Volumetric modulated arc therapy (VMAT) is a novel extension of conventional intensity-modulated radiotherapy (cIMRT), in which an optimized three-dimensional dose distribution may be delivered in a ...single gantry rotation. VMAT is the predecessor to RapidArc (Varian Medical System). This study compared VMAT with cIMRT and with conventional modified wide-tangent (MWT) techniques for locoregional radiotherapy for left-sided breast cancer, including internal mammary nodes.
Therapy for 5 patients previously treated with 50 Gy/25 fractions using nine-field cIMRT was replanned with VMAT and MWT. Comparative endpoints were planning target volume (PTV) dose homogeneity, doses to surrounding structures, number of monitor units, and treatment delivery time.
For VMAT, two 190 degrees arcs with 2-cm overlapping jaws were required to optimize over the large treatment volumes. Treatment plans generated using VMAT optimization resulted in PTV homogeneity similar to that of cIMRT and MWT. The average heart volumes receiving >30 Gy for VMAT, cIMRT, and MWT were 2.6% +/- 0.7%, 3.5% +/- 0.8%, and 16.4% +/- 4.3%, respectively, and the average ipsilateral lung volumes receiving >20 Gy were 16.9% +/- 1.1%, 17.3% +/- 0.9%, and 37.3% +/- 7.2%, respectively. The average mean dose to the contralateral medial breast was 3.2 +/- 0.6 Gy for VMAT, 4.3 +/- 0.4 Gy for cIMRT, and 4.4 +/- 4.7 Gy for MWT. The healthy tissue volume percentages receiving 5 Gy were significantly larger with VMAT (33.1% +/- 2.1%) and IMRT (45.3% +/- 3.1%) than with MWT (19.4% +/- 3.7%). VMAT reduced the number of monitor units by 30% and the treatment time by 55% compared with cIMRT.
VMAT achieved similar PTV coverage and sparing of organs at risk, with fewer monitor units and shorter delivery time than cIMRT.
To report interim cosmetic and toxicity results of a multicenter randomized trial comparing accelerated partial-breast irradiation (APBI) using three-dimensional conformal external beam radiation ...therapy (3D-CRT) with whole-breast irradiation (WBI).
Women age > 40 years with invasive or in situ breast cancer ≤ 3 cm were randomly assigned after breast-conserving surgery to 3D-CRT APBI (38.5 Gy in 10 fractions twice daily) or WBI (42.5 Gy in 16 or 50 Gy in 25 daily fractions ± boost irradiation). The primary outcome was ipsilateral breast tumor recurrence (IBTR). Secondary outcomes were cosmesis and toxicity. Adverse cosmesis was defined as a fair or poor global cosmetic score. After a planned interim cosmetic analysis, the data, safety, and monitoring committee recommended release of results. There have been too few IBTR events to trigger an efficacy analysis.
Between 2006 and 2011, 2,135 women were randomly assigned to 3D-CRT APBI or WBI. Median follow-up was 36 months. Adverse cosmesis at 3 years was increased among those treated with APBI compared with WBI as assessed by trained nurses (29% v 17%; P < .001), by patients (26% v 18%; P = .0022), and by physicians reviewing digital photographs (35% v 17%; P < .001). Grade 3 toxicities were rare in both treatment arms (1.4% v 0%), but grade 1 and 2 toxicities were increased among those who received APBI compared with WBI (P < .001).
3D-CRT APBI increased rates of adverse cosmesis and late radiation toxicity compared with standard WBI. Clinicians and patients are cautioned against the use of 3D-CRT APBI outside the context of a controlled trial.
Radiotherapy is an essential component of the treatment regimens for many cancer patients. Despite recent technological advancements to improve dose delivery techniques, the dose escalation required ...to enhance tumor control is limited due to the inevitable toxicity to the surrounding healthy tissue. Therefore, the local enhancement of dosing in tumor sites can provide the necessary means to improve the treatment modality. In recent years, the emergence of nanotechnology has facilitated a unique opportunity to increase the efficacy of radiotherapy treatment. The application of high-atomic-number (Z) nanoparticles (NPs) can augment the effects of radiotherapy by increasing the sensitivity of cells to radiation. High-Z NPs can inherently act as radiosensitizers as well as serve as targeted delivery vehicles for radiosensitizing agents. In this work, the therapeutic benefits of high-Z NPs as radiosensitizers, such as their tumor-targeting capabilities and their mechanisms of sensitization, are discussed. Preclinical data supporting their application in radiotherapy treatment as well as the status of their clinical translation will be presented.
