Arya Amini

Dose constraints to prevent radiation-induced brachial plexopathy in patients treated for lung cancer.

PURPOSEnAs the recommended radiation dose for non-small-cell lung cancer (NSCLC) increases, meeting dose constraints for critical structures like the brachial plexus becomes increasingly challenging, particularly for tumors in the superior sulcus. In this retrospective analysis, we compared dose-volume histogram information with the incidence of plexopathy to establish the maximum dose tolerated by the brachial plexus.nnnMETHODS AND MATERIALSnWe identified 90 patients with NSCLC treated with definitive chemoradiation from March 2007 through September 2010, who had received >55 Gy to the brachial plexus. We used a multiatlas segmentation method combined with deformable image registration to delineate the brachial plexus on the original planning CT scans and scored plexopathy according to Common Terminology Criteria for Adverse Events version 4.03.nnnRESULTSnMedian radiation dose to the brachial plexus was 70 Gy (range, 56-87.5 Gy; 1.5-2.5 Gy/fraction). At a median follow-up time of 14.0 months, 14 patients (16%) had brachial plexopathy (8 patients [9%] had Grade 1, and 6 patients [7%] had Grade ≥2); median time to symptom onset was 6.5 months (range, 1.4-37.4 months). On multivariate analysis, receipt of a median brachial plexus dose of >69 Gy (odds ratio [OR] 10.091; 95% confidence interval [CI], 1.512-67.331; p = 0.005), a maximum dose of >75 Gy to 2 cm(3) of the brachial plexus (OR, 4.909; 95% CI, 0.966-24.952; p = 0.038), and the presence of plexopathy before irradiation (OR, 4.722; 95% CI, 1.267-17.606; p = 0.021) were independent predictors of brachial plexopathy.nnnCONCLUSIONSnFor lung cancers near the apical region, brachial plexopathy is a major concern for high-dose radiation therapy. We developed a computer-assisted image segmentation method that allows us to rapidly and consistently contour the brachial plexus and establish the dose limits to minimize the risk of brachial plexopathy. Our results could be used as a guideline in future prospective trials with high-dose radiation therapy for unresectable lung cancer.

Modulation of c-Met signaling and cellular sensitivity to radiation: potential implications for therapy.

The c‐Met/hepatocyte growth factor receptor and its family members are known to promote cancer cell migration and invasion. Signaling within and beyond this pathway contributes to the systemic spread of metastases through induction of the epithelial‐mesenchymal transition, a process also implicated in mediating resistance to current anticancer therapies, including radiation. Induction of c‐Met has also been observed after irradiation, suggesting that c‐Met participates in radiation‐induced disease progression through the epithelial‐mesenchymal transition. Therefore, c‐Met inhibition is an attractive target for potentially mitigating radiation resistance. This article summarizes key findings regarding crosstalk between radiotherapy and c‐Met and discusses studies performed to date in which c‐Met inhibition was used as a strategy to increase cellular radiosensitivity. Cancer 2013.

Accelerated hypofractionated radiation therapy compared to conventionally fractionated radiation therapy for the treatment of inoperable non-small cell lung cancer

BackgroundWhile conventionally fractionated radiation therapy alone is an acceptable option for poor prognostic patients with unresectable stage III NSCLC, we hypothesized that accelerated hypofractionated radiotherapy will have similar efficacy without increasing toxicity.MethodsThis is a retrospective analysis of 300 patients diagnosed with stage III NSCLC treated between 1993 and 2009. Patients included in the study were medically or surgically inoperable, were free of metastatic disease at initial workup and did not receive concurrent chemotherapy. Patients were categorized into three groups. Group 1 received 45 Gy in 15 fractions over 3 weeks (Accelerated Radiotherapy (ACRT)) while group 2 received 60-63 Gy (Standard Radiation Therapy 1 (STRT1)) and group 3 received > 63 Gy (Standard Radiation Therapy (STRT2)).ResultsThere were 119 (39.7%) patients in the ACRT group, 90 (30.0%) in STRT1 and 91 (30.3%) in STRT2. More patients in the ACRT group had KPS ≤ 60 (p < 0.001), more commonly presented with weight loss > 5% (p = 0.002), and had stage 3B disease (p < 0.001). After adjusting for clinical variables, there were no differences in the radiation groups in terms of the patterns of local or distant tumor control or overall survival. Some benefit in relapse free survival was seen in the STRT1 group as compared to ACRT (HR = 0.65, p = 0.011). Acute toxicity profiles in the ACRT were significantly lower for grade ≥ 2 radiation dermatitis (p = 0.002), nausea/vomiting (p = 0.022), and weight loss during treatment (p = 0.020).ConclusionsDespite the limitations of a retrospective analysis, our experience of accelerated hypofractionated radiation therapy with 45 Gy in 15 fractions appears to be an acceptable treatment option for poor performance status patients with stage III inoperable tumors. Such a treatment regimen (or higher doses in 15 fractions) should be prospectively evaluated using modern radiation technologies with the addition of sequential high dose chemotherapy in stage III NSCLC.

