Another class of DNA repair inhibitors is those targeting the PARP-1 repair enzyme [58, 60]. It has been demonstrated that in tumor cells which had mutations in certain DDR genes, e.g., BRCA1/2, causing impairment of their DNA damage sensing function, blockade of a back-up repair pathway, e.g., by PARP-1 inhibitors (PARPi) resulted in tumor-specific cell killing, a concept called synthetic lethality. Multiple PARPi, e.g., olaparib, rucaparib, and veliparib were developed and tested in different tumor types, e.g., breast cancer (BC), ovarian carcinoma (OC), and prostate cancer (PCa) (reviewed in [60]). In the context of RT, PARPis are currently tested or planned to be evaluated in several different tumor types (Table 6.7). Apart from the “BRCAness” tumor concept, the PARPi is also explored in tumors driven by other DDR-alterations, e.g., ATM and ATR.


Multiple cyclin-dependent kinase 4 and 6 inhibitors (CDKIs), e.g., palbociclib, ribociclib, and abemaciclib which alter the cell cycle progression, have become an important new treatment of metastatic- or locally advanced BC including combinations with RT [63]. Albeit multiple studies are ongoing, no consensus has been reached underpinning the clinical benefit of combining RT with CDKIs [63]. For palbociclib, there are studies ongoing in BC and HNC, ribociclib is evaluated with RT in multiple trials as is abemaciclib (Table 6.7). In addition, there is an attempt to study abemaciclib in patients with solid tumors that have brain metastasis where CDK genomic testing is done (NCT03994796).


The CDK1/2 is in part controlled by the WEE1 G2 checkpoint kinase which via Ser/Th protein phosphorylation blocks their activity resulting in a G2/M cell cycle checkpoint activation. Indeed, the WEE1 inhibitor adavosertib was assessed alongside a dual RT and gemcitabine treatment regimen in advanced PCa patients where a clear response was evident by an increased overall survival [62].


Constitutively increased activity of epidermal growth factor receptors (EGFRs) by mutation or gene amplification (which is found in multiple tumor types) is responsible for resistance to CT/RT [68]. Moreover, downstream PI3K/AKT or Ras-Raf mitogen-activated protein kinases (MAPK) signaling cascades may also influence RT response via regulation of cell cycle, cell death signaling, or by interfering with the DDR network [73]. Treatment with the antibody cetuximab, a EGF ligand blocker has been shown to improve RT sensitivity in HNC. However, results presented from a meta-analysis covering 13 studies with 5678 patients on CT/RT-based treatment and receptor tyrosine kinase inhibition for solid cancers (ROCKIT) emphasized that targeting EGFR could not ameliorate overall survival yet causing increased toxicity [67]. In the context of metastatic Non-small cell lung cancer (NSCLC) driven by EGFR mutation, there is also an interest in combining small EGFR tyrosine kinase inhibitors (TKIs) together with RT for patients with oligometastatic disease as well as to consolidate tumor lesions resistant to a given EGFR targeting TKI [68].


The transcription factor signal transducer and activator of transcription 3 (STAT3) regulate inflammation, malignant cells initiation, progression, and therapy resistance. STAT3 is overexpressed in cancers of the gastrointestinal tract, NSCLC, OC, and brain tumors and thus it may cover a valuable target for precision therapy. One example is the drug dovitinib which was shown to sensitize hepatocellular carcinoma to RT by targeting Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1)/STAT3 signaling [69].


RT resistance is in part a result of impaired cell death initiation and/or execution (see Chap. 3) and targeted strategies aim to restore such signaling. Multiple signaling components of different apoptotic routes including the B-cell lymphoma 2 (Bcl-2) family members, inhibitor-of-apoptosis-proteins (IAPs), e.g., x-linked IAP (XIAP) or survivin and the Cluster of Differentiation 95 (CD95)/FAS signaling network have all been explored [74, 75]. Inhibition of the IAP survivin, for instance, is reported to increase apoptosis as well as autophagy, to impact on the cell cycle and to hamper DNA damage repair, resulting in a radiosensitization [75].


Another example is the pan-Bcl-2 inhibitor AT-101 (Gossypol), which sensitized HNC cells to RT-induced apoptosis indicating its therapeutic potential for tumors with high Bcl-2 expression levels [64]. An additional  example is navitoclax (ABT-263) which impairs the anti-apoptotic function of Bcl-2/Bcl-xL and which was reported to potentiate RT cell death [76]. Finally, the anti-IAP smac mimetic, xevinapant (Debio 1143) has been tested in HNC in combination with cisplatin and RT where locoregional control was achieved in some patients [66]. Concerning RT sensitization via the extrinsic apoptotic route, focus has been on interfering with the FAS/CD95 signaling cascade [65]. Thus, it was demonstrated in relapsed glioblastoma patients that addition of the Fc-fusion protein asunercept (APG101) which blocks ligand engagement prolonged patient survival.


Targeting the tumor microenvironment is another RT sensitizing approach that involves attack on hypoxia directly or the underlying aberrant angiogenesis/vascularity of tumors, respectively. By this, hyperbaric oxygen therapy (HBOT) and agents which are specifically activated in hypoxic tumor cells/parts of the tumor or are prodrugs which are triggered to activity under hypoxic conditions or impact on angiogenesis/vasculature (by impairing the function of the vascular endothelial growth factor (VEGF) or its receptor signaling) are tested. One prime example is the electron-affinic nitroimidazoles, such as the clinically proven oxygen mimetic nimorazole, which covers the standard of care in HNC patients that are given RT in some countries [72]. Moreover, it has been demonstrated in glioblastoma patients that temozolomide-based CT/RT can be enhanced resulting in improved progression free survival if an anti-VEGF monoclonal antibody bevacizumab (avastin) is included in the treatment regimen [71]. In contrast, addition of bevacizumab to capecitabine and RT did not improve outcome in rectal cancer [77]. Further, vandetanib (ZD6474), a tyrosine kinase inhibitor targeting VEGFR, was shown to improve outcome of esophagogastric carcinoma patients when applied after RT or different CTs [70] (Box 6.6).


Inhibitors of the DDR signaling network, e.g., ATM, ATR, DNA-PKcs, and PARP-1 or interfering with cell some cycle regulating kinases offer sensitization for RT.

Blockade of signaling from oncogenic drivers, e.g., growth factor regulated kinases via antibodies or small molecule inhibitors can sensitize tumors to RT.

Restoring cell death pathways, e.g., apoptosis is another RT sensitizing strategy.

Modulating the tumor microenvironment, e.g. hypoxia and aberrant angiogenesis allow for tumor RT sensitization.


Inhibitors of the DDR signaling network, e.g., ATM, ATR, DNA-PKcs, and PARP-1 or interfering with cell some cycle regulating kinases offer sensitization for RT.


Blockade of signaling from oncogenic drivers, e.g., growth factor regulated kinases via antibodies or small molecule inhibitors can sensitize tumors to RT.


Restoring cell death pathways, e.g., apoptosis is another RT sensitizing strategy.


Modulating the tumor microenvironment, e.g. hypoxia and aberrant angiogenesis allow for tumor RT sensitization.


For a very long time, it was assumed that the X-rays directly, or indirectly through the formation of ROS, only affect the radiation-sensitive DNA in the cell and that other structures are spared. However, today it is clear that in addition to the so-called targeted local effects of radiation on DNA, numerous so-called non-targeted effects occur, such as general stress responses of the irradiated cells, which then also can be transmitted to other cells and even the entire organism.


Radiation-induced oxidative stress and DNA damage activate numerous signaling pathways in cells that influence the expression of genes and consequently trigger a broad spectrum of cellular responses ranging from promotion of cell survival to cell death (see Chap. 3). Thereby, the immunological phenotype of cells as well as the tumor microenvironment may change (see Chap. 5). It has been demonstrated that RT increases the expression of MHCI molecules, death receptors, and stress ligands on the tumor cell surface, and fosters the release of so-called damage-associated molecular patterns/danger-associated molecular patterns (DAMPs) such as adenosine triphosphate (ATP), HMGB1, and Heat Shock Protein 70 (HSP70) (see Chap. 5). Also, RT causes increased levels of immunostimulatory cytokines mainly through the induction of immunogenic tumor cell death (ICD) and in combination with additional immune stimulation [78].


Irradiation of tumors also affect immune cells that circulate through the tumor vasculature even though the functionality of the remaining immune cells is still appropriate. One has to keep in mind that different subtypes of immune cells differ in their radiosensitivity and antigen-presenting cells as key initiators of adaptive antitumor immune responses, are quite radioresistant [79]. RT has also immune suppressive properties directly on the tumor cells and their microenvironment. Local irradiation increases the expression of immune checkpoint molecules such as programmed death-ligand 1 (PD-L1) and induces the release of transforming growth factor (TGF)-beta. Which of these changes that predominates varies greatly from individual to individual and ultimately determines whether, in addition to the local effects of tumor cell killing, local and systemically acting antitumor immune responses are triggered by RT alone [80]. The immune responses triggered by local radiation and acting systemically are referred to as “abscopal effects” of RT (for definition see Chap. 5). However, since radiation has both immune-activating and immune-suppressing effects (Fig. 6.6), the abscopal effect is usually only observed in the clinic when RT is used in combination with immunotherapies.

A diagram presents the tumor enveloped in the micro-environment and normal tissue is targeted in irradiation. The enumerated effects of radiotherapy include fractionation, immune stimulating effects, immune suppressive effects, and primary local effects.

Fig. 6.6
Radiotherapy has multiple immune stimulating and immune suppressive effects which depend on dose


A diagram presents the tumor enveloped in the micro-environment and normal tissue is targeted in irradiation. The enumerated effects of radiotherapy include fractionation, immune stimulating effects, immune suppressive effects, and primary local effects.


If ICD is induced by local tumor irradiation and the tumor vasculature is changed in such a way that more immune cells can migrate into the tumor, this can already trigger effective antitumor immune responses [81]. In terms of radiation immunology, it is now believed that a single dose of 2 Gy is more likely to promote immune cell infiltration and a dose of >2 Gy is more likely to induce ICD [82]. Importantly, non-linear dose–effect relationships often prevail. For example, the immunogenicity of tumor cells is reduced again after irradiation with a single dose that is too high, because enzymes are activated that degrade the immunogenic DNA found in the cytoplasm after irradiation or because immune-suppressing immune checkpoint molecules (ICM) are increasingly expressed on the tumor cells [83].


