The role of a knowledge based dose-volume histogram predictive model in the optimisation of intensity-modulated proton plans for hepatocellular carcinoma patients : Training and validation of a novel commercial system.

PURPOSE: To investigate the performance of a knowledge-based RapidPlan, for optimisation of intensity-modulated proton therapy (IMPT) plans applied to hepatocellular cancer (HCC) patients. METHODS: A cohort of 65 patients was retrospectively selected: 50 were used to "train" the model, while the remaining 15 provided independent validation. The performance of the RapidPlan model was benchmarked against manual optimisation and was also compared to volumetric modulated arc therapy (RapidArc) photon plans. A subanalysis appraised the performance of the RapidPlan model applied to patients with lesions ≤300 cm3 or larger. Quantitative assessment was based on several metrics derived from the constraints of the NRG-GI003 clinical trial. RESULTS: There was an equivalence between manual plans and RapidPlan-optimised IMPT plans, which outperformed the RapidArc plans. The planning dose-volume objectives were met on average for all structures except for D0.5 cm3 ≤30 Gy in the bowels. Limiting the results to the class-solution proton plans (all values in Gy), the data for manual plans vs RapidPlan-based IMPT plans, respectively, showed the following: D99% to the target of 47.5 ± 1.4 vs 47.2 ± 1.2; for organs at risk, the mean dose to the healthy liver was 6.7 ± 3.6 vs 6.7 ± 3.7; the mean dose to the kidneys was 0.2 ± 0.5 vs 0.1 ± 0.2; D0.5 cm3 for the bowels was 33.4 ± 16.4 vs 30.2 ± 16.0; for the stomach was 17.9 ± 19.9 vs 14.9 ± 18.8; for the oesophagus was 17.9 ± 15.1 vs 14.9 ± 13.9; for the spinal cord was 0.5 ± 1.6 vs 0.2 ± 0.7. The model performed similarly for cases with small or large lesions. CONCLUSION: A knowledge-based RapidPlan model was trained and validated for IMPT. The results demonstrate that RapidPlan can be trained adequately for IMPT in HCC. The quality of the RapidPlan-based plans is at least equivalent compared to what is achievable with manual planning. RapidPlan also confirmed the potential to optimise the quality of the proton therapy results, thus reducing the impact of operator planning skills on patient results.

Radiomics based analysis to predict local control and survival in hepatocellular carcinoma patients treated with volumetric modulated arc therapy.

BACKGROUND: To appraise the ability of a radiomics based analysis to predict local response and overall survival for patients with hepatocellular carcinoma. METHODS: A set of 138 consecutive patients (112 males and 26 females, median age 66 years) presented with Barcelona Clinic Liver Cancer (BCLC) stage A to C were retrospectively studied. For a subset of these patients (106) complete information about treatment outcome, namely local control, was available. Radiomic features were computed for the clinical target volume. A total of 35 features were extracted and analyzed. Univariate analysis was used to identify clinical and radiomics significant features. Multivariate models by Cox-regression hazards model were built for local control and survival outcome. Models were evaluated by area under the curve (AUC) of receiver operating characteristic (ROC) curve. For the LC analysis, two models selecting two groups of uncorrelated features were analyzes while one single model was built for the OS analysis. RESULTS: The univariate analysis lead to the identification of 15 significant radiomics features but the analysis of cross correlation showed several cross related covariates. The un-correlated variables were used to build two separate models; both resulted into a single significant radiomic covariate: model-1: energy p < 0.05, AUC of ROC 0.6659, C.I.: 0.5585-0.7732; model-2: GLNU p < 0.05, AUC 0.6396, C.I.:0.5266-0.7526. The univariate analysis for covariates significant with respect to local control resulted in 9 clinical and 13 radiomics features with multiple and complex cross-correlations. After elastic net regularization, the most significant covariates were compacity and BCLC stage, with only compacity significant to Cox model fitting (Cox model likelihood ratio test p < 0.0001, compacity p < 0.00001; AUC of the model is 0.8014 (C.I. = 0.7232-0.8797)). CONCLUSION: A robust radiomic signature, made by one single feature was finally identified. A validation phases, based on independent set of patients is scheduled to be performed to confirm the results.

