Predictive and prognostic value of tumor volume and its changes during radical radiotherapy of stage III non-small cell lung cancer : A systematic review.

PURPOSE: Lung cancer remains the leading cause of cancer-related mortality worldwide. Stage III non-small cell lung cancer (NSCLC) includes heterogeneous presentation of the disease including lymph node involvement and large tumour volumes with infiltration of the mediastinum, heart or spine. In the treatment of stage III NSCLC an interdisciplinary approach including radiotherapy is considered standard of care with acceptable toxicity and improved clinical outcome concerning local control. Furthermore, gross tumour volume (GTV) changes during definitive radiotherapy would allow for adaptive replanning which offers normal tissue sparing and dose escalation. METHODS: A literature review was conducted to describe the predictive value of GTV changes during definitive radiotherapy especially focussing on overall survival. The literature search was conducted in a two-step review process using PubMed®/Medline® with the key words "stage III non-small cell lung cancer" and "radiotherapy" and "tumour volume" and "prognostic factors". RESULTS: After final consideration 17, 14 and 9 studies with a total of 2516, 784 and 639 patients on predictive impact of GTV, GTV changes and its impact on overall survival, respectively, for definitive radiotherapy for stage III NSCLC were included in this review. Initial GTV is an important prognostic factor for overall survival in several studies, but the time of evaluation and the value of histology need to be further investigated. GTV changes during RT differ widely, optimal timing for re-evaluation of GTV and their predictive value for prognosis needs to be clarified. The prognostic value of GTV changes is unclear due to varying study qualities, re-evaluation time and conflicting results. CONCLUSION: The main findings were that the clinical impact of GTV changes during definitive radiotherapy is still unclear due to heterogeneous study designs with varying quality. Several potential confounding variables were found and need to be considered for future studies to evaluate GTV changes during definitive radiotherapy with respect to treatment outcome.

Applied Swarm-based medicine: collecting decision trees for patterns of algorithms analysis.

BACKGROUND: The objective consensus methodology has recently been applied in consensus finding in several studies on medical decision-making among clinical experts or guidelines. The main advantages of this method are an automated analysis and comparison of treatment algorithms of the participating centers which can be performed anonymously. METHODS: Based on the experience from completed consensus analyses, the main steps for the successful implementation of the objective consensus methodology were identified and discussed among the main investigators. RESULTS: The following steps for the successful collection and conversion of decision trees were identified and defined in detail: problem definition, population selection, draft input collection, tree conversion, criteria adaptation, problem re-evaluation, results distribution and refinement, tree finalisation, and analysis. CONCLUSION: This manuscript provides information on the main steps for successful collection of decision trees and summarizes important aspects at each point of the analysis.

Consensus and differences in primary radiotherapy for localized and locally advanced prostate cancer in Switzerland: A survey on patterns of practice.

INTRODUCTION: External beam radiotherapy (EBRT), with or without androgen deprivation therapy (ADT), is an established treatment option for nonmetastatic prostate cancer. Despite high-level evidence from several randomized trials, risk group stratification and treatment recommendations vary due to contradictory or inconclusive data, particularly with regard to EBRT dose prescription and ADT duration. Our aim was to investigate current patterns of practice in primary EBRT for prostate cancer in Switzerland. MATERIALS AND METHODS: Treatment recommendations on EBRT and ADT for localized and locally advanced prostate cancer were collected from 23 Swiss radiation oncology centers. Written recommendations were converted into center-specific decision trees, and analyzed for consensus and differences using a dedicated software tool. Additionally, specific radiotherapy planning and delivery techniques from the participating centers were assessed. RESULTS: The most commonly prescribed radiation dose was 78 Gy (range 70-80 Gy) across all risk groups. ADT was recommended for intermediate-risk patients for 6 months in over 80 % of the centers, and for high-risk patients for 2 or 3 years in over 90 % of centers. For recommendations on combined EBRT and ADT treatment, consensus levels did not exceed 39 % in any clinical scenario. Arc-based intensity-modulated radiotherapy (IMRT) is implemented for routine prostate cancer radiotherapy by 96 % of the centers. CONCLUSION: Among Swiss radiation oncology centers, considerable ranges of radiotherapy dose and ADT duration are routinely offered for localized and locally advanced prostate cancer. In the vast majority of cases, doses and durations are within the range of those described in current evidence-based guidelines.

