Radiotherapy of Lung Cancer - Term Paper Example

Radiotherapy of lung cancer

Definition of volumes in Radiotherapy

In radiotherapy, the description of the volume is important as it enables 3D treatment planning and also ensures accurate reporting on the dosage. The reports by the International Commission on Radiation Units and Measurements (ICRU) number 50 and 62 [2,3]define and explain various target and critical structure volumes that help in the planning process of the treatment while also giving a baseline for comparing the various possible outcomes for treatment. The various principal volumes that are defined by these reports as relating to the planning of 3D treatment include gross turnover volume, clinical target volume, planning target volume and internal target volume. The relationship and interaction between these volumes are reflected by Figure 2.2 shown below.

Figure 2.2: Graphical representation of the volumes-of interest according to the ICRU reports number 50 and 62 [2, 3]

Gross Turnover Volume (GTV)

Gross Turnover Volume (GTV) is one of the main principal volumes that refers to tangible, visible or demonstrable extent and location of uncontrollable growth (ICRU 50) [2]. The volume is identified by using information collection from the combination of various imaging modalities, diagnostic modalities, and clinical examination. Examples of imaging modalities employed in GTV include CT, MRI or Ultrasound whereas diagnostic modalities include pathology and histological reports.

Clinical Target Volume (CTV)

The Clinical Target volume is also another principal volume made up of tissue volume that that either contain Gross Turnover Volume or sub-clinical microscopic malignant disease or a combination of both. According to ICRU report number 50, the CTV has to be adequately treated to ensure that the goal of the therapy or treatment has been achieved. The CTV comprises of the region surrounding the GTV. The area is known to be affected by the microscopic disease and also to be at high risk of infection thus requiring treatment intervention such as positive lymph nodes. Consultation on the condition of the CTV, which is anatomical-clinical volume, can be assessed by such specialists such as pathologists or radiologists or else radiation oncologist.

Defined by GTV, CTV can be explained as a fixed or variable margin around the former, equating to CTV = GTV + 1 cm margin. CTV is, however, the same as GTV in some instances such as the prostate boost to the gland. Some non-contiguous CTVs need different total doses to complete the aim of the medical intervention.

Internal Target Volume (ITV)

Internal Target Volume is known to comprise a CTV and an internal margin. The structure of the internal margin is able to take into consideration the change in size and position of the CTV, being subject to the reference frame of the patient, normally defined by the body anatomy. Such changes in the size and position CTV may be caused by change in the organ motions that may include breathing and change in contents of the bladder or rectal systems (ICRU 62) [3].

Planning Target Volume (PTV)

The other volume of radiotherapy is planning target, a geometrical concept. The planning target volume takes into concept the net impact of all possible geometrical changes thus explained to select relevant beam arrangements (ICRU 50) [2]. That strategy ensures that the dosage prescribed is absorbed in the clinical target volume (CTV). According to ICRU (62) [3], the principal volume also comprises of the internal target margin and additional margin to deal with uncertainties, machine tolerances, and intra-treatment variations. It can be associated with the reference frame of the treatment machine. As a subject to CTV, PTV can be defined as CTV plus a fixed or variable margin, equating to PTV = CTV + 1 cm.

PTV is highly dependent on the accuracy of such tools such as the lasers and devices used in immobilization. It, however, does not comprise of a margin for domestic characteristics of the radiation beam such as the build-up region or the penumbral areas. The reason for the exclusion is because they require additional margin that is available during the planning of treatment and the shielding design.

The organs at risk and radiation tolerance doses

An organ can be viewed to be at risk if the sensitivity of that organ to radiation gained from the dosage provided by the treatment plan is greater when compared to the tolerance of that organ to radiation. When an organ is at high risk, it requires the change in the beam arrangement or even changes in the dose. It is important to consider those organs that have low tolerance dose despite not being immediately adjacent to the CTV. Such organs include eye lens during nasopharyngeal or brain tumor treatments. Those organs that are tolerant to radiations, where the tolerance is dependent on the fractioning scheme, should be identified to avoid bias during the evaluation of the treatment plan. The breast tissues or chest walls and other regional lymphatic are located close to the vital organs such as lung, heart and coronary arteries. Other organs that should also be taken into account includes the contralateral breast and lungs, the brachial plexus, esophagus, spinal cord and the thyroid.

