Biological Effective Dose Research Articles

Partial Stereotactic Ablative Radiotherapy in Bulky Urinary Tract Malignancy: An Update Clinical Outcomes and Dosimetric Analysis

Patients with bulky urinary tract malignancy have poor prognosis. Stereotactic ablative radiotherapy (SABR) needs careful consideration in abdominopelvic bulky tumors because of dose constraints on the OARs. We reported updated clinical outcomes to evaluate the safety and efficacy of partial stereotactic ablative radiotherapy(P-SABR) in bulky urinary tract malignancy. The study also aims to investigate the feasibility of P-SABR in dose and biologic effective dose (BED) escalation inside the tumors with equivalent toxicity. A total of 26 patients with urinary tract malignancy underwent P-SABR radiotherapy from January 2013 to September 2018 were retrospectively analyzed in this study. All the patients were in inoperable locally advanced or metastatic stage with tumor diameter > 4.0 cm. The P-SABR plan consisted of the SABR for gross tumor volume boost (GTVb) and following conventionally fractionated radiotherapy for planning target volume (PTV). The first SABR plan to GTVb was delivered in 15-32Gy/3-5f. The second conventionally fractionated radiotherapy plan to PTV was delivered in 40.0-58.08Gy/15-26f. The total P-SABR plan met the OARs constraints. Local control and overall survival were estimated. Acute and late toxicity were evaluated according to RTOG criteria. Paired conventionally fractionated radiotherapy (CFRT) plans were re-designed for all patients, with the same OARs dose constraints and total dose of PTV margin. Dosimetric and BED parameters were compared in P-SABR and paired CFRT plans. Median age of the patients was 66.5 years (range, 46-90 years). The tumor treated by P-SABR had a median diameter of 8.4 cm (4.1-19.5 cm) and a median volume of 99.2 cc (23.9-631.8 cc). Median follow-up time was 19.1 months. The local control at 1 and 2 years were 83.2%, 77.3%, respectively. The overall survival at 1 and 2 years were 72.2% ,45.5%, respectively. 6 cases have no local recurrence after 36 months. 4 cases remained alive after 60 months. Local symptoms improved in 15/16 cases after P-SABR. Multivariate analysis showed tumor diameter (≥8cm vs. <8cm) was the independent factor affecting local control and overall survival (P=0.033, P=0.016). No patient was observed radiotherapy directly induced ≥grade 3 toxicity. Compared with the paired CFRT plans, the P-SABR plans had no significant difference in most OAR dose parameters, except for the small intestine/colon V15, V45 with an increase of 14.6 cc, 3.4 cc. However, P-SABR plans increased the dose of PTV Dmean, Dmax by 8.7Gy, 14.4Gy (P < 0.001), respectively. In addition, the dose and BED of GTVb had a significant escalation of 15.8Gy and 30.2Gy (P<0.001) respectively in P-SABR plans. We had reported P-SABR is well-tolerated in bulky urinary tract malignancy in previous study. Updated outcomes showed P-SABR may have long-term local control in these people. Compared with traditional CFRT plans, P-SABR plans escalated the dose and BED inside bulky tumors with equivalent toxicity.

Biological Effective Dose (BED) in Evaluation of Rectal Dose in Prostate Cancer Patients with Hydrogel Spacer Who Underwent an EBRT with Different Fractionation Schemes

To evaluate rectal dose sparing in prostate cancer patients with hydrogel spacer who underwent an external beam radiotherapy (EBRT) with different fractionation schemes. In a previous study, we have reported that rectal sparing was achieved in prostate cancer patients with hydrogel spacer who underwent a combination therapy of EBRT and LDR brachytherapy (Zhang H, et al. J Appl Clin Med Phys, 2022). In this study, we focused on evaluation of spacer-related rectal sparing in patients who underwent an EBRT with conventional fractionation (81 Gy in 45 fractions), hypofractionation (70 Gy in 28 fractions), or stereotactic body radiotherapy (SBRT) for 40 Gy or 42.5 Gy in 5 fractions. In 172 patients, 119 patients were applied with injection of polyethylene-glycol hydrogel and others without the injection as control. In VMAT plans, doses to rectal wall were examined and converted to BED according to AAPM TG-137 (α/β ratio = 4 Gy). On average, an interspace of 1cm between prostate and rectum was achieved by spacer insertion. Rectal wall was defined as 0.4cm thickness inside the outer contour of rectum, and the volume ranged from 4.5 cm3 to 21.3cm3 for patients with spacer and from 8.2cm3 to 35.1cm3 for those with no spacer. In conventional scheme, an average rectal BED was 120.0 Gy, 116.9 Gy, 114.0 Gy, 108.6 Gy, 87.6 Gy and 55.6 Gy to the volume of 0.1, 0.5, 1, 2, 5 and 10cm3, respectively, and BEDmean was 55.3 Gy in patients with no spacer. The BED decreased to 105.1 Gy, 96.3 Gy, 86.1 Gy, 75.4 Gy, 51.7 Gy and 26.9 Gy to the volume of 0.1, 0.5, 1, 2, 5 and 10cm3, respectively (p < 0.01), and BEDmean was 46.0 Gy in patients with spacer. In hypofractionation, rectal BED was in average of 115.8 Gy, 112.3 Gy, 109.8 Gy, 103 Gy, 81.6 and 52.8 Gy to the volume of 0.1, 0.5, 1, 2, 5 and 10cm3, respectively, and BEDmean was 48.6 Gy in patients with no spacer. Patients with spacer had significantly decreases of rectal BED, an average of 103 Gy, 91.7 Gy, 84.1 Gy, 72.8 Gy, 48.8 Gy and 26.0 Gy to the volume of 0.1, 0.5, 1, 2, 5 and 10cm3, respectively (p < 0.01), BEDmean was 42.4 Gy. In SBRT, average rectal BED in patients with spacer decreased to 93.6 Gy, 78.4 Gy, 69 Gy, 57.5 Gy, 38.5 Gy and 21.5 Gy, in comparison of 124.1 Gy, 117,4 Gy, 110.9 Gy, 97.3 Gy, 59.7 Gy and 32.3 Gy to the volume of 0.1, 0.5, 1, 2, 5 and 10cm3 in those without spacer, respectively (p <0.01). BEDmean decreased to 32.0 Gy in patient with spacer, compared with 43.2 Gy in those with no spacer. Insertion of hydrogel spacer significantly improved rectal dose sparing, about 11.1% to 50.8% in conventional scheme, 12.4% to 51.6% in hypofractionation scheme, and 24.6% to 40.9% in SBRT patients. Furthermore, relatively more dose sparing on rectum was seen on the volume from 0.1cm3 to 2cm3 in SBRT patients.

