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Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 1  |  Page : 23-28

Recovery and tolerance of the organs at risk during re-irradiation


1 Department of Radiation Oncology, Queen's NRI Cancer Hospital, Visakhapatnam, Andhra Pradesh, India
2 Mahatma Gandhi Cancer Hospital and Research Centre, Visakhapatnam, Andhra Pradesh, India
3 Department of Radiotherapy, Regional Cancer Centre, JIPMER, Puducherry, India

Date of Web Publication18-Jun-2018

Correspondence Address:
Dr. Ashutosh Mukherji
Department of Radiotherapy, Regional Cancer Centre, JIPMER, Puducherry - 605 006
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jco.jco_2_17

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  Abstract 


In the last few decades, there have been major improvements in diagnosis, staging, and management of cancer which has translated into better disease outcomes and longer survival rates and with better quality of life. This improvement in the quality of life is by better normal tissue sparing caused by the increasing use of newer techniques and technologies, especially in surgery and radiotherapy. Along with higher survival, there is now greater acknowledgment of the need to treat local recurrences and hence the increased use of re-irradiation. Better technology such as intensity modulated radiotherapy translates into better sparing of normal tissue, but at the same time, late toxicity is still of concern. Factors such as residual late damage, total dose, fraction size, technique, type of tissue, and time interval to re-irradiation still guide prescription of the re-irradiation dose. Knowledge of long-term recovery of organ at risk is hence of importance in re-irradiation. This review article has emphasized on the recovery and tolerance of organs at risk such as Spinal cord, Brainstem, and Brain. This is important in prescribing doses for the target volume for re-irradiation and in setting constraints for surrounding critical organs during the planning process.

Keywords: Local recurrence, normal tissue tolerance for re-irradiation, organ at risk in re-irradiation, radiotherapy, radiotherapy reactions, re-irradiation


How to cite this article:
Das S, Patro KC, Mukherji A. Recovery and tolerance of the organs at risk during re-irradiation. J Curr Oncol 2018;1:23-8

How to cite this URL:
Das S, Patro KC, Mukherji A. Recovery and tolerance of the organs at risk during re-irradiation. J Curr Oncol [serial online] 2018 [cited 2018 Jul 22];1:23-8. Available from: http://www.journalofcurrentoncology.org/text.asp?2018/1/1/23/234542




  Introduction Top


In the last few decades, there have been major improvements in diagnosis, staging, and management of cancer which has translated into better disease outcomes and survival rates. Patients who receive optimal therapy are now expected to survive longer and with better quality of life compared to perhaps three or four decades back. This improvement in the quality of life is by better normal tissue sparing caused by the increasing use of newer techniques and technologies, especially in surgery and radiotherapy. The present treatment strategies put a higher onus of organ and function preservation and depend more on multimodality therapy to optimize response and survival. The improved cure rate and survival have brought into focus the situation of a localized disease recurrence in an otherwise preserved patient requiring additional modes of treatment measures for local control and palliation.

The availability of newer technologies such as stereotactic radiosurgery/radiotherapy (SRS/SRT), intensity modulated radiotherapy (IMRT), image-guided radiotherapy (IGRT), and brachytherapy has prompted many clinicians to consider re-irradiation because of the ability of these techniques to spare critical and late reacting tissues. The single-most important factor in planning re-irradiation is the ability using these techniques to determine the doses to various tissues in the irradiated volume. There are also other various factors to be considered while considering for the re-irradiation. It is important to remember that tissues which have once been irradiated may or may not have the same tolerance to a repeat course of radiotherapy. There can be many factors which will determine such tolerance, and these may include residual tissue injury present (the presence of residual stem or corrective cell depletion still present in the tissue); the interval between the two courses of radiation which will determine the extent of tissue regeneration; the volume of tissue required to undergo re-irradiation; fractionation schedule used in before course as higher the dose per fraction, more will be the late effects and consequent less tolerance for repeat course of radiotherapy as well as expected survival of the patient after such repeat irradiation. Tissue tolerance is also affected by disease extent and hence expected survival, use of chemotherapy and/or surgery as well as the technique of radiation therapy being used. In this review, we will discuss the importance of respecting tissue tolerances and their recovery after re-irradiation.


