Although promising, the predictive power sometimes evidenced in the pilot studies need to be externally validated in independent datasets with numerous methodological pitfalls including imaging technique standardization.


Q1.
What is meant by the “therapeutic window”? Mention several methods to widen the therapeutic window.
 Q2.
The tumor volume doubling time (VDT) is heterogeneous among tumors and influences RT response. Discuss and reflect on different parameters that control VDT of tumors.
 Q3.
It is important to estimate the growth fraction (GF) of tumors and several methods may be used in vitro and in vivo to assess this. Give some examples of methods and in what context they are applied.
 Q4.
Discuss the link between the Hallmarks of Radiobiology and the Hallmarks of Cancer.
 Q5.
Which of the below statements is wrong?(a)
Lowering the dose rate leads to greater sparing of late responding normal tissues than of tumors.
 (b)
The process of redistribution might push cells from a radioresistant to a radiosensitive cell-cycle phase.
 (c)
During chronic low dose rate exposure, cells with long repair half times will be spared relative to their counterparts with rapid DNA damage repair.
 (d)
Low dose rate irradiation can be considered as a form of extreme fractionation.

 Q6.
How can dose rate affect be explained in terms of linear-quadratic model?
 Q7.
What are the classical factors that are used to predict RT response in a tumor?
 Q8.
List four techniques which are used to measure biomarkers to predict RT response.
 Q9.
Oxygen enhancement ratio (OER) is seen with some but not all IR qualities. Please indicate which type (a–d) that doesn’t have OER.(a)
X-rays
 (b)
Gamma-rays
 (c)
Neutrons
 (d)
α-particles

 Q10.
All of the following statements about hypoxic cell radiosensitizers are true except one, please indicate and explain.(a)
Increases radiosensitivity of hypoxic cells
 (b)
Nitroimidazole groups of drugs are commonly used
 (c)
Presence of nitro group in second position, decreases electron affinity and sensitization
 (d)
Dose-limiting toxicity of Misonidazole is neurotoxicity

 Q11.
Give some examples how photon radiation can induce modification extracellular signaling pathways.
 Q12.
Two principal mechanisms of tumor metabolism participate in radiation resistance. Give their names.
 Q13.
What is radiation-induced abscopal effect in oncology?
 Q14.
Describe the typical acute and late effects following exposure of the skin to radiation. Hints: target cells at risk, latent period, volume effect, pathology, recovery.
 Q15.
Define and describe the late adverse effects of RT.
 Q16.
Can radionecrosis be avoided by choosing a more appropriate radiation modality?
 Q17.
How can access to the forecasted 3D RT isodose curves allow for a better prevention of osteoradionecrosis of the mandible?
 Q18.
What is the main function of the stem cells?
 Q19.
What is the most radiosensitive group of stem cells?
 Q20.
Describe some different characteristics of cancer stem cells which may contribute to RT resistance?
 Q21.
Describe potential role of the intestinal microbiota in RT-induced adverse side effects (gut toxicity) or in RT efficiency concerning anti-tumor effects.


What is meant by the “therapeutic window”? Mention several methods to widen the therapeutic window.


The tumor volume doubling time (VDT) is heterogeneous among tumors and influences RT response. Discuss and reflect on different parameters that control VDT of tumors.


It is important to estimate the growth fraction (GF) of tumors and several methods may be used in vitro and in vivo to assess this. Give some examples of methods and in what context they are applied.


Discuss the link between the Hallmarks of Radiobiology and the Hallmarks of Cancer.


Which of the below statements is wrong?(a)
Lowering the dose rate leads to greater sparing of late responding normal tissues than of tumors.
 (b)
The process of redistribution might push cells from a radioresistant to a radiosensitive cell-cycle phase.
 (c)
During chronic low dose rate exposure, cells with long repair half times will be spared relative to their counterparts with rapid DNA damage repair.
 (d)
Low dose rate irradiation can be considered as a form of extreme fractionation.


Lowering the dose rate leads to greater sparing of late responding normal tissues than of tumors.


The process of redistribution might push cells from a radioresistant to a radiosensitive cell-cycle phase.


During chronic low dose rate exposure, cells with long repair half times will be spared relative to their counterparts with rapid DNA damage repair.


Low dose rate irradiation can be considered as a form of extreme fractionation.


How can dose rate affect be explained in terms of linear-quadratic model?


What are the classical factors that are used to predict RT response in a tumor?


List four techniques which are used to measure biomarkers to predict RT response.


Oxygen enhancement ratio (OER) is seen with some but not all IR qualities. Please indicate which type (a–d) that doesn’t have OER.(a)
X-rays
 (b)
Gamma-rays
 (c)
Neutrons
 (d)
α-particles


All of the following statements about hypoxic cell radiosensitizers are true except one, please indicate and explain.(a)
Increases radiosensitivity of hypoxic cells
 (b)
Nitroimidazole groups of drugs are commonly used
 (c)
Presence of nitro group in second position, decreases electron affinity and sensitization
 (d)
Dose-limiting toxicity of Misonidazole is neurotoxicity


Presence of nitro group in second position, decreases electron affinity and sensitization


Give some examples how photon radiation can induce modification extracellular signaling pathways.


Two principal mechanisms of tumor metabolism participate in radiation resistance. Give their names.


Describe the typical acute and late effects following exposure of the skin to radiation. Hints: target cells at risk, latent period, volume effect, pathology, recovery.


Can radionecrosis be avoided by choosing a more appropriate radiation modality?


How can access to the forecasted 3D RT isodose curves allow for a better prevention of osteoradionecrosis of the mandible?


Describe some different characteristics of cancer stem cells which may contribute to RT resistance?


Describe potential role of the intestinal microbiota in RT-induced adverse side effects (gut toxicity) or in RT efficiency concerning anti-tumor effects.


SQ1.
Therapeutic window: The difference between tumor control probability and normal tissue complication probability at identical irradiation dose. Methods to widen the therapeutic window: Dose fractionation, reduction of the normal tissue/organ at risk exposed volume, combination therapy.
 SQ2.
VDT is influenced by localization of the tumor, i.e., tumor site. It is also influenced if the tumor is a primary or a metastatic lesion where the latter often have reduced VDT as a result of limited nutrition and oxygen levels. VDT is also influenced by histology of the tumor, i.e., the inherited growth capacity of the cells. Finally, VDT is influenced by tumor heterogeneity in proliferative signaling cascades which is a consequence of different genomic- and signaling make ups of the individual tumors.
 SQ3.
In vitro tumor cell progression through S-phase can be monitored by BrdUrd or IdUrd-labeling of cells. These tracers are incorporated into DNA as tumor pass through S-phase and by using an antibody against BrdUrd or IdUrd, cells in S-phase can be determined using flowcytometry. Another method utilizes 3H-thymidine to assess DNA-synthesis by flow cytometry. The third method is based on PET-analyses of tumors in vivo which have been pulsed with radio-labeled 18F-fluoro-3′-deoxy-3′-l-fluorothymidine (FLT). FLT is phosphorylated by Thymidine Kinase 1 which has an S-phase activity. Hence, FLT tracer levels are a surrogate for S-phase cells which can be evaluated by PET scanning. Finally, the proliferation rate in a tumor biopsy can be analyzed by immunohistochemical staining for the nuclear Ki-67 antigen, reflecting S-phase proportion of cells.
 SQ4.
Likely links are shown below.
Hallmark of radiobiology

Hallmark of cancer

Repair

Genomic instability and mutations, enabling replicative immortality

Redistribution

Sustaining proliferative signaling

Repopulation

Evading growth suppressors, sustaining proliferative signaling, tumor-promoting activation

Radiosensitivity

Resisting cell death, deregulating cellular energetics

Reoxygenation

Inducing angiogenesis

Reactivation of the immune response

Avoiding immune destruction, tumor-promoting activation, activation invasion and metastasis

 SQ5.
Alternative (c) is the wrong answer. Accumulation of DNA damage is larger in cells with long repair half times than for cells which show rapid repair of their DNA damages.
 SQ6.
Single-track and double-track actions can both induce DNA double strand breaks. There is no correlation between dose rate and single-track X-ray lesion (αcontribution in the LQ model). In a double-track action, different X-ray photon tracks produce the two interactions of single strand DNA lesions, and therefore the formation of double strand lesions is proportional to the radiation dose squared (β in the LQ model).
 SQ7.
Tumor oxygen status, the degree of repopulation or proliferation rate and intrinsic radiosensitivity.
 SQ8.
Proteomics, genomics, epigenomics, genomics, or transcriptomics, used for measuring proteins, DNA/chromatin, DNA, or RNA and transcription, respectively.
 SQ9.
Alternative (d). OER is 1 for high LET radiation like α- particles.
 SQ10.
Alternative (c). The presence of the nitro group in second position, increases electron affinity and radiosensitization.
 SQ11.
Photon beam activates major oncogenic signaling pathways such as Ras, MAPK/ERK, and PI3K/AKT in part via the epidermal growth factor receptor (EGFR) cascade. Radiation resistance is associated with these signaling cascades due to their pro-survival nature. For example, when AKT is phosphorylated, tumor cells are protected by decreased autophagy and apoptosis, as well as increased DNA repair capacity. Mutated RAS has also been associated with resistance to photons in cancer cells.
 SQ12.
The mitochondrial and or glucose metabolism, respectively.
 SQ13.
Abscopal effects are radiation-induced systemic anti-tumor immune responses in which irradiation of a primary tumor or large metastasis causes remission of distant, non-irradiated lesions.
 SQ14.
Acute effects: Dry skin (impairment of cell production), epilation (injury to hair follicles), erythema (vascular leakage). Latency time: Few weeks. Large volume effect: The smaller the volume, the higher the tolerance to radiation. Transient effect: Reversible injury. Late effects: Gangrene, ulcer, telangiectasia (vascular damage), fibrosis (increase in collagen fibers). Latency: Months-years. Large volume effect: The smaller the volume, the higher the tolerance to radiation. Chronic, irreversible injury.
 SQ15.
Late effects of radiation are progressive, irreversible and occur months, years, or decades after radiation therapy. They are based on an interactive response of parenchymal cells, vascular endothelium and fibroblasts, with a contribution from immune cells, especially macrophages. Tissues and organs are affected by atrophy, fibrosis, or necrosis, which can severely impair their functions and lead to a loss of function.
 SQ16.
No. Since the risk of radionecrosis remains life-long the affected tissues are at danger with the total radiation dose being the primary risk factor for the tissue involved, combined with other risk factors.
 SQ17.
Adapting the preventive extraction of teeth to the risk zone of >50–60 Gy would allow for a more appropriate dental management: more aggressive in the >60 Gy zone and far less aggressive in the other areas of the jaw, improving the quality of life of these patients. The fewer extractions in highly irradiated areas, the lesser the risk for ORN.
 SQ18.
The principal function of stem cells is to maintain tissue homeostasis including continuous regeneration and associated constant number of cells.
 SQ19.
Bone marrow stem cells.
 SQ20.
The answer is displayed in Fig. 5.29. In brief, CSC may have (1) Increased DNA repair capacity which allows them to handle IR-induced DNA DSBs; (2) Increased signaling networks that block IR-induced cell death including deficient pro-apoptotic signaling and increased anti-apoptotic signaling; (3) CSCs have slow proliferation and may therefore not be so sensitivity to IR-induced DNA damage.
 SQ21.
Studies showed evidence of the existence of bidirectional effects of RT on the tumor and on the intestinal microbiota. In prospective clinical studies, a reduction of the fecal microbial diversity during and after pelvic RT was measured in patients suffering from intestinal complications. Also, RT-induced modification of microbiota diversity and composition can modify the host immune response and in turn the effectiveness of the anticancer treatment themselves including RT.


