ONCOLOGY. Vol. 22 No. 1

Pages: 1 2

REVIEW ARTICLE

Radiation-Induced Lung Injury: Assessment, Management, and Prevention

By Paiman Ghafoori, MD¹, Lawrence B. Marks, MD², Zeljko Vujaskovic, MD, PhD³, Christopher R. Kelsey, MD⁴ | January 1, 2008

¹Resident ²Professor and Residency Program Director ³Associate Professor ⁴Assistant Professor, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina

Lung Tolerance and Predicting Injury

Whole-Lung Irradiation

Irradiation of both lungs occurs in multiple clinical contexts including total-body irradiation (TBI) as part of the preparative regimen for stem cell transplants, hemibody irradiation in the setting of diffuse symptomatic metastatic disease, and whole-lung irradiation for pulmonary metastases from various malignancies. Clinical experience in these settings has permitted the tolerance of whole-lung irradiation to be estimated.

FIGURE 4

Pneumonitis, Chemotherapy, and RT Fractionation

• Single Fraction—With single-fraction whole-lung irradiation, the risk of pneumonitis is dependent on dose-rate and whether chemotherapy is also prescribed. The risk of pneumonitis is decreased with low dose-rate schedules (eg, 5–25 cGy/min, typical of TBI) compared with higher dose-rate schedules (400 cGy/min, typical of hemibody irradiation and whole-lung irradiation).[28] Furthermore, the addition of chemotherapy shifts the dose-response curve to the left (Figure 4). The dose-response curve for whole-lung irradiation is steep, such that a difference of only 1 to 2 Gy increases the risk of pneumonitis substantially. The development of pneumonitis after TBI is an ominous sign, proving fatal in up to 80% of patients.[29]

• Multiple Fractions—Two randomized studies of prophylactic, fractionated whole-lung irradiation—one with chemotherapy[30] and the other without[31]—utilized doses of 15 to 17.5 Gy. Lung density corrections were not utilized in either study; thus, the true total physical doses delivered were likely in the neighborhood of 17 to 20 Gy. No cases of pneumonitis were reported in either trial. A retrospective study of whole-lung irradiation for a variety of tumor histologies, mostly pediatric malignancies, reported no cases of pneumonitis after doses ranging from 15 to 25 Gy.[32] Furthermore, in several retrospective studies in which TBI was utilized in the preparative regimen prior to stem cell transplant, the risk of pneumonitis appeared to be lower with fractionation.[33-35]

These studies suggest that fractionated RT is better tolerated by the lungs. In two randomized studies comparing single-fraction TBI with fractionated TBI, the investigators found no difference in the risk of pneumonitis (viral plus idiopathic), but there were fewer cases of idiopathic pneumonitis with fractionation.[36,37] Most TBI regimens are now fractionated and are associated with low rates of pneumonitis.

Partial-Lung Irradiation

FIGURE 5

Pneumonitis and Dosimetric Parameters

• Conventional Fractionation—Most patients receiving partial-lung irradiation undergo fractionated regimens. Determining tolerance doses and accurately predicting the risk of RT-associated pulmonary toxicity after partial-lung irradiation is challenging. Multiple parameters have been associated with an increased risk of developing symptomatic pneumonitis, including underlying lung disease,[19,38] decreased baseline pulmonary function,[19,39] low performance status,[19,39] female gender,[39] lower lobe tumors,[40,41] and history of smoking.[19] However, these findings have been inconsistent across studies, and none of these parameters have been found to be a robust and reliable risk factor for the development of RT-induced lung injury. Similarly, biochemical markers such as TGF-β have not been consistently predictive and are not currently utilized in routine clinical practice.

TABLE 3

Incidence of Pneumonitis Based on Dosimetric Parameters

Conversely, multiple dosimetric parameters have consistently been correlated with an increased risk of acute pneumonitis, including mean lung dose[38,40,42-47] and the percentage of lung receiving a specified amount of radiation (Table 3, Figures 5 and 6).[40,42,44,48,49] These parameters are readily extractable from either a dose-volume histogram (DVH) or treatment planning software.