Expression of immune suppressive ICM was the key starting point for a combination of radiation and immunotherapies. Inhibition of ICM in parallel with or shortly after RT has led to local and systemic antitumor immune responses in animal models and in the clinic, and the so-called radio-immunotherapies are increasingly being used in multimodal oncological treatment [84]. Further, immunologically-based patient selection based on induction chemo-immunotherapies is increasingly taking place [85]. Particularly exciting is the re-emergence of tumor vaccination in this context and the stratification of patients based on immunological factors of the peripheral blood (see Chap. 6) (Box 6.7).


Radiation affects DNA and via stress responses other cellular compartments.

Radiation induces local and systemic effects.

RT has both immune stimulatory and immune suppressive effects.

Non-linear dose relationships also apply for radiation-induced immune effects.

RT is well combinable with immune therapy.


Hormone sensitive tumors which are dependent on certain hormones for their growth can be slowed down or stopped by hormone therapies.

In prostate cancer patients with a high risk of progression, hormone therapy in combination with RT is the treatment of choice as hormone therapy or RT alone remain inadequate


Hormone sensitive tumors which are dependent on certain hormones for their growth can be slowed down or stopped by hormone therapies.


In prostate cancer patients with a high risk of progression, hormone therapy in combination with RT is the treatment of choice as hormone therapy or RT alone remain inadequate


A combination of RT and hormone therapy is used in the management of breast and prostate cancers. Hormone therapy is considered to be quite effective and comparatively non-toxic in tumors that are driven by hormones such estrogen in breast cancer (BC) and testosterone in prostate cancer (PCa). The hypothalamic pituitary gonadal pathway controls the concentration of testosterone and estradiol in the serum. Estradiol is mainly produced in the ovaries of premenopausal women, however, in case of postmenopausal women; aromatase found in the peripheral fat tissue aids the peripheral conversion of adrenal androgens. Hormonal therapy is principally accomplished by chemical castration (usage of chemicals or drugs like the gonadotropin-releasing hormone agonists or luteinizing hormone-releasing agonists that stop the production of the sex hormone) in case of men with PCa and premenopausal women with BC (Box 6.8).


With respect to BC, approximately 50% of all premenopausal and 80% of all postmenopausal women suffer from a hormone receptor-positive malignancy. In the histochemical analysis of such tumor cases, the expression of estrogen (ER) and progesterone receptors (PR) are evaluated to understand the degree of positivity. The levels of ER/PR expression in BC are used as a guiding parameter for prognosis as well as for what systemic treatment to give. Recent studies have also shown that patients who overexpress the human epidermal growth factor receptor 2 (HER-2) have a low probability to benefit from hormone monotherapy. Hence it is necessary to target ER and PR as well as the HER-2 receptor. PCa can be hormone-dependent or non-dependent and have functional androgen receptors (AR). Hormone therapy is frequently part of curative therapy for both BC and PCa and where it is either used neoadjuvantly, i.e., for primary cancer size reduction before RT/radical surgery or adjuvantly, i.e., to decrease the risk of tumor recurrence.


For ER/PR-positive BC patients, hormone therapy is usually given along with postoperatively RT. The combined treatment of tamoxifen with RT has shown a synergistic effect in vivo which can be attributed to the alterations in the tumor microenvironment. Further studies are required to shed light on the complex communications among the 17beta-estradiol and p53/p21(WAF1/CIP1)/Rb signaling pathways. IR is known to induce direct as well as indirect DNA damages via the ROS production. The DNA breaks generated; stimulate various signaling pathways associated with ATM (Ataxia telangiectasia-mutated gene), ATR (Ataxia telangiectasia-mutated gene Rad3-related), and DNA-PK (DNA-protein kinase). These kinases lead to the cell growth arrest after phosphorylation checkpoint kinase 2 (CHK2) or p53. The downstream effectors like p53/p21(WAF1/CIP1)/Rb, CDC25A, 14-3-3 sigma determine if the cell cycle arrest will be in the G1/S or G2/M transition. Interestingly, these pathways can be regulated at various stages by 17beta-estradiol (E2) in the irradiated cells. The ROS production can also be reduced by 17beta-estradiol, thereby reducing the subsequent effects of RT. This can be achieved either by reducing the p53 activation or by suppression of ROS induced DNA damage. Additionally, while 17beta-estradiol acts on S-phase kinase-associated protein 2 (SKP2) and P27 to allow G2/M transition, it also augments the expression of CCND1 and MYC that control the cell cycle promoting the G1/S transition. In contrast, tamoxifen, with its anti-estrogen activity obstructs the effects of 17beta-estradiol. This anti-estrogenic effect can strengthen the IR induced growth inhibition as depicted in Fig. 6.7 [86].

A diagram displays the various signaling pathways of the genomic effect of estradiol, tamoxifen, and Ionising radiation on the cell cycle progression.

Fig. 6.7
Prospective direct genomic effect of estradiol, tamoxifen, and IR on inhibition of cell cycle progression. (Reproduced with permission from [86])


A diagram displays the various signaling pathways of the genomic effect of estradiol, tamoxifen, and Ionising radiation on the cell cycle progression.


The usage of TAM is however limited because of the pharmacological side effects like endometrial changes that can lead to endometrial cancers or the thromboembolic events. Keeping this in mind, other endocrine drugs that might endow a comparable efficiency with boosted acceptability in early disease conditions can be utilized. Hence, Letrozole (LTZ), an aromatase inhibitor, is considered as a potent drug in the adjuvant settings. It can be delivered after surgery or in combination with RT with a long-term follow-up to identify the treatment- associated cardiac side effects and evaluate cancer-specific results. LTZ, when combined with radiation, arrests cancer cells in the G1 phase with a significant decrease of cells in the S phase and G2 phase of the cell cycle [87]. Table 6.8 gives the list of hormone therapies for breast and prostate cancers.Table 6.8
Hormone therapies used for breast and prostate cancer. (Reproduced with permission from [88])

Drug

Type

Dose/route

Mode of action

Tamoxifen

Anti-estrogen

Orally, (20 mg) daily

For ER binding, competes with estradiol

Anastrazole

Non-steroidal aromatase inhibitor

Orally, (1 mg) daily

Inhibition of competitive aromatase

Exemestane

Steroidal aromatase inhibitor

Orally, (25 mg) daily

Irreversible aromatase inhibition

Goserelin

LHRH agonist

(3.6 mg) every 28 days or
(10.8 mg) every 3 months SC

Reduced pituitary production of LH and FSH

Bicalutamide

Non-steroidal antiandrogen

Orally, (50 mg) combination dose or (150 mg) single agent daily

Competitive AR inhibition

Prednisolone

Corticosteroid

Orally, (5–10 mg) daily

Suppression of Adrenal

ER estrogen receptor, LHRH luteinizing hormone-releasing hormone, LH luteinizing hormone, FSH follicle-stimulating hormone, AR androgen receptor, SC subcutaneous, IM intramuscular


During the course of the disease, a majority of PCas express the androgen receptor (AR) which is known to specifically direct the cancer cell behavior and this has solidified the significance of androgen signaling in the pathogenesis of PCa [89]. Hence, androgen deprivation therapy (ADT) is a foundation of PCa therapy. ADT is typically utilized to cut down the levels of serum testosterone to a castrate level. This can be accomplished by surgical or chemical castration. Chemical castration can be accomplished by using estrogens or LHRHa; and it is likely to be reversible. The consequence of initial use of LHRHa results in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone surge in the serum, which makes the symptoms worse. Hence, patients are advised to take oral antiandrogens for 1–2 weeks prior to the LHRHa injection. ADT is mostly given with RT as a neoadjuvant therapy which can be continued throughout and even further than RT. Although evidence suggests that the combinatorial treatment of PCa with ADT and RT has improved therapeutic effects, there is still a lot of improvement that can be made on the biochemical front as demonstrated by the clinical trials. ADT might also boost the efficacy of RT by inhibiting successive PCa cell repopulation and by enhancing reoxygenation and radiosensitization. Many preclinical studies involving tumour cell lines in vitro and in vivo tumor xenografts have suggested that ADT works by suppressing the mechanisms associated with the DNA damage response, particularly the NHEJ repair. This increases the anticancer effect induced by RT. Preclinical studies have also shown that the synergistic effect of RT and ADT enhances apoptosis by suppressing the DNA repair machinery. The combinatorial treatment not only increases the tumor oxygenation but also radiosensitizes the PCa cells. The first phase III, EORTC 22863, study demonstrated a noteworthy overall survival when RT was combined with ADT in men with locally advanced PCa. The results showed that the combination arm had a significantly higher OS compared to that of the RT alone (58.1% vs. 39.8%, p = 0.0004). Short-term and long-term follow-up of the EORTC studies showed that only 74% patients exhibited a 5-year disease-free survival with combined RT and ADT [89, 90].


Hyperthermia as an adjuvant treatment to RT or chemotherapy considers heating of the tumor (area) above a physiological temperature up to 40–43 °C for approximately an hour. Hyperthermia can be applied as whole body, local invasively (intraperitoneal, interstitial, or intracavitary) and locoregional.


Hyperthermia as a radiosensitizer or chemosensitizer has been proven its effectiveness in many different tumor types, such as locally advanced cervical cancer, recurrent breast cancer, malignant melanoma, and head and neck cancer. The size, location, and type of tumor(s) determine whether hyperthermia should be applied only locally in combination with RT or chemotherapy, or whether hyperthermia should be applied to a larger area in combination with only chemotherapy. Hyperthermia has also been demonstrated to regulate the innate and adaptive immune system [91, 92].


For metastases from, e.g., colon or ovarian origin which are located in the peritoneal area, a heated chemotherapy solution can be circulated through the peritoneal area (called hyperthermic intraperitoneal chemotherapy; HIPEC) [93]. For urinary bladder cancer, a heat solution can be circulated through this organ (endocavity). Since all of these heated solutions are combined with chemotherapy, these hyperthermia setups will not be further discussed in this chapter. Generally, hyperthermia modifies the cytotoxicity of many chemotherapeutic agents. Furthermore, for some drugs, like the platinum compounds, hyperthermia was found to make resistant cells platinum-responsive again [94]. Whether hyperthermia has this effect on other drugs, needs to be investigated.


Locoregional hyperthermia combined with RT is an approach for patients with locally advanced cervical carcinoma (deep hyperthermia) or recurrent breast cancer (superficial hyperthermia) in Europe and USA. Locoregional hyperthermia combined with RT has been used in the clinic already since the early 1980s [95]. It is also possible to implant a heat source in the tumor itself (interstitial), which mainly has been used for brain tumors or locally advanced head and neck tumors [96]. Hyperthermia weakens DNA damage repair enzymes and thereby retards the repair of radiation-induced DNA damage. An increased amount of unrepaired DNA damage causes more cells to die from the radiation injury. Importantly, the synergy between radiation and heat is highest when given simultaneously or closely together in time (within 4 h) [97].