Radiobiological Insights of Staged Brachytherapy Using Eye Plaque for Large Uveal Melanoma

I-125 radioactive seeds embedded in an eye plaque is used to deliver the radiation dose of 85Gy to the apex of the tumor. However, it is challenging to treat a lesion in height (>10 mm) because of a high dose (> 500 Gy) to sclera. A staged radiotherapy (SRT) has been implemented successfully in stereotactic radiosurgery when a single dose is risky for a bigger sized lesion. The hypothesis of this work is that the SRT works for eye plaque brachytherapy of uveal melanoma to break the single fraction into two. To apply the concept of SRT, the following questions need to be answered: What are the two fraction doses? What is the time interval between the two fractions? In this work, the two split fraction doses and time interval are calculated using the "incomplete-repair' model. Equation (1) is the linear-quadratic (LQ) model. f(x) is the cell survival curve (SC). Equation (2) and (3) are radiobiological model developed dealing with the split doses by considering the incomplete repair. Ln(f(x)) = -αx - βx2 (1) Ln(fn(x, Ɵ)) = nLn(f(x))-nβx2hn(Ɵ) (2) hn(Ɵ) = (2/n)[ Ɵ/(1- Ɵ)][n-(1- Ɵn)/(1- Ɵ)] (3) Ɵ = exp(-µΔt) (4) x represents the fraction dose, Ɵx is the initial segment of the survival curve, Ɵ determines the rate at which repair proceeds. n is fraction number and µ represent repair constant which equals to ln2/T1/2. T1/2 is the half-life of I-125. For continuous dose vt delivered at dose rate v for time t, with repair constant µ, the LQ model is modified as Ln (f(vt, µ)) = -α(vt) -β(vt)2g(µt) (5) g(µt) = 2[µt-1+exp(-µt)]/(µt)2 (6) Assuming biological effective dose (BED) is the same for the single fraction and split two fractions, SC when n = 1 should be same as when n = 2. Therefore, the equation (7) is derived. Ɵ = [(α/β)x1 - 2(α/β)(x2)2 + (x1)2]/2(x2)2 - 1 (7) x1 is single fraction dose of 85Gy, x2 is the split dose to two fractions. α/β ratio of 10 Gy is used. By fitting the equation (7), the ranges of doses and time intervals were determined. The fraction doses and time interval to get the same BED as single fraction of 85 Gy are determined from 45 Gy to 50 Gy with time interval of 22 days to 76 days for staged brachytherapy eye plaque (SBEP). Our result is matched the treatment protocol for SBEP reported, e.g., 1st fraction dose of 40Gy and 50 Gy of 2nd fraction with 73 days of time interval are used. The max. dose of scleral dose is 328 Gy compared to the single fraction scleral dose of 543Gy. This work could provide guidelines in SBEP in dosage and time interval. The height of tumor matters the most in the SBEP since the taller the tumor, the higher dose to the sclera is. Reference.

Clinical Efficacy and Safety of Once-Weekly Fractionation in Stereotactic Body Radiotherapy for Pulmonary Oligometastatic Lesions

As the oligometastatic disease paradigm has become more widely accepted, further investigation is needed to risk-stratify patients within this spectrum of disease and define optimal treatment methods. Stereotactic Body Radiotherapy (SBRT) has emerged as an efficacious and safe modality to control individual lesions and improve clinical outcomes in the setting of oligometastatic disease. There is scant literature describing ideal SBRT inter-fraction time intervals or their impact on clinical outcomes, especially for treating pulmonary oligometastases. Most institutions appear to offer treatments on consecutive days or every other day. In this abstract, we sought to evaluate the efficacy and safety of delivering SBRT treatments in a once-weekly fractionation scheme. The study was undertaken via retrospective review at a single institution. We included patients with pulmonary metastatic lesions treated with SBRT at our institution between 2015 and 2019. Patients with oligometastatic disease were included, defined as patients with 5 or fewer total metastatic lesions. Treatments were delivered between 3 and 5 fractions and using at least 5 Gy per fraction. Per institutional protocol, all treatments were delivered 7 days apart. From a single institution, 204 lesions from 111 patients were included. Median follow-up was 16.5 months [IQR 7 - 36.3]. Median dose was 40 Gy [IQR 30 - 50], median BED was 80 Gy [IQR 60-100], median dose per fraction was 10 Gy [IQR 8-11]. Median internal target volume (ITV) was 18.5 cc [IQR 9.3 - 45.8]. The most common tumor histologies were lung adenocarcinoma (38.2%), colorectal adenocarcinoma (15.6%), lung squamous cell carcinoma (12.7%), renal cell carcinoma (5.9%), breast invasive ductal carcinoma (5.4%), small cell lung cancer (3.9%), and melanoma (2.9%). 2-year local control (LC) rate was 85.7% and 5-year LC rate was 84.3%. 2-year regional control (RC) rate was 53.9% and 5-year RC was 49%. Median overall survival (OS) was 20 months [IQR 9 - 37.3]. Cox regression analysis revealed biologically effective dose (BED) (HR 0.99 [0.98 - 0.99] p = 0.001) as well as dose per fraction (HR 0.92 [0.86 - 0.97] p = 0.003) were both associated with improved OS. Longest tumor dimension was associated with worse OS independent of BED and dose per fraction (HR 1.26 [1.1 - 1.4] p = 0.001). Total toxicity incidence was 7.3%, which consisted only of G1-G2 cough, dyspnea, and fatigue. Treatment of pulmonary oligometastatic lesions with SBRT delivered via once-weekly fractionation is associated with excellent local control and minimal toxicity. Larger studies are warranted to directly compare clinical outcomes of weekly SBRT fractionation to other conventional SBRT treatment schedules.

