Toxin-Based Therapeutic Approaches

Protein toxins confer a defense against predation/grazing or a superior pathogenic competence upon the producing organism. Such toxins have been perfected through evolution in poisonous animals/plants and pathogenic bacteria. Over the past five decades, a lot of effort has been invested in studying their mechanism of action, the way they contribute to pathogenicity and in the development of antidotes that neutralize their action. In parallel, many research groups turned to explore the pharmaceutical potential of such toxins when they are used to efficiently impair essential cellular processes and/or damage the integrity of their target cells. The following review summarizes major advances in the field of toxin based therapeutics and offers a comprehensive description of the mode of action of each applied toxin

Stereotactic Body Radiation Therapy for Nonspine Bone Metastases: International Practice Patterns to Guide Treatment Planning

Purpose: Stereotactic body radiation therapy (SBRT) is increasingly used for nonspine bone metastases (NSBM); however, there are limited data informing treatment planning. We surveyed international experts to better understand worldwide practice patterns in delivering NSBM-SBRT. Methods and Materials: Nine international radiation oncologists were invited to participate based on demonstrated expertise with NSBM-SBRT. Experts were sent gross tumor volume contours and planning computed tomography and magnetic resonance images for 11 NSBM cases that covered a range of bony sites, including metastases to long bones (femur, humerus), pelvic bones (ilium, ischium, acetabulum, pubic symphysis), and thoracic bones (rib, sternum, scapula, clavicle). Experts were surveyed regarding treatment planning decisions and dose-fractionation selection. Descriptive analysis was conducted on the survey data. Results: All experts participated and completed the survey. Most (56%) routinely fused magnetic resonance imaging with planning computed tomography imaging for target delineation. Dose fractionation schedules included single-fraction (18-24 Gy/1), 2 fractions (24 Gy/2), 3 fractions (28-30 Gy/3), 5 fractions (30-50 Gy/5), and 10 fractions (42-50 Gy/10). Although doses varied considerably, all had a biological equivalent dose of ≤100 Gy10. Five-fraction schedules were most common, specifically 35 Gy/5, with 56% opting for this dose-fractionation in at least 1 case. Other dose-fractionation schedules used by at least 3 experts were 20 Gy/1, 30 Gy/3, and 30 Gy/5. Three experts prescribed 2 dose volumes using a simultaneous integrated boost. The 2 dose volumes were either the gross tumor volume and clinical target volume (CTV) or a smaller CTV (CTV1) encompassed within a larger CTV (CTV2) (eg, 30 Gy/3 to gross tumor volume or CTV1 and 15-24 Gy/3 to CTV or CTV2). Dose de-escalation was recommended by all experts in the setting of previous SBRT and by most in the context of previous convevoltherapy or in weight-bearing bones, especially if moderate-to-severe cortical erosion was present. Conclusions: Significant heterogeneity exists worldwide in radiation technique and dose-fractionation for NSBM-SBRT, which supports the need for consensus guidelines to inform practice and trial design. Nonetheless, these data demonstrate expert agreement on selecting dose schedules with a biologically effective dose ≤100 Gy10, reasons for dose de-escalation, and in determining acceptable dose schedules based on bony site

Use of focal radiotherapy boost for prostate cancer: radiation oncologists’ perspectives and perceived barriers to implementation

BackgroundIn a recent phase III randomized control trial, delivering a focal radiotherapy (RT) boost to tumors visible on MRI was shown to improve disease-free survival and regional/distant metastasis-free survival for patients with prostate cancer-without increasing toxicity. The aim of this study was to assess how widely this technique is being applied in current practice, as well as physicians' perceived barriers toward its implementation.MethodsWe invited radiation oncologists to complete an online questionnaire assessing their use of intraprostatic focal boost in December 2022 and February 2023. To include perspectives from a broad range of practice settings, the invitation was distributed to radiation oncologists worldwide via email list, group text platform, and social media.Results263 radiation oncologist participants responded. The highest-represented countries were the United States (42%), Mexico (13%), and the United Kingdom (8%). The majority of participants worked at an academic medical center (52%) and considered their practice to be at least partially genitourinary (GU)-subspecialized (74%). Overall, 43% of participants reported routinely using intraprostatic focal boost. Complete GU-subspecialists were more likely to implement focal boost, with 61% reporting routine use. In both high-income and low-to-middle-income countries, less than half of participants routinely use focal boost. The most cited barriers were concerns about registration accuracy between MRI and CT (37%), concerns about risk of additional toxicity (35%), and challenges to accessing high-quality MRI (29%).ConclusionsTwo years following publication of a randomized trial of patient benefit without increased toxicity, almost half of the radiation oncologists surveyed are now routinely offering focal RT boost. Further adoption of this technique might be aided by increased access to high-quality MRI, better registration algorithms of MRI to CT simulation images, physician education on benefit-to-harm ratio, and training on contouring prostate lesions on MRI