  Discussion Top


Newer modalities of irradiation whether used upfront or during re-irradiation are expected to cause much less normal tissue damage and hence permit dose escalation to the target volume. Thus, it is important to first calculate the expected dose received from the previous course of radiation to all normal structures in the volume expected to be irradiated (calculation should be for late effects, i.e., biological equivalent dose (BED) for 3 Gy fraction size or BED3Gy) before prescribing a fresh course of radiation therapy. The fractionation and total dose will be guided again by the total of the BED3Gy for both the courses. In the re-irradiated volume also, the normal tissues can be divided into early reacting (skin, mucosa, lung, and intestine) and late reacting (muscle, connective tissue, vasculature, brain, spinal cord, brainstem, lungs, heart, bladder, and kidney). Most of the acutely reacting tissues are thought to recover from the radiation-induced sequelae within a few months at the most; and therefore theoretically, these tissues can tolerate a repeat course of irradiation (depending on the total dose, fractionation, and technique) even 6 months down the line. Some late reacting tissues, however, such as the heart, bladder, and kidney either do not show long-term recovery or limited recovery and therefore even at the first instance are amenable to only partial volume irradiation. For cases in which these tissues need to be re-irradiated, doses have to be carefully calibrated to avoid crossing the BED3Gy tolerance limits at all. The subsequent paragraphs will discuss the tolerances of some of these normal tissues wherein data from re-irradiation studies are available.


  Acute Reacting Tissues – skin and Mucosa Top


As mentioned these tissues are expected to recover faster after the initial course of radiation therapy and the tolerance of these tissues to a subsequent course of irradiation depends on the time interval between the two courses as well as the dose per fraction both times. In general, for re-irradiation, prophylactic lymphatic or connective tissue volumes (for microscopic disease) are not included as target volume which includes only the gross tumor volume with a minimal margin of 0.5–1.0 cm. Most of the data for acute reactions are available from animal studies. A study by Terry et al on mice reported that reirradiation with single doses of 15-30 Gy after more than 2 months of the first course of irradiation did not produce significant damage to mucosa; but when the re-irradiation with higher doses of 34.5-37.5 Gy was done at 1 month after previous radiotherapy, there was complete breakdown of the skin and mucosa.[1] A similar study by Simmonds et al.[2] on pig skin reported similar findings with tolerance improving as the interval was lengthened to beyond 52 weeks (1 year). Similar findings have been reported for both lung mucosa and head and neck mucosa [Table 1].[3],[4],[5],[6],[7] From these studies, we can say that there is a recovery of the viability and function of both skin and mucosa by accelerated repopulation leading to restoration of the original cell number when the interval between two courses of irradiation is higher especially when more than 6 months.[8]
Table 1: Recommended/accepted re-irradiation normal tissue tolerances in acute reacting tissues

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  Spinal Cord Top


The spinal cord is the major dose-limiting organ in radiotherapy. The present era of more aggressive multimodality management of head and neck cancers (HNCs) has improved survival, and many more patients report with either a relapse or a second primary close to the site of the primary tumor. In many of these cases, the target volume is close to or overlies the spinal cord. Radiation-induced myelopathy is the most common catastrophic side effect of radiotherapy involving spinal cord. The risk-benefit ratio is the most important point to be considered during re-irradiation.

Clinical data are very sparse in terms of toxicity and tolerance of spinal cord re-irradiation. There has been significant research in animal models to define the factors responsible for recovery of irradiated spinal cord. Ruifrok et al.[9] noticed that ED50 value was higher for mouse retreated after 6 months. The long-term recovery from primary radiation was 40%–45% after 6 months. Wong et al.[10],[11] also studied sensitivity of the cervical spinal cord in mice to fraction sizes during repeat irradiation as well as long-term recovery and re-irradiation tolerance. He found that the latent time to paralysis (loss of cord function) was inversely proportional to the level of initial injury. Similarly, there have been studies in rhesus monkeys by Ang et al.,[12] in which the researchers noticed that there was significant recovery from the initial average dose of 44 Gy after 2 years' time and single vascular injury showed less recovery than white matter damage. Cumulative doses below 100 Gy2 (2 Gy equivalent dose) did not produce any myelopathy while electrophysiological changes of myelopathy were seen above 130 Gy2.[12] These experiments in animal models showed that the spinal cord recovery following re-irradiation depends on the volume of spinal cord irradiated, total dose received, dose fractionation, and time interval for the retreatment.