Effect of Interval between Neoadjuvant Chemotherapy and Radiation Therapy on Metastasis Risk for Inoperable Non-Metastatic Pancreatic Adenocarcinoma

In inoperable pancreatic cancer patients requiring radiotherapy (RT) after neoadjuvant chemotherapy (CT), there can be delays in starting radiation due to multiple complications. However, pancreatic cancer can progress rapidly during short intervals without treatment. We hypothesize that longer intervals between neoadjuvant chemotherapy and radiation could expediate the development of metastatic disease. We identified patients with inoperable non-metastatic borderline resectable or locally advanced pancreatic cancer treated with neoadjuvant CT followed by RT from 2011 to 2021 at a single institution. Patients who completed palliative RT as defined by a biologic effective dose (BED) of less than 50 Gy, or those who were lost to follow-up within 3 months after completing RT without documented disease progression were excluded. The interval between RT and CT was defined as the time between last date of CT administration and initiation of RT. The primary endpoint was metastasis-free survival (MFS) after RT completion. Differences in MFS between patients who started RT within or after 4, 6, and 8 weeks of completing CT were examined utilizing log rank analysis of MFS generated via the Kaplan-Meier method. At a median follow-up of 5.45 months, twenty-three patients were included. Most patients were male (61%) with cT4 (61%), cN0 (83%) pancreatic adenocarcinoma. Almost all patients completed combination neoadjuvant CT (91%) followed by either intensity modulated RT to 50.4 Gy in 28 fractions with capecitabine (n = 9) or stereotactic body RT to 33-40 Gy in 5 fractions (n = 14). Eleven (48%) patients received adjuvant CT after radiation therapy. The median time between last CT and RT initiation was 34 days (range 13-142). The MFS of patients who initiated RT within 4 weeks of CT compared to after was higher but not significant (16.8 vs 9.9 months, p = 0.144). Those who received RT within 6 or 8 weeks of completing CT exhibited significantly longer MFS compared to later than 6 (16.0 vs 6.9 mo, p = 0.016) or 8 weeks (15.1 vs 2.1 mo, p = 0.004). There was no statistical correlation between MFS and other variables (CA 19-9 before radiation, T-stage, receipt of adjuvant CT, BED). These results suggest that a longer interval between CT and RT is associated with the risk of developing metastatic disease sooner but requires validation in a prospective cohort. Root causes of delays in starting radiation (e.g., insurance authorization) should be investigated as well.

Favorable Toxicity and Local Control with Ultrahypofractionated Radiation Therapy (UH-RT) for Melanoma of the Lower Genital Tract (LGT)

To report our experience using UH-RT +/- immunotherapy (IO) in women with melanoma of the LGT. We retrospectively identified 23 patients who received UH-RT to primary tumor for vulvovaginal melanoma from 2012 to 2022. Median age was 69 years (IQR: 62-76). Stage included localized, node positive, or metastatic. 18 (78%) had tumors involving the vagina/cervix and 5 (22%) had vulvar tumors. 6 patients had c-KIT mutations; 13 patients were wild-type; 4 patients were unknown. 12 (52%) were treated at initial presentation (cohort A) and 11 (48%) at local progression/recurrence following prior therapy (cohort B). In cohort A, most (n = 11) received concurrent IO. In cohort B, 3 recurred after surgery alone, 4 after systemic therapy alone and 4 after surgery and systemic therapy. RT consisted of 6 Gy x 6 (n = 11), 6 Gy x 5 (n = 10) and 5 Gy x 5-6 (n = 2) delivered to the primary tumor + 0.5 cm margin. Patients initiated IO either ≥3 months preRT (n = 8), concurrent with RT (n = 12) or ≥3 months following RT (n = 2). 1 patient in cohort B did not receive IO. Toxicity was graded using CTCAE v 5. Overall survival (OS) was measured from end of RT. Cumulative incidence of local progression was measured from end of RT. Kaplan-Meier method and Cox regression were used for survival analyses. Landmark method was used for timing of IO. Median follow-up as determined by reverse Kaplan-Meier method was 60 months (95% CI: 37-N/A). Overall incidence of acute/late grade 2+ toxicity for the entire cohort was 34%. Grade 2 acute toxicity included: dermatitis (n = 3), urinary (n = 2), vaginitis (n = 2) and diarrhea (n = 1). 3 patients experienced grade 3 acute dermatitis. 1 patient experienced late grade 2 vaginitis. No grade 3 or 4 toxicity was noted. No significant differences in toxicity were noted between RT regimens. Local disease control was achieved in 61% of patients. Local only, local and distant, and distant-only progression were seen in 17%, 22%, and 30% of patients respectively. 2-year cumulative incidence of local progression was 33% for the whole cohort, 28% for cohort A, and 36% for cohort B (p = 0.4). On UVA, factors associated with local progression were vulvar disease (p = 0.02) and c-KIT mutation (p = 0.011). No significant difference in local control was noted based on biologic effective dose (BED10 < = 48Gy vs >48Gy) (p = 0.06). Median OS for entire cohort, cohort A, and cohort B were 46, 72, and 30 months, respectively. 2-year survival (95% CI) was 67% (50%-91%), 73% (51%-100%), and 64% (41%-99%) respectively. On UVA, non-local disease at time of RT (p = 0.016) and receipt of IO ≥3 months prior to RT (p = 0.030) had worse OS. UH-RT+/- IO for melanoma of the LGT is well-tolerated with local disease control achieved in 61% of patients. Vulvar primary and c-Kit mutations were associated with worse local control. Additional follow-up may be necessary to determine the value of dose escalation.

Clinical Outcomes and Dosimetric Predictive Factors in Patients Undergoing Reirradiation for Recurrent Meningiomas