Radiotherapy for lentigo maligna and lentigo maligna melanoma - a systematic review.

Lentigo maligna (LM) is the most common subtype of in situ melanoma und occurs frequently in the sun-exposed head and neck region in elderly patients. The therapeutic "gold standard" is surgical excision, as there is the risk of progression to invasive (lentigo maligna) melanoma (LMM). However, surgery is not feasible in certain patients due to age, comorbidities or patient preference. Radiotherapy using Grenz rays or superficial X-rays has been established as non-invasive alternative for the treatment of LM and LMM. We performed a systematic literature search of MEDLINE and Embase databases in September 2019 and identified 14 patient series using radiotherapy for LM or LMM. No prospective trials were found. The 14 studies reported a total of 1243 lesions (1075 LM and 168 LMM) treated with radiotherapy. Local recurrence rates ranged from 0 to 31% and were comparable to surgical series in most of the reports on radiotherapy. Superficial radiotherapy was prescribed in 5-23 fractions with a total dose of 35-57 Gy. Grenz ray therapy was prescribed in 42-160 Gy in 3-13 fractions with single doses up to 20 Gy. Cosmetic results were reported as "good" to "excellent" for the majority of patients.In conclusion, the available low-level evidence suggests that radiotherapy may be a safe and effective treatment for LM and LMM. Data from prospective trials such as the phase 3 RADICAL trial are needed to confirm these promising findings and to compare radiotherapy to other non-surgical therapies and to surgery.

Impact of treatment decision algorithms on treatment costs in recurrent glioblastoma: a health economic study.

AIMS: Recurrent glioblastoma (GBM) is a disease with poor prognosis. Although several therapeutic approaches such as chemotherapy, irradiation or surgery have been investigated, there is no established standard therapy. A recent survey among Swiss neuro-oncology centres has shown considerable controversy in the treatment recommendations for any specific scenario of recurrent GBM. In view of the cost differences of the available treatment alternatives, the aim of our study was assess the financial impact of different institutional therapeutic strategies for recurrent GBM in Switzerland. METHODS: We created a decision analytic model for each of the eight centres participating in the initial study with a centre-specific treatment algorithm to evaluate the average treatment cost per patient. The probability of decision criteria was varied by univariate and probabilistic sensitivity analysis over a wide range to account for the high level of uncertainty. Treatment costs were calculated from the perspective of the Swiss healthcare payer. RESULTS: Mean treatment costs per patient calculated on the basis of the institutional treatment algorithms ranged from CHF 13,748 to CHF 22,072 depending on the probability of individual decision criteria. The most influential decision factors for the mean treatment costs were the probability of fit patients and the proportion of patients with resectable tumour recurrences. There was a significant correlation between the complexity of treatment algorithms in a centre and the resulting mean treatment costs. CONCLUSIONS: Institutional treatment algorithms can be used to estimate the average treatment costs per patient, which are, however, highly sensitive to probability changes of individual decision criteria. Our study demonstrates a high variability in treatment costs for recurrent GBM among eight Swiss neuro-oncology centres based on individual institutional treatment algorithms.

Skeletal muscle mass correlates with increased toxicity during neoadjuvant radiochemotherapy in locally advanced esophageal cancer: A SAKK 75/08 substudy.

