A method using 4D dose accumulation to quantify the interplay effect in lung stereotactic body radiation therapy.

The purpose of this study was to devise and evaluate a method to quantify the dosimetric uncertainty produced by the interplay between the movement of multileaf collimator and respiratory motion in lung stereotactic body radiation therapy. The method calculates the dose distribution for all control points from a dynamic treatment in all respiratory phases. The methodology includes some characteristics of a patient's irregular breathing patterns. It selects, for each control point, the phases with maximum and minimum mean dose over the tumor and their corresponding adjacent phases, whenever necessary. According to this selection, the dose matrices from each control point are summed up to obtain two dose distributions in each phase, which are accumulated in the reference phase subsequently by deformable image registration (DIR). D 95 and [Formula: see text] were calculated over those accumulated dose distributions for Gross Tumor Volume (GTV), Planning Target Volume-based on Internal Target Volume approach-and Evaluation Target Volume (ETV), a novel concept that applies to 4D dose accumulation. With the ETV, DIR and interplay uncertainties are separated. The methodology also evaluated how variations in the breathing rate and field size affects the mean dose received by the GTV. The method was applied retrospectively in five patients treated with intensity modulated radiotherapy-minimum area defined by the leaves configuration at any control point was at least 4 cm2. Uncertainties in tumor coverage were small (in most patients, changes on D 95 and [Formula: see text] were below 2% for GTV and ETV) but significant over- and under-dosages near ETV, which can be accentuated by highly irregular breathing. Uncertainties in mean dose for GTV tended to decrease exponentially with increasing field size and were reduced by an increase of breathing rate. The implementation of this method would be helpful to assess treatment quality in patients with irregular breathing. Furthermore, it could be used to study interplay uncertainties when small field sizes are used.

A novel concept to include uncertainties in the evaluation of stereotactic body radiation therapy after 4D dose accumulation using deformable image registration.

PURPOSE: To use four-dimensional (4D) dose accumulation based on deformable image registration (DIR) to assess dosimetric uncertainty in lung stereotactic body radiation therapy (SBRT) treatment planning. A novel concept, the Evaluation Target Volume (ETV), was introduced to achieve this goal. METHODS: The internal target volume (ITV) approach was used for treatment planning for 11 patients receiving lung SBRT. Retrospectively, 4D dose calculation was done in Pinnacle v9.10. Total dose was accumulated in the reference phase using DIR with MIM. DIR was validated using landmarks introduced by an expert radiation oncologist. The 4D and three-dimensional (3D) dose distributions were compared within the gross tumor volume (GTV) and the planning target volume (PTV) using the D95 and Dmin (calculated as Dmin,0.035cc ) metrics. For lung involvement, the mean dose and V20 , V10 , and V5 were used in the 3D to 4D dose comparison, and Dmax (D0.1cc ) was used for all other organs at risk (OAR). The new evaluation target volume (ETV) was calculated by expanding the GTV in the reference phase in order to include geometrical uncertainties of the DIR, interobserver variability in the definition of the tumor, and uncertainties of imaging and delivery systems. D95 and Dmin,0.035cc metrics were then calculated on the basis of the ETV for 4D accumulated dose distributions, and these metrics were compared with those calculated from the PTV for 3D planned dose distributions. RESULTS: The target registration error (TRE) per spatial component was below 0.5 ± 2.1mm for all our patients. For five patients, dose degradation above 2% (>4% in 2 patients) was found in the PTV after 4D accumulation and attributed to anatomical variations due to breathing. Comparison of D95 and Dmin,0.035cc metrics showed that the ETV (4D accumulated dose) estimated substantially lower coverage than the PTV (3D planning dose): in six out of the 11 cases, and for at least for one of the two metrics, coverage estimated by ETV was at least 5% lower than that estimated by PTV. Furthermore, the ETV approach revealed hot and cold spots within its boundaries. CONCLUSIONS: A workflow for 4D dose accumulation based on DIR has been devised. Dose degradation was attributed to respiratory motion. To overcome limitations in the PTV for the purposes of evaluating DIR-based 4D accumulated dose distributions, a new concept, the ETV, was proposed. This concept appears to facilitate more reliable dose evaluation and a better understanding of dosimetric uncertainties due to motion and deformation.

Correction: Hypofractionated radiation therapy and temozolomide in patients with glioblastoma and poor prognostic factors. A prospective, single-institution experience.

[This corrects the article DOI: 10.1371/journal.pone.0217881.].

Hypofractionated radiation therapy and temozolomide in patients with glioblastoma and poor prognostic factors. A prospective, single-institution experience.

