Theranostics, the combination of therapy and diagnostics, is emerging in personalized medicine approaches. The main goal is to use diagnostic imaging to follow-up (radio)therapeutic interventions and improve or alter them along the way, thereby increasing efficacy and limiting toxicological effects. The ideal theranostic pair, i.e., for imaging or therapy, respectively, has the same pharmacokinetics, meaning that the pair should be distributed, metabolized, and cleared similarly [137]. If this is the case, the diagnostic counterpart can be used to accurately determine the accumulation and absorbed dose in different organs, including tumor, that would result upon injection of the therapeutic radiopharmaceutical. The imaging thus further allows selection of patients with high probability of response to the therapy (i.e., predictive biomarkers) and can provide guidance on the total activity of the therapeutic counterpart to be administered. It can also be used for treatment response evaluation in follow-up. Several therapeutic radionuclides (e.g., 177Lu, 131I) intrinsically decay via both particle- and γ-emission which can be used for both imaging and therapy that said after administration of vastly different injected activities [137]. Different radioisotopes of the same element have the greatest theoretical appeal to use in the theranostic approach. Examples are the radioisotopes of iodine (123/124/131I), terbium (149/152/155/161Tb), and yttrium (86/90Y) [138]. Although the biological behavior of these radiopharmaceuticals will be similar, the use in clinical practice might be limited due to unfavorable decay properties, long T1/2, availability, and cost of production. In this respect, radiopharmaceuticals which use the same vector molecule but different radiometals are often applied for this purpose as they have similar pharmacokinetics. A prime example is the somatostatin receptor targeting vector DOTATATE, which can be radiolabeled with the PET radionuclide 68Ga and the therapeutic radionuclide 177Lu, harnessing the diagnostic potential of PET (which have higher resolution and sensitivity for radioactivity) to enable efficient therapeutic approaches [139]. Of note, current efforts are being made to include [18F]AIF into the armamentarium to eventually replace 68Ga [140].


Radiotheranostics is being applied to the different branches of radiopharmaceutical development, including radioimmunotherapy (with, for example, nanobodies, antibodies, or similar affinity reagents), peptide receptor radionuclide therapy, radiolabeled microspheres/nanoparticles, and small molecules. This combination of therapy and diagnostics can help to reduce the toxic side effects by appropriate patient selection and determination of administered activity. The benefit and safety of using repeated treatment have also been proven in several studies.


A key aspect to note is the uptake and retention of the radionuclides at the target site. Logically, tumor-to-background ratios should be as high as possible for both diagnostic and therapeutic radionuclides. However, diagnostic imaging is typically performed in a time scale of several minutes to 1 h and thus optimally, radionuclides with a short T1/2 should be applied. On the other hand, radionuclides with a longer T1/2 are typically used for therapy, which can result in a more selective tumor irradiation, with higher dose to the tumor than to the healthy tissues (Fig. 6.22). The most important requirement for a therapeutic radiopharmaceutical is to have a high ratio between the integral of the time-activity curve (previously known as the residence time) of the tumor vs. normal organs (Box 6.17).

2, line graphs of concentration versus time. The area of the timeframe for static imaging between two time-activity curves is denoted in the diagnostic radionuclide and the area of the high selectivity for damage to the tumor over plasma is displayed in the therapeutic radionuclide, left and right, respectively.

Fig. 6.22
Hypothetical representation of time-activity curves (TACs) of a vector radiolabeled with a diagnostic (T1/2 = 30 min) and therapeutic radionuclide (T1/2 = 6 h)


2, line graphs of concentration versus time. The area of the timeframe for static imaging between two time-activity curves is denoted in the diagnostic radionuclide and the area of the high selectivity for damage to the tumor over plasma is displayed in the therapeutic radionuclide, left and right, respectively.


The theranostic approach makes use of diagnostic and therapeutic nuclear medicine.

Theranostics utilizes different isotopes of the same element.

Therapeutic radiopharmaceuticals can use radionuclides with a longer half-life compared to diagnostic radiopharmaceuticals.

Radiopharmaceutical vector molecules can include peptides, antibodies, nanobodies, nanoparticles, and small molecules.


The theranostic approach makes use of diagnostic and therapeutic nuclear medicine.


Therapeutic radiopharmaceuticals can use radionuclides with a longer half-life compared to diagnostic radiopharmaceuticals.


Radiopharmaceutical vector molecules can include peptides, antibodies, nanobodies, nanoparticles, and small molecules.


To obtain specific targeting, a radiopharmaceutical usually comprises a moiety capable of binding a cancer-specific overexpressed entity (e.g., a receptor, an enzyme, a transporter, etc.). However, this is not always required as certain elements show a natural affinity for certain tissues. Examples are iodine, which is concentrated in the thyroid gland, and radium, a calcium mimetic naturally taken up in remodeling bone. This enables specific targeting of these tissues without the need for elaborate organic chemistry nor radiochemistry.


Radiopharmaceutical development started with the research of Hamilton and Soley into diagnosis and treatment of thyroid disease. In the thyroid gland, iodine plays an important role in the production of thyroid hormones, which in turn have important functions in the human body. Naturally, because of the importance of iodine for the thyroid gland, all ingested iodine is taken up by the thyroid gland, where it is converted into iodide and remains trapped. Radioactive iodine (iodine-131) can be used to treat thyroid diseases because the thyroid gland is not able to distinguish between the stable iodine (iodine-127) and its radioactive isotope. Like stable iodine, iodine-131 is concentrated in the thyroid gland after ingestion. Treatment of thyroid disease using iodine-131 in the form of sodium-iodine (Na131I) can be considered as a historic pillar of radiopharmaceutical design as the usage of Na131I has paved the way for further radiopharmaceutical development.


The primary site for metastasis in prostate cancer (PCa) is the bone, resulting in severe morbidity due to so-called skeletal related events (e.g., fractures) and bone marrow failure. To control the disease in castrate-resistant PCa patients, the Food and Drug Administration (FDA) approved radium-223 chloride (223RaCl2, Xofigo®) for treatment of bone metastasis in 2013. Radium-223 is an alpha-emitting radionuclide that accumulates in bone areas with increased bone turnover due to its similarity with calcium ions and its capability to form complexes with hydroxyapatite (which is the mineral component of bone). In the decay process of radium-223 to the stable lead-207, four alpha particles and two beta-particles are generated which induce local damage to bone sites with increased bone turnover, such as areas of bone metastasis.


Na131I is administered in patients suffering from benign thyroid disease such as an overactive thyroid (autonomic hyperthyroidism, Graves’ Disease), goiter (enlarged thyroid), or well differentiated thyroid cancers (papillary or follicular thyroid cancer). The thyroid incorporates iodide in two forms of thyroid hormones, triiodothyronine (T3) and thyroxine (T4). These hormones control metabolism and protein synthesis. An overactive thyroid leads to increased metabolic rate, sweating, fatigue, tachycardia, intestinal problems, and other life debilitating issues. As iodide is taken up in the thyroid in large excess, it is a valuable approach in treating an overstimulated or enlarged thyroid. Due to the high uptake via the intestinal tract, Na131I is administered per os. Iodine-131 is taken up by the sodium-iodide symporter into the thyroid cells and will subsequently irradiate the thyroid cells. One potential side effect of this treatment is a complete loss of thyroid function (hypothyroidism), which can result in the necessity for daily lifelong thyroid hormone (levothyroxine) substitution. The occurrence of hypothyroidism depends on the type of indication, with a low fraction seen in autonomic disease but with a 100% occurrence in patients treated for thyroid cancer (with treatment occurring post-thyroidectomy to ablate the so-called remnant). Of note, these pills are generally inexpensive and are taken per os once daily [141].


To date, 223RaCl2 is the only alpha-emitting radiopharmaceutical that has been FDA approved and is now in routine clinical use for treatment of bone metastasis in patients with metastatic castration-resistant prostate cancer. The ALSYMPCA phase III clinical trial investigated safety and efficacy of 223RaCl2 compared to placebo (i.e., saline injection). The results of this trial led to the FDA approval of 223RaCl2 for patients with metastatic castration-resistant prostate cancer with symptomatic bone metastasis as this clinical trial showed that treatment was well-tolerated, prolonged overall survival, and improved the quality of life of patients [142, 143].


Na131I is typically administered as a pill or in rare cases as a liquid per os. The required activity to treat hyperthyroidism is typically small (148–370 MBq). Usually one treatment cycle will suffice to have a satisfying effect on the thyroid function after 2–3 months [144]. For patients suffering from differentiated thyroid cancer, the administered activity depends on the disease stage (after previous resection in so-called remnant ablation, used as adjuvant therapy, metastatic disease) and can range from 1.1 to 7.4 GBq [145]. Before treatment, patients need to have sufficient blood levels of thyroid-stimulating hormone (TSH) (TSH > 30 mU/L), by stopping uptake of thyroid hormone supplements or by injections of recombinant THS, to increase the uptake of the administered iodine radioisotope. Several days after treatment, a post-therapy scintigraphy is made to document the targeting of thyroid tissue and to detect potential metastatic disease. After ablation, levothyroxine treatment is started to compensate for the loss of thyroid function. Afterwards follow-up is necessary to assess therapy response and to rule out recurrence, with regular determination of thyroid function, thyroglobulin, and thyroglobulin antibodies.


Radium-223 dichloride is injected intravenously in adult patients with castration-resistant prostate cancer with bone metastases. The treatment schedule comprises six injections of 55 kBq per kg body weight at 4-week intervals. A single complete blood count is performed 10 days prior to administration of a treatment cycle. An additional complete blood count might be performed 2–3 weeks after administration if necessary. Clinical follow-up complemented with bone scintigraphy and CT is the cornerstone of follow-up, but with more recent evidence pointing to the utility of also modern imaging tools such as PET/CT or MRI. Several biomarkers, including prostate-specific antigen, lactate dehydrogenase, and alkaline phosphatase, might be checked during the treatment course to monitor treatment response, but they are not considered to be reliable indicators of treatment response.


