分次放射治疗中使用不等分次剂量效果的研究
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摘要
放射治疗的目的就是为了获得较好肿瘤控制概率(TCP)的同时降低正常组织并发症的发生，因此，根据肿瘤组织和正常组织照射后不同的增殖能力和亚致死损伤修复能力，采用分次照射可以达到此目的。
最好的治疗方案就是照射时间、剂量和分次数最佳选择，而研究表明，在对某一照射方案进行预期效果评估时，TCP计算模型是一个较为有效的方法。从理论上讲，对于一定的治疗剂量和治疗时间，有两类不同的照射方案可以被采用，一类方案中分次剂量均相等，即等分次剂量(CFS)照射方案，目前已被广泛应用于放射治疗；另一类方案中分次剂量是变化的，即不等分次剂量(VFS)照射方案，到目前为止还未被系统研究过。
本研究的目的就是要研究VFS照射方案的效果。方法是在假设采用两类便于计算的VFS方案照射(分次剂量间以等比K或等差δ变化)的情况下，从理论和实验两方面进行研究。首先将导出一个包含DNA单链断裂修复、克隆源性细胞复制增殖、再氧合和细胞周期再分布等影响因素的TCP计算模型，并与已提出的其他TCP计算模型比较以确定优劣，然后用此模型对假设的VFS照射方案进行计算，画出TCP与照射剂量(D)的关系曲线并与CFS照射方案时的TCP-D关系曲线进行比较。其次，为了验证理论计算结果的准确性，我们采用了SMMC7721肝癌细胞进行实验研究。具体做法是，将SMMC7721肝癌细胞常规培养后，用上述假设的不同VFS方案及CFS方案进行照射，根据噻唑蓝(MTT)方法测出的吸光度计算出不同方案照射后的细胞存活率并进行比较。
经过比较可知，所导出的TCP计算模型要好于其他模型，因为它的计算结果与临床实际情况最为接近，因此可用于对某一治疗方案效果的评估。理论计算结果表明：①在相同的总治疗剂量情况下，CFS方案治疗所获得的TCP最低，而采用VFS方案治疗时TCP值会略有提高，且VFS方案中分次剂量间的不均匀性越大(K-1和δ绝对值增大)所获得的TCP越高。另外，TCD_(50)值(TCP为50％时所需要的剂量)也是在等比K=1和等差δ=0时(即CFS方案)最大，随着K-1和δ绝对值的增大而逐渐变小。所以，VFS方案能获得比CFS方案更好一些的TCP-D关系曲线和更低的TCD_(50)值。②在以相同变化幅度(K-1或δ的绝对值相同)的分次剂量递增或递减治疗时，分次剂量递减的方案得到的TCP值要略高于分次剂量递增方案得到的TCP值，但变化幅度小时两者之间的差距很小，在以一周为周期的VFS方案治疗时两者更是基本重合，但随着变化幅度的增大，两者的差距越来越明显，而且递减治疗方案的TCD_(50)要略小于递增治疗时的TCD_(50)值。所以变化幅度相同时，以递减剂量分次治疗获得的效果略佳。③以一周为周期的VFS方案获得的TCD_(50)与等比K或等差δ间的关系曲线要较全疗程VFS方案的曲线平缓得多，原因是后一种方案中分次剂量分布的不均匀性在要大于在前一种方案。
实验结果表明：①所有VFS方案获得的细胞存活率(S)均小于CFS方案获得的S值。其中，部分VFS方案获得的S与CFS方案照射后的S值间的差异有显著统计学意义。②比较分次剂量间以相同的变化幅度照射时的结果可以看出，使用递减分次剂量照射可以获得比使用递增分次剂量照射更好的效果，即更低的S值。其中有部分照射方案所获得的S值结果之间的差异有显著的统计学意义。
由理论计算和实验结果可知，使用VFS方案照射所获得的效果要好于传统的CFS照射方案；对于VFS照射方案，使用分次剂量递减的照射方案，其效果要好于使用递增分次剂量照射的效果，所以研究结果提示，VFS方案可能可以用于分次照射以提高TCP。但是，由于分次治疗方案实施的时间太长，我们只用SMMC7721肝癌细胞进行了两个假设VFS方案照射的实验，所以，该结果是否对其他肿瘤也适用仍然需要更多的使用其他肿瘤细胞的实验及临床结果来验证和支持。
The objective of radiotherapy is to obtain the maximum tumor control probability (TCP) or lower tumor cell survival while minimizing the likelihood of significant normal tissue damage around the tumor. Now, the fractionated radiotherapy protocols have been used in clinics. And it's well known that, the TCP calculating model is a good method to estimate the effect of a certain irradiation protocol.Because of the different fractionation radiosensitivity and different recovery kinetics, the tissue response to the same total radiation dose may changed with the different irradiation parameters such as fraction size, fraction numbers and overall treatment time. So the optimum protocol is to optimize the irradiation parameters. For a given irradiation dose and time, there are two kinds of protocols which can be used, one is the protocol with constant fraction sizes(CFS), which has been widely used in clinics; The other is the protocol with variable fraction sizes(VFS), which has not been studied systematically.In our work, the effect of irradiation with VFS protocol was analyzed theoretically and experimentally. It was done in two steps: (1) A TCP model which including the effect of DNA single-strand damage repair, repopulation of clonogens, reoxygenation and redistribution will be derived and compared with the other TCP models. Then with a group of assumed characteristic parameter values for a tumor, the relationship between TCP and total treatment dose of two assumed special VFS protocols(The fraction size changed with the ratio k or differenceδ) were presented and compared with that of CFS