The efficacy of external beam radiotherapy (EBRT) is dose dependent, but the dose that can be applied to solid tumour lesions is limited by the sensitivity of the surrounding tissue. The combination of EBRT with systemically applied radioimmunotherapy (RIT) is a promising approach to increase efficacy of radiotherapy. Toxicities of both treatment modalities of this combination of internal and external radiotherapy (CIERT) are not additive, as different organs at risk are in target. However, advantages of both single treatments are combined, for example, precise high dose delivery to the bulk tumour via standard EBRT, which can be increased by addition of RIT, and potential targeting of micrometastases by RIT. Eventually, theragnostic radionuclide pairs can be used to predict uptake of the radiotherapeutic drug prior to and during therapy and find individual patients who may benefit from this treatment. This review aims to highlight the outcome of pre-clinical studies on CIERT and resultant questions for translation into the clinic. Few clinical data are available until now and reasons as well as challenges for clinical implementation are discussed.External beam radiotherapy (EBRT) alone and in combination with surgery and/or chemotherapy is one of the main modalities for cancer treatment and has a high potential to permanently cure solid tumours even in locally advanced stages by inactivation of cancer stem cells.
1 EBRT can be administered precisely to a target volume during a course of fractionated irradiation. The homogeneous energy dose has a high intensity in solid tumour lesions. For some cancers, survival rates after primary radiotherapy are high [
e.g. early stage larynx cancer and early stage non-small-cell lung cancer (NSCLC)], whereas for many other entities they are not (
e.g. glioblastomas, sarcomas and advanced NSCLC).
2One way to improve radiotherapy is to increase the inactivation of tumour cells. However, the applicable EBRT dose is limited by the radiosensitivity of the surrounding tissue. While EBRT is directed to the local tumour disease, the use of systemic radioimmunotherapy (RIT) offers the possibility to treat both, localized and diffuse tumours and (micro)metastases.
3 Radionuclides are bound to carrier molecules that target tumour cells. Thus, they are distributed according to the properties of the tracer and are continuously effective during a longer period compared with EBRT, although dose rates decrease depending on the half-life of the radionuclide. Some free therapeutic radionuclides are effective for specific indications,
e.g.
131I for treatment of thyroid cancer or palliative use of
223Ra against bone metastases. However, these cannot be translated to treatment of other entities. Besides, radioactive-labelled cytostatic drugs and hormone derivatives,
4 particularly monoclonal antibodies (mAb) have been radiolabelled and investigated.
5 Given a substantial difference in the target receptor expression between the tumour cells and surrounding normal tissues, a dose fall-off between both tissues can be expected. The radiolabelled mAb Zevalin
® ibritumomab tiuxetan (Zevalin
®, Bayer Healthcare Pharmaceuticals, Berlin, Germany) directed against CD20 is approved by the Food and Drug Administration(FDA) and the European Medicines Agency (EMA) for the treatment of follicular B-cell non-Hodgkin''s lymphomas, which are generally considered as radiosensitive. However, mAb are large and are thus taken up slowly into solid tumour tissue followed by a long clearance. Additionally, accumulation in solid tumours depends on vascularization, vessel permeability, tumour size, interstitial pressure and other microenvironmental characteristics.
6,7 Furthermore, mAb are rather susceptible when labelling under rough conditions. Thus, the application of molecules such as fragment antigen-binding (Fab),
8–10 nanobodies,
11,12 affybodies,
13,14 single chain variable fragments (scFvs),
15,16 aptamers
17–19 or peptides
20,21 is considered. In addition to the effects on target cell, radionuclides with sufficient radiation path length (
e.g. β-emitters) can destroy adjacent tumour cells by the crossfire effect, that is through the range of radiation in tissue, cells can be killed without having bound the radionuclide itself.
22 This is regarded as a main advantage of RIT for the treatment of solid tumours as plasticity of tumour cells (
e.g. loss of target antigen) and delivery barriers can be overcome by some extent. However, the dose-limiting organ in non-myelo-ablative RIT is the red bone marrow and myelosuppression the main toxicity.
