Dyspnea evolution after high-dose radiotherapy in patients with non-small cell lung cancer

Purpose

To determine what the influence is of dyspnea (CTCAE3.0) before high-dose radiotherapy (RT) on the incidence and severity of subsequent lung toxicity in patients with non-small cell lung cancer (NSCLC).

Methods

In 197 patients with stage I-III NSCLC maximal dyspnea scores (CTCAE3.0) were obtained prospectively at three time periods: before RT, the first 6 months post-RT and 6-9 months post-RT. Only patients who were clinically progression-free 12 months or more after RT were included, thus minimizing dyspnea due to tumor progression. Time-trends of dyspnea as a function of baseline dyspnea were investigated and correlated with gender, age, chemotherapy, mean lung dose (MLD), lung function parameters (FeV1 and DLCO), stage, PTV dose, overall treatment time and smoking habits.

Results

The proportion developing less, the same or more dyspnea 6-9 months post-treatment according to their baseline dyspnea scores was: Grade 0: none, 82.9%, 17.1%; Grade 1: 21.2%, 51.9%, 26.9%; Grade 2: 27.3%, 54.5%, 18.2%, respectively. Only age was associated with increased dyspnea after RT.

Conclusions

Patients with dyspnea before therapy have a realistic chance to improve after high-dose radiotherapy. Reporting only dyspnea at one time-point post-RT is insufficient to determine radiation-induced dyspnea.     

Postoperative pulmonary complications after preoperative chemoradiation for esophageal carcinoma: correlation with pulmonary dose-volume histogram parameters

PURPOSE: To clarify the relationship between the percentage of lung receiving low radiation doses with concurrent chemotherapy and the occurrence of postoperative pulmonary complications in the treatment of esophageal carcinoma. METHODS: From 117 patients who underwent preoperative chemoradiation for esophageal cancer at our institution between 1998 and 2002, we selected 61 patients for whom complete pulmonary dose-volume histogram (DVH) data were available and analyzed the incidence of pneumonia and acute respiratory distress syndrome (ARDS) in this group. All patients received concurrent chemoradiation therapy, and 39 patients also received induction chemotherapy before concurrent chemoradiation. The median age was 62 years, and the median radiotherapy dose was 45 Gy. The percentage of lung volume receiving at least 10 Gy (V10), 15 Gy (V15), and 20 Gy (V20) were recorded from each pulmonary DVH. RESULTS: Eleven (18%) of the 61 patients had pulmonary complications, 2 of whom died after progression of pneumonia. Pulmonary complications were noted more often (35% vs. 8%, p = 0.014) when the pulmonary V10 was > or =40% vs. <40% and when the V15 was > or /=30% vs. < 30% (33% vs. 10%, p = 0.036). An apparent increase in pulmonary complication rate when V20 was > or =20% vs. <20% (32% vs. 10%, p = 0.079) was not significant. None of the other factors analyzed (surgical procedure, tumor location, use of induction chemotherapy, use of concurrent taxane-based chemoradiation, or smoking history) was associated with the occurrence of pulmonary complications. The median hospital stay was 17 days for patients who had pulmonary complications vs. 12 days for patients who did not (p = 0.08). CONCLUSIONS: The use of multimodality therapy may require minimization of lung volume irradiation to levels lower than previously expected. Radiotherapy techniques that decrease the volume of lung receiving low radiation doses may significantly reduce the risk of this potentially life-threatening complication.     

Differences in pulmonary function before vs. 1 year after hypofractionated stereotactic radiotherapy for small peripheral lung tumors

PURPOSE: To evaluate long-term pulmonary toxicity of stereotactic radiotherapy (SRT) by pulmonary function tests (PFTs) performed before and after SRT for small peripheral lung tumors. METHODS AND MATERIALS: A total of 17 lesions in 15 patients with small peripheral lung tumors, who underwent SRT between February 2000 and April 2003, were included in this study. Twelve patients had primary lung cancer, and 3 patients had metastatic lung cancer. Primary lung cancer was T1-2N0M0 in all cases. Smoking history was assessed by the Brinkman index (number of cigarettes smoked per day multiplied by number of years of smoking). Prescribed radiation doses at the 80% isodose line were 40-60 Gy in 5-8 fractions. PFTs were performed immediately before SRT and 1 year after SRT. Test parameters included total lung capacity (TLC), vital capacity (VC), forced expiratory volume in 1 s (FEV1.0), and diffusing capacity of lung for carbon monoxide (DLCO). PFT changes were evaluated in relation to patient- and treatment-related factors, including age, the Brinkman index, internal target volume, the percentages of lung volume irradiated with >15, 20, 25, and 30 Gy (V15, V20, V25, and V30, respectively), and mean lung dose. RESULTS: There were no significant changes in TLC, VC, or FEV1.0 before vs. after SRT. The mean percent change from baseline in DLCO was significantly increased by 128.2%. Univariate and multivariate analyses revealed a correlation between DLCO and the Brinkman index. CONCLUSIONS: One year after SRT as compared with before SRT, there were no declines in TLC, VC, and FEV1.0. DLCO improved in patients who had been heavy smokers before SRT, suggesting a correlation between DLCO and smoking cessation. SRT seems to be tolerable in view of long-term lung function.     

