Long-term biochemical control of prostate cancer after standard or hyper-fractionation: evidence for different outcomes between low-intermediate and high risk patients.

BACKGROUND AND PURPOSE: To report the long-term biochemical control of a non-randomized trial comparing standard (STD) and hyper-fractionated (HFX) radiation schedules for prostate cancer treatment. MATERIALS AND METHODS: Between 1993 and 2003, 370 patients entered the study; 330/370 (STD: 179; HFX: 151) were evaluable for current analysis. Median doses were 79.2 Gy and 74 Gy for HFX (1.2 Gy/fr, two daily fractions) and STD (2 Gy/fr), respectively; median follow-up was 7.5 yr. The two regimens were compared in terms of biochemical relapse-free survival (according to ASTRO definition, bRFS) by univariate (log-rank test) and multivariate analyses (Cox regression hazard model). Based on published relationships between EQD2 and 5-yr biochemical control, α/ß values for each subgroup could be estimated. RESULTS: 7.5 yr bRFS were 53.4% (± 4.4%, 95% CI) and 65.4% (± 4.0%) for HFX and STD, respectively (p=0.13); HFX was associated with a poorer outcome in NCCN low+intermediate patients (7.5 yr bRFS: 56.6% vs 73.5%, p=0.048) while no differences were seen for high-risk patients (7.5 yr bRFS: 44.1% vs 45.3%). Multivariate analysis revealed that NCCN risk grouping (high vs low+intermediate; OR: 0.59, p=0.009) and age (< vs ≥ 70 yr; OR: 0.67, p=0.03) were the main predictors of worse bRFS. In the subgroups of low+intermediate-risk patients < 70 yr, the poorer outcome of HFX was more evident (7.5 yr bRFS: 47.1% vs 70.9%, p=0.078) while no difference was seen for older patients (7.5 yr bRFS: 69.4% vs 72.0%, p=0.76). Our α/ß estimates differ between low+intermediate-risk and high-risk patients. CONCLUSIONS: The bRFS long-term results of this non-randomized trial are consistent with different sensitivities to fractionation depending on NCCN risk grouping. The impact of age on the outcome of HFX for younger low+intermediate patients is consistent with an incomplete repair effect in older patients.

Adaptive Lévy walks in foraging fallow deer.

BACKGROUND: Lévy flights are random walks, the step lengths of which come from probability distributions with heavy power-law tails, such that clusters of short steps are connected by rare long steps. Lévy walks maximise search efficiency of mobile foragers. Recently, several studies raised some concerns about the reliability of the statistical analysis used in previous analyses. Further, it is unclear whether Lévy walks represent adaptive strategies or emergent properties determined by the interaction between foragers and resource distribution. Thus two fundamental questions still need to be addressed: the presence of Lévy walks in the wild and whether or not they represent a form of adaptive behaviour. METHODOLOGY/PRINCIPAL FINDINGS: We studied 235 paths of solitary and clustered (i.e. foraging in group) fallow deer (Dama dama), exploiting the same pasture. We used maximum likelihood estimation for discriminating between a power-tailed distribution and the exponential alternative and rank/frequency plots to discriminate between Lévy walks and composite Brownian walks. We showed that solitary deer perform Lévy searches, while clustered animals did not adopt that strategy. CONCLUSION/SIGNIFICANCE: Our demonstration of the presence of Lévy walks is, at our knowledge, the first available which adopts up-to-date statistical methodologies in a terrestrial mammal. Comparing solitary and clustered deer, we concluded that the Lévy walks of solitary deer represent an adaptation maximising encounter rates with forage resources and not an epiphenomenon induced by a peculiar food distribution.

Is the alpha-beta ratio of prostate cancer really low? A prospective, non-randomized trial comparing standard and hyperfractionated conformal radiation therapy.

BACKGROUND AND PURPOSE: The objectives of the current study were to compare genito-urinary (GU) and gastro-intestinal (GI) toxicities as well as biochemical control (bRFS) in prostate cancer, utilizing conventional (2.0 Gy daily) (STD) or hyperfractionated (HFX) conformal irradiation (CRT). HFX (1.2 Gy BID) was chosen as a radiobiological method to try to reduce long term sequelae without compromising local control. PATIENTS AND METHODS: Three-hundred-and-seventy consecutive patients (pts) entered this prospective, non-randomized trial in the period January 1993-January 2003; 209 were treated with STD and 161 with HFX CRT. All were evaluable for acute toxicity analysis, 179 (STD) and 151 pts (HFX) being evaluable for late sequelae and bRFS analyses. Pt characteristics were not statistically different in the two groups. CRT consisted of a 4-field technique for prostate and/or pelvic nodes and a 5-field boost with rectal shielding. Median doses were 74 and 79.2 Gy for STD and HFX patients respectively, the latter dose being isoeffective for tumour control assuming alpha/beta=10 (EQD(2)=73.9 Gy). Median follow-up was 29.4 months (25.2 mos for STD; 37.7 mos for HFX; P<0.01). The two regimens were compared in terms of acute and late GU and GI toxicities and 5-year bRFS by univariate and multivariate analyses. RESULTS: Acute grade> or =2 GU toxicity was higher in the STD group (48.6% versus 37.3% in HFX, P=0.03), while no significant difference was found for acute GI toxicity. Late grade> or =2 GU and GI toxicities were lower in the HFX group (5-year actuarial rate: GU: 10.1% versus 20.3%, P=0.05; GI: 6.0% versus 10.6%, P=0.18). Five-year bRFS were 70% (+/-13.8%, 95% CI) and 82.6% (+/-7.2%) for STD and HFX, respectively (P=0.44); a trend favouring HFX was found in the subgroup of pts who did not receive hormonal therapy (5-year bRFS: 85.9%+/-12.4% versus 63.9%+/-23.8%, P=0.15). Multivariate analysis revealed only risk groups and age statistically related to bRFS but not fractionation regimen. Using the Nahum-Chapman TLCP model and prostate parameter set, which includes hypoxia, the TLCPs are approximately equal for the two regimens, whereas assuming alpha/beta=1.5 and no hypoxia we obtain 73% for the STD group but only 36% for the HFX group. CONCLUSIONS: As expected from radiobiological considerations, HFX reduces GI and GU late toxicities. Concerning early bRFS, our clinical findings suggest that HFX is no less effective than STD when delivering an isoeffective (alpha/beta=10) dose. Despite the relatively short follow-up, this result appears to be inconsistent with a low alpha/beta ratio for prostate cancer.