Knowledge-based automatic optimization of adaptive early-regression-guided VMAT for rectal cancer.

PURPOSE: To implement a knowledge-based (KB) optimization strategy to our adaptive (ART) early-regression guided boosting technique in neo-adjuvant radio-chemotherapy for rectal cancer. MATERIAL AND METHODS: The protocol consists of a first phase delivering 27.6 Gy to tumor/lymph-nodes (2.3 Gy/fr-PTV1), followed by the ART phase concomitantly delivering 18.6 Gy (3.1 Gy/fr) and 13.8 Gy (2.3 Gy/fr) to the residual tumor (PTVART) and to PTV1 respectively. PTVART is obtained by expanding the residual GTV, as visible on MRI at fraction 9. Forty plans were used to generate a KB-model for the first phase using the RapidPlan tool. Instead of building a new model, a robust strategy scaling the KB-model to the ART phase was applied. Both internal and external validation were performed for both phases: all automatic plans (RP) were compared in terms of OARs/PTVs parameters against the original plans (RA). RESULTS: The resulting automatic plans were generally better than or equivalent to clinical plans. Of note, V30Gy and V40Gy were significantly improved in RP plans for bladder and bowel; gEUD analysis showed improvement for KB-modality for all OARs, up to 3 Gy for the bowel. CONCLUSIONS: The KB-model generated for the first phase was robust and it was also efficiently adapted to the ART phase. The performance of automatically generated plans were slightly better than the corresponding manual plans for both phases.

Accurate outcome prediction after neo-adjuvant radio-chemotherapy for rectal cancer based on a TCP-based early regression index.

BACKGROUND AND PURPOSE: An early tumor regression index (ERITCP) was previously introduced and found to predict pathological response after neo-adjuvant radio-chemotherapy of rectal cancer. ERITCP was tested as a potential biomarker in predicting long-term disease-free survival. MATERIALS AND METHODS: Data of 65 patients treated with an early regression-guided adaptive boosting technique (ART) were available. Overall, loco-regional relapse-free and distant metastasis-free survival (OS, LRFS, DMFS) were considered. Patients received 41.4 Gy in 18 fractions (2.3 Gy/fr), including ART concomitant boost on the residual GTV during the last 6 fractions (3 Gy/fr, Dmean: 45.6 Gy). Chemotherapy included oxaliplatin and 5-fluorouracil (5-FU). T2-weighted MRI taken before (MRIpre) and at half therapy (MRIhalf) were available and GTVs were contoured (Vpre, Vhalf). The parameter ERITCP = -ln[(1 - (Vhalf/Vpre))Vpre] was calculated for all patients. Cox regression models were assessed considering several clinical and histological variables. Cox models not including/including ERITCP (CONV_model and REGR_model respectively) were assessed and their discriminative power compared. RESULTS: At a median follow-up of 47 months, OS, LRFS and DMFS were 94%, 95% and 78%. Due to too few events, multivariable analyses focused on DMFS: the resulting CONV_model included pathological complete remission or clinical complete remission followed by surgery refusal (HR: 0.15, p = 0.07) and 5-FU dose >90% (HR: 0.29, p = 0.03) as best predictors, with AUC = 0.75. REGR_model included ERITCP (HR: 1.019, p < 0.0001) and 5-FU dose >90% (HR: 0.18, p = 0.005); AUC was 0.86, significantly higher than CONV_model (p = 0.05). Stratifying patients according to the best cut-off value for ERITCP and to 5-FU dose (> vs <90%) resulted in 47-month DMFS equal to 100%/69%/0% for patients with two/one/zero positive factors respectively (p = 0.0002). ERITCP was also the only variable significantly associated to OS (p = 0.01) and LRFS (p = 0.03). CONCLUSION: ERITCP predicts long-term DMFS after radio-chemotherapy for rectal cancer: an independent impact of the 5-FU dose was also found. This result represents a first step toward application of ERITCP in treatment personalization: additional confirmation on independent cohorts is warranted.

Ct radiomic features of pancreatic neuroendocrine neoplasms (panNEN) are robust against delineation uncertainty.

PURPOSE: The aim of this study was to quantify the impact of CT delineation uncertainty of pancreatic neuroendocrine neoplasms (panNEN) on Radiomic features (RF). METHODS: Thirty-one previously operated patients were considered. Three expert radiologists contoured panNEN lesions on pre-surgical high-resolution contrast-enhanced CT images and contours were transferred onto pre-contrast CT. Volume agreement was quantified by the DICE index. After images resampling and re-binning, 69 RF were extracted and the impact of inter-observer variability was assessed by Intra-Class Correlation (ICC): ICC > 0.80 was considered as a threshold for "very high" inter-observer agreement. RESULTS: The median volume was 1.3 cc (range: 0.2-110 cc); a satisfactory inter-observer volume agreement was found (mean DICE = 0.78). Only 4 RF showed ICC < 0.80 (0.48-0.73), including asphericity and three RFs (of five) of the neighborhood intensity difference matrix (NID). CONCLUSIONS: The impact of inter-observer variability in delineating panNEN on RF was minimum, with the exception of the NID family and asphericity, showing a moderate agreement. These results support the feasibility of studies aiming to assess CT radiomic biomarkers for panNEN.

