Validation of a prospective, risk-adapted strategy for early-stage non-small-cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT).
Patients with a T1-3N0M0 (American ...Joint Committee on Cancer 6th edition) NSCLC were accrued. Using the Radiation Therapy Oncology Group definition, patients were treated to a total dose of 60,Gy in three fractions for peripherally located lesions and four fractions for centrally located lesions. The primary endpoint was toxicity, graded according to the Radiation Therapy Oncology Group acute and late morbidity scoring system, and the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. Secondary endpoints were local control and survival.
A total of 40 patients were included, 17 with a centrally located lesion. The lung toxicity-free survival estimate at 2 years was 74% and was related to the location (central vs. peripheral) and the size of the target volume. No dose volumetric parameters could predict the occurrence of lung toxicity. One patient died because of treatment-related toxicity. The 1-year and 2-year local progression-free survival estimates were 97% and 84%, respectively, and were related to stage (T1 vs. T2) related (p = 0.006). Local failure was not more frequent for patients treated in four fractions. The 1-year local progression-free survival estimate dropped below 80% for lesions with a diameter of more than 4 cm.
The proposed risk-adapted strategy for both centrally and peripherally located lesions showed an acceptable toxicity profile while maintaining excellent local control rates. The correlation between local control and tumor diameter calls for the inclusion of tumor stage as a variable in future study design.
The limited ability to control for the location of a tumour compromises the accuracy with which radiation can be delivered to tumour-bearing tissue. The resultant requirement for larger treatment ...volumes to accommodate target uncertainty restricts the radiation dose because more surrounding normal tissue is exposed. With image-guided radiotherapy (IGRT) these volumes can be optimized and tumoricidal doses can be delivered, achieving maximal tumour control with minimal complications. Moreover, with the ability of high-precision dose delivery and real-time knowledge of the target volume location, IGRT has initiated the exploration of new indications for radiotherapy, some of which were previously considered infeasible.
Abstract Progress in radiotherapy is guided by the need to realize improved dose distributions, i.e. the ability to reduce the treatment volume toward the target volume and still ensuring coverage of ...that target volume in all dimensions. Poor ability to control the tumour’s location limits the accuracy with which radiation can be delivered to tumour-bearing tissue. Image-guided radiation therapy (IGRT) aims at in-room imaging guiding the radiation delivery based on instant knowledge of the target location and changes in tumour volume during treatment. Advancements are usually not to be attributed to a single event, but rather a combination of many small improvements that together enable a superior result. Image-guidance is an important link in the treatment chain and as such a major factor in this synergetic process. A historic review shows that many of the so-called new developments are not so new at all, but did not make it into mainstream radiotherapy practice at that time. Recent developments in improved IT infrastructures, novel irradiation techniques, and better knowledge of functional and morphologic information may have created the need and optimal environment to revive the interest in IGRT.
Immunotherapy, where the patient's own immune system is exploited to eliminate tumor cells, has become one of the most prominent new cancer treatment options in the last decade. The main hurdle for ...classical cancer vaccines is the need to identify tumor- and patient specific antigens to include in the vaccine. Therefore,
vaccination represents an alternative and promising approach. This type of immunotherapy involves the direct intratumoral administration of different immunomodulatory agents and uses the tumor itself as the source of antigen. The ultimate aim is to convert an immunodormant tumor microenvironment into an immunostimulatory one, enabling the immune system to eradicate all tumor lesions in the body. In this review we will give an overview of different strategies, which can be exploited for the immunomodulation of the tumor microenvironment and their emerging role in the treatment of cancer patients.
To evaluate the added value of 6-degree of freedom (DOF) patient positioning with a robotic couch compared with 4DOF positioning for intracranial lesions and to estimate the immobilization ...characteristics of the BrainLAB frameless mask (BrainLAB AG, Feldkirchen, Germany), more specifically, the setup errors and intrafraction motion.
