Jessica L. Hubbs

Local Recurrence After Surgery for Early Stage Lung Cancer An 11-Year Experience With 975 Patients

The objective of the current study was to evaluate the actuarial risk of local failure (LF) after surgery for stage I to II nonsmall cell lung cancer (NSCLC) and assess surgical and pathologic factors affecting this risk.

Prospective assessment of radiotherapy‐associated cardiac toxicity in breast cancer patients: Analysis of data 3 to 6 years after treatment

Radiation therapy (RT) to the left breast/chest wall has been linked with cardiac dysfunction. Previously, the authors identified cardiac perfusion defects in approximately 50% to 60% of patients 0.5 to 2 years post‐RT. In the current study, they assessed the persistence of these defects 3 to 6 years post‐RT.

Intensity-Modulated Radiotherapy for Resected Mesothelioma: The Duke Experience

PURPOSE To assess the safety and efficacy of intensity-modulated radiotherapy (IMRT) after extrapleural pneumonectomy for malignant pleural mesothelioma. METHODS AND MATERIALS Thirteen patients underwent IMRT after extrapleural pneumonectomy between July 2005 and February 2007 at Duke University Medical Center. The clinical target volume was defined as the entire ipsilateral hemithorax, chest wall incisions, including drain sites, and involved nodal stations. The dose prescribed to the planning target volume was 40-55 Gy (median, 45). Toxicity was graded using the modified Common Toxicity Criteria, and the lung dosimetric parameters from the subgroups with and without pneumonitis were compared. Local control and survival were assessed. RESULTS The median follow-up after IMRT was 9.5 months. Of the 13 patients, 3 (23%) developed Grade 2 or greater acute pulmonary toxicity (during or within 30 days of IMRT). The median dosimetric parameters for those with and without symptomatic pneumonitis were a mean lung dose (MLD) of 7.9 vs. 7.5 Gy (p = 0.40), percentage of lung volume receiving 20 Gy (V(20)) of 0.2% vs. 2.3% (p = 0.51), and percentage of lung volume receiving 5 Gy (V(20)) of 92% vs. 66% (p = 0.36). One patient died of fatal pulmonary toxicity. This patient received a greater MLD (11.4 vs. 7.6 Gy) and had a greater V(20) (6.9% vs. 1.9%), and V(5) (92% vs. 66%) compared with the median of those without fatal pulmonary toxicity. Local and/or distant failure occurred in 6 patients (46%), and 6 patients (46%) were alive without evidence of recurrence at last follow-up. CONCLUSIONS With limited follow-up, 45-Gy IMRT provides reasonable local control for mesothelioma after extrapleural pneumonectomy. However, treatment-related pulmonary toxicity remains a significant concern. Care should be taken to minimize the dose to the remaining lung to achieve an acceptable therapeutic ratio.

Factors associated with the development of brain metastases: analysis of 975 patients with early stage nonsmall cell lung cancer.

The risk of developing brain metastases after definitive treatment of locally advanced nonsmall cell lung cancer (NSCLC) is approximately 30%‐50%. The risk for patients with early stage disease is less defined. The authors sought to investigate this further and to study potential risk factors.

Regional lung density changes after radiation therapy for tumors in and around thorax.

PURPOSE To study the temporal nature of regional lung density changes and to assess whether the dose-dependent nature of these changes is associated with patient- and treatment-associated factors. METHODS AND MATERIALS Between 1991 and 2004, 118 patients with interpretable pre- and post-radiation therapy (RT) chest computed tomography (CT) scans were evaluated. Changes in regional lung density were related to regional dose to define a dose-response curve (DRC) for RT-induced lung injury using three-dimensional planning tools and image fusion. Multiple post-RT follow-up CT scans were evaluated by fitting linear-quadratic models of density changes on dose with time as the covariate. Various patient- and treatment-related factors were examined as well. RESULTS There was a dose-dependent increase in regional lung density at nearly all post-RT follow-up intervals. The population volume-weighted changes evolved over the initial 6-month period after RT and reached a plateau thereafter (p < 0.001). On univariate analysis, patient age greater than 65 years (p = 0.003) and/or the use of pre-RT surgery (p < 0.001) were associated with significantly greater changes in CT density at both 6 and 12 months after RT, but the magnitude of this effect was modest. CONCLUSIONS There appears to be a temporal nature for the dose-dependent increases in lung density. Nondosimetric clinical factors tend to have no, or a modest, impact on these changes.