Therapeutic window: The difference between tumor control probability and normal tissue complication probability at identical irradiation dose. Methods to widen the therapeutic window: Dose fractionation, reduction of the normal tissue/organ at risk exposed volume, combination therapy.


VDT is influenced by localization of the tumor, i.e., tumor site. It is also influenced if the tumor is a primary or a metastatic lesion where the latter often have reduced VDT as a result of limited nutrition and oxygen levels. VDT is also influenced by histology of the tumor, i.e., the inherited growth capacity of the cells. Finally, VDT is influenced by tumor heterogeneity in proliferative signaling cascades which is a consequence of different genomic- and signaling make ups of the individual tumors.


In vitro tumor cell progression through S-phase can be monitored by BrdUrd or IdUrd-labeling of cells. These tracers are incorporated into DNA as tumor pass through S-phase and by using an antibody against BrdUrd or IdUrd, cells in S-phase can be determined using flowcytometry. Another method utilizes 3H-thymidine to assess DNA-synthesis by flow cytometry. The third method is based on PET-analyses of tumors in vivo which have been pulsed with radio-labeled 18F-fluoro-3′-deoxy-3′-l-fluorothymidine (FLT). FLT is phosphorylated by Thymidine Kinase 1 which has an S-phase activity. Hence, FLT tracer levels are a surrogate for S-phase cells which can be evaluated by PET scanning. Finally, the proliferation rate in a tumor biopsy can be analyzed by immunohistochemical staining for the nuclear Ki-67 antigen, reflecting S-phase proportion of cells.


Likely links are shown below.
Hallmark of radiobiology

Hallmark of cancer

Repair

Genomic instability and mutations, enabling replicative immortality

Redistribution

Sustaining proliferative signaling

Repopulation

Evading growth suppressors, sustaining proliferative signaling, tumor-promoting activation

Radiosensitivity

Resisting cell death, deregulating cellular energetics

Reoxygenation

Inducing angiogenesis

Reactivation of the immune response

Avoiding immune destruction, tumor-promoting activation, activation invasion and metastasis


Alternative (c) is the wrong answer. Accumulation of DNA damage is larger in cells with long repair half times than for cells which show rapid repair of their DNA damages.


Single-track and double-track actions can both induce DNA double strand breaks. There is no correlation between dose rate and single-track X-ray lesion (αcontribution in the LQ model). In a double-track action, different X-ray photon tracks produce the two interactions of single strand DNA lesions, and therefore the formation of double strand lesions is proportional to the radiation dose squared (β in the LQ model).


Tumor oxygen status, the degree of repopulation or proliferation rate and intrinsic radiosensitivity.


Proteomics, genomics, epigenomics, genomics, or transcriptomics, used for measuring proteins, DNA/chromatin, DNA, or RNA and transcription, respectively.


Alternative (d). OER is 1 for high LET radiation like α- particles.


Alternative (c). The presence of the nitro group in second position, increases electron affinity and radiosensitization.


Photon beam activates major oncogenic signaling pathways such as Ras, MAPK/ERK, and PI3K/AKT in part via the epidermal growth factor receptor (EGFR) cascade. Radiation resistance is associated with these signaling cascades due to their pro-survival nature. For example, when AKT is phosphorylated, tumor cells are protected by decreased autophagy and apoptosis, as well as increased DNA repair capacity. Mutated RAS has also been associated with resistance to photons in cancer cells.


Abscopal effects are radiation-induced systemic anti-tumor immune responses in which irradiation of a primary tumor or large metastasis causes remission of distant, non-irradiated lesions.


Acute effects: Dry skin (impairment of cell production), epilation (injury to hair follicles), erythema (vascular leakage). Latency time: Few weeks. Large volume effect: The smaller the volume, the higher the tolerance to radiation. Transient effect: Reversible injury. Late effects: Gangrene, ulcer, telangiectasia (vascular damage), fibrosis (increase in collagen fibers). Latency: Months-years. Large volume effect: The smaller the volume, the higher the tolerance to radiation. Chronic, irreversible injury.


Late effects of radiation are progressive, irreversible and occur months, years, or decades after radiation therapy. They are based on an interactive response of parenchymal cells, vascular endothelium and fibroblasts, with a contribution from immune cells, especially macrophages. Tissues and organs are affected by atrophy, fibrosis, or necrosis, which can severely impair their functions and lead to a loss of function.


No. Since the risk of radionecrosis remains life-long the affected tissues are at danger with the total radiation dose being the primary risk factor for the tissue involved, combined with other risk factors.


Adapting the preventive extraction of teeth to the risk zone of >50–60 Gy would allow for a more appropriate dental management: more aggressive in the >60 Gy zone and far less aggressive in the other areas of the jaw, improving the quality of life of these patients. The fewer extractions in highly irradiated areas, the lesser the risk for ORN.


The principal function of stem cells is to maintain tissue homeostasis including continuous regeneration and associated constant number of cells.


The answer is displayed in Fig. 5.29. In brief, CSC may have (1) Increased DNA repair capacity which allows them to handle IR-induced DNA DSBs; (2) Increased signaling networks that block IR-induced cell death including deficient pro-apoptotic signaling and increased anti-apoptotic signaling; (3) CSCs have slow proliferation and may therefore not be so sensitivity to IR-induced DNA damage.


Studies showed evidence of the existence of bidirectional effects of RT on the tumor and on the intestinal microbiota. In prospective clinical studies, a reduction of the fecal microbial diversity during and after pelvic RT was measured in patients suffering from intestinal complications. Also, RT-induced modification of microbiota diversity and composition can modify the host immune response and in turn the effectiveness of the anticancer treatment themselves including RT.


Radiotherapy (RT) relies on the effect of ionizing radiation (IR) to biological matter, i.e., cells. The radiation is transferring its energy to atoms and molecules present in the cells, which lie in the path of the radiation, and therefore ionizing them. These ionizations, i.e., the removal of electrons from the atom, lead to the breaking of chemical bonds in the molecules. If these ionizations occur in the cell nucleus, the DNA, carrier of the human genome, is damaged. In RT, the capability of radiation to damage the genome is exploited to kill tumor cells. The most important quantity to define the damage, which is caused, is the dose

 (6.1)i.e., the energy transferred from the ion to the matter (dE) by unit mass (dM). In general, one can say that the higher the dose, the larger the damage and the higher the probability of killing a cell. However, the same physical dose of different types of radiation can cause different damage in the cells. Various types of radiation are utilized for RT. These types of radiation can be distinguished by the so-called depth dose distribution, which is the dose which is transferred to matter along the path of radiation as shown in Fig. 6.1.

A line graph presents relative dose versus depth. Cobalt 60, 2 M V photons, and 250 M e V electrons rise before declining, while 15 M e V electrons, 250 M e V per u carbon, and 150 M e V protons rise and drop before plateauing, with 250 M e V electrons having the highest value at the endpoint.

Fig. 6.1
Comparison of the relative depth dose distribution of 15 MeV electrons (green), 250 MeV electrons (purple), 2 MeV photons (red), 150 MeV protons (dark blue), and 250 MeV/u carbon (turquoise) and cobalt 60 (orange)


A line graph presents relative dose versus depth. Cobalt 60, 2 M V photons, and 250 M e V electrons rise before declining, while 15 M e V electrons, 250 M e V per u carbon, and 150 M e V protons rise and drop before plateauing, with 250 M e V electrons having the highest value at the endpoint.


Electron radiation transfers most of its energy just after it interacts with matter, i.e., tissue, making it suitable for the treatment of tumors close to the skin. If one uses electrons with higher energy, such as the shown 250 MeV electrons, the dose peak can be shifted deeper into the tissue. However, this comes with the disadvantage that the maximum range is also longer, resulting in more dose to the normal tissue beyond the tumor. Furthermore, such electron beams are quite complicated to produce. For photon beams used in RT, the dose increases in the so-called build-up region until it reaches the maximal dose and then gradually decreases. The depth of the maximal dose can be a few μm (for kV beams, i.e., beams with particle energy in the kilovolt regime) or several mm or cm (for MV (megavolt) beams). In contrast to electrons and photons, particles such as protons or high linear energy transfer (LET) carbon ions show a totally different dose distribution depth. The ions deliver a low dose when entering tissue. With depth this transfer is slowly increasing, while the ion gets slower. With further energy loss and decreasing speed, the dose drastically increases and reaches a maximum just before the ion stops in the tissue. This unique dose distribution is called the Bragg curve in honor to the physicist William Henry Bragg, who discovered this behavior in 1904 [1]. To widen the treatment depth range, a spread-out Bragg peak (SOBP) is created by varying the energy of the incident proton beam. As a result, a uniform dose can be delivered to the tumor. The radiobiological impact of particles with high LET is higher compared to photons, and it increases dramatically in the distal edge and fall-off. The uncertainty in relative biological effectiveness (RBE) of ion beams is still a limitation in its clinical application and should be considered during the treatment planning as a part of the process leading to a robust treatment plan. A detailed description about the physical and biological interactions of radiation to biological matter and the consequences for the biological effect can be found in Chaps. 2 and 3.


Typical conventionally fractionated irradiation schemes use 2 Gy fractions, 5 fractions per week for 3–7 weeks, depending on the tumor type.

Alternative radiation schemes, i.e., either smaller or larger sized fractions, multiple fractions per day, or different overall treatment time should be based on the various biological processes and response characteristics of both the normal and malignant tissues in the exposed volume.


Typical conventionally fractionated irradiation schemes use 2 Gy fractions, 5 fractions per week for 3–7 weeks, depending on the tumor type.


Alternative radiation schemes, i.e., either smaller or larger sized fractions, multiple fractions per day, or different overall treatment time should be based on the various biological processes and response characteristics of both the normal and malignant tissues in the exposed volume.


