CTCAE Scale Research Articles

Changes in cytokine profile as a criterion for severity prediction of skin toxicity in cancer patients receiving epidermal growth factor receptor inhibitors

BACKGROUND: Globally, colorectal cancer is the third most diagnosed cancer with an increased incidence of 1.93 million cases in 2020 according to World Health Organization. Approximately one quarter of the initial manifestations of colorectal cancer are metastatic, and 40–50% of individuals with early-stage disease eventually develop metastatic colorectal cancer (mCRC). Targeted drugs, which include epidermal growth factor receptor inhibitors (EGFRi), are a frequent choice in the therapy of metastatic colorectal cancer. Clinical observations and in vivo studies have established a significant association between the administration of EGFRi drugs and skin inflammation, particularly acute in the first 3 months. However, the role of proinflammatory cytokines in the formation of severe skin lesions has not been definitively studied. Here we present clinical evidence of the involvement of a few cytokines in the formation of the pathologic cascade of reactions during EGFR blockade on keratinocyte membranes. AIM: Evaluation of changes in cytokine profile parameters based on the MILLIPLEX Analyte MAP panel to identify predictors of the severity of unwanted skin toxicity associated with epidermal growth factor receptor inhibition. MATERIALS AND METHODS: Blood serum samples from 81 patients aged 18–80 years who were taking EGFRi for oncologic disease and had adverse dermatologic reactions of severity 2 or more were analyzed. The data were analyzed using SPSS software and R 4.3.1 programming language and tidyverse, rstatix packages. Detected changes with p 0.05 were analyzed considering subgroup analysis on the basis of selected cutaneous toxicity severity degrees based on the criteria developed by the US National Cancer Institute NCI-CTC v. 4. RESULTS: Blocking of EGF receptor inhibits the expression and release of vascular endothelial growth factor (VEGF), which is the main inducer of vascular proliferation, the consequence of which is inflammation of vascular endothelium of skin capillaries. Significant increase of IFN-γ and decrease of IFN-α2 level was found in patients with manifestations of skin toxicity of 2 and more severity degree. Also, a significant criterion of severity of the skin process was an increase in the level of TNF-α. At such dissociation there is induction of STING protein (interferon gene stimulator) and increase of TNF-β production that, in its turn, leads to increase of concentration of proinflammatory cytokines G-CSF, GM-CSF, IFN-α2, IFN-γ, IL-15, IL-17A, IL-1β, IL-3, IL-6, IL-8, IP-10, TNF-α, TGF-α, IL-9. This contributes not only to the maintenance of tissue inflammation, but also to the formation of a vicious circle leading to an increase in the severity of class-mediated inflammatory response against the background of further EGFRi administration. CONCLUSION: Determination of predictors of severity of adverse dermatologic reactions is extremely important for predicting the development of severity and further personalized tactics for correction of adverse events.

Safety and Feasibility of JAK Inhibitor Ruxolitinib in Newly-Diagnosed High-Grade Gliomas (CRUX): Final Trial Report

INTRODUCTION: Dysregulation of the JAK/STAT pathway in newly-diagnosed high-grade gliomas (nHGG) is linked to enhanced survival and proliferation of tumor cells. Ruxolitinib, a small molecule inhibitor of JAK1, JAK2, and JAK3, limits glioma growth in preclinical models. METHODS: This non-randomized prospective study included 60 WHO Grade 3-4 nHGG patients who received standard of care (SOC) therapy along with ruxolitinib in a 3 + 3 dose-escalation design; level 1 of 10 mg BID, level 2 of 15 mg BID, level 3 of 20 mg BID, level -1 of 5 mg BID. Primary study objective was determination of maximum tolerated dose (MTD) of ruxolitinib in combination with chemoradiation. Secondary objective was the determination of safety as assessed using NIH CTCAE scale, overall survival (OS), and progression-free survival (PFS). Exploratory aims were to investigate relationships between clinical outcomes and genomic signatures. RESULTS: 60 patients were enrolled, with median age 60.5 years (range 22-78), 23 (38%) female, and 37 (62%) were male. Amongst 59 evaluable patients, 29 (49%) were MGMT unmethylated and received ruxolitinib with 60Gy radiation over 6 weeks, while 30 (51%) patients were MGMT methylated and received ruxolitinib with 75mg/m2 of temozolomide (TMZ) with 60Gy radiation over 6 weeks. MTD for both cohorts was 20 mg BID. No dose-limiting toxicities were observed. Toxicities attributable to study medications included four grade 4 AEs including seizure, respiratory distress, somnolence, and thromboembolic event along with 14 grade 3 adverse events (AEs), including respiratory distress, seizure, gait disturbance, weakness, thrombocytopenia, cognitive disturbance, urinary retention, and meningitis. Median follow-up of patients alive was 34.2 months (range 18-52.2) with outcomes. CONCLUSIONS: Ruxolitinib therapy is safe and therapeutically feasible in combination with TMZ and radiation. A randomized phase 2 trial is planned.