protocol by calculation. (2) A concise experiment with SMMC7721 liver malignancy cells was done to analyze the effect of VFS protocols while the total absorbed dose, fraction numbers and treatment time keep constant. The cells were cultured and irradiated with the assumed different VFS protocols, then the cell survival probability(S) after different irradiation protocols were calculated with the absorbance result obtained from the MTT method to testify whether the calculation result is right..
The comparison between the different TCP models shows that, the derived model in this paper is better than the others, and it can be used to estimate the effect of any fractionated irradiation protocols. The calculation result shows that:①All TCP-Dose relationship curves of irradiation with VFS protocols are better than that of CFS protocol, and the TCP-Dose relationship curves will become better when the absolute value of k-1orδincreases. And the TCD_(50) value(the dose needed to get the 50％TCP) is largest whenδ=0 or k=1(i. e. CFS protocol), and it turns to be smaller with the increasing absolute value of k-1orδ. Hence, for the given treatment time, radiation dose and fraction numbers, treatment with the VFS can get the better TCP-DOSE curve and lower TCD_(50) value than treatment with the CFS.②For the same variety range, treatment with the decreasing fraction sizes is slightly better than treatment with the increasing fraction sizes. And the TCD_(50) values of using decreasing fraction sizes protocol is slightly lower than that of using increasing fraction sizes protocol.③The TCD_(50) vs. k or TCD_(50) vs.δrelationship of using VFS over all treatment time is much sharper than that of using VFS in a week with a week cycle period, the reason is that the fraction sizes in the former protocol are more heterogeneous than that in the latter protocol.
The experiment result showed that:①All the S values irradiated with VFS are lower than that irradiated with the CFS. And the significant differences are found between the S value irradiated with the CFS protocol and irradiated with the part of assumed VFS protocols.②As the VFS protocols were used, with the same variety range, irradiated with decreasing fraction sizes can get the lower S value than using increasing fraction sizes, and the significant difference were found between the S value after irradiated with the part of couple VFS protocols.
In general, with the given fraction numbers, treatment time and radiation dose, treatment with VFS can get the better effect than treatment with CFS. As a result, perhaps the VFS protocol, especially the protocol with decreasing VFS can be used in fractionated radiotherapy to improve the tumor control. But how to choose the optimum one within the infinite VFS still need to be studied with a lot of experiments in vivo or in vitro, maybe when the parameter values of a tumor and the variation of these parameters in the process of radiotherapy is known accurately, it will be reality to design and use the optimum VFS in clinics exactly. And in our opinion, before it is really used in fractionated radiotherapy, the effect of this kind of protocols and how to design the optimum one to get the optimum TCP still need to be studied and q
be proved with a lot of experiments.
