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• W2043284501 abstract "Purpose: To create, on the basis of available data, a mathematical model to describe the tumor stage- and field size-dependent risks/benefits of postoperative radiotherapy (PORT) for non–small-cell lung cancer (NSCLC), and to assess whether this simple model can accurately describe the reported changes in overall survival.Methods and Materials: The increase in overall survival afforded by PORT is assumed equal to the increase in cancer-specific survival minus the rate of RT-induced mortality. The increase in cancer-specific survival is the product of the probabilities of (residual local disease) × (sterilization of residual disease with PORT) × (absence of metastatic disease). Data were extracted from the literature to estimate these probabilities. Different models were considered to relate the RT-induced mortality to field size.Results: The rate of RT-induced mortality seems to be proportional to the cube of the field size. When these mortality rates are included in the model, the predicted changes in overall survival approximate the literature values.Conclusion: Clinical data can be explained by a simple model that suggests that RT-induced mortality is strongly dependent on field size and at least partly offsets the benefit afforded by PORT. Smaller RT fields, tailored to treat the areas most at risk for recurrence, provide the highest therapeutic ratio. The data used do not reflect the impact of chemotherapy, which will reduce the rate of distant metastases and enhance the efficacy of RT. Purpose: To create, on the basis of available data, a mathematical model to describe the tumor stage- and field size-dependent risks/benefits of postoperative radiotherapy (PORT) for non–small-cell lung cancer (NSCLC), and to assess whether this simple model can accurately describe the reported changes in overall survival. Methods and Materials: The increase in overall survival afforded by PORT is assumed equal to the increase in cancer-specific survival minus the rate of RT-induced mortality. The increase in cancer-specific survival is the product of the probabilities of (residual local disease) × (sterilization of residual disease with PORT) × (absence of metastatic disease). Data were extracted from the literature to estimate these probabilities. Different models were considered to relate the RT-induced mortality to field size. Results: The rate of RT-induced mortality seems to be proportional to the cube of the field size. When these mortality rates are included in the model, the predicted changes in overall survival approximate the literature values. Conclusion: Clinical data can be explained by a simple model that suggests that RT-induced mortality is strongly dependent on field size and at least partly offsets the benefit afforded by PORT. Smaller RT fields, tailored to treat the areas most at risk for recurrence, provide the highest therapeutic ratio. The data used do not reflect the impact of chemotherapy, which will reduce the rate of distant metastases and enhance the efficacy of RT. IntroductionPostoperative radiotherapy (PORT) for non–small-cell lung cancer (NSCLC) is controversial. The PORT meta-analysis convincingly demonstrated that PORT, as delivered in the studies included in the meta-analysis, increases mortality, despite an improvement in local control (1PORT Meta-analysis Trialists GroupPostoperative radiotherapy in non-small-cell lung cancer: Systematic review and meta-analysis of individual patient data from nine randomised controlled trials.Lancet. 1998; 352: 257-263Abstract Full Text Full Text PDF PubMed Scopus (834) Google Scholar). The findings were stage dependent, with the most unfavorable therapeutic ratio in early-stage patients. These findings are supported by a recent analysis of data from the Surveillance, Epidemiology, and End Results registry and the Adjuvant Navelbine International Trialist Association trials (2Lally B.E. Zelterman D. Colasanto J.M. et al.Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the Surveillance, Epidemiology, and End Results database.J Clin Oncol. 2006; 24: 2998-3006Crossref PubMed Scopus (401) Google Scholar, 3Douillard J.Y. Rosell R. De Lena M. et al.Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): A randomised controlled trial.Lancet Oncol. 