Chris R. Kelsey

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.

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.

Recurrence Dynamics for Non–Small-Cell Lung Cancer: Effect of Surgery on the Development of Metastases

Introduction: We study event rates over time (event dynamics) in patients undergoing surgery for early-stage non–small-cell lung cancer (NSCLC). Methods: Using a database of patients undergoing initial surgery for NSCLC, the event dynamics, based on the hazard rate, were evaluated. Events evaluated included time to any treatment failure, local recurrence, distant metastasis (DM), and development of a second primary lung cancer. Results: Among 1506 patients, time to any treatment failure dynamics demonstrated an initial surge in the hazard rate 9 months after surgery, followed by two smaller peaks at the end of the second and fourth years, respectively. This pattern was dominated by DM events. Two distinguishable peaks were noted for local recurrence in the first and second years. In contrast, the hazard rate for second primary lung cancer exhibited a more uniform pattern over time. The DM dynamics was analyzed by sex and three peaks emerged for both sexes. The timing of the first peak was similar for both sexes, at 7 to 9 months after surgery. The second peak occurred earlier in men (18–20 months) than women (24–26 months). For both sexes the third peak appeared during the fourth year. Conclusions: Recurrence dynamics of resected early-stage NSCLC displays a multipeak pattern, which supports the hypothesis of a metastasis growth model previously described for early-stage breast cancer. The model assumes both cellular and micrometastatic tumor dormancy and a transient phase of acceleration of metastatic growth following surgical excision of the primary tumor.

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.

Impact of consolidation radiation therapy in stage III-IV diffuse large B-cell lymphoma with negative post-chemotherapy radiologic imaging.

PURPOSE While consolidation radiation therapy (i.e., RT administered after chemotherapy) is routine treatment for patients with early-stage diffuse large B-cell lymphoma (DLBCL), the role of consolidation RT in stage III-IV DLBCL is controversial. METHODS AND MATERIALS Cases of patients with stage III-IV DLBCL treated from 1991 to 2009 at Duke University, who achieved a complete response to chemotherapy were reviewed. Clinical outcomes were calculated using the Kaplan-Meier method and were compared between patients who did and did not receive RT, using the log-rank test. A multivariate analysis was performed using Cox proportional hazards model. RESULTS Seventy-nine patients were identified. Chemotherapy (median, 6 cycles) consisted of anti-CD20 antibody rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 65%); cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; 22%); or other (13%). Post-chemotherapy imaging consisted of positron emission tomography (PET)/computed tomography (CT) (73%); gallium with CT (14%); or CT only (13%). Consolidation RT (median, 25 Gy) was given to involved sites of disease in 38 (48%) patients. Receipt of consolidation RT was associated with improved in-field control (92% vs. 69%, respectively, p = 0.028) and event-free survival (85% vs. 65%, respectively, p = 0.014) but no difference in overall survival (85% vs. 78%, respectively, p = 0.15) when compared to patients who did not receive consolidation RT. On multivariate analysis, no RT was predictive of increased risk of in-field failure (hazard ratio [HR], 8.01, p = 0.014) and worse event-free survival (HR, 4.3, p = 0.014). CONCLUSIONS Patients with stage III-IV DLBCL who achieve negative post-chemotherapy imaging have improved in-field control and event-free survival with low-dose consolidation RT.

Local recurrence following initial resection of NSCLC: salvage is possible with radiation therapy.

PURPOSEAfter surgical resection of non-small cell lung cancer, local/ regional recurrence is observed in 20% to 50% of patients, often without evidence of distant metastases. This retrospective study evaluates the utility of salvage radiation therapy in this setting. MATERIALS AND METHODSBetween 1991 and 2003, 29 consecutive patients were treated with definitive radiotherapy (N= 14) or chemoradio-therapy (N = 15) for recurrent non–small cell lung cancer after surgical resection at Duke University Medical Center. The median time from date of surgery to date of recurrence was 18 months (range, 2–151). At the time of recurrence, most patients had mediastinal adenopathy (N = 19), but seven patients had disease confined to the surgical stump and three had hilar adenopathy with (N= 2) or without (N= 1) a stump recurrence. The median radiation therapy dose was 66 Gy (range, 46–74). Local control and overall survival were estimated using the Kaplan-Meier method. A univariate regression analysis was performed to evaluate the effect of several patient- and treatment-related factors on local control and overall survival. RESULTSMedian survival after radiation therapy was 17 months. Of the 29 patients, five are alive without evidence of disease 22, 28, 34, 54, and 158 months since completing radiation therapy. Actuarial local control and overall survival at 2 years were 62% and 38%, respectively. There was a trend toward improved survival with younger age and a longer disease-free interval between surgery and local recurrence, but these findings were not statistically significant. CONCLUSIONSRadiation therapy, with or without chemotherapy, produced a 2-year survival of 38% in our series of patients with local/regional recurrence of non–small cell lung cancer after resection. Aggressive therapy in this population of patients is warranted.