Re-irradiation (reRT) of intracranial meningiomas is often limited by radiation tolerance of the surrounding normal tissue and the risk of side effects. Aim of this retrospective study is to report outcomes, toxicity and prognostic factors of reRT in a large cohort of patients with recurrent meningiomas (RM) treated with different RT techniques. A multi-institutional database of intracranial meningioma patients who recurred after prior radiation treatment was collected. Patients underwent reRT with one of the following techniques: radiosurgery (SRS), multi-fraction stereotactic radiotherapy (f-SRT), proton therapy (PT), Intensity-Modulated radiotherapy (IMRT) and External Beam radiotherapy (EBRT). Biologically Equivalent Doses in 2 Gy-fractions (EQD2) and Biological Effective Dose (BED) for surrounding normal tissue and tumor were estimated for each RT course, assuming an a/b = 2 for brain tissue and a/b = 4 for meningioma. Progression-free survival (PFS) was the primary outcome measure. Secondary outcomes were overall survival (OS) and treatment-related toxicity, according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Kaplan-Meier curves were used to estimate the effect of several parameters on PFS and on OS; Cox regression models assessed predictors of PFS and OS. Between 2003 and 2021, 181 patients (pts) were included. They were re-treated with SRS (n = 75; 41.4%), f-SRT (n = 63; 34.8%), PT (n = 31; 17.1%) and conventional radiotherapy (n = 12; 6.7%). 78 pts were identified with WHO Grade I disease, 65 pts with Grade II and 10 pts had Grade III disease. 28 pts without histologic sampling were included among Grade I patients for further analysis. Median age at re-irradiation was 62 (range 20-89) and median KPS 90 (range 60-100). After a median follow-up of 4.6 years (IQR 1.7-6.8), 3-year PFS was 51.6% and 3-year OS 72.5%. At univariate analysis Ki67 >5% (HR 2.81, 95% CI 1.48-5.34, p = 0.002) and WHO grade > I (HR 3.08, 95% CI 1.80-5.28, p< 0.001) were correlated with worse PFS, whereas f-SRT (HR 0.32, 95% CI 0.19-0.55, p<0.001), longer time to reRT (HR 0.37, 95% CI 0.21-0.67, p = 0.001) and higher tumor BED (HR 0.45 95% CI 0.27-0.76, p = 0.003) favorably correlated with PFS. At multivariate Cox analysis only f-SRT, time to reRT and tumor BED kept their statistically significant prognostic impact on PFS (HR 0.36, 95% CI 0.21-0.64, p<0.001; HR 0.38, 95% CI 0.20-0.72, p = 0.003 and HR 0.47 95% CI 0.26-0.83, p = 0.01, respectively). In addition, larger tumor GTV had a statistically significant higher risk of acute and late toxicity (p = .0.004 and p = 0.005, respectively). Reirradiation of RM progressing after previous RT seems to be feasible, with encouraging outcomes and an acceptable toxicity profile. Prognostic factors in the treatment-algorithm have been identified and should be adopted in clinical daily practice.

Risk Factors for Symptomatic Radiation Pneumonitis after Stereotactic Body Radiotherapy (SBRT) for Early-Stage Lung Cancer

To identify risk factors for symptomatic radiation pneumonitis (RP) after stereotactic body radiotherapy (SBRT) in patients with early-stage lung cancer. We reviewed patients with clinical stage IA1-IIA non-small cell lung cancer treated by SBRT in our institution. The primary endpoint was grade ≥ 2 RP. To evaluate the relationship between clinical risk factors and grade ≥ 2 RP, the Gray test was used for univariate analysis and the Fine-Gray model for multivariate analysis. Dose parameters were univariate analyzed using the Fine-Gray model. Optimal thresholds for dose parameters were tested using receiver operating characteristic (ROC) curves. Among a total of 244 patients analyzed. The median age of patients was 77 years. The median follow-up period was 48 months. The 4-year cumulative incidence of grade ≥ 2 RP was 15.3% for all patients. In univariate analysis, tumor size (p = 0.01), central tumor (p < 0.001), interstitial pneumonia (p = 0.002), biological effective dose (BED, α/β ratio of 10 Gy) (p = 0.017), lung volume (%) receiving at least 8 Gy (V8) (p = 0.012), V10 (p = 0.011), V20 (p = 0.022) and mean lung dose (MLD) (p = 0.014) were significantly associated with the risk of grade ≥ 2 RP. In multivariate analysis, central tumor (hazard ratio [HR], 3.77; 95% confidence interval [CI], 1.88-7.55; p < 0.001) and interstitial pneumonia (HR, 4.88; 95% CI, 1.77-13.43; p = 0.002) were significantly associated with the risk of grade ≥ 2 RP. ROC curve analysis showed that the optimal diagnostic thresholds for lung V8, V10, V20, and MLD were 19.5% (the area under the curve [AUC]-0.629), 16.7% (AUC-0.629), 7.9% (AUC-0.621), and 5.2 Gy (AUC-0.623). The incidence of RP2 was found to be significantly high for values higher than the ROC threshold. The 4-year cumulative incidence of grade ≥ 2 RP in the V10 ≤ 16.7% vs V10 > 16.7% groups were 10% vs. 27% (p = 0.0013). Central tumor and interstitial pneumonia were significant risk factors for RP2 after SBRT. We recommend that lung V10 be kept below 16.7%.

Clinical Sequalae of Initial Insurance Denials in a Large Academic Radiation Oncology Center

The objective of this study is to investigate the clinical sequalae of initial radiation oncology insurance denials. The hypothesis is that while the majority of initial insurance case denials are ultimately overturned, there are potential clinical implications to these initial denials. Data were extracted from an institutional registry of patient cases initially denied authorization by their insurers from January 2022 to December 2022. Chi-Square tests using statistical software were employed. Two hundred six cases from November 2021 to December 2022 were identified. The majority (n = 199 [96.6%]) of insurers were commercial payers, while 7 (3.4%) were Medicare/Medicare Advantage. 161 (78.1%) patients were <65 years of age, and 45 (21.8%) 65 or older. One hundred forty-one (68.4%) cases were metastatic, 60 (29.1%) definitive, and 5 (2.4%) were recurrent. Of the 206 cases, 127 (61.6%) cases were ultimately successful in authorization of the ordered treatment without any change to the requested treatment technique or prescription dose after P2P (Peer to Peer review), second-level appeal, comparison plan submission, employer request, insurance carrier change, and/or external appeal, and 56 (27.2%) cases were authorized though with insurer-requested modification to radiation treatment technique and/or prescription dose. Of 21 cases with a requested change in prescription dose, the median decrease in biologically effective dose (BED) was 24 Gy (range: 2.3-51). Of 58 cases with requested change in RT technique, 20 (34.5%) changed from IMRT to 3D-CRT, 16 (27.6%) SBRT to 3D, 15 (25.9%) SBRT to IMRT, 6 (10.3%) SBRT to 2D, and 1 (1.7%) 3D-CRT to 2D. 19 (9.2%) cases remained unauthorized by the insurer but proceeded with treatment via departmental administrative clearance. Of 196 cases which went on to treatment, 72 (36.7%) cases were delayed for a mean of 7.8 days and median of 5 days (range: 1-49). P2P was performed by the treating radiation oncologist in 169 (82.0%) cases, of which 78 (46.1%) were successful in authorization of the ordered treatment. Of the 91 unsuccessful cases, 62 (68.1%) second-level appeals were performed, of which 39 (62.9%) were successful in overturning denied authorization. Of the 23 cases not authorized either through P2P or second-level appeal, 3 (13.0%) cases were successful in authorization of the requested treatment via employer request, external appeal through an independent review organization, or insurance carrier change. Our institutional analysis suggests that while the majority of initial insurance case denials are ultimately overturned without any change to the requested treatment technique or prescription dose through a number of requests made by the insurer to the radiation oncologist, there are clinical implications with a significant percentage of case denials leading to treatment delays, decrease in prescription BED, and less conformal treatment technique.