22 Therefore, the maximum tolerated activity that was applied in clinical RIT trials (reviewed in Navarro-Teulon et al
23) did not result in tumour doses >33 Gy in large tumours, which is not enough to achieve permanent local control of solid tumours.
Combination of internal and external radiotherapy
The combination of internal (incorporated) and external radiotherapy (CIERT) is a novel promising approach in radiation oncology. In this review, CIERT is defined more specifically by an integrated (without interval) application of EBRT and systemically applied RIT. Other approaches such as the combination of external radiotherapy with selective internal radiotherapy, radioembolization, brachytherapy, seed implantation, other intravenously applied radionuclide therapies or sequential application of any of these treatments will not be considered here. Furthermore, the focus will be on solid tumours.The potential benefit of such a combined irradiation is to increase the energy dose applied to the solid tumour lesion, while respecting the limitations of the surrounding normal tissues and the organs at risk (OARs) that are different for both treatment modalities (see above). summarizes the characteristics and OARs of EBRT and RIT and gives an overview on the advantages of the combinatorial approach. Beyond local treatment intensification, another advantage of CIERT can be the combination of local treatment, directed to the solid tumour, and systemic treatment, directed to the subclinically disseminated disease, that is, microscopic tumour lesions not detectable on imaging.
Open in a separate windowCombination of internal and external radiotherapy (CIERT). Treatment characteristics of external beam radiotherapy (EBRT) and radioimmunotherapy (RIT) are summarized and advantages of the combination strategy (CIERT) are depicted. Local treatment of the solid tumour via precise EBRT is supplemented by a systemically applied radiotherapeutic drug. Thereby, the tumour dose is enhanced without additional toxicity and (micro)metastasis are potentially targeted. Further, usage of theragnostic radionuclide pairs has the potential to predict delivery and dose distribution of RIT before and during treatment. OAR, organ at risk.Many challenges are to be met prior to the initiation of CIERT. For example, thoughts on the treatment schedule of CIERT and dosimetry considerations are inevitable. The EBRT would usually be applied as standard treatment. Considerations on the RIT part equal usual aspects of RIT, for example, application of cold doses as well as the choice of the carrier molecule (according to the tumour target) and radionuclides. Accordingly, new developments in the field of RIT, for example, pre-targeting strategies, might be applicable for CIERT approaches in the future but have not been used in this context so far. Many of those aspects are intensively researched with regard to single treatments and reviewed elsewhere.
3,23–29 This work focuses on the presentation of pre-clinical and clinical investigations on CIERT as a promising treatment strategy.
Choice of radionuclides and theragnostic potential of combination of internal and external radiotherapy
The main factor of radiation toxicity is damage of DNA. If the amount and severity of radiation-induced damage exceeds the repair capacity of the cell, death occurs during mitosis. The linear energy transfer (LET) describes the energy released by the radiation over a certain distance and influences relative biological effectiveness (RBE).
3,30 X-rays as well as
γ- and
β-emitters have low LET and thus produce individual DNA lesions mainly by indirect ionization that can easily be repaired. By contrast, high and intermediate LET particle emitters cause clusters of DNA damage that are difficult to repair. Thus, α-emitters (high LET) and Auger electrons (intermediate LET) are more cytotoxic at equivalent absorbed doses. The track path length of α-emitters covers only some cell layers (50–100 µm), and Auger electrons have an even shorter range (<1 µm), which, together with the high RBE, makes them suitable for treatment of small volumes such as micrometastasis.
3,31 If larger solid tumours are targeted, microenvironmental factors such as perfusion, vessel permeability and the amount of connective tissue influence the distribution of RIT therapeutics. Thus, the application of
β-particles may be most promising for CIERT because their path length of 0.5–12.0 mm enables the crossfire effect.