Stereotactic body radiation therapy in hepatocellular carcinoma: Optimal treatment strategies based on liver segmentation and functional hepatic reserve.

AIM: To discuss current dosage for stereotactic body radiation therapy (SBRT) in hepatocellular carcinoma (HCC) patients and suggest alternative treatment strategies according to liver segmentation as defined by the Couinaud classification. BACKGROUND: SBRT is a safe and effective alternative treatment for HCC patients who are unable to undergo liver ablation/resection. However, the SBRT fractionation schemes and treatment planning strategies are not well established. MATERIALS AND METHODS: In this article, the latest developments and key findings from research studies exploring the efficacy of SBRT fractionation schemes for treatment of HCC are reviewed. Patients' characteristics, fractionation schemes, treatment outcomes and toxicities were compiled. Special attention was focused on SBRT fractionation approaches that take into consideration liver segmentation according to the Couinaud classification and functional hepatic reserve based on Child-Pugh (CP) liver cirrhosis classification. RESULTS: The most common SBRT fractionation schemes for HCC were 3 × 10-20 Gy, 4-6 × 8-10 Gy, and 10 × 5-5.5 Gy. Based on previous SBRT studies, and in consideration of tumor size and CP classification, we proposed 3 × 15-25 Gy for patients with tumor size <3 cm and adequate liver reserve (CP-A score 5), 5 × 10-12 Gy for patients with tumor sizes between 3 and 5 cm or inadequate liver reserve (CP-A score 6), and 10 × 5-5.5 Gy for patients with tumor size >5 cm or CP-B score. CONCLUSIONS: Treatment schemes in SBRT for HCC vary according to liver segmentation and functional hepatic reserve. Further prospective studies may be necessary to identify the optimal dose of SBRT for HCC.

Mini-nutritional assessment predicts functional status and quality of life of patients with hepatocellular carcinoma in Taiwan.

This study aimed to determine the possibility of using the Mini-Nutritional Assessment (MNA) to evaluate the quality of life and functional status in patients with hepatocellular carcinoma (HCC). The study recruited 300 outpatients with HCC from a teaching hospital in Central Taiwan to serve as subjects. All subjects were interviewed with a structured questionnaire for rating the nutritional status with the MNA (long-form and short-form), and for evaluating quality of life and functional status with Global Quality of Life (GQL) and Global Functional Status (GFS), respectively, of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 version-3. Cancer staging and liver cirrhosis indicators, blood biochemical indicators, and self-rated health status and mobility were used as reference standards. Results showed that based on the strength of the correlation and association with the reference standards, both the long-form and short-form of the MNA performed better than GQL and GFS in predicting quality of life and functional status of patients with HCC. These results suggest that the MNA is suitable for identifying the risk of deteriorating quality of life or functional status, in addition to identifying the risk of malnutrition, in patients with HCC.

Comparison of surgery or radiotherapy on complications and quality of life in patients with the stage IB and IIA uterine cervical cancer.

OBJECTIVES: To compare the long-term complications and quality of life of patients with stage IB and stage IIA uterine cervical carcinoma treated by surgery or radiotherapy. METHODS: From August 2003 to May 2004, 202 patients with uterine cervical carcinoma were treated with surgery or radiotherapy at two institutions and were enrolled in this study upon follow-up at least 2 years post treatment. All patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and complications Questionnaire. RESULTS: Constipation (p<0.001), flushing (p<0.001), dysuria (p<0.001), urinary incontinence (p<0.01), dysparia (p<0.05) and vaginal dryness (p<0.05) were statistically higher in the surgery treated group, while diarrhea (p<0.001), bloody stools (p<0.001) and abdominal pain (p<0.01) were higher in the radiotherapy group. Using factor analysis and introducing personal conditioned variables, pelvic neural dysfunction was significantly higher in surgery group and intestinal dysfunction was higher in radiotherapy group. There was no difference in sexual dysfunction between these two modalities. Comparison of EORTC QLQ-C30 showed that the majority of issues had minimal differences between these two treatment modalities, except social functioning (p<0.05; higher in radiotherapy group), constipation (p<0.001; higher in surgery group) and diarrhea (p<0.01; higher in radiotherapy group). CONCLUSIONS: In early stage uterine cervical cancer patients, surgery or radiotherapy resulted in different complications, whereas long-term quality of life showed few differences between these two different modalities. These data were helpful for physicians in regards to the changes of patients, and moreover, for rehabilitation and supportive care of the patients after treatment.