When using radiation for cancer treatment purposes, the total radiation dose is generally applied in a regimen with multiple small fractions, aiming to reach tumor kill while sparing adjacent normal, healthy tissues, and organs. Most tumors are treated with a conventional fractionation regimen, which is characterized by daily fractions of 1.8–2 Gy, 5 days per week, for a duration of 3–7 weeks, reaching a total dose of 30–70 Gy. However, considering the radiation sensitivity and volume of the particular tumor type to be irradiated, as well as that of the normal tissue or organs at risk (OAR), an alternative irradiation regimen might be preferred. The use of an alternative radiation scheme should be motivated, either technically, e.g., by minimizing the volume of the normal tissue in the radiation field by using precision RT or on the basis of the biological characteristics of the malignant tissue, i.e., the 6R’s (see Chap. 5). Apart from technical and radiobiological arguments, department logistics as well as patients’ condition or patients’ comfort might justify the choice of an alternative radiation treatment (Box 6.1). Typical characteristics of fractionation regimens and their radiobiological rationale are presented in Table 6.1 and discussed below.Table 6.1
Characteristics of radiotherapy treatment regimen and involved radiobiological processes. (Reproduced with permission from [2])

Radiation treatment regimen

Conventional fractionation

Hyperfractionation

Accelerated fractionation

Hypofractionation

SBRT and SRS

Total dose (Gy)

70

≥70

<70

<70

<30

Fraction size (Gy)

1.8–2

<1.8

≥2

Mostly 2.5–10

Mostly ~12–25

Number of fractions per day

1

2–3

1

1

1

Treatment (days per week)

5

5

6

≤5

1 or a few

Overall treatment time (weeks)

7

7

Up to ~5

Up to ~5

–

Radiobiological reasoning—note the 6 Rs of Radiobiology

Normal tissue sparing via Repair and Repopulation. Tumor control via Redistribution and Reoxygenation. Reactivation of the immune response.

Exploitation of differences in Radiosensitivity and Repair and—kinetics between normal and tumor cells. Reactivation of the immune response.

Overcoming tumor cell Repopulation. Reactivation of the immune response.

Overcoming tumor cell Repopulation.

Overcoming tumor cell Repopulation.


The relationship between the number of fractions and the total dose for a clinical radiation regimen is presented in Fig. 6.2.

A graph of total doses versus number of fractions. Radiosurgery has a vertical rise from (1, 10) to (1, 25), hypo-fractionation rises from (2, 15) to (10, 30), conventional fractionation rises from (8, 11) to (40, 80), and hyperfractionation increases from (30, 45) to (80, 80). Data are estimated.

Fig. 6.2
Fractionation regimen used in clinical practice. (Reproduced with permission from [3])


A graph of total doses versus number of fractions. Radiosurgery has a vertical rise from (1, 10) to (1, 25), hypo-fractionation rises from (2, 15) to (10, 30), conventional fractionation rises from (8, 11) to (40, 80), and hyperfractionation increases from (30, 45) to (80, 80). Data are estimated.


The biological rationale of hyperfractionation is the advantage of application of multiple small-sized fractions compared with conventional 2 Gy fractions to further spare the normal tissues relative to the malignant tissues. Because of the higher total dose, hyperfractionation could increase the tumor control probability. To limit the duration of the overall treatment time, generally 2–3 fractions per day, typically ~1.4 Gy, separated 4–6 h between the fractions are given. Some hyperfractionation clinical trials, however, showed an increase in late normal tissue side effects, which has been ascribed to the short time interval between fractions for complete repair of sublethal DNA damages, since late-responding tissues do have long repair half times in the order of 2–4 h. Additionally, hyperfractionation puts a heavy logistical burden on the RT department and the patient, especially in children who may need anesthesia.


The rationale of both hypo- and accelerated fractionation strategies can be found in shortening the overall treatment time to anticipate tumor cell proliferation/repopulation. Generally, fractions larger than 2 Gy fractions are applied with few fractions per week, allowing to shorten the overall treatment duration with a few weeks versus conventional regimens. The hypofractionation approach has become feasible because of currently available precision radiation techniques and technology, with optimized radiation dose distribution.


The drawback of using high fraction sizes, the rationale, pro- and contra biological arguments, is discussed in the next Sect. 6.3.


The term accelerated fractionation applies to the use of multiple fractions per day, or increasing the number of treatment days per week (e.g., continue radiation during the weekend) to deliver a higher average total radiation dose than conventionally used. Hence, the overall treatment time of accelerated regimen is reduced. Often, both hypo- and hyperfractionated irradiation fit in this definition of accelerated fractionation. A typical example is the Continuous Hyperfractionated Accelerated RadioTherapy (CHART) treatment scheme, with 36 fractions of 1.5 Gy, total dose of 54 Gy in 12 days. In that scheme three fractions of 1.5 Gy were applied per day, with an interfraction time interval of 6 h, for 12 days, including the weekend. Details regarding the CHART clinical trials and outcomes are available in the literature. In particular, head and neck cancer patients with high epidermal growth factor receptor (EGFR) expressing tumors benefited from CHART [4].


Historically, the term stereotactic radiotherapy was used for a type of external RT of the brain that uses dedicated equipment being a stereotactic frame fixed to the head with screws just penetrating the outer part of the skull. This frame was used to immobilize the head, position the patient, and create a stereotactic “space” with a coordinate system that allows target definition in an X-, Y-, and Z-axis. The term stereotactic radiosurgery (SRS) is used when a single fraction of stereotactically guided conformal irradiation is delivered to a coordinate-defined target. More modern fixation systems no longer require the placement of an invasive frame, but make use of advanced thermoplastic masks combined with position verification and adaptation systems of the treatment machine’s table. Different delivery systems can be used for radiosurgery: the originally SRS-dedicated GammaKnife system (using 201 small 60-Co sources) or linac-based systems (linear accelerator, CyberKnife, Tomotherapy).


Typical indications are single (or up to 3–5) brain metastases, meningiomas, acoustic neuromas, or arteriovenous malformations, all smaller than 3 cm in diameter. Depending on the indication, doses range between 12 Gy (benign lesions) and 20–25 Gy (metastases). Some centers also use radiosurgery to treat benign conditions like epilepsy and trigeminal neuralgia, requiring doses of 20–25 Gy up to 60–80 Gy, respectively.


The appearance of the effect of radiosurgery usually takes several months and may be accompanied by an inflammatory reaction that mimics tumor growth in the first 1–3 years. In some cases, overt brain radionecrosis may develop, requiring treatment with steroids or rarely the need for surgical removal of the affected area (see also Chap. 5) (Box 6.2).


Hypofractionation is the use of radiation dose fractions considerably larger than the conventional fraction size of 2 Gy.

Hypofractionation could be beneficial over conventional fractionation because of precision RT together with specific biological phenomena such as hypoxia and sensitivity to dose fractionation of both the tumor target volume and organs at risk.


Hypofractionation is the use of radiation dose fractions considerably larger than the conventional fraction size of 2 Gy.


Hypofractionation could be beneficial over conventional fractionation because of precision RT together with specific biological phenomena such as hypoxia and sensitivity to dose fractionation of both the tumor target volume and organs at risk.


Fractionated RT, using multiple small-sized fractions of 1.8–2 Gy, is the standard treatment of cancer patients. Over many decades, large evidence has been obtained from experimental studies in vitro or in vivo and later in clinical studies regarding the biological rationale of fractionated irradiation. Abundant evidence exists on the differential effect of fractionation between late-responding normal tissues and early responding normal tissues or tumors. Most normal tissues and organs benefit from fractionated RT, meaning that they can tolerate a higher total dose, while tumors are only slightly spared by dose fractionation. The smaller the fraction size—taking the overall treatment time allowing tumor cell repopulation into account—the wider the therapeutic window. Having learned that fractionation is a great method to spare normal tissues while keeping tumor control equal, hypofractionation, i.e., the use of dose fractions substantially larger than conventional 2 Gy fractions (see also Chap. 5) sounds not as a good idea. However, for two main reasons, hypofractionation has gained importance in radiation oncology: α


(1) Clinical data have shown that some tumor types like prostate carcinoma, malignant melanoma, and liposarcoma, are almost as sensitive to fractionated irradiation as their surrounding normal tissues. Such tumors can tolerate a higher biological dose than formerly thought when treated with 2 Gy fractions, hence behaving like late-responding normal tissues and thus are relatively spared by fractionation. Indeed, these tumor types are characterized with a low 〈α/β value of ~1–2 Gy in the Linear Quadratic (LQ) model. Breast and esophageal cancers also have α/β values close to those for normal tissues, in the order of ~5 Gy. (2) With the implementation of high precision RT techniques, highly conformal 3D dose distributions to the target volume can be obtained, with minimal radiation exposure to adjacent critical normal tissues and OAR. The HyTEC initiative (Hy dose per fraction, hypofractionated Treatment Effects in the Clinic) is to systemically pool published peer-reviewed clinical data to further define dose, volume, and outcome estimates for both normal tissue complication probability and tumor control [5] for SRS and SBRT, where single high radiation doses are common practice. Under certain conditions, like high conformity of RT with steep dose gradients toward the surrounding normal tissues, hypofractionation could be beneficial over conventional fractionation. In this section, the radiobiological pro- and contra arguments of hypofractionation, listed in Table 6.2 are discussed.Table 6.2
Hypofractionation: pro and contra biological arguments

Pros

• If α/β ratio tumor < α/β ratio normal tissue

• Only if small normal tissue/OAR volumes are exposed: high conformity RT

• Direct vascular injury

• Shorter overall time: beneficial in case of rapid proliferating tumors

• If the onset of accelerated tumor cell repopulation is faster using high-dose fractions, dose reduction without loss of tumor control could be achieved while diminishing late toxicity

• ”Biological dose” escalation, which might result in better tumor control

• Activation of the immune response to attack tumor cells inside the irradiated volume and at distance, the abscopal effect

• Lower probability of induction of secondary tumors

Cons

• Mostly, α/β ratio tumor > α/β ratio normal tissue

• High-dose fractions are detrimental for normal tissues: higher probability of normal tissue complications, unless dose gradients are steep and the irradiated volume small

• No benefit from sensitization of hypoxic tumor cells via reoxygenation between fractions

• Radiosensitizing agents are potentially less effective when combined with high-dose fractions


The validity of the LQ model at high fraction sizes above approximately 6 Gy is questionable, and alternative radiobiological models are proposed. However, a strong pro-argument was derived from clinical data from non-small cell lung cancer patients treated with SBRT, either with a single dose or hypofractionated with 3–8 fractions. From the study [6], it was evident that the clinically observed increase in tumor could be ascribed to radiation dose escalation, i.e., an increased Biologically Effective Dose (BED) according to the LQ equation. BED values were calculated for the various hypofractionation schemes including SBRT fraction sizes of 22 Gy. No adaptation or correction was made when using the conventional LQ model. The analysis showed a clear correlation between treatment outcome and the BED, even at extreme high BED values. Hence, there is still a discrepancy between theoretical and experimental validity of the LQ model. However, since the model describes the clinical data on tumor control over a wide range of dose, fraction sizes, and treatment durations [6], it might still be valid in predicting RT outcomes in certain conditions.