Optimal delineation of organs at risk is important in the healthcare setting as it influences the evaluation of the treatment planning. Failure to adequately delineate the organs at risk leads to the misinterpretation of the dose volume histograms (DVH) [70].

Organs at risk dose limits in lung cancer treatments

For patients suffering from lung cancer, the main organs at risk include the lungs, heart, spinal cord, main bronchi, brachial plexus and large vessels. There is a substantial amount of normal tissues in all the target volumes despite efforts being made to technically improve the planning of treatment and delivery. The Clinical Target Volumes and the Planning Target Volume comprise of exclusively normal parenchymal cells. Gross Turnover Volume, on the other hand, comprises of blood vessels and normal connective tissues.

It is unavoidable that the healthy tissues located in the target volumes will be exposed to the tumor prescribed dose but the normal tissues located outside the target volumes are given less but significant dose that is dependent on the physical parameters used in the treatment planning and delivering.

Various body organs contain several functional subunits (FSUs) where each subunit can be regenerated from a single surviving clonogenic cell. The arrangement of these functional units in the exposed organ determines the type of clinical damage on that given organ. The subunits may be arranged in either parallel or series format just like the one employed in the electrical circuit. For organs where the tissues arranged in a parallel pattern, such as the lungs, various critical functional subunits need to be damaged, so the functioning loss becomes detected. The potential of an organ is becoming mainly toxic depends on the distribution of the dose on the whole organ rather than placing the maximum amount of dosage on a small area of the organ. On the other hand, the failure of a single functional subunit of the serial organs such as the spinal cord can result in loss of function for the whole organ. Hot spots rather than the distribution of the dose in the entire organ increase the risk of complication for that specific organ.

The latency time can be used to describe the toxicities where they can either be defined as early as less than 90 days or as late as in more than 90 days since the start of the medical intervention. The effects of radiation that develop in the turnover tissues are mostly dominated by vascular and inflammatory changes and also hypoplasia. The severity and duration of early effects are hugely dependent on the dosage unlike the latency time of thee effects. For the late effects of radiation, an interactive response between the parenchymal cells, the fibroblasts, macrophages and vascular endothelium is required. Through the interactive process the parenchymal cells of the irradiated organs are damaged resulting in loss of their function. The latency time and the dosage have an inverse relationship for the late reaction.

Various studies have been conducted with the goal of explaining the issue of radio-induced toxicities after RT for NSCLC. Some of the common known reproducible predictors of acute and late effects related organs include:

Lungs

Early pneumonitis is commonly observed 4-6 weeks at the end of RT and after several months lasting up to years of fibrosis development. According to Rodrigues et al. (19), the most convenient means of estimating the NTCP for pneumonitis from the dose-volume histogram (DVH) is yet to be identified. Some of the methods such s the percentage of the total lung volume irradiated with defined doses are being employed with the mean lung dose (MLD) excluding any critical volume parameter that is related to the incidence of pneumonitis.

The European Organization for Research and Treatment of Cancer (EORTC) has given recommendations to keep V20Gy at a rate lower than 35 to 37 percent and the mean lung dose lower than 20-23 Gy. Other authors have also suggested for the adoption of lung constraints according to the pulmonary functions. Such constraints include forced expiratory volume in one second (FEV1) and the diffusing capacity (DLCO) [15].

Spinal cord

Lhermitte sign shows that acute radio-induced myelopathy takes place approximately ten to 16 weeks after RT mostly due to transient demyelination lesions. The evolution of the myelopathy tends to be favorable after the symptoms regress after roughly few months or more than a year. It takes place when the dosages are as low as 35Gy in s2 Gy per fraction. That dosage is below the normally admitted tolerance in particular when the long segments of the cord are irradiated. The late myelopathy can take months to years for it to develop after irradiation.

Acute myelopathy that is induced by radiation is quite rare, but it’s extremely severe. It is highly related to poor prognoses such as sensitive, motor and sphincter disorders. For the first syndrome that occurs within 6 to 18 months after RT, its effect is limited to demyelination and necrosis of the white matter while for the other syndrome occurring between one to above four years is in most cases vasculopathy. The risk factor that increases the chances of the complication is TTD and increase in dosage as per fraction that is inserted into the spinal cord. The spinal cord can, however, be able to tolerate a high dosage of radiation when only a few millimeters are irradiated. That tolerance is enabled by the movement of the remaining clonogenic cells towards the end of the irradiated field. The defensive mechanism also explains the partial repair of the RT-induced subclinical damage after a period lasting to several years. However, there is a limit on the maximum amount of tolerance, measuring as approximately 50 Gy, normally measured in2 Gy per fraction. The conventional fractionation can be used to estimate the risk of myelopathy that equates to greater than 1 percent at 54Gy and greater than 10 percent at 61 Gy.