3,30In contrast to mitotic catastrophe caused by irradiation, apoptosis can be induced by some mAb via blockage of the respective receptor and modification of downstream signalling. Thus, the combination of irradiation and mAb may promote the manifestation of sublethal harm to severe damage, which finally lead to cell death. In case of CIERT, radiation is not only applied via EBRT but also by radionuclides bound to the mAb.A fundamental requisite for the success of radioactivity delivery into solid tumours is that the radionuclide reaches the target and accumulates for an appropriate period. Thus, the pharmacological half-life of the carrier and half-life of the radioactive decay of the chosen nuclide need to be balanced.
3,23 Most pre-clinical and clinical studies on CIERT used large mAb (approximately 150 kDa), which show a slow plasma clearance. Thus, intratumoral accumulation peaks usually several days after injection. Accordingly, most studies used
β-emitters or emitters of Auger electrons with half-lives of at least several days. Pickhard et al
32 recently showed the benefit of using
213Bi bound to an antibody against the epidermal growth factor receptor (EGFR) in combination with EBRT. They demonstrated that different cell death pathways are triggered by this
α-emitter and photon irradiation. However, the short half-life of
213Bi (45 min) may limit its usage for solid tumours
in vivo if the nuclide is linked to antibodies, because most doses will be applied before the tracer penetrates into tumour tissue. Thus,
213Bi may only be useful to treat haematological malignancies and therefore is not feasible for CIERT. The concept of pre-targeting is intensively researched in association with RIT as a single treatment. The tumour is pre-targeted with the unlabelled complementary prepared antibody, and the radionuclide is delivered via a small molecule recognizing the antibody by the complementary system in a second step. This may lead to higher tumour uptake with lower normal tissue retention (reviewed in van de Watering et al
29). However, a combination with EBRT has never been investigated and substantial research on scheduling would be mandatory.The concept of theragnostic approaches is applicable for CIERT, as theragnostic radionuclide pairs can be used for the RIT part of the therapy. The goal is to combine a diagnostic tool having an imaging radionuclide (positron or
γ-radiation emitter) with a derived individualized therapeutic procedure using a therapeutic radionuclide (particle emitter). The tumour and normal tissue uptake of the respective drug can be evaluated for individual patients via positron emission tomography (PET) or single photon emission CT (SPECT) and give predictive information on a potential treatment benefit. The selection of appropriate radionuclides for imaging with regard to their replacement by a radionuclide for therapeutic purposes that exhibit similar chemical and physical properties is a crucial matter. Thus, it is important to consider different characteristics of radiation according to the requirements, such as decay characteristics, dose range and physical half-life of the radionuclides.
30 Imaging with radionuclide-labelled conjugates provides pre-therapeutic information such as biodistribution, hints of a limiting or critical organ or tissue, and maximum tolerated dose. Dosimetry is most challenging, as pre-therapeutic imaging may not be congruent to actual delivered doses.
33 However, this field is extensively investigated for peptide receptor radionuclide therapy (PRRT), and results are directly transferable to CIERT approaches. After applying therapeutic nuclide-labelled conjugates, the results of such treatment may again be monitored via imaging. A selection of theragnostic combinations of radionuclides are shown in but its production is difficult and expensive.
52 The positron emitters
86Y and
124I have been described controversially as PET nuclides since besides high
β+-radiation energy they emit multiple high-energy
γ photons that cause so-called multiple coincidences disturbing PET imaging quality. However, different correction methods allow improved quantitative imaging.
50 Moreover, for the application of
90Y-labelled radiopharmaceuticals, it is suggested to estimate the uptake and dosimetry with the nuclide counterpart
86Y.
36 Nevertheless,
86Y-PET is far from clinical routine, at least in the near future. Furthermore,
131I also emits
γ-radiation that has been used for imaging, and
111In and
123I have a potential for treatment owing to their released Auger electrons.
Table 1.
