|Year : 2019 | Volume
| Issue : 1 | Page : 4-13
Radiotherapy and devices in cancer patients: What is new in clinical practice?
Fabiana Luca1, Iris Parrini2, Laura Cipolletta3, Stefania Di Fusco4, Carmelo Massimiliano Rao1, Annamaria Iorio5, Andrea Pozzi5, Sandro Gelsomino6, Domenico Gabrielli7, Nadia Ingianni8, Massimo Zecchin9, Michele Massimo Gulizia10
1 Department of Cardiology, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria, Italy
2 Department of Cardiology, Ordine Mauriziano Hospital, Torino, Italy
3 Department of Cardiology, Umberto I-Lancisi-Salesi University Hospital, Ancona, Italy
4 Division of Cardiology, S. Filippo Neri Hospital, Rome, Italy
5 Cardiology Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy
6 Department of Cardiothoracic, Maastricht University Hospital, Maastricht, The Netherlands
7 Division of Cardiology, Augusto Murri Hospital, Fermo, Italy
8 Department of Cardiothoracic, University Hospital of Trieste, Trieste, Italy
9 Cardiology Division, Paolo Borsellino Hospital, Marsala, Italy
10 Cardiology Division, Garibaldi-Nesima Hospital, Catania; Heart Care Foundation, Florence, Italy
|Date of Web Publication||25-Nov-2019|
Dr. Fabiana Luca
Department of Cardiology, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria
Source of Support: None, Conflict of Interest: None
There has been a significant increase in cancer patients with implanted electronic devices which have been exposed to the risk of malfunction when undergoing radiotherapy in the last few years. In this review, we provide a short summary of radiotherapy principles, later analyzing in vitro and in vivo data and recent recommendations, in order to present the current evidence on predictive factors, risk stratification, and management of patients with implanted electronic devices requiring radiotherapy. The risk of device failure is usually transient, seldom permanent and mainly related to patients' characteristics and cumulative doses administrated during radiotherapy. The strongest predictive factors of implanted electronic device malfunction are higher radiation doses and higher beam energy. Indeed, energy <6 MV and a total dose of 2 Gy are recommended. A close multidisciplinary collaboration involving cardiac electrophysiologists, radiotherapists, and physicists may have important consequences in clinical practice, enabling then to minimize this risk.
Keywords: Cancer, device failure, implanted electronic devices, malfunction, radiotherapy
|How to cite this article:|
Luca F, Parrini I, Cipolletta L, Di Fusco S, Rao CM, Iorio A, Pozzi A, Gelsomino S, Gabrielli D, Ingianni N, Zecchin M, Gulizia MM. Radiotherapy and devices in cancer patients: What is new in clinical practice?. Int J Heart Rhythm 2019;4:4-13
|How to cite this URL:|
Luca F, Parrini I, Cipolletta L, Di Fusco S, Rao CM, Iorio A, Pozzi A, Gelsomino S, Gabrielli D, Ingianni N, Zecchin M, Gulizia MM. Radiotherapy and devices in cancer patients: What is new in clinical practice?. Int J Heart Rhythm [serial online] 2019 [cited 2019 Dec 16];4:4-13. Available from: http://www.ijhronline.org/text.asp?2019/4/1/4/271663
Fabiana Lucà and Iris Parrini contributed equally to this work.
| Introduction|| |
In the last decade, the number of patients implanted with a cardiac implantable electronic device (CIED) has notably increased worldwide. Modern CIEDs are highly reliable and have decreased energetic consumption, nevertheless they have a greater radiation sensitivity with an increased risk of device failure. Protective measures are used to reduce the danger of electromagnetic interferences, for example, filters, bipolar leads, and covering devices with hermetic metal cases, using circuits that avoid interferences. The greatest part of electromagnetic radiation sources in daily use, such as mobile phones, microwave ovens, and surveillance systems, does not interfere with the normal function, while the radiotherapy in neoplastic patients could represent a risk in patients with CIEDs. Ionizing radiations could alter CIED components, causing transient or permanent malfunctions,,,, with an incidence of failure from 3% to 79%.,,,,
Considering the rising number of neoplastic diseases and the high incidence of cardiovascular disease, two-thirds of patients with CIEDs will need radiotherapy.,, Identification of patients at risk of developing CIED malfunction during or after radiotherapy is extremely important.