2006; 7: 719-727Abstract Full Text Full Text PDF PubMed Scopus (1321) Google Scholar); however, in these populations, RT was not assigned in a randomized fashion. Further, the impact of PORT seems to be dependent on the RT field size. The field sizes used in the studies included in the PORT analysis were relatively large. Two recent randomized trials not included in the PORT meta-analysis, using smaller and/or more conformal PORT fields, have suggested a favorable therapeutic ratio for PORT.Using the data from the published randomized trials, we estimated the field size and stage dependence of the therapeutic benefits and normal tissue risks of PORT. We herein present a simple mathematical model and assess whether it can reasonably describe the reported clinical data. This model is constructed with the fundamental assumption that the differences between the studies included in the meta-analysis and the two more recently published series are largely due to field size. There are additional factors that might also account for the differing results (e.g., cobalt vs. linear accelerators, more modern staging, fraction size, beam orientation, number of fields treated per day) that are not considered.Methods and MaterialsSummary and interpretation of published clinical trialsThe PORT meta-analysis included 2,128 patients with Stages I–III NSCLC enrolled onto nine studies. The typical RT field included the bronchial stump, ipsilateral hilum, and the mediastinum. In a majority of the studies a lateral field was used in addition to anteroposterior/posteroanterior fields. With a median follow-up of 4 years, there was an overall survival detriment of 7% (55% vs. 48%) with the addition of PORT. These detrimental effects were seen primarily in patients with Stages I–II disease (N0/1). There was no appreciable effect of RT, either negative or positive, in those with Stage III (N2) disease.The observed changes in overall survival reflect the competing effects of improvements in cancer-specific survival and RT-induced mortality. Thus, for the Stage I patients, PORT must have caused an excess death rate of at least 7%. Because the RT field sizes used for the higher-stage patients would typically be at least as large as those used for the Stage I patients, the RT-associated mortality for Stage III patients was likely approximately the same 7%. This rate may have been slightly higher than 7% if one assumes that the RT field sizes were larger for the Stage III vs. the earlier-stage patients. Alternatively, because the Stage III patients were more likely to die from progressive disease, the absolute risk of RT-associated mortality may have been slightly lower owing to competing risks. In the meta-analysis, the overall net zero effect of PORT on overall survival in the Stage III patients suggests that PORT provides a stage-specific increase in cancer-specific survival that was offset by PORT-associated mortality.Conversely, more recent randomized data suggest an improvement in both local control and overall survival with PORT using smaller, more customized RT fields. This difference provides an opportunity to quantify the impact of field size on the outcomes of tumor control and toxicity.Mayer et al. (4Mayer R. Smolle-Juettner F.M. Szolar D. et al.Postoperative radiotherapy in radically resected non-small cell lung cancer.Chest. 1997; 112: 954-959Crossref PubMed Scopus (107) Google Scholar) reported a single-institution study of 155 patients with completely resected T1–3, N0–2, M0 NSCLC randomized to 50–56 Gy delivered in 2-Gy fractions to the bronchial stump, ipsilateral hilum, and mediastinum. Ipsilateral supraclavicular nodes were included for apical tumors. Conformal RT techniques were used with an anteroposterior/posteroanterior field arrangement with spinal cord blocking after 42 Gy. Chemotherapy was not used concurrently or sequentially. There was a trend toward increased 5-year recurrence-free survival rate, 27.1% vs. 15.6% (p = 0.07), with vs. without PORT. The corresponding overall survival rates at 5 years were 29.7% vs. 20.4%, but the difference was not statistically significant. Summary data by pathologic nodal stage are presented in Table 1.Table 1Outcome data from Mayer et al. (4Mayer R. Smolle-Juettner F.M. Szolar D. et al.Postoperative radiotherapy in radically resected non-small cell lung cancer.Chest. 1997; 112: 954-959Crossref PubMed Scopus (107) Google Scholar)Node statusNo. of patients5-y local control (S + RT vs. S alone)5-y overall survival (S + RT vs. S alone)pN02896% vs. 87%, p > 0.0560% vs 32%, p > 0.05pN15992% vs. 74%, p > 0.0542% vs 22%, p > 0.05pN26896% vs. 73%, p < 0.05⁎Statistically significant.45% vs 41%, p > 0.05Abbreviations: S = surgery; RT = radiotherapy. Statistically significant. Open table in a new tab Trodella et al. (5Trodella L. Granone P. Valente S. et al.Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: Definitive results of a phase III randomized trial.Radiother Oncol. 