Is IMAT the ultimate evolution of conformal radiotherapy? Dosimetric comparison of helical tomotherapy and volumetric modulated arc therapy for oropharyngeal cancer in a planning study

BackgroundIntensity Modulated Arc Therapy (IMAT) can be planned and delivered via several techniques. Advanced Radiotherapy (ARTORL) is a prospective study that aims to evaluate the treatment costs and clinical aspects of implementing these IMAT techniques for head and neck cancers. In this context, we evaluated the potential dosimetric gain of Helical Tomotherapy (TomoTherapy, Accuray, HT) versus VMAT (Rapid'Arc^®, Varian Medical System, RA) for oropharyngeal cancer (OC).Material and methodsThirty patients were selected from our database in whom bilateral neck irradiation and treatment to the primary were indicated. Each patient was planned twice using both HT and RA planning systems using a simultaneous integrated boost approach. For the planning target volumes (PTV) and organs at risk, ICRU 83 reporting guidelines were followed. RA and HT plans were compared using paired Student's t-test.ResultsRA and HT produced plans with a good coverage of PTVs and acceptable sparing of OARs. Although some dosimetric differences were statistically significant, they remained small. However, the near maximal dose to the PRV of spinal cord and brain stem was lower with HT. Regarding normal tissue, HT increased the volume irradiated at doses between 4 and 20 Gy compared to RA.ConclusionIn OC, HT and RA showed similar dosimetric results. They represent the maximum gains obtained with photon beams. The medicoeconomic evaluation of our study is ongoing and may reveal differences between these techniques in terms of MU number, fraction time, and clinical evaluation.     

Should the management of radiation therapy for breast cancer be standardized? Results of a survey on current French practices in breast radiotherapy

BackgroundBreast cancer is the most frequent cancer in women in France. Its management has evolved considerably in recent years with a focus on reducing iatrogenic toxicity. The radiotherapy indications are validated in multidisciplinary consultation meetings; however, questions remain outstanding, particularly regarding hypofractionated radiotherapy, partial breast irradiation, and irradiation of the internal mammary chain and axillary lymph node area.Materials and methodsAn online survey was sent to 47 heads of radiotherapy departments in France. The survey consisted of 22 questions concerning indications for irradiation of the supraclavicular, internal mammary and axillary lymph node areas; irradiation techniques and modalities; prescribed doses; and fractionation.ResultsTwenty-four out of 47 centers responded (response rate of 51%). This survey demonstrated a wide variation in the prescribed dose regimen, monoisocentric radiotherapy, and indications of irradiation of the lymph node areas.ConclusionThis survey provides insight into the current radiotherapy practice for breast cancer in France. It shows the need to standardize practices.     

The fight against tamoxifen resistance in breast cancer therapy: a new target in the battle?

Tamoxifen is one of the most successful and widely used chemopreventive agents ever, and is an effective therapeutic agent for inhibiting growth of hormone receptor positive breast cancers. Tamoxifen and some of its metabolites bind to estrogen receptors and allow subsequent DNA binding at estrogen responsive genes, blocking some estrogenic signals while maintaining others, depending on the tissue. When used therapeutically for up to five years, cases of tamoxifen resistance appear, requiring alternative therapies. One recent proposal uniquely targets a zinc finger of the DNA binding domain of estrogen receptors, rather than the ligand binding domain, to circumvent resistance. In light of the most recent clinical data, however, it is now clear that aromatase inhibitors are the preferred first line therapy for all stages of breast cancer in post-menopausal women, whether they have had previous tamoxifen exposure or resistance.     

Antidiabetic therapy--a new possibility in the complex therapy of cancer?

Nowadays the lack of exercise and improper eating habits are main characteristics of modern life style. This favors not only formation of type 2 diabetes or cardiovascular diseases, but also increaseas the incidence and prevalence of malignant tumors. Today there are many epidemiologic trials that demonstrate the connection between type 2 diabetes and formation of several malignomas. Its cause should be searched in common paths of pathologic processes. One of this is the birth of hyperinsulinsulinemia, which accompanies insulin resistance. Hyperinsulinemia of the host leads to increased glucose uptake in the highly insuline sensitive tumor cells which supports tumor growth. This makes type 2 diabetes a metabolic state favoring tumor formation, suggesting a potential application of oral insulin sensitizers in cancer therapy. Currently several international trials are testing the anti-tumor activity of metformin and thiazolidinedions (TZD). Besides this, encouraging results were obtained with the use of anti-IGFR antibodies in the treatment of tumors. A common therapy of diabetes and tumor may lead to new possibilities in the treatment of malignant tumor diseases. By doing this we could be able to weaken the tumor and strengthen the body, enabling it to fight against cancer. Bánhegyi RJ, Rus-Gal PO, Nagy AK, Martyin T, Varga R, Pikó B. Correlation between type 2 diabetes and malignant tumors - new possibilities in the complex therapy of cancers?     

