the booster, as compared with the third vaccine dose.
On the basis of these data, Dr. Vermorken urged that active specific immunotherapy become standard adjuvant treatment for patients with Dukes B colon cancer. Although considerable data support the value of adjuvant chemotherapy in Dukes C cancer, he said, the benefits are less clear-cut for those with Dukes B cancers.
Many patients have to receive 5-FU with a lot of side effects before you see a gain, he noted. In our vaccine trial, the side effects were minimal but the gain in recurrence-free interval and survival are in the same range as you would see with chemotherapy.
He added that, as expected, the effects of vaccination were most significant in the patients with the least tumor burden, that is, the Dukes B patients.
The Dutch investigators are currently planning to study the effects of combining chemotherapy with active specific immunotherapy in patients with Dukes C colon cancer.