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Dosimetric predictors of radiation-induced lung injury

2002; Elsevier BV; Volume: 54; Issue: 2 Linguagem: Inglês

10.1016/s0360-3016(02)02928-0

1879-355X

Lawrence B. Marks,

Lung Cancer Diagnosis and Treatment

In this issue, Yorke et al. (1Yorke E.D. Jackson A. Rosenzweig K.E. et al.Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 2002; 54: 329-339Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar) from the Memorial Sloan-Kettering Cancer Center describe an association between the dosimetric parameters from the lung dose-volume histogram (DVH) and the incidence of radiation (RT)-induced lung injury. They report that the incidence of Grade 3 or greater pneumonitis correlated well with the mean lung dose, the percentage of lung receiving at least 20 Gy, and parameter estimates from DVH-reduction schemes. This study, involving 49 patients with non-small-cell lung cancer, is consistent with several other clinical studies summarized in Table 1 (2Martel M. Dose volume histogram and 3D treatment planning evalution of patients with pneumonitis.Int J. Radiat Oncol Biol Phys. 1994; 28: 575-581Abstract Full Text PDF PubMed Scopus (252) Google Scholar, 3Oetzel D. Schraube P. Hensley F. et al.Estimation of pneumonitis risk in three-dimensional treatment planning using dose-volume histogram analysis.Int J Radiat Oncol Biol Phys. 1995; 33: 455-460Abstract Full Text PDF PubMed Scopus (191) Google Scholar, 4Graham M.V. Purdy J.A. Emami B. et al.Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small-cell lung cancer (NSCLC).Int J Radiat Oncol Biol Phys. 1999; 45: 323-329Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar, 5Kwa S.L. Lebesque J.V. Theuws J.C. et al.Radiation pneumonitis as a function of mean lung dose An analysis of pooled data of 540 patients.Int J Radiat Oncol Biol Phys. 1998; 42: 1-9Abstract Full Text Full Text PDF PubMed Scopus (645) Google Scholar, 6Hernando M.L. Marks L.B. Bentel G.C. et al.Radiation induced pulmonary toxicity A dose-volume histogram analysis in 201 patients with lung cancer.Int J Radiat Oncol Biol Phys. 2001; 51: 650-659Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar). The findings of each of these studies suggest that dose/volume parameters are important determinants of RT-induced lung injury. In concert, these encouraging studies demonstrate the ability of three-dimensional (3D) tools to predict normal tissue risks. Figure 1 illustrates the association between the mean lung dose and the rate of pneumonitis reported in five studies (including Yorke et al.).Table 1Correlation between dosimetric paramters and the incidence of radiation pneumonitisAuthorPneumonitis end pointNTCP modelsVdoseMean lung doseSubgroupRate (%)SubgroupRate (%)Subgroup (Gy)Rate (%)Martel 2Martel M. Dose volume histogram and 3D treatment planning evalution of patients with pneumonitis.Int J. Radiat Oncol Biol Phys. 1994; 28: 575-581Abstract Full Text PDF PubMed Scopus (252) Google Scholar (n = 42)All grades1st quart.∗Lungs analyzed as separate organs.0†Average probabilities.2nd quart.∗Lungs analyzed as separate organs.5†Average probabilities.3rd quart.∗Lungs analyzed as separate organs.14†Average probabilities.4th quart.∗Lungs analyzed as separate organs.29†Average probabilities.Armstrong et al. 36Armstrong J.G. Zelefsky M.J. Leibel S.A. et al.Strategy for dose escalation using 3-dimensional conformal radiation therapy for lung cancer.Ann Oncol. 1995; 6: 693-697Crossref PubMed Scopus (89) Google Scholar (n = 31)Grade ≥3 3038Oetzel et al. 3Oetzel D. Schraube P. Hensley F. et al.Estimation of pneumonitis risk in three-dimensional treatment planning using dose-volume histogram analysis.Int J Radiat Oncol Biol Phys. 1995; 33: 455-460Abstract Full Text PDF PubMed Scopus (191) Google Scholar‡Data estimated from Figs. 1 and 2 in original article. (n = 66)§Data included 20 patients with esophageal cancer.All grades<30%∗Lungs analyzed as separate organs.13≤15∗Lungs analyzed as separate organs.0≥30%†Average probabilities.2917.5–20∗Lungs analyzed as separate organs.1322.5–25∗Lungs analyzed as separate organs.21≥27.5∗Lungs analyzed as separate organs.43Graham et al. 4Graham M.V. Purdy J.A. Emami B. et al.Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small-cell lung cancer (NSCLC).Int J Radiat Oncol Biol Phys. 1999; 45: 323-329Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar (n = 99)Grade ≥2V20 Gy <220 4036>3025Kwa et al. 5Kwa S.L. Lebesque J.V. Theuws J.C. et al.Radiation pneumonitis as a function of mean lung dose An analysis of pooled data of 540 patients.Int J Radiat Oncol Biol Phys. 1998; 42: 1-9Abstract Full Text Full Text PDF PubMed Scopus (645) Google Scholar (n = 400)Grade ≥20–858–161116–241824–3643Hernando et al. 6Hernando M.L. Marks L.B. Bentel G.C. et al.Radiation induced pulmonary toxicity A dose-volume histogram analysis in 201 patients with lung cancer.Int J Radiat Oncol Biol Phys. 2001; 51: 650-659Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar (n = 201)All grades1st quart.10†Average probabilities.V30 Gy ≤186 182410–20163rd quart.16†Average probabilities.21–30274th quart.33†Average probabilities.