Elsevier

Vaccine

Volume 23, Issues 17–18, 18 March 2005, Pages 2379-2387
Vaccine

Immunotherapy with autologous tumor cell-BCG vaccine in patients with colon cancer: a prospective study of medical and economic benefits

https://doi.org/10.1016/j.vaccine.2005.01.015Get rights and content

Abstract

We have completed a multicenter, randomized controlled phase III clinical trial in Stages II and III colon cancer patients with active specific immunotherapy (ASI) using autologous tumor cells with an immunomodulating adjuvant bacillus Callmette-Guérin (BCG) vaccine (OncoVAX®) in an adjuvant setting. In this study, patients were randomized to receive either OncoVAX® therapy or no therapy after surgical resection of the primary tumor and stratified by stage of disease. Since the biologic essence of the effective tumor immunotherapy is the presence in the vaccine of a minimum number of viable, metabolically active, autologous tumor cells, the processing of the vaccine product, occurred within 48 h after surgery.

Analysis of prognostic benefit in the pivotal phase III trial, with a 5.8 year median follow-up, showed that a beneficial effect of OncoVAX® is statistically significant for all endpoints including recurrence-free interval, overall survival, and recurrence-free survival in Stage II colon cancer patients. Surgery alone cures approximately 65% of Stage II (Dukes B2, B3) colon cancer patients. In the remaining patients, OncoVAX® in an adjuvant setting, significantly prolongs recurrence-free interval (57.1% relative risk reduction) and significantly improves 5-year overall survival and recurrence-free survival. No statistically significant prognostic benefits were achieved in Stage III (Duke's C1–C3) patients.

A health economics assessment was performed on these results in Stage II colon cancer patients using disease-free survival and overall survival (for the entire intent-to-treat population). Cost-effectiveness, cost-utility and sensitivity analysis were applied with, cost of life years, recurrence-free life years and quality adjusted life years (QALYs) as the primary endpoints to this analysis. The perspective of the economic analysis was the current direct medical cost established by the health care providers. The introduction of new technologies often leads to additional costs. This report verified that the use of OncoVAX® for patients with Stage II colon cancer not only has significant prognostic benefit and positive clinical outcomes, but also showed that OncoVAX® therapy yields impressive health economics benefits.

Introduction

Colon cancer is a common malignancy in developed countries. In the United States, it is the second most common type of cancer in men and women. The American Cancer Society estimates that 106,370 cases will be reported in 2004 [1]. Among countries of the European Economic Community (EEC), the numbers are even greater. Approximately 6% of Americans develop the disease within their lifetime [2]. The risk of colon cancer increases after the age of 40 and rises exponentially from the ages of 50 to 55; the risk doubles with each succeeding decade.

Between 1985 and 1997, death rates of colon cancer in the United States declined slightly. The earlier detection of primary tumors, via stool blood tests, sigmoidoscopy, colonoscopy, and screening tests for serum carcinoembryonic antigen concentration (CEA) levels have contributed to the reductions in mortality [3]. Finally, adjuvant chemotherapy with 5-fluorouracil combined with levamisole or leucovorin for Stage III disease has been linked to improved survival rates [4], [5], [6]. Preventive measures are still at their infancy while dietary measures likely will take decades to show benefits at the outcome levels.

Survival of colon cancer is related to the stage of disease at the time of the initial diagnosis. To date, surgery is the primary treatment modality for this disease [7]. However, by the time the patient presents with recurrent symptoms, the disease is rarely curable by surgery even when combined with other therapy. The 5-year survival rates for colon cancer patients is greater than 90% when tumors are detected at a localized early stage; after the cancer has spread regionally and involves adjacent organs or lymph nodes, the rate drops to 40–65%; survival is less than 10% for patients with distant metastases. Hence, there is still an urgent need to develop effective treatment strategies to reduce the morbidity and mortality from colon cancer.

Preliminary evidence showed that active specific immunotherapy (ASI) of colon cancer using autologous tumor cell vaccines has potential as a valuable therapeutic option for improvement in recurrence-free interval and survival [8]. This therapeutic process assumes the presence of distinct tumor antigens on a patient's tumor cells that are either absent or in lower concentration on normal cells. This therapy attempts to activate the host defenses against tumor-associated antigens by enhancing the immunogenicity of the patient's own tumor cells (autologous tumor cells) with an immunomodulating adjuvant, such as bacillus Calmette-Guérin (BCG). The logistics and technical complications of manufacturing autologous tumor cell treatments for individual patients have resulted in a paucity of standardized, multicenter, randomized clinical trials.

We have completed a multicenter, randomized controlled phase III clinical trial in Stages II and III colon cancer patients with active specific immunotherapy (four vaccinations) using autologous tumor cells with an immunomodulating adjuvant bacillus Callmette-Guérin (BCG) vaccine (OncoVAX®) in an adjuvant setting [9]. In this clinical trial, patients were randomized to receive either surgery (control group) or OnvoVAX® therapy, after surgical resection of the primary tumor. Stratification by disease stage was performed.

The presence of a significant delayed cutaneous hypersensitivity (DCH) response to tumor cells after the third and fourth OncoVAX® treatments (which lack BCG), is a measure of immungenicity of the treatment and has been correlated with long-term survival [10]. This correlation may reflect the adequacy of the treatment (cell number and viability; correct intradermal placement of the injection), or some factor relating to the capacity of the patients to be immunized by their autologous treatments, or a combination of the two. In the earlier studies, patients received a three-treatment regimen [8], [11]. However, because the DCH response was found to wane at six months [10], this phase III study utilized a booster dose (fourth treatment) given 6 months after the surgical resection of the primary tumor [9]. The results from this study were used and analyzed to relate the long-term medical benefit to the positive health economics of OncoVAX®.

Section snippets

Patients

This analysis is based on a Phase III, multicenter, randomized trial performed in The Netherlands, involving 254 patients with either Stage II (B2 and B3) or Stage III (C1–C3) colon cancer. The patients were randomly assigned after surgery to OncoVAX® treatment or no further treatment. Eligible patients had undergone curative resection for primary tumor. An adequate number of cells from the primary tumor and a performance status of 0 or 1 were also required. Patients with direct extension of

Design of the decision model

A decision analytic model using MS Excel was developed to model the course of the disease of patients with Stage II colon cancer. In the model, the following conditions were distinguished: recurrence-free survival, having a recurrence (of any kind) and death (of any cause). Transitions are allowed at 6 month intervals for the first and second years, and at once a year thereafter. The transition probabilities are assumed to be dependent on time since treatment, but not on other demographic

Economic data

The economic evaluation focused on the direct health care costs. In this study, these costs consisted of the hospital costs, such as hospital days, outpatient visits, day care treatments, laboratory tests, medical procedures and medication, and costs of home care and terminal care.

For the model, the costs of the several interventions, disease stages and follow-up have been calculated by using literature, an ‘in-house’ cost database and using Dutch tariffs. The base year of the cost study was

Results

In general, the characteristics of patients in the control and OncoVAX® groups were comparable and are presented in Table 1.

Discussion

This study is additional proof of durable and long-term clinical benefits of OncoVAX® and the health economic rationale of this autologous tumor cell vaccine. The mechanism of action of this therapeutic process is distinctly different from conventional cytotoxic drugs to treat malignancies. Standard chemotherapy is directly cytotoxic to tumor cells and normal cells. Tumor vaccines are not directly cytotoxic, but mediates their effect through the induction of a cell-mediated immune response.

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