Mark De Ridder

Delivering affordable cancer care in high-income countries

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

Innovations in image-guided radiotherapy

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.

Stromal contribution to the colorectal cancer transcriptome

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.

Geometric accuracy of a novel gimbals based radiation therapy tumor tracking system.

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.

Prospective, Risk-Adapted Strategy of Stereotactic Body Radiotherapy for Early-Stage Non–Small-Cell Lung Cancer: Results of a Phase II Trial

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 E(90%)<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 E(90%) 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.

Prognostic value of histopathology and trends in cervical cancer: a SEER population study

PURPOSE Validation of a prospective, risk-adapted strategy for early-stage non-small-cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS 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. RESULTS 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. CONCLUSION 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.

Pseudoprogression after radiotherapy with concurrent temozolomide for high-grade glioma: clinical observations and working recommendations

BackgroundHistopathology is a cornerstone in the diagnosis of cervical cancer but the prognostic value is controversial.MethodsWomen under active follow-up for histologically confirmed primary invasive cervical cancer were selected from the United States Surveillance, Epidemiology, and End Results (SEER) 9-registries public use data 1973–2002. Only histologies with at least 100 cases were retained. Registry area, age, marital status, race, year of diagnosis, tumor histology, grade, stage, tumor size, number of positive nodes, number of examined nodes, odds of nodal involvement, extent of surgery, and radiotherapy were evaluated in Cox models by stepwise selection using the Akaike Information Criteria.ResultsThere were 30,989 records evaluable. From 1973 to 2002, number of cases dropped from 1,100 new cases/year to 900/year, but adenocarcinomas and adenosquamous carcinoma increased from 100/year to 235/year. Median age was 48 years. Statistically significant variables for both overall and cause-specific mortality were: age, year of diagnosis, race, stage, histology, grade, hysterectomy, radiotherapy, tumor size and nodal ratio. The histological types were jointly significant, P < 0.001. Cause-specific mortality hazard ratios by histological type relatively to non-microinvasive squamous cell carcinoma were: microinvasive squamous cell carcinoma 0.28 (95% confidence interval: 0.20–0.39), carcinoma not otherwise specified 0.91 (0.79–1.04), non-mucinous adenocarcinoma 1.06 (0.98–1.15), adenosquamous carcinoma 1.35 (1.20–1.51), mucinous adenocarcinoma 1.52 (1.23–1.88), small cell carcinoma 1.94 (1.58–2.39).ConclusionSmall cell carcinoma and adenocarcinomas were associated with poorer survival. The incidental observation of increasing numbers of adenocarcinomas despite a general decline suggests the inefficiency of conventional screening for these tumors. Increased incidence of adenocarcinomas, their adverse prognosis, and the young age at diagnosis indicate the need to identify women who are at risk.

Initial assessment of tumor tracking with a gimbaled linac system in clinical circumstances: A patient simulation study

BACKGROUND Treatment of newly diagnosed GBM with postoperative RT and concomitant TMZ followed by 6 months of TMZ maintenance therapy has been shown to significantly improve overall survival compared with RT alone. Standard clinical assessments of these patients include Gd-MRI as well as neurologic evaluation. Frequently, patients exhibit immediate post-RT changes in enhancement on Gd-MRI that mimic tumor progression (ie, pseudoprogression or radiation-induced imaging changes). With the introduction of concomitant RT plus TMZ for treatment of malignant glioma, there appears to be an increasing incidence of pseudoprogression. CASE DESCRIPTION In our experience, pseudoprogression after concomitant RT plus TMZ is typically not observed at first imaging immediately after completion of the therapy; but delayed focal enhancement mimicking tumor progression frequently occurs during the 6 months of maintenance therapy with TMZ. Pseudoprogression may reflect the radiosensitizing effect of TMZ during concomitant therapy, and retaining patients on treatment allows them to have enhanced survival and preserved quality of life. We observed 3 cases of pseudoprogression among 54 consecutive patients who were treated with this regimen. These patients developed pseudoprogression within 2 to 6 months after completion of concomitant RT plus TMZ, but all 3 patients completed maintenance chemotherapy and remained progression free for at least 15 months after diagnosis. CONCLUSION Functional imaging may improve the noninvasive diagnosis of pseudoprogression, but randomized prospective studies are needed to evaluate the real impact of pseudoprogression and validate neuroradiological techniques able to make a reliable distinction between tumor recurrence and pseudoprogression.

Hypoxic tumor cell radiosensitization through nitric oxide

PURPOSE To have an initial assessment of the Vero Dynamic Tracking workflow in clinical circumstances and quantify the performance of the tracking system, a simulation study was set up on 5 lung and liver patients. METHODS AND MATERIALS The preparatory steps of a tumor tracking treatment, based on fiducial markers implanted in the tumor, were executed allowing pursuit of the tumor with the gimbaled linac and monitoring X-rays acquisition, however, without activating the 6 MV beam. Data were acquired on workflow time-efficiency, tracking accuracy and imaging exposure. RESULTS The average time between the patient entering the treatment room and the first treatment field was about 9 min. The time for building the correlation model was 3.2 min. Tracking errors of 0.55 and 0.95 mm (1σ) were observed in PAN/TILT direction and a 2D range of 3.08 mm. A skin dose was determined of 0.08 mGy/image, with a source-to-skin distance of 900 mm and kV exposure of 1 mAs. On average 1.8 mGy/min kV skin dose was observed for 1 Hz monitoring. CONCLUSION The Vero tracking solution proved to be fully functional and showed performance comparable with other real-time tracking systems.

Treating patients with real-time tumor tracking using the Vero gimbaled linac system: Implementation and first review

Hypoxia is a principal signature of the tumor microenvironment and is considered to be the most important cause of clinical radioresistance and local failure. Oxygen is so far the best radiosensitizer, but tumor oxygenation protocols are compromised by its metabolic consumption and therefore limited diffusion inside tumors. Many chemical radiosensitizers can selectively target hypoxic tumor cells, but their systemic toxicity compromises their adequate clinical use. NO is an efficient hypoxic radiosensitizer, as it may mimic the effects of oxygen on fixation of radiation-induced DNA damage, but the required levels cannot be obtained in vivo because of vasoactive complications. Our laboratory explored whether this problem may be overcome by endogenous production of NO inside tumors. We demonstrated that iNOS, activated by pro-inflammatory cytokines, is capable of radiosensitizing tumor cells through endogenous production of NO, at non-toxic extracellular concentrations. We observed that this radiosensitizing effect is transcriptionally controlled by hypoxia and by NF-kappaB. Tumor-associated immune cells may contribute to the iNOS-mediated radiosensitization by the generation of pro-inflammatory cytokines and NO, which may diffuse towards bystander tumor cells. Our findings indicate a rationale for combining immunostimulatory and radiosensitizing strategies in the future.