Traditional DVHs assume that all regions of the lung contribute equally to pulmonary function, which is often an erroneous assumption since many patients have heterogeneous regional lung function (eg, from tumor or COPD). Furthermore, metrics such as the V20 or V30 (volume of lung receiving at least 20 or 30 Gy, respectively), consider only a single point on the cumulative DVH. Mean lung dose (MLD) might be a preferable metric because it considers the entire 3D dose distribution. In most series, however, the majority of patients are treated to MLDs in the lower aspect of the range shown. Thus, even though the incidence of pneumonitis is less when the MLD is lower, the absolute number of patients with pneumonitis derived from the low-MLD group is relatively high (Figure 6). In this regard, MLD is not particularly sensitive (ie, it does not predict a high fraction of pneumonitis cases).

FIGURE 6

Pneumonitis and Mean Lung Dose

In practice it is not practical to determine which parameter (MLD vs V20) is truly "optimal" since there tends to be a strong correlation between the different dosimetric parameters, at least with relatively uniform treatment techniques.[40,45,50] Kong et al concluded that the parameters predictive for acute pneumonitis and late fibrosis are largely similar.[45]

• Hypofractionation—There is increasing interest in the application of stereotactic body radiation therapy (SBRT) for medically inoperable stage I non–small-cell lung carcinoma (NSCLC) and oligometastases involving the lung. SBRT consists of only a few large (14–20 Gy) fractions given over 5 to 10 days. A representative fractionation scheme is 60 Gy in three fractions. Such biologically potent doses are feasible because only small volumes are treated with highly conformal fields, thereby creating steep dose gradients and minimizing high doses to surrounding critical structures.

Most patients develop increased tissue density on CT in the high-dose region after SBRT.[51,52] This finding can be difficult to differentiate from persistent or progressive tumor. Symptoms consistent with radiation pneumonitis have occurred in 4% to 25% of patients.[53-55] Serious, and sometimes lethal, pulmonary toxicity has been associated with the treatment of perihilar/central tumors.[56] Dose guidelines for SBRT are in a state of rapid flux as the number of clinical reports appears to be rapidly increasing. Currently used fractionation schemes of 20 Gy × 3,[55] 12 Gy × 4,[54] and 10 Gy × 5[57] appear to provide a reasonable therapeutic ratio for small lesions.

• Intensity-Modulated Radiation Therapy—Intensity-modulated radiation therapy (IMRT) facilitates conformal treatment of irregularly shaped and concave targets. This is especially useful for targets adjacent to critical structures. However, IMRT planning usually delivers lower doses of radiation to larger volumes of surrounding normal tissue. The impact of large-volume/low-dose lung irradiation in the context of curative treatment of lung cancer is not known.

The M.D. Anderson Cancer Center recently published the largest clinical experience using IMRT in 68 patients with lung cancer.[58] In this report, the incidence of grade ≥ 3 radiation pneumonitis was significantly lower in patients treated with IMRT vs a comparison group treated with conventional 3D-conformal RT (8% vs 32% at 12 months, P = .002). In the IMRT group, patients with V5 values (volume of lung receiving more than 5 Gy) greater than 70% appeared to be at higher risk of pneumonitis. Other dosimetric parameters (MLD, V20) were not assessed for their association with pneumonitis. Conversely, a smaller report from Memorial Sloan-Kettering Cancer Center noted a slightly higher rate of pneumonitis in 35 patients with inoperable stage III NSCLC treated with IMRT vs 3D-conformal RT (11% vs 5%, respectively, P = NS).[59] Additional experience is necessary to confirm the safety and efficacy of IMRT for lung cancer.

Another important application of IMRT is postoperative treatment of malignant mesothelioma after extrapleural pneumonectomy. An initial report from the M.D. Anderson Cancer Center reported a low rate of lethal radiation pneumonitis (1.6%, 1/62).[60] However, of 13 patients treated with IMRT at the Dana-Farber Cancer Institute, 6 experienced lethal radiation pneumonitis (46%, 6/13).[61] The mean lung dose was 15 Gy for patients who developed pneumonitis (all lethal) vs 13 Gy for those who did not (P = .07). Similarly, the V20 was 18% for patients who developed pneumonitis vs 11% for those who did not (P = .08). In a reanalysis of the same data, fatal pulmonary toxicities (whether previously ascribed to RT or not) were noted to have occurred in 10% of patients. These events were more common in patients with higher V20 values.[62] While IMRT may be particularly suited for the concave targets encountered with the postoperative treatment of mesothelioma, dose to the contralateral lung must be minimized.