Esophagus

The symptoms of severe esophagitis are evident four to eight weeks after the start of the RT while the late stages of esophageal damage tend to develop three to eight months after the end of RT. The risk factors for severe acute esophagus are concurrent chemotherapy and hyper-fractionation, increasing the risk by 30 percent. The most popular measure of the complication is Mean Esophagus Dose (MED), where less than 15 percent of the esophagitis grade is less than or equal to three in instances where MED is low than 28 Gy [29].

Data from various researchers have shown that esophagitis of gradeless or equal to 2 increases above 30 percent when V70 exceeds 20 percent, V50 exceeds 40 percent and V35 exceeds 50 percent [29, 31]. The patient should, however, not be prevented from receiving curative intent CRT by exceeded esophagus constraints since grade 3 or 4 esophagitis heals rapidly with not side effects [27].

Heart

When a heart is exposed to radiation, such crucial organs and tissues as the coronary vessels, myocardium, valves and the pericardium may be damaged. The latency period of effects can range from months for the pericarditis and arrhythmia to decades of the coronary artery disease or myocardial infarction. The risk factors for cardiac events include dose and irradiated volume. The most common cardiac effect is pericarditis and develops into chronic and, or, constrictive pericarditis in the fifth of the cases despite it being asymptomatic.

Exposure to anthracycline-based chemotherapy may increase the risk of cardiomyopathy that is induced by radiation such as congestive heart failure. Damage to the pericardium and the myocardium in late stages may be accompanied by loss of cardiomyocytes, perivascular fibrosis, and interstitial fibrosis. Detection of perfusion myocardium can be as early as six to 24 months after radiotherapy ad their diagnosis is heavily dependent on the volume of the left ventricle that exposed to the radiotherapy field.

Coronary artery diseases that are induced by through radiation are in most cases caused by endothelial dysfunction although the prevalence can be attributed to the risk factors that include age, smoking, and hyperlipidemia [33, 34]. The radiation can also impair aortic and mitral valves although the heart conduction system is hardly affected. One of the severe effects of heart radiation is the blockage of the atrioventricular system requiring the implanting of the pacemaker.

Most of the data regarding the toxicities of the cardiac system are collected from radiotherapy in breast cancer or lymphoma. Retrospective analysis is required to collect data about the dose or volume when an individual has lung cancer. Trail conducted by RTOG 0617 and IDEAL CRT revealed a negative relationship between the overall survival and the volume of the heart receiving 5 Gy and the heart volume receiving the dosage of 65 to 75 Gy. However, there is the need for further research to help understand the effects of radiation on the structure if the heart thus helps in defining the reliable indicators of toxicities.

Brachial plexus

For the tumor located in the apex, brachial plexus tends to be the organ at risk. Some of the symptoms of brachial plexopathy, normally caused by radiation, including pain with sensitive and motor disorders. The plexopathy usually occur within one to 4 years after radiotherapy treatment although some take up to 20 years after treatment. Physiopathology is done to reveal the extent of damage, microvasculature alteration, and fibrosis of those tissues surrounding the brachial plexus and the nervous structures.

The brachial plexus is very sensitive to high doses per fraction where it can only tolerate up to 60 Gy of dosage [40].The tolerance is however difficult to measure due to such reasons as uncertainties in the location of the organ and lack of DVH parameter.

According to Hall et al., cancer radiation treatment of the head and neck emit dosage higher than 60 Gy [41].

Radiobiology

A major principle in radiotherapy is the quantitative description of the association between the dosage sand the death rate of the cell. Derived from theoretical, experimental and clinical studies, the sigmoid dose-response curve is used to estimate the tumor control probability (TCP) for a specific dose. By use of the curve, limiting the local recurrence require an increase of the dosage directed to the tumor. The organs, however, limit such escalation at risk (OARs) as shown by the therapeutic index, a ratio between the TCP and the normal tissue complication probability (NTCP). Biological and physical factors can be employed to help in establishing a favorable ratio by shifting the TCP curve to the left, also known as radiosensitization or moving the curve to the right, also known as radioprotection to help in building tumor control whereas keeping the toxicities levels at a minimum as shown by figure 1.1 below.