BACKGROUND: Hypofractionated radiation therapy is a feasible and safe treatment option in elderly and frail patients with glioblastoma. The aim of this study was to evaluate the effectiveness of hypofractionated radiation therapy with concurrent temozolomide in terms of feasibility and disease control in primary glioblastoma patients with poor prognostic factors other than advanced age, such as post-surgical neurological complications, high tumor burden, unresectable or multifocal lesions, and potential low treatment compliance due to social factors or rapidly progressive disease. MATERIAL AND METHODS: GTV included the surgical cavity plus disease visible in T1WI-MRI, FLAIR-MRI and in the MET-uptake. The CTV was defined as the GTV plus 1.5-2 cm margin; the PTV was the CTV+0.3 cm margin. Forty, fourty-five, and fifty grays in 15 fractions were prescribed to 95% of PTV, CTV, and GTV, respectively. Treatment was delivered using IMRT or the VMAT technique. Simultaneously, 75 mg/m2/day of temozolomide were administered. RESULTS: Between January 2010 and November 2017, we treated a total of 17 patients. The median age at diagnosis was 68-years; median KPS was 50-70%. MGMT-methylation status was negative in 5 patients, and 8 patients were IDH-wildtype. Eight of 18 patients were younger than 65-years. Median tumor volume was 26.95cc; median PTV volume was 322cc. Four lesions were unresectable; 6 patients underwent complete surgical resection. Median residual volume was 1.14cc. Progression-free survival was 60% at 6 months, 33% at 1-year and 13% at 2-years (median OS = 7 months). No acute grade 3-5 toxicities were documented. Symptomatic grade 3 radiation necrosis was observed in one patient. CONCLUSIONS: Patients with poor clinical factors other than advanced age can be selected for hypofractionated radiotherapy. The OS and PFS rates obtained in our series are similar to those in patients treated with standard fractionation, assuring good treatment adherence, low rates of toxicity and probable improved cost-effectiveness.

Long-term results of Perioperative High Dose Rate Brachytherapy (PHDRB) and external beam radiation in adult patients with soft tissue sarcomas of the extremities and the superficial trunk: Final results of a prospective controlled study.

BACKGROUND: To analyze toxicity, patterns of failure, and survival in 106 adult patients with soft tissue sarcomas of the extremity and the superficial trunk treated in a prospective controlled trial of combined Perioperative High Dose Rate Brachytherapy (PHDRB) and external beam radiotherapy (EBRT). METHODS: Patients were treated with surgical resection and 16 Gy or 24 Gy of PHDRB for negative or close/positive margins, respectively. EBRT (45 Gy) was added postoperatively. Adjuvant chemotherapy was given to selected patients with high-grade tumors. RESULTS: The median follow-up was 7.1 years (range, 0.6-16.0). Grade ≥3 adverse events were observed in 22 patients (20.8%), and grade ≥4 events in 14 patients (13.2%). No grade 5 events were noted. Multivariate analysis (p = 0.003) found that Grade ≥3 toxic events increased with increasing implant volume (TV100). Local control, locoregional control, and distant control rates at 5 and 10 years were 89% and 87%, 82% and 80% and 75% and 69%, respectively. Multivariate analysis (p = 0.024) found that positive margins correlated with decreased local control. Disease-free survival and overall survival rates at 5 and 10 years were 64% and 59% and 73% and 62%, respectively. In multivariate analysis, disease-free survival rates decreased with increasing tumor size (p = 0.0001) and inadequate margins (p = 0.024), and overall survival decreased with increasing tumor size (p = 0.001) and male gender (p = 0.039). CONCLUSIONS: The combination of conservative surgery, high-dose PHDRB, and EBRT produces adequate function and local control in the majority of patients with soft tissue sarcomas of the extremities and the superficial trunk, including a substantial percentage of cases with positive margins. Patients with larger tumors are at a higher risk of complications, treatment failure, and cancer-related death and require an individualized treatment approach.

Endovascular treatment of malignant superior vena cava syndrome secondary to lung cancer.