Predictors for Locoregional Recurrence for Clinical Stage III-N2 Non-small Cell Lung Cancer with Nodal Downstaging After Induction Chemotherapy and Surgery

PurposePathologic downstaging following chemotherapy for stage III-N2 NSCLC is a well-known positive prognostic indicator. However, the predictive factors for locoregional recurrence (LRR) in these patients are largely unknown.MethodsBetween 1998 and 2008, 153 patients with clinically or pathologically staged III-N2 NSCLC from two cancer centers in the United States were treated with induction chemotherapy and surgery. All had pathologic N0-1 disease, and none received postoperative radiotherapy. LRR were defined as recurrence at the surgical site, lymph nodes (levels 1–14 including supraclavicular), or both.ResultsMedian follow-up was 39.3xa0months. Pretreatment N2 status was confirmed pathologically (18.2xa0%) or by PET/CT (81.8xa0%). Overall, the 5-year LRR rate was 30.8xa0% (nxa0=xa038), with LRR being the first site of failure in 51xa0% (22/+99877943). Five-year overall survival for patients with LRR compared with those without was 21 versus 60.1xa0% (pxa0<xa00.001). Using multivariate analysis, significant predictors for LRR were pN1 disease at time of surgery (pxa0<xa00.001, HR 3.43, 95xa0% CI 1.80–6.56) and a trend for squamous histology (pxa0=xa00.072, HR 1.93, 95xa0% CI 0.94–3.98). Five-year LRR rate for pN1 versus pN0 disease was 62 versus 20xa0%. Neither single versus multistation N2 disease (pxa0=xa00.291) nor initial staging technique (pxa0=xa00.306) were predictors for LRR. N1 status also was predictive for higher distant recurrence (pxa0=xa00.021, HR 1.91, 95xa0% CI 1.1–3.3) but only trended for poorer survival (pxa0=xa00.123, HR 1.48, 95xa0% CI 0.9–2.44).ConclusionsLRR remains high in resected stage III-N2 NSCLC patients after induction chemotherapy and nodal downstaging, particularly in patients with persistent N1 disease.

Progress in the Management of Limited-Stage Small Cell Lung Cancer

Approximately 15% of lung cancer cases are of the small cell subtype, but this variant is highly aggressive and is often diagnosed at advanced stages. Outcomes after current treatment regimens have been poor, with 5‐year survival rates as low as 25% for patients with limited‐stage disease. Advances in therapy for small cell lung cancer have included the development of more effective chemotherapeutic agents and radiation techniques. For example, hyperfractionated radiotherapy given early in the course of the disease can reduce local recurrence and extend survival. Other technologic advances in radiation planning and delivery such as intensity‐modulated radiotherapy, image‐guided adaptive radiotherapy, and 4‐dimensional computed tomography/positron emission tomography have facilitated the design of treatment volumes that closely conform to the shape of the tumor, which allows higher radiation doses to be given while minimizing radiation‐induced toxicity to adjacent structures. Future improvements in outcomes will require clarifying the molecular basis for this disease. Cancer 2014;120:790–798.