Cardiological Safety of 5-Fraction Whole Breast Irradiation

Our study aims to assess heart toxic effect using a reliable cardiac assessment with standard and 3-dimensional (3D) echocardiography and left ventricular (LV) global longitudinal strain (GLS) in patients receiving a 5-fraction (total dose 26 Gy) postoperative radiation therapy (RT) for breast cancer (BC). SAFE-FORWARD is an observational prospective cohort study (NCT04842409). Inclusion criteria were: (1) patients with invasive BC receiving ultra-hypofractionated whole breast irradiation (WBI) (26 Gy in 5 fractions) after breast conserving surgery (BCS) (2) without cardiovascular comorbidity and (3) previous thoracic irradiation. All enrolled patients are prospectively monitored for 12 months, receiving a complex cardiological assessment before RT start (baseline), and at 2-, 6-, and 12-month after RT end of treatment. Both acute and early-late toxicity are evaluated according to CTCAE (v.5) scales. The primary endpoint is defined as detection of any subclinical impairment in myocardial function and deformation (decrease ≥10%) measured with standard and 3D echocardiography and LV GLS. Overall, 40 women (median age 66 years; range, 48-84) were enrolled in the study. We analyzed patients who had completed the cardiological assessment at 12 months. Baseline patient's characteristics are summarized in Table 1. All patients received ultra-hypofractionated WBI (26 Gy in 5 fractions), 25 patients also received adjuvant endocrine therapy. GLS worsened 4% or less, both for the left- and right-side treated breast, and remained in normal range for all the time points. The only exception was for RVGLS at 6 months for right-sided treatment where it reached a borderline value (-17.4±4.9 SE). 3D-LVEF remains stable during observation, both for the left- and right-side treated breast CONCLUSION: The 5-fraction schedule after BCS is well tolerated and the intensive 1-year cardiological monitoring showed no significant differences overtime in cardiac functioning. DIBH, deep inspiration breath hold; AI, aromatase inhibitors; BCCT, Breast Cancer Conservation Treatment.

30-day morbidity and mortality after transoral robotic surgery for human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma: A retrospective analysis of two prospective adjuvant de-escalation trials (MC1273 & MC1675)

ObjectiveDose de-escalation of adjuvant therapy (DART) in patients with HPV(+)OPSCC was investigated in two prospective Phase II and III clinical trials (MC1273 and MC1675). We report the 30-day morbidity and mortality associated with primary TORS resection in patients enrolled in these trials. Materials and methodsPatients with HPV(+)OPSCC, who underwent TORS resection between 2013 and 2020 were considered in this analysis. The severity of postoperative transoral bleeding was graded using both the Hinni Grade (HG) transoral surgery bleeding scale and the Common Terminology for Adverse Events (CTCAE) v5.0. Post-surgical complications within 30 days of surgery, as well as rates of tracheostomy, PEG and nasogastric tube placement. Results219 patients were included. A total of 7 (3.2 %) patients had a tracheostomy placed at the time of surgery, and all were decannulated within 26 days (median: 5, range: 2–26). There were 33 (15.1 %) returns to the emergency department (ED) with 10 (4.6 %) patients requiring readmission. Using the HG scale, 10 (4.6 %) patients experienced ≥ Grade 3 bleeding with no Grade 5 or 6 bleeds. In contrast, using the CTCAE scale, 15 patients (6.8 %) experienced ≥ Grade 3 bleeding with no Grade 5 bleeds. There was one post-operative death in a patient withdrawn from the trial, and no deaths related to hemorrhage. Conclusion and RelevanceTORS for HPV(+)OPSCC in carefully selected patients at a high volume center was associated with low morbidity and mortality.

Risk of Radiation Dermatitis in Patients with Skin of Color Who Undergo Radiation to the Breast or Chest Wall Irradiation and Regional Nodes

<h3>Purpose/Objective(s)</h3> Radiation dermatitis (RD) is common after RT for breast cancer with data indicating potentially worse RD in African American (AA) patients (pts). Current measures of RD, such as the CTCAE, do not include hyperpigmentation, which may disproportionately affect how RD is classified and treated in pts with skin of color (SOC). We aim to characterize RD in SOC and identify factors, including baseline skin pigmentation (BSP) that predict RD. <h3>Materials/Methods</h3> Pts treated with whole breast (WB) or chest wall (CW) with regional nodal RT or high tangents with 50 Gy in 25 fractions from 2015-2018 were identified. Three dermatologists independently classified BSP using photographs from CT simulation based on the Fitzpatrick scale ([FS], range=I-VI; I=light/pale white to VI=black/ very dark brown). SOC was defined as FS IV-VI. Pt characteristics were investigated for association with interventions to treat RD, clinician-graded acute RD, and late skin toxicity (NCI CTCAE scale) with Chi-squared and logistic regression analyses. <h3>Results</h3> 325 pts met eligibility criteria (58 African American [AA], 42 Asian, 151 Caucasian, 77 other). 40% (n=129) had SOC, 60% underwent CW RT, 40% WB RT and 82% had systemic therapy. Pts with SOC were more likely to be Hispanic (14% vs 8% p=0.007), AA (43% vs 1%, p<0.001) and have greater mean BMI (28.0 vs 26.5, p=0.02). Acute grade 2/3 RD was lower in SOC (FS I 60%, FS II 63%, FS III 52%, FS IV 64%, FS V 40%, FS VI 41%; p=0.049). Increased BSP (OR 0.83; p=0.01) and AA pts (OR: 0.22; p<0.001) had lower odds of acute grade 2/3 RD, whereas bolus and dosimetric parameters such as increased PTV volume had increased odds. On multivariable analysis (MVA), AA pts and bolus remained significant (OR: 0.14, p=0.01; OR: 6.63 p<0.001, respectively). Topical steroid use to treat RD was less frequent and oral analgesic use was more frequent in SOC (43% vs 63%, p<0.001; 50% vs 38%, p=0.05, respectively). Pts with increased BSP (OR 0.73, p<0.001), AA race (OR 0.19, p<0.001) and greater BMI had lower use of topical interventions whereas any boost phase, bolus, IMN RT and increased PTV volume had greater use. On MVA, AA pts (OR 0.27, p=0.04), boost (OR 2.04, p=0.033), IMN RT (OR 2.73, p=0.003) and PTV V105% (OR=1.002, p=0.03) retained significance. Late grade 2/3 hyperpigmentation was greater in SOC (16% vs 3%, p=0.01). Increased BSP (OR 2.14, p=0.001), AA pts (OR 8.18, p=0.02), bolus and CW boost had greater odds of grade 2/3 hyperpigmentation. On MVA, increased BSP (OR: 3.76, p=0.03) and bolus (OR: 14.1, p=0.01) retained significance. <h3>Conclusion</h3> We found less clinician-graded acute RD in SOC and AA pts, less frequent use of topical interventions but more oral analgesic use. We also found higher rates of late pigmentation change with increased BSP independent of race. These findings suggest that RD may be under-diagnosed in SOC. This study confirms the necessity for objective measures of RD that account for variability in BSP to accurately classify the severity of radiation skin toxicity in SOC and treat accordingly.