OBJECTIVES: Superior Vena Cava obstruction results in severe oedema of the upper thorax. Endovascular treatment allows a rapid restoration of the blood flow with a rapid resolution of symptoms. We retrospectively report a single institution's experience in stent placement for malignant Superior Vena Cava Syndrome (SVCS) caused by lung cancer. METHODS: Thirty-three consecutive patients (23 men, 10 women; median age, 57.6 years; range 34-71 years) who underwent endovascular SVCS palliative treatment were enrolled between August 2002 and June 2015. All patients presented SVCS secondary to lung cancer. Signs and symptoms of SVCS were scored. RESULTS: All procedures were successfully completed (100% technical success rate). Twenty-eight patients showed a progressive clinical improvement after endovascular treatment of SVCS (84.8% clinical success rate) within 48 hours, there were five clinical failures which improved progressively with posterior radiotherapy. During follow-up, three patients (9%) suffered intra or post-procedural complications (1 cardiac arrhythmia, 2 stent thrombosis). CONCLUSIONS: Stent placement in malignant SVCS seems to be an effective and rapid treatment for the relief of symptoms and quality of life improvement with a relatively low complications rate with a rapid resolution of symptoms. Therefore, it should be seriously considered as the first option in the SVC obstruction treatment.

Multicatheter breast implant during breast conservative surgery: Novel approach to deliver accelerated partial breast irradiation.

PURPOSE: To assess the safety, feasibility, and efficacy of free-hand intraoperative multicatheter breast implant (FHIOMBI) and perioperative high-dose-rate brachytherapy (PHDRBT) in early breast cancer. METHODS AND MATERIALS: Patients with early breast cancer candidates for breast conservative surgery (BCS) were prospectively enrolled. Patients suitable for accelerated partial breast irradiation (APBI) (low or intermediate risk according GEC-ESTRO criteria) received PHDRBT (3.4 Gy BID × 10 in 5 days). Patients not suitable for APBI (high risk patients according GEC-ESTRO criteria) received PHDRBT boost (3.4 Gy BID × 4 in 2 days) followed by whole breast irradiation. RESULTS: From June 2007 to November 2014, 119 patients were treated and 122 FHIOMBI procedures were performed. Median duration of FHIOMBI was 25 minutes. A median of eight catheters (range, 4-14) were used. No severe intraoperative complications were observed. Severe early postoperative complications (bleeding) were documented in 2 patients (1.6%), wound healing complications in 3 (2.4%), and infection (mastitis or abscess) in 2 (1.6%). PHDRBT was delivered as APBI in 88 cases (72.1%) and as a boost in 34 (27.8%). The median clinical target volume T was 40.8 cc (range, 12.3-160.5); median D90 was 3.32 Gy (range, 3.11-3.85); median dose homogeneity index was 0.72 (range, 0.48-0.82). With a median followup of 38.4 months (range, 8.7-98.7) no local, elsewhere, or regional relapses were observed; there was only one distant failure in PHDRBT boost. No major (acute or late) RTOG grade 3 or higher were documented in any of the 119 patients treated with PHDRBT. Cosmetic outcome in APBI patients was excellent or good in (87.0%) and fair or poor in (11.9%) while in boost patients was excellent or good in (76.4%) and fair in (23.5%). CONCLUSION: The FHIOMBI-PHDRBT program does not add complications to conservative surgery. It allows precise selection of APBI patients and offers excellent results in disease control and cosmetics. It also offers logistic advantages because it dramatically shortens the time of local treatment and avoids further invasive procedures.

Factors Associated With Early Mortality in Patients Treated With Concurrent Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE: Concurrent chemoradiation therapy (con-CRT) is recommended for fit patients with locally advanced non-small cell lung cancer (LA-NSCLC) but is associated with toxicity, and observed survival continues to be limited. Identifying factors associated with early mortality could improve patient selection and identify strategies to improve prognosis. METHODS AND MATERIALS: Analysis of a multi-institutional LA-NSCLC database consisting of 1245 patients treated with con-CRT in 13 institutions was performed to identify factors predictive of 180-day survival. Recursive partitioning analysis (RPA) was performed to identify prognostic groups for 180-day survival. Multivariate logistic regression analysis was used to create a clinical nomogram predicting 180-day survival based on important predictors from RPA. RESULTS: Median follow-up was 43.5 months (95% confidence interval [CI]: 40.3-48.8) and 127 patients (10%) died within 180 days of treatment. Median, 180-day, and 1- to 5-year (by yearly increments) actuarial survival rates were 20.9 months, 90%, 71%, 45%, 32%, 27%, and 22% respectively. Multivariate analysis adjusted by region identified gross tumor volume (GTV) (odds ratio [OR] ≥100 cm(3): 2.61; 95% CI: 1.10-6.20; P=.029) and pulmonary function (forced expiratory volume in 1 second [FEV1], defined as the ratio of FEV1 to forced vital capacity [FVC]) (OR <80%: 2.53; 95% CI: 1.09-5.88; P=.030) as significant predictors of 180-day survival. RPA resulted in a 2-class risk stratification system: low-risk (GTV <100 cm(3) or GTV ≥100 cm(3) and FEV1 ≥80%) and high-risk (GTV ≥100 cm(3) and FEV1 <80%). The 180-day survival rates were 93% for low risk and 79% for high risk, with an OR of 4.43 (95% CI: 2.07-9.51; P<.001), adjusted by region. A clinical nomogram predictive of 180-day survival, incorporating FEV1, GTV, N stage, and maximum esophagus dose yielded favorable calibration (R(2) = 0.947). CONCLUSIONS: This analysis identified several risk factors associated with early mortality and suggests that future research in the optimization of pretreatment pulmonary function and/or functional lung avoidance treatment may alter the therapeutic ratio in this patient population.