A prospective study of pulmonary function in patients treated with paclitaxel and carboplatin

BACKGROUND: Adverse effects of paclitaxel and carboplatin have been well described; however, pulmonary toxicity after patients receive this regimen has not been investigated extensively. METHODS: To clarify this issue, 33 consecutive patients who were treated with paclitaxel and carboplatin underwent prospective evaluation of respiratory function, which included pulmonary symptoms, pulmonary function tests (PFTs), arterial blood gas levels, and radiographic studies. Assessment was performed before and after completion of chemotherapy in all patients. Patients with substantial declines in PFTs, defined as a decline > or = 20 percent in forced expiratory volume in 1 second (FEV1), total lung capacity (TLC), or diffusion capacity for carbon monoxide (DLCO), were reassessed 5 months later. RESULTS: After chemotherapy, there were no significant changes in forced vital capacity (FVC; 111%+/-21% of the predicted value before chemotherapy vs. 111+/-20% of the predicted value after chemotherapy), FEV1 (108%+/-24% of the predicted value before chemotherapy vs. 107%+/-22% of the predicted value after chemotherapy), FEV1/FVC ratio (79%+/-8% before chemotherapy vs. 78%+/-6% after chemotherapy), alveolar volume (VA; 95%+/-14% of the predicted value before chemotherapy vs. 96%+/-14% of the predicted value after chemotherapy), or TLC (96%+/-14% of the predicted value before chemotherapy vs. 97%+/-13% of the predicted value after chemotherapy). In contrast, there was a significant decline in DLCO (101%+/-20% of the predicted value before chemotherapy vs. 96+/-21% of the predicted value after chemotherapy; P < 0.05). Arterial blood gas levels did not change after treatment. No patient had decreased FEV1 or TLC levels by > or = 20%, whereas 4 of 33 patients (12%) exhibited a substantial decline (> or = 20%) in DLCO that persisted 5 months after treatment (DLCO at baseline, immediately after chemotherapy, and 5 months after the completion of chemotherapy, respectively: 99%+/-36% of the predicted value vs. 75%+/-28% of the predicted value vs. 74%+/-31% of the predicted value; P < 0.05). None of the 33 patients developed respiratory symptoms or had radiologic signs suggestive of lung toxicity. Among the various risk factors examined, baseline DLCO and FEV1 levels were associated with changes in DLCO post-treatment. CONCLUSIONS: This prospective analysis showed that the combination of paclitaxel with carboplatin induced an isolated decrease in DLCO level in the absence of clinical or radiologic evidence of toxicity. Further studies are needed to clarify whether this reduction in DLCO is predictive of subsequent pulmonary impairment.     

The impact of induction chemotherapy and the associated tumor response on subsequent radiation-related changes in lung function and tumor response

PURPOSE: To assess the impact of induction chemotherapy, and associated tumor shrinkage, on the subsequent radiation-related changes in pulmonary function and tumor response. METHODS AND MATERIALS: As part of a prospective institutional review board-approved study, 91 evaluable patients treated definitively with thoracic radiation therapy (RT) for unresectable lung cancer were analyzed. The rates of RT-associated pulmonary toxicity and tumor response were compared in the patients with and without pre-RT chemotherapy. In the patients receiving induction chemotherapy, the rates of RT-associated pulmonary toxicity and tumor response were compared in the patients with and without a response (modified Response Evaluation Criteria in Solid Tumor criteria) to the pre-RT chemotherapy. Comparisons of the rates of improvements in pulmonary function tests (PFTs) post-RT, dyspnea requiring steroids, and percent declines in PFTs post-RT were compared in patient subgroups using Fisher's exact test, analysis of variance, and linear or logistic regression. RESULTS: The use of pre-RT chemotherapy appears to increase the rate of radiation-induced pneumonitis (p = 0.009-0.07), but has no consistent impact on changes in PFTs. The degree of induction chemotherapy-associated tumor shrinkage is not associated with the rate of subsequent RT-associated pulmonary toxicity. The degree of tumor response to chemotherapy is not related to the degree of tumor response to RT. CONCLUSIONS: Additional study is needed to better clarify the impact of chemotherapy on radiation-associated disfunction.     