2002; 62: 11-19Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar) reported a single-institution Phase III prospective randomized trial of PORT or no PORT in 104 patients with completely resected pathologic Stage I NSCLC. The median number of resected nodes was 20. Radiation consisted of 50.4 Gy in 1.8-Gy fractions to the bronchial stump and ipsilateral hilum (51 patients) (i.e., without purposeful irradiation of the mediastinum). Chemotherapy was not used concurrently or sequentially. With a median follow-up of 63 months, the local recurrence rate with and without RT was 2% and 23% (p = 0.0019), and the corresponding disease-free survival rate was significantly improved at 71% vs. 60% (p = 0.039). The corresponding overall survival was also significantly improved at 67% vs. 58%, respectively (p = 0.048).The published data from the PORT meta-analysis and the two more recent randomized studies (4Mayer R. Smolle-Juettner F.M. Szolar D. et al.Postoperative radiotherapy in radically resected non-small cell lung cancer.Chest. 1997; 112: 954-959Crossref PubMed Scopus (107) Google Scholar, 5Trodella L. Granone P. Valente S. et al.Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: Definitive results of a phase III randomized trial.Radiother Oncol. 2002; 62: 11-19Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 6Van Houtte P. Rocmans P. Smets P. et al.Postoperative radiation therapy in lung caner: A controlled trial after resection of curative design.Int J Radiat Oncol Biol Phys. 1980; 6: 983-986Abstract Full Text PDF PubMed Scopus (200) Google Scholar, 7The Lung Cancer Study GroupEffects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung.N Engl J Med. 1986; 315: 1377-1381Crossref PubMed Scopus (417) Google Scholar, 8Lafitte J.J. Ribet M.E. Prevost B.M. et al.Postresection irradiation for T2 N0 M0 non-small cell carcinoma: A prospective, randomized study.Ann Thorac Surg. 1996; 62: 830-834Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 9Stephens R.J. Girling D.J. Bleehen N.M. et al.Medical Research Council Lung Cancer Working PartyThe role of post-operative radiotherapy in non-small-cell lung cancer: A multicentre randomised trial in patients with pathologically staged T1-2, N1-2, M0 disease.Br J Cancer. 1996; 74: 632-639Crossref PubMed Scopus (176) Google Scholar, 10Dautzenberg B. Arriagada R. Chammard A.B. et al.Groupe d’Etude et de Traitement des Cancers BronchiquesA controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma.Cancer. 1999; 86: 265-273Crossref PubMed Scopus (235) Google Scholar, 11Debevec M. Bitenc M. Vidmar S. et al.Postoperative radiotherapy for radically resected N2 non-small-cell lung cancer (NSCLC): Randomised clinical study 1988-1992.Lung Cancer. 1996; 14: 99-107Abstract Full Text PDF PubMed Scopus (83) Google Scholar) are summarized in Table 2.Table 2Randomized/published data from PORT meta-analysis and subsequent studiesStudyStageLocal failure, S vs. S + RT (%)Survival, S vs. S + RT (%)Average field size (cm)Clinical target volumePORT meta-analysis studies (GETBC trials combined; unpublished data omitted) Belgium (6Van Houtte P. Rocmans P. Smets P. et al.Postoperative radiation therapy in lung caner: A controlled trial after resection of curative design.Int J Radiat Oncol Biol Phys. 1980; 6: 983-986Abstract Full Text PDF PubMed Scopus (200) Google Scholar)N019 vs. 4 ( crude)43 vs. 24 (5 y)15 × 19M LCSG (7The Lung Cancer Study GroupEffects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung.N Engl J Med. 1986; 315: 1377-1381Crossref PubMed Scopus (417) Google Scholar)II/III19 vs. 1⁎Crude, first failures only.41 vs. 41 (4 y)NSBS, IH, M Lille (8Lafitte J.J. Ribet M.E. Prevost B.M. et al.Postresection irradiation for T2 N0 M0 non-small cell carcinoma: A prospective, randomized study.Ann Thorac Surg. 1996; 62: 830-834Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar)T2N019 vs. 15 ( crude)52 vs. 35 (5 y)12 × 12IH, M MRC (9Stephens R.J. Girling D.J. Bleehen N.M. et al.Medical Research Council Lung Cancer Working PartyThe role of post-operative radiotherapy in non-small-cell lung cancer: A multicentre randomised trial in patients with pathologically staged T1-2, N1-2, M0 disease.Br J Cancer. 1996; 74: 632-639Crossref PubMed Scopus (176) Google Scholar)T1–2, N1-268 vs. 57 (5 y)20 vs. 21 (5 y)NSBS, IH, CH, M GETCB 04CB86/05CB88 (10Dautzenberg B. Arriagada R. Chammard A.B. et al.Groupe d’Etude et de Traitement des Cancers BronchiquesA controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma.Cancer. 1999; 86: 265-273Crossref PubMed Scopus (235) Google Scholar)I–III34 vs. 28 (5 y)43 vs. 30 (5 y)NSBS, IH, M, SC Slovenia (11Debevec M. Bitenc M. Vidmar S. et al.Postoperative radiotherapy for radically resected N2 non-small-cell lung cancer (NSCLC): Randomised clinical study 1988-1992.Lung Cancer. 