Recommended Dose/Volume Constraints

TABLE 4

Recommended Dose-Volume Constraints

The lung is one of the most challenging organs for which to define strict dose/volume constraints, for several reasons. Coexisting diseases (eg, COPD) produce marked interpatient variation in pre-RT lung function, and this must be taken into account in the planning process. On the other hand, there is often tumor-related compromise of pulmonary function, especially with large central tumors, such that lung function may actually improve after treatment. Finally, in order to appropriately treat large tumors, it is sometimes necessary to utilize large RT fields irrespective of baseline function, with the understanding that pulmonary function may decline. Thus, patients need to be carefully counseled about the potential risks of lung injury and the uncertainty in defining individual risk. With these caveats in mind, there are nevertheless some broad guidelines that can be useful clinically (Table 4).

It is important to optimize a patient's medical condition by treating any reversible process (bronchospasm, infection, ischemic heart disease, pulmonary embolus, pleural effusion), particularly in those with poor baseline lung function. The use of elective nodal irradiation is controversial. While we do advocate rational elective nodal irradiation, this should be restricted in cases where lung function is significantly compromised. In patients with central lesions and PFTs of concern, assessment of regional perfusion/ventilation (eg, with SPECT) can be helpful to determine if regional tumor effect is contributing to poor lung function. The University of Michigan has developed a technique for prescribing RT dose based on the estimated risk of injury to the lung, such that a group of patients can be treated at a relatively uniform risk (by using nonuniform doses).[45]

Prevention

TABLE 5

Randomized Trials of Amifostine(Drug information on amifostine)

Amifostine (Ethyol) is a thio-organic prodrug that is believed to scavenge harmful free radicals produced by the interaction of ionizing radiation and water molecules. The utility of amifostine in patients receiving RT for lung cancer has been assessed in multiple randomized studies and a meta-analysis (Table 5).[63] The largest study was performed by the Radiation Therapy Oncology Group.[64] The incidence of grade ≥ 3 pulmonary toxicity was not statistically different between patients receiving amifostine and those who did not. This study has been criticized because the drug was administered once daily (4 d/wk) and the RT was delivered twice daily (5 d/wk), and thus 60% of the RT fractions were delivered without the protector. Conversely, there are several single-institutional randomized trials suggesting a protective effect of amifostine.[65-68]

Such mixed results, combined with the acute toxicities of amifostine (eg, nausea/vomiting, hypotension, infection, rash), have dissuaded many from using the agent in routine practice. Another compound with potential is pentoxifylline(Drug information on pentoxifylline), an immunomodulator that is used primarily for patients with intermittent claudication. One small randomized study demonstrated a smaller decline in DLCO as well as reduced perfusion defects and chest x-ray abnormalities in patients receiving pentoxifylline.[69] However, pentoxifylline is not currently used in routine clinical practice. Keratinocyte growth factor has been suggested in animal studies to protect against RT-induced lung injury.[70]

Chemotherapy

REFERENCE GUIDE

Therapeutic Agents
Mentioned in This Article

Amifostine (Ethyol)
Bleomycin
Carboplatin(Drug information on carboplatin)
Cisplatin
Docetaxel (Taxotere)
Doxorubicin(Drug information on doxorubicin)
Etoposide(Drug information on etoposide)
Mitomycin
Paclitaxel(Drug information on paclitaxel)
Pentoxifylline

Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

Many chemotherapeutic agents have known pulmonary toxicities[71] and may exacerbate RT-induced alveolar/capillary injury. Combinations of RT and chemotherapeutic agents with known pulmonary toxicity have generally been associated with higher rates of radiation pneumonitis, including mitomycin,[38] bleomycin(Drug information on bleomycin),[72] and docetaxel(Drug information on docetaxel) (Taxotere).[73] Interestingly, chemotherapeutic drugs that do not normally induce significant pulmonary toxicity may nonetheless potentiate the toxic effects of RT. For example, in a small series of 24 lung cancer patients treated with 40 Gy of RT concurrent with doxorubicin (10 mg/m²), 13 (54%) developed radiation pneumonitis. Fortunately, the chemotherapeutic agents most commonly used with RT for lung cancer, such as cisplatin(Drug information on cisplatin), carboplatin, paclitaxel, and etoposide, have not consistently been shown to increase the risk of pneumonitis.[39,40,42,74]

Conclusions

RT-induced lung injury continues to be a relevant complication of thoracic RT. The molecular pathways culminating in clinically apparent injury continue to be elucidated and may reveal more effective therapeutic and prophylactic interventions. Our ability to predict an individual's risk of developing radiation pneumonitis is imperfect and relies largely on dosimetric parameters. More predictive methods are needed and are the subject of active research. Our clinical experience with newer RT techniques such as IMRT and SBRT is limited, and investigation of RT-induced lung injury using these modalities is ongoing.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

Acknowledgements: Special thanks to Jessica Hubbs and Lauren Jackson for their assistance in preparing the manuscript and figures.