Studies by Schiff et al.[13] and Grosu et al.[14] have suggested that the human spinal cord after initial exposure of 46 Gy in 2 Gy/Fr may tolerate an additional 23–24 Gy in conventional fraction sizes if there is a gap of 1–2 years between the two courses. Furthermore, it is important to keep the cumulative dose as low as possible as was shown by Nieder et al.[15] in his analysis of 8 reports involving 39 patients with a long-term follow-up in which he concluded that besides the cumulative doses of more than 100–110 Gy2 (especially if larger fraction sizes are used) and an interval <6 months increases the risk of myelopathy [Table 2]. From the “Quantitative Analysis of Normal Tissue Effects in the Clinic” data on spinal cord re-irradiation of the full cord cross-section at 2 Gy/day after prior conventionally fractionated treatment, cord tolerance appears to increase at least 25% at 6 months after the initial course of RT.[29]
Table 2: Recommended/accepted re-irradiation normal tissue tolerances in late reacting tissues

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The introduction of SRS/SRT has revolutionized radiation treatment by its ability to deliver very high dose to a very precisely defined target volume and therefore avoiding the whole circumference of the cord. Sahgal et al.[30] have recommended that the thecal sac point maximumP(max) EQD2 of 20–25 Gy appears safe provided the totalP(max) dose did not exceed 70 Gy and the SBRT thecal sac P(max) EQD2 does not exceed 50% of the total normalized BED [Table 2].


  Brain Top


Brain tumors and especially high-grade gliomas frequently relapse close to or at the margins of the previously irradiated volume and may require re-irradiation. These cases also run the risk of developing radiation necrosis or gliosis with resultant functional deficit if tissue tolerances are not respected. While there is no randomized data evaluating the role of re-irradiation in brain, clinical practice recommendations by Maranzano et al.[18] have suggested that each course of radiation to the brain limit the dose to 60 Gy with a cumulative dose not crossing 140–150 Gy2. They have also suggested practice recommendations for re-irradiation to the brain and spinal cord [Table 2] as well as indications and contraindications. Mayer and Sminia [31] in their analysis of brain re-irradiation in glioma, patients have reported that the normalized total dose (NTD cumulative) ranges from 81.6 Gy-101.9 Gy in conventional re-irradiation to 90 Gy-133.9 Gy in fractionated stereotactic radiotherapy (FSRT) and even up to 111.6–137.2 Gy in stereotactic radiotherapy (SRS).

It has been noted that patients treated with conventional fractionation usually do not show radio-necrosis, but patients receiving FSRT can develop radiation necrosis after an NTD cumulative more than 105 Gy and SRS more than 135 Gy. This total cumulative dose is the most important factor for the development of radiation necrosis in normal brain tissue and while there is not enough literature on the minimum time interval required between two courses of radiotherapy; as with other central nervous system (CNS) sites, a minimum of 3 months is recommended by Mayer and Sminia.[31]


  Brainstem Top


Brainstem is a critical structure and at risk of being radiated during re-irradiation of tumor involving Nasopharynx and Brain tumors. Wang et al.[19] analyzed retrospectively 448 patients totally treated of whom 15 had undergone re-irradiation and reported that patients can tolerate repeat course of irradiation of up to 39 Gy if there is a minimum interval of at least 12 months between the two radiotherapy courses. It is important to note that the EQD2 Dmax is 79 Gy while the BED3Gy is a maximum of 140 Gy3. Point doses were also assessed in this study, and it was found that the tolerated D0.1cc received 71 Gy and D 0.5cc received 65 Gy and D 1.0 cc of 60 Gy. The tolerance to cumulative dose increases further with increase in interval between the primary radiation and re-irradiation.