Hypoxia is a state of reduced oxygen availability or decreased oxygen partial pressure below a critical threshold (generally at pO2 of 2.5 or 5 mmHg). The Oxygen Enhancement Ratio (OER) is around 3 for most cells: for sterilization of hypoxic cells, a three times higher irradiation dose is required than for normoxic cells. Hence, hypoxia can cause resistance to RT, which has been observed in many tumor types. Information about the role of oxygen in RT, the OER, and related radiation sensitivity is given in Chap. 5.


In fractionated RT, during the time interval between daily applied irradiation fractions and during the full course of RT, hypoxic cells can be re-oxygenated and become more sensitive to the next irradiation dose (see Chap. 5). If reoxygenation is efficient between dose fractions, the presence of hypoxic cells does not have a significant effect on the outcome of a multi-fractionation scheme. In a hypofractionation regimen, the time period to obtain full reoxygenation of hypoxic tumor cells might be too short. Animal data on the kinetics of reoxygenation of different tumor types demonstrated that full reoxygenation takes about 72 h [7]. Also, preclinical data and radiobiological modeling studies have demonstrated that tumor hypoxia is a greater detrimental factor for single dose treatments than for repeated conventional fraction sizes. To fully exploit reoxygenation between fractions, 6–8 fractions might be optimal, separated in a time frame of 72 h [7]. However, there are also advantages to large high-dose fractions of ~10 Gy. Relatively radioresistant hypoxic cells might be directly sterilized and vascular endothelial cells might be injured. Since one endothelial cell is subtending about 2000 tumor cells, direct vascular damage might largely contribute to tumor cell kill in hypofractionated RT [8].


Tumor cell repopulation refers to an increase in the number of cells as a result of proliferation of surviving clonogenic tumor cells (see Chap. 5). Accelerated repopulation of tumor cells during the course of RT is starting after a lag period of ~4 weeks. One strategy discussed here is to cope with tumor cell repopulation by limiting the overall treatment time for fast repopulating tumors using a small number of higher sized fractions. As a consequence of high fraction sizes, the total irradiation dose should be reduced to overcome an increase in late normal tissue toxicity. Hypofractionation allows shortening of the overall treatment time, which might be more effective than long duration conventional fractionation in the treatment of rapidly proliferating tumors. However, care should be taken when using too short schedules, because they could lead to an increase in acute toxicity.


To be noticed is the large LQ model based analysis of the tumor control probability (TCP) from randomized trials on in total 7283 head and neck cancer (HNC) patients, featuring wide ranges of doses, times, and fractionation schemes [9]. In the analysis, two different LQ based models were used, assuming a dose-independent (DI) and a dose-dependent (DD) acceleration of tumor cell repopulation. Accelerated Repopulation (AR) was assumed to be triggered by the level of tumor cell killing, with other words, to begin at a time when the surviving fraction of the tumor clonogenic cells falls below a critical value. This starting point of AR of tumor cells was assumed to be dose-dependent and therefore reached at an earlier time point after high fraction sizes than after low fraction sizes. The DD model of AR provided significantly improved descriptions of a wide range of randomized clinical data, relative to the standard DI model. This preferred DD model predicted that, for currently used HNC fractionation regimen, the last 5 fractions did not increase TCP, but simply compensated for increased accelerated repopulation (Fig. 6.3). A hypofractionation scheme of 25 fractions of 2.4 Gy (total dose of 60 Gy in 33 days) was found to be superior over 35 fractions of 2 Gy (total dose of 70 Gy in 47 days), both regarding the probability of tumor control and late normal tissue complications. In a next study, on basis of radiobiological model calculations with the DD model, an optimized hypofractionated treatment scheme for HNC patients was proposed with 18 daily fractions of 3 Gy, i.e., a total dose of 54 Gy in 24 days [10].

A line graph depicts that T C P of 2.4, 2, and 1.8 gray per f x is at around 19 to 28 on X-axis and 0.5 T C P. The N T C P sub late for 2.4, 2, and 1.8 gray per f x is at around 29 to 40 on X-axis and 0.25 N T C P sub late, where 2 and 1.8 gray per f x are below the N T C P sub late values.

Fig. 6.3
Predicted TCP values by the DD model (solid curves) as a function of the number of fractions delivered, for stage T1/2 head and neck cancer (HNC) patients. Dose per fraction (fx): 1.8 Gy (blue), 2.0 Gy (red) or 2.4 Gy (black), administered daily, 5 fx/week. NTCP late predictions for late toxicity (dashed curves) were made with the standard LQ model normalized to a 13.1% value (grade 3–5 late toxicity at 5 years) for 35 × 2 Gy fractions. The solid circles represent current standard treatment regimens. Thus, the final week of 5 fractions could be eliminated without compromising TCP, but resulting in significantly decreased late sequelae due to the lower total dose. (Reproduced with permission from [9])


A line graph depicts that T C P of 2.4, 2, and 1.8 gray per f x is at around 19 to 28 on X-axis and 0.5 T C P. The N T C P sub late for 2.4, 2, and 1.8 gray per f x is at around 29 to 40 on X-axis and 0.25 N T C P sub late, where 2 and 1.8 gray per f x are below the N T C P sub late values.


Radiation has long been thought to suppress the immune system, and total body irradiation is up to date applied for that reason. Studies in the past have demonstrated that local irradiation not only had a direct effect on tumor cells in the treatment volume, but also a systemic effect on the immune system (see Chap. 5). Therewith, local irradiation can induce abscopal effects, i.e., the immunological rejection of tumors or metastatic lesions distant from the irradiated site (see Chap. 5). Different radiation treatment schemes regarding the total dose and fraction size were shown to have diverse effects on the immune response, with a subsequent effect on combination therapy with immune-modulating agents [11]. The abscopal effect might best be exploited using 3–5 fractions of <10 Gy [12]. The immune-editing effects of radiation will probably also benefit from repeated intermediate high fraction sizes [13].


Hyperthermia and chemotherapeutic agents, e.g., cisplatin, gemcitabine, temozolomide and targeted drugs such as inhibitors of PARP-1 and EGFR may potentiate the effects of radiation. The LQ model is a very suitable tool to quantify the effects of the combination of irradiation and radiosensitizers, which can be either additive or synergistic. The most commonly used test to study interaction between irradiation and modulating agents is the clonogenic assay (see Chap. 3), being the golden standard test for determination of cell survival. LQ model analysis of the typical shaped cell survival curve allows to separately establish the effect of combination therapy on the 〈 and ® α/β parameters of the model. The parameter 〈 α determines the effectiveness at low doses, on the initial slope of the cell survival curve, while the parameter ® β represents the increasing contribution from cumulative damage thought to be due to interaction of two or more separate lesions. Preclinical studies have shown that most radiosensitizing agents cause an increase of the α-parameter, while the β-parameter is rarely affected [14]. With conventional small-sized dose fractions, the value of the α-parameter therefore determines to a large extent the effectiveness of combination treatments. The interaction between chemotherapeutic agents and high-dose irradiation fractions will be minimal. For clinical hypofractionation regimen, it is to be expected that effects of radiosensitizing agents are smaller than when combined with conventional fractionation regimen.


Long-term follow-up studies that address carcinogenic effects of fractionated high-dose RT describe the incidence of secondary malignancies, type of induced cancers, latency time, risk period as well as the shape of the dose–risk relationship curve. The dose–risk curve following curative RT is organ specific and is either linear, plateau, or bell-shaped. Radiobiological—LQ model based—calculations for estimation of the cancer risk following exposure to irradiation showed that both carcinoma and sarcoma risk decreased with increasing fraction size [9]. Via model calculations, it has been estimated that hypofractionated RT has the potential to reduce the second cancer risk [15].


The basic principle of SBRT is to deliver a tumoricidal dose to the target in a few fractions and minimize dose to normal tissue using highly conformal radiation.

The high-dose per fraction used in SBRT can cause vascular damage through endothelial cell apoptosis and stem cell death.

SBRT is commonly used in treatment of tumors in lung, liver, spine, prostate, and pancreas.


The basic principle of SBRT is to deliver a tumoricidal dose to the target in a few fractions and minimize dose to normal tissue using highly conformal radiation.


The high-dose per fraction used in SBRT can cause vascular damage through endothelial cell apoptosis and stem cell death.


SBRT is commonly used in treatment of tumors in lung, liver, spine, prostate, and pancreas.


Stereotactic Body Radiation Therapy (SBRT) also known as Stereotactic Ablative Radiotherapy   (SABR) refers to stereotactic image-guided delivery of highly conformal radiation to a small extracranial target using high-dose per fraction delivered in 1–5 fractions with a tumor-ablative intent [16]. The key requirements for SBRT are small well-circumscribed tumors (maximum cross-sectional diameter up to 5 cm), stringent patient immobilization, small or no margin for beam penumbra, high conformality and accurate radiation delivery as well as image guidance for geometric verification [17].


The aim of SBRT is to deliver tumoricidal dose to target in a few fractions and minimize dose to normal tissue by delivering highly conformal radiation under image guidance. A high-dose per fraction is more tumoricidal than conventional fractionation dose by its direct damaging action on tumor cells [6]. As discussed in Chap. 5 and earlier in this chapter, the effect on late-responding normal tissues is greater with high-dose per fraction. Few malignancies such as prostate cancer have low α/β values in the range of 1.5–3 Gy and show high sensitivity to fractionation (similar to late-responding normal tissues). In such malignancies, hypofractionation leads to better therapeutic benefit. On the other hand, delivering high-dose per fraction can increase toxicity in acute-responding tissues(see Chap. 5). To minimize this, a highly focused and conformal dose is delivered to the tumor with a steep dose gradient. It is achieved by reducing planned target volume (PTV) margins under image guidance, using multiple non-coplanar beams with careful treatment planning, and by delivering the total dose in two to five fractions (2–3 fractions per week) [7].


As discussed in Chap. 5, the bigger the tumor size the more is the hypoxic component and vice-versa. The advantage of reoxygenation seen during conventional fractionation is compensated in hypofractionated SBRT by selectively treating small tumors, which are relatively well oxygenated with a little hypoxic component. Furthermore, the hypoxic cells in tumors are depopulated by the direct damaging effect of large doses per fraction [6]. The same effect is responsible for overcoming the disadvantage of lack of reassortment of tumor cells to sensitive phases of cell cycle during fractionation. The high-dose per fraction counteracts the differences in radiosensitivity of cells in different phases of cell cycle by causing cell cycle arrest and interphase death in all phases (see Chap. 3).


Unlike conventional fractionation RT, owing to the short overall treatment time, tumor cell repopulation and interfraction repair of sublethal damage do not play a major role during SBRT (see Sect. 6.3). This is beneficial in terms of tumor control but detrimental to normal tissues. However, when the treatment time of an individual fraction is prolonged for more than half an hour, intrafraction repair of some sublethal damage in rapidly proliferating tumor cells may occur [7]. However, such longer fraction treatment time and faster intrafraction repair result in greater loss of BED [18]. This can be overcome by increasing the dose rate with use of flattening filter free (FFF) beams.