High-Performance Cellular Radiosensitivity Assay Combined to a Polygenic Score to Predict Late Post Radiotherapy Overreaction in Cancer Prostate Patients: A Proof of Concept

<h3>Purpose/Objective(s)</h3> Radioinduced toxicity is a multifactorial problem, related not only to the delivered dose, but also to an intrinsic process within tissues responding to cellular injury. Recently, a novel polygenic risk score (PRS) that for the first time incorporates SNP-SNP interactions (PRSi) was shown to be able to predict late toxicities in the REQUITE prostate cancer cohort (Franco et al, RO 2021). On the other way, recent studies have stressed the role of the ATM protein (pATM) in the response to radiation on lymphocytes from blood and skin fibroblasts (Pereira et al. IJROBP 2018, Deneuve et al. Cancers 2021) and have confirmed that pATM is a relevant biomarker. The main objective of this analysis was to evaluate and validate the prediction assay RadioDTect® (RDT, based on pATM concentration, Deneuve et al, 2021) combined with Single Nucleotide Polymorphisms (SNPs) towards gastrointestinal (GI) and genitourinary (GU) toxicities after radiotherapy (RT) for localized prostate cancer. <h3>Materials/Methods</h3> We considered 48 prostate cancer patients treated with exclusive RT (VMAT) at a single institution at 74-80Gy with conventional fractionation. For all patients, toxicity was prospectively scored before RT and every 6 months till 3 years after the RT end combining CTCAE scale and patient-reported questionnaires. The endpoint of this analysis was any (GI OR GU) grade≥2 toxicity at 3 years after RT. Blood samples were prospectively collected at least 6 months after RT and used to have the RDT and extract germline DNA. We tested a pool of 15 SNPs associated with late RT toxicity from the literature with uni- and multi-variate logistic analysis. We used the multivariable logistic regression predicted probabilities to compute a PRS (using z-standardization of the predicted probability). We investigated the value of a possible RDT+PRS combined biomarker and compared it with the results from dosimetry-based toxicity prediction (including the maximum dose to the rectum and the bladder). <h3>Results</h3> 18/48 patients scored with any grade≥2 late toxicity. Patients with grade≥2 late toxicity were classified using RDT with a previously determined cutoff of 57.8 ng/mL with AUC=0.63 (p=0. 04). 3/15 SNPs from the literature confirmed their association with late toxicity (rs11122573 from Kerns et al. J Natl Cancer Inst 2020, rs2293054 and rs845552 from De Langhe et al. RO 2014). The PRS from these 3 SNPs predicted late toxicity with AUC=0.71 (p=0.01). Combining PRS and RDT led to an improvement of AUC of 7% (p=0.04, AUC=0.78). Adding dosimetric information improved AUC of 2% (p=0.5, AUC=0.8). <h3>Conclusion</h3> The results of this proof of concept allowed us to confirm that biological assays tested in a population of prostate cancer patients treated with VMAT overperformed existing models for toxicity prediction.

Post-radiation complications in children with acute lymphoblastic leukemia who underwent a course of cranial radiation

Purpose of the study. To analyze the physical and neuropsychiatric development of pediatric patients who underwent cranial irradiation in the period from 2015 to 2020 in the radiotherapy department of the National Research Center of Oncology and to assess the risk of post-radiation complications.Materials and methods. 17 children aged from 3 to 17 years were hospitalized under medical supervision in the department of pediatric oncology of the National Medical Research Centre for Oncology. All the children underwent a course of conformal radiation therapy totally on the brain area and the first two cervical vertebrae in the radiotherapy department of the National Medical Research Centre for Oncology. 13 patients (76.7 %) underwent radiation therapy due to the prevention of neuroleukemia with a total dose of 12 Gy (a dose per fraction was 2 Gy), 2 patients with a confirmed relapse of acute lymphoblastic leukaemia (ALL) (11.65 %), 1 patient with a confirmed diagnosis of neuroleukemia (5.8 %) and 1 patient from the high-risk group (5.8 %) – with a total dose of 18 Gy (a dose per fraction was 2 Gy). Further 75 month regular medical checkup was carried out on the basis of the Regional Children's Clinical Hospital for.Results. None of the surviving patients showed growth retardation. Two patients (11.65 %) complained of increased fatigue, decreased concentration; one patient (5.8 %) showed unmotivated irritability and aggression during the examination. Intellectual development corresponded to age in all patients (100 %). One patient (5.8 %) experienced episodes of nausea and vomiting (grade 1 on the CTCAE scale), three patients (17.7 %) suffered from headache (grade 2 on the CTCAE scale), three patients (17.7 %) complained of fever up to 38 °C (1 degree on the CTCAE scale). Two out of 17 ALL patients died due to disease progression.Conclusion. Taking into account the different time intervals between treatment and the moment of the study (from 9 to 75 months), cranial irradiation demonstrates relative safety for patients undergoing treatment during critical periods of development of both physical and neuropsychic spheres. However, an objective assessment of the development prospects is difficult due to the relatively short time after undergoing therapy (from 9 to 75 months) and a small sample of patients.