Pathologic evidence of dose-response and dose-volume relationships for prostate cancer treated with combined external beam radiotherapy and high-dose-rate brachytherapy

PURPOSE: The clinical significance of postradiotherapy (RT) prostate biopsy characteristics is not well understood relative to the known prognostic factors. We performed a detailed pathologic review of posttreatment biopsy specimens in an attempt to clarify their relationship with clinical outcome and radiation dose. METHODS AND MATERIALS: Between 1991 and 1998, 78 patients with locally advanced prostate cancer were prospectively treated with external beam RT in combination with high-dose-rate brachytherapy at William Beaumont Hospital and had post-RT biopsy material available for a complete pathologic review. Patients with any of the following characteristics were eligible for study entry: pretreatment prostate-specific antigen level > or =10.0 ng/mL, Gleason score > or =7, or clinical Stage T2b-T3cN0M0. Pelvic external beam RT (46.0 Gy) was supplemented with three (1991-1995) or two (1995-1998) ultrasound-guided transperineal interstitial (192)Ir high-dose-rate implants. The brachytherapy dose was escalated from 5.50 to 10.50 Gy per implant. Post-RT prostate biopsies were performed per protocol at a median interval of 1.5 years after RT. All pre- and post-RT biopsy specimen slides from each case were reviewed by a single pathologist (N.S.G.). The presence and amount of residual cancer, most common RT-effect score, and least amount RT-effect score were analyzed. The median follow-up was 5.7 years. Biochemical failure was defined as three consecutive prostate-specific antigen rises. RESULTS: Forty patients (51%) had residual cancer in the post-RT biopsies. The 7-year biochemical control rate was 79% for patients with negative biopsies vs. 62% for those with positive biopsies with marked RT damage vs. 33% for those with positive biopsies with no or minimal RT damage. A greater percentage of positive pre-RT biopsy cores (p = 0.01), lower total RT dose (p = 0.001), lower dose per implant (p = 0.001), and greater percentage of positive post-RT biopsy cores (p = 0.01) were each associated with biochemical failure (Cox regression, univariate analysis). For patients with <25% positive post-RT biopsy cores, the 7-year biochemical control rate was 81% vs. a 62% biochemical control rate for those with 25-49% positive cores and only 32% for those with > or =50% positive cores (p = 0.01). On Cox multiple regression analysis, only the percentage of positive pre-RT biopsy cores and RT dose remained significantly associated with biochemical failure. Of all the factors analyzed, only the pretreatment cancer volume and lower RT dose were significantly associated with residual cancer and/or residual cancer with no or minimal RT damage. A greater percentage of positive pre-RT biopsy cores was associated with both a positive post-RT biopsy (p = 0.08) and a greater percentage of positive post-RT biopsy cores (p = 0.04). A lower total RT dose was associated with both a positive post-RT biopsy (p = 0.08) and a greater percentage of positive post-RT biopsy cores (p = 0.02). For patients who received <80 Gy (equivalent in 2-Gy fractions), 73% had positive post-RT biopsies vs. a 56% biopsy positivity rate for those who received 84-90 Gy and only 39% for those who received > or =92 Gy (p = 0.07). CONCLUSION: Patients with positive post-RT biopsies are more likely to experience biochemical failure, especially when the RT damage is minimal. Patients who have a larger pretreatment tumor volume or receive a lower RT dose are more likely to demonstrate post-RT biopsy positivity and biochemical failure.     

The effect of patient-specific factors on radiation-induced regional lung injury.

PURPOSE: To assess the impact of patient-specific factors on radiation (RT)-induced reductions in regional lung perfusion. METHODS: Fifty patients (32 lung carcinoma, 7 Hodgkin's disease, 9 breast carcinoma and 2 other thoracic tumors) had pre-RT and > or = 24-week post-RT single photon emission computed tomography (SPECT) perfusion images to assess the dose dependence of RT-induced reductions in regional lung perfusion. The SPECT data were analyzed using a normalized and non-normalized approach. Furthermore, two different mathematical methods were used to assess the impact of patient-specific factors on the dose-response curve (DRC). First, DRCs for different patient subgroups were generated and compared. Second, in a more formal statistical approach, individual DRCs for regional lung injury for each patient were fit to a linear-quadratic model (reduction = coefficient 1 x dose + coefficient 2 x dose2). Multiple patient-specific factors including tobacco history, pre-RT diffusion capacity to carbon monoxide (DLCO), transforming growth factor-beta (TGF-beta), chemotherapy exposure, disease type, and mean lung dose were explored in a multivariate analysis to assess their impact on the coefficients. RESULTS: None of the variables tested had a consistent impact on the radiation sensitivity of regional lung (i.e., the slope of the DRC). In the formal statistical analysis, there was a suggestion of a slight increase in radiation sensitivity in the dose range >40 Gy for nonsmokers (vs. smokers) and in those receiving chemotherapy (vs. no chemotherapy). However, this finding was very dependent on the specific statistical and normalization method used. CONCLUSION: Patient-specific factors do not have a dramatic effect on RT-induced reduction in regional lung perfusion. Additional studies are underway to better clarify this issue. We continue to postulate that patient-specific factors will impact on how the summation of regional injury translates into whole organ injury. Refinements in our methods to generate and compare SPECT scans are needed.     