A report by Martel et al. has projected that NSCLC patients require a dose of 84Gy for longer local progression free survival to ensure the achievement of significant probability of tumor control.

Various scientists have suggested the need to employ chemotherapy in association with radiotherapy. During radiation inter-fraction intervals, CRT helps in inhibiting the tumor cells proliferation by various drugs. Other radiobiological benefits include modulation of the DNA and chromosome change and repair, synchronization of the cell cycle, induction of apoptosis and re-oxygenation.

The concomitant CRT is superior to one adopted in NSCLC according to a randomized study on the relationship between RT and chemotherapy. The study points out that the five-year overall survival rises from10 percent under the sequential arm to 15 percent under the concomitant arm. The rise in the survival gain has been associated with the increase in the local tumor control.

Another essential factor that influences the outcome is the overall treatment time (OTT) for the radiotherapy. According to Machtay et al., more prolonged treatment time contributes to poorer chances of survival even for the concomitant CRT. Raising the average dosage per week above the 10 Gy, also known as accelerated fractionation, can be applied whereas shortening the overall treatment time can help overcome rapid tumor repopulation taking a period of 3 to 4 weeks of radiotherapy whereas also being compatible with the doubling times of 3 to 3.5 days. In early stages, the normal reactions are expected to increase whereas they are expected to remain constant during the late stages when applying the scheme.

The altered fractioning schemes that differ from the classical 2Gy per fraction for five days each week have also been tested. When the dose per fraction is given during classical overall treatment time is reduced, also known as hyper-fraction, there are therapeutic advantages that are derived from it as a result of the difference in fractionation in sensitivity between the tumor cells and other tissues that tend to have a late response.

A CHART trial aiming to compare continuous hyper-fractionated radiotherapy and accelerated radiotherapy highlighted the benefits of accelerating and hyper0fractioning the treatment by survival and local tumor control. The results showed an increased in the two-year survival from 21 percent in the convectional arm to 30 percent in the CHART arm owing the increase to improvement in the tumor control.

When the dosage per fraction is higher than 2 Gy with a lower number of total fractions, it is referred to hypo-fractionation. There is an increase in the number of curative radiation therapy that is using moderate hypo-fractionation. With the goal of avoiding severe toxicity in the normal tissues during the late stages, it is essential to reduce TTD although the TCP should not be changed as it is not affected due to the shorter overall time treatment time. The demand for moderate hypo-fractionation for dose escalation is on the rise as it is more convenient for the patients and also helps in conserving resources.

The concept has been modified to include the personalization of doses by the normal tissues in collaboration with either hyper or hypo-fractionation of the treatment. The MAASTRO clinic has adopted a strategy to help in the delivery of the highest achievable radiation does to the patients on the basis of the size of the tumor, localization and dose limiting organs at risks.

The results for planning were quite promising in term of TCP whereas the first clinical results showed the possibility of an accelerated scheme. Another research show the increase in the survival chances for stage three NSCLC patients when CRT is done in association with Individualized Isotoxic Accelerate RT (INDAR), despite it being more expensive and less convenient.

Treatment planning evaluation

Dose volume histogram

A dose volume histogram (DVH) can be defined as a visual representation of the radiation dose given as a function of the volume. Some of the parameters indicated by the histogram include different Dv parameters, minimum dose to a volume V, volume receiving a dose greater or equal than D. The histogram also uses a parameter with a minimum dose value in distribution of the dose of D98. When the dose is at a maximum, 2 percent of the volume is received. Figure 2.9 below show the dose volume histogram, a tool essential to the plan evaluation process.

Homogeneity index and conformity index

The homogeneity index (HI) can be used to describe the homogeneity of the dose within the target volume. In an equation, homogeneity index can be defined as:

With D(x) representing the dose at x % of the volume. In instances where the homogeneity index is 1, the dose distribution over the entire target volume is complete. The conformity index (CI) can be employed to help understand how to adapt the dose to the target volume and oit can be calculated as;

The V target volume refers to the volume of delineated target volume, normally the PTV, whereas the V treated volume is the volume that is covered by the entire isodome volume with 90 to 95 percent of the total isodose being common to use. When the conformity index is or near to 1, the conformity is viewed to be good. The measure is faced by several issues one being that it does not take into concept the degree of spatial intersections of the volume or even their shapes. The conformity index can be measured as 1 without necessarily having similar volumes. The tool is therefore applicable most effective when used in conjunction with other visualization tools for the dose distribution. Such collaboration would help minimize the risk of total miss.