最好的治疗方案就是照射时间、剂量和分次数最佳选择，而研究表明，在对某一照射方案进行预期效果评估时，TCP计算模型是一个较为有效的方法。从理论上讲，对于一定的治疗剂量和治疗时间，有两类不同的照射方案可以被采用，一类方案中分次剂量均相等，即等分次剂量(CFS)照射方案，目前已被广泛应用于放射治疗；另一类方案中分次剂量是变化的，即不等分次剂量(VFS)照射方案，到目前为止还未被系统研究过。
本研究的目的就是要研究VFS照射方案的效果。方法是在假设采用两类便于计算的VFS方案照射(分次剂量间以等比K或等差δ变化)的情况下，从理论和实验两方面进行研究。首先将导出一个包含DNA单链断裂修复、克隆源性细胞复制增殖、再氧合和细胞周期再分布等影响因素的TCP计算模型，并与已提出的其他TCP计算模型比较以确定优劣，然后用此模型对假设的VFS照射方案进行计算，画出TCP与照射剂量(D)的关系曲线并与CFS照射方案时的TCP-D关系曲线进行比较。其次，为了验证理论计算结果的准确性，我们采用了SMMC7721肝癌细胞进行实验研究。具体做法是，将SMMC7721肝癌细胞常规培养后，用上述假设的不同VFS方案及CFS方案进行照射，根据噻唑蓝(MTT)方法测出的吸光度计算出不同方案照射后的细胞存活率并进行比较。
经过比较可知，所导出的TCP计算模型要好于其他模型，因为它的计算结果与临床实际情况最为接近，因此可用于对某一治疗方案效果的评估。理论计算结果表明：①在相同的总治疗剂量情况下，CFS方案治疗所获得的TCP最低，而采用VFS方案治疗时TCP值会略有提高，且VFS方案中分次剂量间的不均匀性越大(K-1和δ绝对值增大)所获得的TCP越高。另外，TCD_(50)值(TCP为50％时所需要的剂量)也是在等比K=1和等差δ=0时(即CFS方案)最大，随着K-1和δ绝对值的增大而逐渐变小。所以，VFS方案能获得比CFS方案更好一些的TCP-D关系曲线和更低的TCD_(50)值。②在以相同变化幅度(K-1或δ的绝对值相同)的分次剂量递增或递减治疗时，分次剂量递减的方案得到的TCP值要略高于分次剂量递增方案得到的TCP值，但变化幅度小时两者之间的差距很小，在以一周为周期的VFS方案治疗时两者更是基本重合，但随着变化幅度的增大，两者的差距越来越明显，而且递减治疗方案的TCD_(50)要略小于递增治疗时的TCD_(50)值。所以变化幅度相同时，以递减剂量分次治疗获得的效果略佳。③以一周为周期的VFS方案获得的TCD_(50)与等比K或等差δ间的关系曲线要较全疗程VFS方案的曲线平缓得多，原因是后一种方案中分次剂量分布的不均匀性在要大于在前一种方案。
实验结果表明：①所有VFS方案获得的细胞存活率(S)均小于CFS方案获得的S值。其中，部分VFS方案获得的S与CFS方案照射后的S值间的差异有显著统计学意义。②比较分次剂量间以相同的变化幅度照射时的结果可以看出，使用递减分次剂量照射可以获得比使用递增分次剂量照射更好的效果，即更低的S值。其中有部分照射方案所获得的S值结果之间的差异有显著的统计学意义。
由理论计算和实验结果可知，使用VFS方案照射所获得的效果要好于传统的CFS照射方案；对于VFS照射方案，使用分次剂量递减的照射方案，其效果要好于使用递增分次剂量照射的效果，所以研究结果提示，VFS方案可能可以用于分次照射以提高TCP。但是，由于分次治疗方案实施的时间太长，我们只用SMMC7721肝癌细胞进行了两个假设VFS方案照射的实验，所以，该结果是否对其他肿瘤也适用仍然需要更多的使用其他肿瘤细胞的实验及临床结果来验证和支持。
The objective of radiotherapy is to obtain the maximum tumor control probability (TCP) or lower tumor cell survival while minimizing the likelihood of significant normal tissue damage around the tumor. Now, the fractionated radiotherapy protocols have been used in clinics. And it's well known that, the TCP calculating model is a good method to estimate the effect of a certain irradiation protocol.Because of the different fractionation radiosensitivity and different recovery kinetics, the tissue response to the same total radiation dose may changed with the different irradiation parameters such as fraction size, fraction numbers and overall treatment time. So the optimum protocol is to optimize the irradiation parameters. For a given irradiation dose and time, there are two kinds of protocols which can be used, one is the protocol with constant fraction sizes(CFS), which has been widely used in clinics; The other is the protocol with variable fraction sizes(VFS), which has not been studied systematically.In our work, the effect of irradiation with VFS protocol was analyzed theoretically and experimentally. It was done in two steps: (1) A TCP model which including the effect of DNA single-strand damage repair, repopulation of clonogens, reoxygenation and redistribution will be derived and compared with the other TCP models. Then with a group of assumed characteristic parameter values for a tumor, the relationship between TCP and total treatment dose of two assumed special VFS protocols(The fraction size changed with the ratio k or differenceδ) were presented and compared with that of CFS protocol by calculation. (2) A concise experiment with SMMC7721 liver malignancy cells was done to analyze the effect of VFS protocols while the total absorbed dose, fraction numbers and treatment time keep constant. The cells were cultured and irradiated with the assumed different VFS protocols, then the cell survival probability(S) after different irradiation protocols were calculated with the absorbance result obtained from the MTT method to testify whether the calculation result is right..