Pulmonary function following high-dose radiotherapy of non-small-cell lung cancer

PURPOSE: To study changes of pulmonary function tests (PFTs) after radiotherapy (RT) of non-small-cell lung cancer (NSCLC) in relation to radiation dose, tumor regression, and changes in lung perfusion. METHODS AND MATERIALS: Eighty-two patients with inoperable NSCLC were evaluated with PFTs (forced expiratory volume in 1 s [FEV(1)] and diffusion capacity [T(L,COc)]), a computed tomography (CT) scan of the chest, and a single photon emission CT (SPECT) lung perfusion scan, before and 3-4 months after RT. The reductions of PFTs and tumor volume were calculated. The lung perfusion was measured from pre- and post-RT SPECT scans, and the difference was defined as the measured perfusion reduction (MPR). In addition, the perfusion post-RT was estimated from the dose distribution using a dose-effect relation for regional lung perfusion, and compared with the pre-RT lung perfusion to obtain the predicted perfusion reduction (PPR). The difference between the actually measured and the PPR was defined as reperfusion. The mean lung dose (MLD) was computed and weighted with the pre-RT perfusion, resulting in the mean perfusion-weighted lung dose (MpLD). Changes of PFTs were evaluated in relation to tumor dose, MLD, MpLD, tumor regression, and parameters related to perfusion changes. RESULTS: In a multivariate analysis, the total tumor dose and MLD were not associated with reductions of PFTs. Tumor regression resulted in a significant improvement of FEV(1) (p = 0.02), but was associated with a reduction of T(L,COc) (p = 0.05). The MpLD and the PPR showed a significant (p = 0.01 to 0.04) but low correlation (r = 0.24 to 0.31) with the reduction of both PFTs. The other parameters for perfusion changes, the MPR and reperfusion were not correlated with changes in PFTs. CONCLUSION: The perfusion-related dose variables, the MpLD or the PPR, are the best parameters to estimate PFTs after RT. Tumor regression is associated with an improvement of FEV(1) and a decline of T(L,COc). Reperfusion was not associated with an improvement of global pulmonary function.     

Analysis of the influence of elective nodal irradiation on postirradiation pulmonary function

Irradiation (RT) field selection for bronchogenic carcinoma is based on such factors as extent of disease, pulmonary function, and the perceived need for elective nodal irradiation (ENI). A technique of superimposing a patient's RT treatment film onto his quantitative perfusion lung scan can predict the fractional volume of perfused lung receiving RT and has been shown to reliably estimate the minimum post-RT pulmonary function as measured by the forced expiratory volume in one second (FEV1). This technique has been applied to 20 patients with nonresected clinically staged T1-4N0M0 lesions to quantify the pulmonary impact of varying degrees of ENI. The five treatment volumes selected were as follows: (1) tumor volume plus a 2-cm margin; (2) volume 1 plus ipsilateral hilum; (3) volume 2 plus mediastinum; (4) volume 3 plus supraclavicular fossae; and (5) volume 4 plus contralateral hilum. The median pre-RT FEV1 was 2.0 l, and the median predicted minimal post-RT FEV1 for each proposed field was field 1, 1.7 l; field 2, 1.5 l; field 3, 1.3 l; field 4, 1.1.; and field 5, 1.0 l. The decline in median predicted FEV1 with each increase in field size ranged from 2% to 12%, with a broad range of declines for each field. Such quantification can aid in decisions regarding ENI for patients with impaired pulmonary function.     

MR imaging assessment of irregular shrinkage of tumor morphology and volume in cervical cancer during radiation therapy

Objective: To study the clinical significance of the morphological and volume changes in cervical cancer during an ongoing course of radiation therapy (RT) using MR imaging. Methods: Serial MR imaging examinations were performed in 60 advanced cervical cancer patients.MR imaging was obtained at the start of RT, at 20-25 Gy(2-2.5 weeks of RT), at 45-50 Gy (4-5 weeks of RT), and 1-2 month post-RT. Tumor morphology was classified qualitatively as well-defmed (round/oval with a well-demarcated smooth margin) vs. lobulated vs. irregular and tumor volume was assessed in each serial MR examination independently by ROI volumetry and diameter volumetry. ROI volumetry was traced on the computer workstation with a trackball in each sagittal T2-weighted image and calculated by the summation of all tumor areas in each slice and multiplication by the slice profile. Diameter volumetry was to measure the largest three orthogonal tumor diameters in each orthogonal measurement plane and calculate as an ellipsoid formula (V=d1 x d2 x d3 x π/6).Serial tumor volume was compared between the two measurement methods. Results: The proportion of lobulated and irregular tumors increased early during RT and declined lately post-RT (68% pre-RT, 80% at 2-2.5 weeks of RT, 72% at 4-5 weeks of RT, 33% post-RT). Accordingly,ROI volumetry and diameter volhmetry correlated well pre-RT (r1=0.89) and post-RT (r4=0.80), but poorly during RT (r2 = 0.17 at 2-2.5 weeks of RT, r3 = 0.69 at 4-5 weeks of RT). Conclusions: Cervical cancers regress in a non-uniform fashion during RT and undergo increasingly irregular shrinkage. Measurement with ROI volumetry techniques, which can optimally measure irregular volumes,provides better assessment of radiation response during treatment than diameter volumetry.     

