Radiation-induced narrowing of the tracheobronchial tree: an in-depth analysis.

PURPOSE: Symptomatic narrowing of the tracheobronchial tree is not a common clinical problem after conventional-dose external beam radiation therapy but has been described when higher doses are utilized. This in-depth study quantifies changes in the caliber of the trachea and mainstem bronchi after high-dose external beam radiation therapy (EBRT). METHODS AND MATERIALS: As part of an IRB-approved prospective clinical trial to assess for radiation-induced lung injury, patients with thoracic malignancies had pre- and serial post-RT CT scans in the radiation oncology department. This report focuses on 18 enrolled patients who received high-dose (> or = 73.6 Gy) EBRT for NSCLC. The caliber of the trachea, right mainstem bronchus, and left mainstem bronchus were measured utilizing three-dimensional coordinates in axial and coronal planes such that multiple measurements were made of each structure. The decrease in airway caliber was tested for significance using a one-sided Wilcoxon matched-pairs signed-ranks test. The correlation between airway caliber changes, dose, and follow-up interval was tested using the Spearman rank correlation coefficient and the effect of chemotherapy on airway narrowing was evaluated with a one-sided exact Wilcoxon rank sum test. RESULTS: There was no significant narrowing of the trachea for all dose and time points. There were significant decreases in the caliber of both mainstem bronchi on axial measurements (p = 0.07 and 0.005 for right and left mainstem bronchi, respectively). Decrease in airway caliber ranged from 6 to 57% and appeared to be dose dependent (p = 0.08), progressed with increasing time post-RT (p = 0.04), and was worse in patients who also received chemotherapy (p = 0.04). CONCLUSION: High-dose EBRT (> or = 73.6 Gy) appears to cause narrowing of the mainstem bronchi as early as 3 months post radiation therapy. Additional study is needed to assess the impact of such narrowing on RT-induced pulmonary symptoms.

Challenges in defining radiation pneumonitis in patients with lung cancer.

PURPOSE: To assess the difficulty of assigning a definitive clinical diagnosis of radiation (RT)-induced lung injury in patients irradiated for lung cancer. METHODS: Between 1991 and 2003, 318 patients were enrolled in a prospective study to evaluate RT-induced lung injury. Only patients with lung cancer who had a longer than 6-month follow-up (251 patients) were considered in the current analysis. Of these, 47 of 251 patients had Grade >/=2 (treated with steroids) increasing shortness of breath after RT, thought possibly consistent with pneumonitis/fibrosis. The treating physician, and one to three additional reviewing physicians, evaluated the patients or their medical records, or both. The presence or absence of confounding clinical factors that made the diagnosis of RT-induced uncertain lung injury were recorded. RESULTS: Thirty-one of 47 patients (66%) with shortness of breath had "classic" pneumonitis, i.e., they responded to steroids and had a definitive diagnosis of pneumonitis. In 13 of 47 patients (28%), the diagnosis of RT-induced toxicity was confounded by possible infection; exacerbation of preexisting lung disease (chronic obstructive pulmonary disease); tumor regrowth/progression; and cardiac disease in 6, 8, 5, and 1 patients, respectively (some of the patients had multiple confounding factors and were counted more than once). An additional 3 patients (6%) had progressive shortness of breath and an overall clinical course more consistent with fibrosis. All 3 had evidence of bronchial stenosis by bronchoscopy. CONCLUSIONS: Scoring of radiation pneumonitis was challenging in 28% of patients treated for lung cancer owing to confounding medical conditions. Recognition of this uncertainty is needed and may limit our ability to understand RT-induced lung injury.

Bronchial stenosis: an underreported complication of high-dose external beam radiotherapy for lung cancer?