Assessment of a model based optimization engine for volumetric modulated arc therapy for patients with advanced hepatocellular cancer.

BACKGROUND: To evaluate in-silico the performance of a model-based optimization process for volumetric modulated arc therapy (RapidArc) applied to hepatocellular cancer treatments. PATIENTS AND METHODS: 45 clinically accepted RA plans were selected to train a knowledge-based engine for the prediction of individualized dose-volume constraints. The model was validated on the same plans used for training (closed-loop) and on a set of other 25 plans not used for the training (open-loop). Dose prescription, target size, localization in the liver and arc configuration were highly variable in both sets to appraise the power of generalization of the engine. Quantitative dose volume histogram analysis was performed as well as a pass-fail analysis against a set of 8 clinical dose-volume objectives to appraise the quality of the new plans. RESULTS: Qualitative and quantitative equivalence was observed between the clinical and the test plans. The use of model-based optimization lead to a net improvement in the pass-rate of the clinical objectives compared to the plans originally optimized with standard methods (this pass-rate is the frequency of cases where the objectives are respected vs. the cases where constraints are not fulfilled). The increase in the pass-rate resulted of 2.0%, 0.9% and 0.5% in a closed-loop and two different open-loop validation experiments. CONCLUSIONS: A knowledge-based engine for the optimization of RapidArc plans was tested and lead to clinically acceptable plans in the case of hepatocellular cancer radiotherapy. More studies are needed before a broad clinical use.

Feasibility of stereotactic body radiation therapy with volumetric modulated arc therapy and high intensity photon beams for hepatocellular carcinoma patients.

BACKGROUND: To report technical features, early outcome and toxicity of stereotactic body radiation therapy (SBRT) treatments with volumetric modulated arc therapy (RapidArc) for patients with hepatocellular carcinoma (HCC). METHODS: Twenty patients (22 lesions) were prospectively enrolled in a feasibility study. Dose prescription was 50 Gy in 10 fractions. Seven patients (35%) were classified as AJCC stage I-II while 13 (65%) were stages III-IV. Eighteen patients (90%) were Child-Pugh stage A, the remaining were stage B. All patients were treated with RapidArc technique with flattening filter free (FFF) photon beams of 10 MV from a TrueBeam linear accelerator. Technical, dosimetric and early clinical assessment was performed to characterize treatment and its potential outcome. RESULTS: Median age was 68 years, median initial tumor volume was 124 cm3 (range: 6-848). Median follow-up time was 7.4 months (range: 3-13). All patients completed treatment without interruption. Mean actuarial overall survival was of 9.6 ± 0.9 months (95%C.L. 7.8-11.4), median survival was not reached; complete response was observed in 8/22 (36.4%) lesions; partial response in 7/22 (31.8%), stable disease in 6/22 (27.3%), 1/22 (4.4%) showed progression. Toxicity was mild with only 1 case of grade 3 RILD and all other types were not greater than grade 2. Concerning dosimetric data, Paddick conformity index was 0.98 ± 0.02; gradient index was 3.82 ± 0.93; V95% to the clinical target volume was 93.6 ± 7.7%. Mean dose to kidneys resulted lower than 3.0 Gy; mean dose to stomach 4.5 ± 3.0 Gy; D(3) 1(cm) to spinal cord was 8.2 ± 4.5 Gy; D1% to the esophagus was 10.2 ± 9.7 Gy. Average beam on time resulted 0.7 ± 0.2 minutes (range: 0.4-1.4) with the delivery of an average of 4.4 partial arcs (range: 3-6) of those 86% non-coplanar. CONCLUSIONS: Clinical results could suggest to introduce VMAT-RapidArc as an appropriate SBRT technique for patients with HCC in view of a prospective dose escalation trial.

Radiation treatment with volumetric modulated arc therapy of hepatocellular carcinoma patients. Early clinical outcome and toxicity profile from a retrospective analysis of 138 patients.