| Database Search Strategy|| |
An electronic search of the MEDLINE database for literature describing the effects of radiotherapy on CIEDs was performed between 2002 and 2017 using the following terms: Radiotherapy (MeSH Terms) AND pacemakers (MeSH Terms) AND cardiac defibrillators (MeSH Terms) OR device malfunction (MeSH Terms). The reference list was screened to identify relevant publication. The search retrieved 221 articles. Reviews, retrospective and prospective studies, and relevant case reports were included.
In addition, an electronic search of the MEDLINE database for damage of radiotherapy to pacemaker or cardiac defibrillatorin vitro from 1994 to 2017 was completed with the following search terms: radiotherapy, pacemakers, and cardiac defibrillators, in vitro. The authors focused on the influence of radiotherapy assessed in vitro. Data extraction was independently performed by two reviewers.
| Effects of Radiotherapy on Devices|| |
The deleterious effect of radiotherapy on CIEDs has been analyzed bothin vivo andin vitro,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,[Table 1], [Table 2], [Table 3], [Table 4]; Appendixes 1–3 for basics of radiotherapy, treatment modalities for radiotherapy, and CIED malfunctions].
|Table 1: Effects of radiotherapy on cardiac implantable defibrillators in vitro|
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|Table 3: Effects of radiotherapy on cardiac implantable defibrillators in vivo|
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The damage due to direct irradiation is related to the proximity of CIED to irradiated regions and to the dose. Zaremba et al. compared the effects of radiant dose and beam energy on CIEDs, including five pacemakers (PMs) and one implantable cardioverter-defibrillator (ICD). One ICD directly irradiated with a cumulative dose of 150 Gy had no failure in electronic components, whereas a beam energy of 18 MV resulted in CIED damage (14 device malfunctions in all 5 PMs), suggesting that beam energy is the strongest predictor of device failure.
The influence of radiotherapy on the last generation of ICD was assessedin vitro by Hurkmans et al. Eleven ICDs have been irradiated with 6 MV photon beam with a cumulative dose of 120 Gy. The complete loss of function was observed in four ICDs with a cumulative dose level between 0.5 and 1.5 Gy. ICD, connected to an oscilloscope during the irradiation to mimicin vivo sensing and pacing conditions, showed inappropriate ventricular arrhythmia detection due to oversensing during irradiation in 4/11 cases, which would likely result in inappropriate shock in vivo. These data were not reproduced in more recent studies.
In a large prospective study involving 34,706 patients undergoing radiotherapy, 261 had a CIED (207 – PM and 54 – ICD). In 3.4% of patients, CIED relocation was performed before radiotherapy. During the study, 63.2% of patients required continuous monitoring, 14.6% required device reprogramming, and 18.8% required magnet application before radiotherapy. Device malfunction was found in four patients (1.5%): three had ventricular pacing at the maximum sensor rate and one patient had a complete ICD reset with an irradiation of 18 MV photons.
Zaremba et al. performed a cohort study of 560 patients (450 – PM, 25 – CRT-P, 54 – ICD, and 19 – CRT-D). During follow-up, 9.3% of device malfunctions were found. The median of cumulative dose was 46.5 Gy, and the median of beam energy was 16.5 MV.
Grant et al. analyzed retrospectively 249 radiation courses with 6–16 MV photon and electron-based radiotherapy or Gamma Knife in 215 patients (123 PM and 92 ICD). Radiotherapy damage was found in 18 devices. A CIED malfunction was detected in the setting of notable neutron-producing radiotherapy, with a prevalence of 21%. No device failure was assessed in nonneutron-producing radiotherapy setting, making this treatment more reliable.