Pages: 1 2

This article reviewed

Can Patient Reporting Affect Radiation Pneumonitis?

BENJAMIN MOVSAS, MD, INDRIN CHETTY, PhD, and MUNTHER AJLOUNI, MD

1. Marks LB: The pulmonary effects of thoracic irradiation. Oncology (Williston Park) 8:89-106, 1994.

2. Bentzen SM: Preventing or reducing late side effects of radiation therapy: Radiobiology meets molecular pathology. Nat Rev Cancer 6:702-713, 2006.

3. Mikkelsen RB, Wardman P: Biological chemistry of reactive oxygen and nitrogen and radiation-induced signal transduction mechanisms. Oncogene 22:5734-5754, 2003.

4. Fleckenstein K, Zgonjanin L, Chen L, et al: Temporal onset of hypoxia and oxidative stress after pulmonary irradiation. Int J Radiat Oncol Biol Phys 68:196-204, 2007.

5. Jackson IL, Batinic-Haberle I, Sonveaux P, et al: ROS production and angiogenic regulation by macrophages in response to heat therapy. Int J Hyperthermia 22:263-273, 2006.

6. Novakova-Jiresova A, van Luijk P, van Goor H, et al: Changes in expression of injury after irradiation of increasing volumes in rat lung. Int J Radiat Oncol Biol Phys 67:1510-1518, 2007.

7. Vujaskovic Z, Anscher MS, Feng QF, et al: Radiation-induced hypoxia may perpetuate late normal tissue injury. Int J Radiat Oncol Biol Phys 50:851-855, 2001.

8. Miller KL, Shafman TD, Anscher MS, et al: Bronchial stenosis: An underreported complication of high-dose external beam radiotherapy for lung cancer? Int J Radiat Oncol Biol Phys 61:64-69, 2005.

9. Speiser BL, Spratling L: Radiation bronchitis and stenosis secondary to high dose rate endobronchial irradiation. Int J Radiat Oncol Biol Phys 25:589-597, 1993.

10. Nag S, Kelly JF, Horton JL, et al: Brachytherapy for carcinoma of the lung. Oncology (Williston Park) 15:371-381, 2001.

11. Wheater's Functional Histology, 3rd ed. London, Churchill Livingstone, 1993.

12. Rubin P, Shapiro DL, Finklestein JN, et al: The early release of surfactant following lung irradiation of alveolar type II cells. Int J Radiat Oncol Biol Phys 6:75-77, 1980.

13. Allavena C, Conroy T, Aletti P, et al: Late cardiopulmonary toxicity after treatment for Hodgkin's disease. Br J Cancer 65:908-912, 1992.

14. Bell J, McGivern D, Bullimore J, et al: Diagnostic imaging of post-irradiation changes in the chest. Clin Radiol 39:109-119, 1988.

15. Kelsey CR, Kahn D, Hollis DR, et al: Radiation-induced narrowing of the tracheobronchial tree: An in-depth analysis. Lung Cancer 52:111-116, 2006.

16. Kocak Z, Evans ES, Zhou SM, et al: Challenges in defining radiation pneumonitis in patients with lung cancer. Int J Radiat Oncol Biol Phys 62:635-638, 2005.

17. Salinas FV, Winterbauer RH: Radiation pneumonitis: A mimic of infectious pneumonitis. Semin Respir Infect 10:143-153, 1995.

18. Marks LB, Fan M, Clough R, et al: Radiation-induced pulmonary injury: Symptomatic versus subclinical endpoints. Int J Radiat Biol 76:469-475, 2000.

19. Monson JM, Stark P, Reilly JJ, et al: Clinical radiation pneumonitis and radiographic changes after thoracic radiation therapy for lung carcinoma. Cancer 82:842-850, 1998.