A TCP-based early regression index predicts the pathological response in neo-adjuvant radio-chemotherapy of rectal cancer.

PURPOSE: Introducing a radiobiological index based on early tumor regression during neo-adjuvant radio-chemotherapy (RCT, including oxaliplatin) of rectal adenocarcinoma and testing its discriminative power in predicting the tumor response. METHODS: Seventy-four patients were treated with Helical Tomotherapy following an adaptive (ART) protocol (41.4 Gy/18 fr, 2.3 Gy/fr) delivering a simultaneous integrated boost on the residual tumor in the last 6 fractions up to 45.6 Gy. T2-weighted MRI were taken before (MRIpre) and at mid (MRImid) therapy and the corresponding tumor volumes were considered (Vpre,Vmid). The "Early Regression Index" [Formula: see text] was introduced and its discriminative power was assessed in terms of AUC, sensitivity/specificity, positive/negative predictive value (PPV/NPV). Two end-points were considered: (a) pathological complete response (pCR) or clinical complete response followed by watch-and-wait, (cCR); (b) limited response (residual vital cells (RVC) in the surgical specimen >10%). RESULTS: Complete data were available for 65 patients: pCR, cCR and RVC >10% were 20, 2 and 19 respectively. The discriminative power of ERITCP was moderately high (AUC = 0.81/0.75 for /pCRorcCR/RVC >10% respectively, p < 0.0005). ERITCP was highly sensitive (86-89%) with very high NPV (90-94%). The discriminative power of ERITCP was confirmed on a subgroup of 44/65 patients when considering tumor volumes delineated by a skilled radiologist. CONCLUSION: A radiobiologically consistent index based on early regression showed high performances in predicting the pathological response after neo-adjuvant RCT for rectal cancer with relevant potentialities for ART/treatment customization.

Hypofractionated image-guided IMRT in advanced pancreatic cancer with simultaneous integrated boost to infiltrated vessels concomitant with capecitabine: a phase I study.

PURPOSE: To determine the maximum tolerated radiation dose (MTD) of an integrated boost to the tumor subvolume infiltrating vessels, delivered simultaneously with radical dose to the whole tumor and concomitant capecitabine in patients with pretreated advanced pancreatic adenocarcinoma. METHODS AND MATERIALS: Patients with stage III or IV pancreatic adenocarcinoma without progressive disease after induction chemotherapy were eligible. Patients underwent simulated contrast-enhanced four-dimensional computed tomography and fluorodeoxyglucose-labeled positron emission tomography. Gross tumor volume 1 (GTV1), the tumor, and GTV2, the tumor subvolume 1 cm around the infiltrated vessels, were contoured. GTVs were fused to generate Internal Target Volume (ITV)1 and ITV2. Biological tumor volume (BTV) was fused with ITV1 to create the BTV+Internal Target Volume (ITV) 1. A margin of 5/5/7 mm (7 mm in cranium-caudal) was added to BTV+ITV1 and to ITV2 to create Planning Target Volume (PTV) 1 and PTV2, respectively. Radiation therapy was delivered with tomotherapy. PTV1 received a fixed dose of 44.25 Gy in 15 fractions, and PTV2 received a dose escalation from 48 to 58 Gy as simultaneous integrated boost (SIB) in consecutive groups of at least 3 patients. Concomitant chemotherapy was capecitabine, 1250 mg/m(2) daily. Dose-limiting toxicity (DLT) was defined as any treatment-related G3 nonhematological or G4 hematological toxicity occurring during the treatment or within 90 days from its completion. RESULTS: From June 2005 to February 2010, 25 patients were enrolled. The dose escalation on the SIB was stopped at 58 Gy without reaching the MTD. One patient in the 2(nd) dose level (50 Gy) had a DLT: G3 acute gastric ulcer. Three patients had G3 late adverse effects associated with gastric and/or duodenal mucosal damage. All patients received the planned dose of radiation. CONCLUSIONS: A dose of 44.25 Gy in 15 fractions to the whole tumor with an SIB of 58 Gy to small tumor subvolumes concomitant with capecitabine is feasible in chemotherapy-pretreated patients with advanced pancreatic cancer.

Dosimetric and clinical predictors of toxicity following combined chemotherapy and moderately hypofractionated rotational radiotherapy of locally advanced pancreatic adenocarcinoma.