We enrolled 40 patients with 66 brain metastases treated with frameless stereotactic radiosurgery and a 6DOF robotic couch. Patient positioning was performed with the BrainLAB ExacTrac stereoscopic X-ray system. Positioning results were collected before and after treatment to assess patient setup error and intrafraction motion. Existing treatment planning data were loaded and simulated for 4DOF positioning and compared with the 6DOF positioning. The clinical relevance was analyzed by means of the Paddick conformity index and the ratio of prescribed isodose volume covered with 4DOF to that obtained with the 6DOF positioning.
The mean three-dimensional setup error before 6DOF correction was 1.91 mm (SD, 1.25 mm). The rotational errors were larger in the longitudinal (mean, 0.23°; SD, 0.82°) direction compared with the lateral (mean, -0.09°; SD, 0.72°) and vertical (mean, -0.10°; SD, 1.03°) directions (p < 0.05). The mean three-dimensional intrafraction shift was 0.58 mm (SD, 0.42 mm). The mean intrafractional rotational errors were comparable for the vertical, longitudinal, and lateral directions: 0.01° (SD, 0.35°), 0.03° (SD, 0.31°), and -0.03° (SD, 0.33°), respectively. The mean conformity index decreased from 0.68 (SD, 0.08) (6DOF) to 0.59 (SD, 0.12) (4DOF) (p < 0.05). A loss of prescribed isodose coverage of 5% (SD, 0.08) was found with the 4DOF positioning (p < 0.05). Half a degree for longitudinal and lateral rotations can be identified as a threshold for coverage loss.
With a mask immobilization, patient setup error and intrafraction motions need to be evaluated and corrected for. The 6DOF patient positioning with a 6DOF robotic couch to correct translational and rotational setup errors improves target positioning with respect to treatment isocenter, which is in direct relation with the clinical outcome, compared with the 4DOF positioning.
Abstract Purpose VERO is a novel platform for image guided stereotactic body radiotherapy. Orthogonal gimbals hold the linac-MLC assembly allowing real-time moving tumor tracking. This study ...determines the geometric accuracy of the tracking. Materials and methods To determine the tracking error, an 1D moving phantom produced sinusoidal motion with frequencies up to 30 breaths per minute (bpm). Tumor trajectories of patients were reproduced using a 2D robot and pursued with the gimbals tracking system prototype. Using the moving beam light field and a digital-camera-based detection unit tracking errors, system lag and equivalence of pan/tilt performance were measured. Results The system lag was 47.7 ms for panning and 47.6 ms for tilting. Applying system lag compensation, sinusoidal motion tracking was accurate, with a tracking error 90% percentile E90% < 0.82 mm and similar performance for pan/tilt. Systematic tracking errors were below 0.14 mm. The 2D tumor trajectories were tracked with an average E90% of 0.54 mm, and tracking error standard deviations of 0.20 mm for pan and 0.22 mm for tilt. Conclusions In terms of dynamic behavior, the gimbaled linac of the VERO system showed to be an excellent approach for providing accurate real-time tumor tracking in radiation therapy.
Summary The burden of cancer is growing, and the disease is becoming a major economic expenditure for all developed countries. In 2008, the worldwide cost of cancer due to premature death and ...disability (not including direct medical costs) was estimated to be US$895 billion. This is not simply due to an increase in absolute numbers, but also the rate of increase of expenditure on cancer. What are the drivers and solutions to the so-called cancer-cost curve in developed countries? How are we going to afford to deliver high quality and equitable care? Here, expert opinion from health-care professionals, policy makers, and cancer survivors has been gathered to address the barriers and solutions to delivering affordable cancer care. Although many of the drivers and themes are specific to a particular field—eg, the huge development costs for cancer medicines—there is strong concordance running through each contribution. Several drivers of cost, such as over-use, rapid expansion, and shortening life cycles of cancer technologies (such as medicines and imaging modalities), and the lack of suitable clinical research and integrated health economic studies, have converged with more defensive medical practice, a less informed regulatory system, a lack of evidence-based sociopolitical debate, and a declining degree of fairness for all patients with cancer. Urgent solutions range from re-engineering of the macroeconomic basis of cancer costs (eg, value-based approaches to bend the cost curve and allow cost-saving technologies), greater education of policy makers, and an informed and transparent regulatory system. A radical shift in cancer policy is also required. Political toleration of unfairness in access to affordable cancer treatment is unacceptable. The cancer profession and industry should take responsibility and not accept a substandard evidence base and an ethos of very small benefit at whatever cost; rather, we need delivery of fair prices and real value from new technologies.