Early Experience Using Proton Beam Therapy for Extremity Soft Tissue Sarcoma: A Multi-Institution Study

<h3>Purpose/Objective(s)</h3> Proton beam therapy (PBT) may provide an advantage when planning selected patients with extremity soft tissue sarcoma (STS), especially for larger and anatomically challenging cases. We analyzed our early experience with PBT on toxicity and outcomes. <h3>Materials/Methods</h3> A retrospective study was performed of 20 consecutive patients with extremity STS treated between June 2016 and September 2020, with pencil beam scanning PBT at two institutions with a median age 51.5 years (range, 19-78 years). Demographic, tumor, treatment, and toxicity characteristics were gathered from baseline to end of follow-up or death. Surgery was performed for all patients; chemotherapy and intraoperative electron radiotherapy boost were included for selected patients. Wound complications were defined as secondary operation for wound repair (debridement, drainage, skin graft, and muscle flap) or non-operative management requiring hospitalization. Dermatitis was graded according to the CTCAE scale. Analysis was performed with statistical software. <h3>Results</h3> All patients completed the prescribed course of PBT to a median dose of 5000 cGY RBE (range: 3000 – 6600 cGY RBE). Tumor presentation was primary (n = 17) or recurrent after prior combined modality therapy (n = 3). Tumor location was either lower extremity (n = 13) or upper extremity (n = 7). Median pre-treatment tumor size was 9.2 cm (range: 1.3 – 30.0 cm). Baseline staging for patients prior to PBT follows: 2 (10%) IA, 7 (35%) IB, 4 (20%) II, 3 (15%) IIIA, 3 (15%) IIIB, and 1 (5%) IV. Radiation was delivered pre-operatively in most patients (n = 18). Median follow-up was 13.7 months (range, 1.7 – 48.1 months). Nineteen patients (90%) were alive at the end of follow-up. Locoregional control was 100%. Four patients (20%) had developed metastatic disease by end of follow-up. Acute dermatitis was maximum grade 2 (n = 8, 40%) and grade 3 (n = 3, 15 %). After pre-operative radiation and surgical resection, acute wound complications occurred in 7 patients (39%). Intraoperative debridement and I&D, unplanned skin graft, muscle flap, and IV antibiotic use requiring hospitalization was required in 5 (25%), 3 (15%), 1 (5%), and 2 (10%), respectively. Tumor size was larger in patients with wound complications compared to no complications (median 15.3 cm [range 1.6-30.0 cm] vs 6.9cm [1.3-14.4 cm], <i>P</i> = 0.045). Factors such as patient age, tumor location, histology, chemotherapy, or IORT were not associated with wound complications. Rates of chronic G2+ pain, neuropathy, fibrosis, and lymphedema were 25%, 15%, 5%, and 5% respectively. <h3>Conclusion</h3> This early study of PBT for challenging extremity STS cases demonstrates good local control, similar acute toxicity profile, and wound complication rate comparable to photons. Long term follow-up and further dosimetric analyses will provide further insight into potential advantages of PBT in this patient population.

Acute Radiation Dermatitis Evaluation with Reflectance Confocal Microscopy: A Prospective Study.

Background: During radiotherapy (RT), most breast cancer patients experience ionizing radiation (IR)-induced skin injury—acute radiation dermatitis (ARD). The severity of ARD is determined by a physician according to CTCAE or RTOG scales, which are subjective. Reflectance confocal microscopy (RCM) is a noninvasive skin imaging technique offering cellular resolution. Digital dermoscopy (DD) performed in conjugation with RCM can provide more information regarding skin toxicity. The purpose of this study is to create an RCM and DD features-based ARD assessment scale, to assess the association with CTCAE scale and possible predictive value. Methods: One hundred and three breast cancer patients during RT were recruited; every week, clinical symptoms of ARD (CTCAE scale) were evaluated and RCM, together with digital dermoscopy (DD), was performed. Results: According to RCM; after 2 RT weeks, exocytosis and/or spongiosis were present in 94% of patients; after 3 weeks, mild contrast cells (MMCs) were detected in 45%; disarrayed epidermis (DE) was present in 66% of patients after 4 weeks and in 93% after 5 weeks; abnormal dermal papillae (ADP) were present in 68% of patients after 5 weeks. The coefficients of RCM features (RCMcoef) alone and together with dermoscopically determined erythema (RCM-ERYcoef) were significantly associated with ARD severity grade. RCMcoef is a significant predictive factor for the clinical manifestation of ARD. Conclusions: RCM features of irradiated skin appear earlier than clinical symptoms, have a characteristic course, and allow the severity of ARD to be predicted.