Dose escalation with external beam radiation therapy and high-dose-rate brachytherapy combined with long-term androgen deprivation therapy in high and very high risk prostate cancer: Comparison of two consecutive high-dose-rate schemes.

PURPOSE: To compare rectal toxicity, urinary toxicity, and nadir+2 PSA relapse-free survival (bRFS) in two consecutive Phase II protocols of high-dose-rate (HDR) brachytherapy used at the authors institution from 2001 to 2012. METHODS AND MATERIALS: Patients with National Comprehensive Cancer Network high risk and very high risk prostate cancer enrolled in studies HDR4 (2001-2007, n = 183) and HDR2 (2007-2012, n = 56) were analyzed. Patients received minipelvis external beam radiation therapy/intensity-modulated external radiotherapy to 54 Gy and 2 years of androgen blockade along with HDR brachytherapy. HDR4 protocol consisted of four 4.75 Gy fractions delivered in 48 hours; the HDR2 protocol delivered two 9.5 Gy fractions in 24 hours. Average 2-Gy equivalent dose (α/ß = 1.2) prostate D90 doses for the HDR4 and HDR2 groups were 89.8 Gy and 110.5 Gy, respectively (p = 0.0001). Both groups were well balanced regarding risk factors. Prior transurethral resection of the prostate was more frequent in the HDR2 group (p = 0.001). RESULTS: After a median followup of 7.4 years (range, 2-11.2), there was no difference in adverse grade ≥ 2 rectal events (HDR4 = 10.4% vs. HDR2 = 12.5%; p = ns) or grade ≥3 (HDR4 = 2.2% vs. HDR2 = 3.6%; p = ns). No differences in urinary grade ≥2 adverse events (HDR4 = 23% vs. HDR2 = 26.8%; p = ns) or grade ≥3 (HDR4 = 7.7% vs. HDR2 = 8.9%; p = ns) were detected. The 7-year bRFS for HDR4 and HDR2 protocols was 88.7% and 87.8%, respectively (p = ns). CONCLUSIONS: HDR4 and HDR2 protocols produce similar results in terms of toxicity and bRFS at the intermediate time point of 7 years.

Early Prediction of Disease Progression in Small Cell Lung Cancer: Toward Model-Based Personalized Medicine in Oncology.

Predictive biomarkers can play a key role in individualized disease monitoring. Unfortunately, the use of biomarkers in clinical settings has thus far been limited. We have previously shown that mechanism-based pharmacokinetic/pharmacodynamic modeling enables integration of nonvalidated biomarker data to provide predictive model-based biomarkers for response classification. The biomarker model we developed incorporates an underlying latent variable (disease) representing (unobserved) tumor size dynamics, which is assumed to drive biomarker production and to be influenced by exposure to treatment. Here, we show that by integrating CT scan data, the population model can be expanded to include patient outcome. Moreover, we show that in conjunction with routine medical monitoring data, the population model can support accurate individual predictions of outcome. Our combined model predicts that a change in disease of 29.2% (relative standard error 20%) between two consecutive CT scans (i.e., 6-8 weeks) gives a probability of disease progression of 50%. We apply this framework to an external dataset containing biomarker data from 22 small cell lung cancer patients (four patients progressing during follow-up). Using only data up until the end of treatment (a total of 137 lactate dehydrogenase and 77 neuron-specific enolase observations), the statistical framework prospectively identified 75% of the individuals as having a predictable outcome in follow-up visits. This included two of the four patients who eventually progressed. In all identified individuals, the model-predicted outcomes matched the observed outcomes. This framework allows at risk patients to be identified early and therapeutic intervention/monitoring to be adjusted individually, which may improve overall patient survival.

Is intermediate radiation dose escalation with concurrent chemotherapy for stage III non-small-cell lung cancer beneficial? A multi-institutional propensity score matched analysis.