NTCP modelling

The therapeutic ratio is employed to help in visualizing the objective of the radiation therapy and also help in delivery of the right dosage to the tumor whereas ensuring little or no dose is spilt on the surrounding tissues. It is arrived at by calculating the ratio between the tumor control probability (TCP) and the normal tissue complication probability (NTCP) for specified response. The therapeutic ratio is heavily dependent on the treatment time and technique, target volume, LET, dose ratre and fractionation.

Lyman Kutcher Burman (LKB) Model

The NTCP models are used to predict the probability of normal tissue complications using the DVH used by the treatment planning system thus acting as tools for treatment plan evaluation. The Lyman-Kutcher-Burman (LKB) is one of the most commonly used NTCP model.

The equivalent uniform dose (EUD) was first applied by Niemierko in 1997 to help in reporting non-uniform dose distribution. It uses assumptions that two dose distributions are equal is the have similar radiobiological effect. It is calculated as;

Under the formula, Di signifies the dose to voxel, whereas i and vi are relative to the volume of the voxel. a represents tissue-specific parameter that calcularted by comparing the tumor and normal tissue response. a is greater for serial organs and closer to 1 for the parallel organs.

The LKB model is a practical NTCP model by using the cumulative Gauss function to describe the NTCP. The following mathematical representation has been suggested by NTCP;

With t being calculated as;

The symbol m refer to the steepness of the NNTCP curve whereas TD50 refer to the dose equivalent to NTCP of 50 percent.

D is calculated as;

The conditions needed to calculate NTCP by the use of LKB model can be described as TT50, n and m.

Normal Tissue complications after radiotherapy

Normal Tissue Complication Probability

The benefits of applying specific treatment methods are weighed against the negative side effects in determining the feasible treatment method signifying the need for reliable estimation of possible toxicity. The Normal Tissue Complication Probability (NTCP) models help in formulating the various constraints thus essential in designing new treatment strategies. The application of NTCP models requires well-defined endpoints and a sufficient number of patients and events. The curves are calculated as a subject of dose and volume, and its application requires coverage of wide dose range.

Radiation Induced Lung Toxicity

One of the serious side effects of radiation is the radiation pneumonitis (RP) as it is life-threatening. For the lung cancer patients who have been diagnosed with conventional fractionated RT (CFRT), there is a predetermined relation between lung dose and the incidence of radiation pneumonitis whereas the relation is unknown for patients with hypofractionated schemes.

Since most patients suffering from lung cancer suffer from pulmonary co-morbidities, it is normally challenging to determine whether the complaints are caused by irradiation or other preexisting pulmonary diseases. It is, therefore, to work in collaboration with pulmonologist as well as employ other strategies as pulmonary function tests, long-term follow up to help reveal the predictive and prognostic factors that increase the risk of lung toxicity that is caused by severe radiation.

Radiation Dose

The relationship between cell kill and the radiation dose is dependent on multiple factors. These factors include cellular recovery, cell-cycle progression, proliferation, and hypoxia as they impact the response of tumor tissues and tumor following radiation. The Linear Quadratic (LQ) model is applied to help convert physical irradiation to its biological equivalent. The LQ model uses a linear and quadratic component to explain radiosensitivity as a function of the dose. According to a survey carried by Thames et al. that aimed at assessing the iso-effect curves of various normal tissues in animals, LQ model is an essential tool in explaining the type of relationship between the iso-effect dose and the total physical dose, the dose per fraction and the tissue-specific radio-sensitivity parameter. The curve of log cell survival as a function of the dose defined by the LQ model is linear for the higher dose levels although it is curved for moderate levels.

Pneumonitis and fibrosis

Some of the symptoms of systematic pneumonitis include a cough, fever, and thoracic pain. V2082 is a common dosimetric parameter that is used to evaluate the risk of radiation pneumonitis. The parameter should be kept at a percentage less than 35 percent during radio-chemotherapy with CFRT for the locally advanced NSCLC to help in reducing the risk of pneumonitis. Few weeks after the completion of CFRT, the signs usually start to appear. The cause of that is believed to be inflammation of the alveoli of the lungs. Previous research of acute phase has pointed to edema in the alveolar septae and hyperplasia of the alveolar lining cells. Other causes include an increase in the alveolar macrophages and fibroblasts. Although the incidence of symptomatic radiation pneumonitis post-SBRT may appear as late as 16 months, it normally ranges from9 to 20 percent, therefore, representing a median time of 3 to 5 months84 -87.