20. Skoczylas JZ, Bentzen SM, Overgaard M, et al: Time course of radiological lung density changes after postmastectomy radiotherapy. Acta Oncol 39:181-187, 2000.

21. Koenig TR, Munden RF, Erasmus JJ, et al: Radiation injury of the lung after three-dimensional conformal radiation therapy. AJR Am J Roentgenol 178:1383-1388, 2002.

22. Theuws JC, Kwa SL, Wagenaar AC, et al: Dose-effect relations for early local pulmonary injury after irradiation for malignant lymphoma and breast cancer. Radiother Oncol 48:33-43, 1998.

23. Kocak Z, Marks LB: Radiation-induced lung injury, in Perez CA, Bradey LW, Halperin EC, et al (eds): Principles and Practice of Radiation Oncology, vol 1, 4th ed. New York, Lippincott Williams & Wilkins, 2005.

24. Theuws JC, Seppenwoolde Y, Kwa SL, et al: Changes in local pulmonary injury up to 48 months after irradiation for lymphoma and breast cancer. Int J Radiat Oncol Biol Phys 47:1201-1208, 2000.

25. Woel RT, Munley MT, Hollis D, et al: The time course of radiation therapy-induced reductions in regional perfusion: A prospective study with >5 years of follow-up. Int J Radiat Oncol Biol Phys 52:58-67, 2002.

26. Myers JN, O'Neil KM, Walsh TE, et al: The pulmonary status of patients with limited-stage small cell lung cancer 15 years after treatment with chemotherapy and chest irradiation. Chest 128:3261-3268, 2005.

27. Miller KL, Zhou SM, Barrier RC Jr, et al: Long-term changes in pulmonary function tests after definitive radiotherapy for lung cancer. Int J Radiat Oncol Biol Phys 56:611-615, 2003.

28. Keane TJ, Van Dyk J, Rider WD: Idiopathic interstitial pneumonia following bone marrow transplantation: The relationship with total body irradiation. Int J Radiat Oncol Biol Phys 7:1365-1370, 1981.

29. Fryer CJ, Fitzpatrick PJ, Rider WD, et al: Radiation pneumonitis: Experience following a large single dose of radiation. Int J Radiat Oncol Biol Phys 4:931-936, 1978.

30. Rab GT, Ivins JC, Childs DS Jr, et al: Elective whole lung irradiation in the treatment of osteogenic sarcoma. Cancer 38:939-942, 1976.

31. Breur K, Cohen P, Schweisguth O, et al: Irradiation of the lungs as an adjuvant therapy in the treatment of osteosarcoma of the limbs. An EORTC randomized study. Eur J Cancer 14:461-471, 1978.

32. Newton KA, Spittle MF: An analysis of 40 cases treated by total thoracic irradiation. Clin Radiol 20:19-22, 1969.

33. Cosset JM, Baume D, Pico JL, et al: Single dose versus hyperfractionated total body irradiation before allogeneic bone marrow transplantation: A non-randomized comparative study of 54 patients at the Institut Gustave-Roussy. Radiother Oncol 15:151-160, 1989.

34. Pino y Torres JL, Bross DS, Lam WC, et al: Risk factors in interstitial pneumonitis following allogenic bone marrow transplantation. Int J Radiat Oncol Biol Phys 8:1301-1307, 1982.

35. Shank B, Chu FC, Dinsmore R, et al: Hyperfractionated total body irradiation for bone marrow transplantation. Results in seventy leukemia patients with allogeneic transplants. Int J Radiat Oncol Biol Phys 9:1607-1611, 1983.

36. Deeg HJ, Sullivan KM, Buckner CD, et al: Marrow transplantation for acute nonlymphoblastic leukemia in first remission: Toxicity and long-term follow-up of patients conditioned with single dose or fractionated total body irradiation. Bone Marrow Transplant 1:151-157, 1986.

37. Girinsky T, Benhamou E, Bourhis JH, et al: Prospective randomized comparison of single-dose versus hyperfractionated total-body irradiation in patients with hematologic malignancies. J Clin Oncol 18:981-986, 2000.

38. Rancati T, Ceresoli GL, Gagliardi G, et al: Factors predicting radiation pneumonitis in lung cancer patients: A retrospective study. Radiother Oncol 67:275-283, 2003.