BACKGROUND: Sarcopenia, the critical depletion of skeletal muscle mass, is an independent prognostic factor in several tumor entities for treatment-related toxicity and survival. In esophageal cancer, there have been conflicting results regarding the value of sarcopenia as prognostic factor, which may be attributed to the heterogeneous patient populations and the retrospective nature of previous studies. The aim of our study was therefore to determine the impact of sarcopenia on prospectively collected specific outcomes in a subgroup of patients treated within the phase III study SAKK 75/08 with trimodality therapy (induction chemotherapy, radiochemotherapy and surgery) for locally advanced esophageal cancer. METHODS: Sarcopenia was assessed by skeletal muscle index at the 3rd lumbar vertebra (L3) in cross-sectional computed tomography scans before induction chemotherapy, before radiochemotherapy and after neoadjuvant therapy in a subgroup of 61 patients from four centers in Switzerland. Sarcopenia was determined by previously established cut-off values (Martin et al., PMID: 23530101) and correlated with prospectively collected outcomes including treatment-related toxicity, postoperative morbidity, treatment feasibility and survival. RESULTS: Using the published cut-off values, the prevalence of sarcopenia increased from 29.5% before treatment to 63.9% during neoadjuvant therapy (p < 0.001). Feasibility of neoadjuvant therapy and surgery was not different in initially sarcopenic and non-sarcopenic patients. We observed in sarcopenic patients significantly increased grade ≥ 3 toxicities during chemoradiation (83.3% vs 52.4%, p = 0.04) and a non-significant trend towards increased postoperative complications (66.7% vs 42.9%, p = 0.16). No difference in survival according to sarcopenia could be observed in this small study population. CONCLUSIONS: Trimodality therapy in locally advanced esophageal cancer is feasible in selected patients with sarcopenia. Neoadjuvant chemoradiation increased the percentage of sarcopenia. Sarcopenic patients are at higher risk for increased toxicity during neoadjuvant radiochemotherapy and showed a non-significant trend to more postoperative morbidity.

Assessment of pancreatic colloid carcinoma using 18F-FDG PET/CT compared with MRI and enhanced CT.

Pancreatic colloid carcinoma (CC) is a rare sub-type of pancreatic adenocarcinoma which has an improved prognosis compared with pancreatic ductal carcinoma. Consequently, the early detection of CC by imaging may be of great significance in guiding patient management and therapeutic decisions. The present study aimed to analyze 18F-FDG PET/CT findings of CC in comparison to MRI and CT. PET/CT findings in 5 patients with CC were retrospectively reviewed based on visual interpretation and semi-quantitative index of SUVmax and TNR. Four patients received dual-time-point PET/CT scans. Additionally, one patient underwent contrast-enhanced CT scan, one MRI, and three received both. A total of five lesions were detected in five patients. Visually, two cases presented with mild FDG uptake, two with moderate and one with high. The mean of SUVmax and TNR was 5.1±2.2 and 2.8±0.7, respectively. Compared with CCs with low SUVmax, CCs with high SUVmax were more aggressive. No distant metastases were observed in five cases. Among four patients with dual-time-point PET/CT imaging, SUVmax increased in three cases and decreased in one case. The mean early and delayed SUVmax were 4.2±1.1 and 4.7±1.9, respectively (P>0.05). Radiological findings mainly included septated cystic components, internal sponge-like contrast-enhancement, calcification and 'salt-and-pepper sign' on MRI T2-weighted imaging. Thus, PET/CT provided additional information on metabolic tumor activity as well as locoregional and distant staging, which are important prognostic markers and may improve further patient management. However, PET/CT did not show any findings in addition to MRI and contrast-enhanced CT that were unique to CC and allowed a clear differentiation from other pancreatic malignancies.

Treatment Options in Oncology.