Lymphovascular Invasion in Non–Small-Cell Lung Cancer: Implications for Staging and Adjuvant Therapy

Background: Lymphovascular space invasion (LVI) is an established negative prognostic factor and an indication for postoperative radiation therapy in many malignancies. The purpose of this study was to evaluate LVI in patients with early-stage non–small-cell lung cancer, undergoing surgical resection. Methods: All patients who underwent initial surgery for pT1-3N0-2 non–small-cell lung cancer at Duke University Medical Center from 1995 to 2008 were identified. A multivariate ordinal regression was used to assess the relationship between LVI and pathologic hilar and/or mediastinal lymph node (LN) involvement. A multivariate Cox regression analysis was used to evaluate the relationship of LVI and other clinical and pathologic factors on local failure (LF), freedom from distant metastasis (FFDM), and overall survival (OS). Kaplan-Meier methods were used to generate estimates of LF, FFDM, and OS in patients with and without LVI. Results: One thousand five hundred and fifty-nine patients were identified. LVI was independently associated with the presence of regional LN involvement (p < 0.001) along with lobar (versus sublobar) resections (p < 0.001), and an open thoracotomy (versus video-assisted thoracoscopic surgery). LVI was not independently associated with LF on multivariate analysis (hazard ratio [HR] = 1.23, p = 0.25), but was associated with a lower FFDM (HR 1.52, p = 0.005) and OS (HR 1.26, p = 0.015). In addition, multivariate analysis showed that LVI was strongly associated with increased risk of developing distant metastases (HR = 1.75, p = 0.006) and death (HR = 1.53, p = 0.003) in adenocarcinomas but not in squamous carcinomas. Conclusions: LVI is associated with an increased risk of harboring regional LN involvement. LVI is also an adverse prognostic factor for the development of distant metastases and long-term survival.

Stereotactic body radiotherapy: A critical review for nonradiation oncologists

Stereotactic body radiotherapy (SBRT) involves the treatment of extracranial primary tumors or metastases with a few, high doses of ionizing radiation. In SBRT, tumor kill is maximized and dose to surrounding tissue is minimized, by precise and accurate delivery of multiple radiation beams to the target. This is particularly challenging, because extracranial lesions often move with respiration and are irregular in shape, requiring careful treatment planning and continual management of this motion and patient position during irradiation. This review presents the rationale, process workflow, and technology for the safe and effective administration of SBRT, as well as the indications, outcome, and limitations for this technique in the treatment of lung cancer, liver cancer, and metastatic disease. Cancer 2014;120:942–954.

Defining the Optimal Planning Target Volume in Image-Guided Stereotactic Radiosurgery of Brain Metastases: Results of a Randomized Trial

PURPOSE To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (SRS) of brain metastases, minimizing toxicity and local recurrence. METHODS AND MATERIALS Adult patients with 1 to 3 brain metastases less than 4 cm in greatest dimension, no previous brain radiation therapy, and Karnofsky performance status (KPS) above 70 were eligible for this institutional review board-approved trial. Individual lesions were randomized to 1- or 3- mm uniform expansion of the GTV defined on contrast-enhanced magnetic resonance imaging (MRI). The resulting planning target volume (PTV) was treated to 24, 18, or 15 Gy marginal dose for maximum PTV diameters less than 2, 2 to 2.9, and 3 to 3.9 cm, respectively, using a linear accelerator-based image-guided system. The primary endpoint was local recurrence (LR). Secondary endpoints included neurocognition Mini-Mental State Examination, Trail Making Test Parts A and B, quality of life (Functional Assessment of Cancer Therapy-Brain), radionecrosis (RN), need for salvage radiation therapy, distant failure (DF) in the brain, and overall survival (OS). RESULTS Between February 2010 and November 2012, 49 patients with 80 brain metastases were treated. The median age was 61 years, the median KPS was 90, and the predominant histologies were non-small cell lung cancer (25 patients) and melanoma (8). Fifty-five, 19, and 6 lesions were treated to 24, 18, and 15 Gy, respectively. The PTV/GTV ratio, volume receiving 12 Gy or more, and minimum dose to PTV were significantly higher in the 3-mm group (all P<.01), and GTV was similar (P=.76). At a median follow-up time of 32.2 months, 11 patients were alive, with median OS 10.6 months. LR was observed in only 3 lesions (2 in the 1 mm group, P=.51), with 6.7% LR 12 months after SRS. Biopsy-proven RN alone was observed in 6 lesions (5 in the 3-mm group, P=.10). The 12-month DF rate was 45.7%. Three months after SRS, no significant change in neurocognition or quality of life was observed. CONCLUSIONS SRS was well tolerated, with low rates of LR and RN in both cohorts. However, given the higher potential risk of RN with a 3-mm margin, a 1-mm GTV expansion is more appropriate.