  Aorta and Great Vessels Top


Dose limitations to the great vessels, the heart, the lung as well as the coronary arteries have been traditionally the limitations in planning thoracic radiation both as initial and during re-irradiation. New techniques such as IMRT or SRT have helped achieve these dose targets while sparing the organs at risk in the thorax. A study by Evans et al.[21] retrospectively analyzed 360 patients with non-small cell lung cancers of whom 35 patients received re-irradiation. All of these patients had the aorta inside the target volume. The authors reported that aortic toxicities (stenosis or rupture) was seen in 1%–2% of treated patients only and have estimated the tissue tolerance to a cumulative Dmax (to 1 cc of tissue) at 100 Gy2 with normalized dose calculations pointing at a cutoff of 120 Gy2 for raw dose and 90 Gy2 after correction for tissue recovery.

The carotid blowout syndrome (CBOS) is a much-discussed side effect of radiation, especially in HNC radiotherapy. Yamazaki et al.[32] analyzed 7 Japanese Cyberknife ® studies and they suggested CBOS index a predictive model which includes >180° of carotid invasion, the presence of ulceration and lymph node irradiation (0–3 points). The incidence of this infrequent but often fatal complication ranges from 7% to 77% depending on the technique used, the area being treated and the extent of carotid sheath involvement.[33] CBOS is less frequently seen when IMRT is used or conventional or hyperfractionated regimens are used.[6] Yazici et al. compared occurrences of CBOS in re-irradiation with 3DCRT compared to use of SBRT and reported a significant decrease (48% vs. 21%, P < 0.05).[7] The authors also reported that treating on alternate days with SBRT instead of daily fractions resulted in fewer CBOS. In addition, Yazici et al.[7] reported that SBRT doses above 34 Gy (in 4–6 fractions) and encasement of more than 270° of the carotid resulted in more CBOS.


  Lungs Top


Radiation pneumonitis is a common side effect of irradiation to the lung. Due to limited survival after relapse and re-irradiation of lung tumors, there are sparse data on re-irradiation. Terry et al.[34] analyzed in murine model and reported that a low initial dose is the most important factor for re-irradiation. Clinical data are limited, but the available literature supports the results of animal model. Jackson and Ball [5] observed no symptomatic radiation pneumonitis in 22 patients with non-small cell lung cancer re-irradiated to 20–30 Gy in 2 Gy per fraction after a primary dose of 55 (50–60) Gy @ 2–2.2 Gy per fraction after 15 (6–48) months. A similar effect was reported by Montebello et al.[4] who assessed re-irradiation to a dose of 30 Gy after an initial 60 Gy. However, late effects have not been described in this study as the median survival was only 5.5 months.


  Heart Top


The cardiac tolerance dose was defined as the dose causing at least 50% function loss (ED50). Wondergem et al.[35] assessed re-irradiation tolerance in mouse model and suggested the priming dose and interval between the primary radiation and re-irradiation being the most influential factor for heart. However, definite clinical data is still lacking. According to an analysis by Sumita et al., the cumulative dose to the heart (BED3Gy) should not exceed 70 Gy3 and the point dose (0.1 cc) Dmax not more than 49 Gy3.[20] In this study, it was also seen that the late toxicities to re-irradiation were lesser if the interval between the two courses of radiation was more than 24 months.


  Head and Neck Irradiation Top


The target volume and field size is the most significant factor in determining tissue tolerance; elective volume irradiation is not recommended. Prominent late sequelae of re-irradiation to the head and neck region include soft-tissue fibrosis, carotid blowouts (discussed previously), cartilage necrosis, osteoradionecrosis (ORN) especially of the mandible, and arytenoid edema. The various central nervous system CNS organs such as spinal cord and brainstem; and soft tissues in the area are the dose-limiting structures. Most studies on head and neck re-irradiation have assessed doses to the target volume, and very few studies have commented on tolerable doses for the various organs at risk in this area apart from brainstem, spinal cord, carotid, mandible, and larynx. According to a review by Sunku and Jagtap,[22] re-irradiation dose with conventional fractionation which can be tolerated is 58–60 Gy at an interval of at least 6 months; while according to Roh et al., for Stereotactic Radiation recommended doses range from 18 to 40 Gy over 3–5 fractions.[6] In both these studies, the soft tissues could tolerate up to 90% of the previous prescribed dose provided the volume of tissue irradiated was limited.[22] The American College of Radiology expert panel for HNCs has also recommended that re-irradiation be given to a limited volume and up to a dose more than 60 Gy with care that the mandibular mean dose is kept at 50% of the initial prescribed dose.[36] Soft-tissue volumes can be further reduced by adopting newer techniques such as IMRT or IGRT with daily portal image monitoring as well as by use of adaptive techniques to minimize volumes being treated. Even with all precautions, dysphagia during re-irradiation can be seen in as much as 40%–50% of patients.[22],[37] Severe soft-tissue reactions such fibrosis or necrosis may occur in 20%–30% of patients.[22] It has also been seen that rates of clinically significant oral or pharyngeal mucositis is less common than in primary radiotherapy [6] which is probably due to the absence of prophylactic regional irradiation during re-irradiation as well as the necessity to minimize volumes as much as possible. Such effects increase especially if the volume is over 50 cm 3.[37]

