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BackgroundPerioperatory chemoradiotherapy (CRT) improves local control and survival in patients with locally advanced rectal cancer (LARC). The objective of the current study was to evaluate the addition of bevacizumab (BEV) to preoperative capecitabine (CAP)-based CRT in LARC, and to explore biomarkers for downstaging.MethodsPatients (pts) were randomized to receive 5 weeks of radiotherapy 45 Gy/25 fractions with concurrent CAP 825 mg/m2 twice daily 5 days per week and BEV 5 mg/kg once every 2 weeks (3 doses) (arm A), or the same schedule without BEV (arm B). The primary end point was pathologic complete response (ypCR: ypT0N0).ResultsNinety pts were included in arm A (44) or arm B (46). Grade 3–4 treatment-related toxicity rates were 16% and 13%, respectively. All patients but one (arm A) proceeded to surgery. The ypCR rate was 16% in arm A and 11% in arm B (p =0.54). Fifty-nine percent vs 39% of pts achieved T-downstaging (arm A vs arm B; p =0.04). Serial samples for biomarker analyses were obtained for 50 out of 90 randomized pts (arm A/B: 22/28). Plasma angiopoietin-2 (Ang-2) levels decreased in arm A and increased in arm B (p <0.05 at all time points). Decrease in Ang-2 levels from baseline to day 57 was significantly associated with tumor downstaging (p =0.02).ConclusionsThe addition of BEV to CAP-based preoperative CRT has shown to be feasible in LARC. The association between decreasing Ang-2 levels and tumor downstaging should be further validated in customized studies.Trial registryClinicaltrials.gov identifier NCT01043484. Trial registration date: 12/30/2009.

BACKGROUND Sensitive procedures for quantitative measurement of tumor cell spread as a function of time and primary tumor size are necessary to generate models of metastasis and formulate therapies. METHODS Prostate carcinoma cells PC‐3.luc expressing the luciferase gene were intramuscularly inoculated in nude mice to generate experimental tumors. Metastatic cells in target organs were easily counted by their capacity to produce light. RESULTS Tumor cells were very mobile and migrated to all the target organs examined: lymph nodes, brain, bone, lungs, liver, kidney, spleen, testicles, prostate, seminal vesicle, and scrotum. Organ colonization started very early, 14 days after inoculation, when primary tumors were very small and produced an amount of light equivalent to that generated by 2 × 104 tumor cells in vitro (tumor cell equivalents, TCEs). Tumor cell burden could be quantitatively described by power functions of time or primary tumor light‐producing capacity. The ratio of metastatic TCEs to primary tumor TCEs clustered around organ characteristic values: 10−3 for femur and lumbar lymph nodes, 10−6 for the spleen, and 10−3 for the added set of organs. CONCLUSIONS Dispersal of PC‐3 tumor cells from IM experimental tumors started early before the third week postinoculation and when primary tumors had 2 × 104 TCEs. Tumor cells were found widely spread in all the organs tested. The possibility of easily quantifying tumor cell burden should make this approach useful for the study of metastasis and the development of antimetastatic therapies. Prostate 44:133–143, 2000. © 2000 Wiley‐Liss, Inc.