Ketogenic diets are high in fat and low in carbohydrates as well as protein which forces cells to rely on lipid oxidation and mitochondrial respiration rather than glycolysis for energy metabolism. ...Cancer cells (relative to normal cells) are believed to exist in a state of chronic oxidative stress mediated by mitochondrial metabolism. The current study tests the hypothesis that ketogenic diets enhance radio-chemo-therapy responses in lung cancer xenografts by enhancing oxidative stress.
Mice bearing NCI-H292 and A549 lung cancer xenografts were fed a ketogenic diet (KetoCal 4:1 fats: proteins+carbohydrates) and treated with either conventionally fractionated (1.8-2 Gy) or hypofractionated (6 Gy) radiation as well as conventionally fractionated radiation combined with carboplatin. Mice weights and tumor size were monitored. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modified proteins as a marker of oxidative stress as well as proliferating cell nuclear antigen (PCNA) and γH2AX as indices of proliferation and DNA damage, respectively.
The ketogenic diets combined with radiation resulted in slower tumor growth in both NCI-H292 and A549 xenografts (P < 0.05), relative to radiation alone. The ketogenic diet also slowed tumor growth when combined with carboplatin and radiation, relative to control. Tumors from animals fed a ketogenic diet in combination with radiation showed increases in oxidative damage mediated by lipid peroxidation as determined by 4HNE-modified proteins as well as decreased proliferation as assessed by decreased immunoreactive PCNA.
These results show that a ketogenic diet enhances radio-chemo-therapy responses in lung cancer xenografts by a mechanism that may involve increased oxidative stress.
Cancer cells, relative to normal cells, demonstrate significant alterations in metabolism that are proposed to result in increased steady-state levels of mitochondrial-derived reactive oxygen species ...(ROS) such as O2(•-)and H2O2. It has also been proposed that cancer cells increase glucose and hydroperoxide metabolism to compensate for increased levels of ROS. Given this theoretical construct, it is reasonable to propose that forcing cancer cells to use mitochondrial oxidative metabolism by feeding ketogenic diets that are high in fats and low in glucose and other carbohydrates, would selectively cause metabolic oxidative stress in cancer versus normal cells. Increased metabolic oxidative stress in cancer cells would in turn be predicted to selectively sensitize cancer cells to conventional radiation and chemotherapies. This review summarizes the evidence supporting the hypothesis that ketogenic diets may be safely used as an adjuvant therapy to conventional radiation and chemotherapies and discusses the proposed mechanisms by which ketogenic diets may enhance cancer cell therapeutic responses.
Determine the degree of interfraction prostate motion and its components measured by using daily megavoltage (MV) cone beam computed tomography (CBCT) imaging.
A total of 984 daily MV CBCT images ...from 24 patients undergoing definitive intensity-modulated radiotherapy for localized prostate cancer were analyzed retrospectively. Pretreatment couch shifts, based on physician registration of MV CBCT to planning CT data sets, were used as a measure of daily interfraction motion. Off-line bony registration was performed to separate bony misalignment from internal organ motion. Interobserver and intraobserver variation studies were performed on 20 MV CBCT images.
Mean interfraction prostate motion was 6.7 mm, with the greatest single-axis deviation in the anterior-posterior (AP) direction. The largest positional inaccuracy was accounted for by systematic deviations in bony misalignment, whereas random deviations occurred from bony misalignment and internal prostate motion. In the aggregate, AP motion did not correlate with days elapsed since beginning therapy or on average with rectal size at treatment planning. Interobserver variation was greatest in the AP direction, decreased in experienced observers, and further decreased in intraobserver studies. Mean interfraction motion during the first 6 days of therapy, when used as a subsequent offset, reduced acceptable AP planning target volume margins by 50%.
The MV CBCT is a practical direct method of daily localization that shows significant interfraction motion with respect to conventional three-dimensional conformal and intensity-modulated radiotherapy margins, similar to that measured in other modalities.
The purpose of the present prospective clinical trial was to determine the efficacy of (18)Ffluorothymidine (FLT)-identified active bone marrow sparing for pelvic cancer patients by correlating the ...FLT uptake change during and after chemoradiation therapy with hematologic toxicity.
Simulation FLT positron emission tomography (PET) images were used to spare pelvic bone marrow using intensity modulated radiation therapy (IMRT BMS) for 32 patients with pelvic cancer. FLT PET scans taken during chemoradiation therapy after 1 and 2 weeks and 30 days and 1 year after completion of chemoradiation therapy were used to evaluate the acute and chronic dose response of pelvic bone marrow. Complete blood counts were recorded at each imaging point to correlate the FLT uptake change with systemic hematologic toxicity.