It is postulated that the radiobiologic effect of SBRT also depends on two other mechanisms. One is the vascular damage due to endothelial cell apoptosis caused by high-dose per fraction. It has been reported that this occurs due to the structural abnormalities of tumor vessels that are dilated, tortuous, elongated and have a thin basement membrane [19]. The second mechanism is through radiation-induced immunologic responses. The strong T-cell response triggered after exposure to high-dose per fraction RT enhances cytotoxic effects [12]. In addition, SBRT when combined with immune checkpoint inhibitors, i.e., Programmed Cell Death Protein-1/Programmed Cell Death Ligand-1 (PD-1/PD-L1) targeting antibodies, e.g., pembrolizumab or cytotoxic T-lymphocyte-associated protein-4 (CTLA4) antibodies, e.g., ipilimumab has shown to trigger an immunologic response that produces an abscopal effect [12] as described in Chap. 5.


Conventional fractionation RT is modelled by the LQ model cell survival curve but at higher dose per fraction, it is thought that LQ model overestimates the effects of radiation [20]. Therefore, alternative radiobiological models like universal survival curve (USC) were proposed. Instead of the BED in the LQ model, USC calculates the standard effective dose (SED) which is the total dose administered in 2 Gy per fraction to produce the same effect [21]. There are arguments that the LQ model still holds good till a certain level of dose per fraction.


The RT treatment planning for SBRT involves various steps allowing proper delivery of SBRT. After appropriate patient selection, VacLoc bags are used for stringent patient immobilization and setup. The next step is to acquire treatment planning images using computed tomography (CT)/magnetic resonance (MR)/18F-fluorodeoxyglucose (18FDG) positron emission tomography (PET) simulator with patient setup in treatment position with immobilization devices [22]. Usually, images are taken in 1–3 mm slice thickness and scan length extends at least 5–10 cm superior and inferior beyond RT treatment field borders for coplanar beams and 15 cm for non-coplanar beams [22]. For tumors in the thorax and upper abdomen, respiration-induced organ and tumor motion may be an issue. Therefore, motion management strategies are utilized while treating these tumors (Table 6.3).Table 6.3
Motion management methods in radiotherapy. Adapted from [23]

Motion management method

Rationale

Free breathing technique
• Based on 4D CT

Generating of internal target volume (ITV) which covers the full range of tumor motion

Motion dampening techniques
• Abdominal compression using paddle, pneumatic belts, etc.
• Breath holding technique such as deep inspiratory breath hold (DIBH), active breath coordinator (ABC)

Limiting the diaphragm expansion and tumor motion by devices or by controlling breathing

Respiratory gating technique
• Internal gating using internal surrogates for tumor motion
• External gating using external devices to monitor respiration, a surrogate for tumor motion [such as real-time position management (RPM) system]

Treating the tumor only in discrete phases of respiratory cycle

Real-time tumor tracking
• ExacTrac (Kilo-Voltage image-based system)
• Cyberknife (Kilo-Voltage image-based robotic system)
• Calypso (radiofrequency localization system)

Intrafraction tumor localization and repositioning of treatment beam toward the target


For SBRT, the target volumes and OARs are contoured as per the The International Commission on Radiation Units and Measurements (ICRU) 50 and 62 reports. The RT treatment planning is based on the American Association of Physicists in Medicine Task Group (AAPM TG) 101 recommendations [22]. Unlike uniform dose prescription in conventional RT, in SBRT, dose is prescribed to the low isodoses (e.g., 80% isodose line) with small or no margin for beam penumbra to improve sharp dose falloff outside the target volume, thereby reducing dose to adjacent normal tissues. Hence, dose heterogeneities and hotspots occurring within the target volumes are accepted in SBRT, unlike traditional RT where homogeneous dose distribution is desired. For obtaining an optimal SBRT treatment plan with better target dose conformality as well as isotropic dose gradient, multiple planar or non-coplanar treatment beams are used, and treatment is delivered using multileaf collimator (MLC) of width 5 mm or less [24]. The calculation grid size used in the treatment planning system (TPS) affects the accuracy of calculated dose distribution. Hence, an isotropic grid size of 2 mm or finer is recommended.


The normal tissue tolerances derived from conventional fractionation studies do not apply to the high fractional doses delivered in SBRT. Therefore, bioeffect measures such as BED, normalized total dose (NTD), and equivalent uniform dose (EUD) are calculated to evaluate the effectiveness and safety of SBRT dose distributions [18, 25, 26]. BED and NTD are used to determine the biologic effectiveness of different dose fractionation schedules, whereas EUD is applied to rank different treatment plans based on their expected tumor effect [22]. The normal tissue tolerances for different SBRT fractionation schemes are still evolving. Apart from the traditional metrics reported in a RT treatment plan, SBRT plans must specify conformity index (CI = prescription isodose volume/PTV), heterogeneity index (HI = highest dose received by 5% of PTV/lowest dose received by 95% of PTV), and intermediate dose spillage (D50% = volume of 50% of prescription isodose curve/PTV or D2 cm = maximum dose at 2 cm from PTV) [22].


Recent advances in RT techniques and machines facilitate delivery of SBRT. Volumetric modulated arc therapy (VMAT) is an advanced RT technique that delivers radiation dose continuously in arcs where gantry rotation speed, treatment aperture, and dose rate vary simultaneously [27]. The newer linear accelerators (LINAC) capable of delivering flattening filter free (FFF) beams increases dose rate from 300 to 600 monitor units (MU)/min to 1200 to 2400 MU/min. Thereby, the time required to deliver the large number of MUs needed for high-dose per fraction in SBRT is decreased [28]. The FFF beams also have other advantages such as less off-axis beam hardening, less photon head scatter, less field size dependence, and less leakage outside beam collimators [29].


The clinical application of SBRT gained much interest over the past two decades. SBRT is commonly used in treatment of malignant tumors in lung, liver, pancreas, prostate, kidney, and spine (Table 6.4). It is also widely recommended for treating oligometastatic disease that has spread to liver, lung, bone, adrenals, or lymph nodes. Its clinical utility in breast cancer as well as head and neck cancers is being investigated. The common cancer subsites and clinical scenarios where SBRT has a role are summarized in Table 6.4.Table 6.4
Clinical application of SBRT at various cancer subsites. (Adapted from [30])

Cancer subsite

Indications

Lung

• Early-stage inoperable non-small cell lung cancer (NSCLC)—T1, T2, usually <5 cm, N0

• Boost following definitive chemoradiation for locally advanced NSCLC

• Recurrence/re-irradiation

• Oligometastatic disease

Liver

• Hepatocellular carcinoma (HCC)—unresectable/medically inoperable patients, unsuitable/refractory to radiofrequency ablation, or transarterial chemoembolization

• Oligometastatic disease

• Portal vein tumor thrombosis (PVTT)

Pancreas

• Locally advanced unresectable disease—radical SBRT/SBRT boost following conventional fractionated RT

• Borderline resectable disease—poor performance status

• Re-irradiation

Prostate

• Low risk—SBRT monotherapy

• Low volume intermediate risk—SBRT monotherapy/boost

• High/very high/node positive disease—SBRT boost

• Residual disease after RT—salvage/re-irradiation

Spine metastases

• Primary spinal cord neoplasms: medically inoperable/adjuvant/salvage SBRT

• Spine metastases: limited disease, life expectancy more than 3 months, medically inoperable

• Re-irradiation

Kidney

• Unilateral, medically inoperable disease

• Bilateral/recurrent contralateral disease

Head and neck

• Re-irradiation: single, small volume recurrence, node negative

• SBRT boost following definitive chemoradiation in locally advanced nasopharyngeal cancer

• Palliation


Numerous phase 1/2 clinical trials have shown encouraging results regarding safety and efficacy of SBRT in different types and stages of cancer [31]. However, the major drawbacks of these trials are the adoption of variable radiation dose, fractionation schemes, and limited number of treated patients. Therefore, randomized phase 3 trial results on clinical outcomes and long-term toxicities are needed to recommend SBRT as the standard of care.


FLASH RT is emerging as a new tool for sparing normal tissue from ablative doses, as it is able to protect normal tissue while maintaining antitumor ablation [32]. FLASH RT targets tumors with ultra-high dose rates (>100 Gy/s) to reduce the administration time from minutes to less than 200 ms, as this is key to sparing normal tissue [32]. The biological mechanism behind the sparing of normal tissue, known as the “FLASH effect,” is based on the following hypothesis:


The oxygen depletion hypothesis describes the rapid consumption of local oxygen by ultra-high dose rates resulting in transient radioprotection and transient local tissue hypoxia. It is known that hypoxic tissue is more radioresistant because the low concentration of molecular oxygen during radiation-induced DNA damage allows DNA repair, while in the presence of molecular oxygen, the DNA lesion binds to molecular oxygen and produces peroxyl radicals leading to the degradation of nucleic acids and lipids [32]. Therefore the oxygen depletion hypothesis suggests that FLASH RT may be able to prevent or reduce Reactive Oxygen Species (ROS)-mediated cellular damage [33]. However, this hypothesis has recently been challenged as studies showed that FLASH RT does not significantly decrease tissue oxygen concentration compared with conventional RT when measured with a solid optical sensor [34]. The differential ROS-damage recovery hypothesis describes that normal and tumor cells have different capabilities to “detoxify” themselves from ROS [32]. According to this hypothesis, normal cells have a greater capacity to eliminate peroxidized compounds compared to tumors. This would explain why tumors exposed to FLASH RT respond equally under either physiologic or hypoxic conditions.


Preclinical studies of FLASH RT confirmed its efficacy in various animal models (mice, pigs, cats, zebrafish) as well as in different tissues (lung, brain, intestine, skin) and led to the first use of FLASH RT in the clinic. One example is a man that had a cutaneous lymphoma that had spread over the entire surface of his skin. He had already received several sessions of conventional RT and the skin’s tolerance was exhausted. FLASH RT was indicated as a way to spare the skin while achieving equivalent tumor control to conventional RT. The lesion received 15 Gy as a single dose in 90 ms. The treatment was successful, with no skin toxicity and complete ablation of the tumor as reported 6 months after treatment [33] (Fig. 6.4).

3 photos of a treated lesion. A displays day 0 where P T V delineated limits around the lesion at 4 inches in diameter. B is the lesion after 3 weeks, which presents the lesion healing and decreasing in diameter. C is the lesion after 5 months where 4 arrows denote the fully healed lesion on the skin.