Peptide receptor radionuclide therapy (PRRT) consists of the injection of a tumor-targeting peptide into the systemic circulation of a patient. This radiopharmaceutical will subsequently bind to a specific peptide receptor leading to tumor-specific retention. Several receptors have been studied over the last few years, including the somatostatin receptor (SSTR), glucagon-like peptide-1 receptor, cholecystokinin type 2, and melanocortin receptors. At present, SSTR is the only target that is used in routine clinical practice. The SSTR is overexpressed on a range of tumors, including neuroendocrine tumors (NETs), which arise from neuroendocrine cells present in a range of organs (e.g., gastrointestinal tract, pancreas, and bronchi) and neural-crest derived tumors (e.g., pheochromocytoma, paraganglioma, neuroblastoma). Humans have five subtypes of SSTRs, with subtype 2 being the most important for theranostics. The randomized controlled trials PROMID and CLARINET have proven that treatment with non-radioactive somatostatin analogues (SSAs) leads to an antiproliferative effect in metastatic enteropancreatic NETs. In the late 1980s and early 1990s, the Rotterdam group uncovered the potential of using the SSTR for radionuclide-based imaging and demonstrated that radiolabeled SSAs have a high uptake and retention in tumoral tissue and a limited uptake in normal, mainly endocrine, organs. An interesting therapeutic avenue was explored: treatment of SSTR-positive tumors with radionuclide therapy (RNT). Several radiopharmaceuticals were developed in the last two decades including the first generation 111In-pentetreotide (an Auger emitter), the second generation 90Y-DOTATOC (a high-energy β−-emitter), and the third generation 177Lu-DOTATATE (a low-energy β−-emitter and a γ-emitter). A major benefit of lutetium-177 is that its decay is associated with γ-emission, which allows imaging and dosimetry of absorbed doses to tumors and risk-organs (e.g., kidneys and bone marrow). The combination of the high-energy yttrium-90 β−-emitter for targeting lesions with a larger size and/or heterogeneous uptake (with more crossfire effect), and the medium-energy lutetium-177 emitter/γ-emitter for targeting smaller lesions (with a higher fraction of the total energy deposited within the tumor itself, and not in the surrounding tissue), is called “tandem or duo PRRT.” Theoretically, a synergistic effect can be achieved by combining these two radionuclides with different absorption properties, but RCTs are awaited to demonstrate the superiority of this concept before widespread clinical use can take place. At present, 177Lu-DOTATATE is considered the clinical standard and is the only radiopharmaceutical approved for PRRT by the American Food and Drug Administration (FDA 2018) and European Medicines Agency (EMA 2017). A promising fourth generation of PRRT-radiopharmaceuticals is emerging, with the entrance of α-emitters in the radionuclide therapy scene. PRRT α-emitters include 213Bi-DOTATOC, 225Ac-DOTATATE, and 212Pb-DOTAMTATE. Preliminary clinical results provide proof-of-principle evidence that α-PRRT can overcome resistance to β-PRRT, reflected by higher objective response rates (ORRs) in favor of α-emitters [146].


Patients with advanced NET and clinical, biochemical, and/or radiological disease progression after first-line treatment with SSA are eligible for second-line treatment with PRRT if sufficient tracer uptake on a so-called theranostics SSTR scintigraphy is present. The development of PRRT and its clinical trials were academia-driven which contrasts with the current novel anticancer drugs which are mainly pharma industry-driven. For a long period, no standard radiopharmaceutical or standard regimen was determined, which explains the heterogeneous literature involving PRRT [146]. At present, the only published randomized controlled trial with 177Lu-DOTATATE is the phase III NETTER-1 trial, which included patients with advanced midgut NETs. One hundred sixteen patients were randomized to the PRRT arm (4 cycles of 7.4 GBq 177Lu-DOTATATE plus best supportive care including octreotide long-acting repeatable (LAR) 30 mg) and 113 patients were randomized to the control arm (octreotide LAR 60 mg). An ORR of 18% was seen in the 177Lu-DOTATATE group versus 3% in the control group (p < 0.001). An estimated progression-free survival (PFS) at 20 months of 65.2% (95% confidence interval (CI): 50.0–76.8%) was achieved in the PRRT arm and 10.8% (95% CI: 3.5–23.0%) in the control arm, with a hazard ratio for progression or death of 0.21 (95% CI: 0.13–0.33; p < 0.001) [147]. The final overall survival (OS) analysis revealed a median OS of 48 months in the 177Lu-DOTATATE group versus 36.3 months in the control group. This difference was not statistically significant but can be considered as clinically significant. The lack of statistical significance was most likely caused by a high rate (36%) of crossover of patients in the control group to PRRT after progression. In addition, the NETTER-1 trial has confirmed that PRRT causes a significant improvement in the quality of life of patients and aids to substantially reduce tumoral symptoms (e.g., abdominal pain, diarrhea, and flushing) [146].


The eligibility for PRRT is determined via mandatory pre-treatment SSTR imaging, preferentially by SSTR PET, blood analysis, and clinical evaluation. 18F-FDG PET/CT provides additional information, and all lesions should show sufficient SSTR expression, in particular the 18F-FDG-avid ones. The conventional treatment schedule for 177Lu-DOTATATE is based on the Rotterdam/NETTER-1 protocol. This consists of four cycles of 7.4 GBq administered in 8-week intervals. Nephroprotection is performed by administering a co-infusion of an amino acid solution during PRRT-administration; this solution will reduce renal uptake of the radiopeptide by ~25–50%. Acute side effects include nausea and vomiting which are provoked by the co-infusion of the nephroprotective amino acids and which can be controlled by an antiemetic treatment. Four to six weeks after each cycle of PRRT, a blood analysis and clinical evaluation are performed. After completion of the four cycles PRRT, further follow-up with SSTR and 18F-FDG PET/CT, blood analysis, and clinical evaluation are warranted. The most severe long-term side effect of PRRT is the development of persistent hematological dysfunction (PHD) caused by bone marrow irradiation. However, PHD after PRRT has a low incidence of 1.8–4.8%, with a median latency of 41 months after completion of the treatment [146]. Other subacute (occurring within days/week) side effects include subacute myelosuppression (typically mild and transient), fatigue, and hair loss. Long-term side effects, besides PHD, are kidney failure, observed in up to 9.2% of patients treated with 90Y-DOTATOC and <1% in patients with 177Lu-DOTATATE [148, 149]. In patients with good response after a first PRRT regimen, with disease control for at least a year, a novel course of PRRT can be administered with 177Lu-DOTATATE, called “salvage PRRT,” if the patient’s organ function is still adequate and SSTR expression is still present on all lesions. As such, PRRT has proven to be an adequate treatment in patients with advanced NETs. Several promising prospective trials are ongoing to further optimize PRRT (e.g., α-emitters, individualized dosimetry, and SSTR-antagonists) (Box 6.18).


PRRT consists of the injection of a tumor-targeting radiolabeled peptide, which will subsequently bind to a specific receptor leading to tumor-specific binding and retention.

Several radiopharmaceuticals were developed in the last two decades, with the third generation 177Lu-DOTATATE being the current clinical standard and the only radiopharmaceutical approved for PRRT by the FDA and EMA.

Multiple promising prospective trials are ongoing to further optimize PRRT (e.g., α-emitters, individualized dosimetry, and SSTR-antagonists).


PRRT consists of the injection of a tumor-targeting radiolabeled peptide, which will subsequently bind to a specific receptor leading to tumor-specific binding and retention.


Several radiopharmaceuticals were developed in the last two decades, with the third generation 177Lu-DOTATATE being the current clinical standard and the only radiopharmaceutical approved for PRRT by the FDA and EMA.


Multiple promising prospective trials are ongoing to further optimize PRRT (e.g., α-emitters, individualized dosimetry, and SSTR-antagonists).


At present, another well-known example of radioligand therapy (RLT) has demonstrated a significant survival benefit in patients with metastatic castration-resistant PCa. [177Lu]Lu-PSMA-617 is a prostate-specific membrane antigen (PSMA) targeting small molecule consisting of PSMA-617 with the β−-emitting radionuclide lutetium-177 (Fig. 6.23). The PSMA-617 binds to the enzymatic pocket of PSMA after which it is internalized, resulting in the delivery of toxic doses of IR to PCa cells. The VISION trial has demonstrated a significant increase in imaging-based PFS and OS in a randomized controlled trial where it was compared to standard of care (i.e., chemotherapy, RT and ADT), resulting in the FDA approval of [177Lu]Lu-PSMA-617 for patients with metastatic castration-resistant PCa in March 2022 [150]. Since PSMA poses such an interesting target for RLT, due to the high overexpression on PCa cells, more PSMA-targeting radioligands are currently under clinical investigation, as summarized in Table 6.10.

A schematic diagram of the P S M A 617 structure displays the linker in between the D O T A chelator and P S M A targeting moiety.

Fig. 6.23
Schematic representation of the structure of the PSMA-targeting compound PSMA-617. The blue circle shows the PSMA-targeting moiety. The purple circle highlights the DOTA-chelator used to entrap radionuclides. The grey circle represents the linker molecule that connects the PSMA-targeting moiety with the DOTA-chelator
Table 6.10
Examples of RLT compounds under clinical investigation

Compound

Clinical trial phase

Trial numbera

Disease

PSMA-targeting RLT

[177Lu]Lu-PSMA-617

Phase III

NCT03511664

Metastatic castration-resistant PCa

[64Cu]Cu-SAR-PSMA

Phase II

NCT04868604

Metastatic castration-resistant PCa

[177Lu]Lu-PSMA-I&T

Phase II

NCT04188587

Metastatic castration-resistant PCa

[225Ac]Ac-PSMA

Early phase I

NCT04225910

Metastatic castration-resistant PCa

[177Lu]Lu-PSMA-R2

Phase I/II

NCT03490838

Metastatic castration-resistant PCa

[131I]I-PSMA-1095

Phase II

NCT04085991, NCT03939689

Metastatic castration-resistant PCa

Bombesin-targeting RLT

[177Lu]Lu-NeoB

Phase I/IIa

NCT03872778

Advanced or metastatic solid tumors: breast, lung, prostate, GIST, GBM tumor

Others

[177Lu]Lu-FAP-2286

Phase I

NCT04939610

Advanced metastatic solid tumor

[177Lu]Lu-DOTA-Biotin (ST2210)

Phase I

NCT02053324

Colorectal cancer with liver metastases

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


A schematic diagram of the P S M A 617 structure displays the linker in between the D O T A chelator and P S M A targeting moiety.


The development of RLT is not strictly limited to PCa and targeting PSMA. Several other compounds with other targets are also undergoing clinical trials. One such target is the bombesin receptor family. Many common tumors, including breast, prostate, and lung cancer, show overexpression of one of the bombesin receptors, resulting in the development of several compounds targeting this receptor family [151]. Compared to the development of PSMA-targeting compounds, the development of bombesin-targeting agents is still in its infancy as illustrated in Table 6.10 by the limited number of compounds undergoing clinical investigation. Thus, at present, research into bombesin-targeting compounds remains largely preclinical.


Besides PSMA and bombesin, other targets can also be used for RLT of a variety of human cancers. Other examples of clinical trials of radioligand therapy using other targets are summarized in Table 6.10.