IMRT BMS plans significantly reduced the dose to the pelvic regions identified with FLT uptake compared with control IMRT plans (P<.001, paired t test). Radiation doses of 4 Gy caused an ∼50% decrease in FLT uptake in the pelvic bone marrow after either 1 or 2 weeks of chemoradiation therapy. Additionally, subjects with more FLT-identified bone marrow exposed to ≥4 Gy after 1 week developed grade 2 leukopenia sooner than subjects with less marrow exposed to ≥4 Gy (P<.05, Cox regression analysis). Apparent bone marrow recovery at 30 days after therapy was not maintained 1 year after chemotherapy. The FLT uptake in the pelvic bone marrow regions that received >35 Gy was 18.8% ± 1.8% greater at 30 days after therapy than at 1 year after therapy. The white blood cell, platelet, lymphocyte, and neutrophil counts at 1 year after therapy were all lower than the pretherapy levels (P<.05, paired t test).
IMRT BMS plans reduced the dose to FLT-identified pelvic bone marrow for pelvic cancer patients. However, reducing hematologic toxicity is challenging owing to the acute radiation sensitivity (∼4 Gy) and chronic suppression of activity in bone marrow receiving radiation doses >35 Gy, as measured by the FLT uptake change correlated with the complete blood cell counts.
Ketogenic diets are low in carbohydrates and high in fat, which forces cells to rely more heavily upon mitochondrial oxidation of fatty acids for energy. Relative to normal cells, cancer cells are ...believed to exist under a condition of chronic mitochondrial oxidative stress that is compensated for by increases in glucose metabolism to generate reducing equivalents. In this study we tested the hypothesis that a ketogenic diet concurrent with radiation and chemotherapy would be clinically tolerable in locally advanced non-small cell lung cancer (NSCLC) and pancreatic cancer and could potentially exploit cancer cell oxidative metabolism to improve therapeutic outcomes. Mice bearing MIA PaCa-2 pancreatic cancer xenografts were fed either a ketogenic diet or standard rodent chow, treated with conventionally fractionated radiation (2 Gy/fraction), and tumor growth rates were assessed daily. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modfied proteins as a marker of oxidative stress. Based on this and another previously published preclinical study, phase 1 clinical trials in locally advanced NSCLC and pancreatic cancer were initiated, combining standard radiation and chemotherapy with a ketogenic diet for six weeks (NSCLC) or five weeks (pancreatic cancer). The xenograft experiments demonstrated prolonged survival and increased 4HNE-modfied proteins in animals consuming a ketogenic diet combined with radiation compared to radiation alone. In the phase 1 clinical trial, over a period of three years, seven NSCLC patients enrolled in the study. Of these, four were unable to comply with the diet and withdrew, two completed the study and one was withdrawn due to a dose-limiting toxicity. Over the same time period, two pancreatic cancer patients enrolled in the trial. Of these, one completed the study and the other was withdrawn due to a dose-limiting toxicity. The preclinical experiments demonstrate that a ketogenic diet increases radiation sensitivity in a pancreatic cancer xenograft model. However, patients with locally advanced NSCLC and pancreatic cancer receiving concurrent radiotherapy and chemotherapy had suboptimal compliance to the oral ketogenic diet and thus, poor tolerance.
Paddle‐based rotating‐shield brachytherapy Liu, Yunlong; Flynn, Ryan T.; Kim, Yusung ...
Medical physics (Lancaster),
October 2015, Letnik:
42, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Purpose:
The authors present a novel paddle‐based rotating‐shield brachytherapy (P‐RSBT) method, whose radiation‐attenuating shields are formed with a multileaf collimator (MLC), consisting of ...retractable paddles, to achieve intensity modulation in high‐dose‐rate brachytherapy.
Methods:
Five cervical cancer patients using an intrauterine tandem applicator were considered to assess the potential benefit of the P‐RSBT method. The P‐RSBT source used was a 50 kV electronic brachytherapy source (Xoft Axxent™). The paddles can be retracted independently to form multiple emission windows around the source for radiation delivery. The MLC was assumed to be rotatable. P‐RSBT treatment plans were generated using the asymmetric dose–volume optimization with smoothness control method Liu et al., Med. Phys. 41(11), 111709 (11pp.) (2014) with a delivery time constraint, different paddle sizes, and different rotation strides. The number of treatment fractions (fx) was assumed to be five. As brachytherapy is delivered as a boost for cervical cancer, the dose distribution for each case includes the dose from external beam radiotherapy as well, which is 45 Gy in 25 fx. The high‐risk clinical target volume (HR‐CTV) doses were escalated until the minimum dose to the hottest 2 cm3 (D2cm3) of either the rectum, sigmoid colon, or bladder reached their tolerance doses of 75, 75, and 90 Gy3, respectively, expressed as equivalent doses in 2 Gy fractions (EQD2 with α/β = 3 Gy).