Based on the preclinical knowledge gained in the last few years [91, 92], ongoing clinical trials are conducted with complementary translational studies focusing on immune alterations of patients receiving hyperthermia in combination with RT and/or chemotherapy. These data will form the basis for the design of multimodal cancer therapies in which hyperthermia will be combined additionally to radio- and/or chemotherapy with immune therapies such as immune checkpoint inhibitors.


Hyperthermia can be applied using different techniques such as capacitive radiofrequency heating, radiative radiofrequency and microwave heating, infrared and laser, ultrasound, conductive heating, and by hyperthermic perfusion [63]. One of the most commonly used techniques which is validated within clinical trials is microwave heating and hyperthermia is induced with one or more antennas. An applicator containing one antenna is used for superficial hyperthermia, such as breast cancer or malignant melanomas. This applicator can be placed on the surface area. For deep hyperthermia, the patient lies on a mobile bed that can move through a circle with 4 or 6 antennas. This non-invasive method is used for deeper located tumors such as cervical cancers.


Macroscopical effects of hyperthermia: Hypoxic and nutrient-deprived areas of a tumor are the least sensitive to RT or chemotherapy, while these areas are especially sensitive to hyperthermia. By local heating of the tumor, an increased blood flow occurs, which increases reoxygenation [95]. As a consequence, more radiation-induced DNA damages are formed and fixed (Fig. 6.8). Moreover, increased tumor perfusion by hyperthermia allows the chemotherapeutic agent to penetrate deeper into the tumor.

Microscopical effects of hyperthermia: Besides increasing the radiation-induced DNA breaks within cancer cells, hyperthermia temporality inhibits DNA DSB repair (Fig. 6.8). This occurs by degrading the essential BRCA2 protein, and thereby temporarily inhibiting the homologous recombination DNA repair pathway. In HPV-positive cervical cancers, hyperthermia was found to disrupt the interaction between the HPV protein (E6) which in normal circumstances suppresses p53. Activation of p53 in these cancer cells results in cell death [95].

Immune effects of hyperthermia: Dependent on the temperature, certain immunological processes are triggered by hyperthermia (Fig. 6.8). Starting with temperatures of 39 °C, an increased infiltration and activation of immune cells in the tumor can be observed in preclinical model systems. At higher temperatures, heat-induced cell death has certain characteristics of “immunogenic cell death” (ICD). This means that the dying and dead cells activate rather than suppress the immune system. In this scenario, the heat shock protein 70 (HSP70) is a major player. While inside the cell, it acts as chaperon and protects cells (known as thermotolerance), outside of the cell when being, e.g., released by heat-induced necrotic cells, it activates dendritic cells and delivers antigen to these key immune cells that bridge innate and adaptive immunity. Thus, dendritic cells take up tumor antigens, present them with co-stimulation to CD8+ T cells, and subsequently trigger cellular antitumor immunity by priming cytotoxic T cells [99]. Additionally, HSP70 can directly activate further cells of the innate immune system, such as natural killer cells [100]. Based on this preclinical knowledge gained in the last years, ongoing clinical trials are conducted with complementary translational studies focusing on immune alterations of patients receiving hyperthermia in multimodal settings.

A diagram illustrates that radiotherapy induces D N A damage, but with the addition of mild hyperthermia, there is perfusion and reoxygenation, and immune response among others, and inhibition of D N A repair temporarily which causes D N A damage, cell cycle arrest, and apoptosis in the tumor cell.

Fig. 6.8
Mild hyperthermia enhances radiotherapy by initiating multiple intracellular and intercellular processes. While radiotherapy induces DNA damages, hyperthermia can enhance the induction of radiation-induced DNA damage by increasing the perfusion and reoxygenation; hyperthermia can temporarily inhibit the DNA repair processes which causes cell cycle arrest and subsequently cell death of the tumor cells such as apoptosis; hyperthermia can also trigger an immune response and disturb the tumor microenvironment eventually all causes of increased tumor cell kill


Macroscopical effects of hyperthermia: Hypoxic and nutrient-deprived areas of a tumor are the least sensitive to RT or chemotherapy, while these areas are especially sensitive to hyperthermia. By local heating of the tumor, an increased blood flow occurs, which increases reoxygenation [95]. As a consequence, more radiation-induced DNA damages are formed and fixed (Fig. 6.8). Moreover, increased tumor perfusion by hyperthermia allows the chemotherapeutic agent to penetrate deeper into the tumor.


Microscopical effects of hyperthermia: Besides increasing the radiation-induced DNA breaks within cancer cells, hyperthermia temporality inhibits DNA DSB repair (Fig. 6.8). This occurs by degrading the essential BRCA2 protein, and thereby temporarily inhibiting the homologous recombination DNA repair pathway. In HPV-positive cervical cancers, hyperthermia was found to disrupt the interaction between the HPV protein (E6) which in normal circumstances suppresses p53. Activation of p53 in these cancer cells results in cell death [95].


Immune effects of hyperthermia: Dependent on the temperature, certain immunological processes are triggered by hyperthermia (Fig. 6.8). Starting with temperatures of 39 °C, an increased infiltration and activation of immune cells in the tumor can be observed in preclinical model systems. At higher temperatures, heat-induced cell death has certain characteristics of “immunogenic cell death” (ICD). This means that the dying and dead cells activate rather than suppress the immune system. In this scenario, the heat shock protein 70 (HSP70) is a major player. While inside the cell, it acts as chaperon and protects cells (known as thermotolerance), outside of the cell when being, e.g., released by heat-induced necrotic cells, it activates dendritic cells and delivers antigen to these key immune cells that bridge innate and adaptive immunity. Thus, dendritic cells take up tumor antigens, present them with co-stimulation to CD8+ T cells, and subsequently trigger cellular antitumor immunity by priming cytotoxic T cells [99]. Additionally, HSP70 can directly activate further cells of the innate immune system, such as natural killer cells [100]. Based on this preclinical knowledge gained in the last years, ongoing clinical trials are conducted with complementary translational studies focusing on immune alterations of patients receiving hyperthermia in multimodal settings.


A diagram illustrates that radiotherapy induces D N A damage, but with the addition of mild hyperthermia, there is perfusion and reoxygenation, and immune response among others, and inhibition of D N A repair temporarily which causes D N A damage, cell cycle arrest, and apoptosis in the tumor cell.


Superficial tumors: Hyperthermia is, e.g., standard of care in the Netherlands, Germany, and Japan for patients with recurrent breast cancer (BC), who have received a full radiation treatment course for treatment of their primary tumor. Retreatment with a similar radiation dose as used for their primary tumors is not possible, therefore hyperthermia is applied to prevent severe radiation-induced toxicities. To accomplish the same effectiveness without severe normal tissue toxicity, RT is combined with hyperthermia. The latter gives a boost to the treatment effectiveness. Nevertheless, hyperthermia treatment is not refunded by insurances for treatment of most heatable tumor entities, since big randomized trials are still missing. Besides BC, malignant melanoma and head and neck cancers are prominent superficial tumor entities which are accessible for hyperthermia. The clinical outcomes using locoregional hyperthermia with RT and-/or chemotherapy have been summarized [101]. For soft tissue sarcomas, optimized strategies with multimodality approaches including chemotherapy, regional hyperthermia, and immunotherapeutic agents have been shown to improve survival in high-risk patients [102]. However, more randomized phase III studies, as carried out in an exemplary manner for soft tissue sarcoma [103], are urgently needed to bring hyperthermia as standard tumor therapy in multimodal settings into the clinics (Figs. 6.9 and 6.10).

Deeper located tumors: In most countries, RT combined with chemotherapy is standard treatment of care for cervical cancer patients. However, chemoradiation is less beneficial in tumors of higher stage, whereas hyperthermia as an adjuvant to RT has shown its additional value. Especially in this group, chemoradiation was found to be not very effective. Moreover, chemoradiation seems to result in more toxicities, whereas hyperthermia in addition to RT did not increase radiation-induced toxicities [104].

Treatment course: Both superficial and deep hyperthermia are applied in combination with either RT or chemotherapy. Depending on the tumor type, e.g., BC, cervical cancer, etc. and The International Federation of Gynecology and Obstetrics (FIGO) stage, a radiotherapy or chemotherapy scheme is chosen. While external beam RT is mainly given in daily fractions with low doses, hyperthermia is only applied once or twice per week, for 5 weeks in a row. For each treatment session, the target temperature should be above 40 °C for approximately 1 h. Moreover, a short time interval on the day that both RT and hyperthermia are given can be more beneficial, but research is ongoing in providing more evidence [105, 106] (Box 6.9).

4 diagrams present how addition of hyperthermia to R T for patients suffering from melanoma, breast cancer and H N S C C increases C R from 35, 41 and 42.4% to 62, 59 and 76.6%, respectively and also drives an increase in 10 year overall survival in patients suffering from sarcoma.

Fig. 6.9
Improved clinical responses after addition of hyperthermia in superficial tumor types. In malignant melanoma, superficial breast cancer and head and neck squamous cell carcinoma, complete responses were much better in patients treated with RT combined with hyperthermia, compared to RT alone. In soft tissue sarcoma, the addition of RT plus hyperthermia to neoadjuvant chemotherapy, leads to a8.6% higher 10-year overall survival

 Three diagrams of the improved clinical responses and additional effects after addition of hyperthermia in cervix cancer. The complete response to radiotherapy plus hyperthermia patients is 83% in C R, 37% in O S, and 56% in P C.

Fig. 6.10
The additional effect of hyperthermia in a deep located tumor (cervical cancer)


Superficial tumors: Hyperthermia is, e.g., standard of care in the Netherlands, Germany, and Japan for patients with recurrent breast cancer (BC), who have received a full radiation treatment course for treatment of their primary tumor. Retreatment with a similar radiation dose as used for their primary tumors is not possible, therefore hyperthermia is applied to prevent severe radiation-induced toxicities. To accomplish the same effectiveness without severe normal tissue toxicity, RT is combined with hyperthermia. The latter gives a boost to the treatment effectiveness. Nevertheless, hyperthermia treatment is not refunded by insurances for treatment of most heatable tumor entities, since big randomized trials are still missing. Besides BC, malignant melanoma and head and neck cancers are prominent superficial tumor entities which are accessible for hyperthermia. The clinical outcomes using locoregional hyperthermia with RT and-/or chemotherapy have been summarized [101]. For soft tissue sarcomas, optimized strategies with multimodality approaches including chemotherapy, regional hyperthermia, and immunotherapeutic agents have been shown to improve survival in high-risk patients [102]. However, more randomized phase III studies, as carried out in an exemplary manner for soft tissue sarcoma [103], are urgently needed to bring hyperthermia as standard tumor therapy in multimodal settings into the clinics (Figs. 6.9 and 6.10).