Automatic contouring of brachial plexus using a multi-atlas approach for lung cancer radiation therapy

PURPOSEnTo demonstrate a multi-atlas segmentation approach to facilitating accurate and consistent delineation of low-contrast brachial plexuses on computed tomographic images for lung cancer radiation therapy.nnnMETHODS AND MATERIALSnWe retrospectively identified 90 lung cancer patients with treatment volumes near the brachial plexus. Ten representative patients were selected to form an atlas group, and their brachial plexuses were delineated manually. We used deformable image registration to map each atlas brachial plexus to the remaining 80 patients. In each patient, a composite contour was created from 10 individual segmentations using the simultaneous truth and performance level estimation algorithm. This auto-delineated contour was reviewed and modified appropriately for each patient. We also performed 10 leave-one-out tests using the 10 atlases to validate the segmentation accuracy and demonstrate the contouring consistency using multi-atlas segmentation.nnnRESULTSnThe multi-atlas segmentation took less than 2 minutes to complete. Contour modification took 5 minutes compared with 20 minutes for manual contouring from scratch. The multi-atlas segmentation from the 10 leave-one-out tests had a mean 3-dimensional (3D) volume overlap of 59.2% ± 8.2% and a mean 3D surface distance of 2.4 mm ± 0.5 mm. The distances between the individual and average contours in the 10 leave-one-out tests demonstrated much better contouring consistency for modified contours than for manual contours. The auto-segmented contours did not require substantial modification, demonstrated by the good agreement between the modified and auto-segmented contours in the 80 patients. Dose volume histograms of auto-segmented and modified contours were also in good agreement, showing that editing auto-segmented contours is clinically acceptable in view of the dosimetric impact.nnnCONCLUSIONSnMulti-atlas segmentation greatly reduced contouring time and improved contouring consistency. Editing auto-segmented contours to delineate the brachial plexus proved to be a better clinical practice than manually contouring from scratch.

Factors associated with local-regional failure after definitive chemoradiation for locally advanced esophageal cancer

AbstractBackgroundnLocally advanced esophageal cancer is often treated with a trimodality approach. While a substantial proportion of such patients initially achieve a clinical complete response (cCR) after chemoradiation, only a small proportion achieve durable control. We analyzed patients who reached cCR after definitive chemoradiation for esophageal cancer to identify clinical predictors of local disease recurrence.nMethodsWe identified 141 patients who obtained initial cCR after definitive chemoradiation without surgery for esophageal cancer from 2002 through 2009. The initial response to treatment was assessed by endoscopic evaluation and biopsy results, with cCR defined as having no evidence of disease present. Patterns of failure were categorized as in-field (within the planned treatment volume [PTV]), outside the radiation treatment field, or both.ResultsAt a median follow-up of 22xa0months (range, 6–87xa0months), 77 patients (55xa0%) had experienced disease recurrence (local or both). Of first failures, 32 (23xa0%) were outside the radiation field, followed by 30 (21xa0%) within the field, and 15 (11xa0%) were both. By multivariate analysis, in-field failure after cCR was associated with a pretreatment standardized uptake value on positron emission tomography of >10 (subhazard ratio [SHR] 3.31, pxa0=xa00.023) and poorly differentiated tumors (SHR 3.69, pxa0=xa00.031). All failures, in-field and out-of-field, correlated with non-Caucasian ethnicity (SHR 2.55, pxa0=xa00.001), N1 disease (SHR 2.05, pxa0=xa00.034), T3/T4 disease (SHR 3.56, pxa0=xa00.011), and older age (SHR 0.96, pxa0=xa00.008).ConclusionsOur data suggest that selected clinical characteristics can be used to predict failure patterns after definitive chemoradiation. Such risk-assessment strategies can help individualize therapy.

Celiac Node Failure Patterns After Definitive Chemoradiation for Esophageal Cancer in the Modern Era

PURPOSEnThe celiac lymph node axis acts as a gateway for metastatic systemic spread. The need for prophylactic celiac nodal coverage in chemoradiation therapy for esophageal cancer is controversial. Given the improved ability to evaluate lymph node status before treatment via positron emission tomography (PET) and endoscopic ultrasound, we hypothesized that prophylactic celiac node irradiation may not be needed for patients with localized esophageal carcinoma.nnnMETHODS AND MATERIALSnWe reviewed the radiation treatment volumes for 131 patients who underwent definitive chemoradiation for esophageal cancer. Patients with celiac lymph node involvement at baseline were excluded. Median radiation dose was 50.4 Gy. The location of all celiac node failures was compared with the radiation treatment plan to determine whether the failures occurred within or outside the radiation treatment field.nnnRESULTSnAt a median follow-up time of 52.6 months (95% CI 46.1-56.7 months), 6 of 60 patients (10%) without celiac node coverage had celiac nodal failure; in 5 of these patients, the failures represented the first site of recurrence. Of the 71 patients who had celiac coverage, only 5 patients (7%) had celiac region relapse. In multivariate analyses, having a pretreatment-to-post-treatment change in standardized uptake value on PET >52% (odds ratio [OR] 0.198, p = 0.0327) and having failure in the clinical target volume (OR 10.72, p = 0.001) were associated with risk of celiac region relapse. Of those without celiac coverage, the 6 patients that later developed celiac failure had a worse median overall survival time compared with the other 54 patients who did not fail (median overall survival time: 16.5 months vs. 31.5 months, p = 0.041). Acute and late toxicities were similar in both groups.nnnCONCLUSIONSnAlthough celiac lymph node failures occur in approximately 1 of 10 patients, the lack of effective salvage treatments and subsequent low morbidity may justify prophylactic treatment in distal esophageal cancer patients.