Therefore, an assessment of cumulative dose is important to evaluate the limit dose of radiation exposure. In clinical settings, this measurement could be calculated using radiotherapy planning software orin vivo dosimetry during the first 1–3 sessions.,
The recommendation to protect the device with a lead shield during radiotherapy, in order to maintain the lowest dose possible,,, has a limited value if the device is outside the irradiation area. Moreover, some authors suggested that scattered neutron radiation may not be attenuated by the lead shields because a photonic beam of 6 MV can be attenuated of 90% by a lead shield with a thickness of >0.5 cm. Beyond device damage, the effectiveness of radiotherapy treatment may be reduced if the device is in the radiant field, altering the radiation dose. Several authors recommend to maintain at least 3–5 cm of distance between the radiant field and the device.,,
The threshold for cumulative dosage that may increase the risk of CIED failure is estimated around 2 Gy.,
Considering that there is an inverse relation between the dose of the CIED and the square of the distance from the radiotherapy target, patients irradiated from the lowest part of the neck to the upper part of the thorax should be considered at higher risk., However, more recent studies suggest that the cumulative dose and the direct irradiation dose may not be the main cause of malfunctions during radiotherapy.
Malfunctions were observed even at very low cumulative doses, whereas in other cases, high doses were well tolerated., According to Zaremba et al., the risk of malfunctions was higher when the target was below the diaphragm, due to higher energies and higher probability of neutron production. In other experiences, device malfunction was observed during radiotherapy of tumors far away from the CIED site, especially using an energy >15 MV (OR: 5.73).,,,
Hashii et al. exposing ten ICDs to scattered irradiation derived from high-energy photon beam of 18 MV and 10 MV demonstrated that 18 MV irradiation induced more soft errors than 10 MV photons.
Scattered neutron radiation, produced by the emission of high-energy electrons from the linear accelerators (LINACs) necessary to reach deep structures (such as prostate, bladder, and gut), may provoke damage on CIEDs. At photon beam energies >10 MV, neutrons are produced by a reaction in the head of the LINAC that can be captured by CIED causing malfunctions due to soft errors.
Moreover, modern LINACs are sufficiently shielded, and generally, electromagnetic interferences do not represent a threat for the correct function of CIEDs.,,,
| Current Recommendations: General Considerations and Differences among Published Documents|| |
Before radiotherapy, the patient has to perform “ first radiotherapy visit,” during which the radiation oncologist decides which radiotherapy is needed, identifies the presence of a CIED, and informs the referring cardiologist/electrophysiologist reporting dose received by the device. The radiation oncologist and the medical physicist make a virtual simulation by computed tomography (CT) scan to assess the dose absorbed by CIED. Therefore, the assessment of cumulative dose is needed to assess the maximal dose absorbed by each part of the CIED.,, The patients should be informed regarding risks connected with pacemaker/ICD presence in case of radiotherapy.
After CT, the following phase is the countering phase, during which gross tumor volume, clinical target volume, planning target volume, and organs at risk are encircled. The device is labeled as organs at risk.
Several datain vitro support preventive measures although data about inappropriate shocksin vivo have not been published; oversensing could theoretically occur during radiotherapy. In PM-dependent patients, if a 90–130 gauss magnet is positioned over the PM pocket, sensing capabilities are disabled, so pacing is guaranteed in asynchronous mode. In ICD patients, only the delivery of antitachycardia therapies is disabled, avoiding the risk of inappropriate shocks due to oversensing in the presence of electromagnetic interferences.
Since 1994, as recommeded by the American Association of Physicians in Medicine, the threshold dose of 2 Gy has been adopted, beyond which there could be a malfunctioning of the device.
In 2012, the guidelines from the Dutch Society of Radiotherapy and Oncology for the management of radiotherapy in patients with CIED were published. The main clinical consequences of device failure depend on pacing dependency or cumulative dose.
Hence, the patients have been classified into three risk categories according to the dose received by the CIED: a dose of less than 2 Gy was considered at low risk, unless pacing dependency, between 2 and 10 Gy at medium risk, while above 10 Gy as high risk. Similarly, in 2015, the interdisciplinary German guidelines, DEGRO/DGK, reported that the patient's risk depends on the type of device, the estimated radiation dose, and the concomitant heart disease.