Radiation-Induced Reductions in Regional Lung Perfusion: 0.1–12 Year Data From a Prospective Clinical Study

PURPOSE To assess the time and regional dependence of radiation therapy (RT)-induced reductions in regional lung perfusion 0.1-12 years post-RT, as measured by single photon emission computed tomography (SPECT) lung perfusion. MATERIALS/METHODS Between 1991 and 2005, 123 evaluable patients receiving RT for tumors in/around the thorax underwent SPECT lung perfusion scans before and serially post-RT (0.1-12 years). Registration of pre- and post-RT SPECT images with the treatment planning computed tomography, and hence the three-dimensional RT dose distribution, allowed changes in regional SPECT-defined perfusion to be related to regional RT dose. Post-RT follow-up scans were evaluated at multiple time points to determine the time course of RT-induced regional perfusion changes. Population dose response curves (DRC) for all patients at different time points, different regions, and subvolumes (e.g., whole lungs, cranial/caudal, ipsilateral/contralateral) were generated by combining data from multiple patients at similar follow-up times. Each DRC was fit to a linear model, and differences statistically analyzed. RESULTS In the overall groups, dose-dependent reductions in perfusion were seen at each time post-RT. The slope of the DRC increased over time up to 18 months post-RT, and plateaued thereafter. Regional differences in DRCs were only observed between the ipsilateral and contralateral lungs, and appeared due to tumor-associated changes in regional perfusion. CONCLUSIONS Thoracic RT causes dose-dependent reductions in regional lung perfusion that progress up to approximately 18 months post-RT and persists thereafter. Tumor shrinkage appears to confound the observed dose-response relations. There appears to be similar dose response for healthy parts of the lungs at different locations.

Local failure after complete resection of N0-1 non-small cell lung cancer

PURPOSE To estimate the risk of local-regional failure (LRF) after surgery for operable NSCLC, and the effect of clinical/pathologic factors on this risk. METHODS Records of 335 patients undergoing complete resection (lobectomy, pneumonectomy) for pathological T1-4 N0-1 NSCLC (without post-operative radiation) from 1996 to 2006 were reviewed. Crude and actuarial estimated failure rates were computed; local-regional sites included ipsilateral lung, surgical stump, hilar, mediastinal, or supraclavicular nodes. Failure times in sub-groups were calculated with the Kaplan-Meier method and compared via log-rank test. Independent factors adversely affecting LRF were determined with Cox regression. RESULTS The median follow-up duration for event-free surviving patients was 40 months (range: 1-150). The crude and actuarial 5-year probability of any failure (LR or distant) were 33% and 43%, respectively. Of all failures; 37% were LR only, 35% LR and distant and 28% distant only. The 5-year crude and actuarial probability of LRF were 24% and 35% (95% CI: 29-42%). Five-year crude LRF rates for T1-2N0, T1-2N1, T3-4N0 and T3-4N1 disease were 19% (41/216), 27% (16/59), 37.5% (15/40) and 40% (8/20), respectively. The corresponding actuarial estimates were T1-2N0 28%, T1-2N1 39%, T3-4N0 50% and T3-4N1 67%. In Cox multiple regression analysis, lymphovascular space invasion (p=0.03, HR: 1.7) and tumor size (p=0.01, HR: 1.67 for 5 cm increment) were associated with an increased risk of LRF. CONCLUSION Five-year LRF rates are ≥19% in essentially all patient subsets.