Autophagy is a cell survival process essential for the regulation of immune responses to infections. However, the role of T cell autophagy in anti-tumor immunity is less clear. Here, we demonstrate a ...cell-autonomous role for autophagy in the regulation of CD8+ T-cell-mediated control of tumors. Mice deficient for the essential autophagy genes Atg5, Atg14, or Atg16L1 display a dramatic impairment in the growth of syngeneic tumors. Moreover, T cells lacking Atg5 have a profound shift to an effector memory phenotype and produce greater amounts of interferon-γ (IFN-γ) and tumor necrosis factor α (TNF-α). Mechanistically, Atg5−/− CD8+ T cells exhibit enhanced glucose metabolism that results in alterations in histone methylation, increases in H3K4me3 density, and transcriptional upregulation of both metabolic and effector target genes. Nonetheless, glucose restriction is sufficient to suppress Atg5-dependent increases in effector function. Thus, autophagy-dependent changes in CD8+ T cell metabolism directly regulate anti-tumor immunity.
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•Inactivation of T cell autophagy results in enhanced tumor rejection•T cells deficient in autophagy show increased glucose uptake and lactate production•Reduction in SAM transcriptionally reprograms immune cells toward effector memory
DeVorkin et al. show that loss of autophagy enhances CD8+ T-cell-mediated rejection of tumors. Mechanistically, suppression of autophagy shifts T cells to a glycolytic phenotype and causes a reduction in S-adenosylmethionine. As a consequence, autophagy-deficient T cells transcriptionally reprogram immune response genes to an effector memory state.
Dermatitis is a frequent adverse effect of adjuvant breast radiotherapy. It is more likely in full-breasted women and when the radiation is distributed nonhomogeneously in the breast. Breast ...intensity-modulated radiation therapy (IMRT) is a technique that ensures a more homogeneous dose distribution.
A multicenter, double-blind, randomized clinical trial was performed to test if breast IMRT would reduce the rate of acute skin reaction (notably moist desquamation), decrease pain, and improve quality of life compared with standard radiotherapy using wedges. Patients were assessed each week during and up to 6 weeks after radiotherapy.
A total of 358 patients were randomly assigned between July 2003 and March 2005 in two Canadian centers, and 331 were included in the analysis. Breast IMRT significantly improved the dose distribution compared with standard radiation. This translated into a lower proportion of patients experiencing moist desquamation during or up to 6 weeks after their radiation treatment; 31.2% with IMRT compared with 47.8% with standard treatment (P = .002). A multivariate analysis found the use of breast IMRT (P = .003) and smaller breast size (P < .001) were significantly associated with a decreased risk of moist desquamation. The use of IMRT did not correlate with pain and quality of life, but the presence of moist desquamation did significantly correlate with pain (P = .002) and a reduced quality of life (P = .003).
Breast IMRT significantly reduced the occurrence of moist desquamation compared with a standard wedged technique. Moist desquamation was correlated with increased pain and reduction in the quality of life.
Abstract
Recent clinical trials show docetaxel (DTX), given in conjunction with radiation therapy (RT) and androgen suppression, improves survival in high-risk prostate cancer. Addition of gold ...nanoparticles (GNPs) to this current DTX/RT protocol is expected to further improve therapeutic benefits remarkably. However, the foundation for the triple combination of RT, DTX, and GNPs must be elucidated to ensure quicker facilitation to the clinic. In this study, we explored the use of low concentrations of DTX combined with GNPs in two prostate cancer cell lines in a two-dimensional monolayer, a three-dimensional spheroid, and a mouse xenograft model. When used together, DTX and GNPs induced a nearly identical relative increase in uptake of gold in both the spheroid model and the mouse xenograft, which saw a 130% and 126% increase respectively after 24 h, showcasing the benefit of using spheroids as an in vitro model to better optimize in vivo experiments. Further, the benefits of using low concentrations of DTX combined with GNPs extended for over 72 h, allowing for less frequency in dosing when translating to the clinic. Overall, these results highlight the benefits of using DTX combined with GNPs and lays the groundwork for the translation of the triple combination of RT, GNPs, and DTX to the clinic.
Background
Much in vitro research on the applicability of gold nanoparticles (GNPs) in cancer treatment has been focused on two-dimensional (2D) monolayer models. To improve this, we explored the ...effect of the combination of GNPs and docetaxel (DTX) with radiotherapy (RT) in a more complex three-dimensional (3D) spheroid that can better mimic a real tumour microenvironment.
Methods
Two cell lines, prostate cancer LNCaP and cervical cancer HeLa, were grown in monolayer and spheroids. Cells were dosed with GNPs at a concentration of 10
μ
g
/
mL
and with DTX at a dose that inhibited growth-rate by 50%. Samples were irradiated 24 h after drug dosing with 2 Gy, 5 Gy, or 10 Gy using a 6 MV beam. Monolayer cells had the DNA double-strand breaks (DSBs) probed 24 h post-radiation, and cell proliferation observed over 7 days. Spheroid proliferation was monitored over 14 days along with spheroid volume measurements.
