Addition of an induction regimen of antiangiogenesis and antitumor immunity to standard chemotherapy improves survival in advanced malignancies

Abstract

Studies have shown that cancer requires two conditions for tumor progression: cancer cell proliferation and an environment permissive to and conditioned by malignancy. Chemotherapy aims to control the number and proliferation of cancer cells, but it does not effectively control the two best-known conditions of the tumor-permissive environment: neoangiogenesis and tolerogenic immunity. Many malignant diseases exhibit poor outcomes after treatment with chemotherapy. Therefore, we investigated the potential benefits of adding an induction regimen of antiangiogenesis and antitumor immunity to chemotherapy in poor outcome disease. In a prospective, randomized trial, we included patients with advanced, unresectable pancreatic adenocarcinomas, non-small cell lung cancer, or prostate cancer. Two groups of each primary condition were compared: group 1 (G1), n = 30, was treated with the standard chemotherapy and used as a control, and group 2 (G2), n = 30, was treated with chemotherapy plus an induction regimen of antiangiogenesis and antitumor immunity. This induction regimen included a low dose of metronomic cyclophosphamide, a high dose of Cox-2 inhibitor, granulocyte colony-stimulating factor, a sulfhydryl (SH) donor, and a hemoderivative that contained autologous tumor antigens released from patient tumors into the blood. After treatment, the G2 group demonstrated significantly longer survival, lower blood level of neoangiogenesis and immune-tolerance mediators, and higher blood levels of antiangiogenesis and antitumor immunity mediators compared with the G1 group. Toxicity and quality of life were not significantly different between the groups. In conclusion, in several advanced malignancies of different primary localizations, an increase in survival was observed by adding an induction regimen of antiangiogenesis and antitumor immunity to standard chemotherapy.

Fig. 1

Induction regimen of antiangiogenic and antitumor immunity agents administered in an 8-week series. The dashed lines indicate the targeted mechanism proposed

Fig. 2

The Kaplan–Meier survival curves plotted for patients with pancreatic cancer, NSCLC, and prostate cancer with poor prognoses. G1 groups of patients treated with standard chemotherapy; G2 groups of patients treated with standard chemotherapy and an induction regimen of antiangiogenic and antitumor immunity agents. Mean survival is significantly longer for G2 than for G1 for patients with the three primary malignancies analyzed: 18.0 versus 10.2 months (log-rank, p = 0.036), 16.7 versus 12.1 months (log-rank, p = 0.042), and 20.4 versus 16.8 months (log-rank, p = 0.048) for pancreatic cancer, NSCLC, and prostate cancer, respectively

Fig. 3

Percentage of baseline (pretreatment) values (mean ± SD) at 3 months of follow-up in the 90G1 cohort treated with standard chemotherapy compared with the 90G2 cohort treated with the same chemotherapy and an induction regimen of antiangiogenic and antitumor immunity agents. Antiangiogenesis was monitored by measuring VEGF and angiostatin blood levels. Antitumor immunity conditioning was determining by assessing the number and presence of T-Regs and aDCs. Antitumor immunity was tested with DTH and IFN-ELISPot assays challenged with an autologous hemoderivative containing tumor antigens

Fig. 4

The safety and toxicity profiles of the 90G2 cohort treated with the induction regimen of antiangiogenic and antitumor immunity agents in combination with chemotherapy and the 90G1 cohort treated with standard chemotherapy alone were not statistically different in the 2-year follow-up period (p > 0.05). Toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v3.0 of the National Cancer Institute. Quality of life was scored using the current core questionnaire of the EORTC QLQ-C30