Radiation induced lung damage - Chapter 1 Introduction

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Radiation induced lung damage

Seppenwoolde, Y.

Publication date

2002

Link to publication

Citation for published version (APA):

Seppenwoolde, Y. (2002). Radiation induced lung damage.

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Chapterr 1

Introduction n

Introduction n

Althoughh lung cancer is the most preventable malignancy in humans (trends in lung cancerr incidence are related to trends in past smoking behavior), its tnddenoB and mortaftyy is very high. In the period 1989-1997 me incidence among men has declined graduallyy from 109 to 93 per 100,000 person years (Janssen-Heijnen 2001). However, this beneficiall trend was partly offset by an increase of the incidence among women: from 18 toto 23 per 100.000 person years. In me Netherlands the incidence of lung cancer was high inn comparison to other European countries. Although the incidence and mortality decreased,, m 1997 still almost 20 men died each day of lung cancer in the Netherlands. Amongg women the end of the increase has not been reached and in 1997 over 5 women diedd each day of lung cancer (Janssen-Heijnen 2001). m the year 2000,8800 new cases andd 8600 deaths due to rung cancer were reported (Dutch Cancer Registration 2000).

Radiotherapyy for lung cancer patients

Non-smalll cell lung cancer (NSCLC) is diagnosed in eighty percent of the lung cancer patients. Off these patients 20-30% can be treated with surgery, while 70-80%, is inoperable due to locallyy advanced disease, a poor performance index, distant metastases or co-morbkJity. For 30%% of the inoperable patients, the only potentially curative therapy is radical irradiation of the tumorr (Dutch Cancer Registration 2000). Patients treated with radiotherapy alone have a mediann survival of merely 8 to 10 months. The 2-year survival is about 10 to 20% and the 5-yearr survival is only 3 to 7% (Perez 1986,1987, Schaake-Koning 1992).

Locall failure of radiotherapy with conventional doses is a major cause for the disappointing curee rate (Arriagada 1991). To improve clinical outcome new treatment approaches were designed,, consisting of combined radiotherapy and chemotherapy. Another approach is to use highh dose radiotherapy Hi order to improve focal control. A study based on tumor control probabilityy model calculations (Martel 1999) estimated that the dose to achieve a 50% probabilityy of tumor control might be in the order of 84 Gy. it is obvious that with an increasing radiotherapyy dose, the incidence of radiation-induced damage to surrounding healthy tissue willl increase as well.

Dosee escalation

Inn several RTOG trials (Perez 1986,1987, Cox 1990,1993, Sause 1995), patients with higher radiotherapyy doses showed a greater proportion of complete responses and subsequently improvedd survival. Total doses higher than the conventional 60 Gy are associated with improvedd focal tumor control (Byhardt 1995). Preliminary results of prospective trials using high-dosee 30 conforms! radiotherapy for NSCLC patients are suggesting that improvement of locall control can be reached by delivering higher radiation doses (Cox 1990, Armstrong 1993, Robertsonn 1997, Befderbos 2000, Mehta 2001, Hayman 2001).

Normall tissue damage

Increasingg the prescribed dose to the tumor will inherently increase dose to the surrounding tissuetissue in the thorax, causing extra radiation induced damage to the surrounding healthy tissue. inn addition to radiation pneumonitis, which is a binary type of complication, it is clinically relevantt to evaluate and predict the graded response of lung tissue by measuring changes in overalll pulmonary function. Graded response is also reflected in local changes in lung tissue densityy and lung perfusion.

ChapterChapter 1

Locall dose effects

Locall damage to lung tissue can be measured with 30 imaging techniques. Changes in lung perfusionn (and thus the distribution of the lung capillaries) can be measured by comparison of follow-upp 3D Single Photon Emission Computed Tomography (SPECT) scans with the pre-treatmentt scan. To obtain an image of the 3D local lung perfusion, ""Technetium-laoefled (T1/2

== 6 h) albumin micro aggregates are injected intravenously and the relatively targe albumin getss trapped in the small capillaries in the lungs. A dual head gamma camera rotates around thee patient and obtains 30 images per camera head at 6 intervals. Using a filtered back projectionn algorithm, trans-axial slices of the 3D perfusion can be made. These images can be matchedd to the CT scan of the patient (Kwa 1998b) and correlated with the 3D dose distribution.. With a pre-treatment and post-treatment SPECT-scan the local changes in lung perfusionn can be calculated. In previous studies (Boersma 1994, Marks 1997b, Theuws 1998a,, Garipagaoglu 1999, Theuws 2000) dose effect relations for radiation induced perfusion damagee were obtained for patients without intrathoracic tumor or pre-existent pulmonary diseasee ('healthy' lungs). For lung cancer patients the presence of reperfusion (Marks 1995) andd pre-existent pulmonary disease complicates the determination of a dose-effect relation. Thee SPECT lung perfusion information on local functionality of lung tissue provides additional informationn to design a treatment plan that minimizes the complication risk for perfusion damagee (Marks 1995) because the high dose regions can be directed through non-functioning lungg tissue (Marks 1993). The group of Marks (1999) suggested that the perfusion weighted lungg dose-volume histogram (where the volume receiving a certain dose is weighted with the averagee perfusion in that dose-region) could be a valuable tool in designing the optimal RT plan. .