Results
In DTX and GNP-treated monolayer samples, there is decreased survival after irradiation with 5 and 10 Gy of 16–24% and an increase in DSBs of 91.6–109.9%, compared to DTX. In spheroids, GNPs decreased the surviving cells by 10.54–15.61% compared to control, while GNPs and DTX decreased survival by 20.9–31.04%. There is reduced spheroid volume 14 days after treatment with the triple combination.
Conclusions
Combining GNPs and DTX leads to a synergistic radiosensitization effect in spheroids, which can better mimic the tumour microenvironment. Testing treatment modalities with spheroids and RT may allow a quicker translation to the clinic.
Pancreatic cancer stands among the deadliest forms of cancer, and the existing treatments fall short of providing adequate efficacy. Novel and more effective treatment approaches are urgently ...required to address this critical medical challenge. In this study, we aimed to evaluate the anti-cancer efficacy of gold nanoparticles (GNPs) in combination with radiotherapy (RT). A 3D pancreatic cancer co-culture spheroid model of MIA PaCa-2 cancer cells and patient-derived cancer-associated fibroblasts (CAF-98) was used. The spheroids were treated with GNPs (7.5 μg/mL) and 2 Gy of RT. The spheroids' cell viability was assessed through the CellTiter-Glo 3D assay, and an immunofluorescence assay was used to assess the DNA DSBs via the expression of the DNA damage marker 53BP1. Co-culture samples showed a 10.8% (
< 0.05) increase in proliferation and a 13.0% (
< 0.05) decrease in DNA DSB when compared to monoculture samples, However, they displayed a 175% (
< 0.001) increase in GNPs uptake when compared to monoculture spheroids. Using GNPs/RT, we were able to show a significant reduction of 6.2% (
< 0.05) in spheroid size and an increase of 14.3% (
< 0.05) in DNA DSB damage in co-culture samples. The combination of GNPs with RT demonstrated remarkable radiosensitization effects, representing a promising approach to enhance cancer treatment efficacy. These effects were particularly noteworthy in the more treatment-resistant co-culture spheroid model.
Abstract Background and purpose Multi-leaf collimator (MLC) positional errors occur during intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) deliveries. The ...impact of such errors has been evaluated for IMRT but not VMAT. The purpose of this work is to understand how random and systematic VMAT MLC positional errors affect the patient dose distribution. Materials and methods Eight head and neck single arc (360°) VMAT treatment plans were created. Random and two types of systematic MLC errors were simulated for error magnitudes of 0.25, 0.5, 1, 2 and 5 mm. The two types of systematic MLC errors were: (1) MLC banks are shifted in the same direction (left or right) and (2) MLC banks are shifted in opposing directions resulting in smaller or larger field shapes. The MLC errors were simulated, for all control points, on both banks of active MLC leaves only. Results There is a linear correlation of MLC errors with gEUD for all error types. The gEUD dose sensitivities with MLC error for the PTV70 were −0.2, −0.9, −2.8 and 1.9 Gy/mm for random, systematic shift, systematic close and systematic open MLC errors, respectively. The sensitivity of VMAT plans to MLC positional errors was similar to those of IMRT plans with less than 50 segments but much less than those created for a step and shoot with more than 50 segments or sliding-window delivery technique. To maintain the PTV70 to within 2% would require that MLC open/close errors be within 0.6 mm. Conclusions Radiation therapy centers should have adequate quality assurance programs in place to assess open/close MLC errors (i.e. leaf gap errors) as they tend to be more impactful than random or systematic MLC shift errors.
Cancer is defined as the uncontrolled proliferation of heterogeneous cell cultures in the body that develop abnormalities and mutations, leading to their resistance to many forms of treatment. Left ...untreated, these abnormal cell growths can lead to detrimental and even fatal complications for patients. Radiation therapy is involved in around 50% of cancer treatment workflows; however, it presents significant recurrence rates and normal tissue toxicity, given the inevitable deposition of the dose to the surrounding healthy tissue. Chemotherapy is another treatment modality with excessive normal tissue toxicity that significantly affects patients' quality of life. To improve the therapeutic efficacy of radiotherapy and chemotherapy, multiple conjunctive modalities have been proposed, which include the targeting of components of the tumour microenvironment inhibiting tumour spread and anti-therapeutic pathways, increasing the oxygen content within the tumour to revert the hypoxic nature of the malignancy, improving the local dose deposition with metal nanoparticles, and the restriction of the cell cycle within radiosensitive phases. The tumour microenvironment is largely responsible for inhibiting nanoparticle capture within the tumour itself and improving resistance to various forms of cancer therapy. In this review, we discuss the current literature surrounding the administration of molecular and nanoparticle therapeutics, their pharmacokinetics, and contrasting mechanisms of action. The review aims to demonstrate the advancements in the field of conjugated nanomaterials and radiotherapeutics targeting, inhibiting, or bypassing the tumour microenvironment to promote further research that can improve treatment outcomes and toxicity rates.
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