BACKGROUND AND PURPOSE: Hypofractionated radiotherapy (RT) of pancreatic adenocarcinoma is limited by the tolerance of adjacent normal tissues. A better understanding of the influence of dosimetric variables on the rate of toxicity after RT must be considered an important goal. METHODS AND MATERIALS: Sixty-one patients with histologically proven locally advanced disease (LAPD) were analyzed. The therapeutic strategy consisted of induction chemotherapy (ChT) followed by concurrent chemoradiotherapy (CRT). In 39 out of 61 patients the target volume was based on a four-dimensional CT (4D-CT) procedure. Delivered dose was 44.25Gy in 15 fractions to PTV2, which consisted of pancreatic tumor and regional lymph nodes considered radiologically involved; 23 out of 61 patients received a simultaneous integrated boost (SIB) to a tumor sub-volume infiltrating the great abdominal vessels (PTV1) with dose in the range of 48-58Gy. RT was delivered with Helical Tomotherapy. Dose-volume histograms (DVHs) of target volumes and organs at risk (OARs) were collected for analysis. The predictive value of clinical/dosimetric parameters was tested by univariate/multivariate analyses. RESULTS: The crude incidence of acute gastrointestinal (GI) grade 2 toxicity was 33%. The 12-month actuarial rate of "anatomical" (gastro-duodenal mucosa damage) toxicity was 13% (95% CI: 4-22%). On univariate analysis, several stomach and duodenum DVH endpoints are predictive of toxicity after moderately hypofractionated radiotherapy. Multivariate analysis confirmed that baseline performance status and the stomach V20[%] were strong independent predictors of acute GI grade ⩾2 toxicity. The high-dose region of duodenum DVH (V45[%]; V40[%]) was strongly correlated with grade ⩾2 "anatomical" toxicity; the best V40[%] and V45[%] cut-off values were 16% and 2.6% respectively. CONCLUSION: Regarding dosimetric indices, stomach V20[%] correlates with a higher rate of acute toxicity; more severe acute and late anatomical toxicities are related to the high dose region of duodenum DVH.

Validation of an elastic registration technique to estimate anatomical lung modification in non-small-cell lung cancer tomotherapy.

BACKGROUND: The study of lung parenchyma anatomical modification is useful to estimate dose discrepancies during the radiation treatment of Non-Small-Cell Lung Cancer (NSCLC) patients. We propose and validate a method, based on free-form deformation and mutual information, to elastically register planning kVCT with daily MVCT images, to estimate lung parenchyma modification during Tomotherapy. METHODS: We analyzed 15 registrations between the planning kVCT and 3 MVCT images for each of the 5 NSCLC patients. Image registration accuracy was evaluated by visual inspection and, quantitatively, by Correlation Coefficients (CC) and Target Registration Errors (TRE). Finally, a lung volume correspondence analysis was performed to specifically evaluate registration accuracy in lungs. RESULTS: Results showed that elastic registration was always satisfactory, both qualitatively and quantitatively: TRE after elastic registration (average value of 3.6 mm) remained comparable and often smaller than voxel resolution. Lung volume variations were well estimated by elastic registration (average volume and centroid errors of 1.78% and 0.87 mm, respectively). CONCLUSIONS: Our results demonstrate that this method is able to estimate lung deformations in thorax MVCT, with an accuracy within 3.6 mm comparable or smaller than the voxel dimension of the kVCT and MVCT images. It could be used to estimate lung parenchyma dose variations in thoracic Tomotherapy.

Planning design of locally advanced pancreatic carcinoma using 4DCT and IMRT/IGRT technologies.

BACKGROUND AND PURPOSE: to study the impact of the 4DCT imaging technique on radiotherapy planning for pancreatic carcinoma. To evaluate the possibility of IMRT/IGRT to increase the dose to PTV subvolume. MATERIAL AND METHODS: contrast-enhanced 4DCT scans of 15 patients (PTs) with unresectable pancreatic cancer were acquired. A 4DCT based PTV (4D-PTV) was created by the convolution of contours and then expanded for geometric uncertainties; a standard PTV (STD-PTV) was derived from a single CTV plus conventional margins. Two 3D conformal treatment (3DCRT) plans and one Helical Tomotherapy (HT) plan were generated with a prescription of 60 Gy. Regarding the 3DCRT plans, the 4D-PTV was considered as the target volume for one, and the STD-PTV for the other; the HT plans were performed only for 4D-PTV. Twelve of 15 PTs were admitted to a Phase I hypofractionated study (15 fractions). The prescribed dose was 44.25 Gy to the 4D-PTV and the PTV subvolume around vascular involvement was boosted from 50 to 55 Gy; before treatment, daily patient position was corrected using MVCT. RESULTS: 4D-PTVs were smaller than STD-PTVs with a volume reduction equal to 37%. 3DCRT plans on 4D-PTV showed a significant sparing of most OARs, the use of IMRT allowed a further significant dose reduction. In the Phase I study the PTV subvolume received up to 55 Gy with modest increase in dose to OARs. CONCLUSIONS: the 4DCT procedure decreases the overlap between PTV and OARs. HT technique, compared with 3DCRT, allows efficient dose sparing in particular for the duodenum. The IMRT/IGRT approach allows a safe dose escalation to PTV subvolume.

Contrast enhanced 4D-CT imaging for target volume definition in pancreatic ductal adenocarcinoma.

A procedure to improve target volume definition in pancreatic ductal adenocarcinoma by contrast enhanced 4D-CT imaging has been implemented for radiotherapy planning. The procedure allows good quality images to be obtained over the whole patient's breathing cycle in terms of anatomical details, pancreatic enhancement and vessel definition.