The Prognostic Value of the Systemic Immune-Inflammation Index (SII) and Red Cell Distribution Width (RDW) in Patients with Cervical Cancer Treated Using Radiotherapy.

INTRODUCTION: There is growing interest in the prognostic value of routinely performed pre-treatment blood test indices, such as the RDW or SII, with the latter combining the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). These indices were shown to be prognostic for survival in some malignancies. The purpose of this study was to evaluate the association between pre-treatment RDW and SII, and OS in patients treated with radiotherapy for primary localised cervical cancer. MATERIAL AND METHODS: This retrospective analysis included patients treated with definitive CRT between 2011 and 2017 for histopathologically confirmed FIGO 2018 stage IB2-IVA cervical cancer. Statistical analysis was performed using the Kaplan-Meier method, two-sided log-rank tests, and Cox proportional hazards models, with the AIC serving as a prediction error estimator. RESULTS: The study group included 249 patients with a median age of 57.2 years and a median follow-up of 75.8 months. The majority were diagnosed with squamous cell carcinoma (237; 95.2%) and had FIGO stage III (211; 84.7%). Approximately half of the patients (116; 46.4%) had regional lymph node metastases. Patients with a low RDW (≤13.4%) and low SII (≤986.01) had a significantly longer OS (p = 0.001 and p = 0.002). The RDW remained as an independent prognostic factor in the multivariable model (high vs. low; HR = 2.04; 95% CI: 1.32-3.16; p = 0.001). Including RDW in the model decreased the Akaike Information Criterion from 1028.25 to 1018.15. CONCLUSIONS: The RDW is a cheap and widely available index that is simultaneously an independent prognostic factor for survival and could be used to improve pre-treatment prognosis assessments in patients with cervical cancer undergoing CRT. Available data encourage assessing the RDW as a prognostic factor in prospective trials to aid the identification of candidates for treatment escalation.

Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial.

BACKGROUND: Concurrent chemoradiotherapy has been the standard of care for locally advanced cervical cancer for over 20 years; however, 30-40% of treated patients have recurrence or progression within 5 years. Immune checkpoint inhibition has improved outcomes for patients with PD-L1 positive metastatic or recurrent cervical cancer. We assessed the benefit of adding durvalumab, a PD-L1 antibody, with and following chemoradiotherapy for locally advanced cervical cancer. METHODS: The CALLA randomised, double-blind, phase 3 trial included 105 hospitals across 15 countries. Patients aged at least 18 years with previously untreated locally advanced cervical cancer (adenocarcinoma, squamous, or adenosquamous; International Federation of Gynaecology and Obstetrics [FIGO] 2009 stage IB2-IIB lymph node positive, stage ≥III any lymph node status) and WHO or Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) through an interactive web response system using a permuted block size of 4 to receive durvalumab (1500 mg intravenously once every 4 weeks) or placebo with and following chemoradiotherapy, for up to 24 cycles. Chemoradiotherapy included 45 Gy external beam radiotherapy at 5 fractions per week concurrent with intravenous cisplatin (40 mg/m2) or carboplatin (area under the concentration-time curve 2) once weekly for 5 weeks, followed by image-guided brachytherapy (high-dose rate, 27·5-30 Gy or low-dose/pulse-dose rate, 35-40 Gy). Randomisation was stratified by disease stage status (FIGO stage and node status) and geographical region. Chemoradiotherapy quality was continuously reviewed. The primary endpoint was progression-free survival, assessed by the investigator using Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03830866. FINDINGS: Between Feb 15, 2019, and Dec 10, 2020, 770 women were randomly assigned (385 to durvalumab and 385 to placebo; median age 49 years [IQR 41-57]). Median follow-up was 18·5 months (IQR 13·2-21·5) in the durvalumab group and 18·4 months (13·2-23·7) in the placebo group. At data cutoff, median progression-free survival had not been reached (95% CI not reached-not reached) for either group (HR 0·84; 95% CI 0·65-1·08; p=0·17); 12-month progression-free survival was 76·0% (71·3-80·0) with durvalumab and 73·3% (68·4-77·5) with placebo. The most frequently reported grade 3-4 adverse events in both groups were anaemia (76 [20%] of 385 in the durvalumab group vs 56 [15%] of 384 in the placebo group) and decreased white blood cells (39 [10%] vs 49 [13%]). Serious adverse events occurred for 106 (28%) patients who received durvalumab and 89 (23%) patients who received placebo. There were five treatment-related deaths in the durvalumab group (one case each of urinary tract infection, blood loss anaemia, and pulmonary embolism related to chemoradiotherapy only; one case of endocrine disorder related to durvalumab only; and one case of sepsis related to both durvalumab and chemoradiotherapy). There was one treatment-related death in the placebo group (pneumonia related to chemoradiotherapy). INTERPRETATION: Durvalumab concurrent with chemoradiotherapy was well tolerated in participants with locally advanced cervical cancer, however it did not significantly improve progression-free survival in a biomarker unselected, all-comers population. Concurrent durvalumab plus chemoradiotherapy warrants further exploration in patients with high tumoral PD-L1 expression. Rigorous monitoring ensured high chemoradiotherapy compliance with advanced technology and allowed patients to receive optimal care. FUNDING: AstraZeneca.