Predictive value of dose-volume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer

PURPOSE: To clarify whether the percentage of pulmonary volume irradiated to >20 Gy (V20) is related to the incidence and grade of radiation pneumonitis (RP) in cases of lung cancer treated with concurrent chemoradiation. METHODS AND MATERIALS: The subjects comprised 71 patients with lung cancer who were treated with conventionally fractionated definitive concurrent chemoradiation. The chemotherapy agents were carboplatin or cisplatin combined with taxane for most patients. Radiotherapy was delivered at 1.8-2.0 Gy fractions once daily to a total of 48-66 Gy (median 60). We analyzed the relation between RP grade and V20. Univariate and multivariate analyses were performed to assess patient- and treatment-related factors, including age, gender, smoking history, pulmonary function (forced expiratory volume in 1 s), tumor location (upper lobe vs. middle/lower lobe), chemotherapy regimen (platinum + taxane vs. other), total dose, overall radiation periods in addition to V20. RESULTS: With a median follow-up of 7.5 months, an RP grade of 0, 1, 2, 3, and 5 was observed in 16, 35, 17, 1, and 2 patients, respectively; the corresponding mean V20 values were 20.1%, 22.0%, 26.3%, 27.0%, and 34.5%. The 6-month cumulative incidence of RP greater than Grade 2 was 8.7%, 18.3%, 51%, and 85% in patients with a V20 of or=31%, respectively (p <0.0001). According to both univariate and multivariate analyses, V20 was the only factor associated with RP of Grade 2 or greater. CONCLUSION: The incidence and grade of RP are significantly related to the V20 value. Thus, V20 appears to be a factor that can be used to predict RP after concurrent chemoradiation for lung cancer.     

A prospective study on lung toxicity in patients treated with gemcitabine and carboplatin: clinical, radiological and functional assessment.

BACKGROUND: Small series and retrospective studies have suggested that treatment with gemcitabine may be associated with pulmonary toxicity. However, a prospective evaluation of cancer patients treated with gemcitabine-based chemotherapy without neoplastic involvement of the thorax and without administration of radiotherapy has not been performed. PATIENTS AND METHODS: To investigate this issue, 41 consecutive patients receiving gemcitabine and carboplatin underwent prospective evaluation of lung function, which included pulmonary symptoms, pulmonary function tests, arterial blood gases and radiographic studies. Assessment was performed before and after completion of chemotherapy in all patients. Patients with a substantial decline in diffusion capacity for carbon monoxide (DLCO), defined as a drop of > or = 20%, were reassessed 2 months later. RESULTS: After chemotherapy, there were no significant changes in forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, alveolar volume or total lung capacity. In contrast, there was a significant decline in DLCO (73 +/- 22 versus 67 +/- 24% predicted; P = 0.017) and in carbon monoxide transfer coefficient (KCO) (89 +/- 24 versus 80 +/- 24% predicted; P = 0.004). Arterial blood gases did not change following treatment. Ten of the 41 patients (24%) exhibited a substantial decline in DLCO, which, however, recovered within 2 months (DLCO at baseline, immediately after therapy and at 2 months after completion of treatment, 84 +/- 14, 58 +/- 16 and 77 +/- 17% predicted, respectively; P < 0.001; baseline DLCO versus DLCO at 2 months, P > 0.05). Four of the 41 patients (10%) experienced dyspnea, which was self-limiting, with the exception of one patient who developed interstitial lung fibrosis. Among the various risk factors examined, older age, female gender and lower baseline DLCO were associated with more profound changes in DLCO post-treatment. CONCLUSIONS: This prospective analysis showed that the combination of gemcitabine and carboplatin induces a significant, but reversible, decrease in diffusion capacity, which is mostly asymptomatic. Thus, this regimen is safe as regards clinically significant lung toxicity.     

Impaired diffusion capacity predicts for decreased treatment tolerance and survival in limited stage small cell lung cancer patients treated with concurrent chemoradiation