How Well Does the New Lung Cancer Staging System Predict for Local/Regional Recurrence After Surgery?: A Comparison of the TNM 6 and 7 Systems

Introduction: To evaluate how well the tumor, node, metastasis (TNM) 6 and TNM 7 staging systems predict rates of local/regional recurrence (LRR) after surgery alone for non-small cell lung cancer. Methods: All patients who underwent surgery for non-small cell lung cancer at Duke between 1995 and 2005 were reviewed. Those undergoing sublobar resections, with positive margins or involvement of the chest wall, or those who received any chemotherapy or radiation therapy (RT) were excluded. Disease recurrence at the surgical margin, or within ipsilateral hilar and/or mediastinal lymph nodes, was considered as a LRR. Stage was assigned based on both TNM 6 and TNM 7. Rates of LRR were estimated using the Kaplan-Meier method. A Cox regression analysis evaluated the hazard ratio of LRR by stage within TNM 6 and TNM 7. Results: A total of 709 patients were eligible for the analysis. Median follow-up was 32 months. For all patients, the 5-year actuarial risk of LRR was 23%. Conversion from TNM 6 to TNM 7 resulted in 21% stage migration (upstaging in 13%; downstaging in 8%). Five-year rates of LRR for stages IA, IB, IIA, IIB, and IIIA disease using TNM 6 were 16%, 26%, 43%, 35%, and 40%, respectively. Using TNM 7, corresponding rates were 16%, 23%, 37%, 39%, and 30%, respectively. The hazard ratios for LRR were statistically different for IA and IB in both TNM 6 and 7 but were also different for IB and IIA in TNM 7. Conclusions: LRR risk increases monotonically for stages IA to IIB in the new TNM 7 system. This information might be valuable when designing future studies of postoperative RT.

Timing of Local and Distant Failure in Resected Lung Cancer: Implications for Reported Rates of Local Failure

Introduction: Most adjuvant lung cancer trials only report first sites of failure. The relative timing of local (i.e., local/regional) versus distant recurrence after surgery could potentially affect reported rates of local failure. We assessed this phenomenon in a large group of patients undergoing surgery for early-stage lung cancer. Methods: This institutional review board-approved retrospective study identified all patients who underwent surgery at Duke University Medical Center for pathologic stages I to II non-small cell lung cancer between 1995 and 2005. Medical records and pertinent radiographs were reviewed to assess for local and distant sites of recurrence. Both first and subsequent failures were examined. The time interval between surgery and date of local and/or distant failure was compared using the Mann-Whitney U test. Results: Of 975 patients undergoing surgery, 250 patients developed recurrent disease (43 local only, 110 distant only, and 97 both). The median time from surgery to local failure was 13.9 months (range, 1–79). The median time to distant failure was 12.5 months (range, 1–79 months). These were not significantly different (p = 0.34). Among 97 patients who experienced both local and distant failure, 72 (74%) failed at both sites simultaneously, 19 (20%) failed at local sites first, and 6 (6%) failed at distant sites first. Conclusions: The time interval from surgery to either local or distant failure is not significantly different. Patterns of failure analyses in which only first sites of failure are scored will underestimate the frequency of local recurrence. Nevertheless, the magnitude of this error is expected to be small.

Association Between RT-Induced Changes in Lung Tissue Density and Global Lung Function

PURPOSE To assess the association between radiotherapy (RT)-induced changes in computed tomography (CT)-defined lung tissue density and pulmonary function tests (PFTs). METHODS AND MATERIALS Patients undergoing incidental partial lung RT were prospectively assessed for global (PFTs) and regional (CT and single photon emission CT [SPECT]) lung function before and, serially, after RT. The percent reductions in the PFT and the average changes in lung density were compared (Pearson correlations) in the overall group and subgroups stratified according to various clinical factors. Comparisons were also made between the CT- and SPECT-based computations using the Mann-Whitney U test. RESULTS Between 1991 and 2004, 343 patients were enrolled in this study. Of these, 111 patients had a total of 203 concurrent post-RT evaluations of changes in lung density and PFTs available for the analyses, and 81 patients had a total of 141 concurrent post-RT SPECT images. The average increases in lung density were related to the percent reductions in the PFTs, albeit with modest correlation coefficients (range, 0.20-0.43). The analyses also indicated that the association between lung density and PFT changes is essentially equivalent to the corresponding association with SPECT-defined lung perfusion. CONCLUSION We found a weak quantitative association between the degree of increase in lung density as defined by CT and the percent reduction in the PFTs.