International Multi-institutional Patterns of Contouring Practice and Clinical Target Volume Recommendations for Stereotactic Body Radiation Therapy for Non-Spine Bone Metastases

PURPOSE Despite the increasing use of stereotactic body radiation therapy for non-spine bone metastases (NSBM), there is no established standard for target delineation. The objective of this study was to provide consensus recommendations on clinical target volume (CTV) delineation based on international expert contours. METHODS AND MATERIALS Eleven cases of NSBM were contoured by 9 international radiation oncologists. For each case, the gross tumor volume was provided on the simulation computed tomography scans with accompanying magnetic resonance imaging. Participants contoured the CTV and completed a clinical survey. Agreement between CTV contours were analyzed with simultaneous truth and performance level estimation using the kappa coefficient and the Dice similarity coefficient (DSC) and summarized to establish contouring recommendations. A direction-dependent analysis was applied to the consensus contours to quantify margins. RESULTS All CTV contours were completed. Six participants used a single-dose level, whereas 3 used a 2-dose level simultaneous integrated boost (SIB) technique. For the SIB cases, the largest volume receiving a stereotactic body radiation therapy (SBRT) dose was used for contour analysis. There was substantial agreement between contours across cases with a mean kappa of 0.72 (mean sensitivity 0.85, mean specificity 0.97). The mean DSC value was 0.77 (range, 0.67-0.87). Consensus CTV contouring recommendations were (1) an intraosseous CTV margin of 5 to 10 mm should be strongly considered within contiguous bone; (2) an extraosseous margin of 5 to 10 mm should be strongly considered where there is soft tissue disease or cortical bone disruption; (3) CTVs should be manually cropped to respect anatomic barriers to spread (eg, peritoneal cavity, pleura, uninvolved joint space and cortical bone). CONCLUSIONS CTV contouring recommendations for NSBM-SBRT were established based on analysis of international expert consensus contours with a high level of agreement. These principles may provide guidance to treating physicians and inform future study until prospective clinical data can provide further refinement

Stereotactic Body Radiation Therapy for Metastases in Long Bones

PURPOSE To evaluate the cumulative incidence of fracture and local failure and associated risk factors after stereotactic body radiation therapy (SBRT) for long bone metastases. METHODS AND MATERIALS Data from 111 patients with 114 metastases in the femur, humerus, and tibia treated with SBRT in 7 international centers between October 2011 and February 2021 were retrospectively reviewed and analyzed using a competing risk regression model. RESULTS The median follow-up was 21 months (range, 6-91 months). All but 1 patient had a Karnofsky performance status ≥70. There were 84 femur (73.7%), 26 humerus (22.8%), and 4 tibia (3.5%) metastases from prostate (45 [39.5%]), breast (22 [19.3%]), lung (15 [13.2%]), kidney (13 [11.4%]), and other (19 [16.6%]) malignancies. Oligometastases accounted for 74.8% of metastases and 28.1% were osteolytic. The most common total doses were 30 to 50 Gy in 5 daily fractions (50.9%). Eight fractures (5 in the femur, 2 in the tibia, and 1 in the humerus) were observed with a median time to fracture of 12 months (range, 0.8-33 months). In 6 out of 8 patients, fracture was not associated with local failure. The cumulative incidence of fracture was 3.5%, 6.1%, and 9.8% at 1, 2, and 3 years, respectively. The cumulative incidence of local failure (9/110 metastases with imaging follow-up) was 5.7%, 7.2%, and 13.5% at 1, 2, and 3 years, respectively. On multivariate analysis, extraosseous disease extension was significantly associated with fracture (P = .001; subhazard ratio, 10.8; 95% confidence interval, 2.8-41.9) and local failure (P = .02; subhazard ratio, 7.9; 95% confidence interval, 1.4-44.7). CONCLUSIONS SBRT for metastases in long bones achieved high rates of durable local metastasis control without an increased risk of fracture. Similar to spine SBRT, patients with extraosseous disease extension are at higher risk of local failure and fracture