The majority of guidelines suggest keeping the CIED dose lower than 2 Gy despite a clear dose threshold has not been identified, while it is advisable to avoid that CIED is localized in the beam. Furthermore, these recommendations consider the cancer localization: the upper portion of the thorax and the lower part of the neck as being the zone of the greater risk of device malfunctioning.,
Two consensus documents, one from Italy and one from America,, recommended, before starting radiotherapy, a complete knowledge of device programming and patient-related risk. A limitation in planning is the estimate CIED dose, because these measures could be inaccurate, especially when the device is on the edge or outside the treatment field.
On the one hand, new American consensus declares that a photon beam energy >10 MV (or protons) causes a significant neutron production and produces transient or permanent damage.
On the other hand, the Italian document recommends a LINAC energy of ≤6 MV, considering that neutrons may be produced even with a beam energy of 7 MV. The patients were classified at low, intermediate, or high risk according to multiple parameters (energy type and intensity, patients' characteristics, and dose at the CIED site). Moreover, another difference between Italian and American consensuses is the distance between CIED and radiation field. The Italian consensus suggests that it should be held at least 3 cm, whereas the American guidelines suggest avoiding direct radiation exposure of device, without explicitly defining a distance.
In recent Italian guidelines, the placement of a magnet (90–130 gauss) is recommended in patients with a PM without spontaneous ventricular activity or in ICD patients,,, whereas it is not considered in the American guidelines for low risk of oversensing due to electromagnetic interferences.
During treatment, all guidelines recommend to maintain continuous visual and vocal contacts with the patient. Furthermore, Italian consensus suggests performing persistent electrocardiogram monitoring only in patients with intermediate or high risk. Furthermore, the availability of a cardiologist (or a nurse/technician with experience in CIED management) should be considered in high-risk patients, whereas the presence of anesthesiologist mainly depends on the patient conditions.
None significant differences in the scheduling of the CIED interrogations in the high-risk patients should be performed weekly and in the low- and medium-risk patients at the end and half course of radiation therapy. In the Italian consensus, the capability of remote monitoring for a close evaluation is considered.
After radiotherapy, some late malfunctions have been described; thus, CIED interrogations are recommended, but a time schedule has not been established yet.,,, However, Italian consensus suggests a follow-up in office/remote at 1 and 6 months.
According to American guidelines, the choice of delocalization is a difficult decision-making process considering the patient's clinical condition, the planned radiation beam, and the increased infective risk of the procedure. The decision to relocate CIED should be preferred when it interferes with an appropriate therapy. Italian consensus suggests device relocation just few centimeters out of therapy field in the same side. Relocation is not recommended for devices receiving a cumulative dose <5 Gy.
Finally, all device manufacturers provide their own recommendations, not based on scientific evidence. Medtronic suggests a limitation of 1–5 Gy depending on the device; St. Jude does not provide any recommendations, while Boston Scientific and BIOTRONIK declare that there is no safe radiation dose. All manufacturers recommend relocating the CIED generator outside of the radiant field.
| Conclusions|| |
Due to the increasing number of patients implanted with CIEDs needing radiotherapy, the interest of scientific societies is focused on their appropriate management. According to the last guidelines, the risk is mainly due to the scattered radiation of neutrons and only high doses directly on the CIED should be avoided. Some differences among consensus can be observed in terms of patients' evaluation, management during radiotherapy sessions, and follow-up. Therefore, new recommendations are needed to assume a standardized approach in patients with CIEDs during radiotherapy.
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Conflicts of interest
There are no conflicts of interest.
| Appendixes|| |
Appendix 1: Basics of radiotherapy
Radiotherapy uses ionizing radiations to deliver electromagnetic energy into cancer cells with a consequent DNA damage and cellular death.
Ionizing radiations can be delivered in different ways, such as external radiation beam, systemic therapy with radionuclides, and local irradiation with radioisotope inserted temporary or permanently (brachytherapy) inside the target organ. The most common radiation sources used for the radiotherapy are photons and electrons followed by protons. The radiation energy used during radiotherapy is related to tumor localization. Low X-ray energy (orthovoltage) is used for superficial tumors (such as skin and superficial structures), while high X-ray energy (megavoltage) for deep structures (such as prostate, lung, and bladder).