39. Robnett TJ, Machtay M, Vines EF, et al: Factors predicting severe radiation pneumonitis in patients receiving definitive chemoradiation for lung cancer. Int J Radiat Oncol Biol Phys 48:89-94, 2000.

40. Graham MV, Purdy JA, 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 45:323-329, 1999.

41. Seppenwoolde Y, De Jaeger K, Boersma LJ, et al: Regional differences in lung radiosensitivity after radiotherapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 60:748-758, 2004.

42. Hernando ML, Marks LB, Bentel GC, et al: Radiation-induced pulmonary toxicity: A dose-volume histogram analysis in 201 patients with lung cancer. Int J Radiat Oncol Biol Phys 51:650-659, 2001.

43. Kwa SL, Lebesque JV, Theuws JC, 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 42:1-9, 1998.

44. Kim TH, Cho KH, Pyo HR, et al: Dose-volumetric parameters for predicting severe radiation pneumonitis after three-dimensional conformal radiation therapy for lung cancer. Radiology 235:208-215, 2005.

45. Kong FM, Hayman JA, Griffith KA, et al: Final toxicity results of a radiation-dose escalation study in patients with non-small-cell lung cancer (NSCLC): Predictors for radiation pneumonitis and fibrosis. Int J Radiat Oncol Biol Phys 65:1075-1086, 2006.

46. Oetzel 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 33:455-460, 1995.

47. Yorke ED, Jackson A, Rosenzweig KE, 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 54:329-339, 2002.

48. Tsujino K, Hirota S, Endo M, et al: Predictive value of dose-volume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer. Int J Radiat Oncol Biol Phys 55:110-115, 2003.

49. Willner J, Jost A, Baier K, et al: A little to a lot or a lot to a little? An analysis of pneumonitis risk from dose-volume histogram parameters of the lung in patients with lung cancer treated with 3-D conformal radiotherapy. Strahlenther Onkol 179:548-556, 2003.

50. Fan M, Marks LB, Hollis D, et al: Can we predict radiation-induced changes in pulmonary function based on the sum of predicted regional dysfunction? J Clin Oncol 19:543-550, 2001.

51. Hof H, Herfarth KK, Munter M, et al: Stereotactic single-dose radiotherapy of stage I non-small-cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 56:335-341, 2003.

52. Kyas I, Hof H, Debus J, et al: Prediction of radiation-induced changes in the lung after stereotactic body radiation therapy of non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 67:768-774, 2007.

53. Hoyer M, Roed H, Hansen AT, et al: Prospective study on stereotactic radiotherapy of limited-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 66:S128-135, 2006.

54. Nagata Y, Takayama K, Matsuo Y, et al: Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame. Int J Radiat Oncol Biol Phys 63:1427-1431, 2005.

55. Timmerman R, Papiez L, McGarry R, et al: Extracranial stereotactic radioablation: Results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 124:1946-1955, 2003.

56. Timmerman R, McGarry R, Yiannoutsos C, et al: Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 24:4833-4839, 2006.

57. Xia T, Li H, Sun Q, et al: Promising clinical outcome of stereotactic body radiation therapy for patients with inoperable stage I/II non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 66:117-125, 2006.

58. Yom SS, Liao Z, Liu HH, et al: Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 68:94-102, 2007.

59. Rosenzweig K, Gupta V, Jackson A, et al: Intensity-modulated radiation therapy for inoperable stage III non-small-cell lung cancer (abstract 58). Oncology (Williston Park) 20(suppl 5):21, 2006.

60. Stevens C, Forster K, Zhu X, et al: Excellent local control and survival after extrapleural pneumonectomy and IMRT for mesothelioma. Int J Radiat Oncol Biol Phys 63:S103, 2005.

61. Allen AM, Czerminska M, Janne PA, et al: Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma. Int J Radiat Oncol Biol Phys 65:640-645, 2006.

62. Rice D, Liao Z, Vaporciyan AA, et al: V20 predicts fatal pulmonary toxicity after extrapleural pneumonectomy and intensity modulated radiation therapy (abstract). Int J Radiat Oncol Biol Phys 66:S63, 2006.

63. Sasse AD, Clark LG, Sasse EC, et al: Amifostine reduces side effects and improves complete response rate during radiotherapy: Results of a meta-analysis. Int J Radiat Oncol Biol Phys 64:784-791, 2006.

