Radiation is an effective means of treating localized prostate cancer. However, up to 40% of men with certain risk factors will develop biochemical failure 5 years after radiotherapy. CV706, a prostate cell-specific adenovirus variant, is currently in clinical trials for the treatment of recurrent organ-confined prostate cancer. We demonstrated previously that a single administration of CV706 at 5 x 10(8) particles/mm3 of tumor eliminated established tumors within 6 weeks in nude mouse xenografts (Rodriguez et al., Cancer Res. 57: 2559-2563, 1997). We now demonstrate that CV706-mediated cytotoxicity is synergistic with radiation. In vitro, addition of radiation to CV706 resulted in a synergistic increase of cytotoxicity toward the human prostate cancer cell line LNCaP and a significant increase of virus burst size, with no reduction in specificity of CV706-based cytopathogenicity for prostate cancer cells. In vivo, prostate-specific antigen (+) LNCaP xenografts of human prostate cancer were treated with CV706 (1 x 10(7) particles/mm3 of tumor), 10 Gy of single fraction local tumor radiation, or both. Tumor volumes of the group treated with CV706 or radiation was 97% or 120% of baseline 6 weeks after treatment. However, when the same dose of CV706 was followed 24 h later with the same dose of radiation, the tumor volume dropped to 4% of baseline at this time point and produced antitumor activity that was 6.7-fold greater than a predicted additive effect of CV706 and radiation. Histological analyses of tumors revealed that, compared with CV706 or radiation alone, combination treatment with two agents increased necrosis by 180% and 690%, apoptosis by 330% and 880%, and decreased blood vessel number by 1290% and 600%, respectively. Importantly, no increase in toxicity was observed after combined treatment when compared with CV706 or radiation alone. These data demonstrate that CV706 enhances the in vivo radioresponse of prostate tumors and support the clinical development of CV706 as a neoadjuvant agent with radiation for localized prostate cancer.

Purpose: To determine the anti-tumor activity in vitro and in vivo of CV706, a PSA-selective, replication-competent, cytolytic adenovirus combined with radiation in the treatment of the human prostate cancer (PCa) cell line, LNCaP, and to determine if synergy exists between the two treatments. Materials and Methods: CV706 was constructed by deleting E3 from an Ad5 adenovirus and adding a minimal promoter-enhancer construct of the human PSA gene 5' of E1A resulting in regulation of E1A expression and, thus, regulated replication. The LNCaP cell line was used for all in vitro and in vivo analyses. MTT assays were performed to determine cell viability following treatment with CV706 alone, radiation alone and a combination of CV706 and radiation at 5, 10 and 20 Gy. Isobolograms were constructed. One-step growth curves were obtained after infection of monolayers with CV706 +− radiation. Virus yield was then determined by plaque assay. For the in vivo studies, xenografts were established subcutaneously in nude mice and were treated with a single, intratumoral injection of PBS alone, a single, intratumoral injection of CV706 alone, 10 Gy radiation alone or a single, intratumoral injection of CV706 + 10 Gy. Differences in relative tumor volumes between groups were compared at 6 weeks following treatment. Results: Addition of radiation to CV706 resulted in a synergistic increase in cytotoxicity in LNCaP cells compared to CV706 alone or radiation alone, with a reduction in cell viability by a factor of 7 (combined data points fell to the left of the envelope of additivity). Moreover, this combination also significantly increased viral burst size. Treatment of LNCaP xenografts with this combination therapy resulted in a statistically-significant decrease in relative tumor volume compared to virus alone or radiation alone (p < 0.01). This translated into a 6.7 fold greater inhibition of tumor growth over that expected if the treatments were additive. Conclusion: These data demonstrate that CV706 enhances the in vitro and in vivo radiation response of human PCa cells. It also supports the concept that radiation can actually augment, not inhibit adenoviral replication, which may be the mechanism by which the synergistic effects are elicited. These data, together with our previous Phase I/II clinical data with CV706, support our clinical translation of CV706 in combination with radiation in the treatment of localized PCa. Supported by NIH S.P.O.R.E. in Prostate Cancer

The management of patients with colorectal liver metastases is still controversial. Recent evidence suggests benefit for resection of localized metastases within a single lobe of the liver. A series of 49 patients undergoing liver resection for localized liver metastases is presented. Resection involved right hepatectomy (23), left hepatectomy (8) and segmental excision (18). The median age was 62 (range 40-77). Patients have been followed for a period of up to seven years. The overall median survival was 24 months. The actuarial 3-year survival was 57.9%. There was no significant correlation of survival with the degree of differentiation or Dukes staging of the primary tumour. This series adds further weight to the evidence supporting resection in selected patients with colorectal liver metastases.