P. Giraud

Evaluation of microscopic tumor extension in non-small-cell lung cancer for three-dimensional conformal radiotherapy planning.

PURPOSE One of the most difficult steps of the three-dimensional conformal radiotherapy (3DCRT) is to define the clinical target volume (CTV) according to the degree of local microscopic extension (ME). In this study, we tried to quantify this ME in non-small-cell lung cancer (NSCLC). MATERIAL AND METHODS Seventy NSCLC surgical resection specimens for which the border between tumor and adjacent lung parenchyma were examined on routine sections. This border was identified with the naked eye, outlined with a marker pen, and the value of the local ME outside of this border was measured with an eyepiece micrometer. The pattern of histologic spread was also determined. RESULTS A total of 354 slides were examined, corresponding to 176 slides for adenocarcinoma (ADC) and 178 slides for squamous cell carcinoma (SCC). The mean value of ME was 2.69 mm for ADC and 1.48 mm for SCC (p = 0.01). The usual 5-mm margin covers 80% of the ME for ADC and 91% for SCC. To take into account 95% of the ME, a margin of 8 mm and 6 mm must be chosen for ADC and SCC, respectively. Aerogenous dissemination was the most frequent pattern observed for all groups, followed by lymphatic invasion for ADC and interstitial extension for SCC. CONCLUSION The ME was different between ADC and SCC. The usual CTV margin of 5 mm appears inadequate to cover the ME for either group, and it must be increased to 8 mm and 6 mm for ADC and SCC, respectively, to cover 95% of the ME. This approach is obviously integrated into the overall 3DCRT procedure and with other margins.

Respiratory gating for liver tumors: use in dose escalation.

Abstract Purpose: To determine the clinical impact of the Varian Real-Time Position Monitor (RPM) respiratory gating system for treatment of liver tumors. Methods and Materials: Ten patients with liver tumors were selected for evaluation of this passive system, which tracks motion of reflective markers mounted on the abdomen with an infrared-sensitive camera. At simulation, a fluoroscopic movie, breathing trace, and CT scans synchronized at end-expiration (E-E) and end-inspiration were acquired in treatment position using the RPM system. Organs and gross tumor volume were contoured on each CT. Each organ’s positional change between two scan sets was quantified by calculation of the center of volume shift and an “index coefficient,” defined as the volume common to the two versions of the organ to the volume included in at least one (intersection/union). Treatment dose was determined by use of normal tissue complication probability calculations and dose-volume histograms. Gated portal images were obtained to monitor gating reproducibility with treatment. Results: Eight patients received 177 treatments with RPM gating. Average superior-to-inferior (SI) diaphragm motion on initial fluoroscopy was reduced from 22.7 mm without gating to 5.1 mm with gating. Comparing end-inspiration to E-E CT scans, average SI movement of the right diaphragm was 11.5 mm vs. 2.2 mm for two E-E CT scans. For all organs, average E-I SI organ motion was 12.8 mm vs. 2.0 mm for E-E studies. Index coefficients were closer to 1.0 for E-E than end-inspiration scans, indicating gating reproducibility. The average SI displacement of diaphragm apex on gated portal images compared with DRR was 2.3 mm. Treatment was prolonged less than 10 minutes with gating. The reproducible decrease in organ motion with gating enabled reduction in gross tumor volume-to-planning target volume margin from 2 to 1 cm. This allowed for calculated dose increases of 7%–27% (median: 21.3%) in 6 patients and enabled treatment in 2. Conclusion: Gating of radiotherapy for liver tumors enables safe margin reduction on tumor volume, which, in turn, may allow for dose escalation.

Conformal radiotherapy (CRT) planning for lung cancer: analysis of intrathoracic organ motion during extreme phases of breathing

PURPOSE Conformal radiotherapy beams are defined on the basis of static computed tomography acquisitions by taking into account setup errors and organ/tumor motion during breathing. In the absence of precise data, the size of the margins is estimated arbitrarily. The objective of this study was to evaluate the amplitude of maximum intrathoracic organ motion during breathing. METHODS AND MATERIALS Twenty patients treated for non-small-cell lung cancer were included in the study: 10 patients at the Institut Curie with a personalized alpha cradle immobilization and 10 patients at Tenon Hospital with just the Posirest device below their arms. Three computed tomography acquisitions were performed in the treatment position: the first during free breathing and the other two during deep breath-hold inspiration and expiration. For each acquisition, the displacements of the various intrathoracic structures were measured in three dimensions. RESULTS Patients from the two centers were comparable in terms of age, weight, height, tumor site, and stage. In the overall population, the greatest displacements were observed for the diaphragm, and the smallest displacements were observed for the lung apices and carina. The relative amplitude of motion was comparable between the two centers. The use of a personalized immobilization device reduced lateral thoracic movements (p < 0.02) and lung apex movements (p < 0.02). CONCLUSION Intrathoracic organ movements during extreme phases of breathing are considerable. Quantification of organ motion is necessary for definition of the safety margins. A personalized immobilization device appears to effectively reduce apical and lateral displacement.