Radiotherapy is a mainstay treatment for many types of cancer and kills cancer cells via generation of reactive oxygen species (ROS). Incorporating radiation with pharmacological ROS inducers, ...therefore, has been widely investigated as an approach to enhance aerobic radiosensitization. However, this strategy was overlooked in hypoxic counterpart, one of the most important causes of radiotherapy failure, due to the notion that hypoxic cells are immune to ROS insults because of the shortage of ROS substrate oxygen. Paradoxically, evidence reveals that ROS are produced more in hypoxic than normoxic cells and serve as signaling molecules that render cells adaptive to hypoxia. As a result, hypoxic tumor cells heavily rely on antioxidant systems to sustain the ROS homeostasis. Thereby, they become sensitive to insults that impair the ROS detoxification network, which has been verified in diverse models with or without radiation. Of note, hypoxic radioresistance has been overviewed in different contexts. To the best of our knowledge, this review is the first to systemically summarize the interplay among radiation, hypoxia, and ROS, and to discuss whether perturbation of ROS homeostasis could provide a new avenue to tackle hypoxic radioresistance.
Gini's mean difference (GMD, mean absolute difference between any two distinct quantities) of the restricted mean survival times (RMSTs, expectation of life at a given time limit) has been proposed ...as a new metric where higher GMD indicates better prognostic value. GMD is applied to the RMSTs at 25 years time-horizon to evaluate the long-term overall survival of women with breast cancer who received neoadjuvant chemotherapy, comparing a classification based on the number (pN) versus a classification based on the ratio (LNRc) of positive nodes found at axillary surgery. A total of 233 patients treated in 1980-2009 with documented number of positive nodes (npos) and number of nodes examined (ntot) were identified. The numbers were categorized into pN0, npos = 0; pN1, npos = 1,3; pN2, npos = 4,9; pN3, npos ≥ 10. The ratios npnx = npos/ntot were categorized into Lnr0, npnx = 0; Lnr1, npnx = (0,0.20; Lnr2, npnx = (0.20,0.65; Lnr3, npnx > 0.65. The GMD for pN-classification was 5.5 (standard error: ± 0.9) years, not much improved over a simple node-negative vs. node-positive that showed a GMD of 5.0 (± 1.4) years. The GMD for LNRc-classification was larger, 6.7 (± 0.8) years. Among other conventional metrics, Cox-model LNRc's c-index was 0.668 vs. pN's c = 0.641, indicating commensurate superiority of LNRc-classification. The usability of GMD-RMSTs warrants further investigation.
Recent studies identified a poor-prognosis stem/serrated/mesenchymal (SSM) transcriptional subtype of colorectal cancer (CRC). We noted that genes upregulated in this subtype are also prominently ...expressed by stromal cells, suggesting that SSM transcripts could derive from stromal rather than epithelial cancer cells. To test this hypothesis, we analyzed CRC expression data from patient-derived xenografts, where mouse stroma supports human cancer cells. Species-specific expression analysis showed that the mRNA levels of SSM genes were mostly due to stromal expression. Transcriptional signatures built to specifically report the abundance of cancer-associated fibroblasts (CAFs), leukocytes or endothelial cells all had significantly higher expression in human CRC samples of the SSM subtype. High expression of the CAF signature was associated with poor prognosis in untreated CRC, and joint high expression of the stromal signatures predicted resistance to radiotherapy in rectal cancer. These data show that the distinctive transcriptional and clinical features of the SSM subtype can be ascribed to its particularly abundant stromal component.
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