PURPOSE: The clinical benefits and risks of dose escalation (DE) for stage III non-small-cell lung cancer (NSCLC) remain uncertain despite the results from Radiation Therapy Oncology Group (RTOG) protocol 0617. There is significant heterogeneity of practice, with many clinicians prescribing intermediate dose levels between the 0617 study arms of 60 and 74 Gy. This study investigated whether this strategy is associated with any survival benefits/risks by analyzing a large multi-institutional database. METHODS AND MATERIALS: An individual patient database of stage III NSCLC patients treated with radical intent concurrent chemoradiation therapy was created (13 institutions, n=1274 patients). Patients were divided into 2 groups based on tumor Biological Effective Dose at 10 Gy (BED 10): those receiving standard dose (SD; n=552), consisting of 72Gy ≤ BED 10 ≤ 76.8 Gy (eg 60-64 Gy/30-32 fractions [fr]), and those receiving intermediate dose (ID; n=497), consisting of 76.8Gy < BED 10 < 100.8 Gy (eg >64 Gy/32 fr and <74 Gy/37 fr), with lower-dose patients (n=225) excluded from consideration. Patients were then matched using propensity scores, leading to 2 matched groups of 196 patients. Outcomes were compared using various statistics including interquartile range (IQR), Kaplan-Meier curves, and adjusted Cox regression analysis. RESULTS: Matched groups were found to be balanced except for N stage (more N3 disease in SD), median treatment year (SD in 2003; ID in 2007), platinum and taxane chemotherapy (SD in 28%; ID in 39%), and median follow-up (SD were 89 months; ID were 40 months). Median dose fractionation was 60 Gy/30 fr in SD (BED 10 IQR: 72.0-75.5 Gy) and 66 Gy/33 fr (BED 10 IQR: 78.6-79.2 Gy) in ID. Survival curves for SD and ID matched cohorts were statistically similar (P=.27); however, a nonstatistically significant trend toward better survival for ID was observed after 15 months (median survival SD: 19.3 months; ID: 21.0 months). There was an increase in grades III to V lung toxicity associated with ID (13.0% vs 4.9%, respectively). CONCLUSIONS: No significant overall survival benefits were found with intermediate DE; however, more grade III or greater lung toxicity was observed. The separation of survival curves after 15 months of follow-up suggests that a small overall survival improvement associated with intermediate DE cannot be excluded.

Pneumomediastinum as a complication of SABR for lung metastases.

BACKGROUND: Stereotactic ablative body radiation (SABR) is a novel and sophisticated radiation modality that involves the irradiation of extracranial tumors through precise and very high doses in patients with oligometastatic lung disease and primary lung tumors. CASE PRESENTATION: A 52-year-old female with subclinical idiopathic interstitial lung disease (ILD) and oligometastatic lung disease from squamous urethral cancer who was treated with SABR for a metastatic lesion located in the right lower pulmonary lobe. The patient received a hypo-fractionated course of SABR. A 3D-conformal multifield technique was used with six coplanar and one non-coplanar statics beams. A 48 Gy total dose in three fractions over six days was prescribed to the 95% of the PTV. The presence of idiopathic ILD and other identifiable underlying lung conditions were not taken into account as a constraint to prescribe a different than standard total dose or fractionation schedule. Six months after the SABR treatment, a CT-scan showed the presence of a pneumomediastinum with air outside the bronchial tree and within the subcutaneous tissue without co-existing pneumothorax. To our knowledge, this is the first case of pneumomediastinum appearing 6 months after SABR treatment for a lung metastasis located in the perihiliar/central tumors region as defined by the RTOG protocols as the proximal bronchial tree. CONCLUSION: Radiation oncologist should be aware of the potential risk of severe lung toxicity caused by SABR in patients with ILD, especially when chemotherapy-induced pulmonary toxicity is administered in a short time interval.

Salvage wide resection with intraoperative electron beam therapy or HDR brachytherapy in the management of isolated local recurrences of soft tissue sarcomas of the extremities and the superficial trunk.