The Japanese Nationwide Cohort Data of Particle Beam Therapy for Liver Oligometastasis in Esophagogastric Cancer Patients

A nationwide multicenter cohort study on particle therapy was launched by the Japanese Society for Radiation Oncology (JASTRO) in Japan in May 2016. We analyzed the outcome of proton beam therapy (PBT) for liver oligometastasis of esophagogastric cancers. Cases in which PBT was performed at all PBT facilities in Japan between May 2016 and February 2019 were enrolled. The patients were selected based on the following criteria: controlled primary cancer; liver recurrence without extrahepatic tumors; and no more than three liver lesions. The dose and fraction of PBT were determined using unified treatment policy established by JASTRO. We used the following protocol, 64 gray (relative biological effect) (Gy (RBE))/8 fractions (fr) for the peripheral region, and 72.6 GyE/22fr for the central region. For safety aspect, the hepatocellular carcinoma irradiation protocols of 66 Gy (RBE)/10fr, 72.6-76 Gy (RBE)/20-22fr, and 74-76 Gy (RBE)/37-38fr could be allowed. The overall survival (OS), local control (LC), and adverse events (AEs) were examined. The OS and LC rates were calculated using the Kaplan-Meier method. Factors possibly related to OS, such as tumor size (for multiple lesions, the largest size), number of liver tumors, as well as the presence or absence of prior, concurrent, and post-PBT chemotherapy, were investigated. The cut-off values were estimated using the receiver operating characteristic curve and area under the curve. Univariate analysis was performed using the log-rank test. Statistical significance was P-values < 0.05. Twenty-three males and two females with a median age of 69 (range, 52-80) years and 36 lesions were included. This study included six patients with esophageal and 19 patients with gastric cancer. The median lesion size, fraction size, and biological effective dose (BED)10 were 31 (7-104) mm, 3.8 gray (relative biological effect)/fractions (Gy (RBE)/fr) (2-8 Gy (RBE)/fr), and 96.9 (88.8-115.2) Gy, respectively. The median follow-up period was 18 (4-47) months. The 1-, 2-, and 3-year OS rates were 76.0, 49.5, and 43.3%, respectively, and the median OS was 19 months. The 1-, 2-, and 3-year OS rates of esophageal cancer were 83.3% for all. The 1-, 2-, and 3-year OS rates of gastric cancer were 73.7, 40.2, and 32.2%, respectively, and the median OS was 18 months. The 1-, 2-, and 3-year LC rates were 96.3, 91.5, and 91.5%, respectively. The 1-, 2-, and 3-year LC rates of esophageal cancer were 100% for all. The 1-, 2-, and 3-year LC rates of gastric cancers were 94.7, 88.0, and 88.0%, respectively. Tumor size was the only significant OS-related factor (P < 0.01). No grade 3 or higher adverse events were observed. Owing to the low incidence of adverse events and the high LC rate, PBT is a feasible option for liver oligometastasis of esophagogastric cancers.

The Japanese Nationwide Cohort Data of Proton Beam Therapy for Liver Oligometastasis in Breast Cancer Patients

A nationwide multicenter cohort study on particle therapy was launched by the Japanese Society for Radiation Oncology (JASTRO) in Japan. We analyzed the outcome of proton beam therapy (PBT) for liver oligometastasis in breast cancers. Cases in which PBT was performed at all Japanese proton therapy facilities between May 2016 and February 2019 were enrolled. The patients were selected based on the following criteria: the primary cancer was controlled, liver recurrence without extrahepatic tumors, and no more than three liver lesions. The treatment indication and strategy were discussed at cancer boards in each institution. The dose and fraction of PBT were determined by referring to the unified treatment policy established by JASTRO. We used the following protocol: 64 gray (Gy) (relative biological effectiveness [RBE])/8 fraction (fr) for the hepatic periphery area away from the GI tract, and 72.6 GyE/22 fr for the adjacent hilar region type. Regarding safety, the HCC irradiation protocols of 66 GyE/10 fr, 72.6-76 GyE/20-22 fr, and 74-76 GyE/37-38 fr could be used. The local control (LC), overall survival (OS), and progression free survival (PFS) rates were calculated using the Kaplan-Meier method. Factors possibly related to OS, such as tumor size, number of liver tumors, intervention of chemotherapy, and/or hormone therapy, were investigated. The cut-off values were estimated using the receiver operating characteristic curve and area under the curve. Univariate analysis was performed using the log-rank test. Fourteen females, with a median age of 57 (range, 44-73) years and twenty-two lesions were included. Nine patients had one lesion, two patients had two lesions, and three patients had three lesions. PBT was selected because nine patients had underlying disease and five patients had general conditions (age, etc.). The median lesion size, fraction size, and biological effective dose using the linear-quadratic model with α/β = 10 Gy ((BED)10) were 44 (20-130) mm, 6.6 (2-8) (relative biological effectiveness [RBE])/fraction (fr), and 109.6 (52.7-115.2) Gy, respectively. The median follow-up period of breast cancers was 22.8 (4-54) months. The 1-, 2-, and 3-year LC rates of liver metastasis from breast cancers were 100% for all. The 1-, 2-, and 3-year OS rates were 85.7%, 62.5%, and 62.5%, respectively. The 1-, 2-, and 3-year PFS rates were 50.0%, 33.3%, and 16.7%, respectively, and median PFS time was 16 months. Tumor size, the number of liver tumors, and the intervention of chemotherapy and/or hormone therapy at any time were not significantly related to the OS. Only one patient did not complete PBT due to current disease progression. The other patients completed PBT without interruption. One patient had grade 3 radiation-induced dermatitis. Based on the low incidence of adverse events and the high LC rate, PBT appears to be a feasible option for liver oligometastasis in breast cancer patients.