Dose escalation in advanced floor of the mouth cancer: a pilot study using a combination of IMRT and stereotactic boost

PurposeWe evaluated the efficiency and toxicity of stereotactic hypofractionated boost in combination with conventionally fractionated radiotherapy in the treatment of advanced floor of the mouth cancer.MethodsThirty-seven patients with advanced stage of the floor of the mouth cancer, histologically confirmed squamous cell carcinoma (p16 negative) ineligible for surgical treatment, were indicated for radiochemotherapy or hyperfractionated accelerated radiotherapy (HART). The radiotherapy protocol combined external beam radiotherapy (EBRT) and a stereotactic hypofractionated boost to the primary tumor. The dose delivered from EBRT was 70–72.5 Gy in 35/50 fractions. The hypofractionated boost followed with 10 Gy in two fractions. For the variables—tumor volume, stage and grade a multivariate analysis was performed to find the relationship between overall survival, local progression and metastasis. Toxicity was evaluated according to CTCAE scale version 4.ResultsAfter a median follow-up of 16 months, 23 patients (62%) achieved complete remission. The median time to local progression and metastasis was 7 months. Local control (LC) at 2 and 5-years was 70% and 62%, respectively. Progression-free survival (PFS) and overall survival (OS) were 57% and 49% at 2 years and 41% and 27% at 5 years, respectively. Statistical analysis revealed that larger tumors had worse overall survival and a greater chance of metastasis. Log-Rank GTV > 44 ccm (HR = 1.96; [95% CI (0.87; 4.38)]; p = 0.11). No boost-related severe acute toxicity was observed. Late osteonecrosis was observed in 3 patients (8%).ConclusionThe combination of EBRT and stereotactic hypofractionated boost is safe and seems to be an effective option for dose escalation in patients with advanced floor of the mouth tumors who are ineligible for surgical treatment and require a non-invasive approach.

Preoperative stereotactic ablative body radiotherapy with postoperative conventional irradiation of soft tissue sarcomas: Protocol overview with a preliminary safety report

Preoperative radiotherapy in patients with soft tissue sarcomas is characterized by important advantages: high precision of dose delivery, reduction of tumor volume and implantation potential, induction of immunologic response. Postoperative irradiation is associated with a reduced risk of complication, and a comprehensive radiotherapy planning in accordance with the pathologic report. Combination of pre- and postoperative irradiation gives the opportunity to use the best of both methods. ObjectiveTo analyze feasibility and safety of radiotherapy protocol that combined pre- and postoperative radiotherapy in patients with soft tissues sarcomas of extremities. Materials and methodsFrom 06.2018 to 01.2021, 23 patients with soft tissue sarcomas of extremities were included in the protocol (NCT04330456) and 14 cases with at least 12 months follow-up were eligible for analysis. Preoperative stereotactic ablative body radiotherapy (SBRT) was performed as 5 fraction of 7 Gy with dose reduction (5 fractions of 5 Gy) on the margins of the tumor. Postoperative radiotherapy started 5–8 weeks after the surgery and was performed as standard compartmental irradiation in 25 fractions of 2 Gy. Complications were determined according to CTCAE and wound complication scales. ResultsPreoperative SBRT and subsequent radical resection with tumor free surgical margins were performed in all 14 cases. Primary wound closure was mentioned in all patients. Postoperative radiotherapy started 51.8 days (range 33–99 days) days after the surgery. With a relatively short follow-up of 21.5 (13–30) months, we recorded 2 cases (14%) of severe complications (Canadian sarcoma group criteria), and there were no local recurrences. ConclusionOur preliminary results demonstrate that the combination of preoperative SBRT and postoperative conventional radiotherapy is feasible and does not increase the risk of postoperative complications.

Preoperative stereotactic ablative body radiotherapy with postoperative conventional irradiation of soft tissue sarcomas: Protocol overview with a preliminary safety report.

e23546 Background: Preoperative radiotherapy in patients with soft tissue sarcomas is characterized by important advantages: high precision of dose delivery, reduction of tumour volume and implantation potential, induction of immunologic response. Postoperative irradiation is associated with a reduced risk of complication, and a comprehensive radiotherapy planning in accordance with the pathologic report. Combination of pre- and postoperative irradiation gives the opportunity to use the best of both methods. Methods: from 06.2018 to 01.2021 24 patients with soft tissue sarcomas of extremities were included in the protocol (NCT04330456) and 14 cases with at least 12 months follow-up were eligible for analysis. Preoperative stereotactic ablative body radiotherapy (SBRT) was performed as 5 fraction of 7 Gy with dose reduction (5 fractions of 5 Gy) on the margins of the tumor. Postoperative radiotherapy started 5-8 weeks after the surgery and was performed as standard compartmental irradiation in 25 fractions of 2Gy. Complications were determined according to CTCAE and wound complication scales. Results: Preoperative SBRT and subsequent radical resection with tumor free surgical margins were performed in all 14 cases. Primary wound closure was mentioned in all patients. Postoperative radiotherapy started 51.8 days (range 33-99 days) days after the surgery. With a relatively short follow-up of 21.5 (13-30) months, we recorded 2 cases (14%) of severe complications (Canadian sarcoma group criteria), and there were no local recurrences. Conclusions: Our preliminary results demonstrate that the combination of preoperative SBRT and postoperative conventional radiotherapy is feasible and does not increase the risk of postoperative complications. Clinical trial information: NCT04330456.