At present, [177Lu]Lu-PSMA-617 is FDA approved in PCa patients with metastatic castration-resistant disease in whom standard treatments, including hormone deprivation therapy and chemotherapy, have failed. Patients eligible for treatment also need to have at least one PSMA-positive lesion (observed by 68Ga-PSMA-11 PET–CT imaging at baseline), a life-expectancy of at least 6 months, sufficient organ function (e.g., bone marrow, kidney), and capability of self-care (defined by Eastern Cooperative Oncology Group performance status ≤2) [150]. Other types of RLT are under investigation for treatment of other types of advanced tumors, such as advanced solid tumors of breast and lung or colorectal cancer with liver metastases.


For the different types of RLT, treatment schedules can differ. For PSMA-RLT, and [177Lu]Lu-PSMA-617 in particular, a conventional treatment schedule consists of four treatment cycles administered in 6-week intervals. In each cycle, the administered activity ranges from 6 to 7.5 GBq. After each therapy cycle, treatment response and the overall condition of the patient are monitored in order to decide if treatment can be continued or not [152]. The VISION trials showed that [177Lu]Lu-PSMA-617 (hazard ratio 0.46) therapy was generally well tolerated and was able to improve both OS and PFS compared to standard of care treatment [150]. These clinical trials and the recent FDA approval of [177Lu]Lu-PSMA-617 show the potential of RLT for treatment of PCa and in the future, results of the ongoing clinical trials of RLT using other targets will also be published and contribute to the development of RLT as a new cancer treatment modality (Box 6.19).


Besides peptide receptor radionuclide therapy, other radioligand therapies are also under investigation for treatment of different cancer types (e.g., PCa).

An FDA-approved compound for RLT is [177Lu]Lu-PSMA-617 for the treatment of metastatic-castration resistant PCa.

More compounds for RLT are under clinical investigation for multiple cancer types (summarized in Table 6.11).
Table 6.11
Comparison of the accelerator types used for therapy

Accelerator types

Properties

Cyclotron

Circular

Small

Mainly for protons

Synchrotron

Circular

Large

Suitable also for heavier ions

LINAC

Linear

Long but slim

Technically challenging


Besides peptide receptor radionuclide therapy, other radioligand therapies are also under investigation for treatment of different cancer types (e.g., PCa).


An FDA-approved compound for RLT is [177Lu]Lu-PSMA-617 for the treatment of metastatic-castration resistant PCa.


More compounds for RLT are under clinical investigation for multiple cancer types (summarized in Table 6.11).


In 1900, the German Nobel laureate Paul Ehrlich was the first person to introduce the “magic bullet” concept, with reference to antibodies that can be used to treat diseases by specifically targeting receptors or biochemical pathways in bacteria or cancer cells. More than half a century later, the invention of hybridoma technology by Georges Kohler and César Milstein paved the way for the production of monoclonal antibodies against almost any antigen. Kohler and Milstein received a Nobel Prize in 1984 for their work.


A large proportion of therapeutic antibodies have since then been developed and approved by the FDA or EMA for the treatment of cancer. There are several mechanisms through which immunoglobulins function in the body, including, but not limited to antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), alteration of signal transduction, inhibition of angiogenesis, and immune checkpoint blockade [153].


Another important modality through which antibodies can mediate a therapeutic effect is through their conjugation to a radionuclide that emits IR in the form of α particles, β particles, γ-rays, or Auger electrons. By virtue of the antibody’s specificity and selectivity, it will bind to a specific target overexpressed on a cancer cell and deliver a lethal dose of radiation to the cell. This approach is called radioimmunotherapy (RIT), though several other names have also been used in the literature. Most radioimmunoconjugates use the IgG class of antibodies, with an average molecular weight of 150 kDa and a biological half-life from 2 to 5 days.


Early clinical trials with radioimmunoconjugates used the readily available 131I radionuclide which allowed for their application in SPECT imaging as well as therapy. Today, a wide arsenal of radionuclides has been used in different RIT studies, each with different properties.


There is currently only one FDA-approved RIT targeting the CD20 antigen on B-Cell Non-Hodgkin’s Lymphoma (B-NHL): 90Y-ibritumomab tiuxetan or Zevalin®. The immunoconjugate is a result of the conjugation of the monoclonal antibody ibritumomab to the chelator tiuxetan. The antibody is a murine IgG-1 kappa antibody toward CD20, and the tiuxetan chelator is ideal for the chelation of Indium-111 or Yttrium-90. In the following paragraphs, we will look with more details into the use of 90Y-ibritumomab tiuxetan.


The Zevalin® therapeutic regimen is used to treat adult patients either with newly diagnosed follicular NHL following a response to initial anticancer therapy, or patients with low-grade or follicular B-cell NHL that have relapsed during or after treatment with other chemotherapies. The prescription medication consists of three parts: two infusions of rituximab to reduce the number of B-cells in blood, and one injection of 90Y-ibritumomab to treat the NHL.


The Zevalin® therapeutic regimen should be initiated between 6 and 12 weeks following the last dose of first-line chemotherapy, after platelet counts have recovered to 150,000/mm3 or more. Patients with platelet counts less than 100,000/mm3 are not treated with Zevalin®.


Treatment is initiated with an IV infusion of 20 mg/m2 rituximab. The same infusion is re-administered 7–9 days after the first infusion. Within 4 h of administering the second rituximab infusion, an IV injection of 90Y-ibritumomab tiuxetan is administered at a dose of 0.4 mCi/kg for patients with normal platelet count, or 0.3 mCi/kg for relapsed or refractory patients with lower platelet counts (100,000–149,000/mm3). The total dose administered should not exceed 32 mCi (or 1184 MBq).


Although Zevalin® is the only FDA-approved RIT that is currently in use, there are a lot of other radioimmunoconjugates at different stages of clinical development, targeting different cancer-associated antigens. Figure 6.24 shows some of the antigens targeted in RIT.

A schematic diagram of the antigens targeted in R I T. Inset images of the tumour cell, B cell, A M L, and targeting vectors that target for radioimmunotherapy include antibodies, nanobodies, diabodies, affibodies, and minibodies.

Fig. 6.24
Different targeting vectors and molecular targets used in RIT. In RIT, the targeting vectors are designed to recognize certain molecules present on the surface of tumor cells (e.g., PSMA, CEA, B7-H3, CAIX, or CD45), cancer-associated fibroblasts (FAPɑ), tumor-infiltrating T cells (CD4 or CD8), and/or circulating immune (e.g., CD45, CD19, CD37, or CD22) or tumor cells (e.g., CD45 or CD33)


A schematic diagram of the antigens targeted in R I T. Inset images of the tumour cell, B cell, A M L, and targeting vectors that target for radioimmunotherapy include antibodies, nanobodies, diabodies, affibodies, and minibodies.


Clinical trials designed with a direct comparison of the radiolabeled antibody with its non-radiolabeled counterpart allow to tease out the therapeutic benefit of RIT over conventional mAb immunotherapy for cancer patients. One example of such a study is a phase III randomized controlled trial of patients with relapsed or refractory CD20-positive NHL patients [154]. In this study, 143 patients were divided into two groups, a “control” group receiving intravenously (IV) the CD20-targeting antibody rituximab for 4 weeks, while the other group received a single (IV) dose of Zevalin® RIT. The latter group was pretreated with two rituximab doses to improve biodistribution and one dose of 111In-ibritumomab tiuxetan for imaging and dosimetry. The control group had an overall response rate (ORR) of 56% while the RIT group showed an ORR of 80%. The complete response (CR) rates were 16% and 30%, respectively. The primary toxicity observed with Zevalin® was reversible myelosuppression, which is also the most common side effect of conventional cancer therapies [155].


It is worth mentioning that the clinical impact observed in RIT of hematological cancers has not been replicated in solid tumors yet, due to a number of outstanding challenges encountered which lead to high bone marrow absorbed doses and insufficient dose delivery to tumors. Several promising strategies have been developed to overcome these challenges, such as the use of antibody fragments (e.g., single-domain antibodies and affibodies) instead of whole immunoglobulins, allowing for higher imaging contrast, deeper tumor penetration, and improved pharmacokinetics [156]. Another important strategy, known as pretargeting, is based on separating the antibody from the radionuclide and letting the two agents combine in vivo. A review by Verhoeven et al. nicely summarizes the different RIT in which pretargeting has been applied [157].


The undisputable efficacy of radionuclide therapy (RNT) has been documented in the last decade in a series of landmark trials. With a plethora of targeting vectors directed to tumor-specific molecular targets (some in routine clinical use, others in development) and a large panel of radionuclides characterized by different physical properties, the targeted treatment of both solid and hematological tumors is now a clinical reality. The concept of RNT emerged in the 1940s with the use of iodine-131 for thyroid cancer management and was the first FDA-approved radiopharmaceutical (in 1951). Since then, numerous other RNT radiopharmaceuticals have been developed and successfully used, including the most recent FDA- and EMA-approved radiopharmaceutical 177Lu-DOTATATE. However, their success may be limited by healthy tissue toxicity and/or tumor intrinsic or acquired resistance. One strategy to overcome these limitations is the use of combination therapies aiming at achieving an increase in treatment efficacy while remaining at a low toxicity level [158]. This will subsequently lead to an increased therapeutic index and hence improved treatment outcome. If rationally designed, these combination therapies can lead to synergistic effects by targeting adequate molecular pathways, ultimately causing lethal damage to the tumor cell. Indeed, radiobiological mechanisms underlying the effects of RNTs could serve as a very promising basis for the design of combination clinical trials.


The rationale behind the use of the combination approach with RNT, using two or more therapeutic agents, may be multiple and vary according to the physical properties of the radioisotope used and the biology of the tumor considered. Combination strategies may aim at reducing hypoxia, improving the radiopharmaceutical delivery (in case of a poor tumor vasculature preventing drug delivery) via increased perfusion of the tumor, enhancing the therapeutic effect based on radiosensitization mechanisms, or improving the immune control. RNT has been basically evaluated in combination with all cancer pillar therapies, e.g., chemotherapy, external beam RT(EBRT), immune and targeted therapies. Different combination strategies with RNT are summarized in Fig. 6.25.

A circular diagram of the combination therapies with radionuclide therapy. It include chemotherapy, D D R inhibitors, E B R T, tandem or duo, immunotherapy, and targeted agents.

Fig. 6.25
Overview of combination therapies with radionuclide therapy


A circular diagram of the combination therapies with radionuclide therapy. It include chemotherapy, D D R inhibitors, E B R T, tandem or duo, immunotherapy, and targeted agents.


The use of chemotherapy with EBRT in many common cancers (including lung, head and neck, cervical cancers) and different settings (e.g., neoadjuvant, curative, etc.) has fostered its combination with RNT.