Deeper located tumors: In most countries, RT combined with chemotherapy is standard treatment of care for cervical cancer patients. However, chemoradiation is less beneficial in tumors of higher stage, whereas hyperthermia as an adjuvant to RT has shown its additional value. Especially in this group, chemoradiation was found to be not very effective. Moreover, chemoradiation seems to result in more toxicities, whereas hyperthermia in addition to RT did not increase radiation-induced toxicities [104].


Treatment course: Both superficial and deep hyperthermia are applied in combination with either RT or chemotherapy. Depending on the tumor type, e.g., BC, cervical cancer, etc. and The International Federation of Gynecology and Obstetrics (FIGO) stage, a radiotherapy or chemotherapy scheme is chosen. While external beam RT is mainly given in daily fractions with low doses, hyperthermia is only applied once or twice per week, for 5 weeks in a row. For each treatment session, the target temperature should be above 40 °C for approximately 1 h. Moreover, a short time interval on the day that both RT and hyperthermia are given can be more beneficial, but research is ongoing in providing more evidence [105, 106] (Box 6.9).


4 diagrams present how addition of hyperthermia to R T for patients suffering from melanoma, breast cancer and H N S C C increases C R from 35, 41 and 42.4% to 62, 59 and 76.6%, respectively and also drives an increase in 10 year overall survival in patients suffering from sarcoma.


Three diagrams of the improved clinical responses and additional effects after addition of hyperthermia in cervix cancer. The complete response to radiotherapy plus hyperthermia patients is 83% in C R, 37% in O S, and 56% in P C.


Hyperthermia enhances blood perfusion and reoxygenation, triggers an immune response, and disturbs the tumor microenvironment.

Hyperthermia increases RT and chemotherapy-induced DNA damage, inhibits the DNA damage repair pathways, increases cell cycles arrest, and induces cell death such as apoptosis and necrosis.

Hyperthermia was proven to be effective in many different tumor types, such as superficial breast cancer, soft tissue sarcoma, and cervical cancer.


Hyperthermia enhances blood perfusion and reoxygenation, triggers an immune response, and disturbs the tumor microenvironment.


Hyperthermia increases RT and chemotherapy-induced DNA damage, inhibits the DNA damage repair pathways, increases cell cycles arrest, and induces cell death such as apoptosis and necrosis.


Hyperthermia was proven to be effective in many different tumor types, such as superficial breast cancer, soft tissue sarcoma, and cervical cancer.


Voluntary fasting is a part of religious services in many cultures like Buddhism, Christianity, Hinduism, etc. Fasting/short-term fasting (STS) is also known as calorie restriction (CR) which is associated with diets with a wide alteration in the growth factors and the metabolites levels. This produces a milieu that diminishes the cancer cell competency to get acclimatized and endure which results in improved outcomes for cancer therapy. In normal cells, STS and fasting selectively boost the chemotherapy resistance which is not the case with cancer cells. STS endorses rejuvenation of normal cells, thereby averting the toxic and harmful effects of the treatment. Clinical as well as in vivo studies suggest that the low calorie-fasting mimicking diet (FMD) cycles are promising and also safe, in patients that can barely endure STS/fasting. Hence, it can be predicted that the combination of STS or FMDs with chemotherapy, immunotherapy as well as other therapies holds a promise in increasing the cancer treatment efficacy, preventing the acquired resistance and minimizing the aftereffects [107]. This can be correlated with one of the emerging hallmarks of cancer, i.e., the susceptibility of cancer cells to nutrient deficiency and their addiction for explicit metabolites. Three of the nutritional interventions of food withdrawal strategies like fasting, FMD, and calorie CR from the myriad of strategies have increasingly exhibited a valuable effect on metabolism and shown a promising anticancer activity. STS is typically done on an average of 3–5 successive days. In fasting, only water is consumed, for a time-span ranging from 12 h to 3 weeks. For CR, there is a 20–40% decrease in calorie ingestion with decrease in all constituents without intercepting the ingestion of minerals and vitamins, typically used by specialists as a synonym to dietary restriction.


Cancer cells are distinguished from normal cells by means of their irregular metabolic and signaling pathways that lead to circumventing the antiproliferative signals, distorted mitochondrial function, and increased glucose uptake. Fasting or STS exhibits a differential consequence on cancer cells and normal cells which can be attributed to drop in the glucose, insulin-like growth factor-1, and insulin levels, amplification in ketone bodies and insulin-like growth factor-binding protein 1 (IGFBP1). This phenomena force cancer cells to depend on the limited amounts of factors and metabolites that are present in the blood, thereby eventually resulting in cell death. The response mechanisms of differential stress sensitization (DSS) and differential stress resistance (DSR) caused by fasting/STS stimulate the normal cell protection but pushes the cancer cell toward cell death. One of the major classical responses of radiation is the dys-functioning of the cell cycle arrest [108].


There is a growing body of evidence from the preclinical studies on STS which enhances the efficacy of a wide variety of chemotherapy drugs that are used in treatments of several types of tumors. Some of clinical trials (NCT00757094, NCT00936364, NCT01304251, and NCT01954836) have proven to be safe and feasible with reduction in the chemotherapy associated side effects. Since STS has demonstrated favorable traits to fight cancer, it would be logical to combine STS with RT as it presents clinical gain. In preclinical studies, combining STS with RT has already exhibited enhanced RT effects. Clinical and preclinical trials of STS and RT are also picking pace to exhibit the efficacy of this combination. STS can be considered as a personalized dietary approach that can be conveniently combined with RT in clinics in the path forward (Box 6.10).


Short-term starvation (STS) in combination with RT leads to an increased effect of RT on metastatic cancer cells, and at the same time also protects normal cells.

Short-term starvation (STS) or fasting can particularly safeguard normal cells in mice and probably in patients receiving chemo without reducing the therapeutic effect on cancer cells.

Fasting dependent decrease in IGF-1 and glucose are arbitrate components involved in the DSR and DSS effects.


Short-term starvation (STS) in combination with RT leads to an increased effect of RT on metastatic cancer cells, and at the same time also protects normal cells.


Short-term starvation (STS) or fasting can particularly safeguard normal cells in mice and probably in patients receiving chemo without reducing the therapeutic effect on cancer cells.


Fasting dependent decrease in IGF-1 and glucose are arbitrate components involved in the DSR and DSS effects.


Spatial fractionation is a method that reduces damage to normal tissue.

Small beams of radiation are applied in a grid-like pattern.

High doses are applied in the beam path, while (almost) no or very low dose is delivered between the beams, resulting in high peak-to-valley dose ratio  (PVDR).


Spatial fractionation is a method that reduces damage to normal tissue.


High doses are applied in the beam path, while (almost) no or very low dose is delivered between the beams, resulting in high peak-to-valley dose ratio  (PVDR).


Spatial fractionation of photons is in clinical use.

GRID therapy uses 2D pattern with beam width of ~1–1.25 cm and center to center (ctc) of 2.2–2.4 cm.

LATTICE is the 3D extension of GRID therapy.


GRID therapy uses 2D pattern with beam width of ~1–1.25 cm and center to center (ctc) of 2.2–2.4 cm.


Minibeam RT (MBRT) is a modern therapy approach using protons and heavier ions, which is at the moment in preclinical stage or investigated in clinical trials.

In proton MBRT, the beam widen and overlap in the tumor.

Further sparing of healthy tissue can be achieved using interlacing methods.


Minibeam RT (MBRT) is a modern therapy approach using protons and heavier ions, which is at the moment in preclinical stage or investigated in clinical trials.


In proton MBRT, the beam widen and overlap in the tumor.


Further sparing of healthy tissue can be achieved using interlacing methods.


The concept of spatial fractionation of radiation in tumor therapy aims to widen the therapeutic window by sparing healthy tissue by simply sparing parts of it from radiation. It was introduced as GRID therapy by Alban Köhler in 1909 by the use of a grid of centimeter-wide pencil beams in X-ray therapy [109]. In the 1990s, when more powerful X-rays became available from synchrotron facilities, GRID therapy was moved to the micro level with the development of microbeam radiotherapy (MRT) and to the submillimeter level in the later 2000s with minibeam radiotherapy (MBRT) [110]. It was then that GRID, MRT, and MBRT were classified under a broader term of spatially fractionated radiation therapy (SFRT).


In SFRT, the spatial arrangement of the radiation allows irradiating tumors with a heterogeneous dose, with high doses in the radiation channels and low doses in the so-called valleys in between.


In recent years, advances in the use of spatial fractionation in particle therapy have also been investigated. Proton minibeam radiotherapy (pMBRT) is making rapid progress [111]. Thanks to small-angle scattering, the radiation channels overlap and the tumor is irradiated with a homogeneous dose, while the normal tissue is spared due to the spatial fractionation of the dose (Box 6.11, 6.12, and 6.13).


Schematic representations of SFRT, proton and ion MBRT is shown in Fig. 6.11.

A schematic displays conv and grid where the tumor is at the center under photons, and conv, proton and ion M B R Ts where the tumor is at the tail end on the right under particles. Below is a table that provides information on dose pattern, photon S F R T, proton and ion M B R T.

Fig. 6.11
Schematic view of spatial fractionation in RT. The blue object represents the tumor


A schematic displays conv and grid where the tumor is at the center under photons, and conv, proton and ion M B R Ts where the tumor is at the tail end on the right under particles. Below is a table that provides information on dose pattern, photon S F R T, proton and ion M B R T.


Spatial fractionation of radiation means that new parameters must be introduced and controlled in treatment planning and therapy. First and foremost, beam size and the distance between two beams become the most important variables. Beam size, or beam width, is the full width at half maximum (FWHM) of the lateral intensity profile of a beam. The distance between two beams, also called center-to-center distance (ctc), is defined as the length of the direct connection between the maximum intensity (also called center) of the two beams [112].


Another important quantity is the dose ratio between the dose in the center of the beam (peaks) DP and the dose in the middle between two beams (valleys) DV, the peak-to-valley dose ratio (PVDR):

 (6.3)The PVDR defines the strength of spatial fractionation. It is ~1 for homogeneous irradiation and approaches infinity for small valley doses [113].


The parameters of beam width, ctc, and PVDR determine the possibility of sparing normal tissue and also the dose applied to the tumor, thus influencing tumor control.