64. Movsas B, Scott C, Langer C, et al: Randomized trial of amifostine in locally advanced non-small-cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: Radiation Therapy Oncology Group trial 98-01. J Clin Oncol 23:2145-2154, 2005.

65. Antonadou D, Coliarakis N, Synodinou M, et al: Randomized phase III trial of radiation treatment +/- amifostine in patients with advanced-stage lung cancer. Int J Radiat Oncol Biol Phys 51:915-922, 2001.

66. Antonadou D, Throuvalas N, Petridis A, et al: Effect of amifostine on toxicities associated with radiochemotherapy in patients with locally advanced non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 57:402-408, 2003.

67. Komaki R, Lee JS, Milas L, et al: Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non-small-cell lung cancer: Report of a randomized comparative trial. Int J Radiat Oncol Biol Phys 58:1369-1377, 2004.

68. Leong SS, Tan EH, Fong KW, et al: Randomized double-blind trial of combined modality treatment with or without amifostine in unresectable stage III non-small-cell lung cancer. J Clin Oncol 21:1767-1774, 2003.

69. Ozturk B, Egehan I, Atavci S, et al: Pentoxifylline in prevention of radiation-induced lung toxicity in patients with breast and lung cancer: A double-blind randomized trial. Int J Radiat Oncol Biol Phys 58:213-219, 2004.

70. Chen L, Brizel DM, Rabbani ZN, et al: The protective effect of recombinant human keratinocyte growth factor on radiation-induced pulmonary toxicity in rats. Int J Radiat Oncol Biol Phys 60:1520-1529, 2004.

71. Meadors M, Floyd J, Perry MC: Pulmonary toxicity of chemotherapy. Semin Oncol 33:98-105, 2006.

72. Einhorn L, Krause M, Hornback N, et al: Enhanced pulmonary toxicity with bleomycin and radiotherapy in oat cell lung cancer. Cancer 37:2414-2416, 1976.

73. Kouroussis C, Mavroudis D, Kakolyris S, et al: High incidence of pulmonary toxicity of weekly docetaxel and gemcitabine in patients with non-small cell lung cancer: Results of a dose-finding study. Lung Cancer 44:363-368, 2004.

74. Hope AJ, Lindsay PE, El Naqa I, et al: Modeling radiation pneumonitis risk with clinical, dosimetric, and spatial parameters. Int J Radiat Oncol Biol Phys 65:112-124, 2006.

75. Lind PA, Bylund H, Wennberg B, et al: Abnormalities on chest radiographs following radiation therapy for breast cancer. Eur Radiol 10:484-489, 2000.

76. Borst GR, De Jaeger K, Belderbos JS, et al: Pulmonary function changes after radiotherapy in non-small-cell lung cancer patients with long-term disease-free survival. Int J Radiat Oncol Biol Phys 62:639-644, 2005.

77. Choi NC, Kanarek DJ: Toxicity of thoracic radiotherapy on pulmonary function in lung cancer. Lung Cancer 10(suppl 1):S219-S230, 1994.

78. Abratt RP, Willcox PA: The effect of irradiation on lung function and perfusion in patients with lung cancer. Int J Radiat Oncol Biol Phys 31:915-919, 1995.

79. Fay M, Tan A, Fisher R, et al: Dose-volume histogram analysis as predictor of radiation pneumonitis in primary lung cancer patients treated with radiotherapy. Int J Radiat Oncol Biol Phys 61:1355-1363, 2005.

80. Wang S, Liao Z, Wei X, et al: Analysis of clinical and dosimetric factors associated with treatment-related pneumonitis (TRP) in patients with non-small-cell lung cancer (NSCLC) treated with concurrent chemotherapy and three-dimensional conformal radiotherapy (3D-CRT). Int J Radiat Oncol Biol Phys 66:1399-1407, 2006.

81. Marks LB, Yu X, Vujaskovic Z, et al: Radiation-induced lung injury. Semin Radiat Oncol 13:333-345, 2003.

82. Sampath S, Schultheiss TE, Wong J: Dose response and factors related to interstitial pneumonitis after bone marrow transplant. Int J Radiat Oncol Biol Phys 63:876-884, 2005.

83. Marks LB, Ma J: Challenges in the clinical application of advanced technologies to reduce radiation-associated normal tissue injury. Int J Radiat Oncol Biol Phys 69:4-12, 2007.