Several clinical studies have been published combining PRRT with 5-fluorouracil (5-FU), capecitabine or temozolomide, a therapy called peptide receptor chemoradionuclide therapy (PRCRT). A population of interest for PRCRT are the highly proliferating NETs characterized by tumor dedifferentiation, higher tumor grade, worse OS outcome, and most commonly 18F-FDG-avidity of the tumor lesions. PRCRT (combination of 177Lu-DOTATATE and 5-FU) was retrospectively investigated in 52 patients with 18F-FDG-avid disease and the majority having grade 2 advanced NETs [159]. A high DCR of 98% was achieved and 27% of the patients achieved complete metabolic response on 18F-FDG PET/CT despite having residual SSTR-positive disease, most likely due to the eradication of the dedifferentiated lesions by PRCRT. It was expected that the prognosis in this patient cohort would be poor, however a median PFS of 48 months was achieved and a median OS was not reached during a median follow-up time of 36 months. Toxicity was low, despite the fact that 67% of the patients had received prior chemotherapy.


Capecitabine, a prodrug of 5-FU, has the additional advantage that it can be administered orally. A 2-arm cohort analysis compared concomitant 177Lu-DOTATATE plus capecitabine (n = 88) with 177Lu-DOTATATE monotherapy (n = 79) and revealed an increased OR in favor of 177Lu-DOTATATE plus capecitabine (43.1% and 14%, respectively). In addition, a significant lengthening of OS in the 177Lu-DOTATATE plus capecitabine group was observed compared to the 177Lu-DOTATATE monotherapy group (median OS not reached vs. 48 months, respectively, after a mean follow-up of 32.4 months; p = 0.0042) [160]. The combination of 177Lu-DOTATATE and capecitabine was also evaluated in paragangliomas, however the study failed to prove the superiority of the combination over 177Lu-DOTATATE monotherapy [161] which might be attributed to a too small number of patients included and the typically lower proliferation rate in this cancer type.


A decreased sensitivity of tumors to the alkylating agent temozolomide has been associated with the expression of O(6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein involved in the removal of O(6)-methylguanine DNA lesions induced by temozolomide. MGMT deficiency was more frequently observed in pancreatic NET (pNET) compared to lung or small intestine NET and may explain the different sensitivity profiles of pNET compared to NET of other origins. A synergistic effect is apparent when combining capecitabine and temozolomide (CAPTEM), most likely due to the depletion of MGMT caused by capecitabine, which strengthens the effect of temozolomide. This is the reason why the treatment regimens add temozolomide after substantial exposure to capecitabine [162]. Preliminary results of the phase II “CONTROL NET” RCT have been presented. This trial compares a combination of 177Lu-DOTATATE plus CAPTEM (experimental arm) versus 177Lu-DOTATATE monotherapy (control arm) in patients with low to intermediate grade midgut NETs. Forty-seven patients were included. The 15-months PFS was 90% versus 92% and ORR was 25% versus 15% for PRRT plus CAPTEM versus PRRT monotherapy, respectively. However, grade 3/4 toxicity occurred more frequently in the PRRT plus CAPTEM arm.


Overall, combining RNT with chemotherapy appears safe and efficient based on data with the beta-emitter lutetium-177. However, multicenter prospective RCTs are lacking to prove superiority of the combination over RNT alone. Although the mechanism of the radiosensitizing effect of chemotherapy is not elucidated, it is thought to act as a radiosensitizer of RNT by increasing DNA damage. However, one preclinical study also pointed out the effect of increased perfusion induced by a chemotherapeutic agent, temozolomide, which may improve 177Lu-DOTATATE delivery to the tumor, as well as increase tumor oxygenation which may also have a radiosensitizing effect [163].


177Lu-PSMA and radium-223 have also been combined with chemotherapy, although less data are available compared to 177Lu-DOTATATE. A phase I/II study showed that the alpha-emitter radium-223 (55 kBq/kg every 6 weeks for 5 cycles) in combination with docetaxel (60 mg/m2 every 3 week) was well tolerated in bone-predominant metastatic castration-resistant prostate cancer patients. Exploratory efficacy data even suggested enhanced antitumor activity in the combination arm [164]. This will be further explored in a phase III clinical trial that is currently recruiting patients (NCT03574571).


The combination of 177Lu-PSMA with docetaxel, a taxane impairing microtubules polymerization dynamics and therefore preventing cell mitosis, is currently evaluated in metastatic hormone-naïve prostate cancer in a randomized phase II study (UpFrontPSMA trial—NCT04343885) [165]. Patients are randomized 1:1 to the 177Lu-PSMA plus docetaxel arm (177Lu-PSMA 7.5 GBq, 2 cycles intended, every 6 weeks followed 6 weeks later by docetaxel 75 mg/m2, 6 cycles intended, every 3 weeks) or the docetaxel monotherapy arm.


In addition to chemotherapy, RNT has also been evaluated in combination with targeted agents in order to potentiate the therapeutic effect of RNT. Targeting relevant pathways may aid in eliminating (radio-)resistant clones as well as overcoming tumor heterogeneity.


The mammalian target of rapamycin (mTOR) inhibitor everolimus was combined with 177Lu-DOTATATE in the phase I NETTLE proof-of-concept study in order to establish an optimal safe dose of everolimus in this combination setting. Nephrotoxicity was the dose-limiting factor, leading to the maximum tolerated dose of 7.5 mg everolimus in combination with PRRT [166].


Among targeted agents, DNA damage response (DDR) inhibitors have recently been widely adopted. Preventing the repair of radiopharmaceutical-induced DNA damage by targeting DNA repair pathways is considered an interesting strategy. PARP is involved in the repair of DNA SSBs and has been targeted by PARP inhibitors (PARPi) in combination with chemotherapy and EBRT. Following favorable results from preclinical studies combining 177Lu-DOTATATE and PARPi [167], the combination is now assessed in phase I/II clinical trials with 177Lu-DOTATATE (NCT05053854, NCT04375267, NCT04086485) and 177Lu-PSMA (NCT03874884). Different treatment schedules are used within the trials, with PARPi commencing either before or after RNT administration, and also with variable duration of PARPi (first few days of each RNT administration or daily continuous administration). Study results are awaited and might already provide some evidence about the optimal treatment schedule to be used.


Phase I studies evaluating the combination of 177Lu-DOTATATE and other DDR inhibitors, such as peposertib (NCT04750954) and triapine (NCT04234568), are also underway. Peposertib is an inhibitor of DNA-PK, a serine/threonine protein kinase playing a critical role in DNA DSB repair via the NHEJ pathway while triapine is an inhibitor of ribonucleotide reductase, an essential enzyme for DNA replication and repair.


Other promising combinations are evaluated in the preclinical setting [168]. These include inhibitors of several pathways or molecules: DNA damage response, HSP 90, DNA topoisomerase, hedgehog signaling pathway, and EGFR.


Combining RNT with EBRT has several advantages [169]. Firstly, there should not be overlapping toxicities because of different dose-limiting organs, being the surrounding tissues (the ones close to the tumor or that are in the path of incident beams) for EBRT and mainly bone marrow and kidneys for RNT (but will depend according to the RNT type). Therefore, an escalation of the combined radiation absorbed dose without exceeding the maximum tolerated dose of the limiting organs should be allowed. Secondly, the advantages of both radiation-based therapies may be combined: EBRT delivers a precise and homogeneous high dose of radiation locally, to the bulk tumor, while the administration of RNT allows the targeted treatment of systemic disease, including (micro)-metastases and residual tumor cells, albeit with less control of the tumor dose and a heterogeneous dose depending on perfusion and target expression.


Very few clinical studies are being conducted, and most of them are based on sequential and not concurrent administration of both therapies. This combined regimen is mostly studied in bone metastases as well as in brain and liver tumors but also meningioma. Promising data have been obtained in meningioma where 177Lu-DOTATATE and EBRT have been combined and showed the feasibility of such an approach. Interestingly, in seven patients out of ten, for which a follow-up 68Ga-DOTATATE PET/CT was available, increased uptake of the radiotracer was observed compared to the pre-therapeutic scan [170]. This observation was corroborated in several preclinical studies in which up-regulation of somatostatin receptors was observed following low doses of EBRT [171]. Increased tumor perfusion might also be the cause of an increased radiotracer uptake seen on PET/CT. This finding is significant, as such a combination could be beneficial to patients currently not eligible for peptide receptor radionuclide therapy due to a too low uptake on 68Ga-DOTA-SSA PET/CT.


A synergistic effect of 4-l-[131I]iodo-phenylalanine (131I-IPA) and EBRT has been observed in preclinical models of glioblastoma multiforme, and the first results of a phase I/II trial (IPAX-1 trial—NCT03849105) should be available soon.


RT with EBRT has been shown to increase tumor immunogenicity and antigen presentation and therefore enhance tumor cell destruction by T cells. Hence there is a rationale to investigate the combination of immunotherapy and RNT. Preclinical studies have shown the added value of an immune checkpoint blockade to RNT on survival.


The combination of PRRT with the immune checkpoint inhibitor nivolumab has recently been explored clinically in a phase I study including nine patients with advanced lung neuroendocrine neoplasms [172]. Dose level 1 consisted of 177Lu-DOTATATE 3.7 GBq (8-week interval, 4 cycles intended) plus nivolumab 240 mg (2-week interval), and dose level 2 consisted of 177Lu-DOTATATE 7.4 GBq (8-week interval, 4 cycles intended) plus nivolumab 240 mg (2-week interval). Only one dose-limiting toxicity, consisting of a grade 3 rash, was noted in one patient being treated at dose level 2.


Phase I and II clinical trials combining 177Lu-DOTATATE (NCT03325816, NCT04261855, NCT03457948) or 177Lu-PSMA (PRINCE trial—NCT03658447, NCT03805594) with anti-PD1 or PD-L1 antibodies are under way.


There exists a huge potential in terms of a combined regimen with RNT. Promising combination strategies used with EBRT frequently serve as arguments to extrapolate to RNT. However, EBRT and RNT are characterized by major differences such as the delivery route (external versus “internal”), the dose (homogeneous dose versus heterogeneous dose), and the dose rate (very high and constant versus low and exponentially decreasing dose rate). The maximum therapeutic benefit one can derive from RNT will be achieved thanks to clever combinations exploiting synergistic interactions, used in the optimal doses and sequences [173] and using biomarkers with an individualized approach. Preclinical studies can bring valuable information and can serve as a basis to design proper clinical trials.


Novel treatment combinations are emerging and are now in the early phases of clinical trials, aiming at evaluating the feasibility and the toxicity of the combinations. Later, large prospective randomized trials will be needed to prove the superiority of the combinations over the monotherapies. Combination strategies might also enter in an entirely new realm when targeted alpha-emitters will become available for clinical trials in the upcoming years, with many new combination possibilities.