Role of the autotaxin–lysophosphatidate axis in the development of resistance to cancer therapy

Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidate (LPA), which signals through six G-protein coupled receptors (GPCRs). Signaling through LPA is terminated by its degradation by a family of three lipid phosphate phosphatases (LPPs). LPP1 also attenuates signaling downstream of the activation of LPA receptors and some other GPCRs. The ATX-LPA axis mediates a plethora of activities such as cell proliferation, survival, migration, angiogenesis and inflammation, which perform an important role in facilitating wound healing. This wound healing response is hijacked by cancers where there is decreased expression of LPP1 and LPP3 and increased expression of ATX. This maladaptive regulation of LPA signaling also causes chronic inflammation, which has been recognized as one of the hallmarks in cancer. The increased LPA signaling promotes cell survival and migration and attenuates apoptosis, which stimulates tumor growth and metastasis. The wound healing functions of increased LPA signaling also protect cancer cells from effects of chemotherapy and radiotherapy. In this review, we will summarize knowledge of the ATX-LPA axis and its role in the development of resistance to chemotherapy and radiotherapy. We will also offer insights for developing strategies of targeting ATX-LPA axis as a novel part of cancer treatment. This article is part of a Special Issue entitled Lysophospholipids and their receptors: New data and new insights into their function edited by Susan Smyth, Viswanathan Natarajan and Colleen McMullen.     

Role of the autotaxin–lysophosphatidate axis in cancer resistance to chemotherapy and radiotherapy

High expression of autotaxin in cancers is often associated with increased tumor progression, angiogenesis and metastasis. This is explained mainly since autotaxin produces the lipid growth factor, lysophosphatidate (LPA), which stimulates cell division, survival and migration. It has recently become evident that these signaling effects of LPA also produce resistance to chemotherapy and radiation-induced cell death. This results especially from the stimulation of LPA₂ receptors, which depletes the cell of Siva-1, a pro-apoptotic signaling protein and stimulates prosurvival kinase pathways through a mechanism mediated via TRIP-6. LPA signaling also increases the formation of sphingosine 1-phosphate, a pro-survival lipid. At the same time, LPA decreases the accumulation of ceramides, which are used in radiation therapy and by many chemotherapeutic agents to stimulate apoptosis. The signaling actions of extracellular LPA are terminated by its dephosphorylation by a family of lipid phosphate phosphatases (LPP) that act as ecto-enzymes. In addition, lipid phosphate phoshatase-1 attenuates signaling downstream of the activation of both LPA receptors and receptor tyrosine kinases. This makes many cancer cells hypersensitive to the action of various growth factors since they often express low LPP1/3 activity. Increasing our understanding of the complicated signaling pathways that are used by LPA to stimulate cell survival should identify new therapeutic targets that can be exploited to increase the efficacy of chemo- and radio-therapy. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.     

Estrogen receptor-β activation in combination with letrozole blocks the growth of breast cancer tumors resistant to letrozole therapy

Treatment with anti-estrogens or aromatase inhibitors (AI) is the main therapeutic strategy used against estrogen receptor ERα-positive breast cancer. Resistance to these therapies presents a major challenge in the management of breast cancer. Little is known about ERβ in breast carcinogenesis. Our aim in this study is to examine potential novel strategies utilizing ERβ activity to overcome AI resistance. We provide evidence that ERβ agonist can reduce the growth of AI-resistant breast cancer cells. Our data further confirm that therapeutic activation of ERβ by DPN, an ERβ agonist, blocks letrozole-resistant tumor growth in a xenograft model. Interestingly, DPN exerted tumor growth inhibition only in the presence of the AI letrozole, suggesting that combination therapy including ERβ activators and AI may be used in the clinical setting treating AI resistant breast cancer. An increase in ERβ levels, with diminished ERα/ERβ ratio, was observed in the tumors from mice treated with DPN/letrozole combination compared to single agents and control. Decreased Cyclin D1 and increased CyclinD1/CDK inhibitors p21 and p27 levels in DPN/letrozole treated tumors were observed, suggesting that the combination treatment may inhibit tumor growth by blocking G1/S phase cell cycle progression. Our data show a decrease in MAPK phosphorylation levels without affecting total levels. In addition to providing evidence suggesting the potential use of ERβ agonists in combination with letrozole in treating AI resistant breast cancer and prolonging sensitivity to AI, we also provide mechanistic evidence supporting the role of ERβ in altering the expression profile associated with resistance.     