Hypofractionated Accelerated Radiation Dose-Painting (HARD) vs. Standard Radiotherapy for Unresected Soft-Tissue Sarcoma

Conventionally fractionated radiotherapy (CFRT) offers modest local control (LC) for unresected soft tissue sarcoma (STS). Although STS has a low α/β (∼2 - 6) that may benefit from a hypofractionated radiotherapy regimen, it is often limited due to the toxicity risk to surrounding organs. A simultaneous integrated boost to gross disease (2.5 - 3 Gy/fraction), with lower doses to the intermediate and low risk target volume, may offer a safe isotoxic dose escalation approach. We hypothesize that this hypofractionated accelerated radiotherapy dose-painting (HARD) will improve local control compared to CFRT. We performed a single institution retrospective analysis of patients who received external beam radiotherapy with definitive intent (≥50 Gy) for unresected STS. CFRT was defined as 1.8 - 2 Gy/fraction (Gy/fx). HARD regimens consisted of 60 - 66 Gy at 3 Gy/fx or 70 Gy at 2.5 Gy/fx to gross disease, with 1.8 - 2.4 Gy/fx to intermediate and low risk regions. All anatomical sites and histologies were included. Local control (LC) was defined from date of current diagnosis, estimated by Kaplan-Meier methods via log-rank tests or Cox regression for univariate analysis (UVA), when appropriate. Cox regression multivariate analysis (MVA) included regimen, biological effective dose (α/β 6; BED6), lesion size, age, and grade. We identified 77 patients with primary and metastatic STS treated with HARD (n = 40) or CFRT (n = 37) between 1990 and 2022, with a median follow up of 24 months in surviving patients. The mean dose for CFRT and HARD are 56.8 Gy (50 - 77.4 Gy) and 64.9 Gy (60 - 70 Gy), respectively. HARD was comprised of 65% for 3 Gy/fx and 35% for 2.5 Gy/fx regimens. At the time of RT, grade 3 (69%) and extremity (39%) tumors were the most common. Tumor histology was very heterogenous across both cohorts, with undifferentiated pleomorphic sarcoma being the most common for HARD (33%) and CFRT (19%). HARD was more often utilized in stage IV patients (55% vs. 19%, p = 0.001) and had a higher mean BED6 (96 vs. 74.2 Gy, p < 0.001) than CFRT, but without differences in age (67 vs. 59 years), tumor size (8 vs. 10 cm), concurrent chemotherapy (35% vs. 30%), Karnofsky performance status (86 vs. 85), follow-up (19 vs. 28 months), and grade (all p > 0.1). On UVA, there was a LC benefit associated with higher BED6 (HR 0.94, 95% CI 0.9 - 0.98, p = 0.002) and the HARD regimen (2-year LC 95% vs. 62%, p < 0.001). On MVA, only HARD (HR 0.07, 95% CI 0.006 - 0.729, p = 0.027) was independently associated with LC. Although the HARD regimen and higher BED6 were both associated with significant improvement in LC, only the HARD regimen independently associated with a local control benefit for unresected STS. These results suggest biologic dose-intensification exploiting the low α/β of STS with an isotoxic hypofractionated regimen may be a favorable strategy for unresectable STS. Future prospective studies are necessary to validate these findings.

Multimodality Dosimetric Evaluation for the Treatment of Recurrent Brain Tumors

GammaTile Surgically Targeted Radiation Therapy (STaRT) are bioresorbable collagen tiles containing four Cesium-131 radioactive seeds which are permanently implanted into the operative bed immediately following the surgical resection of a brain tumor. Alternative radiation treatment approaches for recurrent brain tumors include external beam radiation therapy (EBRT) with either proton or photon (volumetric modulated arc therapy, or VMAT) radiation. The purpose of this study is to perform a comparative dosimetric study of these three modalities for cases of recurrent brain tumors. We hypothesize that GammaTile would be dosimetrically superior at sparing radiation dose to surrounding organs at risk. A total of 5 patients have received GammaTile StaRT therapy at our institute for recurrent brain tumors in 2021-2022. Out of these 5 patients, 3 were recurrent glioblastoma (GBM) and 2 were brain metastasis (brain-met) cases. All patients were previously treated with radiation. Typical prescription for GammaTile therapy is 60 Gy to the High Risk CTV (HR_CTV), specified by 5mm depth from the plane of the seeds. For recurrent GBM cases, the alternative methods of radiation are proton therapy and photon therapy using VMAT. The standard re-irradiation dose for proton and photon therapy is 35 Gy in 10 fractions prescribed to PTV (3 mm expansion of EBRT CTV). For brain-met cases, an alternate method is hypo-fractionation radiation therapy with Linac-based SBRT. Linac-based SBRT prescription depends on the volume of EBRT CTV. For one of the brain-met cases, the SBRT prescription was 30 Gy in 5 fractions, and for the other case it was 27 Gy in 3 fractions to PTV (2 mm expansion from EBRT CTV). Proton and photon plans were generated in a treatment planning system using a double scattering Mevion system and a VersaHD with agility head, respectively. All the physical doses were converted to biological effective dose (BED) for evaluation. The dosimetric quantities are summarized in table 1. These quantities were evaluated using HR_CTV and EBRT_CTV for GammaTile therapy and EBRT (proton/photon), respectively. GammaTile therapy reduces dose to normal brain tissue considerably. However, it may have more uncertainty in the dose delivered compared to proton and photon EBRT. It appears that all three treatment modalities are adequate for treating recurrent brain tumors. However, GammaTile therapy may allow to deliver higher dose to the targets while reducing the irradiation to adjacent normal tissue.