PURPOSE: To assess the incidence of clinically significant bronchial stenosis in patients treated with high doses (i.e., >70 Gy) of twice-daily external beam radiation therapy (RT). METHODS AND MATERIALS: The outcomes of 103 patients with unresectable non-small-cell lung cancer, treated twice daily to doses ranging from 7080 to 8640 cGy between 1992 and 2001, were analyzed. Most were treated on prospective clinical trials. For the dose-effect comparison, the patients were divided on the basis of the total dose: 67 received 74 Gy (range, 70.8-74.5 Gy; median, 73.6 Gy), 20 received 80 Gy, and 16 received 86 Gy (range, 85.2-86.4 Gy; median, 86.4 Gy). Sixty-six patients received sequential chemotherapy before RT. RT-induced bronchial stenosis was defined as symptomatic airway narrowing diagnosed by bronchoscopy or computed tomography scan without evidence of recurrent tumor in that region. RESULTS: Eight patients developed RT-induced, clinically significant, bronchial stenosis 2-48 months (median, 6 months) after RT. The 1-year and 4-year actuarial rate of stenosis was 7% and 38%, respectively. The median overall survival was 2.5 years (5 of 8 were alive at the writing of this report). A suggestion was also found of a dose-response effect with external beam radiotherapy-induced stenosis, with a rate of 4% and 25% at a dose of approximately 74 Gy and 86 Gy, respectively. CONCLUSION: Radiation therapy-induced bronchial stenosis is a significant clinical complication of dose escalation for lung cancer. This complication has been previously mentioned in the literature, but ours is the largest report to date, and the findings suggest that the risk rises with increasing dose. It is likely that this process would manifest in more patients if their disease were controlled well enough for more prolonged survival.

Preliminary report of the 6-minute walk test as a predictor of radiation-induced pulmonary toxicity.

PURPOSE: To assess the 6-minute walk test (6MWT) as a predictor of radiation therapy-induced lung injury (RTLI). METHODS AND MATERIALS: The 6MWT is a simple, economical, and reproducible test that measures both how far a person can walk in 6 min and any associated changes in vital signs. As part of a prospective trial to study RTLI, a pre-RT 6MWT was performed in 41 patients. The predictive capacities of pre-RT 6MWT, forced expiratory volume in 1 s (FEV1), and single-breath diffusing capacity for carbon monoxide (DLCO) for the development of RTLI were assessed with receiver operating curve (ROC) techniques. To evaluate the 6MWT, alone or with mean lung dose (MLD) of radiation, as a predictor of RTLI, the rates of RTLI in patient subgroups defined by 6MWT results were compared by using Fisher's exact test. RESULTS: Thirty-one patients with > or =3 months' follow-up were evaluable. The median baseline 6MWT result was 1400 ft. Of 31 patients, 7 developed Grade > or =2 RTLI. Of 15 patients with an MLD >18 Gy (the median), 5 developed RTLI, compared with 2 of 16 with MLD < or =18 Gy (p = 0.22). Among those with an MLD < or =18 Gy, the RTLI rates were 0 of 8 and 2 of 8 for 6MWT results > or =1400 ft or <1400 ft, respectively, p = 0.46. The ROC area under the curve for individual metrics was as follows: FEV1 0.66, MLD 0.70, DLCO 0.61, and 6MWT 0.47. Combining FEV1 with 6MWT increased the ROC to 0.71, suggesting that the ratio might be a better predictor than the individual values. Patients with a high 6MWT/FEV1 ratio had a lower rate of RTLI than those with a relatively low ratio. CONCLUSIONS: The 6MWT might provide prognostic information beyond pulmonary function tests and dosimetric parameters in predicting RTLI. Additional work is needed to better assess the utility of these functional metrics.

A practical approach to pulmonary risk assessment in the radiotherapy of lung cancer.

The risk of lung injury is a significant limiting factor in the use of thoracic radiotherapy for lung cancer. Given the high mortality and local failure rates in patients with unresectable lung cancer, a goal has been to increase the dose to the tumor as much as possible while trying to limit the damage to normal tissue. Efforts have been made to predict the risks for lung injury pretreatment, based on the planned dose and volume of lung treated, with mixed results. Complicating factors include performance status, underlying medical conditions, possible genetic predisposition to injury, and tumor location-associated changes in lung function. Much as a thoracic surgeon stratifies a patient's risk for pulmonary morbidity before resection, radiation oncologists should perform an assessment of patient specific factors that will impact on the potential toxicity of a given course of treatment. We present a proposed approach to the evaluation, risk assessment, and follow-up of patients treated with thoracic radiotherapy for lung cancer.