BACKGROUND: To report early outcome and toxicity for inoperable patients with hepatocellular carcinoma (HCC) treated with volumetric modulated arc therapy (VMAT). METHODS: One hundred and thirty eight patients were retrospectively analysed. Dose prescription ranged from 45 to 66 Gy with conventional fractionation regime. Based on AJCC staging, 88.4% presented stage III or IV. Two-thirds (69.6%) were Child-Pugh stage A, the remaining were stage B. According to Barcelona Clinic Liver Cancer staging, 72.5% of patients were classified as stage C. RESULTS: Median age was 66 years, median tumor volume was 516 cm(3) (28 to 3620 cm(3)). The most patients (83%) were treated with 60 Gy. Median follow-up time was 9 months. One-year overall survival rate was 45% (100% for AJCC stage I, 83% for stage II, 45% for stage III and 28% for stage IV), median survival was 10.3 months (95% C.I. 7.2-13.3). Local control was achieved in 94% (of 109 assessable patients), stable disease in 29%, partial response in 53%, complete response in 11%, and progression in 6%. Radiation-induced liver disease was observed in 34 patients (25%). Gastrointestinal grade 3 toxicity was modest with a total of 17 (12.3%) cases for all endpoints. CONCLUSIONS: Clinical results could suggest to introduce VMAT as an appropriate technique for the patients with HCC.

Results of three-dimensional conformal radiotherapy and thalidomide for advanced hepatocellular carcinoma.

PURPOSE: To evaluate the effectiveness of three-dimensional conformal radiotherapy and thalidomide in the treatment of advanced hepatocellular carcinoma. METHODS: Between 1999 and 2003, 121 patients (mean age, 54.4 +/- 12.4 years; range, 20-81 years) with advanced hepatocellular carcinoma received three-dimensional conformal radiotherapy and thalidomide. Radiation was delivered in 1.5 Gy fractions twice daily for 5 days a week, for a total dose of 45-75 Gy. Mean treatment volume was 429.52 +/- 408.50 cm(3) (range, 26.89-2284.82 cm(3)). Thalidomide was given concomitantly: 200 mg/day in 109 patients, 300 mg/day in 8 patients and 400 mg/day in 4 patients. Treatment responses, survival rates and factors affecting survival were analyzed. RESULTS: Treatment responses were observed in 61% of the patients. Liver cirrhosis (P = 0.001) and tumor size (P = 0.001) significantly affected the tumor responses. Overall survival at 6, 12 and 24 months was 84.8, 60.0 and 44.6%, respectively. On univariate analysis, liver cirrhosis (P = 0.003), Karnofsky performance status (P = 0.007), tumor size (P < 0.001), portal vein tumor thrombosis (P < 0.001) and alpha-fetoprotein level (P = 0.003) were shown to significantly affect survival. On multivariate analysis, only thrombosis (P = 0.039) and alpha-fetoprotein level (P = 0.006) were shown to be factors affecting survival. CONCLUSIONS: Three-dimensional conformal radiotherapy with thalidomide seems to be effective in the treatment of advanced hepatocellular carcinoma.

Impact of magnetic resonance imaging versus CT on nasopharyngeal carcinoma: primary tumor target delineation for radiotherapy.

BACKGROUND: Our aim was to assess the capacity of CT versus MRI for delineating to the primary tumor extent of nasopharyngeal carcinoma (NPC) in treated patients. METHODS: From December 1997 to April 2000, 258 patients with NPC were enrolled. We focused on the primary tumor extension and the discrepancy between CT and MRI. The delineation of tumor invasion was crucial for determination of the gross tumor volume (GTV) before radiation therapy. RESULTS: A total of 104 patients (40.3%) had intracranial infiltration detected by MRI, whereas CT showed negative findings (p = 6.879 x 10(-11)). Once the pterygopalatine fossa was involved, the chance of intracranial invasion was increased (96.1%). The detectable percentage of pterygopalatine fossa involvement accompanying intracranial invasion was higher with MRI than with CT (96.1% vs 56.9%). CONCLUSIONS: More detailed information about T and N classification of NPC was provided by MRI than by CT, which led to better target delineation for radiotherapy.