Results:
P‐RSBT outperformed the two other RSBT delivery techniques, single‐shield RSBT (S‐RSBT) and dynamic‐shield RSBT (D‐RSBT), with a properly selected paddle size. If the paddle size was angled at 60°, the average D90 increases for the delivery plans by P‐RSBT on the five cases, compared to S‐RSBT, were 2.2, 8.3, 12.6, 11.9, and 9.1 Gy10, respectively, with delivery times of 10, 15, 20, 25, and 30 min/fx. The increases in HR‐CTV D90, compared to D‐RSBT, were 16.6, 12.9, 7.2, 3.7, and 1.7 Gy10, respectively. P‐RSBT HR‐CTV D90‐values were insensitive to the paddle size for paddles angled at less than 60°. Increasing the paddle angle from 5° to 60° resulted in only a 0.6 Gy10 decrease in HR‐CTV D90 on average for five cases when the delivery times were set to 15 min/fx. The HR‐CTV D90 decreased to 2.5 and 11.9 Gy10 with paddle angles of 90° and 120°, respectively.
Conclusions:
P‐RSBT produces treatment plans that are dosimetrically and temporally superior to those of S‐RSBT and D‐RSBT, although P‐RSBT systems may be more mechanically challenging to develop than S‐RSBT or D‐RSBT. A P‐RSBT implementation with 4–6 shield paddles would be sufficient to outperform S‐RSBT and D‐RSBT if delivery times are constrained to less than 15 min/fx.
Abstract Purpose The adrenal glands are a common site of metastases because of their rich blood supply. Previously, adrenal metastases were treated with systemic chemotherapy or, more rarely, with ...surgical resection or palliative radiation therapy. Stereotactic body radiation therapy (SBRT) has recently emerged as an attractive noninvasive approach to definitively treat these lesions. We present our experience in treating adrenal metastases using SBRT and review the current literature. Methods and materials This is a single-institution retrospective review of patients who received SBRT to adrenal metastases originating from various primary malignancies. Patients who were eligible for SBRT included those with limited metastatic disease (≤5 sites) with otherwise controlled metastatic disease and uncontrolled adrenal metastases. Results Ten patients met the study's inclusion criteria and received SBRT doses of 30 to 48 Gy in 3 to 5 fractions. Acute sequelae of SBRT treatment included 4 patients with grades 1 or 2 nausea, 3 patients with grade 1 fatigue, and 1 with grade 1 diarrhea. The median follow-up was 6 months with a median overall survival of 9.9 months. One patient demonstrated progressive adrenal gland disease 18.8 months after SBRT treatment. Seven patients developed new distant metastases after treatment, with a median progression-free survival of 3.4 months. Three months after SBRT to the adrenal gland, 1 patient developed a gastrointestinal bleed. Conclusions These results complement the limited existing body of literature by demonstrating that SBRT provides good control of treated adrenal gland metastasis; however, high-grade late toxicities may occur. More stringent dose constraint limits may prevent associated serious adverse events.
To quantify the dosimetric impact of applicator displacements and applicator reconstruction-uncertainties through simulated planning studies of virtual applicator shifts.
Twenty randomly selected ...high-dose-rate (HDR) titanium tandem-and-ovoid (T&O) plans were retrospectively studied. MRI-guided, conformal brachytherapy (MRIG-CBT) plans were retrospectively generated. To simulate T&O displacement, the whole T&O set was virtually shifted on treatment planning system in the cranial (+) and the caudal (-) direction after each dose calculation. Each shifted plan was compared to an unshifted plan. To simulate T&O reconstruction-uncertainties, each tandem and ovoid was separately shifted along its axis before performing the dose calculation. After the dose calculation, the calculated isodose lines and T&O were moved back to unshifted T&O position. Shifted and shifted-back plan were compared.