A small case series about safety and effectiveness of a hypofractionated electron beam radiotherapy schedule in five fractions for facial non melanoma skin cancer among frail and elderly patients.

The aim of the study was to evaluate local control and toxicities of strongly hypofractionated electron beam radiotherapy (RT) in elderly and fragile patients with facial nonmelanoma skin cancer (NMSC). We enrolled patients aged ≥ 65 years with facial NMSC, Karnofsky Performance Status (KPS) ≥ 40 and life expectancy ≥ 6 months, amenable neither to daily RT nor surgery. Radiotherapy consisted of 35 Gy, delivered with 6 MeV electron beam, in 5 fractions of 7 Gy/day twice a week (tw). Prescription isodoses were 100% for cT1-cT2 and 90% for cT3-cT4. Objective response was assessed clinically 4 and 8 weeks after the end of RT and then monitored every 6 months. Side effects were assessed according to the CTCAE scale. 12 patients of median age 89.5 years with a total of 23 NMSC cN0 achieved a median follow-up time of 6 months (range 1-10), with total treatment compliance. 10/12 patients had a 40 ≤ KPS < 70 and 2/12 a 70 ≤ KPS < 90. 5/12 patients had synchronous lesions. 22/23 lesions were classified as T1-T2 and had complete response (CR), 1/23 as T4 with partial response (PR). Within 4 weeks after the end of treatment, G1 toxicity was reported for 12/23 lesions, G2 for 8/23, G3 for 3/23, G4 for 0/23, all disappeared 8 weeks later, with or without topical therapy. After last follow-up (1 June 2020) 1/12 patients died with PR from senile marasmus, 11/12 are alive with CR and widely tolerated toxicities. Extreme hypofractionation of radiotherapy dose for facial NMSC is effective, safe and suitable for elderly patients.

Non-contact Low-frequency Ultrasound (NCLF) to Improve Dermatitis and Quality of Life after Radiation Therapy: The Soothe Study

Radiation dermatitis is the most common acute sequela of radiation therapy in the treatment of breast cancer. Radiation dermatitis not only affects quality of life but can also interfere with the treatment course. Acute dermatitis typically continues to progress up to 14 days after completion of radiation therapy. Dependent on the severity, management may include the use of topical emollients, steroids, and/or silver sulfadiazine, along with oral analgesics. Non-contact low-frequency ultrasound (NCLF) is well established in the management of chronic cutaneous wounds but has never been studied specifically on radiation induced dermatitis. The mechanism of action of NCLF is not well understood, but believed to decrease bacterial count and inflammatory cytokines while stimulating cellular activity. Our aim was to investigate whether the addition of NCLF to standard of care results in accelerated resolution of acute radiation dermatitis and improvement in patient’s quality of life compared to standard of care alone. Eligible patients were those who completed post-lumpectomy or post-mastectomy radiation therapy and acquired grade 2 dermatitis or above (per NCI CTCAE scale). Once enrolled, patients were randomized to receive standard of care (SOC) treatment with daily applications of silver sulfadiazine cream (control group) or SOC plus NCLF (treatment group) utilizing NCLF once per day for approximately 10 minutes to the affected area until grade 1 dermatitis was achieved. All patients agreed to a photograph daily of the affected area. The number of days it took for the treated area to reduce to grade 1 dermatitis was recorded. The patient was then discharged from the study and instructed to continue SOC treatment as needed. All patients completed the Health State Visual Analogue Scale (VAS) at enrollment and again at the end of the study period. Sixty-three female breast cancer patients with grade 2 radiation dermatitis were prospectively enrolled. 33 patients were randomized to SOC and 30 patients randomized to SOC plus NCLF. Patients in the SOC plus NCLF group took less time to resolve to a grade 1 dermatitis (Mean = 7.77 days, SE = 0.569), than those who received SOC alone (Mean = 10.52 days, SE = 0.698). This difference was clinically and statistically significant at 2.75 days (t = 3.053, p = 0.0017). The SOC plus NCLF group had a larger increase in their VAS score than those who received SOC alone (17 vs 12 respectively), however this was not statistically significant (t = -0.96, p = 0.34). When added to the standard of care, non-contact low frequency ultrasound accelerates the transition of grade 2 to grade 1 radiation dermatitis in breast cancer patients undergoing post-operative radiation therapy. The reduction in days of healing may translate to an improvement in quality of life in the immediate post-radiation period. Further investigation is necessary to determine cost effectiveness of NCLF and wider range of its applications in radiation therapy.

Treprostinil iontophoresis in systemic sclerosis-related digital skin ulcers: A single ascending dose safety study