PURPOSE: To assess the toxicity and efficacy of salvage wide resection (SWR) with intraoperative electron beam radiation therapy (IOERT) or perioperative high-dose-rate brachytherapy (PHDRB) in previously unirradiated patients (PUP) vs. previously irradiated patients (PIP) with isolated local recurrence of soft tissue sarcomas (STS) of the extremities and the superficial trunk. METHODS AND MATERIALS: PUP received SWR and IOERT/PHDRB with external beam radiation therapy. PIP received SWR and IOERT/PHDRB only. RESULTS: Fifty patients were analyzed retrospectively. PUP (n = 24; 48%) received IOERT (n = 13) or PHDRB (n = 11). PIP (n = 26; 52%) received IOERT (n = 10) or PHDRB (n = 16). Reintervention because of complications was not required in PUP. Nine of 26 (34%) PIP required reintervention (p = 0.01). After a median followup of 3.7 years (range, 0.2-18.3), the 5-year rates of locoregional control, distant control, and overall survival were 54%, 66%, and 56%, respectively. Five-year locoregional control was higher in PUP than in PIP (81% vs. 26%, p = 0.01) and in the extremity locations compared with trunk locations (68% vs. 28%, p = 0.001). Five-year overall survival was superior in unifocal vs. multifocal presentations (70% vs. 36%, p = 0.03) and for tumor sizes <4 vs. ≥4 cm (74% vs. 50%, p = 0.05). CONCLUSIONS: Prior irradiation is the main determinant of locoregional control in patients with isolated local recurrence of STS. The locoregional control rates in PUP were similar to those described in primary STS. In PIP, SWR + IOERT/PHDRB reirradiation yielded modest locoregional control rates and was associated with significant morbidity, especially in PHDRB cases.

A population pharmacodynamic model for lactate dehydrogenase and neuron specific enolase to predict tumor progression in small cell lung cancer patients.

The development of individualized therapies poses a major challenge in oncology. Significant hurdles to overcome include better disease monitoring and early prediction of clinical outcome. Current clinical practice consists of using Response Evaluation Criteria in Solid Tumors (RECIST) to categorize response to treatment. However, the utility of RECIST is restricted due to limitations on the frequency of measurement and its categorical rather than continuous nature. We propose a population modeling framework that relates circulating biomarkers in plasma, easily obtained from patients, to tumor progression levels assessed by imaging scans (i.e., RECIST categories). We successfully applied this framework to data regarding lactate dehydrogenase (LDH) and neuron specific enolase (NSE) concentrations in patients diagnosed with small cell lung cancer (SCLC). LDH and NSE have been proposed as independent prognostic factors for SCLC. However, their prognostic and predictive value has not been demonstrated in the context of standard clinical practice. Our model incorporates an underlying latent variable ("disease level") representing (unobserved) tumor size dynamics, which is assumed to drive biomarker production and to be influenced by exposure to treatment; these assumptions are in agreement with the known physiology of SCLC and these biomarkers. Our model predictions of unobserved disease level are strongly correlated with disease progression measured by RECIST criteria. In conclusion, the proposed framework enables prediction of treatment outcome based on circulating biomarkers and therefore can be a powerful tool to help clinicians monitor disease in SCLC.

Predicting esophagitis after chemoradiation therapy for non-small cell lung cancer: an individual patient data meta-analysis.

PURPOSE: Concurrent chemoradiation therapy (CCRT) improves survival compared with sequential treatment for locally advanced non-small cell lung cancer, but it increases toxicity, particularly radiation esophagitis (RE). Validated predictors of RE for clinical use are lacking. We performed an individual-patient-data meta-analysis to determine factors predictive of clinically significant RE. METHODS AND MATERIALS: After a systematic review of the literature, data were obtained on 1082 patients who underwent CCRT, including patients from Europe, North America, Asia, and Australia. Patients were randomly divided into training and validation sets (2/3 vs 1/3 of patients). Factors predictive of RE (grade≥2 and grade≥3) were assessed using logistic modeling, with the concordance statistic (c statistic) used to evaluate the performance of each model. RESULTS: The median radiation therapy dose delivered was 65 Gy, and the median follow-up time was 2.1 years. Most patients (91%) received platinum-containing CCRT regimens. The development of RE was common, scored as grade 2 in 348 patients (32.2%), grade 3 in 185 (17.1%), and grade 4 in 10 (0.9%). There were no RE-related deaths. On univariable analysis using the training set, several baseline factors were statistically predictive of RE (P<.05), but only dosimetric factors had good discrimination scores (c>.60). On multivariable analysis, the esophageal volume receiving ≥60 Gy (V60) alone emerged as the best predictor of grade≥2 and grade≥3 RE, with good calibration and discrimination. Recursive partitioning identified 3 risk groups: low (V60<0.07%), intermediate (V60 0.07% to 16.99%), and high (V60≥17%). With use of the validation set, the predictive model performed inferiorly for the grade≥2 endpoint (c=.58) but performed well for the grade≥3 endpoint (c=.66). CONCLUSIONS: Clinically significant RE is common, but life-threatening complications occur in <1% of patients. Although several factors are statistically predictive of RE, the V60 alone provides the best predictive ability. Efforts to reduce the V60 should be prioritized, with further research needed to identify and validate new predictive factors.