Fig. 6.4
Temporal evolution of the treated lesion: (a) before treatment with the limits of the PTV delineated in black; (b) at 3 weeks, at the peak of the skin reaction (grade 1 epithelitis NCI-CTCAE v 5.0); (c) at 5 months. (Reproduced with permission from [33])


3 photos of a treated lesion. A displays day 0 where P T V delineated limits around the lesion at 4 inches in diameter. B is the lesion after 3 weeks, which presents the lesion healing and decreasing in diameter. C is the lesion after 5 months where 4 arrows denote the fully healed lesion on the skin.


Apart from this successful case, the current use of FLASH RT in the clinic is limited to enrolling participants in clinical trials. However, in the near future patients with tumors in organs described as late-responding tissues would be good candidates for FLASH RT, as preclinical studies have shown that ultra-high dose rates dramatically reduce the incidence of pulmonary fibrosis and neurocognitive impairment. Patients with painful bone metastases in the extremities would also be good candidates to investigate the feasibility and safety of FLASH RT.


Before starting treatment with FLASH RT, one needs to be aware of the importance of the radiation source, the quality of the radiation, and the physical parameters of the beam.
Radiation sources are currently standardized to deliver dose rates of about 0.1–0.4 Gy/s in 2 Gy daily fractions. FLASH RT, on the other hand, relies on facilities capable of delivering ultra-high dose rates in large doses in one or more pulses over microseconds. This capability has only been achieved in a few places by modifying clinical devices to deliver photons, protons, or electrons. There are large irradiation facilities such as the European Synchrotron that can deliver X-rays at dose rates of up to 16,000 Gy/s [35]. However, clinical trials using synchrotrons are not yet an option.

The quality of the radiation must also be considered, as most research on FLASH RT has been done with electrons. FLASH RT with electrons has been shown to be effective in at least one human patient, while FLASH RT with photons and protons is still in the preclinical phase. Regardless of preclinical or clinical status, the quality of radiation needs to be considered to account for (1) the impact of the linear energy transfer on the mechanisms behind the FLASH effect and (2) the use of a continuous beam in the case of protons versus a pulsed beam in the case of electrons and synchrotron X-rays [32].

The physical parameters of FLASH RT need to be defined much more precisely than in conventional RT. A team of experts from Switzerland has suggested that the number of pulses, the instantaneous intra-pulse dose rate (≥104 Gy/s), and the total exposure time (<100 ms) should be included in all studies of FLASH RT [33, 35]. These parameters mostly derive from FLASH RT with electrons and therefore should be carefully applied to FLASH RT with photons or protons.


Radiation sources are currently standardized to deliver dose rates of about 0.1–0.4 Gy/s in 2 Gy daily fractions. FLASH RT, on the other hand, relies on facilities capable of delivering ultra-high dose rates in large doses in one or more pulses over microseconds. This capability has only been achieved in a few places by modifying clinical devices to deliver photons, protons, or electrons. There are large irradiation facilities such as the European Synchrotron that can deliver X-rays at dose rates of up to 16,000 Gy/s [35]. However, clinical trials using synchrotrons are not yet an option.


The quality of the radiation must also be considered, as most research on FLASH RT has been done with electrons. FLASH RT with electrons has been shown to be effective in at least one human patient, while FLASH RT with photons and protons is still in the preclinical phase. Regardless of preclinical or clinical status, the quality of radiation needs to be considered to account for (1) the impact of the linear energy transfer on the mechanisms behind the FLASH effect and (2) the use of a continuous beam in the case of protons versus a pulsed beam in the case of electrons and synchrotron X-rays [32].


The physical parameters of FLASH RT need to be defined much more precisely than in conventional RT. A team of experts from Switzerland has suggested that the number of pulses, the instantaneous intra-pulse dose rate (≥104 Gy/s), and the total exposure time (<100 ms) should be included in all studies of FLASH RT [33, 35]. These parameters mostly derive from FLASH RT with electrons and therefore should be carefully applied to FLASH RT with photons or protons.


In summary, FLASH RT is not yet actively used in the clinic. However, it is now clear that FLASH RT requires very precise management of the radiation quality and beam.


The patient population that would benefit from clinical trials with FLASH RT are those who still have radioresistant tumors for which even the most sophisticated intensity-modulated RT has not been successful. In this context, FLASH RT could be combined with immunotherapy to achieve a synergistic effect. This strategy is supported by the immune hypothesis, which builds on the oxygen depletion hypothesis by proposing that FLASH RT protects circulating and resident immune cells that are normally radiosensitive. This radiosensitivity is particularly important when radiation fields affect bone marrow and/or circulating blood cells [36], as doses as low as 0.5 Gy can reduce lymphocyte survival by 90% [37]. Therefore, FLASH RT has the potential to spare immune cells from the radiation dose and allow recognition of tumor antigens to potentially trigger an antitumor immune response [33].


The basic principle of BNCT is selective targeting of tumor cells while sparing normal tissues using boron-carrier agents and low-energy neutrons.

Three boron-delivery agents approved for human clinical trials are sodium borocaptate (BSH), boronophenylalanine (BPA), and sodium decaborane (GB-10).

The clinical trials on BNCT were conducted predominantly in brain malignancies, malignant melanoma, and recurrent head and neck cancers.


The basic principle of BNCT is selective targeting of tumor cells while sparing normal tissues using boron-carrier agents and low-energy neutrons.


Three boron-delivery agents approved for human clinical trials are sodium borocaptate (BSH), boronophenylalanine (BPA), and sodium decaborane (GB-10).


The clinical trials on BNCT were conducted predominantly in brain malignancies, malignant melanoma, and recurrent head and neck cancers.


The basic principle of BNCT is to deliver a boron-containing drug that selectively attaches to cancer cells and has a large cross-section capable of capturing a low-energy neutron. After administration of the boron-containing compound, the patient is exposed to a beam of thermal or epithermal neutrons. The compound goes into an excited state after neutron capture and undergoes a nuclear fission reaction to produce densely ionizing alpha particles. The range of these high LET particles in tissues is limited around 7.6 μm on an average (range 5–9 μm) [38, 39]. Therefore, these particles lead to localized release of a substantial amount of energy within the tumor, sparing the normal tissues. The boron neutron chemical reaction is as follows:

 (6.2)


A photon of 0.48 MeV is released in most of the fission events which is useful for monitoring the reaction and has little significance in terms of cell killing [40]. Similarly, the radiobiologic effect of the low-energy thermal neutrons themselves is little.


The success of BNCT largely depends on the properties of the boron compound used. An ideal boron compound should be non-toxic, have a high absolute boron concentration in tumors, have high specificity for malignant cells, and accumulate in low concentrations in adjacent normal tissues and blood [40]. To summarize, an ideal boron-carrier compound should have a high tumor-to-normal tissue ratio (around 3–4:1) [41].


Based on the molecular weight, there are two classes of boron compounds such as low-molecular weight (LMW) agents and high-molecular weight (HMW) agents. The LMW agents can cross the cell membrane and retain inside the cell. Examples are sodium borocaptate and boronophenylalanine. HMW agents are boron-containing monoclonal antibodies, bispecific antibodies, liposomes, nanoparticles, or conjugates of epidermal growth factor. They are highly specific to tumors but cannot cross the blood–brain barrier in adequate concentration to be of some utility clinically. However, they can be used only when blood–brain barrier is disrupted, or when delivered directly intracerebrally [41].


The boron-carrier agents that are approved for human clinical trials are sodium mercaptoundecahydro-closo-dodecaborate (Na2B12H11SH) also known as sodium borocaptate (BSH), (l)-4-dihdroxy-borylphenyalanine also known as boronophenylalanine (BPA) and sodium decaborane (GB-10) [42]. Among the three, only BPA has a relatively higher tumor-specific uptake. It gets concentrated in cells synthesizing melanin. BPA is capable of taking up 18F, therefore 18F incorporated BPA positron emission tomography (PET) imaging is done to assess the boron concentration in tumor cells [43].


The low-energy neutrons used in BNCT are produced from nuclear reactors through nuclear fission reactions and are either thermal neutrons or epithermal neutrons (Table 6.5).Table 6.5
Neutrons used in BNCT and their characteristics. (Adapted from [41])

Type of neutrons

Energy (eV)

Characteristics

Thermal/slow neutrons

0.025

1. Attenuates rapidly in tissues
2. Half value layer is about 1.5 cm
3. Reacts with boron to produce high-LET particles

Epithermal

1–10,000

1. Peak dose at about 2–3 cm
2. Rapid falloff beyond peak dose
3. Do not react with boron but degrades to thermal neutrons by collisions with hydrogen atoms in tissues


Thermal neutrons have the same average kinetic energy as gas molecules in the environment, which is little. Whereas epithermal neutrons are intermediate energy range neutrons formed during the transition of energetic neutrons to slow/thermal neutrons [44]. If a tumor at a depth of more than few centimeters is to be treated effectively with BNCT using thermal neutrons, then the normal tissues at the surface will be irradiated with a very high dose. Whereas with epithermal neutrons, the very high surface dose can be avoided [41]. But the depth dose distribution with both the types of neutrons is poor. In addition, the low-energy neutrons produced in nuclear reactors are contaminated with gamma rays and fast neutrons, both of which have different radiobiologic properties. Apart from this, there are capture reactions taking place with the naturally occurring isotopes in tissues such as 1H, 12C, 14Ni, 16O, 35Cl, etc. These contaminants cause biologic damage even in normal tissues without 10B concentration.


The dose in the radiation field is expressed as RBE-weighted dose, Gyw. A weighted dose is used to take into consideration the radiobiological effects of alpha particles, gamma rays, fast neutrons and capture reactions occurring with the use of nuclear reactor-generated neutron beams. The weighting factor depends on the boron-delivery agent used, which determines the concentration of 10B in cells and which in turn dictate the effectiveness of BNCT [42, 45]. Boron levels in a patient’s blood can be measured but the concentration in tumor cells and adjacent normal tissues are based on earlier experimental studies [42]. Therefore, different weighting factors are used for tumor cells and normal tissues in the region of interest.


The Monte Carlo method is utilized for RT dose calculation. Unlike conventional dose planning algorithms, the Monte Carlo method takes into consideration the influence of inhomogeneities on dose delivered by primary radiation as well as scattered radiation [46]. This makes it appropriate from the BNCT standpoint where the dose contribution is from different by-products of nuclear fission reactions and contaminants in low-energy neutron beams from nuclear reactors. RT is delivered in single fraction or multiple fractions using oppositional or multiple fields.


The early human clinical trials carried out in Brookhaven National Laboratory and Japan did not show encouraging results with BNCT. It was widely tried out for treating central nervous system (CNS) malignancies. In these trials, 10B-enriched boric acid derivatives were used as boron-delivery agents, which showed high blood-to-tumor 10B concentration leading to endothelial damage in blood vessels but with no therapeutic benefit [47]. In the Japanese trials, BSH was used as a boron-carrier agent [48]. Though BSH achieved better tumor-to-blood concentration compared to previous boron-carrier agents used, it was however excluded by normal blood–brain barrier, and the 10B concentration in brain tumors was suboptimal [49, 50]. In addition, the thermal neutrons used in these trials were poorly penetrating. Therefore, open craniotomy and general anesthesia during the entire treatment time (about 4–8 h) were needed to deliver BNCT [50]. The shortcomings of earlier studies were rectified in the modern clinical trials. In majority of the subsequent trials, high energy epithermal neutron beam was used instead of thermal neutron beam. Thereby, avoiding the need for open craniotomy. Instead of previous boron-carrier agents, newer agents such as BPA were used, either alone or in combination with BSH.


