Fowler Jack F, Ritter Mark A, Chappell Rick J, Brenner David J
Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA.
Int J Radiat Oncol Biol Phys. 2003 Jul 15;56(4):1093-104. doi: 10.1016/s0360-3016(03)00132-9.
Recent analyses of clinical results have suggested that the fractionation sensitivity of prostate tumors is remarkably high; corresponding point estimates of the alpha/beta ratio for prostate cancer are around 1.5 Gy, much lower than the typical value of 10 Gy for many other tumors. This low alpha/beta value is comparable to, and possibly even lower than, that of the surrounding late-responding normal tissue in rectal mucosa (alpha/beta nominally 3 Gy, but also likely to be in the 4-5 Gy range). This lower alpha/beta ratio for prostate cancer than for the surrounding late-responding normal tissue creates the potential for therapeutic gain. We analyze here possible high-gain/low-risk hypofractionated protocols for prostate cancer to test this suggestion.
Using standard linear-quadratic (LQ) modeling, a set of hypofractionated protocols can be designed in which a series of dose steps is given, each step of which keeps the late complications constant in rectal tissues. This is done by adjusting the dose per fraction and total dose to maintain a constant level of late effects. The effect on tumor control is then investigated. The resulting estimates are theoretical, although based on the best current modeling with alpha/beta parameters, which are discussed thoroughly.
If the alpha/beta value for prostate is less than that for the surrounding late-responding normal tissue, the clinical gains can be rather large. Appropriately designed schedules using around ten large fractions can result in absolute increases of 15% to 20% in biochemical control with no evidence of disease (bNED), with no increase in late sequelae. Early sequelae are predicted to be decreased, provided that overall times are not shortened drastically because of a possible risk of acute or consequential late reactions in the rectum. An overall time not shorter than 5 weeks appears advisable for the hypofractionation schedules considered, pending further clinical trial results. Even if the prostate tumor alpha/beta ratio turns out to be the same (or even slightly larger than) the surrounding late-responding normal tissue, these hypofractionated regimens are estimated to be very unlikely to result in significantly increased late effects.
The hypofractionated regimens that we suggest be tested for prostate-cancer radiotherapy show high potential therapeutic gain as well as economic and logistic advantages. They appear to have little potential risk as long as excessively short overall times (<5 weeks) and very small fraction numbers (<5) are avoided. The values of bNED and rectal complications presented are entirely theoretical, being related by LQ modeling to existing clinical data for approximately intermediate-risk prostate cancer patients as discussed in detail.
近期对临床结果的分析表明，前列腺肿瘤的分次敏感性非常高；前列腺癌的α/β比值的相应点估计约为1.5 Gy，远低于许多其他肿瘤典型的10 Gy值。这个低α/β值与直肠黏膜周围晚反应正常组织的值相当，甚至可能更低（α/β名义上为3 Gy，但也可能在4 - 5 Gy范围内）。前列腺癌的α/β比值低于周围晚反应正常组织，这为治疗带来了潜在获益。我们在此分析前列腺癌可能的高获益/低风险大分割方案，以验证这一推测。
使用标准的线性二次（LQ）模型，可以设计一组大分割方案，其中给出一系列剂量步长，每个步长使直肠组织中的晚期并发症保持恒定。这通过调整每次分割剂量和总剂量来维持晚期效应的恒定水平来实现。然后研究对肿瘤控制的影响。所得估计值是理论性的，尽管基于当前具有α/β参数的最佳模型，对此进行了充分讨论。
如果前列腺的α/β值小于周围晚反应正常组织的α/β值，临床获益可能相当大。使用大约十次大分割的适当设计方案可使无疾病证据（bNED）的生化控制绝对增加15%至20%，且晚期后遗症无增加。预计早期后遗症会减少，前提是总治疗时间不会因直肠急性或后续晚期反应的可能风险而大幅缩短。对于所考虑的大分割方案，在等待进一步临床试验结果之前，总治疗时间不短于5周似乎是可取的。即使前列腺肿瘤的α/β比值与周围晚反应正常组织相同（甚至略大），这些大分割方案预计也极不可能导致晚期效应显著增加。
我们建议用于前列腺癌放疗测试的大分割方案显示出高潜在治疗获益以及经济和后勤方面的优势。只要避免总治疗时间过短（<5周）和分割次数过少（<5次），它们似乎几乎没有潜在风险。所呈现的bNED值和直肠并发症完全是理论性的，通过LQ模型与如详细讨论的大约中度风险前列腺癌患者的现有临床数据相关。