Optimal control of vaccination in a vector-borne reaction–diffusion model applied to Zika virus

Journal of Mathematical Biology - Zika virus has acquired worldwide concern after a recent outbreak in Latin America that started in Brazil, with associated neurological conditions such as...     

Adaptive doses of irradiation—an approach to a new therapy concept for bladder cancer?

Radiation adaptive response in terms of induced radioresistance or hyperradiosensitivity, has been studied in HCV29 (human bladder epithelium) and RT4 (human bladder carcinoma) cell lines. After pre-irradiation doses of 0.05 Gy or 0.1 Gy, HCV29 cells showed induced radioresistance, whereas after pre-irradiation doses of 0.05 Gy, 0.1 Gy, 0.2 Gy, and 0.5 Gy, the RT4 cells clearly showed hyperradiosensitivity. On the basis of these results, an approach has been developed that may lead to a concept for a new radiotherapeutic regimen of bladder cancer that includes protection of normal cells, on the one hand, and the potential of tumor cell damage, on the other hand. These findings need to be confirmed in further studies for the benefit of the patients.     

AlignRT®, Catalyst™ and RPM™ in locoregional radiotherapy of breast cancer with DIBH. Is IGRT still needed?

BackgroundIn locoregional radiotherapy of breast cancer with deep inspiration breath hold (DIBH), setup accuracy may depend on hospital protocol. At present, comparison between different positioning devices is challenging due to differing hospital protocols. The aim of this study was to evaluate the setup accuracy obtained with surface-guided radiation therapy (SGRT; AlignRT®, Catalyst™) or with lasers and real-time position management (RPM™) in DIBH.Materials and methodsA total of 1692 image pairs were analyzed in three groups: positioning using AlignRT® surface guidance system (Group A, n = 45), Catalyst™ (Group C, n = 50) and conventional lasers and tattoos (Group L, n = 46). We evaluated residual errors for the bony chest wall, th1 and humeral head in kV images with laser- or SGRT-based setup with and without daily image-guided radiation therapy (IGRT).ResultsLess isocenter variance was found in Group A than in Group L or C (p ≤ 0.05) and in Group C than in L (p = 0.02–0.6). With SGRT only, the smallest random rotation error was found in Group A (p = 0.01). With daily IGRT, only a small difference was found for residual errors between the groups.ConclusionSetup with SGRT improves the isocenter reproducibility compared to lasers and RPM™. Only small differences were found in setup accuracy between the SGRT devices. Due to improved isocenter accuracy, daily orthogonal IGRT is suggested in all the groups.     

Elapsed time from breast cancer detection to first adjuvant therapy in a Canadian province, 1999–2000