Hippocampal Avoidance Whole Brain Radiotherapy with Reduced Whole Brain Dose in Patients with Non-Small Cell Lung Cancer Brain Metastases

Hippocampal avoidance whole brain radiation (HA-WBRT) results in improved neurocognitive function (NCF) compared to standard WBRT, but > 50% of patients still experience NCF failure. We examined whether gentler fractionation of HA-WBRT with lower biologically effective dose (BED), typically delivering 30 Gy over 15 versus 10 fractions, may allow for better hippocampal sparing without impacting intracranial disease control in patients with non-small cell lung cancer (NSCLC). We conducted a retrospective study of patients with NSCLC receiving HA-WBRT between 2014-2022. Endpoints were distant brain failure free survival (DBFFS), local brain failure free survival (LBFFS), left and right hippocampal mean BED2 and BED21%. Kaplan-Meier survival analysis and Welch's t-test were performed. NCF outcomes were graded with CTCAEv5. The IRB approved this study. Sixty-nine consecutive patients treated with HA-WBRT were included, with median follow up of 51.2 weeks. Median age was 63 years and 29% had a targetable mutation. Thirty-six patients received standard HA-WBRT with median dose of 30 Gy (range 30-35 Gy) in 10 fractions (range 10-14). Thirty-three patients received reduced BED HA-WBRT, with median dose of 30 Gy (range 23-30) in 15 fractions (range 9-15) to the radiographically uninvolved brain. All patients in the reduced BED (RD) group had a simultaneous integrated boost (SIB) to gross disease (median 37.5 Gy (range 36-37.5 Gy)), while 18/36 in the standard dose (SD) group had an SIB (median 35 Gy (range 34-39 Gy)). There were no significant differences between SD and RD cohorts in age, systemic therapy use before WBRT or targetable mutations. There was no significant difference in median DBFFS of the SD [23.1 weeks (IQR 11.3-49.3)] and RD groups [40 weeks, (IQR 20.9-109.1)] (p = 0.27). There was also no difference in LBFFS of the SD (median 26.4 weeks, IQR 11.3-76.2) and RD groups (median 40 weeks, IQR (21-71.4) (p = 0.84). For the left and right hippocampi, both mean BED2 and D1% were significantly lower in the RD group (Table 1). Median cognitive disturbance was Grade (G) 0 (range 0-3) in both groups, with 4 G>2 events in the SD cohort vs. 3 in the RD cohort. In this single-institution cohort, HA-WBRT using a gentler fractionation with SIB was associated with improved hippocampal sparing without compromising intracranial control in patients with NSCLC. We suggest that further optimization of HA-WBRT dose and schedule may improve both intracranial control and NCF outcomes. This study is limited by its retrospective nature and potential selection bias. A phase II prospective study to test these concepts is ongoing.

Validation of the Prognostic Index for Spine Metastasis (PRISM) Score for Stratifying Survival in Patients Treated with Spinal Stereotactic Radiosurgery

Stereotactic spinal radiosurgery (SSRS) has been increasingly utilized as a first-line treatment for the management of spine metastases due to its ability to prolong survival and improve symptom control. Studies have shown that SSRS is helpful for select patients; however, there is no universal scoring system utilized to predict patient response to treatment. The Prognostic Index for Spinal Metastases (PRISM) score was shown to predict the likelihood of patients benefiting from SSRS. We sought to further demonstrate its generalizability by performing validation with a large dataset from a second high-volume institution. We performed a retrospective review from 2017-2019 of 424 patients treated with SSRS at a single institution. Patients were stratified on the previously described PRISM criteria: Female sex (+2), solitary bone disease (+3), performance status (0 through +3.5), prior surgery at the SSRS site (+1), number of other metastatic sites (-N), prior radiation at the SSRS site (-1), and latency to treatment ≥ 5 months (+3). Patients were grouped based on PRISM scores: >7, Group 1; 4-7, Group 2; 1-3, Group 3; <1 Group 4. There were 89, 188, 88, and 59 patients in Groups 1, 2, 3, and 4, respectively. Most patients were male (70%) with a performance status of 0 (53%). The most common tumor histologies were prostate (34%), renal (18%), and lung (11%). The median biological effective dose (BED10) was 60 Gy (interquartile range [IQR], 60-82). We performed Cox proportional hazards analysis on overall survival (OS) based on PRISM score and patient and tumor characteristics. Concordance indices created from PRISM criteria and the multivariate Cox proportional analysis were compared. The median follow-up time was 50.5 months (95% confidence interval [CI], 45.8-54.7) with a median overall survival of 30.3 months (95% CI, 27.3-38.4). The median overall survivals for PRISM Groups 1, 2, 3, and 4 were 57.1, 37, 23.7, and 8.8 months, respectively. There were significant differences in overall survival among PRISM groups with hazard ratios of 0.49 (95% CI, 0.35-0.69; P<0.001) for Group 1, 0.71 (95% CI, 0.55-0.91); P<0.007) for Group 2, 1,45 (95% CI, 1.08-1.94); P = 0.010) for Group 3, and 3.47 (95% CI, 2.56-4.70; P<0.001) for Group 4. Multivariable Cox analysis for patient and tumor characteristics revealed only the number of organs involved and performance status as significant clinicopathologic prognostic attributes. However, the C-index using the PRISM criteria was 0.76, which was superior to the C-index when using the significant clinicopathologic attributes by themselves (0.71). These data demonstrate robust validation of the PRISM score to stratify OS in patients treated with SSRS and may help guide optimal treatment selection in prospective trials and clinical settings.

RADIOTHERAPY TREATMENT PLANNING OPTIMIZATION IMPROVED 3D-SURFACTAL ISODOSELINES SERIES FOR PROSTATE CANCER WITH BED PARETO-MULTIOBJECTIVE MODEL 3D-DATASET

3D Isodoselines innovation with Interior Optimization (IO) for prostate tumor BED model hyperfractionated Treatment Planning Optimization (TPO) application is further demonstrated. The implemented data was got with additional-dual constrained evolutionary algorithm for BED-LQ model (Biological Effective Dose) in this cancer type. Results for TPO with 3D IO-Graphical Optimization show a number of surfactal IO 3D Isodoselines with proven accuracy-feasibility of the novelty of the technique. Programming software for surfactal-isodoselines methods solutions show a series of 3D IO graphs for TPO. Applications for prostate tumors radiotherapy and stereotactic radiosurgery treatments are briefed.