The recent trials have aimed to find the optimal radiation fractionation, radiation fields, radiation dose, normal tissue tolerance, and pharmacokinetics of boron-carrier agents used in BNCT for treatment of different cancer subsites. In the twenty-first century, there were clinical studies experimenting and expanding the role of BNCT in other cancer subsites such as recurrent head and neck cancers as summarized in Appendix. However, there are no randomized controlled clinical trials on BNCT reported so far.


There are few limitations that hamper the widespread use of BNCT in cancer treatment. The main shortcoming is the lack of 10B carrier agents capable of achieving high tumor specificity and boron concentration. Secondly, the poor penetration of thermal neutrons into tissues. Thirdly, usage of nuclear reactors as the source of thermal neutrons for BNCT. The problems with nuclear reactors are that the low energy-neutron beams produced from them are contaminated with gamma rays and fast neutrons, which can cause damage to normal tissues even without boron concentration. Additionally, there is a shortage of nuclear reactors capable of delivering BNCT with a treatment delivery and monitoring room and they are also often located far away from population center. Fourthly, the interaction of low-energy neutrons with normal tissues results in capture reactions that cause biological damage.


Currently, active translational and clinical research focused on overcoming the above hurdles are being conducted. Newer boron-carrier agents based on purines, pyrimidines, thymidines, nucleotides, nucleosides, peptides, and porphyrin derivatives are being designed [39, 51, 52]. To avoid the hindrances associated with nuclear reactor-based treatment, alternative sources of neutrons such as radioactive decay of californium-252 (252Cf) and particle accelerators are being investigated. 252Cf is not available in the required amount to be utilized for BNCT [40]. On the other hand, particle accelerator-based treatment appears to be a promising alternative and would make hospital-based delivery BNCT feasible. However, the applicability of results from previous clinical trials conducted in reactor-based treatment centers to a larger population to be treated in particle accelerator-based treatment centers in future is questionable and warrants further studies [50].


Combining RT with other oncological treatments is central for clinical management of tumors. A key approach is to combine RT with other pharmaceutical treatments. Given that RT has an effect on diverse cellular signaling networks, there are a number ways to combine it with agents and/or regiments that affect such processes, e.g., chemotherapy, targeted therapy, immunotherapy, hyperthermia, hormonal therapy, short-term starvation, etc. (Fig. 6.5).

A circular diagram of the radiation resistent phenotype surrounded by the different radiotherapy combinations. It includes evading cell death, hyperthermia, D N A repair, short time starvation, cell cycle proliferation, inflammation immune evasion, hypoxia angiogenesis, and hormone therapy.

Fig. 6.5
Overview of radiotherapy combinations influencing different hallmarks of cancer


A circular diagram of the radiation resistent phenotype surrounded by the different radiotherapy combinations. It includes evading cell death, hyperthermia, D N A repair, short time starvation, cell cycle proliferation, inflammation immune evasion, hypoxia angiogenesis, and hormone therapy.


RT is often combined with chemotherapy in a diverse set of tumor types to increase locoregional control as well as to combat metastatic growth [53]. These combined regiments have emerged as a result of exploring chemotherapeutic agents that presented some single drug activity in a certain cancer malignancies for additive or synergistic effect when combined with RT at doses and time frames that had acceptable toxicity [54].


Combined chemotherapy and RT might refer to sequential association or to concomitant association. Chemotherapy may sensitize for RT by influencing one or several cellular effects including chromosome or DNA damage and subsequent repair, effect on cell cycle progression allowing cells to be accumulating in a RT sensitive phase, impact on different cell death routes including apoptosis, mitotic catastrophe as well as on autophagy. Moreover, in the tissue such combination may also impact on the hypoxic tumor environment/reoxygenation status. In a clinical setting it is most likely that a key benefit is the inhibition of tumor cell proliferation by drugs during the radiation interfraction interval [54].


The combined use of chemotherapy with RT has typically translated into a significant benefit in overall survival in sites where RT plays a substantial role.


Concurrent RT and chemotherapy yielded an almost 10% higher survival rate relative to RT alone. Unfortunately, the complication rates of combined regimens are also higher than those of RT only [54].


Concomitant administration of chemotherapy and radiation gives increased early normal tissue toxicity due to inhibition of stem cell or precursor-cell proliferation. Late normal tissue damage is likely to be enhanced through inhibition of DNA repair, and by specific mechanisms of drug toxicity in sensitive tissues [55].


Several randomized trials with concomitant chemoradiotherapy have been conducted in most cancer types showing a significant increase in locoregional control in many disease sites with a consequent improvement in patient survival. Meta-analyses of available data of randomized trials in head and neck cancer (HNC) undertaken a few years ago showed that despite a high initial response rate, multi-agent chemotherapy given before radiation treatment (i.e. in a neoadjuvant setting) has a small impact on the locoregional control and survival rates [54]. Numerous single institutions and cooperative groups have investigated the use of concurrent RT and chemotherapy in the management of patients with localized esophageal and gastric cancer, either as definitive or adjuvant therapy. A significant body of information suggests that chemotherapeutic agents such as 5-fluorouracil, capecitabine, cisplatin, oxaliplatin, carboplatin, mitomycin C, gemcitabine, irinotecan, docetaxel, and paclitaxel have a greater additive effect when used in combination with RT [54].


In all the reported studies, the therapeutic ratio (defined as the advantage in efficacy over the disadvantage in toxicity) was, however, less clearly assessed and/or reported. In general, an increase in early toxicity was observed in all the trials. For late toxicity, systematic reporting of data is lacking, but the few available reports also indicate an increase in late radiation effects.


A drug may sensitize the radiation or may kill cells by independent means. Alternatively, a drug may inhibit cellular repopulation or act as a cytoprotector. Limited studies have presented drug mechanisms mathematically in order to estimate the equivalent radiation effect of a drug. In fact if cytotoxic drug effects could be expressed in terms of equivalent biologically effective dose of radiation, then relative contributions of radiation and chemotherapy in combined treatments could be assessed and consequently optimum schedules could be designed [54].


An ideal global model of tumor control in an attempt to simulate clinical reality would incorporate the effects of radiation dose, fractionation, hypoxia, blood flow, and concomitant drug therapy [55].


Chemotherapy combined with RT improves the therapeutic ratio by the following mechanisms:1.
Spatial cooperation—consists of administering the chemotherapeutic agent and RT separately in different anatomical sites.
 2.
Toxicity independence—both treatments have different side effects, the treatment with the combination modality is less toxic.
 3.
Normal tissue protection—chemotherapy drugs with a protective effect against normal tissue allow a higher dose of radiation to be administered.
 4.
Radiosensitivity—is a mechanism that leads chemotherapeutic agents to enhance the cytotoxic effects of RT treatment. Increased damage from radiation, inhibition of repair processes, interferance with the cell cycle progression through different phases, exerting greater activity against hypoxic cells, and helping to improve RT are some mechanisms of radiosensitivity that can influence these treatments.


Spatial cooperation—consists of administering the chemotherapeutic agent and RT separately in different anatomical sites.


Toxicity independence—both treatments have different side effects, the treatment with the combination modality is less toxic.


Normal tissue protection—chemotherapy drugs with a protective effect against normal tissue allow a higher dose of radiation to be administered.


Radiosensitivity—is a mechanism that leads chemotherapeutic agents to enhance the cytotoxic effects of RT treatment. Increased damage from radiation, inhibition of repair processes, interferance with the cell cycle progression through different phases, exerting greater activity against hypoxic cells, and helping to improve RT are some mechanisms of radiosensitivity that can influence these treatments.


Combination of chemotherapy with RT can be in three ways, with a sequential treatment where RT is followed by chemotherapy or chemotherapy is followed by RT. These treatments can reduce large tumor mass with a first modality and with the second one can increase the effectiveness, and thus control the disease. In concurrent treatment, chemotherapy and RT are given together. RT can be given daily, while chemotherapy could be given once a week or every 3–4 weeks. Finally, alternative treatment would be based on giving chemotherapy and RT on alternately weeks, such as every 1–3 weeks, with no concurrent treatments. This last option would reduce side effects and also allow full administration of the dose for each modality.


Molecular mechanisms of interaction between combination therapies [53]:1.
Enhance DNA/chromosome damage and repair
Little is known about the capacity of chemotherapeutic agents to increase the efficiency with which IR induces DNA damage. Several commonly used chemotherapy agents have been shown to inhibit the repair of radiation damage (i.e., DNA and/or chromosome damage). Some of these drugs inhibit the repair processes by interfering with the enzymatic machinery involved in the restoration of the DNA/chromosome integrity.
 2.
Cell cycle synchronization
Many of the chemotherapeutic agents inhibit cell division, that is, they exert their action on proliferating cells.
Due to this cell cycle selective cytotoxicity by the cell cycle phase after the action of chemotherapeutic drugs, the remaining surviving cells will synchronize.
If RT is given when cells are synchronized in the most radiosensitive phase of the cell cycle, then the effect of radiation is enhanced.
 3.
Enhanced apoptosis
Apoptosis is a mechanism of cell death induced by chemotherapeutic agents. These can trigger one or more pathways of apoptosis. To ensure a robust apoptotic response, chemotherapeutics must be incorporated into DNA. The combination of these therapies, where RT is very effective in inducing DNA single strand breaks (SSBs) or double strand breaks (DSBs), could facilitate the incorporation of these agents into DNA and thus induce an enhanced apoptotic reaction.
 4.
Reoxygenation
Hypoxia is associated with a worse response to RT treatment, and the reason is the inadequate diffusion of oxygen in the tumor mass due to insufficient tumor vascularization.
If we combine the treatments, chemoRT, chemotherapy induces a certain degree of shrinkage in the tumor that facilitates the diffusion of oxygen in a more uniform way, increasing tumor oxygenation and therefore tumor radiosensitivity.
 5.
Inhibition of cell proliferation
A mechanism of interaction between both treatments combined is the possible inhibition of cell proliferation, a mechanism that occurs during dose fractionation in RT. The exact timing and schedule between the chemotherapy and RT must be taken into account, since it would be best to administer the drug toward the end of radiation treatment because that is when tumor cell repopulation has been activated.


Little is known about the capacity of chemotherapeutic agents to increase the efficiency with which IR induces DNA damage. Several commonly used chemotherapy agents have been shown to inhibit the repair of radiation damage (i.e., DNA and/or chromosome damage). Some of these drugs inhibit the repair processes by interfering with the enzymatic machinery involved in the restoration of the DNA/chromosome integrity.