BackgroundA number of studies have examined time intervals between care steps in breast cancer diagnosis and treatment. The objective of this study was to document the elapsed time from first clinical or mammographic detection of breast abnormality to initiation of first adjuvant therapy in women with invasive breast cancer in Nova Scotia and to examine the effect of age, disease stage and place of residence on these intervals.MethodsAll dates were abstracted from patient charts and the Oncology Patient Information System. Eligible women were those with invasive breast cancer detected by Sept. 1, 1999, who were referred to 1 of 2 provincial cancer treatment centres by Sept. 1, 2000. All time intervals were calculated in days, and only patients experiencing both care events defining an interval were included in the analysis of time to event for that interval. We used proportional hazards regression analysis to evaluate the influence of patient age, disease stage and place of residence on times between care events.ResultsA total of 776 new diagnoses of breast cancer were reported to the Nova Scotia Cancer Registry over the study period. Of the 776, 467 met the inclusion criteria, and 364 patients were eligible for analysis. The overall median time from clinical or mammographic detection of breast cancer to initiation of first adjuvant therapy was 91 days (interquartile range 72–123 days). Disease stage was the strongest predictor of elapsed time: the median interval from disease detection to initiation of first adjuvant therapy for patients with stage I disease was 118 days, as compared with 85 days for those with stage II disease and 75 days for those with stage III disease (adjusted hazard ratio [HR] 2.1, 95% confidence interval [CI] 1.6–2.8). Patients aged 70 years or more at diagnosis experienced longer elapsed times (median interval 98 days) than did younger patients (93 days for those aged 50–69 years and 82 days for those aged 49 years or less) (adjusted HR 1.6, 95% CI 1.1–2.4).InterpretationWomen aged 70 or more and those with stage I breast cancer experienced longer elapsed times from disease detection to initiation of first adjuvant therapy than did younger women and those with more advanced disease. These findings may have implications for the design of interventions to minimize intervals between steps in breast cancer care and should be validated within the Canadian context. Future investigation exploring the full spectrum of breast cancer care may lead to a more complete understanding of processes and gaps in the current system.Time intervals for isolated care steps in the diagnosis and management of breast cancer have been evaluated in a number of publications from Canada, Germany and the United Kingdom. These studies have focused on time to first surgical intervention,¹ time to pathological confirmation of invasive disease² or a composite interval spanning onset of symptoms to initiation of first treatment, which, in the vast majority of cases, is surgical intervention.^3,4,5,6 The spectrum of care for potentially curable breast cancer, however, extends from initial detection to completion of all adjuvant therapies and has become increasingly complex and multidisciplinary. Patients interact with a sequence of various health care professionals and undergo a series of procedures at various medical facilities or in different areas of a large hospital. Most patients are referred for 1 or more adjuvant therapies (radiation, chemotherapy or hormonal therapy), all of which have been shown to reduce the risk of locally recurrent or metastatic disease and to improve overall survival in appropriately selected patients.^7,8,9 Although the time from referral to initiation of adjuvant therapy is a critical component in breast cancer care, it has not been included in previous analyses of elapsed times in breast cancer care.The first objective of our study was to document elapsed times from date of mammographic or clinical detection of breast abnormality to initiation of first adjuvant therapy for women with invasive breast cancer. Our second objective was to examine the influence of age, disease stage and place of residence at the time of diagnosis on this elapsed time.     

Lymph node status as a guide to selection of available prognostic markers in breast cancer: the clinical practice of the future?

Prognosticators evaluating survival in breast cancer vary in significance in respect to lymph node status. Studies have shown e.g. that HER2/neu immunohistochemistry or HER2/neu gene amplification analysis do perform well as prognosticators in lymph node positive (LN +) patients but are less valuable in lymph node negative (LN -) patients. We collected data from different studies and tried to evaluate the relative significance of different prognosticators in LN+/LN- patient groups. In LN+ patients HER2/neu and E-cadherin immunohistochemistry were the statistically most significant prognosticators followed by proliferation associated features (mitotic counts by SMI (standardised mitotic index) or MAI (mitotic activity index), or S-phase fraction). Bcl-2 immunohistochemistry was also significant but p53 and cystatin A had no significance as prognosticators. In LN- patients proliferation associated prognosticators (SMI, MAI, Ki-67 index, PCNA immunohistochemistry, S-phase fraction) are especially valuable and also Cathepsin D, cystatin A, and p53 are significant, but HER2/neu or bcl-2, or E-cadherin less significant or without significance. We find that in studies evaluating single prognosticators one should distinguish between prognosticators suitable for LN+ and LN- patients. This will allow the choice of best prognosticators in evaluating the prospects of the patient. The distinction between LN+ and LN- patients in this respect may also be of special value in therapeutic decisions.     

Are online prediction tools a valid alternative to genomic profiling in the context of systemic treatment of ER-positive breast cancer?

Background

Clinicians use clinical and pathological parameters, such as tumour size, grade and nodal status, to make decisions on adjuvant treatments for breast cancer. However, therapeutic decisions based on these features tend to vary due to their subjectivity. Computational and mathematical algorithms were developed using clinical outcome data from breast cancer registries, such as Adjuvant! Online and NHS PREDICT. More recently, assessments of molecular profiles have been applied in the development of better prognostic tools.

Methods

Based on the available literature on online registry-based tools and genomic assays, we evaluated whether these online tools could be valid and accurate alternatives to genomic and molecular profiling of the individual breast tumour in aiding therapeutic decisions, particularly in patients with early ER-positive breast cancer.