Multiple treatment strategies exist for many oncologic problems. In this review, we provide a summary of various reasons for the existence of multiple treatment options in oncology, including factors that concern the treating physician (eg, treatment preferences), environmental factors (eg, financial, regulatory, and scientific aspects), and individual patient-specific factors (eg, medical condition, preferences). We demonstrate the vital role of available treatment options and their origins for clinical decision making and patient communication. These aspects are particularly helpful in the process of shared decision making, which is increasingly favored in situations where there are multiple medically reasonable options.

A cost-effectiveness analysis of consolidative local therapy in oligometastatic non-squamous non-small cell lung cancer (NSCLC).

BACKGROUND: Novel systemic therapies have improved the prognosis of metastatic non-small cell lung cancer (NSCLC), but costs of some of these drugs are a matter of ongoing debate. More recently, local therapies (LT) such as radiotherapy and surgery have been suggested as additional treatment in oligometastatic NSCLC demonstrating an improved progression-free survival (PFS) in a phase II trial compared to maintenance chemotherapy (MC) alone. The aim of this analysis was to assess the cost-effectiveness of local therapies in oligometastatic NSCLC. METHODS: We constructed a Markov model comparing the cost-effectiveness of LT versus MC for oligometastatic NSCLC from the Swiss healthcare payer's perspective. Treatment specifications and PFS were based on the phase II trial (NCT01725165). Overall survival (OS) was inferred from a recent phase III trial. Utilities were taken from published data. Primary outcome was the incremental cost-effectiveness-ratio (ICER, costs in Swiss Francs (CHF) per quality-adjusted life-year (QALY) gained). RESULTS: PFS in the model was 3.8 months for MC and 11.4 months for LT (compared to 3.9 months and 11.9 months in the trial). OS in the model was 15.5 months in both arms. LT was cost-effective with a gain of 0.24 QALYs at an additional cost of CHF 9641, resulting in an ICER of CHF 40,972/QALY gained. Probabilistic sensitivity analyses demonstrated that LT was dominant or cost-effective at a willingness-to-pay threshold of CHF 100,000 per QALY in 61.7% of the simulations. CONCLUSIONS: LT may be cost-effective for selected patients with oligometastatic NSCLC responding to first-line systemic therapy.

Role of 18F-FDG PET/CT Imaging in Intrahepatic Cholangiocarcinoma.

PURPOSE: Although intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy after hepatocellular carcinoma, there are limited data available on PET/CT imaging in ICC. This retrospective study analyzed the role of PET/CT imaging in the evaluation of ICC. METHODS: FDG PET/CT findings were reviewed in 65 patients with histologically confirmed ICC. PET/CT was evaluated based on visual interpretation and the semiquantitative index of SUVmax and tumor-to-normal liver tissue ratio (TNR), which were consequently further analyzed and correlated with tumor localization, differentiation, size, and serum levels of tumor markers. Forty-five cases also underwent abdominal MRI examinations. RESULTS: Nineteen patients had hilar ICC, whereas 46 patients had peripheral ICC. Sixty cases of ICC showed elevated FDG uptake with an average SUVmax of 8.3 ± 4.7 and TNR of 3.1 ± 1.7. Five cases located in the hilum were false negative on PET/CT imaging. Compared with hilar ICC, SUVmax and TNR of peripheral ICC were significantly higher (P < 0.05). FDG accumulation correlated with the degree of ICC differentiation. SUVmax and TNR correlated with tumor size, whereas there was no correlation observed with serum levels of carbohydrate antigen 19-9. The sensitivity, specificity, and accuracy of PET/CT and MRI in the diagnosis of regional lymph node metastases were 70.0% versus 50%, 91.7% versus 83.3%, and 81.8% versus 68.2%, respectively. PET/CT upstaged 12.3% and downstaged 3.1% of cases and had no impact on patient management in the remaining 84.6% of cases. CONCLUSIONS: Combination of FDG PET/CT and abdominal MRI might improve the diagnostic accuracy for ICC.

Objective consensus from decision trees.