>3044Abbreviations: NTCP = normal tissue complication probability; Vdose = percent of lung receiving at least that dose; quart. = quartile.Some of the patients in Hernando et al. 6Hernando M.L. Marks L.B. Bentel G.C. et al.Radiation induced pulmonary toxicity A dose-volume histogram analysis in 201 patients with lung cancer.Int J Radiat Oncol Biol Phys. 2001; 51: 650-659Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar were included in the pooled analysis of Kwa et al. 5Kwa S.L. Lebesque J.V. Theuws J.C. et al.Radiation pneumonitis as a function of mean lung dose An analysis of pooled data of 540 patients.Int J Radiat Oncol Biol Phys. 1998; 42: 1-9Abstract Full Text Full Text PDF PubMed Scopus (645) Google Scholar.Adapted from Hernando et al. 6Hernando M.L. Marks L.B. Bentel G.C. et al.Radiation induced pulmonary toxicity A dose-volume histogram analysis in 201 patients with lung cancer.Int J Radiat Oncol Biol Phys. 2001; 51: 650-659Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar.∗ Lungs analyzed as separate organs.† Average probabilities.‡ Data estimated from Figs. 1 and 2 in original article.§ Data included 20 patients with esophageal cancer. Open table in a new tab Before outlining some of the limitations of these predictive models, let us take a moment to bask in this exciting observation. Our field is rapidly embracing high technologic methods, such as 3D planning, to care for an increasing proportion of our patients. It is nice to know that the additional information provided by 3D tools is useful in predicting outcome. Predictive models for lung injury are particularly important, given the high incidence of lung cancer and RT-induced lung injury. Furthermore, it is likely more difficult to develop predictive models for the lung than for many other organs. There are marked interpatient differences in pre-RT overall lung function and the degree of spatial variation in regional lung function (e.g., because of tumor or preexisting lung diseases such as emphysema) that make modeling the lung particularly challenging. Thus, the predictive abilities of metrics such as the mean lung dose, that do not consider any of these interpatient differences, is hopeful. In the future, I anticipate that reasonably accurate methods to predict normal tissue and tumor outcomes will be available. Encouraging normal tissue predictive models based on other 3D dosimetric data have been suggested for several organs, including the brain, rectum, liver, parotid, and esophagus.A variety of different dosimetric parameters have been related to RT-induced lung injury (Table 1). It is not known which, if any, of these parameters are superior. This cannot be adequately assessed because the different dosimetric parameters are highly correlated with each other (4Graham M.V. Purdy J.A. Emami B. et al.Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small-cell lung cancer (NSCLC).Int J Radiat Oncol Biol Phys. 1999; 45: 323-329Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar, 7Kwa S.L.S. Theuws J.C.M. Wagenaar A. et al.Evaluation of two dose-volume histogram reduction models for the prediction of radiation pnemonitis.Radiother Oncol. 1998; 48: 61-69Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 8Fan M. Marks L.B. Hollis D. et al.Can we predict radiation-induced changes in pulmonary function based on the sum of predicted regional dysfunction?.J Clin Oncol. 2001; 19: 543-550Crossref PubMed Scopus (70) Google Scholar). This correlation occurs because a relatively uniform treatment technique is typically used in each individual study. Thus, it is likely that the predictive ability of at least some metrics will be technique-dependent. The existing data were generated from patients largely treated with conventional techniques and doses. Their validity in the realm of high-dose/IMRT is unknown. It is intuitive that metrics based on the entire DVH (e.g., mean lung dose) may be better predictors than metrics derived from only a single point on the DVH (e.g. V20), although, to my knowledge, this has not yet been demonstrated.Dosimetric parameters alone are not ideal predictors for lung injury. As seen in Table 1, most patients in the "high-risk" subgroups did not develop symptoms. Furthermore, symptoms develop in a significant proportion of the patients in the more favorable subgroups. One needs to be careful in defining cutpoints for segregating patients into high- versus low-risk groups. Using such cutpoints, the sensitivity and specificity of the predictive models are both never very good. For example, when one raises the threshold for defining high risk, the positive predictive value will increase, but the sensitivity and negative predictive value will decrease. Consider Graham's data and the cutpoint of V20 Gy at 40%. Among the patients who had a V20 > 40%, 36% developed pneumonitis. However, approximately one-half of the patients with pneumonitis in that series had a lower V20 Gy, resulting in a sensitivity of approximately 50% (4Graham M.V. Purdy J.A. Emami B. et al.Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small-cell lung cancer (NSCLC).Int J Radiat Oncol Biol Phys. 1999; 45: 323-329Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar).Predictive models that include functional information, such as pre-RT pulmonary function and biologic determinants of radiation sensitivity (e.g., transforming growth factor-β and/or interleukin-6) might be better (9Marks L.B. Munley M.P. Bentel G.C. et al.Physical and biological predictors of changes in whole lung function following thoracic irradiation.Int J Radiat Oncol Biol Phys. 1997; 39: 563-570Abstract Full Text PDF PubMed Scopus (199) Google Scholar, 10Fu X. Huang H. Bentel G. et al.Predicting the risk of symptomatic radiation-induced lung injury using the physical and biologic parameters V30 and TGF-β.Int J Radiat Oncol Biol Phys. 2001; 50: 899-908Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 11Vujaskovic Z. Groen H.J.M. Preservation of the lung function after thoracic irradiation Role of transforming growth factor beta (TGF-beta).Radiol Oncol. 1997; 31: 233-235Google Scholar, 12Vujaskovic Z. Groen H.J.M. Transforming growth factor beta (TGF-beta), radiation-induced pulmonary injury and lung cancer.Int J Radiat Biol. 2000; 76: 511-516Crossref PubMed Scopus (65) Google Scholar, 13Robnett T.J. Factors predicting severe radiation pneumonitis in patients receiving definitive chemoradiation for lung cancer.Int J Radiat Oncol Biol Phys. 2000; 48: 89-94Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 14Chen Y. Williams J. Ding I. et al.Radiation pneumonitis and early circulatory cytokine markers.Semin Radiat Oncol. 2002; 12: 26-33Abstract Full Text PDF PubMed Scopus (212) Google Scholar, 15Marks L.B. Fan M. Hollis D. et al.Dosimetric and/or functional predictors of RT-induced pulmonary injury A comparison using receiver operating characteristic curves.Int J Radiat Oncol Biol Phys. 2001; 3 (ASTRO 43rd Annual Meeting, San Francisco, CA, Nov. 3–7, 2001.): 50Abstract Full Text Full Text PDF Google Scholar). We have found that predictive models based solely on dosimetric parameters (e.g., mean lung dose or DVH-based normal tissue complication probability) are more accurate when patients with extremely poor pre-RT pulmonary function are excluded (9Marks L.B. Munley M.P. Bentel G.C. et al.Physical and biological predictors of changes in whole lung function following thoracic irradiation.Int J Radiat Oncol Biol Phys. 1997; 39: 563-570Abstract Full Text PDF PubMed Scopus (199) Google Scholar, 15Marks L.B. Fan M. Hollis D. et al.Dosimetric and/or functional predictors of RT-induced pulmonary injury A comparison using receiver operating characteristic curves.Int J Radiat Oncol Biol Phys. 2001; 3 (ASTRO 43rd Annual Meeting, San Francisco, CA, Nov. 3–7, 2001.): 50Abstract Full Text Full Text PDF Google Scholar, 16Lind P.A. Marks L.B. Hollis D. et al.Utility of receiver operator curves (ROC) in assessing predictors of radiation-induced symptomatic lung injury.Int J Radiat Oncol Biol Phys. 2002; 54: 340-347Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). In these patients, the models may be less accurate, their underlying lung disease may predispose them to injury, or it may be more difficult to score RT-induced lung injury accurately. Higher rates of pneumonitis have also been associated with a variety of "low-tech" predictors such as chemotherapy exposure, male gender, low pre-RT clinical performance status, field size, and fraction size (4Graham M.V. Purdy J.A. Emami B. et al.Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small-cell lung cancer (NSCLC).Int J Radiat Oncol Biol Phys. 1999; 45: 323-329Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar, 13Robnett T.J. Factors predicting severe radiation pneumonitis in patients receiving definitive chemoradiation for lung cancer.Int J Radiat Oncol Biol Phys. 2000; 48: 89-94Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 17Yamada M. Kudoh S. Hirata K. et al.Risk factors of pneumonitis following chemoradiotherapy for lung cancer.Eur J Cancer. 1998; 34: 71-75Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 18Robert F. Childs H.A. Spencer S.A. et al.Phase I/IIa study of concurrent paclitaxel and cisplatin with radiation therapy in locally advanced non-small cell lung cancer Analysis of early and late pulmonary morbidity.Semin Radiat Oncol. 1999; 9: 136-147PubMed Google Scholar, 19Lee J.S. Scott C. Komaki R. et al.Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small-cell lung cancer Radiation Therapy Oncology Group protocol 91-06.J Clin Oncol. 1996; 14: 1055-1064Crossref PubMed Scopus (166) Google Scholar, 20Roach III, M. Gandara D.R. Yuo H.S. et al.Radiation pneumonitis following combined modality therapy for lung cancer Analysis of prognostic factors.J Clin Oncol. 1995; 13: 2606-2612Crossref PubMed Scopus (241) Google Scholar, 21Byhardt R.W. Martin L. Pajak T.F. et al.The influence of field size and other treatment factors on pulmonary toxicity following hyperfractionated irradiation for inoperable non-small-cell lung cancer (NSCLC)—Analysis of a Radiation Therapy Oncology Group (RTOG) protocol.Int J Radiat Oncol Biol Phys. 1993; 27: 537-544Abstract Full Text PDF PubMed Scopus (80) Google Scholar, 22Brooks Jr, B.J. Seifter E.J. Walsh T.E. et al.Pulmonary toxicity with combined modality therapy for limited stage small-cell lung cancer.J Clin Oncol. 1986; 4: 200-209Crossref PubMed Scopus (63) Google Scholar).Yorke et al. (1Yorke E.D. Jackson A. Rosenzweig K.E. et al.Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 2002; 54: 329-339Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar) divided the lung into superior and inferior approximate halves. They reported that the mean dose to the inferior lung half was far more predictive for pneumonitis than was the dose to the superior lung half. Others have noted that pneumonitis is more common in patients with lower vs. upper lobe tumors (4Graham M.V. Purdy J.A. Emami B. et al.Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small-cell lung cancer (NSCLC).Int J Radiat Oncol Biol Phys. 1999; 45: 323-329Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar). Similarly, Wennberg et al. (23Wennberg B. Gagliardi G. Sundbom L. et al.Early response of lung in breast cancer irradiation Radiologic density changes measured by CT and symptomatic radiation pneumonitis.Int J Radiat Oncol Biol Phys. 2002; 52: 1196-1206Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar) studied the relationship between RT-induced changes in CT-defined regional lung density and symptomatic pneumonitis in patients irradiated for breast cancer. Symptoms correlated better with changes in density in the anterior regions of the central lung (the portion included within tangent photon fields or en-face electron fields) than with density changes in the lung apex (because of photon treatment of the supraclavicular region).In a series of elegant mouse experiments, Travis and colleagues demonstrated that the target cells for radiation pneumonitis were preferentially distributed in the inferior and superior regions of the lung and that irradiating the central lung was physiologically less consequential (24Travis E.L. Liao Z. Tucker S.L. Spatial heterogeneity of the volume effect for radiation pneumonitis in mouse lung.Int J Radiat Oncol Biol Phys. 1997; 38: 1045-1054Abstract Full Text PDF PubMed Scopus (66) Google Scholar, 25Tucker S.L. Liao Z. Travis E.L. Estimation of the spatial distribution of target cells for radiation pneumonitis in mouse lung.Int J Radiat Oncol Biol Phys. 1997; 38: 1055-1066Abstract Full Text PDF PubMed Scopus (55) Google Scholar). Travis et al. used CT images to define the lung volumes. The contours of the lung on axial images through the vicinity of the hilum likely included the airways, thus overestimating the volume of "functioning lung". As stated by Travis et al. "the proportion of alveoli to non-gas-exchange structures (i.e., conducting airways) will be critical in determining the dose-volume relationship for morbidity from pneumonitis." It is possible that the inclusion of much of the proximal conducting airways within the CT-defined superior lung might, in part, explain Yorke's observation that the dose to the superior lung is not predictive of pneumonitis. Although Yorke defined the lung halves geometrically, rather than anatomically, the plane dividing the lung was typically below or at the inferior region of the hilum (Yorke ED, personal communication, 2002).An additional possibility to explain the relative lack of importance of dose to the superior lung half is that lung cancers often cause reduced perfusion in adjacent lung tissue that remains visually grossly normal on CT, presumably from compression of the regional vessels. Irradiation, or resection, of such hypofunctional areas is less likely to have a negative impact on whole lung function than is treatment to similarly sized regions of perfused lung (26Marks L.B. Hollis D. Munley M. et al.The role of lung perfusion imaging in predicting the direction of radiation-induced changes in pulmonary function tests.Cancer. 2000; 88: 2135-2141Crossref PubMed Scopus (40) Google Scholar, 27Choi N.C. Kanarek D.J. Kazemi H. Physiologic changes in pulmonary function after thoracic radiotherapy for patients with lung cancer and role of regional pulmonary function studies in predicting post-radiotherapy pulmonary function before radiotherapy.Cancer Treat Symptoms. 1985; 2: 119-130Google Scholar, 28Abratt R.P. Willcox P.A. Smith J.A. Lung cancer in patients with borderline lung functions Zonal lung perfusion scans at presentation and lung function after high dose irradiation.Radiother Oncol. 1990; 19: 317-322Abstract Full Text PDF PubMed Scopus (69) Google Scholar, 29Wernley J.A. DeMeester T.R. Kirchner P.T. et al.Clinical value of quantitative ventilation Perfusion lung scans in the surgical management of bronchogenic carcinoma.J Thorac Cardiovasc. 1980; 80: 535-543PubMed Google Scholar). Since most of the tumors in the patients of Yorke et al. (1Yorke E.D. Jackson A. Rosenzweig K.E. et al.Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 2002; 54: 329-339Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar) were in the superior regions of the lung, such hypoperfused areas were probably more prevalent in the superior, than in the inferior, lung. Therefore, the dose to the CT-defined superior lung would be less physiologically relevant than the dose to the inferior lung. Furthermore, the mean dose to the inferior lung may be a barometer for incidental cardiac irradiation that may increase a patient's risk of developing pulmonary symptoms. Because the heart is located in the inferior portion of the thorax in mice, incidental cardiac irradiation may partly explain the observation of Travis et al. as well. In a recent study with rats (in which the heart is located in the superior left hemithorax), irradiation of the superior or left lung was more functionally consequential than similar treatment to the right or inferior lung (30Jiresova A. Wiegman E.M. Kampinga H.H. et al.Dose-volume-region effects in partial irradiation of rat lung. 2002; ([Abstract]: Programs and Abstract, Radiation Research Society and North American Hyperthermia Society): 114Google Scholar). Additional study of the role of cardiac irradiation on "pulmonary" toxicity is needed.Compared with CT, single photon emission CT (SPECT) lung perfusion scans may provide an improved definition of the "functioning lung," because it images the alveolar capillary network. We have found that the SPECT perfusion-weighted mean lung dose correlated better with pneumonitis than the CT-defined mean lung dose (16Lind P.A. Marks L.B. Hollis D. et al.Utility of receiver operator curves (ROC) in assessing predictors of radiation-induced symptomatic lung injury.Int J Radiat Oncol Biol Phys. 2002; 54: 340-347Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Analysis of the mean dose to the superior and inferior SPECT-defined lung halves might help to study this issue better. Theuws et al. (31Theuws J.C.M. Seppenwoolde Y. Kwa S.L.S. et al.Changes in local pulmonary injury up to 48 months after irradiation for lymphoma and breast cancer.Int J Radiat Oncol Biol Phys. 2000; 47: 1201-1208Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 32Theuws J.C. Kwa S.L. Wagenaar A.C. et al.Dose-effect relations for early local pulmonary injury after irradiation for malignant lymphoma and breast cancer.Radiother Oncol. 1998; 48: 33-43Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar) at the Netherlands Cancer Institute reported regional differences in RT-induced dose-dependent changes in regional perfusion, ventilation, and tissue density. Inherent biologic/physiologic differences between the superior and inferior lung (33Khan M.A. van Dyk J. Hipp R.P. Unilateral lower lung irradiation. 2002; ([Abstract]. Programs and Abstract, Radiation Research Society and North American Hyperthermia Society): 175Google Scholar, 34Moiseenko V.V. Battista J.J. Hill R.P. et al.In-field and out-of-field effects in partial volume lung radiation in rodents Possible correlations between early DNA damage and functional end points.Int J Radiat Oncol Biol Phys. 2000; 48: 1539-1548Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), such as a more favorable perfusion/ventilation ratio in the latter (35West J.B. Corylee P.A. Respiratory physiology—The essentials. 5th ed. Williams & Wilkins, Baltimore1995Google Scholar), may help to explain these observations. DVHs discard spatial information and hence implicitly assume that function is uniformly distributed. Possible regional differences in "functional-density" and radiation-response challenge a foundation of DVHs.In summary, the report by Yorke et al. (1Yorke E.D. Jackson A. Rosenzweig K.E. et al.Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 2002; 54: 329-339Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar) is encouraging, because it confirms that dosimetric parameters derived from 3D planning systems can be predictive of RT-induced lung injury. The observation that the dose to the inferior lung may be more clinically relevant than the dose to the upper lung is interesting, warrants further study, and highlights a potential shortcoming of DVHs. In this issue, Yorke et al. (1Yorke E.D. Jackson A. Rosenzweig K.E. et al.Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 2002; 54: 329-339Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar) from the Memorial Sloan-Kettering Cancer Center describe an association between the dosimetric parameters from the lung dose-volume histogram (DVH) and the incidence of radiation (RT)-induced lung injury. They report that the incidence of Grade 3 or greater pneumonitis correlated well with the mean lung dose, the percentage of lung receiving at least 20 Gy, and parameter estimates from DVH-reduction schemes. This study, involving 49 patients with non-small-cell lung cancer, is consistent with several other clinical studies summarized in Table 1 (2Martel M. Dose volume histogram and 3D treatment planning evalution of patients with pneumonitis.Int J. Radiat Oncol Biol Phys. 1994; 28: 575-581Abstract Full Text PDF PubMed Scopus (252) Google Scholar, 3Oetzel D. Schraube P. Hensley F. et al.Estimation of pneumonitis risk in three-dimensional treatment planning using dose-volume histogram analysis.Int J Radiat Oncol Biol Phys. 1995; 33: 455-460Abstract Full Text PDF PubMed Scopus (191) Google Scholar, 4Graham M.V. Purdy J.A. Emami B. et al.Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small-cell lung cancer (NSCLC).Int J Radiat Oncol Biol Phys. 1999; 45: 323-329Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar, 5Kwa S.L. Lebesque J.V. Theuws J.C. et al.Radiation pneumonitis as a function of mean lung dose An analysis of pooled data of 540 patients.Int J Radiat Oncol Biol Phys. 1998; 42: 1-9Abstract Full Text Full Text PDF PubMed Scopus (645) Google Scholar, 6Hernando M.L. Marks L.B. Bentel G.C. et al.Radiation induced pulmonary toxicity A dose-volume histogram analysis in 201 patients with lung cancer.Int J Radiat Oncol Biol Phys. 2001; 51: 650-659Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar). The findings of each of these studies suggest that dose/volume parameters are important determinants of RT-induced lung injury. In concert, these encouraging studies demonstrate the ability of three-dimensional (3D) tools to predict normal tissue risks. Figure 1 illustrates the association between the mean lung dose and the rate of pneumonitis reported in five studies (including Yorke et al.). Abbreviations: NTCP = normal tissue complication probability; Vdose = percent of lung receiving at least that dose; quart. = quartile. Some of the patients in Hernando et al. 6Hernando M.L. Marks L.B. Bentel G.C. et al.Radiation induced pulmonary toxicity A dose-volume histogram analysis in 201 patients with lung cancer.Int J Radiat Oncol Biol Phys. 2001; 51: 650-659Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar were included in the pooled analysis of Kwa et al. 5Kwa S.L. Lebesque J.V. Theuws J.C. et al.Radiation pneumonitis as a function of mean lung dose An analysis of pooled data of 540 patients.Int J Radiat Oncol Biol Phys. 1998; 42: 1-9Abstract Full Text Full Text PDF PubMed Scopus (645) Google Scholar. Adapted from Hernando et al. 6Hernando M.L. Marks L.B. Bentel G.C. et al.Radiation induced pulmonary toxicity A dose-volume histogram analysis in 201 patients with lung cancer.Int J Radiat Oncol Biol Phys. 2001; 51: 650-659Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar. Before outlining some of the limitations of these predictive models, let us take a moment to bask in this exciting observation. Our field is rapidly embracing high technologic methods, such as 3D planning, to care for an increasing proportion of our patients. It is nice to know that the additional information provided by 3D tools is useful in predicting outcome. Predictive models for lung injury are particularly important, given the high incidence of lung cancer and RT-induced lung injury. Furthermore, it is likely more difficult to develop predictive models for the lung than for many other organs. There are marked interpatient differences in pre-RT overall lung function and the degree of spatial variation in regional lung function (e.g., because of tumor or preexisting lung diseases such as emphysema) that make modeling the lung particularly challenging. Thus, the predictive abilities of metrics such as the mean lung dose, that do not consider any of these interpatient differences, is hopeful. In the future, I anticipate that reasonably accurate methods to predict normal tissue and tumor outcomes will be available. Encouraging normal tissue predictive models based on other 3D dosimetric data have been suggested for several organs, including the brain, rectum, liver, parotid, and esophagus. A variety of different dosimetric parameters have been related to RT-induced lung injury (Table 1). It is not known which, if any, of these parameters are superior. This cannot be adequately assessed because the different dosimetric parameters are highly correlated with each other (4Graham M.V. Purdy J.A. Emami B. et al.Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small-cell lung cancer (NSCLC).Int J Radiat Oncol Biol Phys. 1999; 45: 323-329Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar, 7Kwa S.L.S. Theuws J.C.M. Wagenaar A. et al.Evaluation of two dose-volume histogram reduction models for the prediction of radiation pnemonitis.Radiother Oncol. 1998; 48: 61-69Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 8Fan M. Marks L.B. Hollis D. et al.Can we predict radiation-induced changes in pulmonary function based on the sum of predicted regional dysfunction?.J Clin Oncol. 2001; 19: 543-550Crossref PubMed Scopus (70) Google Scholar). This correlation occurs because a relatively uniform treatment technique is typically used in each individual study. Thus, it is likely that the predictive ability of at least some metrics will be technique-dependent. The existing data were generated from patients largely treated with conventional techniques and doses. Their validity in the realm of high-dose/IMRT is unknown. It is intuitive that metrics based on the entire DVH (e.g., mean lung dose) may be better predictors than metrics derived from only a single point on the DVH (e.g. V20), although, to my knowledge, this has not yet been demonstrated. Dosimetric parameters alone are not ideal predictors for lung injury. As seen in Table 1, most patients in the "high-risk" subgroups did not develop symptoms. Furthermore, symptoms develop in a significant proportion of the patients in the more favorable subgroups. One needs to be careful in defining cutpoints for segregating patients into high- versus low-risk groups. Using such cutpoints, the sensitivity and specificity of the predictive models are both never very good. For example, when one raises the threshold for defining high risk, the positive predictive value will increase, but the sensitivity and negative predictive value will decrease. Consider Graham's data and the cutpoint of V20 Gy at 40%. Among the patients who had a V20 > 40%, 36% developed pneumonitis. However, approximately one-half of the patients with pneumonitis in that series had a lower V20 Gy, resulting in a sensitivity of approximately 50% (4Graham M.V. Purdy J.A. Emami B. et al.Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small-cell lung cancer (NSCLC).Int J Radiat Oncol Biol Phys. 1999; 45: 323-329Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar). Predictive models that include functional information, such as pre-RT pulmonary function and biologic determinants of radiation sensitivity (e.g., transforming growth factor-β and/or interleukin-6) might be better (9Marks L.B. Munley M.P. Bentel G.C. et al.Physical and biological predictors of changes in whole lung function following thoracic irradiation.Int J Radiat Oncol Biol Phys. 1997; 39: 563-570Abstract Full Text PDF PubMed Scopus (199) Google Scholar, 10Fu X. Huang H. 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Fan M. Hollis D. et al.Dosimetric and/or functional predictors of RT-induced pulmonary injury A comparison using receiver operating characteristic curves.Int J Radiat Oncol Biol Phys. 2001; 3 (ASTRO 43rd Annual Meeting, San Francisco, CA, Nov. 3–7, 2001.): 50Abstract Full Text Full Text PDF Google Scholar, 16Lind P.A. Marks L.B. Hollis D. et al.Utility of receiver operator curves (ROC) in assessing predictors of radiation-induced symptomatic lung injury.Int J Radiat Oncol Biol Phys. 2002; 54: 340-347Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). In these patients, the models may be less accurate, their underlying lung disease may predispose them to injury, or it may be more difficult to score RT-induced lung injury accurately. Higher rates of pneumonitis have also been associated with a variety of "low-tech" predictors such as chemotherapy exposure, male gender, low pre-RT clinical performance status, field size, and fraction size (4Graham M.V. Purdy J.A. 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Walsh T.E. et al.Pulmonary toxicity with combined modality therapy for limited stage small-cell lung cancer.J Clin Oncol. 1986; 4: 200-209Crossref PubMed Scopus (63) Google Scholar). Yorke et al. (1Yorke E.D. Jackson A. Rosenzweig K.E. et al.Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 2002; 54: 329-339Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar) divided the lung into superior and inferior approximate halves. They reported that the mean dose to the inferior lung half was far more predictive for pneumonitis than was the dose to the superior lung half. Others have noted that pneumonitis is more common in patients with lower vs. upper lobe tumors (4Graham M.V. Purdy J.A. Emami B. et al.Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small-cell lung cancer (NSCLC).Int J Radiat Oncol Biol Phys. 1999; 45: 323-329Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar). Similarly, Wennberg et al. (23Wennberg B. Gagliardi G. Sundbom L. et al.Early response of lung in breast cancer irradiation Radiologic density changes measured by CT and symptomatic radiation pneumonitis.Int J Radiat Oncol Biol Phys. 2002; 52: 1196-1206Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar) studied the relationship between RT-induced changes in CT-defined regional lung density and symptomatic pneumonitis in patients irradiated for breast cancer. Symptoms correlated better with changes in density in the anterior regions of the central lung (the portion included within tangent photon fields or en-face electron fields) than with density changes in the lung apex (because of photon treatment of the supraclavicular region). In a series of elegant mouse experiments, Travis and colleagues demonstrated that the target cells for radiation pneumonitis were preferentially distributed in the inferior and superior regions of the lung and that irradiating the central lung was physiologically less consequential (24Travis E.L. Liao Z. Tucker S.L. Spatial heterogeneity of the volume effect for radiation pneumonitis in mouse lung.Int J Radiat Oncol Biol Phys. 1997; 38: 1045-1054Abstract Full Text PDF PubMed Scopus (66) Google Scholar, 25Tucker S.L. Liao Z. Travis E.L. Estimation of the spatial distribution of target cells for radiation pneumonitis in mouse lung.Int J Radiat Oncol Biol Phys. 1997; 38: 1055-1066Abstract Full Text PDF PubMed Scopus (55) Google Scholar). Travis et al. used CT images to define the lung volumes. The contours of the lung on axial images through the vicinity of the hilum likely included the airways, thus overestimating the volume of "functioning lung". As stated by Travis et al. "the proportion of alveoli to non-gas-exchange structures (i.e., conducting airways) will be critical in determining the dose-volume relationship for morbidity from pneumonitis." It is possible that the inclusion of much of the proximal conducting airways within the CT-defined superior lung might, in part, explain Yorke's observation that the dose to the superior lung is not predictive of pneumonitis. Although Yorke defined the lung halves geometrically, rather than anatomically, the plane dividing the lung was typically below or at the inferior region of the hilum (Yorke ED, personal communication, 2002). An additional possibility to explain the relative lack of importance of dose to the superior lung half is that lung cancers often cause reduced perfusion in adjacent lung tissue that remains visually grossly normal on CT, presumably from compression of the regional vessels. Irradiation, or resection, of such hypofunctional areas is less likely to have a negative impact on whole lung function than is treatment to similarly sized regions of perfused lung (26Marks L.B. Hollis D. Munley M. et al.The role of lung perfusion imaging in predicting the direction of radiation-induced changes in pulmonary function tests.Cancer. 