Results and conclusions

Early breast cancer is currently considered a systemic disease and a complex ecosystem with behaviour determined by the complex genetic and molecular signatures of the tumour cells, mammary stem cells, microenvironment and host immune system. We anticipate that molecular profiling will continue to evolve, expanding beyond the primary tumour to include the tumour microenvironment, cancer stem cells and host immune system. This should further refine therapeutic decisions and optimise clinical outcome.This article was specially invited by the editors and represents work by leading researchers.

     

‘Son et lumière’: a new combined optical and Doppler ultrasound approach to the detection of breast cancer

X-ray mammography is the gold standard for diagnosis of lesions within the female breast. It is also recognized as the technique of choice for breast cancer screening in women over 50-years-old. Notwithstanding these important roles it has shortcomings in terms of limited sensitivity and specificity, especially in younger women. This paper describes the concept of a combined optical density and Doppler ultrasound method proposed initially as a supplement to mammography. A specially devised tissue compressor is also described. Results obtained using test phantoms and initial clinical studies are presented. Neovascularization at the advancing front of neoplastic lesions is believed to underlie detection of lesions by both telediaphanography and Doppler ultrasound.     

Investigation of the eIF2α phosphorylation mechanism in response to proteasome inhibition in melanoma and breast cancer cells

The 26S proteasome is an ATP-dependent proteolytic complex found in all eukaryotes, archaebacteria, and some eubacteria. Inhibition of the 26S proteasome causes pleiotropic effects in cells, including cellular apoptosis, a fact that has led to the use of the 26S proteasome inhibitor, bortezomib, for treatment of the multiple myeloma cancer. We previously showed that in addition to the effects of proteolysis, inhibition of the 26S proteasome causes a rapid decrease in the protein synthesis rate due to phosphorylating alfa subunit of the eukaryotic translation initiation factor 2 (eIF2α) by the heme-regulated inhibitor kinase (HRI). In order to test whether inhibition of the 26S proteasome causes the same effect in cancer cells, we have investigated the influence of two commonly used proteasome inhibitors, bortezomib and MG132, on the phosphorylation status of eIF2α in B16F10 melanoma and 4T1 breast cancer cells. It was found that both of the inhibitors caused rapid phosphorylation of eIF2α. Taking into account that the Hsp70 is a critical component needed for the HRI activation and enzymatic activity, we have tested a possible participation of this protein in the eIF2α phosphorylation event. However, treatment of the cells with two structurally different Hsp70 inhibitors, quercetin and KNK437, in the presence of the proteasome inhibitors did not affect the eIF2α phosphorylation. In addition, neither protein kinase C (PKC) nor p38 mitogen-activated protein kinase (MAPK) was required for the proteasome inhibitor-induced eIF2α phosphorylation; furthermore, both the PKC inhibitor staurosporine and the p38 MAPK inhibitor SB203580 caused enchanced phosphorylation of eIF2α. Zinc(II) protoporphyrine IX (ZnPP), an inhibitor of the heme-oxygenase-1 (HO-1), which has also been previously reported to be involved in HRI activation, also failed to prevent the induction of eIF2α phosphorylation in the presence of the proteasome inhibitor bortezomib or MG132.     

Decentralisation of radiation therapy. Is it possible and beneficial to patients? Experience of the first 5 years of a satellite radiotherapy unit in the province of Tarragona,Spain

Background

The concept of satellite radiotherapy originates in countries whose populations are largely dispersed in order to treat homogenously the population by a unique fixed team.

Aim

This report describes the creation and management of a satellite radiotherapy unit in Spain (RUTE-Radiotherapy Unit, Terres de l’Ebre). It is managed by the Radiation Oncology Department at Hospital Universitari Sant Joan de Reus. We report the benefit gained in the comfort of patients and the economic benefit gained by reducing the expense of transport for the health care system.

Materials and methods

RUTE is equipped with a linear accelerator. A team of 10 physicians, specialised in different oncology pathologies, travel to RUTE on a rotational basis from the main Radiation Oncology Department. Simulation and planning of treatment is managed at the Radiation Oncology Department in Reus. Patients from RUTE only have to visit the centre in Reus once throughout the treatment process.

Results

Since August 2008, 1500 patients have completed treatment in the satellite unit. The implementation of RUTE has greatly improved the comfort of patients and along with that, there have been important savings in transport costs to the regional health care system.

Conclusions

Despite the high technological requirements of our speciality, decentralising radiotherapy is feasible. We can guarantee the highest standards of treatment with no differences from attending the main centre. It implies a clear benefit for the comfort of the patients and an economic benefit by decreasing transport costs.