Compared to conventional RT (using X-rays), particle therapy has major advantages. The depth of penetration into the body is determined by the particle’s acceleration energy and thus energy deposition increases over distance up to a high peak at the end of their range, the so-called Bragg peak. Simply said, the energy transfer is proportional to the inverse square of its velocity where the ionization density increases as the speed of the particle slows down:

 (6.5)where Z is the charge of the particle and v its velocity. This happens until very close to the end of their range where the high-dose Bragg peak phenomenon is formed (Fig. 6.26a). In the clinics, expanded Bragg peak also known as Spread out Bragg peak (SOBP) is then used to cover the entire tumor volume, this is formed by adding up all single Bragg curves for ions of different energy and therefore range (Fig. 6.26b).

A. Dose versus water depth plots a line that peaks at around (10.5, 1) before declining. B. Dose versus z, where the spread out Bragg peak rises and fluctuates before declining, and the pristine Bragg peaks rises to their highest peaks before declining and plateauing. Below, 4 magnetic resonance images of intensity-modulated radiation therapy and protons dose distribution.

Fig. 6.26
(a) Absorbed dose of a 121 MeV proton in water forming the Bragg peak [174]. (b) Spread Out Bragg Peak formed by overlaying ions with different energy forms the spread out Bragg peak as used for therapy [175]. (c) Dose distribution of one patient with locally advanced non-small cell lung cancer (NSCLC) planned with intensity-modulated radiation therapy (IMRT) (left) or protons (right), depositing no dose behind the tumor [176


A. Dose versus water depth plots a line that peaks at around (10.5, 1) before declining. B. Dose versus z, where the spread out Bragg peak rises and fluctuates before declining, and the pristine Bragg peaks rises to their highest peaks before declining and plateauing. Below, 4 magnetic resonance images of intensity-modulated radiation therapy and protons dose distribution.


Beyond the Bragg peak (known as tail), there is a rapid falloff of the dose, allowing for sparing of the normal tissue [177] as the tissue behind the tumor doesn’t receive any radiation dose. Tumors which have an organ at risk (OAR) lying close to the tumor are especially suited for radiotherapy using particles, as this unique dose distribution can be exploited here. The OAR behind the tumor can thus effectively be spared from radiation damage (Fig. 6.26c).


At the moment, mainly protons are used in particle therapy but also carbon ions. Furthermore other ions such as helium are getting more and more in the focus of particle RT.


These physical advantages ensure precise localization of dose distribution to the tumor while minimizing dose (thus DNA damage) to the surrounding normal tissues. Currently, particles heavier than carbon are not well investigated for clinical purposes due to the dose distribution at the tail where the dose increases with the charge of the particle resulting in increased dose to normal tissue. Furthermore, for equal velocities, the ionization density for carbon ions (Z = six, A = 12) is 36 times greater than that of the proton. However, a carbon ion has 12 times more total kinetic energy, so the range of the carbon ion is about three times lower. Thus, the heavier the particle, the shorter the penetration depth. Finally, following the recommendations of the Ion Beam Therapy Workshop Report, heavy ion beam therapy should be limited to tumors (a) exhibiting a high risk of local failure post photon (or proton) RT, (b) radioresistance due to histology, hypoxia, and other factors, (c) recurring, (d) efficient at repairing cellular damage, or (e) adjacent to critical normal structures, in particular if resection could lead to a substantial loss of organ function.


Proton therapy is nowadays widely used all over the world and in some cases is more appropriate for patient treatment than the mostly used X-ray RT, due to the physical properties of protons (the Bragg curve). A detailed historical overview can be found in Elaimy et al. [178].


Clinical advantages of a proton beam were first suggested by Wilson in 1946 in his paper about the radiological use of high-energy protons. Animal studies began as soon as the first high-energy synchrocyclotron (340 MeV) was completed at the University of California Lawrence Berkeley Laboratory, USA (LBL). These first experiments on mice, Tradescantia microspores, and yeast cells showed that the RBE of high-energy protons (340 MeV) is comparable to that of 200 kVp X-rays.


The first patient proton treatment in LBL took place in 1954. A few years later, in the late 1950s, the Gustaf Werner Institute in Uppsala, Sweden also used protons for patient treatment. In 1961, the Massachusetts General Hospital began treating small intracranial targets with radiosurgical techniques at the Harvard Cyclotron Laboratory (HCL) in Cambridge. Prior to the patient treatment, a radiobiological investigation on monkeys demonstrated experimentally the feasibility of the method. Later Koehler and others developed a technique to scatter the beam laterally and also range modulation wheels to produce SOBP to cover extended target volumes, thus it was possible to start treating larger treatment volumes in HLC in 1974.


During the late 1960s and in the decade of the 1970s, several Russian physics research facilities initiated their proton therapy programs. For example, the Joint Institute for Nuclear Research in Dubna in 1968, the Moscow Institute for Theoretical and Experimental Physics in 1969, and the Central Research Institute of Roentgenology and Radiology in Saint Petersburg in 1975.


The National Institute for Radiological Sciences in Chiba, Japan started proton therapy treatments in 1979. They were also the first that developed a spot scanning system for proton treatment delivery in 1980. Since then is proton therapy spread more and more—Clatterbridge, England in 1989, France at Nice and Orsay (1991), iThemba Labs in Cape Town, Africa (1993), Paul Scherrer Institut at Villigen, Switzerland (1996), Hahn Meitner Institute in Berlin, Germany (1998), National Cancer Center in Kashiwa, Japan (1998), and Joint Institute for Nuclear Research in Dubna, Russia (1999).


The first hospital specialized in proton therapy started treating patients in 1990 at the Loma Linda University Medical Center in Loma Linda, California, USA. In the same period, the Proton Therapy Cooperative Group was formed, later renamed to the Particle Therapy Cooperative Group (PTCOG) [179]. It is a non-profit organization making statistics and organizing meetings about protons, light ions, and heavy charged particles RT.


Nowadays, there are more than 100 proton therapy centers all over the world with technological equipment from several companies such as IBA, Varian, Mitsubishi, Sumitomo, Hitachi, Mevion, ProNova, Protom based on cyclotrons or synchrotrons. More about the facilities and also patient statistics can be found, for example, on the PTCOG website.


The generation of protons is obtained via hydrogen ionization. Protons are then accelerated inside a particle accelerator, typically a cyclotron or a synchrotron. A cyclotron produces a proton beam with a fixed energy, on the other hand, the proton energy in a synchrotron is adjustable [180].


In both cases (cyclotron and synchrotron), the beam needs to be spread longitudinally, to produce an SOBP for the patient treatment. This is done by superposing several beams with different energies and weights. In the case of a cyclotron, an adjustable amount of material has to be placed in the way of the beam to reduce the beam energy to the one needed. This is achieved by the use of a degrader just after the beam extraction or by placing a stack with a variable number of plates (a range shifter), a plate with ripples (a ridge filter), or a rotating wheel with an azimuthally changing thickness (a range modulation wheel) inside the nozzle in the irradiation room. In the case of synchrotron, the energy is adjusted inside the accelerator, as was already mentioned, so there is no need for any additional devices [180].


The physical depth dose curve of a SOBP has a broad, quite homogeneous dose region, as is shown in Fig. 6.30. This makes it possible to deliver a higher dose to the tumor region than to the OAR, and therefore to spare these tissues.


There are two modes enabling the lateral beam spread, passive or active modes. Examples of passive modes are the Single or Double Scattering (SiS or DS) and an example of active mode is the Pencil Beam Scanning (PBS). For the passive modes, the beam passes through scatters (one or two, SiS or DS, respectively). In the active modes, scanning magnets are used, which redirect the narrow proton beam to several positions according to the treatment plan. The dose is then delivered to each layer of the volume spot by spot.


The energy spectrum, and thus the LET of protons in the SOBP is changing with depth in tissue, since the protons are slowing down traveling through the tissue. At the distal parts of the SOBP, the LET is much higher than in the proximal part. High LET values are connected to increased DNA damage, and thus to lower cell survival.


The International Commission on Radiation Units and Measurements (ICRU) has recommended the use of a generic RBE value equal to 1.1 in the whole range of proton therapy, and most of the proton therapy centers around the world have adopted this value [181]. This means that the same fractionation scheme as for X-ray RT can be used, with the difference that instead of 2 Gy 1.82 Gy per fraction will be used with protons.


This recommended value is based on experimental studies done in vitro and in vivo mostly using passive scattering modes in the early days of proton therapy. From the in vitro studies, mostly performed on Chinese Hamster cell lines, with cells placed in the middle of SOBP, the range of estimated RBE values was from 0.86 to 2.10 with a mean of 1.22 ± 0.02. The RBE from the mid-SOBP in vivo studies ranged from 0.73 to 1.55 with a mean of 1.10 ± 0.01 [181].


Later studies showed that the RBE is not a constant value but it varies depending on a wide range of parameters, such as the beam range, dose per fraction, position in the SOBP, cell line or tissue origin, and also the studied biological endpoint [182]. Another problem when comparing RBE values from different publications is the reference radiation used for the establishment of the RBE values. Several reviews on this topic exist, as, for example, where a collection of data from several groups are sorted by cell lines referring also to the used reference radiation [183].


Some studies report RBE values at the distal falloff of the SOBP near to 3 [184]. One of the claimed advantages of proton therapy is the steep distal falloff of the Bragg peak. Due to this fact, many times the proton beam is often directed to stop in the proximity of the patient’s OAR. The mentioned studies highlight the inaccuracies in the generic RBE value used in the whole range of proton therapy. These inaccuracies are much more crucial at the distal falloff of the beam and can lead to the damage of healthy tissues behind the treatment volumes.


In recent years, there is an increased interest in using the PBS mode, thanks to the spot-weighted dose delivery, which facilitates a more conformal dose delivery to the treatment volumes and sparing of healthy tissue. Another advantage of PBS is the much lower secondary-induced radiation (mostly neutrons) from the components of the technological constructions or patient-specific devices (i.e., collimators and compensators) needed in passive modes.


The dose rate in each spot is however much higher than the dose rate in passive modes, which could maybe influence the cell response inside the treated volume in a different way than it is expected. Anyhow, there are several studies showing that there is not any significant difference between the biological response of cells using passive or active modes [185]. In clinical applications, there is some evidence that passive scattering may be associated with more toxicity than pencil beam scanning techniques [186].