Finally, the geometric arrangement of the beams is also crucial. Spatial fractionation uses beams that have either a pencil (Fig. 6.12a, b) or a planar structure (Fig. 6.12c). Pencil beams have a completely round or Gaussian shape and can be arranged in either a square or hexagonal lattice. For treatment planning, it is important to know the dimensions of a beam. For this purpose, the unit cell of a beam is used. The unit cell is the smallest unit in which a beam can be considered a beam and the entire dose distribution is covered. The unit cell is assembled to form the entire lattice and cover the tumor.

3 diagrams, a to c, with respective minibeams and c t c sub q. A depicts c t c sub q connects 2 unit cells above the square. B depicts c t c sub h diagonally connects the unit cell inside and outside the hexagon. C depicts the unit cell and c t c sub p is parallel with each other.

Fig. 6.12
Quadratic (a) and hexagonal (b) pencil minibeam and planar minibeam (c) arrangements on a 2D lattice with view direction in the direction of the beam. The dose is color coded and normalized to a mean dose D0. The black lines indicate the unit cell, and the white lines indicate the corresponding ctc. (Reproduced with permission from (CCBY) [112])


3 diagrams, a to c, with respective minibeams and c t c sub q. A depicts c t c sub q connects 2 unit cells above the square. B depicts c t c sub h diagonally connects the unit cell inside and outside the hexagon. C depicts the unit cell and c t c sub p is parallel with each other.


The basic mechanism of tissue sparing by spatial fractionation lies in the ability of undamaged cells in the vicinity of the radiation beam paths to migrate to this region and support wound healing. This is described as the dose-volume effect, i.e., the ability of skin and subcutaneous tissue in particular to tolerate more dose as the irradiated volume decreases. Furthermore, the microscopic prompt tissue repair is another beneficial effect resulting in better tolerance of tissue to submillimeter sized beams. When tissue is damaged in such small areas, capillary blood vessels can be rapidly restored within days or even hours by the regeneration of cells from the undamaged area. The intact blood vessels also support healing of the damaged tissue located between the beams. The extent to which the bystander effect plays a role is still unknown and is currently being investigated.


Spatial fractionation of photons is already being used clinically, but other treatment strategies are being tested simultaneously in preclinical and clinical studies. The application of photon SFRT in the clinic can be distinguished into GRID and LATTICE therapy. In GRID therapy, based on the original method of Koehler et al. in 1909, portions of the radiation field are blocked by the use of collimators placed in front of the patient to produce a non-conformal dose in both healthy tissue and tumor, as shown in a therapy plan in Fig. 6.13b [109].

Two sets of three magnetic resonance images in lattice and 2 D grid configurations.

Fig. 6.13
Treatment planning of a lung tumor patient in LATTICE (a) and GRID (b) therapy. (Reproduced with permission from [114])


Two sets of three magnetic resonance images in lattice and 2 D grid configurations.


Optimal geometries of collimators for tissue sparing and therapeutic outcome are hole sizes from 1 to 1.25 cm and ctc from 2.2 to 2.4 cm [114]. The pattern can be generated either with a block collimator with a defined hole pattern or with multileaf collimators (MLCs), which can be flexibly adapted to the needs of the treated tumor. The disadvantage of MLCs in the clinic is that treatment time is prolonged because each spot must be applied in a step-and-shoot procedure. Although faster irradiations are possible with MLCs by moving the target across the beam, this is currently only possible preclinically. A more advanced method is the hybrid use of an MLC and a block collimator, which combines the advantages of both methods but has the disadvantage of lower PVDR along the diagonal [115].


The efficiency of GRID therapy has been demonstrated in various clinical trials with different tumor types and by using different collimators [114, 115]. A modern approach to photon SFRT is LATTICE therapy, which can be used with arc-based therapy and is the 3D extension of GRID therapy. In LATTICE therapy, the beams are applied to form multiple small spheres of high dose, called vertices, in the tumor (Fig. 6.13a). The LATTICE application further reduces damage to normal tissue and has also been used in clinical trials [116].


While the use of SFRT in the clinic started with GRID and LATTICE, there are two other spatially fractionated modalities that are being studied preclinically. These are MRT, which uses spatially fractionated photons in the form of rectangular beams 25–100 μm wide (Fig. 6.14), and MBRT, which also uses rectangular photon beams but 400–700 μm wide.

A hematoxylin and eosin stain image of the cerebellum of a rat displays the leftward arrows denote the track of the microbeams. An immunostaining image of the different section of the cerebellum of a rat exhibits the four vertical green staining.

Fig. 6.14
Cerebellum of a rat 8 h after exposure to synchrotron MRT. The peak dose was 350 Gy, and each microbeam was 25 μm wide and spaced 200 μm from the center of the next microbeam. (a) H&E staining of the cerebellum. The track of the microbeams can be seen as two vertical bands of dark blue dots (yellow arrows) consisting of cells with nuclear pyknosis (irreversible condensation of chromatin in the nucleus of cells undergoing necrosis). (b) Immunostaining of a different section of the cerebellum with gamma-H2AX. The track of the microbeam can be seen as green staining, indicating large amounts of DNA damage. The blue color indicates nuclear staining with DAPI


A hematoxylin and eosin stain image of the cerebellum of a rat displays the leftward arrows denote the track of the microbeams. An immunostaining image of the different section of the cerebellum of a rat exhibits the four vertical green staining.


MRT has the distinction of using extremely thin microbeams, which exploits the dose-volume effect and allows very high doses of radiation (300–600 Gy) to be delivered with minimal toxicity to normal tissue. In addition, synchrotron facilities such as the European Synchrotron can deliver radiation at ultra-high dose rates (12,000–16,000 Gy/s), making synchrotron MRT a spatially fractionated FLASH RT [117].


The benefits of MRT over conventional RT are many:
Normal tissue is spared from the effects of radiation by two unique mechanisms: (1) volumetric sparing due to spatial fractionation of microbeams and (2) sparing of normal tissue due to ultra-high dose rates, known as the FLASH effect [117]. More details of FLASH radiotherapy are discussed in Sect. 6.4.2.

MRT produces unique vascular effects that preferentially damage tumor vessels rather than those of healthy tissue. Peak doses selectively affect rapidly growing “immature” tumor vasculature, triggering transient tumor ischemia and neutrophil infiltration [117].

Strong immune responses have been observed after MRT. For example, MRT can activate natural killer and cytotoxic CD8+ T cells, induce higher levels of pro-inflammatory genes in tumors, trigger the release of chemokines that attract monocytes, and recruit leukocytes to malignant tissues [118].


Normal tissue is spared from the effects of radiation by two unique mechanisms: (1) volumetric sparing due to spatial fractionation of microbeams and (2) sparing of normal tissue due to ultra-high dose rates, known as the FLASH effect [117]. More details of FLASH radiotherapy are discussed in Sect. 6.4.2.


MRT produces unique vascular effects that preferentially damage tumor vessels rather than those of healthy tissue. Peak doses selectively affect rapidly growing “immature” tumor vasculature, triggering transient tumor ischemia and neutrophil infiltration [117].


Strong immune responses have been observed after MRT. For example, MRT can activate natural killer and cytotoxic CD8+ T cells, induce higher levels of pro-inflammatory genes in tumors, trigger the release of chemokines that attract monocytes, and recruit leukocytes to malignant tissues [118].


MRT currently requires ultra-high dose rates to deliver the radiation fast enough to prevent the beam from smearing across tissue due to the cardiovascular motion. Therefore, preclinical and future clinical research on MRT is currently limited to synchrotron facilities. However, a compromise can be achieved by delivering photon MBRT, since beam smearing is not a problem with submillimeter beams. The same logic is now being applied to MBRT ion therapy research and will be discussed next.


The method of applying spatially fractionated RT using particles, also called minibeam RT, is still in its infancy. Preclinical research points to drastically lowered side effects, with at least same tumor control, thus clearly widening the therapeutic window. In MBRT, one distinguishes between proton MBRT and ion MBRT, most commonly carbon and helium. The major difference lies in the application of the dose to the tumor originating from different physical properties of the particles. When particles traverse matter, interactions with the atoms and molecules occur. At high energies, as used for therapy, the interactions are dominated by Coulomb interactions with the electrons of the target material. These mechanisms mainly cause the ions to lose energy and define the well-known Bragg curve of energy loss. But these interactions also cause scattering of the ions and thus deflection, called small-angle (Coulomb) scattering. In each interaction, the particle is only scattered by a small angle, causing a roughly gaussian broadening of an incident ion beam. The beam is thus widening with increasing penetration depth. The FWHM of the beam due to scattering, which is in the order of several millimeters for therapy relevant energies, is proportional to the ion charge z its kinetic energy Ekin and the distance covered in medium x:

 (6.4)Therefore for helium and carbon ions, this results in a reduction of beam width compared to protons of a factor of ~2 and ~3, respectively, as shown in Fig. 6.15.

Line graph A presents f w h m versus depth in water. The proton, helium, carbon, and neon exhibit an upward trend, with proton having the highest value. B exhibits width in centimeters versus distance in centimeters where helium ion and proton beam widen as the distance increases.

Fig. 6.15
(a) Beam width for proton, helium, and carbon ion beams with penetration depth. No incident beam size and divergence is used, both have to be added to the FWHM. (b) Widening of a helium ion and a proton beam with penetration depth


Line graph A presents f w h m versus depth in water. The proton, helium, carbon, and neon exhibit an upward trend, with proton having the highest value. B exhibits width in centimeters versus distance in centimeters where helium ion and proton beam widen as the distance increases.


Therefore MBRT for protons works with the principle that the beams start to clearly widen, while traversing tissue as shown in Fig. 6.16. The planning is done in a way that at the beginning of the tumor, the beams overlap and the tumor is irradiated with a small PVDR or even a homogeneous dose distribution.

2 conceptual therapy plans of homogenous and minibeam for a box-shaped tumor. Minibeam exhibits the pencil and the planar beams overlap and penetrate the skin and the healthy tissue and then widen at the beginning of the tumor. On the right is the scale for dose distribution from 0% to above 120%.

Fig. 6.16
Conceptual therapy plans comparing conventional proton therapy (homogeneous) with pMBRT (Minibeam) for a box-shaped tumor


2 conceptual therapy plans of homogenous and minibeam for a box-shaped tumor. Minibeam exhibits the pencil and the planar beams overlap and penetrate the skin and the healthy tissue and then widen at the beginning of the tumor. On the right is the scale for dose distribution from 0% to above 120%.


For helium and carbon, the beams don’t overlap, thus giving potential for further sparing of healthy tissue also close to the tumor volume. Although there is evidence for tumor control using heterogeneous tumor dose, it seems appropriate to find a way of applying an (almost) homogeneous dose to the tumor [119]. This is achieved through so-called interlacing, where the beams of different irradiation fields are arranged in a way that in the tumor the dose peaks interlock and homogeneous dose distribution is formed. Figure 6.17 shows different possibilities of interlacing using either pencil or planar beams compared to single direction irradiation.