Regarding the dosimetric impact of the simulated T&O displacements, rectal D2cc values were observed as being the most sensitive to change due to T&O displacement among all dosimetric metrics regardless of point A (p < 0.013) or MRIG-CBT plans (p < 0.0277). To avoid more than 10% change, ± 1.5 mm T&O displacements were accommodated for both point A and MRIG-CBT plans. The dosimetric impact of T&O displacements on sigmoid (p < 0.0005), bladder (p < 0.0001), HR-CTV (p < 0.0036), and point A (p < 0.0015) were significantly larger in the MRIG-CBT plans than point A plans. Regarding the dosimetric impact of T&O reconstruction-uncertainties, less than ± 3.0 mm reconstruction-uncertainties were also required in order to avoid more than 10% dosimetric change in either the point A or MRIG-CBT plans.
The dosimetric impact of simulated T&O displacements was significantly larger in the MRIG-CBT plans than in the point A plans. Either ± 3 mm T&O displacement or a ± 4.5 mm T&O reconstruction-uncertainty could cause greater than 10% dosimetric change for both point A plans and MRIG-CBT plans.
In this treatment planning study, the potential benefits of a rotating shield brachytherapy (RSBT) technique based on a partially-shielded electronic brachytherapy source were assessed for treating ...cervical cancer. Conventional intracavitary brachytherapy (ICBT), intracavitary plus supplementary interstitial (IS+ICBT), and RSBT treatment plans for azimuthal emission angles of 180° (RSBT-180) and 45° (RSBT-45) were generated for five patients. For each patient, high-risk clinical target volume (HR-CTV) equivalent dose in 2 Gy fractions (EQD2) (α/β = 10 Gy) was escalated until bladder, rectum, or sigmoid colon tolerance EQD2 values were reached. External beam radiotherapy dose (1.8 Gy × 25) was accounted for, and brachytherapy was assumed to have been delivered in 5 fractions. IS+ICBT provided a greater HR-CTV D90 (minimum EQD2 to the hottest 90%) than ICBT. D90 was greater for RSBT-45 than IS+ICBT for all five patients, and greater for RSBT-180 than IS+ICBT for two patients. When the RSBT-45/180 plan with the lowest HR-CTV D90 that was greater than the D90 the ICBT or IS+ICBT plan was selected, the average (range) of D90 increases for RSBT over ICBT and IS+ICBT were 16.2 (6.3-27.2)and 8.5 (0.03-20.16) Gy, respectively. The average (range) treatment time increase per fraction of RSBT was 34.56 (3.68-70.41) min over ICBT and 34.59 (3.57-70.13) min over IS+ICBT. RSBT can increase D90 over ICBT and IS+ICBT without compromising organ-at-risk sparing. The D90 and treatment time improvements from RSBT depend on the patient and shield emission angle.
Purpose:
The authors present a rapid emission angle selection (REAS) method that enables the efficient selection of the azimuthal shield angle for rotating shield brachytherapy (RSBT). The REAS ...method produces a Pareto curve from which a potential RSBT user can select a treatment plan that balances the tradeoff between delivery time and tumor dose conformity.
Methods:
Two cervical cancer patients were considered as test cases for the REAS method. The RSBT source considered was a Xoft AxxentTM electronic brachytherapy source, partially shielded with 0.5 mm of tungsten, which traveled inside a tandem intrauterine applicator. Three anchor RSBT plans were generated for each case using dose-volume optimization, with azimuthal shield emission angles of 90°, 180°, and 270°. The REAS method converts the anchor plans to treatment plans for all possible emission angles by combining neighboring beamlets to form beamlets for larger emission angles. Treatment plans based on exhaustive dose-volume optimization (ERVO) and exhaustive surface optimization (ERSO) were also generated for both cases. Uniform dwell-time scaling was applied to all plans such that that high-risk clinical target volume D
90 was maximized without violating the D
2cc tolerances of the rectum, bladder, and sigmoid colon.
Results:
By choosing three azimuthal emission angles out of 32 potential angles, the REAS method performs about 10 times faster than the ERVO method. By settingD
90 to 85–100 Gy10, the delivery times used by REAS generated plans are 21.0% and 19.5% less than exhaustive surface optimized plans used by the two clinical cases. By setting the delivery time budget to 5–25 and 10–30 min/fx, respectively, for two the cases, the D
90 contributions for REAS are improved by 5.8% and 5.1% compared to the ERSO plans. The ranges used in this comparison were selected in order to keep both D
90 and the delivery time within acceptable limits.
Conclusions:
The REAS method enables efficient RSBT treatment planning and delivery and provides treatment plans with comparable quality to those generated by exhaustive replanning with dose-volume optimization.
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