Carbon ion radiobiology finds its origin from the use of ions in cancer RT. Research on carbon ions and their clinical potential started in 1975, with the installation of the BEVALAC at the Lawrence Berkeley Laboratory [187]. In response to the initial success, the Japanese government began construction on the world’s first heavy ion facility designated for medical applications at the National Institute of Radiological Sciences (NIRS) in 1984. The Heavy Ion Medical Accelerator in Chiba (HIMAC) was completed in 1993 and carbon ion RT clinical trials began in June 1994 [188].


Talking about energy deposition, it is important to mention the Linear Energy Transfer (LET—keV/μm) which is the energy deposited per unit of length along the particle track

 (6.6)with dE = deposited energy and dx = distance covered. Therapeutic beams of carbon ions (100–400 MeV/n) have LET ranging from 10 to 100 keV/μm [189]. LET is also at the origin of produced biological effects that cause radiation damage. As the particle species and their energy influence LET, the LET of carbon ions is higher than the LET of photons and hence causes a higher fraction of clustered DNA damage foci from direct DNA-ion interaction (Fig. 6.27).

A schematic diagram of the g H 2 A X arranged in a diagonal line in carbon ions and the scattered g H 2 A X in photons.

Fig. 6.27
Schematic representation of gH2AX after exposure to carbon ions versus photons. DAPI in blue, gH2AX in green


A schematic diagram of the g H 2 A X arranged in a diagonal line in carbon ions and the scattered g H 2 A X in photons.


Comparison of biological effects of different LET (beam qualities) is expressed as the relative biological effectiveness (RBE). For the same biological effect, RBE is described as the dose ratio of the reference beam quality experiment to the test beam quality experiment

 (6.7)with Dr = Absorbed dose at reference beam quality experiment (usually photon) and D = Absorbed dose at test beam quality experiment.


RBE is a function of multiple parameters such as the dose, dose rate, LET, oxygen concentration, and cell cycle phase to mention a few. The dependency of these parameters is particularly true at low LET (<10 keV/μm) but less with increasing LET (>10 keV/μm) such as for carbon ions. The RBE value of photons (<10 keV/μm) is considered equal to ~1.0 and tends to increase gradually until it comes to a maximum at around LET = 100 keV/μm and finally decreases. This phenomenon is also known as the overkill effect. Generally, the RBE of carbon ions is around 3.0. However, with increasing LET, dose delivered to the surrounding tissue (entrance dose and tail) also increases. Therefore, a compromise between RBE and dose delivered to the surrounding tissue is needed. As an optimal RBE is said to be achieved around a LET of 100 keV/μm, carbon ions became the best compromise between RBE and dose delivered to the surrounding tissue and is therefore the most studied and clinically applied ion in particle therapy [188, 190]. Yet, little is known on healthy tissue toxicity and the correlated molecular and cellular mechanisms linked to carbon ion irradiation.


Under normoxic conditions, DNA damage caused by low LET radiation (such as photons or protons) is enhanced by generated DNA radicals, which in the presence of molecular oxygen are fixed or become permanent (also known as the indirect interaction). The existing oxygen also hinders repair mechanisms. Under hypoxic conditions, this phenomenon is not present, DNA radicals become reduced by sulfhydryl groups causing less damage and repair mechanisms are promoted. Consequently, a major cause of radiation resistance in RTy has been attributed to hypoxic cancer cells. On the other hand, with high LET radiation (such as carbon ions), the particle directly acts on the phosphodiester bond of DNA inducing thus clustered damage which is then less amenable to be repaired. From these observations came the concept of Oxygen Enhancement Ratio (OER), which is an inverse relationship between dependence on oxygen, inducing cellular damage and the mass of the ion species (Fig. 6.28).

A line graph presents R B E versus L E T. The O E R and R B E curves intersect, where O E R slowly declines while R B E rises to its highest peak before declining.

Fig. 6.28
Schematic representation of the relationship between OER and RBE in function of LET


A line graph presents R B E versus L E T. The O E R and R B E curves intersect, where O E R slowly declines while R B E rises to its highest peak before declining.


The cell cycle status has been shown to be influential in determining radiation sensitivity [191]. Cells in the G2/M phases of the cell cycle are most sensitive to radiation while cells in late S phase are most resistant. This increased radiation sensitivity in G2/M appears to be related to chromatin condensation as effective DNA damage repair is hindered. Unlike low LET radiation, no significant effects of radiation sensitivity on the cell cycle distribution were observed when employing high LET radiation such as carbon ions [192].


The rationale behind fractionated RT, beside the cell-sparing effect, is based on cell cycle radiation sensitivity. Fractionation allows tumor cells in a radiation resistant cell cycle phase to switch/move into a more radiation sensitive phase before the next fraction is applied [193]. However, as the cell cycle distribution is not affecting radiation sensitivity for high LET radiation, fractionated RT would therefore be less beneficial. Overall, carbon ion RT has several benefits (Fig. 6.29).

A diagram illustrates that the energy, L E T, and R B E are represented by isosceles triangles with the apex pointing to the left, while O E R, cell cycle dependence, and fractionation dependence have the apex of isosceles triangles pointing to the right.

Fig. 6.29
Summary comparison between photon irradiation and carbon ion irradiation


A diagram illustrates that the energy, L E T, and R B E are represented by isosceles triangles with the apex pointing to the left, while O E R, cell cycle dependence, and fractionation dependence have the apex of isosceles triangles pointing to the right.


Hadrontherapy with carbon ion (carbon therapy, CT) is a RT technique intended to destroy cells by irradiating them with a beam of carbon ions particles. This therapy requires heavy, specific equipment derived from research in particle physics including source and particle accelerator (synchrotron or cyclotron), device for controlling the treatment beam and preparation devices, for the conduct and control of processing. This equipment leads to very heavy material and financial investments and the need for multidisciplinary cooperation for their use.


Compared to X-rays (conventional RT) which pass through the whole body and therefore irradiate as healthy cells pass, the carbon ions stop at the desired depth (therefore at the level of the tumor). These ions, once arrived in the tumor cells, create more serious lesions than with other treatments at the level of its genetic material. As their action is intense and the beam precisely defined, tumor cells can be very precisely targeted. These tumor cells do not die immediately, but they are no longer able to multiply and lose their immortality. In addition, the number of sessions in carbon therapy can be much smaller than that required in conventional RT. Moreover, additional chemotherapy is rarely required, which means less fatigue for the patient.


Carbon therapy can target inoperable tumors and particularly radioresistant, in particular when they are in a situation of hypoxia, a common cause of failure of conventional RT. Accordingly, carbon therapy is intended for the treatment of inoperable tumors or incompletely resectable as well as radioresistant surrounded by radiosensitive healthy tissue. The main indications of this therapy are cystic adenoid carcinomas, tumors of the sinuses of the face and salivary glands, mucous malignant melanomas, chordomas and chondrosarcomas of the base of the skull, sarcomas of the axial skeleton and soft tissues, unresectable or in resection incomplete, unresectable local recurrences of rectal cancer, large hepatocarcinomas (diameter greater than 4–5 cm), choroid malignant melanomas and eye tumors, prostate tumors, tumors of the cervix, and stage I NSCLC [188, 194].


All these pathologies to which carbon therapy is applied form a heterogeneous group for which there is a wide variety of therapeutic approaches ranging from surgery to very high-techRT, with or without the combination of several other treatments. According to the ClinicalTrials.gov website, 31 clinical trials comparing C-ions to either protons or photon therapy were found as recruiting, active or completed.


According to a global assessment of clinical experiences in Japan, the optimization of the therapeutic protocol has progressed over many years and is dependent on the tumor site [195]. For a given disease entity, the therapeutic schedule (e.g., carbon therapy alone, with chemotherapy or in a preoperative setting) is initially based on scientific evidence.


Some of the previously published clinical studies suggest that carbon-therapy would potentially be more effective than conventional RT in case of cystic adenoid carcinomas of the head and neck, tumors of the salivary glands in absence of complete resection, chordomas and chondrosarcomas of the base of the skull, and NSCLC tumors while late toxicities which have been reported in particular in some cases of chordomas and skull base chondrosarcomas, soft tissue and skeletal sarcomas axial, choroid melanomas and eye tumors [196–198].


In total, the analysis of the most recent literature and agency reports of evaluations are consistent to indicate that there is still little data available to conclude definitively on the efficiency-safety balance. Carbon therapy appears to be a promising technique for the treatment of certain not resectable or radioresistant tumors, surrounded by healthy radiosensitive tissue and is currently studied in clinical trials. The long-term side effects are also not yet well known. Indeed, looking at the dose/depth profile of particle beams, the effect of entrance dose and fragment tail on the surrounding healthy tissue is highly reduced compared to conventional therapy. Yet, this dose is not negligible and is an underdeveloped field in radiation research.


As described previously, only protons and carbon ions are the types of hadrons used to treat solid tumors so far, however several kind of hadrons, such as neutrons, charged pions, antiprotons, helium ions, and other light ions nuclei (like lithium, oxygen, up to silicon ions) have been either used or planned to be tested for oncological treatment [199].


In recent years, thanks to their physical and biological properties complementary to protons and carbon ions, a renewed interest in using helium ions (4He) for RT has been observed. This is also tangible from the fact that the first European He-ion treatment is about to go into operation at the Heidelberg Ion-beam Therapy (HIT) center and that at NIRS, in Japan, a multi-ion therapy concept including He ions is currently set up [200, 201]. In addition, the National Center for Oncological Hadrontherapy (CNAO) in Italy is also planning to treat patients with He ions in the future since a source will be available for non-clinical/preclinical research by Spring 2023. In the past, about 2000 patients were successfully treated at the Lawrence Berkeley National Laboratory with passively scattered He ions in the US heavy ion therapy project [202].


He ions are very attractive for cancer treatment because they can overcome some of the limitations of protons and carbon ions, while keeping their advantages. Specifically, they can provide favorable biophysical characteristics like the reduced lateral scattering and enhanced biological damage to deep-seated tumors like heavier ions, while simultaneously lessening particle fragmentation in distal healthy tissues as observed with lighter protons [203].


Radiobiologically speaking, helium ions, being in a similar LET range as protons, offer an improved RBE and OER, while potentially allowing for less demanding biological modeling compared to carbon ions. The helium ions radiobiological characterizations performed so far showed a higher RBE in the Bragg Peak region of up to 1.6, and the OER at 10% survival was found to decrease from 2.9 to 2.6 in the peak region when compared to protons [204]. These are certainly advantageous features for eradication of radioresistant hypoxic tumors. In addition, helium offers a decreased lateral scatter effect versus proton, with less fragmentation tail dose versus carbon [205].