The Role of Consolidation Therapy for Stage III Non-Small Cell Lung Cancer With Persistent N2 Disease After Induction Chemotherapy

BACKGROUNDnPersistent pathologic mediastinal nodal involvement after induction chemotherapy and surgical resection is a negative prognostic factor for stage III-N2 non-small cell lung cancer patients. This population has high rates of local-regional failure and distant failure, yet the effectiveness of additional therapies is not clear. We assessed the role of consolidative therapies (postoperative radiation therapy and chemotherapy) for such patients.nnnMETHODSnIn all, 179 patients with stage III-N2 non-small cell lung cancer at MD Anderson Cancer Center were treated with induction chemotherapy followed by surgery from 1998 through 2008; 61 patients in this cohort had persistent, pathologically confirmed, mediastinal nodal disease, and were treated with postoperative radiation therapy. Local-regional failure was defined as recurrence at the surgical site or lymph nodes (levels 1 to 14, including supraclavicular), or both. Overall survival was calculated using the Kaplan-Meier method, and survival outcomes were assessed by log rank tests. Univariate and multivariate Cox proportional hazards models were used to identify factors influencing local-regional failure, distant failure, and overall survival.nnnRESULTSnAll patients received postoperative radiation therapy after surgery, but approximately 25% of the patients also received additional chemotherapy: 9 (15%) with concurrent chemotherapy, 4 (7%) received adjuvant sequential chemotherapy, and 2 (3%) received both. Multivariate analysis indicated that additional postoperative chemotherapy significantly reduced distant failure (hazard ratio 0.183, 95% confidence interval: 0.052 to 0.649, p=0.009) and improved overall survival (hazard ratio 0.233, 95% confidence interval: 0.089 to 0.612, p=0.003). However, additional postoperative chemotherapy had no affect on local-regional failure.nnnCONCLUSIONSnAggressive consolidative therapies may improve outcomes for patients with persistent N2 disease after induction chemotherapy and surgery.

Evaluating proton stereotactic body radiotherapy to reduce chest wall dose in the treatment of lung cancer

Stereotactic body radiotherapy (SBRT) can produce excellent local control of several types of solid tumor; however, toxicity to nearby critical structures is a concern. We found previously that in SBRT for lung cancer, the chest wall (CW) volume receiving 20, 30, or 40Gy (V20, V30, or V40) was linked with the development of neuropathy. Here we sought to determine whether the dosimetric advantages of protons could produce lower CW doses than traditional photon-based SBRT. We searched an institutional database to identify patients treated with photon SBRT for lung cancer with tumors within < 2.5cm of the CW. We found 260 cases; of these, chronic grade ≥ 2 CW pain was identified in 23 patients. We then selected 10 representative patients from this group and generated proton SBRT treatment plans, using the identical dose of 50Gy in 4 fractions, and assessed potential differences in CW dose between the 2 plans. The proton SBRT plans reduced the CW doses at all dose levels measured. The median CW V20 was 364.0cm(3) and 160.0cm(3) (p < 0.0001), V30 was 144.6cm(3)vs 77.0cm(3) (p = 0.0012), V35 was 93.9cm(3)vs 57.9cm(3) (p = 0.005), V40 was 66.5cm(3)vs 45.4cm(3) (p = 0.0112), and mean lung dose was 5.9Gy vs 3.8Gy (p = 0.0001) for photons and protons, respectively. Coverage of the planning target volume (PTV) was comparable between the 2 sets of plans (96.4% for photons and 97% for protons). From a dosimetric standpoint, proton SBRT can achieve the same coverage of the PTV while significantly reducing the dose to the CW and lung relative to photon SBRT and therefore may be beneficial for the treatment of lesions closer to critical structures.