A phase II study of active specific immunotherapy and5-FU/Leucovorin as adjuvant therapy for stage III colon carcinoma

Abstract

Active specific immunotherapy, using vaccines with autologous tumour cells and BCG, significantly reduces the rate of tumour recurrence in stage II colon cancer patients, while no clinical benefit has yet been observed in stage III patients. Adjuvant treatment with 5-Fluorouracil/Leucovorin is now considered standard therapy for stage III colon carcinoma and results in an absolute survival benefit of approximately 10%. Yet, the 5-year overall survival rate of stage III colon cancer patients is only 40 -50%. Combining chemotherapy and immunotherapy might improve prognosis for stage III patients, especially when considering that active specific immunotherapy and chemotherapy have shown synergistic effects in pre-clinical tumour models. We performed a phase II study with 56 patients, using the combination of active specific immunotherapy and chemotherapy as an adjuvant therapy in stage III colon cancer patients to assess the influence of 5-Fluorouracil/Leucovorin on anti-tumour immunity induced by autologous tumour cell vaccinations. Anti-tumour immunity was measured before and after chemotherapy by means of delayed type hypersensitivity reactions, taken 48 h after the third and the fourth vaccination. We also investigated the toxicity of this combined immuno-chemotherapy treatment. Delayed type hypersensitivity reactions before chemotherapy had a median size of 20.3 mm, while after chemotherapy delayed type hypersensitivity size was 18.4 mm (P=0.01), indicating that chemotherapy hardly affected anti-tumour immunity. The severity of ulcers at the BCG vaccination sites was comparable to previous studies. In 30% of the patients grade III or grade IV chemotherapy related toxicity was seen; this is comparable to what is normally observed after adjuvant chemotherapy alone. This study shows that the active specific immunotherapy-induced anti-tumour immune response is only minimally impaired by consecutive chemotherapy and that the combined treatment of stage III colon cancer patients with active specific immunotherapy and 5-Fluorouracil/Leucovorin does not cause unexpected toxicity. Colon cancer is one of the most prevalent malignancies in the industrialised world, with approximately 240 000 new cases diagnosed each year in the USA and Western Europe. When colon cancer is detected early, in stages I or II (Dukes A or B), the 5 year survival rate with surgery alone is 60 -90%, depending on the depth of invasion of the tumour into the bowel wall. When the cancer has spread to the regional lymph nodes, or stage III (Dukes C), the 5 year survival rate is 25 -60%. Important prognostic factors in stage III colon carcinoma include the number of positive nodes, extra-nodal growth, invasion of adjacent organs, grade of histologic differentiation and post-operative CEA level. When distant metastases are diagnosed, stage IV (Dukes D), the 5 year survival rate is less than 5% (Cohen et al, 1997).Currently most patients with stage III colon carcinoma receive an adjuvant treatment with 5-Fluorouracil (5-FU) and Leucovorin. Several lar...

Tumor Antigens and Proteomics from the Point of View of the Major Histocompatibility Complex Peptides

“…Therapeutic vaccination with specific tumor antigens was attempted in many clinical trials, resulting in partial response in some of the treated patients, while a complete tumor regression was observed in only a small fraction of the patients. It was suggested that the preferred time for immunotherapy is at the minimal residual disease stage, because micro-metastases are expected to be more responsive than large tumors with their immune suppressing microenvironment (21,22, reviewed in Ref. 23).…”

Randomized comparative study of surgical adjuvant chemotherapy using 5‐fluorouracil and dl‐leucovorin with CDDP, 5‐FU and dl‐leucovorin for advanced colorectal cancer

“…Recently, active specific immunotherapy (ASI) consisting of autologous tumor cells mixed with BCG (OncoVAX) administered through intradermal vaccinations has become a treatment option for stage II colon cancer patients in an adjuvant setting 26–28 . Combining chemotherapy and immunotherapy might improve prognosis for stage III colon cancer patients, especially if ASI and chemotherapy, mainly 5‐FU + LV, truly show synergistic effects on each other 29 …”

Vaccine Immunotherapy Strategies in Colorectal Cancer Treatment

“…Vaccine preparations based on autologous tumor tissue frequently consist of autologous single tumor cell suspensions, obtained from tumor tissue. Before reinjection, the tumor cells are irradiated and usually combined with immune-stimulating agents: heat shock proteins [78], Ulster strain of the Newcastle disease virus (NDV) [25,79,80], BCG [81][82][83][84][85] and IL-2-transfected fibroblasts [86].…”

“…Six out of the eight clinical Phase II [25,80,83] and Phase III [80][81][82][83][84][85] studies, determined the effect on prognosis and specifically, three studies reported that tumor cell reinjection combined with BCG had an effect on survival in two subgroups: stage II patients [81,82] and patients with colon cancer [85]. Furthermore, one randomized Phase III trial (where NDV-infected autologous tumor cells were injected) reported a significant effect on survival when compared with non vaccinated patients [80].…”