Routine use of approximately 60 Gy once-daily thoracic irradiation for patients with limited-stage small-cell lung cancer.

PURPOSE: To review the outcome of patients with limited-stage small-cell lung cancer receiving daily thoracic irradiation (RT) to approximately 60 Gy. METHODS AND MATERIALS: The records of patients treated with RT for limited-stage small-cell lung cancer between 1991 and 1999 at Duke University were retrospectively reviewed. Sixty-five patients were identified who had received continuous course once-daily 1.8-2 Gy fractions to approximately 60 Gy (range 58-66). All patients received chemotherapy (CHT); 32 received concurrent RT/CHT and 33 sequential CHT and then RT. Prophylactic cranial RT was administered to 17 patients. The time from diagnosis to local failure, tumor progression, and death was assessed using actuarial methods. The median follow-up for all patients was 16.7 months and for surviving patients was 29.6 months. The median age was 64 years (range 36-83), and the median Karnofsky performance status was 80 (range 50-100). RESULTS: The 3-year actuarial rate of local failure, progression-free survival, and overall survival was 40%, 25%, and 23%, respectively. One case of acute Grade 3 esophagitis developed. Ten late complications occurred: four pulmonary, two esophageal, two infectious, one leukemia, and one retinal toxicity with prophylactic cranial RT. Six were mild and resolved with treatment. CONCLUSION: CHT plus approximately 60 Gy of once-daily RT for limited-stage small-cell lung cancer was generally well tolerated. The survival rates were less than have been reported using 45 Gy in 1.5-Gy twice-daily fractions (2-year overall survival rate 47% compared with 30% in this study), but may be comparable because fewer than one-half our patients received concurrent CHT/RT and only 26% received prophylactic cranial RT. The relatively low rate of normal tissue morbidity in our patients supports the use of conventional once-daily fractionation to > or = 60 Gy. A randomized trial would be required to compare the outcomes after maximally tolerated dose twice-daily RT vs. maximally tolerated dose daily RT.

Long-term changes in pulmonary function tests after definitive radiotherapy for lung cancer.

PURPOSE: To evaluate the long-term changes in pulmonary function tests (PFTs) in patients surviving at least 2 years after definitive radiotherapy (RT) for unresectable lung cancer. METHODS AND MATERIALS: Between 1992 and 2000, 277 patients were enrolled in a prospective clinical study to relate RT-induced changes in lung function with dosimetric and functional metrics. Of these, 128 received definitive RT for lung cancer, and 13 of these had follow-up PFTs for approximately >/=2 years without evidence of recurrent or progressive cancer. PFTs were obtained before RT and approximately every 6 months after RT. The results were evaluated on the basis of each study's "percentage of predicted" of normal values (i.e., adjusted for age, gender, height), and a patient's sequential examinations were compared with their initial study and a percentage of the baseline value was calculated. Follow-up PFTs were available for a median of 38 months (range 23-95). The median patient age was 65 years (range 40-74), 6 patients were men, and 10 were white. Most had Stage T2-T4 and N2-N3. The median RT dose was 71.4 Gy (range 60-73), 6 had twice-daily RT. Four patients received chemotherapy, one concurrent and three neoadjuvant. None of the patients continued to smoke after their treatment. The median pre-RT PFT results were (percentage of predicted) forced expiratory volume in 1 s, 67% (range 24-121); forced vital capacity, 72% (range 45-116); and diffusing capacity of lung for carbon monoxide, 70% (range 41-129). RESULTS: At 6 months, all PFT values had declined, with some stabilization by 1 year. However, after 1 year, a gradual reduction occurred in all three parameters. Ten patients (77%) developed RT-induced respiratory symptoms (2 cough only, 8 dyspnea) at 2-21 months (median 5) after treatment. Two patients required inhalers, another required long-term steroids and oxygen. Of the 8 patients with dyspnea, 7 had an increase in symptoms beyond 2 years. No patient died of RT-induced pulmonary insufficiency. CONCLUSION: RT caused a decline in PFTs that was apparent at 6 months and continued well beyond 1 year. The continued decline in PFTs is suggestive of progressive/evolving RT-induced lung injury. "Late" pulmonary symptoms have also occurred in these patients. Because of the high mortality rate of unresectable lung cancer, few patients can be evaluated for long-term analysis. Additional studies and pooling of data from multiple institutions may help to clarify better the long-term impact of RT on pulmonary function in this subset of patients.