1996; 14: 99-107Abstract Full Text PDF PubMed Scopus (83) Google Scholar)T1–3, N0-216 vs. 28†Estimated from published graph.28 vs. 33 (5 y)12 × 9IH, MPost-PORT meta-analysis studies Mayer et al. (4Mayer R. Smolle-Juettner F.M. Szolar D. et al.Postoperative radiotherapy in radically resected non-small cell lung cancer.Chest. 1997; 112: 954-959Crossref PubMed Scopus (107) Google Scholar)T1–3, N0-224 vs. 6 ( crude)20 vs. 30 (5 y)NSBS, IH, M, SC Trodella et al. (5Trodella L. Granone P. Valente S. et al.Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: Definitive results of a phase III randomized trial.Radiother Oncol. 2002; 62: 11-19Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar)T1–2, N023 vs. 2 ( crude)58 vs. 67 (5 y)6.5 × 7BS, IHAbbreviations: PORT = postoperative radiotherapy; S = surgery; GETBC = Groupe d’Etude et de Traitement des Cancers Bronchiques; M = mediastinum; LCSG = Lung Cancer Study Group; NS = not specified; BS = bronchial stump; IH = ipsilateral hilum; MRC = Medical Research Council; CH = contralateral hilum; SC = supraclavicular fossa. Crude, first failures only.† Estimated from published graph. Open table in a new tab Thus, the more recent randomized data indicate that limiting the RT field to include the areas most at risk for relapse and using conformal techniques to minimize incidental irradiation of nontarget tissues may decrease the risk of radiation-induced morbidity and improve the therapeutic ratio (12Liu H.H. Wang X. Dong L. et al.Feasibility of sparing lung and other thoracic structures with intensity-modulated radiotherapy for non-small-cell lung cancer.Int J Radiat Oncol Biol Phys. 2004; 58: 1268-1279Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar). The model below computes the field-size dependence of RT-associated mortality and tumor control from these clinical data.Summary of the modelWe constructed a logical, simple, and reasonable mathematical model to characterize the impact of PORT on local control, morbidity, and overall survival. The field-size dependence of these effects was extrapolated from the available data.The increase in overall survival afforded by PORT is assumed to be equal to the increase in cancer-specific survival minus the rate of RT-induced mortality:Overall Survival Increase=(Cancer Specific SurvivalIncrease)−(PORT Mortality).(1) Further, the increase in cancer-specific survival can be approximated as the product of three probabilities, as shown:Overall Survival Increase=(Probability of residual disease)×(Probability of PORT sterilizing residual disease)×(Probability of absence of metastatic disease).(2) Combining Eqs. 1 and 2 yields Eq. 3:Overall Survival Increase=(Probability of residual disease)×(Probability of PORT sterilizing residual disease)×(Probability of absence of metastatic disease)−(PORT Mortality).(3) Equation 3 was then rewritten six times, for large and smaller/customized fields, each applied to the pN0, N1, and N2 situations. Each of the six situations are represented by a row in Table 3. The various parameters from Eq. 3 are listed as the headings of the columns in Table 3. We then attempted to solve these six equations simultaneously to assess whether the model-based estimates for PORT-associated changes in overall survival would approximate that reported in the literature. The values for the various parameters in the six equations were estimated from available randomized clinical data, as follows.Table 3Field size/stage dependence of PORT effect on local control and overall survivalField sizePathologic nodal statusExtracted from the literatureModel-based computed probability of improving cancer-specific survival with PORT (overall)Estimated mortality of PORT (field-size dependent)Model-based computed resultant increase in OS with PORT (%)⁎Values represent improvements in overall survival, negative values are declines.Literature-reported change in OS with PORT (1PORT Meta-analysis Trialists GroupPostoperative radiotherapy in non-small-cell lung cancer: Systematic review and meta-analysis of individual patient data from nine randomised controlled trials.Lancet. 1998; 352: 257-263Abstract Full Text Full Text PDF PubMed Scopus (834) Google Scholar, 10Dautzenberg B. Arriagada R. Chammard A.B. et al.Groupe d’Etude et de Traitement des Cancers BronchiquesA controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma.Cancer. 