Especially for pediatric patients, helium ions could have the potential to reduce the volume of irradiated normal tissue, without bringing the disadvantage of additional dose caused by the fragmentation tail, like it is observed for carbon ions [206]. This could not only improve the dose distribution for small tumor lesions, but also reduce the total overall dose for children suffering from large tumors, also considering that it is expected that the number of secondary neutrons is very low and the dose due to neutrons may even be lower than in proton therapy [207]. Last but not least, it is important to take into account that helium hadrontherapy would also be less expensive than carbon ions, as they may be produced in cyclotrons rather than synchrotrons.


From the modeling point of view, the very few RBE models existing for these ions still need to be integrated and benchmarked by experimental data on radiation-induced tumor cell killing, as well as normal cell response. However, He-ion RBE data for cell survival are still very scarce, and intensive experimental campaigns need to be performed [203].


Oxygen ions are currently considered as a potential alternative to carbon ions. Because of their mass, they have less lateral scattering which is in favor of the tumor conformality. The high LET of oxygen ions when compared to carbon ions is associated with higher RBE and therefore to better treatment effectiveness in particular with respect to hypoxic tumors. Compared to carbon ions, oxygen ions produce more nuclear fragments, which need to be carefully investigated, not only in-field but also out-of-field, laterally and beyond the Bragg peak, to study the effect of the mixed radiation field in the healthy tissues surrounding the tumor target [208] (Box 6.20).


Helium ions versus Protons:
↓ Lateral scattering

↑ RBE

↑ OER

↓ Secondary neutrons

Helium ions versus carbon ions:
↓ Fragmentation tail

↓ Costs


Helium ions versus Protons:
↓ Lateral scattering

↑ RBE

↑ OER

↓ Secondary neutrons


Particles used for therapy need to have sufficient energy to penetrate the patient’s body to the desired depth, i.e., several hundred MeV/u. At therapy centers, the acceleration is done by the use of circular accelerators, which can be divided into two types, the cyclotron and the synchrotron. Another way of accelerating particles is through the use of high-frequency linear accelerators, so-called LINACS, which at the moment are getting more and more in the focus. The different accelerator types are summarized in Table 6.11.


A classical cyclotron consists of a large electromagnet with hollow, D-shaped electrodes, called Dees in-between. The Dees are separated by a small gap, which is the acceleration region of the cyclotron. The electromagnet has a constant magnetic field perpendicular to the plane of the movement of the particles. The electrodes induce a radiofrequency electric field, which is changing polarization in resonance with the particle movement. The particles are injected in the middle of the gap. In this gap, the ions are accelerated the first time, upon entering the first Dee there is no electric acceleration field, keeping the particle at constant velocity. Within the electrode, the magnetic field bends the particle due to the Lorentz force and brings it on a circular path with radius

 (6.8)with m0 the mass, v the velocity, q the charge of the particle, and B the magnetic field of the electromagnet. After a half circle, the particle enters the acceleration gap and is accelerated until the second Dee is entered, where again a half circle is formed, which has a larger radius but is traveled within the same time. Acceleration only happens if the frequency f of the electric field, the so-called cyclotron frequency, is adapted to the time, the particle needs to traverse the Dee and therefore to the charge q and the mass m of the particle and the magnetic field B:

 (6.9)but stays constant in time. This process happens until the radius corresponds to the extraction radius R and the particle is extracted with an energy of

 (6.10)Classical cyclotrons are using iron magnets which limit the magnetic field to 1–2 T, if superconducting magnets are used, the magnetic field can be increased, and therefore the size of the cyclotron decreased. This kind of cyclotron only works for non-relativistic particles with velocities v ≪ c. For higher energies and thus higher velocities, the time for the half circle is not constant anymore. Therefore, they get asynchronous to the constant acceleration frequency. For relativistic particles, the mass m is no longer constant but increases by the factor

 (6.11)The cyclotron frequency is now dependent on particle velocity

 (6.12)This limits the maximum energies achievable using classical cyclotrons to, e.g., approx. 20 MeV for protons, which is much smaller than the needed energies for particle therapy. This problem is overcome by two new types: the synchrocyclotron and the isochronous cyclotron. As the synchrocyclotron has a very low duty cycle, it is not usable for particle therapy.


The isochronous cyclotron makes use of a non-constant magnetic field. Here the magnetic field gets larger by the factor γ with increasing radius to increase the Lorentz force and balance the mass increase, resulting again in a constant travel time. This increase in magnetic field leads to a defocusing of the beam, which is compensated by alternating-gradient (also called strong) focusing. Technically it is realized by changing the magnet design, into the so-called hill-valley design, in so-called sector cyclotrons. This design results in regions with higher and lower magnetic fields as shown in Fig. 6.30b. At the transition between hill and valley, the magnetic field is bent and a defocusing (valley to hill) and focusing effect (hill to valley) can be achieved. Using this design acceleration to clinical relevant energies for protons is achievable. Furthermore using the isochronous mode together with superconducting magnets allows for small cyclotron sizes of only a few meters diameter. These properties make the isochronous cyclotron the most popular accelerator for proton therapy.

2 diagrams. Diagram A displays the top view and side view of a classical cyclotron. Diagram B exhibits the hill-valley magnet design that connects the higher and lower magnetic fields.

Fig. 6.30
(a) Principle of a classical cyclotron. (b) Hill-valley magnet design


2 diagrams. Diagram A displays the top view and side view of a classical cyclotron. Diagram B exhibits the hill-valley magnet design that connects the higher and lower magnetic fields.


A classical synchrotron consists of an injector, a set of bending and focusing magnets, guiding the particle on a circular track and linear acceleration tracks without magnetic field in between and an extractor as shown in Fig. 6.31a. The injector is basically a linear pre-accelerator, which injects the particles in the ring with a certain energy and a set of inflection magnets which initially bend the particles into the acceleration tube. In contrast to the cyclotron where the particle track is spiral, the particle track stays circular in the synchrotron at all times. To achieve a circular particle track, dipole bending magnets, which bend the particles to stay in the circle, are placed all along the cyclotron. The magnetic field needs to be increased in synchronization with increasing energy and therefore velocity of the accelerated particle, to keep the particles on track. The particles are accelerated close to the speed of light; therefore, the processes happen in the relativistic regime. In the synchrotron, the following requirement, due to the Lorentz force, has to be fulfilled at all times:

 (6.13)One can see that the magnetic field has to be increased proportionally to the increased velocity and therefore energy of the particles. Furthermore, quadrupole and even higher order magnets are necessary to focus the particle beam within the vacuum acceleration tube. The quadrupole magnets are able to spatially focus the beam and therefore work as a lens. In contrast to optical lenses, magnetic lenses only focus in one direction and even worse defocuses in the other direction. Therefore magnetic lenses always come in units of pairs, one focusing the x-direction and the other the y-direction. The higher order magnets are able to correct even the smallest aberrations and therefore ensure that the beam keeps on track. Modern synchrotrons also take advantage of the strong focusing to further reduce beam diameter, as in the isochronous cyclotron. The energy of the particles is increased in the linear acceleration tracks, where high-frequency electric fields are applied in cavity resonators, which again have to be synchronized with the velocity of the particles. Both magnetic field strength and phase of the electric field have to be adapted to the particle’s energy in each circle. The vacuum chamber for particles in a synchrotron can, due to the circular path, be a thin torus rather than a disk as it is for cyclotrons, which allows a more cost-efficient construction. The last part is the extractor, which consist of sets of dipole magnets which extract the particles once the desired energy is reached. The synchrotron by design can only operate in a quite slow pulsed mode, but has the advantage that the energy can be easily varied pulse by pulse. Synchrotrons are mainly used when different particle types (protons, carbon ions, and others) are used in the same facility, as the magnet tuning allows flexibility to flexibly change the accelerated ions, which is not possible in cyclotrons (Box 6.21).

2 diagrams. Diagram A exhibits the circular synchrotron principle which includes extraction magnets, particle beam, acceleration cavity, injector, inflector, bending magnets, and focussing magnets. Diagram B displays the dipole magnets and the x and y-focused quadrupole magnets.

Fig. 6.31
(a) Principle of a synchrotron. (b) A positively charged beam coming from the front is deflected by Dipole magnets and focused by quadrupole magnets


2 diagrams. Diagram A exhibits the circular synchrotron principle which includes extraction magnets, particle beam, acceleration cavity, injector, inflector, bending magnets, and focussing magnets. Diagram B displays the dipole magnets and the x and y-focused quadrupole magnets.


Cyclotrons consist of a big magnet and two, complex shaped electrodes.

Compact design of asynchronous cyclotrons allows for small sizes of a few meters diameter.

Asynchronous cyclotrons most popular accelerator for proton therapy.

Synchrotrons consist of a set of bending and focusing magnets and field free drift tracks, which are arranged in a circle.

Synchrotrons can accelerate different particle types (protons, helium, carbon, and also heavier ions) with the same design.


Cyclotrons consist of a big magnet and two, complex shaped electrodes.


Compact design of asynchronous cyclotrons allows for small sizes of a few meters diameter.


Synchrotrons consist of a set of bending and focusing magnets and field free drift tracks, which are arranged in a circle.


Synchrotrons can accelerate different particle types (protons, helium, carbon, and also heavier ions) with the same design.


A high-frequency linear accelerator (LINAC) represents a complementary type of accelerator compared to cyclotron and synchrotron. It is based on the same principle as the modern clinical LINACs for X-ray therapy, as commonly used worldwide to accelerate electrons to high energies and stimulate them to emit X-rays at several MeV energies. Due to the light weight of the electrons, these accelerators can be very compact and directly mounted on the application gantry. For particles such as protons and heavier ions in contrast, more complex technological developments are necessary. Although already proposed in the 1990s, the technology for particle LINACs still is in its infancy, with only a few projects worldwide [209, 210]. Radiofrequency LINACs are based on the principle to accelerate a bunch of particles in cavity resonators as shown in Fig. 6.32a. The particles are synchronized to the applied alternating electric field. They are accelerated when they are in the acceleration space. When the field commutes, the particles are shielded in a field free drift space. The shielding also serves as electrodes for the electric field. When the particles enter the next acceleration space, due to alternation of field again see an acceleration electric field. This process is continued until the final energy is reached. Particle LINACs in the so-called all-linac approach consist of different types of acceleration cavities shown in Fig. 6.32b, after the ion source, each suited for a different particle energy range. For energies up to ~5 MeV, a radiofrequency quadrupole (RFQ) is used for acceleration. For energies between 5 and 70 MeV, the acceleration is performed in a SCDTL (side-coupled drift tube LINAC), followed by the coupled cavity LINAC (CCL) up to the maximum energies of ~250 MeV. The acceleration is performed in an electric field in which the resonators are oscillating with 3 GHz allowing for high electric fields and a shrink the system length to approximate of ~30 m, which can be fit into a clinical building. The RFQ is a quadrupole electromagnet, which is oscillating with a 3 GHz radiofrequency. Special longitudinal design of the electrodes makes it possible to push the particle beam through the RFQ and therefore accelerate it. Furthermore, the RFQ bunches the particle beam so that it fits the needs of the SCDTL and CCL structures, which can only accelerate a bunch of particles. The SCDTL accelerates the beam in the mid energy range 5 and 70 MeV. The SCDTL structure as shown in Fig. 6.32c consists of a huge cavity resonator where drift tubes are mounted. In the cavity, the alternating electric field is built and the tubes serve as field free drift space. The length of the drift tube must be synchronized to the velocity of the particles, so that the particles only see the acceleration of the oscillating field. The length of the ith tube is:

 (6.14)with

 (6.15)describing the velocity v of the particle in units of velocity of light c and λRF being the wavelength of the oscillating field. For a 3 GHz radiofrequency, the wavelength is

 (6.16)For an acceleration between 5 MeV (β = 0.1) and 70 MeV (β = 0.36), this results in a drift tube length of 1–3.6 cm. For higher energies, a coupled cavity LINAC (CCL) system is used (Fig. 6.32d). The design of the structure is different compared to SCDTL. Here the field is coupled in through a cavity, which makes them more efficient for higher particle velocities. The manufacturing of SCDTL and CCL structures is quite complicated as material defects such as welding seams or supernatant material will disturb the electric field. New production techniques such as 3D metal printing will offer possibilities of high precision manufacturing of such structures.