6 diagrams of the interlacing geometries in M B R T. 1- and 2-direction pencil p M B R T, 1- and 2-direction planar p M B R T, and 2- and 4-direction planar p M B R T, where the beams of different irradiation fields are arranged for the homogeneous irradiation of a box-shaped tumor.

Fig. 6.17
Possible interlacing geometries in MBRT for pencil (a, b) or planar (c–f) beams for homogeneous irradiation of a box-shaped tumor (black dashed line). (Reproduced with permission (CCBY) from [119])


6 diagrams of the interlacing geometries in M B R T. 1- and 2-direction pencil p M B R T, 1- and 2-direction planar p M B R T, and 2- and 4-direction planar p M B R T, where the beams of different irradiation fields are arranged for the homogeneous irradiation of a box-shaped tumor.


Up to now, the method of MBRT is still in the preclinical state and especially proton MBRT is investigated here, as the possible spreading is more promising as more proton therapy centers than other particle therapy centers exist worldwide. Up to now it could be shown that pMBRT has lower early and late side effects in the skin of mice and rats [113, 120]. Furthermore, in a rat brain model, it could be shown that less histological and behavioral changes occur after pMBRT [120]. Already tumor treatment was performed in glioma bearing rats, where animal survival could be clearly enhanced while tumor control was kept. First therapy planning in brain tumor patients shows reduced dose to organs at risk, while the same dose distribution in PTV could be achieved (Fig. 6.18) [121]. These promising preclinical results cleared the way for clinical trials. First results on treatment of ten patients treated with pMBRT, called proton GRID therapy, in a clinical study (NCT01255748) show the possible advantages of pMBRT, regarding sparing of healthy tissue and tumor control [122]. Furthermore, the integration of pMBRT to clinical facilities is under investigation and especially the combination with FLASH RT seems promising [113]. An important task which needs to be solved is the production of mini beams with a small enough size without producing secondary radiation, which can harm the patient. The two possible ways of minibeam production are via the focusing of a proton beam or via the use of a collimator. Both methods are complementary, and their use in clinical practice needs to be further investigated.

4 treatment plans for meningioma. Plans 1 and 2 are homogeneous plans while 3 and 4 display single field p M B R T plans that directly target P T V in the brain. Below, a line graph of volume versus dose. Right lobe, brain, and brain stem depict a downward trend while P T V plateau before declining.

Fig. 6.18
(a) Treatment plan comparison of a meningioma patient. Plan 1 and 2 are homogeneous plans, with different planning methods. Plan 3 and 4 show single field pMBRT plans with ctc of 4 mm and 6 mm, respectively. (b) Comparison of dose-volume histograms for plan 2 (homogeneous, dashed line) and plan 3 (pMBRT, solid line)


4 treatment plans for meningioma. Plans 1 and 2 are homogeneous plans while 3 and 4 display single field p M B R T plans that directly target P T V in the brain. Below, a line graph of volume versus dose. Right lobe, brain, and brain stem depict a downward trend while P T V plateau before declining.


According to the dose rate brachytherapy can be divided into three types: low dose rate (LDR) with dose rates 0.4–2 Gy/h, medium dose rate (MDR) with dose rates 2–12 Gy/h, and high-dose rate (HDR) with dose rates excessing 12 Gy/h.

Brachytherapy can be delivered with sealed radionuclide sources and electronic brachytherapy using kV X-rays.

Brachytherapy is mostly used for treatment of cervix, prostate, and skin cancers and some rare sarcomas.


According to the dose rate brachytherapy can be divided into three types: low dose rate (LDR) with dose rates 0.4–2 Gy/h, medium dose rate (MDR) with dose rates 2–12 Gy/h, and high-dose rate (HDR) with dose rates excessing 12 Gy/h.


Brachytherapy can be delivered with sealed radionuclide sources and electronic brachytherapy using kV X-rays.


Brachytherapy is mostly used for treatment of cervix, prostate, and skin cancers and some rare sarcomas.


Brachytherapy is a treatment technique in which radiation sources are placed into the tumor (or the tumor bed to be treated after surgery) or its proximity. For conventional brachytherapy, sealed radionuclide sources are used, but electronic brachytherapy with X-ray has recently become available. The advantage of brachytherapy is a very high dose gradient around the sources, which are, contrary to external RT, extremely close to the treated area. Sharp dose decrease allows for a high level of conformity when dose is delivered locally. However, the technique is available only for easily accessible treatment areas.


The fractionation scheme is different in comparison to the external RT with lower number of fractions and higher doses per fraction.


Usually, radionuclide implants are applied to deliver the treatment which can be either temporary or permanent. The radionuclides need to have convenient physical characteristics (half-life, type of disintegration, mean energy, nominal specific activity, etc.).


According to the dose rate brachytherapy can be divided into three types: low dose rate (LDR) with dose rates 0.4–2 Gy/h, medium dose rate (MDR) with dose rates 2–12 Gy/h, and high dose rate (HDR) with dose rates exceeding 12 Gy/h (which is 0.2 Gy/min). Higher source energies are used for temporary brachytherapy with HDR sources compared to permanent LDR brachytherapy. Pulsed dose rate (PDR) uses series of short exposures of 10–30 min every hour to approximately the same total dose in the same overall treatment time as with the LDR. Characteristics of frequently used radionuclides are presented in Table 6.9.Table 6.9
Physical characteristics of radionuclides used for brachytherapy

Characteristic

192Ir

60Co

137Cs

125I

103Pd

Type of disintegration

β− (95.1%), Electron capture (4.9%)

β−

β−

Electron capture

Electron capture

Half-life

73.83 days

5.27 years

30.07 years

59.4 days

17.0 days

Mean gamma energy (keV)

372.2

1252.0

661.7

35.5

137.1

Nominal specific activity (×105 TBq/kg)

3.4

0.41

3.2 × 10−2

6.5

27

Air kerma-rate constant (×10−18 Gy m2/(Bq s))

15

85

6.1 × 10−5

9.9

9.0


Electronic brachytherapy is a non-invasive procedure and is a good option for skin cancers in the facial area, especially around the eye and nose. It is also an option after breast conserving surgery to treat the tumor bed when intraoperative RT is used according to an accelerated partial breast irradiation (APBI) procedure. Kilovoltage X-rays generators are used with voltage potential 30–50 kVp.


There are several types of brachytherapy depending on the site and organ type to be treated [123].


Intracavitary brachytherapy uses sources that are placed in body or organ cavities. It is mostly used to treat early cervical and uterine (endometrial) cancer, but also in a heterogeneous group of gynecological cancers (ovary, fallopian tubes, body of the uterus, vagina, and vulva). Early rectal cancer can be treated with electron brachytherapy, but the standard of care in rectal cancer is still surgery, especially in case of bulky tumors and more advanced disease, preceded by radio(chemo)therapy.


Interstitial brachytherapy employs sources placed into the tumor, or to its proximity, using needles. It has primarily been used to treat prostate or breast cancer (PCa, BC), but recently it has also been combined with intracavitary brachytherapy to treat bulky cervix tumors. This combination improves coverage of the target volume which was not achievable intracavitary techniques only. PCa brachytherapy can be performed with permanent seeds (for LDR) or temporary sources (for HDR). For breast brachytherapy, interstitial multicatheter brachytherapy is used for boost or partial breast irradiation (PBI)/accelerated PBI (APBI). APBI treats only the lumpectomy bed with 1–2 cm margin, rather than the whole breast [124]. HDR sources are usually applied to deliver prescribed doses of 30.3–34 Gy in 7–10 fractions for APBI and 15–20 fractions with LDR/PDR (pulsed dose rate) or 8.5–10 Gy with HDR for breast boost treatment. Soft tissue sarcomas are sometimes also treated with brachytherapy alone or in combination with external RT after surgery.


When sources are placed into tubular organs such as trachea, lungs, esophagus, or bile duct, the term intraluminal brachytherapy is used. For lung cancer, the ability of patients to tolerate bronchoscopy is essential. The main indication is treatment of significant, endotracheal, or endobronchial symptoms. Endobronchial brachytherapy is mainly palliative, however it has been used with curative intent in a small number of cases of early-stage tumors with good results.


Skin cancer can usually be treated by placing the sources on the skin in the desired geometry, therefore it is sometimes referred to as contact brachytherapy. Skin cancer is a very common cancer, and brachytherapy is used mainly for areas such as face, scalp, ears, hands, legs, especially when surgery would result in poor cosmetic results or require (extensive) plastic reconstructions. Most cancers are either squamous or basal cell carcinomas. Contact applicators or surface molds can be used. The applied dose is tumor size dependent. For LDR and PDR brachytherapy, doses of 60–66 Gy are delivered to tumors less than 4 cm and 75–80 Gy for those more than 4 cm. For HDR brachytherapy, typical total dose is 30–40 Gy delivered in 8–10 fractions. Other options for skin treatment include superficial X-rays, orthovoltage X-rays, megavoltage photons, or electron beam irradiation.


Ocular brachytherapy can be used to treat uveal malignant melanoma. Currently, the most frequently used radionuclides are I-125, Ru-106/Rh-106, Pd-103, Cs-131.


Intravascular brachytherapy is a rarely used treatment option. It can be used to treat restenosis following percutaneous angioplasty of cardiac arteries. The sources are temporarily placed within cardiac stents in which restenosis has occurred to prevent restenosis. Typically, beta emission sources like P-32, Ir-192, or Rh-188 are used for the treatment. P-32 coated stents have also been used, but with the development of drug-eluting stents, intravascular brachytherapy has lost a lot of its attractivity.


The application of brain brachytherapy has decreased a lot since highly conformal RT radiotherapy and stereotactic radiosurgery are available. However, brachytherapy can still be used to treat gliomas with a maximum diameter of 5 cm if not too close to organs at risk.


Three main radiobiology parameters in brachytherapy are dose rate, cell cycle redistribution, and reoxygenation.


Brachytherapy can be used as a single strategy or can be combined with other treatment modalities. When combining brachytherapy with external beam RT, total dose to the tumor and organs and risk must be considered. As an example, for the cancer of the cervix, both radiation treatment modalities are usually combined [125]. In such a case, the doses to the tumor and to the critical organs should be always considered as a summation of radiobiological doses to each structure. The LQ model l is recommended with the concept of equi-effective dose (EQD2) [126]. For simple estimations and HDR brachytherapy, the LQ model without any corrections can be applied to calculated EQD2. However, there are some radiobiological factors relevant to brachytherapy for continuous treatment or for multiple fractions per day. Repair rates (called μ values) are used to correct doses for repair of sublethally damaged cells. Average repair half-lives for mammalian tissues are usually 0.5–3 h. There exists evidence that tumor recovery half-lives are probably shorter than those for late-reacting normal tissues.