Pulmonaryy function

Radiationn induced lung damage on the overall lung function was measured by repeated pulmonaryy function tests (PFTs). The vital capacity, the forced expiratory volume in one second,, the alveolar volume and diffusion capacity for carbon monoxide, corrected for hemoglobinn (VC, FEV1t VA and T^coc respectively) were determined with spirometry, before

andd after radiotherapy for patients with healthy lungs (Theuws 1998b, 1999). The presence of reperfusionn and pre-existent pulmonary disease in NSCLC patients can obscure the outcome off the measurements. Until now, the radiation-induced reduction in pulmonary function was correlatedd with 'pure' dose parameters. For patients with 'healthy* lungs this was considered to bee a good strategy because their lung tissue was functioning homogeneously (Theuws 1998b).. This is different for patients with lung cancer because of the inhomogeneity of their lungg tissue: none of the dose-volume parameters that correlated with the risk of pneumonitis weree successful in predicting changes in pulmonary function in NSCLC patiënte treated to high dosee (Allen 2001).

Radiationn pneumonitis

Radiationn pneumonitis is a more serious complication that may occur after radiotherapy. It becomess manifest between one and six months after treatment The clinical symptoms of radiationn pneumonitis range from mild symptoms such as fever, dyspnea and cough to death duee to respiratory failure. In patients who survive this pneumonitis phase, the type and severity

Introduction Introduction

off the early response may have bearing on the type and severity of the ensuing late response. Thee amount of irradiated volume and radiation dose have an effect on radiation-induced lung injury.. The severity and probability of developing radiation pneumonitis for an individual patient beforee treatment can be estimated using simple parameters as the mean lung dose or the volumee of lung receiving more tiran a threshold dose (Marks 1997a, Kwa 1998a, Graham 19919).. Although all the studied parameters showed correlationn with the incidence of radiation pneumonitis,, until now no consensus has been reached on the best model to predict radiation pneumonitis. .

Treatmentt optimization

Reducingg the volume of irradiated surrounding tissue, whilst keeping the dose to the tumor constantt decreases the incidence of normal tissue complications. There are several ways to reducee the irradiated lung volume: for example by using 3D conformal fields instead of conventionall radiation fields. This reduces the volume of irradiated normal tissue by 35% (Armstrongg 1993). Excluding irradiation of clinical and radiological uninvolved lymph nodes (electivee nodal irradiation) decreases lung toxicity (Belderbos 1997, McGibney 1999) because off the resulting smaller field sizes. Prospective studies (Robertson 1997, Hayman 2001) suggestt that it is safe to exclude the clinical and radiological uninvolved nodal areas.

Marginn reduction

Anotherr way to decrease field sizes is to reduce the safety margins around the clinical target volumee (CTV), by controlling the factors that determine the size of the margin between CTV andd planning target volume (PTV): systematic (setup) errors and tumor motion.

Setupp errors

Thee introduction of electronic portal imaging devices has enabled images to be acquired of the patientt in the treatment position. These images can be compared to digitally reconstructed radiographss (DRR) derived from the planning CT scan, to correct errors In setup. Systematic errorss occur mainly during the preparation of the treatment. These can be due to several factorss such as target delineation errors, position of the patient and tumor when the planning CTT scan is acquired or the use of simulator images rather than ORRs for setup reference imagess (Bel 1994, de Boer 2001). Setup errors are mainly due to day-to-day variations in patientt and organ position. To identify setup inaccuracies using thoracic portal images, comparisonn must be made to areas of relative stability. Samson et al. (1999) demonstrated thatt thoracic wall, trachea and clavicle are the most stable structures and the comparison of thee position of two of these landmarks in the reference image and the portal image, produces thee most reliable comparison. The extent of systematic and random (setup) errors can differ perr institute as it depends on imaging, immobilization and verification techniques.

Tumorr motion

Tumorss in lung tissue move due to breathing and/or heartbeat. When a part of the tumor movess out of the irradiation field, this part gets less dose than planned and the surrounding normall tissue receives a higher dose. Irradiation of lung cancer is done with the patient breathingg freely and therefore a targe margin is drawn around the tumor to ensure accurate targett coverage (ICRU Report 50 1993). In the absence of precise data, the size of the marginss is estimated rather roughly during fluoroscopy measurements (Ekberg 1998). Strategiess to compensate for breathing motion include the use of real-time tumor tracking (Shrratoo 2000a), gated radiotherapy (Ohara 1989), abdominal pressure (Blomgren 1995),

ChapterChapter 1

voluntaryy breath hold at variable phases of the respiratory cycle (Rosenzweig 2000, Kim 2001) andd active breathing control (ABC), (Wong 1999). In CT-scans, significant under- and overestimationn of the tumor size and distortions of the shape of the tumor can be due to breathingg (Baiter 1996). To construct a representative pfanning-CT scan it is important that the magnitudee and the direction of tumor motion can be modelled.

Aimm of the study

Thee aim of this study is two-fold:

1.. Factors associated with radiation induced pulmonary damage will be identified and quantifiedd by measuring local and overall dose-effects.

2.. The results of the first objective will be used to optimize the treatment, in combination with modellingg of factors that hinder accurate dose delivery such as patient setup inaccuracy and tumorr motion.