PURPOSE: To determine if stratification of limited stage small cell lung cancer (LSCLC) patients by pre-treatment pulmonary function test (PFT) prognostic indicators predicts for treatment-related toxicity risks and survival following concurrent chemoradiation. MATERIALS AND METHODS: From 1989 to 1999, 215 LSCLC patients received six cycles of alternating cyclophosphamide/doxorubicin/vincristine and etoposide/cisplatin (EP). Thoracic radiation (RT) was initiated only with EP and at cycle 2 or 3. RT dose was: 40 Gy/15 fractions/3 weeks or 50 Gy/25 fractions/5 weeks. RT fields encompassed gross and suspected microscopic disease with a 2 cm margin. Pre-treatment PFT values analyzed included forced expiratory volume in 1s (FEV1) (in liter and as % predicted) and diffusion capacity for carbon monoxide (DLCO) (as % predicted). The "marker" for toxicity during concurrent chemoradiation was the duration of any RT breaks initiated for severe hematologic or locoregional symptomatology. Patient outcomes were analyzed for associations between recognized PFT cut-offs (FEV1 <2l, > or =2l; FEV1 <60%, > or =60% predicted; DLCO <60%, > or =60% predicted), toxicity rates, and survival. RESULTS: For the whole study cohort, median, 2- and 5-year overall survivals were: 14.7 months, 22.7 and 7.2%, respectively. Fifty-six patients (26%) required treatment breaks due to toxicity. FEV1 and DLCO results were available for 96 (45%) and 86 (40%) patients, respectively. Two thirds of FEV1s measured were <2l. On statistical analysis, the incidence of toxicity-related interruptions was significant for DLCO<60% (P=0.043), suggestive for FEV1<2l (P=0.1) and non-significant for FEV1<60%. Patients with simultaneous DLCO<60% and FEV1<2l showed a trend toward increase toxicity risk (P=0.1). For selected PFT measures, median overall survivals were: 12.7 months versus 14.8 months for DLCO<60% versus > or =60%; 13.4 months versus 17.7 months for FEV1<2l versus > or =2l; 15.4 months versus 19.9 months for DLCO<60% + FEV1<2l versus DLCO> or =60% + FEV1> or =2l. Although absolute differences favored all patients with PFT values above the prognostic cut-offs, differences were not statistically significant on this analysis. Patients with both a treatment break and a DLCO<60% had the poorest median survival of all patient subsets, at 11.4 months (P=0.09). CONCLUSIONS: Impaired DLCO (i.e. <60%) is a novel predictor of increased treatment-related toxicity leading to interruptions. The present study suggests a probable role for DLCO and FEV1 (in l) as prognostic factors for predicting survival but larger patient samples are required for confirmation. Patients with impaired DLCOs experiencing treatment interruptions have the poorest survival. Assessment of pre-treatment PFTs contributes to determining optimal management strategies for LSCLC patients receiving definitive chemoradiation.     

Factors predicting severe radiation pneumonitis in patients receiving definitive chemoradiation for lung cancer

PURPOSE: To identify factors that may predict for severe radiation pneumonitis or pneumonopathy (RP), we reviewed a set of simple, commonly available characteristics. METHODS AND MATERIALS: Medical records of 148 lung cancer patients with good performance status (ECOG 0-1) treated definitively with chemoradiation from 6/92-6/98 at the University of Pennsylvania were reviewed. Actuarial survival and the crude rate of severe radiation pneumonitis were determined as a function of several variables. Potential predictive factors examined included age, gender, histology, stage, pulmonary function, performance status (0 vs. 1), weight loss, tumor location, radiation dose, initial radiation field size, chemotherapy regimen, and timing of chemotherapy. Univariate analysis (log-rank test) was performed for each variable. Multivariate analysis was performed using linear regression. RESULTS: Median survival for the entire cohort was 14.7 months. Four patients were inevaluable for pneumonitis due to early death from progressive disease. Of the remaining 144 evaluable patients, 12 (8.3%) experienced severe RP. The most significant factor predicting for severe RP was performance status (p < 0.003). The risk of severe RP was 16% for PS-1 patients vs. 2% for PS-0 patients. Women were significantly more likely to develop severe RP than men (p = 0.01). Among 67 patients for whom pre-radiation therapy pulmonary function data were available, forced expiratory volume of the lung in 1 second (FEV(1)) was also significant (p = 0. 03). No patient suffering severe RP had a pretreatment FEV(1) > 2.0 liters. The median radiation dose was 59.2 Gy and median initial radiation field size was 228 cm(2). Neither radiotherapy factor predicted for RP. Other factors studied, including chemotherapy drugs, and schedule, also were not significant predictors of severe RP. CONCLUSIONS: Pretreatment performance status, gender, and FEV(1) are significant predictors of severe radiation pneumonopathy, at least when using conventional radiation fields and doses. Complex radiation dose-volume algorithms that attempt to predict lung complication probabilities should probably incorporate these simply obtained clinical parameters.     