1999; 86: 265-273Crossref PubMed Scopus (235) Google Scholar, 12Liu H.H. Wang X. Dong L. et al.Feasibility of sparing lung and other thoracic structures with intensity-modulated radiotherapy for non-small-cell lung cancer.Int J Radiat Oncol Biol Phys. 2004; 58: 1268-1279Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar) (%)Probability of postoperative residual disease (14Martini N. Burt M.E. Bains M.S. et al.Survival after resection of stage II non-small cell lung cancer.Ann Thorac Surg. 1992; 54 (discussion 466): 460-465Abstract Full Text PDF PubMed Scopus (164) Google Scholar)Probability of local/regional control with PORT (9Stephens R.J. Girling D.J. Bleehen N.M. et al.Medical Research Council Lung Cancer Working PartyThe role of post-operative radiotherapy in non-small-cell lung cancer: A multicentre randomised trial in patients with pathologically staged T1-2, N1-2, M0 disease.Br J Cancer. 1996; 74: 632-639Crossref PubMed Scopus (176) Google Scholar, 10Dautzenberg B. Arriagada R. Chammard A.B. et al.Groupe d’Etude et de Traitement des Cancers BronchiquesA controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma.Cancer. 1999; 86: 265-273Crossref PubMed Scopus (235) Google Scholar, 12Liu H.H. Wang X. Dong L. et al.Feasibility of sparing lung and other thoracic structures with intensity-modulated radiotherapy for non-small-cell lung cancer.Int J Radiat Oncol Biol Phys. 2004; 58: 1268-1279Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 15Hernando 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)Probability of no metastatic disease (16Kwa 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)LargeN00.20.90.60.1080.15†Reference 1.−4.2−7N10.30.90.40.1080.15†Reference 1.−4.2NRN20.750.90.20.1350.15†Reference 1.−1.50CustomizedN00.20.750.60.0900.00+9.09–20N10.30.750.40.0900.014+7.616N20.750.900.20.1350.13+0.55Abbreviations: PORT = postoperative radiotherapy; OS = overall survival; NR = not reported; ns = not significant. Values represent improvements in overall survival, negative values are declines.† Reference 1PORT Meta-analysis Trialists GroupPostoperative radiotherapy in non-small-cell lung cancer: Systematic review and meta-analysis of individual patient data from nine randomised controlled trials.Lancet. 1998; 352: 257-263Abstract Full Text Full Text PDF PubMed Scopus (834) Google Scholar. Open table in a new tab Estimation of model parametersThe probability of residual disease was assumed to be stage-dependent and was estimated from the postoperative local/regional failure rates reported without PORT in the control arm of the studies by Dautzenberg et al. (10Dautzenberg B. Arriagada R. Chammard A.B. et al.Groupe d’Etude et de Traitement des Cancers BronchiquesA controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma.Cancer. 1999; 86: 265-273Crossref PubMed Scopus (235) Google Scholar), as well as the more recent data from Trodella et al. (5Trodella L. Granone P. Valente S. et al.Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: Definitive results of a phase III randomized trial.Radiother Oncol. 2002; 62: 11-19Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar) and Mayer et al. (4Mayer R. Smolle-Juettner F.M. Szolar D. et al.Postoperative radiotherapy in radically resected non-small cell lung cancer.Chest. 1997; 112: 954-959Crossref PubMed Scopus (107) Google Scholar). These values were stage-dependent but independent of field size.The probability of sterilizing residual is assumed to be related to the RT field size. For the large-field situation, the probability of sterilizing residual disease was estimated from the PORT meta-analysis, because large fields were typically used in the studies included in the meta-analysis (Table 2). This single value was applied to all stages. To estimate the impact of smaller RT field sizes on the local/regional recurrence rate, data were considered from a recent patterns-of-failure analysis (13Kelsey C.R. Light K.L. Marks L.B. Patterns of failure after resection of non-small-cell lung cancer: Implications for postoperative radiation therapy volumes.Int J Radiat Oncol Biol Phys. 2006; 65: 1097-1105Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). In that analysis, the pattern of failure after surgical resection was based on both the site of initial disease and the initial stage. Figure 1 shows an example recurrence pattern figure from that article for an initially-resected lesion in the right upper lobe. Similar data for primary lesions in each lobe were presented.On the basis of the patterns of failure data for all lobes, one can estimate the percentage of local/regional recurrences that could potentially have been prevented for varying field sizes (e.g., bronchial stump alone, stump and hilum, stump/hilum/mediastinum). These data, along with similar local control data from Trodella et al. (5Trodella L. Granone P. Valente S. et al.Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: Definitive results of a phase III randomized trial.Radiother Oncol. 