Single-fraction Stereotactic Body Radiation Therapy versus Conventionally Fractionated Radiation Therapy for the Treatment of Prostate Cancer Bone Metastases

Purpose: This study aimed to compare outcomes of patients with prostate cancer with bone metastases treated with stereotactic body radiation therapy (SBRT) versus conventionally fractionated radiation therapy (CFRT). Methods and materials: An institutional, retrospective review was conducted of patients with prostate cancer receiving radiation therapy to bone metastases. In-field failure (IFF) was the primary outcome of the study, and distant failure (DF) and biochemical failure (BF) were secondary outcomes. Results: A total of 249 metastases (191 SBRT; 58 CFRT) in 201 patients with a median follow-up of 2.2 years were analyzed. The SBRT prescription dose was predominantly 18 Gy (45.5%) or 20 Gy (46.6%) in a single fraction. CFRT was given either as 8 Gy in 1 fraction (56.9%) or 20 Gy in 5 fractions (41.4%). Imaging follow up was performed most frequently with 11C-choline positron emission tomography/computed tomography (79%) or bone scan (10%). The median time to IFF was 1.6 years for CFRT-treated lesions and not met (>4.4 years) for SBRT. The 1- and 3-year IFF estimates were 34.4% (95% confidence interval [CI], 19.9-46.2) and 53.3% (95% CI, 34.3-66.8) for lesions treated with CFRT compared with 4.5% (95% CI, 1.4-7.5) and 12.9% (95% CI, 6.6-18-8) for those treated with SBRT (P < .01). On multivariate regression, the hazard ratio (HR) for IFF with CFRT compared with SBRT was 6.8 (95% CI, 3.7-12.5; P < .01). There were nonsignificant reduced rates of BF (HR, 1.4; 95% CI, 1.0-2.1; P = .05) and DF (HR, 1.3; 95% CI, 1.0-1.8; P = .08) in patients who received SBRT. The 3-year BF and DF estimates in these patients were 88.6% (95% CI, 82.0-92.8) and 82.2% (95% CI, 74.5-87.6), respectively. Conclusions: SBRT for the management of prostate cancer bone metastases significantly reduces radiographic IFF. However, the high rate of subsequent DF and BF highlights the challenges in selecting patients who may benefit from aggressive radiation therapy

Long-term outcomes of intraoperatively-placed applicator brachytherapy for rapid completion of breast conserving treatment: An analysis of a prospective registry data

Background and purpose: To evaluate the long-term outcome of accelerated partial breast irradiation utilizing intraoperatively placed applicator-based brachytherapy (ABB) in early-stage breast cancer. Materials and methods: From our prospective registry, 223 patients with pTis-T2, pN0/pN1mic breast cancer were treated with ABB. The median treatment duration including surgery and ABB was 7 days. The prescribed doses were 32 Gy/8 fx BID (n = 25), 34 Gy/10 fx BID (n = 99), and 21 Gy/3 fx QD (n = 99). Endocrine therapy (ET) adherence was defined as completion of planned ET or ≥ 80% of the follow-up (FU) period. Cumulative incidence of ipsilateral breast tumor recurrence (IBTR) was estimated and influencing factors for IBTR-free survival rate (IBTRFS) were analyzed. Results: 218/223 patients had hormone receptor-positive tumors, including 38 (17.0%) with Tis and 185 (83.0%) with invasive cancer. After a median FU of 63 months, 19 (8.5%) patients had recurrence [17 (7.6%) with an IBTR]. Rates of 5-year IBTRFS and DFS were 92.2% and 91.1%, respectively. The 5-year IBTRFS rates were significantly higher for post-menopausal women (93.6% vs. 66.4%, p = 0.04), BMI < 30 kg/m2 (97.4% vs. 88.1%, p = 0.02), and ET-adherence (97.5% vs. 88.6%, p = 0.02). IBTRFS did not differ with dose regimens. Conclusions: Postmenopausal status, BMI < 30 kg/m2, and ET- adherence predicted favorable IBTRFS. Our results highlight the importance of careful patient selection for ABB and encouragement of ET compliance