Robotic Stereotactic Radiotherapy for Intracranial Meningiomas-An Opportunity for Radiation Dose De-Escalation.

OBJECTIVE: To evaluate the possibility of dose de-escalation, with consideration of the efficacy and safety of robotic stereotactic CyberKnife radiotherapy in patients diagnosed with intracranial meningiomas. METHODS: The study group consisted of 172 patients (42 men and 130 women) treated in III Radiotherapy and Chemotherapy Clinic of Maria Sklodowska-Curie National Research Institute of Oncology in Gliwice between January 2011 and July 2018. The qualification for dose de-escalation was based on MRI (magnetic resonance imaging) features: largest tumor diameter less than 5 cm, well-defined tumor margins, no edema, and no brain infiltration. The age of patients was 21-79 years (median 59 years) at diagnosis and 24-80 years (median 62 years) at radiotherapy. Sixty-seven patients (Group A) were irradiated after initial surgery. Histopathological findings were meningioma grade WHO 1 in 51 and WHO 2 in 16 cases. Group B (105 patients) had no prior surgery and the diagnosis was based on the typical features of meningioma on MRI. All patients qualified for the robotic stereotactic CyberKnife radiotherapy, and the total dose received was 18 Gy in three fractions to reference isodose 78-92%. RESULTS: Follow-up period was 18 to 124 months (median 67.5 months). Five- and eight-year progression free survival was 90.3% and 89.4%, respectively. Two patients died during the follow-up period. Progression of tumor after radiotherapy was registered in 16 cases. Four patients required surgery due to progressive disease, and three of them were progression free during further follow-up. Twelve patients received a second course of robotic radiotherapy, 11 of them had stable disease, and one patient showed further tumor growth but died of heart failure. Crude progression free survival after both primary and secondary treatment was 98.8%. Radiotherapy was well-tolerated: acute toxicity grade 1/2 (EORTC-RTOG scale) was seen in 10.5% of patients. We did not observe any late effects of radiotherapy. CONCLUSION: Stereotactic CyberKnife radiotherapy with total dose of 18 Gy delivered in three fractions showed comparable efficacy to treatment schedules with higher doses. This could support the idea of dose de-escalation in the treatment of intracranial meningiomas.

Intracranial Germinoma-Association between Delayed Diagnosis, Altered Clinical Manifestations, and Prognosis.

BACKGROUND: Intracranial germinoma is a rare malignant neoplasm of the central nervous system (CNS) that occurs in children and young adults. The aim of our study was to assess the initial manifestation of the disease, and to find differences in outcomes dependent on time of diagnosis. METHODS: The study group consisted of 35 consecutive patients (adults and children) who were treated for intracranial germinoma with radiotherapy at a tertiary centre, and their data were retrospectively collected. We evaluated time from the first symptoms to diagnosis and divided patients into early and delayed diagnosis groups. Delayed diagnosis has been defined as the time from initial presentation to final diagnosis longer than six months. RESULTS: A total of 17 (48.6%) of the patients had delayed diagnoses. Patient survival data spanned a median of six (interquartile range 3-12) years. At the time of the diagnosis, patients presented exclusively neurological symptoms in 16 (45.7%) cases, exclusively endocrinological symptoms in five (14.3%) cases, and mixed symptoms in the remaining cases (n = 14; 40.0%). Patients with neurological symptoms had shorter time (p < 0.001) from first symptoms to the final diagnosis (5.91 months) than in patients without them (19.44 months). The delayed diagnosis group presented significantly smaller tumour size (mean maximal dimension 2.35 cm) compared to early diagnosis group (3.1 cm). The 5-year and 10-year survival rates of our patients were 94.3% and 83.4%, respectively. Patients with a delayed diagnosis (n = 17) had a significantly worse (p = 0.02) 10-year OS (63%) compared to the early diagnosis group (n = 18; OS = 100%). Importantly, in five patients (14.29%), initial manifestation occurred before radiological signs of the disease. CONCLUSION: Our study stresses the need for timely diagnosis in intracranial germinoma, as a delay has a significant impact on the prognosis. In particular, if the tumour is small or causes exclusively endocrinological symptoms, the diagnosis may be difficult and delayed.