The role of lung perfusion imaging in predicting the direction of radiation-induced changes in pulmonary function tests

BACKGROUND: The aim of this study was to determine whether preradiation (pre-RT) single photon emission computed tomography (SPECT) lung perfusion scans can be used to predict RT-induced changes in pulmonary function tests (PFTs). METHODS: Ninety-four patients irradiated for thoracic tumors had pre-RT SPECT lung perfusion scans. The presence of SPECT hypoperfusion distal to a central mediastinal tumor was qualitatively assessed visually without knowledge of PFT changes. Patients were grouped based on whether the diffusion capacity (DLCO) ever increased post-RT. Comparisons of patient groups were performed using 1-tailed Fisher exact tests. Patient follow-up was 6-56 months (mean, 30 months). To assess SPECT hypoperfusion objectively, the average dose to the computed tomography (CT)-defined lung was compared with the weighted-average dose (based on relative perfusion) to the SPECT-defined lung. The ratio between the CT- and SPECT-defined mean lung dose provided a quantitative assessment of hypoperfusion. The mean ratio for patients with central tumor and adjacent hypoperfusion was compared with that of the others (Wilcoxon rank-sum one-sided test). RESULTS: In patients with central tumors, 41% (9 of 22) with adjacent hypoperfusion had improvements in DLCO following radiation, versus 18% (3 of 17) of those without hypoperfusion (P = 0.11). In patients with lung carcinoma, the corresponding ratios were 40% (8 of 20) and 10% (1 of 10), respectively (P = 0.10). The mean ratio of CT dose to SPECT dose was 1.35 for patients with central tumors and adjacent hypoperfusion versus 1.16 for others (P = 0.017). CONCLUSIONS: The presence of SPECT hypoperfusion adjacent to a central mediastinal mass may identify patients likely to have improved PFTs following RT. Thus, SPECT imaging may be useful in models for predicting radiation-induced changes in PFTs.     

Quantitative assessment of lung density changes after 3-D radiotherapy for breast cancer

Our aim was to reduce the rates of clinical and radiological pneumonitis in local-regional radiotherapy (RT) for breast cancer compared to a previous treatment series by applying a pre-planned lung dose volume constraint. 3-D dose planning was performed in 66 women with the aim of not exceeding an ipsilateral V20 of 30%. The patients were followed for short-term signs/symptoms of post-RT pneumonitis and radiological changes on chest CT 4 months after RT. Radiological abnormalities were scored with a CT-adapted modification of a semi-quantitative classification system originally proposed by Arriagada which accounts for severity and affected lung regions. The abnormal subvolumes were contoured and the mean doses were calculated. Three cases of mild and one case of moderate symptomatic pneumonitis were diagnosed. The mean V20 was higher in symptomatic than in unaffected patients, 29% vs. 24% (p =0.04). Mild/moderate radiological changes were frequently observed on CT in regions with average doses >30 Gy. According to multivariate modeling, a trend for association was found between the studied dosimetric factors V13, V20, V30 and mean lung dose, and moderate-severe changes on CT but not with patient specific covariates, e.g. chemotherapy or tamoxifen exposure. 3-D planned local-regional RT with a preplanned lung dose volume constraint of V20 <30% resulted in few cases of moderate symptomatic pneumonitis. Mild/moderate radiological changes were still detectable on CT in subvolumes receiving doses >30 Gy. Long-term follow-up for evaluation of possible late morbidity is warranted.     

Radiation-induced pulmonary toxicity: a dose-volume histogram analysis in 201 patients with lung cancer

PURPOSE: To relate lung dose-volume histogram-based factors to symptomatic radiation pneumonitis (RP) in patients with lung cancer undergoing 3-dimensional (3D) radiotherapy planning. METHODS AND MATERIALS: Between 1991 and 1999, 318 patients with lung cancer received external beam radiotherapy (RT) with 3D planning tools at Duke University Medical Center. One hundred seventeen patients were not evaluated for RP because of <6 months of follow-up, development of progressive intrathoracic disease making scoring of pulmonary symptoms difficult, or unretrievable 3D dosimetry data. Thus, 201 patients were analyzed for RP. Univariate and multivariate analyses were performed to test the association between RP and dosimetric factors (i.e., mean lung dose, volume of lung receiving >or=30 Gy, and normal tissue complication probability derived from the Lyman and Kutcher models) and clinical factors, including tobacco use, age, sex, chemotherapy exposure, tumor site, pre-RT forced expiratory volume in 1 s, weight loss, and performance status. RESULTS: Thirty-nine patients (19%) developed RP. In the univariate analysis, all dosimetric factors (i.e., mean lung dose, volume of lung receiving >or=30 Gy, and normal tissue complication probability) were associated with RP (p range 0.006-0.003). Of the clinical factors, ongoing tobacco use at the time of referral for RT was associated with fewer cases of RP (p = 0.05). These factors were also independently associated with RP according to the multivariate analysis (p = 0.001). Models predictive for RP based on dosimetric factors only, or on a combination with the influence of tobacco use, had a concordance of 64% and 68%, respectively. CONCLUSIONS: Dosimetric factors were the best predictors of symptomatic RP after external beam RT for lung cancer. Multivariate models that also include clinical variables were slightly more predictive.     

Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy

PURPOSE: To investigate the rate of high-grade treatment-related pneumonitis (TRP) in patients with advanced non-small-cell lung cancer (NSCLC) treated with concurrent chemotherapy and intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: From August 2002 to August 2005, 151 NSCLC patients were treated with IMRT. We excluded patients who did not receive concurrent chemotherapy or who had early-stage cancers, a history of major lung surgery, prior chest RT, a dose <50 Gy, or IMRT combined with three-dimensional conformal RT (3D-CRT). Toxicities were graded by Common Terminology Criteria for Adverse Events version 3.0. Grade > or = 3 TRP for 68 eligible IMRT patients was compared with TRP among 222 similar patients treated with 3D-CRT. RESULTS: The median follow-up durations for the IMRT and 3D-CRT patients were 8 months (range, 0-27 months) and 9 months (range, 0-56 months), respectively. The median IMRT and 3D-CRT doses were 63 Gy. The median gross tumor volume was 194 mL (range, 21-911 mL) for IMRT, compared with 142 mL (range, 1.5-1,186 mL) for 3D-CRT (p = 0.002). Despite the IMRT group's larger gross tumor volume, the rate of Grade > or = 3 TRP at 12 months was 8% (95% confidence interval 4%-19%), compared with 32% (95% confidence interval 26%-40%) for 3D-CRT (p = 0.002). CONCLUSIONS: In advanced NSCLC patients treated with chemoradiation, IMRT resulted in significantly lower levels of Grade > or = 3 TRP compared with 3D-CRT. Clinical, dosimetric, and patient selection factors that may have influenced rates of TRP require continuing investigation. A randomized trial comparing IMRT with 3D-CRT has been initiated.     

Changes in pulmonary function after incidental lung irradiation for breast cancer: A prospective study

PURPOSE: The aim of this study was to analyze changes in pulmonary function after radiation therapy (RT) for breast cancer. METHODS AND MATERIALS: A total of 39 consecutive eligible women, who underwent postoperative irradiation for breast cancer, were entered in the study. Spirometry consisting of forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), carbon monoxide diffusing capacity (DLCO), and gammagraphic (ventilation and perfusion) pulmonary function tests (PFT) were performed before RT and 6, 12, and 36 months afterwards. Dose-volume and perfusion-weighted parameters were obtained from 3D dose planning: Percentage of lung volume receiving more than a threshold dose (Vi) and between 2 dose levels (V(i-j)). The impact of clinical and dosimetric parameters on PFT changes (Delta PFT) after RT was evaluated by Pearson correlation coefficients and stepwise lineal regression analysis. RESULTS: No significant differences on mean PFT basal values (before RT) with respect to age, smoking, or previous chemotherapy (CT) were found. All the PFT decreased at 6 to 12 months. Furthermore FVC, FEV(1), and ventilation recovered almost to their previous values, whereas DLCO and perfusion continued to decrease until 36 months (-3.3% and -6.6%, respectively). Perfusion-weighted and interval-scaled dose-volume parameters (pV(i-j)) showed better correlation with Delta PFT (only Delta perfusion reached statistically significance at 36 months). Multivariate analysis showed a significant relation between pV(10-20) and Delta perfusion at 3 years, with a multiple correlation coefficient of 0.48. There were no significant differences related to age, previous chemotherapy, concurrent tamoxifen and smoking, although a tendency toward more perfusion reduction in older and nonsmoker patients was seen. CONCLUSIONS: Changes in FVC, FEV1 and ventilation were reversible, but not the perfusion and DLCO. We have not found a conclusive mathematical predictive model, provided that the best model only explained 48% of the variability. We suggest the use of dose-perfused volume and interval-scaled parameters (i.e., pV(10-20)) for further studies.     

Dynamic imaging response following radiation therapy predicts long-term outcomes for diffuse low-grade gliomas

Quantitative imaging assessment of radiation therapy (RT) for diffuse low-grade gliomas (DLGG) by measuring the velocity of diametric expansion (VDE) over time has never been studied. We assessed the VDE changes following RT and determined whether this parameter can serve as a prognostic factor. We reviewed a consecutive series of 33 adults with supratentorial DLGG treated with first-line RT with available imaging follow-up (median follow-up, 103 months). Before RT, all patients presented with a spontaneous tumor volume increase (positive VDE, mean 5.9 mm/year). After RT, all patients demonstrated a tumor volume decrease (negative VDE, mean, -16.7 mm/year) during a mean 49-month duration. In univariate analysis, initial tumor volume (>100 cm(3)), lack of IDH1 expression, p53 expression, high proliferation index, and fast post-RT tumor volume decrease (VDE at -10 mm/year or faster, fast responders) were associated with a significantly shorter overall survival (OS). The median OS was significantly longer (120.8 months) for slow responders (post-RT VDE slower than -10.0 mm/year) than for fast responders (47.9 months). In multivariate analysis, fast responders, larger initial tumor volume, lack of IDH1 expression, and p53 expression were independent poor prognostic factors for OS. A high proliferation index was significantly more frequent in the fast responder subgroup than in the slow responder subgroup. We conclude that the pattern of post-RT VDE changes is an independent prognostic factor for DLGG and offers a quantitative parameter to predict long-term outcomes. We propose to monitor individually the post-RT VDE changes using MRI follow-up, with particular attention to fast responders.