Diagram A depicts field free drift space and acceleration denoted by leftward arrows in the linear acceleration principle. Diagram B exhibits the proton L I N A C system which includes ion source and R F Q which has low energy, and S C D T L structures with mid energy among others. Diagram C indicates a field free drift space and acceleration cavity in a side-coupled drift tube structure. Diagram D displays coupling cavity, and others in a coupled cavity structure.

Fig. 6.32
(a) Linear acceleration principle. (b) A proton LINAC system. (c) Principle of a side-coupled drift tube LINAC (SCDTL) structure (cut through). (d) Principle of a coupled cavity LINAC structure (cut through)


Diagram A depicts field free drift space and acceleration denoted by leftward arrows in the linear acceleration principle. Diagram B exhibits the proton L I N A C system which includes ion source and R F Q which has low energy, and S C D T L structures with mid energy among others. Diagram C indicates a field free drift space and acceleration cavity in a side-coupled drift tube structure. Diagram D displays coupling cavity, and others in a coupled cavity structure.


High-frequency LINACs for particle therapy are an emerging technology.

Complex cavities accelerate beams with a GHz frequency.

Cavity size has to be precisely aligned with particle velocity.


After the accelerator, the particle beam needs to be guided to the patient. For beam guiding as in the acceleration process of the synchrotron, sets of magnets are used. Dipole magnets are used for bending the beam, whereas quadrupole magnets are used to keep the beam on track in the vacuum tube. Before the patient also beam diagnostics, such as a dosimetry chamber is placed. A quite important step is also the beam shaping, which defines the energy and size of the beam. In most centers, pencil beam scanning is used, which allows to get rid of a collimator close to the patient and therefore reduce unwanted exposure of the patient with neutrons coming from the collimator. The energy selection can be done away from the patient, and it must only be guaranteed that the beam has a defined profile modern therapy centers mostly rely on the application of radiation from different angles, which makes it necessary to move the beam around the patient. This is done by the use of so-called gantries, which are rotatable. The beam is deflected on the gantry and then can be delivered at a defined position. In particle therapy, due to the velocity of the particles and their rigidity, i.e., the resistance of a particle to be bent by a magnetic field, huge and especially heavy magnets must be used, which make gantries quite large and heavy. A conventional proton gantry is in the order of 150 t with a size of several meters, whereas for carbon ions it can be up to 600–700 t (Box 6.22).


Nano-objects exhibit different physical and chemical properties compared to the related bulk materials due to a high surface-to-volume ratio, a metric that decreases with the size of the object.

The surface of nanoparticles can be functionalized to actively target cancer cells opening avenues for a use in nanomedicine field. Recognition and clearance of the nano-objects from the bloodstream by the reticuloendothelial system (i.e., resident macrophages in liver, spleen, lungs) remain the main challenge.

Nanoparticles have the potential to be used to efficiently and specifically deliver drugs to the tumor, to produce heat in hyperthermia therapy, and to sensitize cancer cells to radiotherapy.

Translation of nanoparticles to the clinic remains poor due to hurdles related to their large-scale manufacturing and toxicity studies.


Nano-objects exhibit different physical and chemical properties compared to the related bulk materials due to a high surface-to-volume ratio, a metric that decreases with the size of the object.


The surface of nanoparticles can be functionalized to actively target cancer cells opening avenues for a use in nanomedicine field. Recognition and clearance of the nano-objects from the bloodstream by the reticuloendothelial system (i.e., resident macrophages in liver, spleen, lungs) remain the main challenge.


Nanoparticles have the potential to be used to efficiently and specifically deliver drugs to the tumor, to produce heat in hyperthermia therapy, and to sensitize cancer cells to radiotherapy.


Translation of nanoparticles to the clinic remains poor due to hurdles related to their large-scale manufacturing and toxicity studies.


In the last few decades, the use of nanomaterials in medicine has attracted increased interest. A nanoparticle is a particle with at least one of its external dimensions in the size range of 1–100 nm. Due to this small size, nanoparticles exhibit physical, chemical, and optical properties that significantly differ from those of their bulk material, which makes them emerge as promising tools to improve the efficacy of cancer diagnosis and therapy. This section describes how nanoparticles have the potential to contribute to certain cancer therapies that are discussed in Sects. 6.4 and 6.5, including the delivery of chemotherapeutic drugs, targeted therapy, hyperthermia, and RT (Box 6.23).


Nanoparticles can typically be classified based upon their material (organic or inorganic), shape, surface, or size (Fig. 6.33). As such, a broad and versatile spectrum of nanoparticles exists. Organic nanoparticles include liposomes, polymeric nanoparticles, dendrimers, and micelles. On the other hand, examples of inorganic nanoparticles are metallic nanoparticles, magnetic nanoparticles, silica nanoparticles, carbon-based nanoparticles, and quantum dots. The type of nanoparticle to use depends on its application in medicine.

A diagram displays the surface with charge and functionalization, material, size, and shape of a nanoparticle and its applications that include drug delivery, hyperthermia, and radiosensitization.

Fig. 6.33
The versatility of nanoparticles and their potential applications in cancer therapy


A diagram displays the surface with charge and functionalization, material, size, and shape of a nanoparticle and its applications that include drug delivery, hyperthermia, and radiosensitization.


A major challenge in nanomedicine is the immediate and inevitable “masking” of nanoparticles by proteins, lipids, carbohydrates, and nucleic acids once the nanoparticles are introduced into the blood circulation, forming a “biocorona.” Subsequently, the adsorbed surface proteins are recognized by the abundant phagocytic cells in the liver and the spleen, causing the rapid trapping and removal of nanoparticles from the bloodstream. A limited blood circulation time prevents nanoparticles from reaching the tumor cells. In order to improve the biocompatibility, solubility, and stability of the nanoparticles in physiological media, the surface of nanoparticles is usually coated with polymers, generating an electrostatic repulsion and/or a physical barrier between the nanoparticles. Depending on the applied coating, the net surface charge of the nanoparticle can be positive, negative, or neutral, which strongly influences the biological fate and effects of the nanoparticles. One of the most commonly used polymers for nanoparticle coating is polyethylene glycol (PEG), which reduces the biocorona formation by neutralizing the nanoparticle surface charge and giving the nanoparticle a “stealth” character. This delays their recognition and subsequent sequestration of the nanoparticles by the reticuloendothelial system (RES), prolonging the blood circulation time.


An important physical property of nanoparticles is the large surface area-to-volume ratio. When the size of the nanoparticles decreases, a larger proportion of their atoms or molecules are displayed on the particle’s surface, rather than in the particle’s core, increasing the surface area-to-volume ratio. This ratio decreases with the size of nanoparticles modifying their physical and chemical properties compared to bulk materials. Furthermore, the large surface area-to-volume ratio facilitates the functionalization of the nanoparticle surface with multiple moieties, supporting their multifunctional applications in cancer diagnosis and therapy, which is discussed in more detail below.


In order to use nanoparticles in cancer remediation applications, nanoparticles need to reach and accumulate in the tumor tissue. Rapidly growing tumors stimulate the formation of new blood vessels to supply the tumor cells with a sufficient amount of oxygen and nutrients. The newly formed tumor vasculature is usually characterized by the presence of abnormal, leaky, and immature blood vessels, which are poorly aligned with a defective endothelium. Consequently, nano-sized particles can efficiently pass through inter-endothelial gaps and accumulate in the tumor. Furthermore, the decreased level of lymphatic drainage promotes the nanoparticle tumor retention. This “passive” process is known as the enhanced permeability and retention (EPR) effect. Importantly, the efficacy of the EPR effect is limited due to the heterogeneity of the vascular structure within the tumor, at different tumor stages and between different tumor types. Furthermore, despite the success of the EPR effect in preclinical tumor models, the efficacy and clinical translation of cancer nanomedicine remain poor, indicating that the EPR effect is less reliable in human tumors. In fact, research demonstrated that extravasation of nanoparticles into the tumor via active trans-endothelial transport pathways occurs more frequently than passive diffusion and thus should not be underestimated [211].


A strategy to complement the EPR effect and to improve the tumor accumulation efficiency of nanoparticles is the functionalization of the nanoparticle surface with cancer-targeting ligands. Cancer-targeting ligands are often specific for factors that are unique or upregulated in cancer cells and that are mostly involved in processes such as tumor progression, invasion, metastasis, and angiogenesis. In general, these targeting ligands can be categorized in five main classes: small molecules, peptides, protein domains, antibodies, and nucleic-acid based aptamers. Examples of cancer-specific targeting ligands are folic acid (FA) (essential for DNA synthesis), cyclic arginine-glycine-aspartic acid (cRGD) peptide (a cell adhesion motif with a high affinity for αβ-integrins), and targeting ligands that can bind to membrane receptors, such as EGFR or VEGFR. Thanks to the large surface area-to-volume ratio of nanoparticles, multiple targeting molecules can be conjugated to the nanoparticles, which enables multivalent interaction with membrane receptors, increasing the tumor uptake and the intratumoral retention time.


Nanoparticles can be used as promising tools to enhance the efficiency of multiple anticancer therapies, including the delivery of chemotherapeutic drugs, hyperthermal therapy, and RT.