2000; 88: 2135-2141Crossref PubMed Scopus (40) Google Scholar, 27Choi N.C. Kanarek D.J. Kazemi H. 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Rosenzweig K.E. et al.Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 2002; 54: 329-339Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar) were in the superior regions of the lung, such hypoperfused areas were probably more prevalent in the superior, than in the inferior, lung. Therefore, the dose to the CT-defined superior lung would be less physiologically relevant than the dose to the inferior lung. Furthermore, the mean dose to the inferior lung may be a barometer for incidental cardiac irradiation that may increase a patient's risk of developing pulmonary symptoms. Because the heart is located in the inferior portion of the thorax in mice, incidental cardiac irradiation may partly explain the observation of Travis et al. as well. In a recent study with rats (in which the heart is located in the superior left hemithorax), irradiation of the superior or left lung was more functionally consequential than similar treatment to the right or inferior lung (30Jiresova A. Wiegman E.M. Kampinga H.H. et al.Dose-volume-region effects in partial irradiation of rat lung. 2002; ([Abstract]: Programs and Abstract, Radiation Research Society and North American Hyperthermia Society): 114Google Scholar). Additional study of the role of cardiac irradiation on "pulmonary" toxicity is needed. Compared with CT, single photon emission CT (SPECT) lung perfusion scans may provide an improved definition of the "functioning lung," because it images the alveolar capillary network. We have found that the SPECT perfusion-weighted mean lung dose correlated better with pneumonitis than the CT-defined mean lung dose (16Lind P.A. Marks L.B. Hollis D. et al.Utility of receiver operator curves (ROC) in assessing predictors of radiation-induced symptomatic lung injury.Int J Radiat Oncol Biol Phys. 2002; 54: 340-347Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Analysis of the mean dose to the superior and inferior SPECT-defined lung halves might help to study this issue better. Theuws et al. (31Theuws J.C.M. Seppenwoolde Y. Kwa S.L.S. et al.Changes in local pulmonary injury up to 48 months after irradiation for lymphoma and breast cancer.Int J Radiat Oncol Biol Phys. 2000; 47: 1201-1208Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 32Theuws J.C. Kwa S.L. Wagenaar A.C. et al.Dose-effect relations for early local pulmonary injury after irradiation for malignant lymphoma and breast cancer.Radiother Oncol. 1998; 48: 33-43Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar) at the Netherlands Cancer Institute reported regional differences in RT-induced dose-dependent changes in regional perfusion, ventilation, and tissue density. Inherent biologic/physiologic differences between the superior and inferior lung (33Khan M.A. van Dyk J. Hipp R.P. Unilateral lower lung irradiation. 2002; ([Abstract]. Programs and Abstract, Radiation Research Society and North American Hyperthermia Society): 175Google Scholar, 34Moiseenko V.V. Battista J.J. Hill R.P. et al.In-field and out-of-field effects in partial volume lung radiation in rodents Possible correlations between early DNA damage and functional end points.Int J Radiat Oncol Biol Phys. 2000; 48: 1539-1548Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), such as a more favorable perfusion/ventilation ratio in the latter (35West J.B. Corylee P.A. Respiratory physiology—The essentials. 5th ed. Williams & Wilkins, Baltimore1995Google Scholar), may help to explain these observations. DVHs discard spatial information and hence implicitly assume that function is uniformly distributed. Possible regional differences in "functional-density" and radiation-response challenge a foundation of DVHs. In summary, the report by Yorke et al. (1Yorke E.D. Jackson A. Rosenzweig K.E. et al.Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 2002; 54: 329-339Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar) is encouraging, because it confirms that dosimetric parameters derived from 3D planning systems can be predictive of RT-induced lung injury. The observation that the dose to the inferior lung may be more clinically relevant than the dose to the upper lung is interesting, warrants further study, and highlights a potential shortcoming of DVHs. Thanks to Donna Wimberley for secretarial assistance and Drs. Mitchell Anscher, Leonard Prosnitz, Edward Halperin, and Sumin Zhou for their comments and suggestions.