Re-irradiation of nasopharyngeal carcinoma with intensity-modulated radiotherapy.

BACKGROUND AND PURPOSE: To evaluate the treatment outcome in patients with locally recurrent nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: Between October 2001 and May 2004, 31 patients with locally recurrent NPC received re-irradiation using IMRT. The rT classification distribution was 3 for rT1, 5 for rT2, 9 for rT3, and 14 for r T4. Median time from first course of radiotherapy to re-irradiation was 51 months. IMRT was performed using step-and-shoot method with nine 4-6 MV photon fields and median prescribed dose was 54 Gy (range: 50-60 Gy). Additional treatments included cisplatin-based induction chemotherapy in 68% and radiosurgery boost with a single dose which ranged from 8.5 to 12.5 Gy in 32%. Median follow-up time was 11 months. RESULTS: After re irradiation, 58% of patients had complete regression of primary tumor. One-year loco-regional progression-free, distant metastasis-free and overall survival rates were 56, 90, and 63%, respectively. Significantly better 1-year local progression-free rate was observed in rT1-3 than r T4 tumor (100 vs. 35%). Grade 3 late toxicities, mostly ototoxicity/cranial neuropathy, occurred in six patients (19%). One-year actuarial rates of late toxicities were 70% for all grades and 25% for Grade 3. CONCLUSION: Our preliminary results showed that good control of rT1-3 NPC can be achieved using IMRT with a dose between 50 and 60 Gy, whereas the outcome for r T4 tumor remained poor. Late toxicities were common but incidence of severe toxicities was relatively low.     

Combination bcl-2 antisense and radiation therapy for nasopharyngeal cancer.

PURPOSE: A wide variety of tumors depend on the dysregulation of Bcl-2 family proteins for survival. The resulting apoptotic block can often provide a mechanism for resistance to anticancer treatments, such as chemotherapy and radiation. This current study evaluates the efficacy of combining systemically delivered Bcl-2 phosphorothioate antisense (Bcl-2 ASO) and radiation for nasopharyngeal cancer therapy. RESULTS: Antisense uptake was unaffected by 0, 3, or 6 Gy radiation. Radiation decreased the fraction of viable C666-1 cells to 60%, with a further decrease to 40% in combination with Bcl-2 ASO. Despite a modest in vitro effect, Bcl-2 ASO alone caused the regression of established xenograft tumors in mice, extending survival by 15 days in a C666-1 and by 6 days in a C15 model. The survival times for mice treated with both Bcl-2 ASO and radiation increased by 52 days in C666-1 and by 20 days in C15 tumors. This combination resulted in a more-than-additive effect in C666-1 tumors. Less impressive gains observed in C15 tumors might be attributable to higher expression of antiapoptotic Bcl-2 family proteins and limited drug distribution in the tumor. Retreatment of C666-1 tumors with the Bcl-2 ASO-radiation combination, however, was effective, resulting in mice surviving for >80 days relative to untreated controls. CONCLUSIONS: Our results show that the Bcl-2 ASO and radiation combination is a highly potent therapy for nasopharyngeal cancer. Further examination of combination therapy with radiation and other Bcl-2 family-targeted anticancer agents in both preclinical and clinical settings is definitely warranted.     

Circulating Fibronectin Controls Tumor Growth

Fibronectin is ubiquitously expressed in the extracellular matrix, and experimental evidence has shown that it modulates blood vessel formation. The relative contribution of local and circulating fibronectin to blood vessel formation in vivo remains unknown despite evidence for unexpected roles of circulating fibronectin in various diseases. Using transgenic mouse models, we established that circulating fibronectin facilitates the growth of bone metastases by enhancing blood vessel formation and maturation. This effect is more relevant than that of fibronectin produced by endothelial cells and pericytes, which only exert a small additive effect on vessel maturation. Circulating fibronectin enhances its local production in tumors through a positive feedback loop and increases the amount of vascular endothelial growth factor (VEGF) retained in the matrix. Both fibronectin and VEGF then cooperate to stimulate blood vessel formation. Fibronectin content in the tumor correlates with the number of blood vessels and tumor growth in the mouse models. Consistent with these results, examination of three separate arrays from patients with breast and prostate cancers revealed that a high staining intensity for fibronectin in tumors is associated with increased mortality. These results establish that circulating fibronectin modulates blood vessel formation and tumor growth by modifying the amount of and the response to VEGF. Furthermore, determination of the fibronectin content can serve as a prognostic biomarker for breast and prostate cancers and possibly other cancers.