CT and 18F-deoxyglucose (FDG) image fusion for optimization of conformal radiotherapy of lung cancers

PURPOSE To validate a computed tomography (CT) and (18)F-deoxyglucose (FDG) image fusion procedure and to evaluate its usefulness to facilitate target definition and treatment planning in three-dimensional conformal radiation therapy (3D-CRT) for non-small-cell lung cancer. METHODS AND MATERIALS Twelve patients were assessed by CT and FDG-coincidence mode dual-head gamma camera (CDET) before radiotherapy. The patients were placed in a similar position during CT and FDG-CDET. Matching was achieved by minimizing the cost function by 3D translation and rotation between four landmarks drawn on the patients skin. Virtual simulation was performed from image fusion and estimated dose-volume histograms (DVH) were calculated. RESULTS Quantitative analysis indicated that the matching error was < 5 mm. Fusion of anatomic and metabolic data corrected staging of lymph nodes (N) for 4 patients and staging of metastases for 1 patient. In these 5 patients, DVH revealed that the lung volume irradiated at 20 Gy (Vl(20)) was decreased by an average of 22.8%, and tumor volume irradiated at the 95% isodose (V(95)) was increased by 22% and 8% for 2 patients, respectively, and was decreased by an average of 59% for 3 patients after fusion. No difference in terms of Vl(20) and V(95) was observed for the other 7 patients. CONCLUSION We have validated CT and FDG-CDET lung image fusion to facilitate determination of lung cancer volumes, which improved the accuracy of 3D-CRT.

Intensity-modulated radiotherapy in head and neck cancer: Results of the prospective study GORTEC 2004–03

BACKGROUND AND PURPOSE In 2003, the French Authority for Health (HAS) recommended the use of intensity modulated radiotherapy (IMRT) in prospective trial before its routine use. The Oncology and Radiotherapy Group for Head and Neck Cancer (GORTEC) proposed to evaluate prospectively acute and late toxicities, locoregional control and overall survival for patients treated for head and neck cancer (HNC) with IMRT and bilateral neck irradiation. MATERIALS AND METHODS Between 2002 and 2008, 208 patients with HNC were treated with IMRT in 8 centres. There were 38 nasopharynx, 117 oropharynx, 25 pharyngo-larynx, 24 oral cavity and 4 unknown primary (28.5% stage I-II and 71% Stage III-IV). Ninety-three patients (46%) had postoperative IMRT and 78 patients (37.5%) received concurrent chemotherapy. The doses were 70 Gy to the gross tumour, 66 Gy to the high-risk postoperative sites and 50 Gy to the subclinical disease. Toxicities were graded according to the RTOG-EORTC scales. RESULTS The median follow-up was 25.3 months (range: 0.4-72 months). There were 29 local-regional failures: 24 were in-field, three were marginal and one was out-field. The two-year loco-regional control and overall survival were 86% and 86.7%, respectively. At 18 months, grade ≥ 2 xerostomia was 16.1%. A mean dose to the spared parotid below 28 Gy led to significantly less grade ≥ 2 xerostomia (8.5% vs 24%) with a relative risk of 1.2 [95% CI: 1.02-1.41, p = 0.03]. Grade ≥ 2 xerostomia increased by approximately 3% per Gy of mean parotid dose up to 28, Gy then 7% per Gy above 33 Gy. CONCLUSIONS IMRT for HN cancer seems to reduce late toxicities without jeopardising local control and overall survival.

Respiratory gating techniques for optimization of lung cancer radiotherapy

Purpose: The primary objective of the STIC 2003 project was to compare the clinical and economic aspects of respiratory-gated conformal radiotherapy (RGRT), an innovative technique proposed to limit the impact of respiratory movements during irradiation, versus conventional conformal radiotherapy, the reference radiation therapy for lung cancer. Methods and Materials: A comparative, nonrandomized, multicenter, and prospective cost toxicity analysis was performed in the context of this project between April 2004 and June 2008 in 20 French centers. Only the results of the clinical study are presented here, as the results of the economic assessment have been published previously. Results: The final results based on 401 evaluable patients confirm the feasibility and good reproducibility of the various RGRT systems. The results of this study demonstrated a marked reduction of dosimetric parameters predictive of pulmonary, cardiac and esophageal toxicity as a result of the various respiratory gating techniques. These dosimetric benefits were mainly observed with deep inspiration breath-hold (DIBH) techniques (ABC and SDX systems), which markedly increased the total lung volume compared with the inspiration-synchronized system based on tidal volume (Real-time Position Management). These theoretical dosimetric benefits were correlated clinically with a significant reduction of pulmonary acute toxicity, and the pulmonary, cardiac, and esophageal late toxicities, especially with DIBH techniques. Pulmonary function parameters, although more heterogeneous, especially DLCO, showed a tendency to reduction of pulmonary toxicity in the RGRT group. Conclusions: RGRT seems to be essential to reduce toxicities, especially the pulmonary, cardiac, and esophageal late toxicities with the DIBH methods.