Another important dose-limiting sequelae is the occurrence of mandibular ORN which was characteristically seen in more than 10%–15% of patients on re-irradiation when conventional treatment fields were used. This was even after observation of traditional dose limits of Dmax below 70 Gy and mean dose below 55 Gy. The rate of ORN is thought to range from 10% to 15% in uninvolved bone to as high as 35% when the cortex is breached at repeat doses over 45–50 Gy. Therefore, it is important that patients with existing late effects or those still suffering from the effects of early reactions to previous course of radiotherapy should not be considered for re-irradiation.[22] Other organs at risk in the head and neck area that need to be considered are the orbit (10 Gy ≤5% of volume); optic nerve and chiasma (8 Gy ≤5% of volume); and temporal lobe (10 Gy ≤10% of volume).[24] Parotid function was found to be affected significantly at or above cumulative doses of 45 Gy [Table 2].[23]


  Soft Tissues Such as Muscle or Connective Tissue: Pelvic Organs Such as Bladder or Rectum Top


Irradiation of soft tissues and bones occurs significantly during the treatment of HNCs, pelvic tumors as well extremity or truncal sarcomas. Large-scale prospective studies are not available in this set of patients and analogies can only be drawn from limited case series' present. However, in most of these, the cumulative dose has been limited to below 150 Gy2 with little or no late effects.[16],[17] Rectal cancers which relapse locally have been re-irradiated by many different techniques; and hence, it is difficult to produce matching sets of data to draw conclusions for dose tolerance recommendations. Various studies by Mohiuddin et al.,[27] and Alektiar et al.,[28] among others have put a cumulative tolerance dose of 70–100 Gy2 for the rectum. Late complications such as small bowel obstruction, persistent diarrhea and coloanal fistula are seen when doses exceed 100–110 Gy2 for a maximum volume of 10 cm 3 in 20%–30% of patients [Table 2].[27] Similar late effects have been noted in patients with recurrent gynecological cancers [38] along with occurrence of ureteral stenosis in cases where intraoperative radiotherapy was used.[26] The bladder is expected to have more tolerance to re-irradiation and can tolerate point cumulative doses of up to 120 Gy3.[25]


  Conclusion Top


In the present day, the possibility of re-irradiation has increased due to the availability of image guidance, IMRT, etc., but at the same time the risk-benefit ratio should be considered before deciding on the treatment. The performance status and availability and feasibility of other less toxic treatment alternatives should also be taken into consideration. The knowledge of previous radiation field, portals, dose per fraction, technique, dose distribution, and exact dose of critical organs are important determinants in prescribing dose and volume for re-irradiation. Although there have been substantial research in animal models regarding the recovery of organ at risk for re-irradiation they cannot be exactly applied into clinical practice. While there is an increasing body of data in favor of re-irradiation in select sites and situations using newer modalities to respect tissue tolerances; in many other sites, limited survival data hampers long-term tolerance studies. Many acutely reacting tissues such as skin and mucosa usually recover early after first dose of radiation and tolerate re-irradiation; and there are data in select situations for late reacting tissues such as brain, spinal cord, rectum, breast, and even HNCs and soft-tissue sarcomas. Other tissues such as heart, vessels, and lungs lack robust prospective data.

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Conflicts of interest

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    Tables

  [Table 1], [Table 2]



 

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  In this article
Abstract
Introduction
Discussion
Acute Reacting T...
Spinal Cord
Brain
Brainstem
Aorta and Great ...
Lungs
Heart
Head and Neck Ir...
Soft Tissues Suc...
Conclusion
References
Article Tables

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