In fractionated treatment with HDR, there should be at least 6 or 8 h between individual fractions to enable the cells of normal tissues to repair. HDR brachytherapy delivers treatment with dose rates exceeding 12 Gy/h with 192-Ir or 60-Co sealed sources. Pulsed dose rate (PDR) brachytherapy is fractionated treatment but with a special time schedule. The treatment is delivered with continuous hourly pulses. This approach is supposed to give a similar effect as a hyperfractionation. It was shown that if the time interval between pulses does not exceed 1 h, overall treatment time is not modified, total dose is the same, and the dose rate is not above 0.5–0.6 Gy/h.


Radiobiological modeling demonstrated that the PDR technique rather than continuous LDR radiation allows to exploit differences between the half times for sublethal damage repair (T1/2) of late-responding normal tissues and tumors. Repair half times for tumors are estimated to be in the range of 1–2 h, while for late-responding normal tissues, these could be as long as 3–4 h. By matching the pulse frequency with tissue repair kinetics, in a fixed overall treatment time, a therapeutic benefit, i.e., normal tissue sparing while keeping the same tumor control probability, can be obtained relative to continuous LDR radiation. On the basis of those modeling data, an office hours PDR boost regimen was designed for substitution of the continuous LDR boost in breast conserving therapy [127]. A next theoretical study on the optimal fraction size in hypofractionated HDR brachytherapy demonstrated large dependency on the treatment choices (the number of fractions, the overall time, and time between the fractions) and the treatment conditions (reference LDR dose rate tissue repair parameters). The data revealed that hypofractionated HDR might have its opportunities for widening of the therapeutic window for a specific combination of those choices and conditions.


In general, tumor reoxygenation occurs during fractionated treatment. In LDR brachytherapy, the contribution of reoxygenation is low. The lower the dose rate, the lower the oxygen enhancement ratio due to the reduction in sublethal damage repair capability in hypoxic cells.


It is well known that cells have different sensitivity to radiation due to their position in the cell cycle phases. With HDR brachytherapy, delivered in fractions, it can be more difficult to synchronize cells in these cell cycle phases. On the other hand, with LDR brachytherapy the cell distribution in certain cycle phases can be better and earlier synchronized. Cell cycle changes were also observed later for PDR, however, which were more long-lasting and more pronounced [128].


Radioembolization is based on a vascular selectivity process resulting in a differential effect that leads to a higher concentration of radioactivity within tumor tissue than in non-tumoral liver.

Treatment course includes several steps, notably a treatment planification process aiming to personalize the activity of radioembolization to administer.

Radioembolization is commonly used in treatment of primary and metastatic liver diseases.


Radioembolization is based on a vascular selectivity process resulting in a differential effect that leads to a higher concentration of radioactivity within tumor tissue than in non-tumoral liver.


Treatment course includes several steps, notably a treatment planification process aiming to personalize the activity of radioembolization to administer.


Radioembolization is commonly used in treatment of primary and metastatic liver diseases.


Yttrium-90 radioembolization, also called Yttrium-90 selective internal radiotherapy (SIRT), is a type of brachytherapy based on intrahepatic arterial administration of yttrium-90 (90Y)-loaded biocompatible microspheres (90Y-microspheres) [129]. Two types of microsphere loaded with 90Y are commercially available: one made of resin (SIR-Spheres®, Sirtex, St. Leonards, Australia) and an alternative made of glass (TheraSphere®, Boston Scientific, Marlborough, MA, USA). The rationale for this approach is that both primary and metastatic tumors in the liver receive their blood supplies primarily from the hepatic artery, whereas the non-tumoral liver (NTL) is fed essentially entirely via the portal vein rather than the hepatic artery [130].


90Y is a therapeutic radionuclide with a physical half-life of 2.67 days (64.05 h) and combined electron (β−) and positron (β+) emission. The maximum and average energies of β− emissions from 90Y are 2.28 MeV and 934 keV, with a mean tissue penetration of 4.1 mm and a maximum of 11 mm. As in other RTs, 90Y β− absorbed dose deposition induces direct or indirect damage to DNA in exposed tissue, leading to early or delayed cellular death [130]. To avoid serious adverse events such as radiation pneumonitis secondary to lung contamination via hepato-pulmonary shunts or radioembolization-induced liver disease (REILD), the irradiation of liver malignancies is limited by unintended exposure to NTL and lung parenchyma.


Although the branching ratio is very low, the β+ emission enables 90Y-microsphere positron emission tomography (PET) imaging after radioembolization. It is also possible to image the 90Y-microsphere distribution based on the β− bremsstrahlung emission spectrum by bremsstrahlung emission computed tomography (BECT).


Therefore, the efficacy of radioembolization is based on a vascular selectivity process resulting in a differential effect that leads to a higher concentration of radioactivity within tumor tissue than in NTL. The stronger the differential effect, the more effective the treatment will be. Due to their size, the tumor’s vascular properties, and the hemodynamics of the vascular system used for targeting, 90Y-microspheres are permanently implanted into the micro-vessels of the tumor/NTL without any biological degradation (although physical decay of 90Y still occurs).


Radioembolization has been broadly adopted as a locoregional therapy for advanced primary or metastatic liver disease [129, 130]. The most common indications for radioembolization are hepatocellular carcinoma (HCC), liver metastases from colorectal cancer (mCRC), intrahepatic cholangiocarcinoma (IH-CCA), and neuroendocrine tumors (NET) [129, 131]. Very little scientific evidence (level 1 or 2) derived from prospective randomized controlled trials supports the use of radioembolization as a first- or second-line treatment option in various treatment algorithms. Prospective data have been obtained for HCC and mCRC patients, and prospective studies in IH-CCA and NET are underway [132]. In the HCC management guidelines for the European Association of Medical Oncology (ESMO), radioembolization is considered as the last-line treatment. The ESMO guidelines for the management of mCRC patients include radioembolization as a second-line treatment for patients with liver-limited disease in whom the available chemotherapeutic options have failed.


The treatment course, illustrated in Fig. 6.19, includes several steps [132]:
First, patients are selected for radioembolization by the multidisciplinary tumor board, based upon individual characteristics. Radioembolization requires a holistic view of the patient and the disease. Disease stage, long-term and immediate treatment aims, morphological features [assessed using computed tomography (CT) or magnetic resonance imaging (MRI)], metabolic/functional properties [e.g., assessed using [18F]-fluorodeoxyglucose (18F-FDG) hybrid PET coupled with CT (PET/CT) imaging], and biological characteristics of the tumor, and the surrounding liver are all considered when establishing a radioembolization treatment plan.

Then, a pre-treatment 3D hepatic CT angiogram is performed. The goal is to decide into which artery the 90Y-resin microspheres will be injected and to determine the best catheter position to optimize the selectivity of treatment.

To simulate the treatment, a 2D hepatic angiogram is performed, generally accompanied by a 3D cone-beam CT (CBCT). The catheter is placed at the position defined by the 3D CT angiogram, and 99mTc-labeled macroaggregated-albumin (99mTc-MAA) is injected into the hepatic artery. Given the similar median size of MAA particles (10–50 μm) and resin microspheres (20–60 μm), the MAA distribution pattern serves as a surrogate for how 90Y-microspheres will localize.

To visualize the distribution of 99mTc-MAA, planar scintigraphy, generally accompanied by hybrid single-photon emission CT and CT imaging (SPECT/CT), is acquired within 2 h after administration. This allows validation of the catheter position, identification of potential extrahepatic visceral contamination, and evaluation of the lung shunt and the targeting of the lesions; in addition, it can be used to determine the activity to administer in future therapy. This practice prevents post-therapy complications and selects patients with a good potential outcome.

After this pre-treatment phase, treatment with 90Y-microspheres is performed according to the pre-treatment catheter position and prescribed activity. With catheter-directed therapies such as radioembolization, it is important to verify that the position/location of the catheter during the 99mTc-MAA simulation is consistent with the position during the administration of 90Y-microspheres to best reproduce the MAA distribution.

Following administration of 90Y-microspheres, a qualitative and quantitative assessment is performed (1) to verify that the treatment was performed as planned and identify any technical failures and (2) to detect any possible extrahepatic activity, which could cause serious complications such as gastrointestinal bleeding. Post-radioembolization imaging of 90Y distribution may be performed using hybrid 90Y-PET/CT or 90Y-BECT/CT. However, many studies show qualitatively superior resolution and contrast with 90Y-PET/CT relative to 90Y-BECT/CT, and only 90Y-PET/CT is available for quantification in clinical routine (90Y-BECT/CT quantitative imaging is still under development).

Finally, treatment response is evaluated. Clinical and biochemical assessment after radioembolization for any significant side effects is typically performed 1–2 months post-radioembolization. Imaging assessment of the tumor response should be performed 1–3 months post-radioembolization and every 2–3 months thereafter. The clinically relevant “treatment response,” and thus the most suitable imaging technique, is defined differently depending on the type of tumor (e.g., variable 18F-FDG avidity) and treatment intent (e.g., bridging-to-surgery, downstaging, etc.) [131].

A flow diagram of the treatment course. It involves patient selection, treatment planning, treatment 7 to 15 days after simulation, and patient follow up 6 to 8 weeks after treatment.

Fig. 6.19
90Y-resin microspheres radioembolization treatment course. Example of a patient treated for neuroendocrine neoplasia


First, patients are selected for radioembolization by the multidisciplinary tumor board, based upon individual characteristics. Radioembolization requires a holistic view of the patient and the disease. Disease stage, long-term and immediate treatment aims, morphological features [assessed using computed tomography (CT) or magnetic resonance imaging (MRI)], metabolic/functional properties [e.g., assessed using [18F]-fluorodeoxyglucose (18F-FDG) hybrid PET coupled with CT (PET/CT) imaging], and biological characteristics of the tumor, and the surrounding liver are all considered when establishing a radioembolization treatment plan.


Then, a pre-treatment 3D hepatic CT angiogram is performed. The goal is to decide into which artery the 90Y-resin microspheres will be injected and to determine the best catheter position to optimize the selectivity of treatment.


To simulate the treatment, a 2D hepatic angiogram is performed, generally accompanied by a 3D cone-beam CT (CBCT). The catheter is placed at the position defined by the 3D CT angiogram, and 99mTc-labeled macroaggregated-albumin (99mTc-MAA) is injected into the hepatic artery. Given the similar median size of MAA particles (10–50 μm) and resin microspheres (20–60 μm), the MAA distribution pattern serves as a surrogate for how 90Y-microspheres will localize.


