Marta Moreno-Jiménez

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.

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.

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

BackgroundStereotactic 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 presentationA 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.ConclusionThough 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.

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.

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/m2) and cisplatin (100 mg/m2) 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/m2) and cisplatin (30 mg/m2). 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).

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.

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.

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/β = 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.

Relationship between Day 0 dosimetric parameters and biochemical relapse-free survival in patients treated with transperineal permanent prostate interstitial brachytherapy with 125I 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) </=147Gy subsets using the ASTRO, nadir+2, and combined definitions were 96.5% vs. 89.7% (ASTRO, p=0.076); 93.7% vs. 70.5% (nadir+2, p=0.064); and 94.4 vs. 75.5% (combined, p=0.033). The V(100) (%) cutoff value of 92% predicted by the ROC analysis was not significant. Among other cutoff values, only D(90)=140Gy (p=0.050) and D(90)=160Gy (p=0.098) showed a trend toward statistical significance when the nadir+2 and the ASTRO definitions were used. The rest of dosimetric, tumor, and patient parameters did not show statistical correlation with bRFS in the Kaplan-Meier analysis. CONCLUSIONS The cutoff value of D(90)=147Gy obtained on postimplantation Day 0 showed a trend toward significant correlation with bRFS when the standard ASTRO and nadir+2 definitions were used and a weak but statistically significant correlation with bRFS as per the nonstandard combined definition in a series of patients with predominantly low-risk disease (70.4%) treated at high radiation doses (median D(90)=152.9Gy, median V(100)=92.5%).