Digital skin ulcers are a severe complication of systemic sclerosis(SSc). The first-line treatment is intravenous iloprost, but it induces dose-limiting adverse effects. Local administration of treprostinil through skin iontophoresis may be a safe alternative. We conducted a two-stage, randomized, placebo-controlled single ascending dose study in healthy volunteers and patients with SSc-related digital ulcer (SSc-DU). We further explored the effect of the procedure on skin blood flux. The objectives were to assess the safety of an iontophoresis of treprostinil hydrogel administered on healthy volunteers finger pad, leg and foot and asses the safety of ascending doses in patients with SSc-DU. In a first group of healthy subjects, treprostinil and placebo iontophoresis were performed at 3 different locations (i.e. 6 skin sites): the sole of the foot, the leg, and the fingers. We used a 1 mg/mL hydrogel of treprostinil. We then randomly treated SSc-DUs in a 3/1 ratio treprostinil or placebo respectively. We used concentrations from 0.1 to 1 mg/mL. All adverse events were recorded and rated (according to the CTCAE), while skin microvascular blood flux was recorded with laser speckle contrast imaging. Among the 12 healthy volunteers, we observed 60 local adverse effects: burns, skin pain, erythema and pruritus, graded 1 or 2 on the 5-point CTCAE scale. Treprostinil iontophoresis significantly increased skin blood flux on the leg (AUC0-4 h at 88460 ± 6436 versus 12730 ± 3397%BL.min respectively, P < 0.001) and on the sole of the foot (AUC0-3 h at 20124 ± 6119 versus 3142 ± 3036% BL.min respectively, P = 0.018) with a trend on the finger (AUC0-3 h was 10773 ± 4888). Among five patients with SSc-UD, 2 resolutive local adverse effects were reported. Iontophoresis of treprostinil was safe in SSc patients with digital ulcers. Treprostinil at 1 mg/mL will be used in the next study, i.e. repeated iontophoresis in SSc-related ulcer.

Salvage I-125 brachytherapy for locally-recurrent prostate cancer after radiotherapy.

Retrospective, single-institution analysis of clinical outcomes and treatment-related toxicity in patients treated with salvage I-125 low-dose rate (LDR) brachytherapy (BT) for locally-recurrent prostate cancer after radiotherapy. Between 2008 and 2018, 30 patients with biopsy-confirmed prostate cancer recurrence underwent salvage treatment with I-125 LDR-BT. Of these 30 patients, 14 were previously treated with primary external beam radiotherapy (EBRT; median dose, 73 Gy) and 16 with primary I-125 LDR-BT (145 Gy and 160 Gy in 14 and 2 cases, respectively). At seed implantation, the mean age was 75.8 years, with a median Gleason score of 7 and pre-salvage PSA of <10 ng/mL. Six patients received androgen deprivation therapy for six months after relapse diagnosis. The prescribed salvage I-125 BT dose to the gland was 120-130 Gy, with dose restrictions of Dmax <135% (urethra) and <100% (rectum). Toxicity was evaluated according to the CTCAE scale (v4.0). At a median follow-up of 45 months, the biochemical recurrence-free survival rates at 1, 3 and 5 years were 86.7%, 56.7% and 53.3%, respectively. Overall survival at 5 years was 87%. On the multivariate analysis, two variables were significant predictors of recurrence: PSA at relapse and nadir PSA post-salvage. Grade 3 genitourinary toxicity was observed in 5 patients (radiation-induced cystitis in 3 cases and urethral stenosis in 2) and G3 gastrointestinal toxicity in 3 patients (rectal bleeding). Salvage therapy with I-125 brachytherapy is a safe and effective treatment option for locally-recurrent prostate cancer in previously-irradiated patients. High pre-salvage PSA and post-salvage nadir PSA values were significantly associated with a worse disease control after salvage I-125 LDR-BT. In well-selected patients, I-125 LDR-BT is comparable to other salvage therapies in terms of disease control and toxicity. However, more research is needed to determine the optimal management of locally-recurrent prostate cancer.

Adaptación transcultural del componente de síntomas gastrointestinales de la escala CTCAE versión 4.02

Objetivo: Realizar la traducción y adaptación transcultural del componente de síntomas gastrointestinales (SGI) de la escala CTCAE Versión 4.02, en pacientes ambulatorios tratados con quimioterapia en el Instituto Nacional de Cancerología en Bogotá.&#x0D; Métodos: Se realizó una búsqueda manual en medios electrónicos, de escalas en idiomas inglés o español, que evaluarán la presencia, frecuencia o intensidad de SGI en pacientes oncológicos. La selección de los ítems fue efectuada por consenso informal de un comité técnico, que verificó la concordancia entre los principales SGI descritos en la literatura y los incluidos en la escala, todos los cuales podrían afectar el estado nutricional. Para la adaptación transcultural se siguieron los pasos y recomendaciones del manual ISPOR y del grupo de calidad de vida EORTC. La prueba piloto se efectuó en 25 pacientes seleccionados por conveniencia, que cumplieron los criterios de inclusión.&#x0D; Resultados: El 52% fueron hombres; la edad promedio fue 54,2 años (+/- 15,3 años). Los cánceres más frecuentes fueron: colorrectal (28%), estómago (16%) y mama (12%). Los 14 SGI incluidos en la escala fueron experimentados por todos los pacientes, por lo cual se conservaron, y no se requirió adicionar ningún otro. El tiempo promedio de aplicación del instrumento fue de 5 minutos y el 90% de los participantes lo consideró adecuado.&#x0D; Conclusiones: Se generó un instrumento de 14 ítems para medir SGI en pacientes oncológicos ambulatorios sometidos a quimioterapia, que es de rápida aplicación y utiliza lenguaje de fácil comprensión para el paciente. Quedan por definir sus propiedades clinimétricas.

Home-based management of cancer patients (CPs) experiencing toxicities while on anticancer treatment: The impact of a nurse-led telephone triage (NTT).