The comparison between the different TCP models shows that, the derived model in this paper is better than the others, and it can be used to estimate the effect of any fractionated irradiation protocols. The calculation result shows that:①All TCP-Dose relationship curves of irradiation with VFS protocols are better than that of CFS protocol, and the TCP-Dose relationship curves will become better when the absolute value of k-1orδincreases. And the TCD_(50) value(the dose needed to get the 50％TCP) is largest whenδ=0 or k=1(i. e. CFS protocol), and it turns to be smaller with the increasing absolute value of k-1orδ. Hence, for the given treatment time, radiation dose and fraction numbers, treatment with the VFS can get the better TCP-DOSE curve and lower TCD_(50) value than treatment with the CFS.②For the same variety range, treatment with the decreasing fraction sizes is slightly better than treatment with the increasing fraction sizes. And the TCD_(50) values of using decreasing fraction sizes protocol is slightly lower than that of using increasing fraction sizes protocol.③The TCD_(50) vs. k or TCD_(50) vs.δrelationship of using VFS over all treatment time is much sharper than that of using VFS in a week with a week cycle period, the reason is that the fraction sizes in the former protocol are more heterogeneous than that in the latter protocol.
The experiment result showed that:①All the S values irradiated with VFS are lower than that irradiated with the CFS. And the significant differences are found between the S value irradiated with the CFS protocol and irradiated with the part of assumed VFS protocols.②As the VFS protocols were used, with the same variety range, irradiated with decreasing fraction sizes can get the lower S value than using increasing fraction sizes, and the significant difference were found between the S value after irradiated with the part of couple VFS protocols.
In general, with the given fraction numbers, treatment time and radiation dose, treatment with VFS can get the better effect than treatment with CFS. As a result, perhaps the VFS protocol, especially the protocol with decreasing VFS can be used in fractionated radiotherapy to improve the tumor control. But how to choose the optimum one within the infinite VFS still need to be studied with a lot of experiments in vivo or in vitro, maybe when the parameter values of a tumor and the variation of these parameters in the process of radiotherapy is known accurately, it will be reality to design and use the optimum VFS in clinics exactly. And in our opinion, before it is really used in fractionated radiotherapy, the effect of this kind of protocols and how to design the optimum one to get the optimum TCP still need to be studied and q
be proved with a lot of experiments.
引文
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