Optimal Radiation Therapy Fractionation Regimens for Early-Stage Non-Small Cell Lung Cancer

A series of radiobiological models were developed to study tumor control probability (TCP) for stereotactic body radiation therapy (SBRT) of early-stage non-small cell lung cancer (NSCLC) per the Hypofractionated Treatment Effects in the Clinic (HyTEC) working group. This study was conducted to further validate 3 representative models with the recent clinical TCP data ranging from conventional radiation therapy to SBRT of early-stage NSCLC and to determine systematic optimal fractionation regimens in 1 to 30 fractions for radiation therapy of early-stage NSCLC that were found to be model-independent. Recent clinical 1-, 2-, 3-, and 5-year actuarial or Kaplan-Meier TCP data of 9808 patients from 56 published papers were collected for radiation therapy of 2 to 4 Gy per fraction and SBRT of early-stage NSCLC. This data set nearly triples the original HyTEC sample, which was used to further validate the HyTEC model parameters determined from a fit to the clinical TCP data. TCP data from the expanded data set are well described by the HyTEC models with α/β ratios of about 20 Gy. TCP increases sharply with biologically effective dose and reaches an asymptotic maximal plateau, which allows us to determine optimal fractionation schemes for radiation therapy of early-stage NSCLC. The HyTEC radiobiological models with α/β ratios of about 20 Gy determined from the fits to the clinical TCP data for SBRT of early-stage NSCLC describe the recent TCP data well for both radiation therapy of 2 to 4 Gy per fraction and SBRT dose and fractionation schemes of early-stage NSCLC. A steep dose response exists between TCP and biologically effective dose, and TCP reaches an asymptotic maximum. This feature results in model-independent optimal fractionation regimens determined whenever safe for SBRT and hypofractionated radiation therapy of early-stage NSCLC in 1 to 30 fractions to achieve asymptotic maximal tumor control, and T2 tumors require slightly higher optimal doses than T1 tumors. The proposed optimal fractionation schemes are consistent with clinical practice for SBRT of early-stage NSCLC.

Practical Guideline for Prevention of Patchy Hair Loss following CyberKnife Stereotactic Radiosurgery for Calvarial or Scalp Tumors: Retrospective Analysis of a Single Institution Experience

Introduction: Patchy alopecia is a common adverse effect of stereotactic radiosurgery (SRS) on the calvarium and/or scalp, yet no guidelines exist for its prevention. This study aims to investigate the incidence and outcomes of patchy alopecia following SRS for patients with calvarial or scalp lesions and establish preventive guidelines. Methods: The study included 20 patients who underwent CyberKnife SRS for calvarial or scalp lesions, resulting in a total of 30 treated lesions. SRS was administered as a single fraction for 8 lesions and hypofractionated for 22 lesions. The median SRS target volume was 9.85 cc (range: 0.81–110.7 cc), and the median prescription dose was 27 Gy (range: 16–40 Gy), delivered in 1–5 fractions (median: 3). The median follow-up was 15 months. Results: Among the 30 treated lesions, 11 led to patchy alopecia, while 19 did not. All cases of alopecia resolved within 12 months, and no patients experienced other adverse radiation effects. Lesions resulting in alopecia exhibited significantly higher biologically effective dose (BED) and single-fraction equivalent dose (SFED) on the overlying scalp compared to those without alopecia. Patients with BED and SFED exceeding 60 Gy and 20 Gy, respectively, were 9.3 times more likely to experience patchy alopecia than those with lower doses. The 1-year local tumor control rate for the treated lesions was 93.3%. Chemotherapy was administered for 26 lesions, with 11 lesions receiving radiosensitizing agents. However, no statistically significant difference was found. Conclusion: In summary, SRS is a safe and effective treatment for patients with calvarial/scalp masses regarding patchy alopecia near the treated area. Limiting the BED under 60 Gy and SFED under 20 Gy for the overlying scalp can help prevent patchy alopecia during SRS treatment of the calvarial/scalp mass. Clinicians can use this information to inform patients about the risk of alopecia and the contributing factors.

Clinically Driven Alpha/Beta Ratios for Melanoma Brain Metastases and Investigation of Biologically Effective Dose as a Predictor for Local Control After Radiosurgery: A Proof of Concept in a Retrospective Longitudinal Series of 274 Consecutive Lesions.

Brain metastases (BM) develop in nearly half of the patients with advanced melanoma. The aim of this retrospective historical cohort study was to analyze radiological response of melanoma BM to single-fraction Gamma Knife radiosurgery (GKRS), in relation to biologically effective dose (BED) for various alpha/beta ratios. Included in the study were 274 lesions. Primary outcome was local control (LC). Mean marginal dose was 21.6 Gy (median 22, range 15-25). Biologically effective dose was calculated for an alpha/beta ratio of 3 (Gy 3 ), 5 (Gy 10 ), 10 (Gy 10 ), and 15 (Gy 15 ). Receiver operating characteristic value for LC and BED was 85% (most statistically significant odds ratio 1.14 for BED Gy 15 , P = .006), while for LC and physical dose was 79% ( P = .02). When comparing equality of 2 receiver operating characteristic areas, this was statistically significant ( P = .02 and .03). Fractional polynomial regression revealed BED (Gy 10 and Gy 15 ) as statistically significant ( P = .05) with BED of more than 63 Gy 10 or 49 Gy 15 as relevant, also for higher probability of quick decrease in volume first month after GKRS and lower probability of radiation necrosis. Shorter irradiation time was associated with better LC ( P = .001), particularly less than 40 minutes (LC below 90%, P = .05). BED Gy 10 and particularly Gy 15 were more statistically significant than physical dose for LC after GKRS for radioresistant melanoma BM. Irradiation time (per lesion) longer than 40 minutes was predictive for lower rates of LC. Such results need to be validated in larger cohorts.

Deceiving The Myths of Nanotechnology in Relation to Nanotoxicity

The toxicity of nanoparticles (NPs) is a critical research topic in nanotechnology, as it is essential to understand thehazards posed by the wide spectrum of NPs that vary in shape, size, and composition. Previous reviews have yet to thoroughlyexplore the Biological Effective Doses of NPs, which drive toxicity and are influenced by factors such as solubility, charge, shape,contaminants, and the ability of NPs to translocate from the deposition site in the lungs. This review aims to fill the gap in theliterature by providing an overview of the possible toxicity of nanoparticles in zebrafish during growth stages, with a focus onoxidative stress, and exploring the available modes of toxicity that are relevant to conventional pathogenic particles. This reviewalso discusses the effects of nanomaterials on the reproductive system in animal models, providing insight into the potential toxicityof nanoparticles in humans. This review aims to provide a comprehensive overview of the toxicity of nanoparticles and to criticallyexplore the challenges associated with implementing nanotechnology, particularly in the pharmaceutical development of noveltherapeutic products and regulatory issues. The review also considers recent uses and projected nanotechnology advancements,providing a basis for future research in this field. In conclusion, this review rectifies the lacunae in previously published reviews byproviding a comprehensive overview of the toxicity of nanoparticles and exploring the challenges associated with implementingnanotechnology. The aim and objective of this review are to provide a comprehensive understanding of the toxicity of nanoparticlesand to guide future research in this field.