BACKGROUND: Consensus-based approaches provide an alternative to evidence-based decision making, especially in situations where high-level evidence is limited. Our aim was to demonstrate a novel source of information, objective consensus based on recommendations in decision tree format from multiple sources. METHODS: Based on nine sample recommendations in decision tree format a representative analysis was performed. The most common (mode) recommendations for each eventuality (each permutation of parameters) were determined. The same procedure was applied to real clinical recommendations for primary radiotherapy for prostate cancer. Data was collected from 16 radiation oncology centres, converted into decision tree format and analyzed in order to determine the objective consensus. RESULTS: Based on information from multiple sources in decision tree format, treatment recommendations can be assessed for every parameter combination. An objective consensus can be determined by means of mode recommendations without compromise or confrontation among the parties. In the clinical example involving prostate cancer therapy, three parameters were used with two cut-off values each (Gleason score, PSA, T-stage) resulting in a total of 27 possible combinations per decision tree. Despite significant variations among the recommendations, a mode recommendation could be found for specific combinations of parameters. CONCLUSION: Recommendations represented as decision trees can serve as a basis for objective consensus among multiple parties.

Ultrasound and microbubble-mediated gene delivery in cancer: progress and perspectives.

Ultrasound-mediated gene delivery with microbubbles has emerged as an attractive nonviral vector system for site-specific and noninvasive gene therapy. Ultrasound promotes intracellular uptake of therapeutic agents, particularly in the presence of microbubbles, by increasing vascular and cell membrane permeability. Several preclinical studies have reported successful gene delivery into solid tumors with significant therapeutic effects using this novel approach. This review provides background information on gene therapy and ultrasound bioeffects and discusses the current progress and overall perspectives on the application of ultrasound and microbubble-mediated gene delivery in cancer.

Ultrasound-mediated gene delivery with cationic versus neutral microbubbles: effect of DNA and microbubble dose on in vivo transfection efficiency.

OBJECTIVE: To assess the effect of varying microbubble (MB) and DNA doses on the overall and comparative efficiencies of ultrasound (US)-mediated gene delivery (UMGD) to murine hindlimb skeletal muscle using cationic versus neutral MBs. MATERIALS AND METHODS: Cationic and control neutral MBs were characterized for size, charge, plasmid DNA binding, and ability to protect DNA against endonuclease degradation. UMGD of a codon optimized firefly luciferase (Fluc) reporter plasmid to endothelial cells (1 MHz, 1 W/cm², 20% duty cycle, 1 min) was performed in cell culture using cationic, neutral, or no MBs. In vivo UMGD to mouse hindlimb muscle was performed by insonation (1 MHz, 2 W/cm², 50% duty cycle, 5 min) after intravenous administration of Fluc combined with cationic, neutral, or no MBs. Gene delivery efficiency was assessed by serial in vivo bioluminescence imaging. Efficiency of in vivo UMGD with cationic versus neutral MBs was systematically evaluated by varying plasmid DNA dose (10, 17.5, 25, 37.5, and 50 µg) while maintaining a constant MB dose of 1x10(8) MBs and by changing MB dose (1x10(7), 5x10(7), 1x10(8), or 5x10(8) MBs) while keeping a constant DNA dose of 50 µg. RESULTS: Cationic and size-matched control neutral MBs differed significantly in zeta potential with cationic MBs being able to bind plasmid DNA (binding capacity of 0.03 pg/MB) and partially protect DNA from nuclease degradation while neutral MBs could not. Cationic MBs enhanced UMGD compared to neutral MBs as well as no MB and no US controls both in cell culture (P < 0.001) and in vivo (P < 0.05). Regardless of MB type, in vivo UMGD efficiency increased dose-dependently with DNA dose and showed overall maximum transfection with 50 µg DNA. However, there was an inverse correlation (ρ = -0.90; P = 0.02) between DNA dose and the degree of enhanced UMGD efficiency observed with using cationic MBs instead of neutral MBs. The delivery efficiency advantage associated with cationic MBs was most prominent at the lowest investigated DNA dose (7.5-fold increase with cationic versus neutral MBs at a DNA dose of 10 µg; P = 0.02) compared to only a 1.4-fold increase at a DNA dose of 50 µg (P < 0.01). With increasing MB dose, overall in vivo UMGD efficiency increased dose-dependently with a maximum reached at a dose of 1x10(8) MBs with no further significant increase with 5x10(8) MBs (P = 0.97). However, compared to neutral MBs, cationic MBs enhanced UMGD efficiency the most at low MB doses. Relative enhancement of UMGD efficiency using cationic over neutral MBs decreased from a factor of 27 for 1x10(7) MBs (P = 0.02) to a factor of 1.4 for 1x10(8) MBs (P < 0.01) and no significant difference for 5x10(8) MBs. CONCLUSIONS: Cationic MBs enhance UMGD to mouse skeletal muscle relative to neutral MBs but this is dependent on MB and DNA dose. The enhancement effect of cationic MBs on UMGD efficiency is more evident when lower doses of MBs or DNA are used, whereas the advantage of cationic MBs over neutral MBs is substantially reduced in the presence of excess MBs or DNA.