Many of the chemotherapeutic agents inhibit cell division, that is, they exert their action on proliferating cells.


Due to this cell cycle selective cytotoxicity by the cell cycle phase after the action of chemotherapeutic drugs, the remaining surviving cells will synchronize.


If RT is given when cells are synchronized in the most radiosensitive phase of the cell cycle, then the effect of radiation is enhanced.


Apoptosis is a mechanism of cell death induced by chemotherapeutic agents. These can trigger one or more pathways of apoptosis. To ensure a robust apoptotic response, chemotherapeutics must be incorporated into DNA. The combination of these therapies, where RT is very effective in inducing DNA single strand breaks (SSBs) or double strand breaks (DSBs), could facilitate the incorporation of these agents into DNA and thus induce an enhanced apoptotic reaction.


Hypoxia is associated with a worse response to RT treatment, and the reason is the inadequate diffusion of oxygen in the tumor mass due to insufficient tumor vascularization.


If we combine the treatments, chemoRT, chemotherapy induces a certain degree of shrinkage in the tumor that facilitates the diffusion of oxygen in a more uniform way, increasing tumor oxygenation and therefore tumor radiosensitivity.


A mechanism of interaction between both treatments combined is the possible inhibition of cell proliferation, a mechanism that occurs during dose fractionation in RT. The exact timing and schedule between the chemotherapy and RT must be taken into account, since it would be best to administer the drug toward the end of radiation treatment because that is when tumor cell repopulation has been activated.


The combination of these treatments can increase both acute and late toxicity. ChemoRT as two cytotoxic treatments produces an increase in damage in the volume of damaged normal cells, being more evident during the concurrent chemoRT. By combining these therapies, if these side effects appear, you may require to reduce the dose of chemotherapy.


Side effects from combining chemotherapy with RT can be increased fatigue, lowering of blood counts, cardiac dysfunction, cognitive dysfunction, and second malignancies.


Some aspects to consider to reduce toxicity when combining both treatments are:
If we optimize the schedule and sequence of the combined treatments, we can reduce toxicity.

With an adequate selection of patients, we can avoid these side effects in patients with a poor performance status or patients with comorbidities.

Using a genetic and molecular analysis of the tumor, we can avoid chemotherapy for patients with lower scores, avoiding chemotherapy toxicity.

In patients with p16 oropharyngeal cancer, it has been possible to reduce the dose of RT and thus reduce toxicities.

Advances in imaging techniques, such as IMRT and IGRT, have led to a decrease in the dose around normal tissues, resulting in minimizing the risk of complications from chemoRT.

Finally, supportive care that involves adequate nutrition, adequate hydration, managing nausea, pain, and depression are essential to mitigate side effects when both therapies are combined (Table 6.6).
Table 6.6
Chemotherapeutic agents used in combination with radiotherapy in different tumor types and associated side effects

Tumor type

Treatment

Side effects

Brain tumors

Carmustine

Myelosuppression

Temozolomide

Neutropenia, anemia, thrombocytopenia, constipation

Head and neck cancer

Cisplatin

Nephrotoxicity, ototoxicity, nausea, vomiting, neurotoxicity/neuropathy

Docetaxel

Myelosuppression

Fluorouracil

Myelosuppression, gastrointestinal (GI) effects, mucositis, oral ulcers, diarrhea

Breast cancer

Cyclophosphamide

Hemorrhagic cystitis, myelosuppression, nausea, vomiting

Docetaxel

Myelosuppression

Doxorubicin

Cardiotoxicity (including recall effect)

Methotrexate

Stomatitis, leucopenia and nausea

Lung cancer

Carboplatin

Nephrotoxicity, ototoxicity, nausea, vomiting, neurotoxicity

Docetaxel

Myelosuppression

Etoposide

Myelosuppression

Gastrointestinal cancer

Fluorouracil

Myelosuppression and mucositis

Gemcitabine

Anemia, thrombocytopenia, nausea/vomiting

Oxaliplatin

Nephrotoxicity, ototoxicity, nausea, vomiting and neurotoxicity

Irinotecan

Diarrhea, immunosuppression

Mitomycin C

Bone marrow damage, lung fibrosis, renal damage

Lymphoma

Bleomycin

Lung fibrosis

DTIC (dacarbazine)

Loss of appetite, vomiting, low white blood cell or platelets count

Doxorubicin

Cardiotoxicity

Vinblastine

Peripheral neuropathy, bone marrow suppression

Vincristine

Hair loss, constipation, difficulty walking, headaches, neuropathic pain, lung damage, or low white blood cell counts


If we optimize the schedule and sequence of the combined treatments, we can reduce toxicity.


With an adequate selection of patients, we can avoid these side effects in patients with a poor performance status or patients with comorbidities.


Using a genetic and molecular analysis of the tumor, we can avoid chemotherapy for patients with lower scores, avoiding chemotherapy toxicity.


In patients with p16 oropharyngeal cancer, it has been possible to reduce the dose of RT and thus reduce toxicities.


Advances in imaging techniques, such as IMRT and IGRT, have led to a decrease in the dose around normal tissues, resulting in minimizing the risk of complications from chemoRT.


Finally, supportive care that involves adequate nutrition, adequate hydration, managing nausea, pain, and depression are essential to mitigate side effects when both therapies are combined (Table 6.6).


The incorporation of targeted therapies into treatment regimens helps to improve radiosensitization. Multimodal therapy uses these agents on a concurrent schedule [53].


Multimodal management for optimum cancer treatment with surgery, chemotherapy, and RT is one of the most significant advances in cancer treatment in the last 25 years. This combined therapy increases locoregional control and patient survival, as well as reduces the side effects of treatment, toxicities [53].


It is difficult to know the real underlying mechanisms of the interaction of this combination therapy of chemotherapy and RT, normally the clinical trials that are carried out do not allow to obtain this information [56] (Box 6.5).


RT and chemotherapy can, when combined, improve locoregional disease control.

Concomitant administration of RT with chemotherapy gives increased early normal tissue toxicity but late toxicity of normal tissues may also be increased.


Concomitant administration of RT with chemotherapy gives increased early normal tissue toxicity but late toxicity of normal tissues may also be increased.


Radiation-induced signaling is multifaceted, and these cellular events are affected by different growth factor signaling cascades controlled by oncogenic drivers and activated kinases in the tumors [57]. These radiation-induced signaling events as well as the tumor microenvironment interplay have been explored for RT sensitization purposes (Fig. 6.5).


Some of the RT sensitizing approaches based on targeting oncogenic drivers, DNA damage and repair, chromatin remodeling, cell cycle progression, cell death regulation and angiogenesis/hypoxia are shown in Table 6.7.Table 6.7
RT sensitizing strategies and examples of drugs that are in clinical evaluation in combination with RT or in combined RT and chemotherapy regimen

Type of mechanism

Target or target mechanism

Example inhibitors

RT sensitized tumor

Reference or clinical trial No.a

DNA damage and repair

ATM

AZD1390

Glioblastoma, other brain tumors

NCT03423628

ATR

BAY-1895344; M6620

Advanced solid tumor, esophageal cancers

[58]
NCT03641547

DNA-PKcs

Nedisertib, peposertib, AZD7648

Head and neck cancer, advanced solid tumors

[59]
NCT03907969

PARP

Olaparib, veliparib, rucaparib, niraparib

Breast cancer, prostate cancer, non-small cell lung cancer, small-cell lung cancer, glioblastoma/glioma, rectal cancer, cervical cancer, head and neck cancer

[60]
NCT03542175; NCT04837209; NCT01477489; NCT02227082; NCT03945721; NCT03598257; NCT03109080; NCT03212742; NCT03581292; NCT01514201; NCT04790955; NCT04728230; NCT02412371; NCT01589419; NCT03644342; NCT02229656

Chromatin remodeling

Histone deacetylase (HDAC)

Vorinostat

Head and neck cancer

[61]

Cell cycle progression

WEE1

Adavosertib

Pancreatic cancer

[62]

CDK 4/6

Palbociclib, ribociclib, abemaciclib

Glioma, breast cancer, head and neck cancer, meningiomas

[63]
NCT03691493; NCT03870919; NCT04563507; NCT03024489; NCT03389477; NCT03355794; NCT02607124; NCT04585724; NCT04298983; NCT04923542; NCT04220892; NCT02523014

Cell death regulation

Bcl-2

AT-101 (Gossypol)

Head and neck cancer
Brain tumors

[64]
NCT00390403

CD95/FAS ligand

Asunercept (APG101)

Glioblastoma

[65]

SMAC mimetics

Xevinapant (Debio 1143)

Advanced head and neck cancer

[66]

Oncogenic drivers

EGFR

Erlotinib/gefitinib/osimertinib cetuximab

Non-small cell lung cancer, head and neck cancer

[67, 68]

STAT3

Dovitinib

Hepatocellular carcinoma

 [69]

Angiogenesis

VEGF, VEGFR2

Bevacizumab, vandetanib (Caprelsa)

Glioblastoma, esophagogastric cancer

[70, 71]

Hypoxia

Oxygen mimetic

Nimorazole

Head and neck cancer

[72]

aThe trial number refers to its citation on https://clinicaltrials.gov/


Three principal DNA damage response (DDR) kinases, the phosphatidylinositol-3-kinase-related kinases (PIKKs), ataxia-telangiectasia mutated (ATM), ATM- and Rad3-related (ATR), and the non-homologous end joining (NHEJ) component, DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) are central in RT responses (see Chap. 3). These kinases execute their cellular action by phosphorylating targets that regulate DNA repair, e.g., histone H2AX, or cell cycle progression, e.g., WEE-1 and cell cycle checkpoint kinases (CHKs).


Multiple trials of ATR inhibitors are ongoing as single agents or combined with chemotherapy, yet fewer attempts have been made with ATR inhibitors and RT [60]. The ATR inhibitors BAY-1895344 and M6620 (see clinicaltrial.gov; NCT03641547) were tested in phase I trials in various solid tumors in an advanced stage setting including esophageal cancer [58]. As the kinase pocket of ATM is similar to other PIKKs, early attempts to develop specific inhibitors were unsuccessful [60]. However, the ATM inhibitor AZD1390 is currently undergoing trials in conjunction with RT in glioblastoma patients (NCT03423628). Attempts have also been made to target DNA-PKcs, a key component of the NHEJ repair cascade (see Chap. 3) [60]. Thus, AZD7648 has been demonstrated to enhance RT effect when combined with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in both tumor cell lines in vitro as well as in tumor-bearing mice. This DNA-PKcs inhibitor is at present tested further in a phase I clinical trial (NCT03907969). Moreover, other DNA-PKcs inhibitors are similarly evaluated when combined with RT in phase I trials involving patients with, e.g., head and neck (HNC) cancer where a clear improved local control was found.