2002 Background: Novel organization models are needed to ensure early management of new treatment-related toxicity of anticancer treatments. Aim of this prospective observational study was to evaluate the impact of the introduction of NTT in reducing hospitalization of CPs. Methods: CPs on active medical treatment at the Department of Oncology of San Bortolo Hospital (Vicenza, Italy) were given instructions to refer to NTT in case of treatment-related adverse events (TRAEs). The service was opened Mon to Fri from 8am to 8pm. Assessment of TRAEs was performed by trained oncology nurses according to the CTCAE scale and subsequent actions were taken according to the severity of the events. The assessment was made under supervision of a medical oncologist in charge of the service while on duty. Primary endpoint of the study was to compare the rate of hospitalization of CPs on anticancer treatment after the introduction of NTT compared to 2017-2018 period. Results: From September 2018 to September 2019 1,075 patients received systemic anticancer treatment (versus 936 patients in the equivalent 2017 – 2018 period). Total consultations at NTT were 429; 581 TRAEs were reported. 117 patients reported more than one TRAE. CTCAE were graded as G1 237 (40.8%), G2 231 (39.8%) or G3-G4 113 (19.4%). The most common grade ≥ 3 TRAE was fever (38 events (33.6%) that resulted a febrile neutropenia in 7 cases) followed by cancer pain (15 (13.3%)) and fatigue (9 (8%)). In the observation period, 109 CPs on treatment were hospitalized versus 138 in the 2017-2018 period with a normalized hospitalization rate of 10.1% versus 14.7 % (p = 0.002, chi-square) with a reduction of normalized number of hospitalizations of 44 (estimated cost savings of 380.160 euros). Conclusions: Our results provided evidence of successful implementation of the NTT system in reducing rates of hospitalization through emergency room in cancer patients receiving modern medical treatments.

Impact of metastases directed radiation therapy on CDK4/6 inhibitors dose reduction and treatment discontinuation for metastatic HR+/HER2- breast cancer (MBC).

562 Background: Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) represent the standard I-II line for hormonal receptors positive/human epidermal growth factor receptor 2 negative metastatic breast cancer (MBC) patients. Metastases directed radiotherapy (RT) for these patients is commonly used with palliative or radical schedules during systemic treatment. Although encouraging preliminary results were published, there is still a lack of robust data on the safety concerning RT during CDK4/6i treatment. Methods: we analyzed at Our Institution 85 consecutive patients treated in I (n=47) and II line (n=38) for MBC with CDK4/6i between April 2017 and September 2019 (22 ribociclib, 63 palbociclib). Overall, 25 (29.4%) patients received metastases directed RT during CDK4/6i treatment, including 14 concomitant (16.5%) and 11 sequential (12.9%). Estimated CDK4/6i half-life is 26 and 30 hours for palbociclib and ribociclib, respectively. Five half-lives are required to reduce drug concentration by 95-97%; thus, we also analyzed CDK4/6i treatment as non-concomitant or sequential to RT. Main endpoints of our analysis were impact of RT on CDK4/6i dose reduction and discontinuation, overall adverse events rate (any grade and grade ≥2), and neutropenia grade ≥2 as per CTCAE scale version 5.0. Results: at a median follow up of 12 months (range 3-29), we observed a CDK4/6i dose reduction in 35 patients (41.2%) and 5 patients (5.9%) discontinued treatment due to adverse events; 82 patients (96.5%) experienced any grade of toxicity, 72 (84.7%) a grade ≥2 and 70 patients (82.4%) neutropenia grade ≥2. We did not observe significant difference in terms of CDK4/6i dose reduction or discontinuation, any grade or grade ≥2 toxicity, neutropenia grade ≥2 in the comparison between patients receiving RT versus no RT and between patients receiving concomitant RT versus sequential RT versus no-RT (Table). Conclusions: our results showed that the prescription of a metastases directed RT during treatment with a CDK4/6i as I-II line for MBC did not significantly impact on dose reduction or discontinuation caused by an exceeding in adverse event rate. Although these promising results, caution should be used and cooperative initiatives strongly encouraged. [Table: see text]

RESULTS OF COMBINED TREATMENT PATIENTS WITH SOFT TISSUE SARCOMAS USING STEREOTACTIC ABLATIVE BODY RADIOTHERAPY

Preoperative radiotherapy in patients with soft tissue sarcomas characterized by important advantages: high precision of dose delivery, reduction of tumour volume and implantation potential, induction of immunologic response. Postoperative radiotherapy associated with decreased complication rate, delivery of treatment to microscopic disease according to pathologic report. Combination of pre- and postoperative irradiation gives the opportunity to use best of both methods. The aim: analyses of feasibility and safety of radiotherapy protocol that combined pre- and postoperative radiotherapy in patients with soft tissues sarcomas of extremities. Materials and methods: from 06.2018 to 01.2020 ten patients with soft tissue sarcomas of extremities were included in the protocol. Preoperative stereotactic ablative body radiotherapy (SABR) was performed as 5 fraction of 7 Gy on the main tumor volume with dose reduction to 5Gy in 5 fraction on the margins of the field. Postoperative radiotherapy started 5-8 weeks after surgery and was performed as standard compartmental irradiation in 25 fractions of 2Gy. Complications were determined according to CTCAE and wound complication scales. Results: from 06.2018 to 01.2020 10 patients with soft tissue sarcomas of extremities were included in the study. Pre-opeartive SABR and subsequent radical resection with tumor free surgical margins were performed in all 10 cases. Primary wound closure was mentioned in all patients. With relatively short follow-up of 9.1 (3-20) months we didn’t mentioned any case of grade II or more toxicity and no local recurrences. Conclusion: Our preliminary results demonstrate that combination of preoperative SABR and postoperative conventional radiotherapy is feasible and associated with low probability of grade II (and higher) toxicity.