Assessment and monitoring tumor vascularity with contrast-enhanced ultrasound maximum intensity persistence imaging.

OBJECTIVES: Contrast-enhanced ultrasound imaging is increasingly being used in the clinic for assessment of tissue vascularity. The purpose of our study was to evaluate the effect of different contrast administration parameters on the in vivo ultrasound imaging signal in tumor-bearing mice using a maximum intensity persistence (MIP) algorithm and to evaluate the reliability of in vivo MIP imaging in assessing tumor vascularity. The potential of in vivo MIP imaging for monitoring tumor vascularity during antiangiogenic cancer treatment was further evaluated. MATERIALS AND METHODS: In intraindividual experiments, varying contrast microbubble concentrations (5 × 105, 5 × 106, 5 × 107, 5 × 108 microbubbles in 100 µL saline) and contrast injection rates (0.6, 1.2, and 2.4 mL/min) in subcutaneous tumor-bearing mice were applied and their effects on in vivo contrast-enhanced ultrasound MIP imaging plateau values were obtained using a dedicated small animal ultrasound imaging system (40 MHz). Reliability of MIP ultrasound imaging was tested following 2 injections of the same microbubble concentration (5 × 107 microbubbles at 1.2 mL/min) in the same tumors. In mice with subcutaneous human colon cancer xenografts, longitudinal contrast-enhanced ultrasound MIP imaging plateau values (baseline and at 48 hours) were compared between mice with and without antiangiogenic treatment (antivascular endothelial growth factor antibody). Ex vivo CD31 immunostaining of tumor tissue was used to correlate in vivo MIP imaging plateau values with microvessel density analysis. RESULTS: In vivo MIP imaging plateau values correlated significantly (P = 0.001) with contrast microbubble doses. At 3 different injection rates of 0.6, 1.2, and 2.4 mL/min, MIP imaging plateau values did not change significantly (P = 0.61). Following 2 injections with the same microbubble dose and injection rate, MIP imaging plateau values were obtained with high reliability with an intraclass correlation coefficient of 0.82 (95% confidence interval: 0.64, 0.94). In addition, in vivo MIP imaging plateau values significantly correlated (P = 0.01; R² = 0.77) with ex vivo microvessel density analysis. Tumor volumes in treated and nontreated mice did not change significantly (P = 0.22) within 48 hours. In contrast, the change of in vivo MIP imaging plateau values from baseline to 48 hours was significantly different (P = 0.01) in treated versus nontreated mice. CONCLUSIONS: Contrast-enhanced ultrasound MIP imaging allows reliable assessment of tumor vascularity and monitoring of antiangiogenic cancer therapy in vivo, provided that a constant microbubble dose is administered.