Potential theragnostic radionuclides
aPair | Half-life | Radiation (keV) | Application examples
|
---|
Study | Imaging | Model | Entity |
---|
64Cu/67Cu | 12.7 h/2.6 days | β+ 653 (17.5%)/β− 562 (100%)b | Anderson and Ferdani34/Novak-Hofer and Schubiger35 | PET; small animal PET/SPECT; biodistribution | Patients hypoxia; mice (tm) mAb/patients mAb; mice mAb Fabs | lc, cc; SCC/NHL, colc, bc; nb, colc |
86Y/90Y | 14.7 h/2 days | β+ 2766 (17.5%)c/β− 2280 (100%) | Lopci et al36/McKinney and Beaven37 | Small animal PET | mice (tm) mAb/patients mAb (Zevalin®) | Different xenografts/NHL |
89Zr/90Y | 3.3 days/2.7 days | β+ 902 (22.7%)c/β− 2280 (100%) | Osborne et al38/Perk et al39 | PET; biodistribution | Patients mAb/patient mice (tm) mAb (Zevalin) | pc/NHL |
86Y/177Lu | 14.7 h/6.6 days | β+ 2766 (17.5%)c/β− 498 (79%) A.e. 4.3–65.3 | Lopci et al36/Liu et al40 | Small animal PET/small animal SPECT | mice (tm) mAb/mice (tm) mAb | Different xenografts/HNSCC |
89Zr/177Lu | 3.3 days/6.6 days | β+ 902 (22.7%)c/β− 498 (79%) A.e. 4.3–65.3 | Osborne et al38 | PET | Patients mAb | pc |
99mTc/186Re | 6 h/3.7 days | γ 140 (99%)/β− 1069 (71%) A.e. 4.5–69.5 | Nagar et al41 | SPECT | Patients MIBI | Parathyroid adenoma |
99mTc/188Re | 6 h/17 h | γ 3140 (99%)/β− 1069 (71%) A.e. 47.7–69.9 | Müller et al42 | Biodistribution | mice (tm) folate | nasc |
111In/90Y | 2.8 days/2.7 days | γ 171; 245 (100%)/β− 2280 (100%) | O''Donnell et al43 | SPECT | Patients mAb | pc |
123I/131I | 13.2 h/8 days | γ 159 (97%)/β− 606 (89%) | Bravo et al44 | SPECT | Patients NaI | thc |
124I/131I | 4.2 days/8 days | β+ 3673 (23%)c/β− 606 (89%) | Van Nostrand et al45 | PET | Patients NaI | thc |
124I/186Re | 4.2 days/3.7 days | β+ 3673 (23%)c/β− 1069 (71%) A.e. 4.5–69.5 | Verel et al46 | Biodistribution | mice (tm) mAb | HNSCC |
124I/188Re | 4.2 days/17 h | β+ 3673 (23%)c/β− 2120 (71%) A.e. 47.7–69.9 | Verel et al46/Torres et al47 | Biodistribution/SPECT | mice (tm) mAb/patients mAb | HNSCC/glioma |
Open in a separate windowA.e, Auger electrons; bc, bladder cancer; cc, cervical carcinoma; colc, colon carcinoma; Fab, Fragment antigen binding; HNSCC, head and neck squamous cell carcinoma; lc, lung carcinoma; mAb, monoclonal antibodies; MIBI, methoxy isobutyl isonitrile; nasc, nasopharyngeal carcinoma; nb, neuroblastoma; NHL, non-Hodgkin''s lymphoma; pc, prostate cancer; PET, positron emission tomography; SCC, squamous cell carcinoma (A431); SPECT, single photon emission CT; thc, thyroid cancer; tm, tumour model.
aData from Laboratoire National Henri Becquerel:
http://www.nucleide.org/DDEP_WG/DDEPdata.htm.
48bhttp://periodictable.com/Isotopes/029.67/index3.p.full.dm.prod.html.
49cData from Lubberink and Herzog.
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