Increased sectioning of pathologic specimens with ductal carcinoma in situ of the breast: are there clinical consequences?

To assess if there has been increased sectioning of pathologic specimens with ductal carcinoma in situ (DCIS), identify sources of this change, and consider the clinical consequences, pathologic data from patients who underwent initial excisional biopsies at our institution and were referred to the radiation oncology department with DCIS from 1992-2002 were retrospectively reviewed. One hundred forty-four of 480 patients with DCIS were eligible for review. Specimen size was recorded as length, to the nearest 0.1 cm, in 3 dimensions. Specimen volume was approximated by the product of the 3 dimensions of the specimen. The primary endpoint was the number of microscopic sections taken from gross specimens, corrected for specimen size. Other analysis included margin status, use of a previous stereotactic needle biopsy, and whether a subsequent repeat excision was performed. Over time, there was an increase in size of the excisional biopsy specimens (mean of 49 cm3 from 1992 to 1994 and 90 cm3 from 2001 to 2002; P = 0.045). Mean numbers of slides per centimeter of specimen were 2.5, 2.7, 3.9, and 5.8 for the intervals 1992-1994, 1995-1997, 1998-2000, and 2001-2002, respectively (P < 0.001 for 1992-1997 vs. 1998-2002). Adjusting for volume, the increase over time in the number of slides per specimen was statistically significant (parameter significance, P < 0.001). For a given volume, the number of slides increased approximately 9.1% per year, on average, during the study period. The positive margin rates were 52%, 46%, 23%, and 25% from 1992 to 1994, from 1995 to 1997, from 1998 to 2000, and from 2001 to 2002, respectively. The degree of sectioning, corrected for specimen length and volume, increased over time.

Palliative thoracic radiotherapy in lung cancer: An American Society for Radiation Oncology evidence-based clinical practice guideline.

PURPOSE: To provide guidance to physicians and patients with regard to the use of external beam radiotherapy, endobronchial brachytherapy, and concurrent chemotherapy in the setting of palliative thoracic treatment for lung cancer, based on available evidence complemented by expert opinion. METHODS AND MATERIALS: A Task Force authorized by the American Society for Radiation Oncology (ASTRO) Board of Directors synthesized and assessed evidence from 3 systematic reviews on the following topics: (1) dose fractionation in thoracic external beam radiotherapy (EBRT); (2) clinical utility of initial and salvage endobronchial brachytherapy (EBB); and (3) use of concurrent chemotherapy (CC) with palliative thoracic radiotherapy. Practice guideline recommendations were produced and are contained herein. RESULTS: Studies suggest that higher dose/fractionation palliative EBRT regimens (eg, 30 Gy/10 fraction equivalent or greater) are associated with modest improvements in survival and total symptom score, particularly in patients with good performance status. As these improvements are associated with an increase in esophageal toxicity, various shorter EBRT dose/fractionation schedules (eg, 20 Gy in 5 fractions, 17 Gy in 2 weekly fractions, 10 Gy in 1 fraction), which provide good symptomatic relief with fewer side effects, can be used for patients requesting a shorter treatment course and/or in those with a poor performance status. No defined role for EBB in the routine initial palliative treatment of chest disease has been demonstrated; however, EBB can be a reasonable option for the palliation of endobronchial lesions causing obstructive symptomatology including lung collapse, or for hemoptysis after EBRT failure. The integration of concurrent chemotherapy with palliative intent/fractionated radiotherapy is not currently supported by the medical literature. CONCLUSION: This Guideline is intended to serve as a guide for the use of EBRT, EBB, and CC in thoracic palliation of lung cancer outside the clinical trial setting. Further prospective clinical investigations with relevant palliative endpoints into the respective roles of EBB and CC/targeted therapy in the thoracic palliation of lung cancer are warranted, given the current state of the medical literature in these areas.