The multimodal management of locally advanced N2 non-small cell lung cancer: is there a role for surgical resection? A single institution's experience.

BACKGROUND: The management of operable locally advanced N2 non-small cell lung cancer (NSCLC) is a controversial topic. Concurrent chemoradiation (CT-RT) is considered the standard of care for inoperable or unresectable patients, but the role of trimodality treatment remains controversial. We present our institution's experience with the management of stage III (N2) NSCLC patients, analyzing whether the addition of surgery improves survival when compared with definitive CT-RT alone. METHODS: From 1996 to 2006, 72 N2 NSCLC patients were treated. Thirty-four patients received cisplatin-based induction chemotherapy, followed by paclitaxel-cisplatin CT-RT, and 38 patients underwent surgery preceded by induction and/or followed by adjuvant therapy. Survival curves were estimated by Kaplan-Meier analysis, and the differences were assessed with the log-rank test. RESULTS: Most of the patients (87 %) were men. The median age was 59 years. A statistically significant association between T3-T4c and definitive CT-RT as well as between T1-T2c and surgery was noted (p < 0.0001). After a median follow-up period of 35 months, the median overall survival (OS) was 42 months for the surgery group versus 41 months for the CT-RT patients (p = 0.590). The median progression-free survival (PFS) was 14 months after surgery and 25 months after CT-RT (p = 0.933). Responders to radical CT-RT had a better OS than non-responders (43 vs. 17 months, respectively, p = 0.011). No significant differences were found in the OS or PFS between the pN0 [14 (37.8 %) patients] and non-pN0 patients at thoracotomy. Three treatment-related deaths (7.8 %) were observed in the surgical cohort and none in the CT-RT group. CONCLUSIONS: The addition of surgery did not render a median OS or PFS benefit when compared with CT-RT alone in our series of stage III-N2 NSCLC patients, in accordance with previously published data. However, responses to CT-RT had a greater impact in terms of OS and PFS. Although the patients selected for management including surgery showed a favorable T clinical staging in comparison to patients exclusively treated with definitive CT-RT, similar survival outcomes were found.

Pathological vertebral fracture after stereotactic body radiation therapy for lung metastases. Case report and literature review.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is a radiation technique used in patients with oligometastatic lung disease. Lung and chest wall toxicities have been described in the patients but pathological vertebral fracture is an adverse effect no reported in patients treated with SBRT for lung metastases. CASE PRESENTATION: A 68-year-old woman with the diagnosis of a recurrence of a single lung metastatic nodule of urothelial carcinoma after third line of chemotherapy. The patient received a hypo-fractionated course of SBRT.A 3D-conformal multifield technique was used with six coplanar and one non-coplanar statics beams. A total dose of 48 Gy in three fractions over six days was prescribed to the 95% of the CTV. Ten months after the SBRT procedure, a CT scan showed complete response of the metastatic disease without signs of radiation pneumonitis. However, rib and vertebral bone toxicities were observed with the fracture-collapse of the 7th and 8th vertebral bodies and a fracture of the 7th and 8th left ribs. We report a unique case of pathological vertebral fracture appearing ten months after SBRT for an asymptomatic growing lung metastases of urothelial carcinoma. CONCLUSION: Though SBRT allows for minimization of normal tissue exposure to high radiation doses SBRT tolerance for vertebral bone tissue has been poorly evaluated in patients with lung tumors. Oncologists should be alert to the potential risk of fatal bone toxicity caused by this novel treatment. We recommend BMD testing in all woman over 65 years old with clinical risk factors that could contribute to low BMD. If low BMD is demonstrated, we should carefully restrict the maximum radiation dose in the vertebral body in order to avoid intermediate or low radiation dose to the whole vertebral body.

Relationship between Day 0 dosimetric parameters and biochemical relapse-free survival in patients treated with transperineal permanent prostate interstitial brachytherapy with (125)I seeds.