Big Data and machine learning in radiation oncology: State of the art and future prospects

Precision medicine relies on an increasing amount of heterogeneous data. Advances in radiation oncology, through the use of CT Scan, dosimetry and imaging performed before each fraction, have generated a considerable flow of data that needs to be integrated. In the same time, Electronic Health Records now provide phenotypic profiles of large cohorts of patients that could be correlated to this information. In this review, we describe methods that could be used to create integrative predictive models in radiation oncology. Potential uses of machine learning methods such as support vector machine, artificial neural networks, and deep learning are also discussed.

Epidermal Growth Factor Receptor Protein Detection in Head and Neck Cancer Patients: A Many-Faceted Picture

Purpose: Epidermal growth factor receptor (EGFR) overexpression is associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC). Despite intensive biomarker studies, a consensual method for assessing EGFR protein expression is still lacking. Here we set out to compare three EGFR detection methods in tumor specimens from HNSCC patients. Experimental Design: Tumors were prospectively excised from a series of 79 high-risk HNSCC patients enrolled in a GORTEC-sponsored clinical trial. EGFR expression was determined using a ligand-binding assay on membranes, Western blotting (WB) on membranes and total homogenates, and immunohistochemistry (IHC) on tissue microarrays. In addition, phosphorylated EGFR (pEGFR) was measured by WB on membranes. Results: Distributions and ranges of tumor EGFR expression were method dependent. Moderate positive correlations (Spearman coefficient r ≈ 0.50) were observed between EGFR expression measured by the binding assay and WB or IHC. pEGFR levels positively and significantly correlated with total EGFR expression measured by WB or ligand binding, but not by IHC. The highest correlation (r = 0.85) was observed between EGFR and pEGFR levels, both measured by WB on membranes. Interestingly, the fraction of phosphorylated receptor (pEGFR/EGFR both measured by WB on membranes) significantly declined with increasing tumor EGFR expression, by all assessment methods used. Conclusion: This study shows significant correlations between EGFR detection methods. The observed relationships between EGFR and pEGFR indicate that high-throughput pEGFR/EGFR analyses merit further investigations and consideration for routine use in patient samples. Clin Cancer Res; 18(5); 1313–22. ©2012 AACR.

Male pattern baldness and the risk of prostate cancer

BACKGROUND Androgens play a role in the development of both androgenic alopecia, commonly known as male pattern baldness, and prostate cancer. We set out to study if early-onset androgenic alopecia was associated with an increased risk of prostate cancer later in life. PATIENTS AND METHODS A total of 669 subjects (388 with a history of prostate cancer and 281 without) were enrolled in this study. All subjects were asked to score their balding pattern at ages 20, 30 and 40. Statistical comparison was subsequently done between both groups of patients. RESULTS Our study revealed that patients with prostate cancer were twice as likely to have androgenic alopecia at age 20 [odds ratio (OR) 2.01, P = 0.0285]. The pattern of hair loss was not a predictive factor for the development of cancer. There was no association between early-onset alopecia and an earlier diagnosis of prostate cancer or with the development of more aggressive tumors. CONCLUSIONS This study shows an association between early-onset androgenic alopecia and the development of prostate cancer. Whether this population can benefit from routine prostate cancer screening or systematic use of 5-alpha reductase inhibitors as primary prevention remains to be determined.

Fully 4D list-mode reconstruction applied to respiratory-gated PET scans

(18)F-fluoro-deoxy-glucose ((18)F-FDG) positron emission tomography (PET) is one of the most sensitive and specific imaging modalities for the diagnosis of non-small cell lung cancer. A drawback of PET is that it requires several minutes of acquisition per bed position, which results in images being affected by respiratory blur. Respiratory gating techniques have been developed to deal with respiratory motion in the PET images. However, these techniques considerably increase the level of noise in the reconstructed images unless the acquisition time is increased. The aim of this paper is to evaluate a four-dimensional (4D) image reconstruction algorithm that combines the acquired events in all the gates whilst preserving the motion deblurring. This algorithm was compared to classic ordered subset expectation maximization (OSEM) reconstruction of gated and non-gated images, and to temporal filtering of gated images reconstructed with OSEM. Two datasets were used for comparing the different reconstruction approaches: one involving the NEMA IEC/2001 body phantom in motion, the other obtained using Monte-Carlo simulations of the NCAT breathing phantom. Results show that 4D reconstruction reaches a similar performance in terms of the signal-to-noise ratio (SNR) as non-gated reconstruction whilst preserving the motion deblurring. In particular, 4D reconstruction improves the SNR compared to respiratory-gated images reconstructed with the OSEM algorithm. Temporal filtering of the OSEM-reconstructed images helps improve the SNR, but does not achieve the same performance as 4D reconstruction. 4D reconstruction of respiratory-gated images thus appears as a promising tool to reach the same performance in terms of the SNR as non-gated acquisitions while reducing the motion blur, without increasing the acquisition time.