In the presence of high X-ray energy, a scattering neutron radiation may be produced interacting with some components of the devices with a consequent risk of temporary or permanent impairment.
The absorbed radiation dose is defined as the amount of radiation dose deposited in any medium (water, tissue, and air), and it is measured in grays (Joule/kg, symbol: Gy, International System of Units); 1 Gy is equivalent to 1 J of absorbed ionizing radiation per kg.
The amount of absorbed radiation causes both tumor regression but also damage to the healthy tissue. Radiotherapy is administered for several weeks, with a daily dose ranging from 1.8 to 2 Gy to allow for DNA restoration in the normal cells. Radiotherapy may reach a cumulative dose of more than 80 Gy for treatment of solid tumors, approximately 50 Gy for breast cancer and 60–66 Gy for lung cancer.,
Appendix 2: Treatment modalities for radiotherapy
External beam radiotherapy is characterized by a radiation source located outside the patient. According to the delivery modality, several techniques can be identified:
- Three-dimensional (3D) conformal radiotherapy is the most common technique that combines 3D computed tomography visualization of the tumor with the LINAC giving the highest possible radiation dose to the tumor, sparing the normal tissue as much as possible
- Intensity-modulated radiotherapy uses computers and LINAC to define a 3D radiation dose map, specific to the target's location, shape, and motion characteristics
- Volumetric modulated arc therapy is a fast form of intensity-modulated radiotherapy that can deliver the dose in a 360° rotation
- Image-guided radiotherapy integrates multimodal image equipment to reduce organ motion and the uncertainty of patient position.
Radiosurgery and stereotactic radiotherapy can administer precise high-dose radiotherapy targeting an intra- or extracranial focus with high accuracy and precision, reducing the radiation dose to the normal tissue.
Brachytherapy includes the positioning of selected radioactive sources into contact with or very close to the target tissue in order to quickly deliver high doses to a localized region.
Intraoperative radiotherapy consists of the delivery of radiation therapy during surgery through electrons or low-energy X-ray.
Hadron therapy involves the use of heavy charged particles and combines physical advantages with a dense-ionizing radiation making it a resource for resistant lesions or close to organs at risk.
Proton beam scan treats tumors located close to sensitive organs. The main treatment options are:
- The “passive scattering system” that uses a large uniform field combined with collimators and compensators related to the target
- The “active scanning system” that irradiates the tumor volume using small field scanning and it is classified into two categories: the “pencil beam scanning” that is able to deliver a beam of variable intensity during scanning and the “uniform scanning.”
Different factors contribute to determine the impact of radiotherapy on an implanted device.
The greater technological improvements of complementary metal oxide semiconductor consented a relevant reduction of device dimension, extended battery life, and allowed the implementation of sophisticated algorithms. On the other hand, it has a higher frailty to ionizing radiations compared to older devices, increasing the risk of device malfunction with a consequent need of software reprogramming, inappropriate triggering, and therapy inhibition up to complete failure.,,
Appendix 3: CIED malfunctions
CIED malfunctions are usually divided into two groups: hard errors and soft errors.
Hard errors consist of a permanent and irreparable damage in the electronic circuit with the loss of therapeutic functions, while soft errors result in data error and can be usually (but not always) solved using the programmer. The main soft errors are power-on reset, consisting of the accidental data overwriting of pacing and arrhythmia detection programming, and partial electrical reset that is the accidental data overwriting on the random-access memory unable to cause changes in pacing function. Soft errors are mainly due to scattered radiation of neutrons, which interact with some device components resulting in production of charged particles.
Damage depends on several factors:
- Type of CIED
- Distance between the device and radiant beam
- Type and level of LINAC energy
- Orientation of beam compared to CIED position
- Dose rate
- Total delivered dose in CIED lifespan
- CIED shield
- Patient's anatomy and physiology
- Frequency of radiant treatment
- Concomitant therapy and diagnostic examinations.
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[Table 1], [Table 2], [Table 3], [Table 4]