OBJECTIVES: To determine the relationship between dosimetric parameters obtained on postimplantation Day 0 and biochemical relapse-free survival (bRFS) in patients treated with (125)I transperineal interstitial permanent prostate brachytherapy (TIPPB). METHODS: Two-hundred twenty men with low-risk (n=155, 70.4%), low-volume intermediate-risk (n=63, 28.7%), or high-risk (n=2, 0.9%) prostate cancer were treated with TIPPB between December 2000 and June 2006. Seventy-four (33.6%) patients received short-term (3-6 months) androgen suppression therapy before TIPPB. The median followup for patients free of biochemical failure was of 37.9 months (range, 24.0-84.5 months). RESULTS: The receiver operating characteristic (ROC) analysis established a best-fit cutoff value for the quantifiers D(90) and V(100) of 147Gy and 92%, respectively. The Kaplan-Meier analysis of bRFS at the cutoff value of D(90)=147Gy using the ASTRO, nadir+2, and combined (ASTRO and nadir+2) definitions showed a trend toward statistical significance for the ASTRO (p=0.076) and nadir+2 (p=0.064) definitions and a statistically significant correlation for the combined definition (p=0.033). The corresponding 7-year bRFS for the D(90) >147Gy and D(90)

Concomitant cisplatin, paclitaxel, and hyperfractionated radiotherapy in locally advanced head and neck cancer: comparison of two different schedules.

PURPOSE: To determine feasibility and efficacy of concurrent paclitaxel and cisplatin with definitive hyperfractionated radiotherapy (HFRT) in locally advanced head-and-neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Forty-two patients stages III to IV head-and-neck squamous cell carcinoma were enrolled in 2 consecutive prospective trials from August 1998 to January 2006. In study 1, 16 patients received HFRT in 2 courses of 39.6 Gy each with a split of 2 weeks with concurrent paclitaxel (175 mg/m) and cisplatin (100 mg/m) on days 1, 21, 36, and 57. In study 2, 26 patients received a continuous course of 74.4 Gy of HFRT with concurrent weekly paclitaxel (50 mg/m) and cisplatin (30 mg/m). RESULTS: Tumor locations included oropharynx 48%, hypopharynx 24%, larynx 12%, paranasal sinuses 7%, salivary gland 2%, oral cavity 2% and unknown primary 5%. In study 1, all patients received 3 to 4 cycles of chemotherapy and completed the programmed radiotherapy course. In study 2, 69% received 5 to 6 cycles of chemotherapy and 92% completed the irradiation. Overall, 93% of objective responses were observed (complete 76%, partial 17%). Median follow-up was 50 months (range: 12-97). Pattern of recurrence was local 8%, distant 13%, and combined 3%. Acute toxicity grades 3 to 4 in studies 1 and 2 was 75% and 88%, respectively (P = ns). Globally, 5-year overall survival were 68%, with a median of 71 months (range: 50-91). On multivariate analysis, male gender (P = 0.04) and complete response (P = 0.01) were predictive of improved survival. CONCLUSION: HFRT combined with cisplatin and paclitaxel is very active but at the expense of severe toxicity. Efficacy and toxicity in studies.1 and 2 were not different despite completely different treatment strategies (chemotherapy dose intensity vs. radiotherapy dose intensity).

Dosimetric analysis of the patterns of local failure observed in patients with locally advanced non-small cell lung cancer treated with neoadjuvant chemotherapy and concurrent conformal (3D-CRT) chemoradiation.

PURPOSE: Three-dimensional conformal radiation therapy (3D-CRT) represents an advance in the better delineation of the target contours and more accurate dose distributions. The purpose of this study was to identify local control prognostic factors in patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with 3D-CRT. MATERIAL AND METHODS: Between April 1995 and March 2002, 65 patients (NSCLC stage IIIA: 20%, IIIB: 77%) were treated with cisplatin-based induction and concurrent chemotherapy chemotherapy and hyperfractioned 3D-CRT (1.2Gy b.i.d.; median dose: 72.8 (range: 67-85.9). Clinical parameters (sex, age, performance status, stage, histology, tumor location), therapeutic factors (chemotherapy schedule, 3D-CRT dose, treatment response) and dosimetric factors (volume and dose of GTV, PTV-2, CTV and PTV-1) were evaluated. Local recurrences were divided into three dosimetric categories: those with more than 80% of their volume within high dose region (95% of prescription dose) were considered "central"; those between 20% and 80% were considered "marginal", and those with less than 20% of their volume within high dose region were considered "out-of-field". Local-failure free survival (LFFS) was obtained using the Kaplan-Meier method. Univariate and multivariate analyses were performed. RESULTS: There were 18 local failures (nine central, eight marginal and one out-of-field). The 2 and 5 year LFFS were 73% and 53%, respectively. In multivariate analysis, PTV-1>1146cc (HR=2.9, CI 95%: 1.1-7.5, p=0.026) was the only factor associated with worse LFFS. CONCLUSIONS: This study shows that local control was independently related to PTV-1 size. The great majority of local recurrences were located in the high-dose region. Dosimetric parameters may contribute to improving radiotherapy results in multidisciplinary treatment for LA-NSCLC.