The reports investigating the risk factors point out to lack of consistency with some identifying dose-volumetric risk factors such as MLD89 84, 86,87, V589, V1089,90, V2086, 87, V2585 and PTV85, 91. In another risk involving 483 patients, no dose-volume risk factors were identified to be possible predictor for pneumonitis greater than or equal to grade 235. Another study investigating 236 patients where 12 percent had symptomatic pneumonitis pointed out that there was no dosimetric frisk factor although identified the female gender, smoking history and larger IGTV and PTV to be huge influencers. The conflicting opinions resulted in no factor being selected in determining the incidence of lung toxicity.

Another view of radiation-induced lung injury is whether patients with reduced pulmonary function are at a greater risk for pneumonitis as compared to those patients with normal lung function. One research failed to show an increase in the risk for the radiation pneumonitis for the patients with severe COPD as compared to patients with cardiovascular disease5. The study showed that patients with severe COPD have a possibility of having reduced risk for radiation pneumonitis when compared to those with a milder one. That is explained by the concept of tissue amount theory where patients with severe COPD have fewer lung tissues to generate an inflammatory response thus lowering the risk of pneumonitis. Another explanation is the high risk for radiations pneumonitis among patients with radiological signs of interstitial lung disease93.

Fibrosis that is induced by radiation is a condition related to dose-volume interaction and is characterized by fibrotic changes. It is a dynamic process that starts between six to twelve months after treatment with remodeling although it may take several years94. Although the radiological characteristics are seen in almost all patients, only a few of them are symptomatic.

Low Doses in Thoracic Cancers

Although relatively high dosage levels cause most causes of toxicities of tissues for patients suffering from thoracic cancers according to dosimetric parameters, there is a growing concern regarding lower doses similarly contributing to toxicities. Studies have measured possible toxicities with the low dose that range from 0 to 20 Gy over a large volume. These studies measured several parameters that include the volume of the dose received by the heart, and the lung.

According to Taylor et al. in his review of the cardiac disease for patients with breast cancer, there is an increase in the risk of heart toxicity caused b radiation therapy among the patients with a heart volume ranging between0 and 5 Gy31.

Other two studies investigating the different treatment methods for pneumonitis also identified that the volume of normal lung receiving 5 Gy is hugely associated with high toxicity. Another research investigating non-small lung cancer (NSCLC) patients, who have undergone 3DCRT simultaneous to chemotherapy, identified that patients who had pneumonitis or were in need of oxygen were in associated with clinical and dosimetric parameters. The research also found that comparative normal lung volume receiving 5Gy is hugely associated with an increase in the risk of developing pneumonitis. Normal slung volume in the case is calculated as the total lung minus the gross tumor volume.

The patients with V5 that was either less or equal to 42 percent are less likely to have an incidence that was Grade 3 or higher. Other studies focused on investigating the IMRT plans for patients with mesothelioma who had extrapleural pneumonectomies. Data from these studies revealed a 10 percent incidence of pneumonitis for those patients with mean lung dosage close or equal to 15 Gy. For most of the patients who had developed pneumonitis, V5 was pointed to be above 81 percent although V20 was less than 20percent. For the normal healthy individuals, the V5 was identified to be greater than 90 percent drawing the conclusion that the parameter may have been the cause of pulmonary toxicity that is common among the patients [19]. The results from the two studies can be used to arrive at the conclusion that V5 can be used in predicting the prevalence of radiation pneumonitis.

According to an analysis of pulmonary toxicity among the NSCLC patients that were undergoing chemoradiation simultaneous with amifostine, conducted by Gopal, there is a sharp decrease in the diffusion capacity at a dose of 13Gy. Lee et al. [33] also found a relationship between pulmonary complications among the esophageal patients who had been previously treated with chemoradiation who were irradiating more than 40 percent of the lung volume with 10Gy.

It can at this moment be concluded that low doses can be more harmful than it was previously perceived and any constraints on the doses can be beneficial to the thoracic patients.