To visualize the distribution of 99mTc-MAA, planar scintigraphy, generally accompanied by hybrid single-photon emission CT and CT imaging (SPECT/CT), is acquired within 2 h after administration. This allows validation of the catheter position, identification of potential extrahepatic visceral contamination, and evaluation of the lung shunt and the targeting of the lesions; in addition, it can be used to determine the activity to administer in future therapy. This practice prevents post-therapy complications and selects patients with a good potential outcome.


After this pre-treatment phase, treatment with 90Y-microspheres is performed according to the pre-treatment catheter position and prescribed activity. With catheter-directed therapies such as radioembolization, it is important to verify that the position/location of the catheter during the 99mTc-MAA simulation is consistent with the position during the administration of 90Y-microspheres to best reproduce the MAA distribution.


Following administration of 90Y-microspheres, a qualitative and quantitative assessment is performed (1) to verify that the treatment was performed as planned and identify any technical failures and (2) to detect any possible extrahepatic activity, which could cause serious complications such as gastrointestinal bleeding. Post-radioembolization imaging of 90Y distribution may be performed using hybrid 90Y-PET/CT or 90Y-BECT/CT. However, many studies show qualitatively superior resolution and contrast with 90Y-PET/CT relative to 90Y-BECT/CT, and only 90Y-PET/CT is available for quantification in clinical routine (90Y-BECT/CT quantitative imaging is still under development).


Finally, treatment response is evaluated. Clinical and biochemical assessment after radioembolization for any significant side effects is typically performed 1–2 months post-radioembolization. Imaging assessment of the tumor response should be performed 1–3 months post-radioembolization and every 2–3 months thereafter. The clinically relevant “treatment response,” and thus the most suitable imaging technique, is defined differently depending on the type of tumor (e.g., variable 18F-FDG avidity) and treatment intent (e.g., bridging-to-surgery, downstaging, etc.) [131].


A flow diagram of the treatment course. It involves patient selection, treatment planning, treatment 7 to 15 days after simulation, and patient follow up 6 to 8 weeks after treatment.


Curative setting: Radioembolization can be used in a preoperative setting (for solitary or limited-multifocal/oligometastatic tumor) when the ambition is to cure the patient. It can be used as bridging-to-surgery, to stabilize or slow down tumor growth and multiplicity thereby keeping a patient as a potential surgical candidate for liver resection or transplantation. Alternatively, radioembolization can be applied as a downstaging approach to induce a clinical shift from a non-resectable stage to a potentially resectable or transplantable stage by decreasing tumor size or number [129, 130].

Non-curative setting: In patients with advanced multifocal bilobar/lobar tumor distribution in whom curative approaches are not feasible, radioembolization can be used alone or in combination with other therapies as a life-prolonging treatment and palliative care [129, 130].


Curative setting: Radioembolization can be used in a preoperative setting (for solitary or limited-multifocal/oligometastatic tumor) when the ambition is to cure the patient. It can be used as bridging-to-surgery, to stabilize or slow down tumor growth and multiplicity thereby keeping a patient as a potential surgical candidate for liver resection or transplantation. Alternatively, radioembolization can be applied as a downstaging approach to induce a clinical shift from a non-resectable stage to a potentially resectable or transplantable stage by decreasing tumor size or number [129, 130].


Non-curative setting: In patients with advanced multifocal bilobar/lobar tumor distribution in whom curative approaches are not feasible, radioembolization can be used alone or in combination with other therapies as a life-prolonging treatment and palliative care [129, 130].


Whole-liver treatments: In the case of bilobar multifocal tumor distribution, the whole liver must be treated. Single injection within the common hepatic artery or a bilobar (left and right hepatic artery) approach is performed. The bilobar approach can be performed on the same day or staged (i.e., on separate days).

Lobar and segmental treatments: Unilobar or segmental treatments are considered when the disease is limited to a unique lobe or a segment. These approaches enable the preservation of the untreated liver, and if some loss of function in the treated lobe/segment is permissible, they allow more aggressive treatment.

Lobectomy and Segmentectomy: Radiation lobectomy, with the intent to induce contralateral lobe hypertrophy while achieving tumor control, may be considered in patients with unilobar disease and a small anticipated future liver remnant in an attempt to facilitate curative surgical resection.

Radiation: segmentectomy may be considered for localized disease (one or two segments) supplied by a segmental artery that is not amenable to other curative therapies because of tumor localization or patient comorbidities.


Whole-liver treatments: In the case of bilobar multifocal tumor distribution, the whole liver must be treated. Single injection within the common hepatic artery or a bilobar (left and right hepatic artery) approach is performed. The bilobar approach can be performed on the same day or staged (i.e., on separate days).


Lobar and segmental treatments: Unilobar or segmental treatments are considered when the disease is limited to a unique lobe or a segment. These approaches enable the preservation of the untreated liver, and if some loss of function in the treated lobe/segment is permissible, they allow more aggressive treatment.


Lobectomy and Segmentectomy: Radiation lobectomy, with the intent to induce contralateral lobe hypertrophy while achieving tumor control, may be considered in patients with unilobar disease and a small anticipated future liver remnant in an attempt to facilitate curative surgical resection.


Radiation: segmentectomy may be considered for localized disease (one or two segments) supplied by a segmental artery that is not amenable to other curative therapies because of tumor localization or patient comorbidities.


Until recently, the prescription of 90Y-microspheres was based upon the body surface area method (resin microspheres) or on a dose limit to the whole treated liver volume without distinction between tumor and non-tumoral liver (glass microspheres). Both approaches lead to inherent risks of under- or overdosing, with considerable interpatient variations [130, 132]. To tackle those pitfalls, the concept of personalized radioembolization has recently emerged and provides an optimal framework to improve patient selection and maximize tumor response while sparing non-targeted tissues undesired toxicities. The patient-specific definition of a radioembolization therapeutic window is now assessed by integrating multidisciplinary teamwork, multimodal imaging techniques, advanced treatment planning algorithm, and by considering relationships between radiation dose and treatment outcomes. Precision radioembolization with dosimetry is now recommended as the standard approach in recent international recommendations [132, 133]. Recently, a prospective randomized phase II clinical study in HCC, the DOSISPHERE-01 trial, provided the first level one scientific evidence that personalized radioembolization significantly improves overall survival compared to the standard semi-empirical approach [134].


The concept of using radiation to treat cancer and other diseases found its origin in the discovery of X-rays in 1895. After Pierre and Marie Sklodowska-Curie discovered radium as a source of IR further interest was sparked. However, it wasn’t until the 1950s that external beam radiation became a key treatment modality for cancer. Since then, external beam RT has become one of the most efficient tools for treatment of locally confined cancers. However, its effect is limited for treatment of more advanced and disseminated disease. In the early twentieth century, first potential for using Iodine-131 as a targeted therapeutic was discovered by nuclear pioneers such as Saul Hertz [135]. This discovery was the start of the field of radionuclide therapy and today, several types of radionuclide therapy exist. Each of the different types will be discussed in this section.


Cancer cells often express certain molecules on their membrane surface, called receptors, which are not or to a lesser extent present on healthy cells. These receptors on cancer cells can be targeted by several molecules, being a peptide, small molecule or (parts of) antibodies, which will be termed as the ligand. When talking about radiopharmaceuticals, the cancer-targeting moiety is linked to a chelator molecule, responsible for entrapping a radionuclide into the structure as shown in Fig. 6.20.

A schematic diagram of the radiopharmaceutical structure. From bottom to top, targeting moiety is connected to the linker molecule which entraps the chelator plus radionuclide.

Fig. 6.20
Schematic representation of the structure of a radiopharmaceutical. The purple circle represents the cancer-targeting moiety, which can be a peptide, small molecule, or antibody. This targeting moiety is connected to a chelator (blue circle) entrapping a radionuclide (for diagnostics or therapy) directly to the targeting moiety or via a linker molecule (grey)


A schematic diagram of the radiopharmaceutical structure. From bottom to top, targeting moiety is connected to the linker molecule which entraps the chelator plus radionuclide.


As already explained in Chap. 2, based on the purpose of the radiopharmaceutical, being diagnostic or therapeutic, different radionuclides can be used. For diagnostic purposes, gamma (γ)-emitting radionuclides are used. Radionuclides that are usually used for therapy are alpha (e.g., actinium-225), beta (e.g., lutetium-177), or Auger electron (e.g., iodine-125) emitters.


Upon binding of the ligand to its receptor, the radioligand complex gets internalized. Upon internalization, the radionuclide will emit its toxic IR from inside the cell and cause damage to cellular structures including DNA and cell membrane, resulting in cancer cell death, as shown in Fig. 6.21.

A schematic depicts oral and systemic routes of administration will enter the bloodstream in a systemic circulation and proceeds to the target issue either through natural affinity radionuclides with affinity based uptake or vectorized radionuclide therapy with uptake based on protein expression.

Fig. 6.21
Overview of the general principle or radioligand therapy. A radionuclide (either ingested orally or injected systemically) will enter the bloodstream. Via the bloodstream, the radionuclide will find its way to the target tissue either through its natural affinity for the target tissue (i.e., the natural affinity radionuclides) or via expression of certain molecules on the target tissue (i.e., vectorized radionuclide therapy)


A schematic depicts oral and systemic routes of administration will enter the bloodstream in a systemic circulation and proceeds to the target issue either through natural affinity radionuclides with affinity based uptake or vectorized radionuclide therapy with uptake based on protein expression.


Radioligand therapy (RLT) can in theory be used to target any type of cells (over)expressing the target molecule and can thus be used to attack multiple (micro) metastases instead of only targeting the primary tumor, in contrast to external beam RT (EBRT) that focus on one or several, geographically limited target volumes. Furthermore, RLT enables specific targeting of cancer lesions (including metastatic cancer cells), while causing minimal damage to surrounding healthy tissues and thus minimizing the amount of side effects [136] (Box 6.16).


Human cancers express molecules on their membrane surface that can be targeted for therapy.

A radioligand is comprised of a cancer-targeting moiety (small molecule, peptide, or (part of) antibody) linked to a chelator entrapping the radionuclide.

Radioligand therapy enables specific targeting of cancer cells, with minimal harm to surrounding healthy tissues.


Human cancers express molecules on their membrane surface that can be targeted for therapy.


A radioligand is comprised of a cancer-targeting moiety (small molecule, peptide, or (part of) antibody) linked to a chelator entrapping the radionuclide.


Radioligand therapy enables specific targeting of cancer cells, with minimal harm to surrounding healthy tissues.