2002; 62: 11-19Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar) and Mayer et al. (4Mayer R. Smolle-Juettner F.M. Szolar D. et al.Postoperative radiotherapy in radically resected non-small cell lung cancer.Chest. 1997; 112: 954-959Crossref PubMed Scopus (107) Google Scholar) are shown in Fig. 2 and can be used to estimate the field-size dependence of the utility of PORT in preventing local/regional failures. On the basis of these data, we estimated that 75% of local/regional recurrences could potentially be prevented with smaller/customized fields in N0 and N1 patients, and 90% could be prevented with larger fields that would approximate the coverage used in the PORT meta-analysis studies.Fig. 2Chart of the percent of patients in which gradually enlarging radiotherapy fields would have covered all sites of local/regional recurrent disease, and local control percentages from more recent studies. Data from Kelsey et al. (13Kelsey C.R. Light K.L. Marks L.B. Patterns of failure after resection of non-small-cell lung cancer: Implications for postoperative radiation therapy volumes.Int J Radiat Oncol Biol Phys. 2006; 65: 1097-1105Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar), Mayer et al. (4Mayer R. Smolle-Juettner F.M. Szolar D. et al.Postoperative radiotherapy in radically resected non-small cell lung cancer.Chest. 1997; 112: 954-959Crossref PubMed Scopus (107) Google Scholar), and Trodella et al. (5Trodella L. Granone P. Valente S. et al.Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: Definitive results of a phase III randomized trial.Radiother Oncol. 2002; 62: 11-19Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). PORT = postoperative radiotherapy.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The probability of no metastatic disease was estimated according to the ultimate cure rate reported by Martini et al. (14Martini N. Burt M.E. Bains M.S. et al.Survival after resection of stage II non-small cell lung cancer.Ann Thorac Surg. 1992; 54 (discussion 466): 460-465Abstract Full Text PDF PubMed Scopus (164) Google Scholar), because most deaths are due to systemic relapse. This value was assumed to be stage dependent but independent of field size.The mortality of PORT is difficult to extract from the available clinical data. The mortality rate ascribed to large-field PORT was assumed to be independent of stage and, as noted above, is likely ≥7%. Smaller RT fields are almost certainly associated with a lower rate of mortality than are larger fields. To estimate the impact of smaller/conformal RT field sizes on RT-induced mortality, we considered summary data relating surrogates of field size to RT-induced cardiopulmonary injury. For example, Fig. 3a illustrates data from four centers reporting the relationship between the rate of steroid-requiring radiation pneumonitis (Radiation Therapy Oncology Group Grade ≥3) and mean lung dose (15Hernando 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, 16Kwa 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, 17Yorke 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, 18Rancati T. Ceresoli G.L. Gagliardi G. et al.Factors predicting pneumonitis in lung cancer patients: A retrospective study.Radiother Oncol. 2003; 67: 275-283Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar, 19Kim T.H. Cho K.H. Pyo H.R. et al.Dose-volumetric parameters for predicting severe radiation pneumonitis after three-dimensional conformal radiation therapy for lung cancer.Radiology. 2005; 235: 208-215Crossref PubMed Scopus (123) Google Scholar). Similar unpublished data from Duke University Medical Center relating pericarditis to the mean heart dose are shown in Fig. 3b (20Marks L.B. Kocak Z. Zhou S. et al.The association between mean heart dose, mean lung dose, tumor location, and RT-associated heart and lung toxicity.Int J Radiat Oncol Biol Phys. 2005; 63 ([Abstract]): S42Abstract Full Text Full Text PDF Google Scholar). According to these data, there seems to be very steep volume dependence for such toxicities. For both, the rate of toxicity is fairly well approximated by a graph of y = x3.Fig. 3(a) Correlation between mean lung dose and rate of steroid-requiring (Radiation Therapy" @default.
• W2043284501 created "2016-06-24" @default.
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• W2043284501 date "2007-07-01" @default.
• W2043284501 modified "2023-10-17" @default.
• W2043284501 title "Estimating the Magnitude and Field-Size Dependence of Radiotherapy-Induced Mortality and Tumor Control After Postoperative Radiotherapy For Non–Small-Cell Lung Cancer: Calculations From Clinical Trials" @default.
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• W2043284501 doi "https://doi.org/10.1016/j.ijrobp.2007.02.028" @default.
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