Safety and Feasibility of Radiation Therapy Combined with CDK 4/6 Inhibitors in the Management of Advanced Breast Cancer.

The addition of CDK4/6 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK4/6i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast cancer patients (pts) treated with CDK4/6i was performed, and 100 pts also received RT. Forty-six pts received 63 RT courses concurrently and fifty-four sequentially before CDK4/6i initiation (76 RT courses). Neutropenia was common (79%) and more frequent during and after concurrent RT than sequential RT (86% vs. 76%); however, CDK4/6i dose reduction rates were similar. In patients treated with CDK4/6i alone, the dose reduction rate was 42% (79 pts) versus 38% with combined therapy, and 5% discontinued treatment due to toxicity in the combined group. The risk of CDK4/6i dose reduction was correlated with neutropenia grade, RT performed within the first two CDK4/6i cycles, and more than one concurrent RT; a tendency was observed in concurrent bone irradiation. However, on multivariate regression analysis, only ECOG 1 performance status and severe neutropenia at the beginning of the second cycle were found to be associated with a higher risk of CDK4/6i dose reduction. This largest single-center experience published to date confirmed the acceptable safety profile of the CDK4/6i and RT combination without a significantly increased toxicity compared with CDK4/6i alone. However, one might delay RT for the first two CDK4/6i cycles, when myelotoxic AE are most common.

The Impact of Robotic Fractionated Radiotherapy for Benign Tumors of Parasellar Region on the Eye Structure and Function.

PURPOSE: To evaluate the radiation effect of fractionated robotic radiotherapy of benign tumors located in the parasellar region on the anterior and posterior segments of the eye. METHODS: A prospective observational study based on the expanded ophthalmological examination. The pre-treatment baseline was used as a control for the post-radiotherapy follow-up examinations. The study group consists of 34 patients (68 eyes) irradiated using the CyberKnife system. There were ten patients with cavernous sinus meningioma, nine with pituitary adenoma, five with meningioma of the anterior and middle cranial fossa, five with meningioma in the region close to optic chiasm, three with craniopharyngioma, and two with meningioma of the orbit. All patients were treated using three fractions of 600-800 cGy. We assessed the impact of radiation on the eye based on changes in anatomical and functional features. The condition of the eye surface, central corneal thickness (CCT), endothelial cell density (ECD), lens densitometry, central macular thickness (CMT), and retinal nerve fiber layer (RNFL) were the anatomical features assessed. The functional tests were best-corrected visual acuity (BCVA), intraocular pressure (IOP), visual field (VF) and visual-evoked potentials (VEP). An ophthalmologic examination was performed before and 6, 12, 18, and 24 months after radiotherapy. RESULTS: We did not observe any significant changes in BCVA, IOP, CCT, CMT, VF, and VEP, nor in the slit-lamp examination during the two-years observation. We found a significant decrease in ECD at all follow-up measurements. The drop in ECD exceeded approximated age-related physiological loss. The reduction in ECD was not large enough to disrupt corneal function and thus affect vision. We also observed a statistically significant reduction of RNFL in all observation time points. However, there was no correlation between the dose delivered to the optic pathway and the decrease in RNFL thickness. The thinning of the RNFL was not significant enough to impair visual function. CONCLUSION: Fractionated robotic radiotherapy of the tumors located close to the optical pathway is safe and does not impair patient's vision. Minor changes found in optic nerve anatomy (RNFL thinning) might be related to radiation effect or tumor compression. The causal relation between low doses of radiation delivered to the cornea and the observed significant but slight decrease in ECD is uncertain. The observed changes did not cause visual disturbances perceivable by the patients.

Grade migration and important prognostic factors in a pathology specimen for radical radiotherapy in prostate cancer patients.

The study aimed to evaluate grade migration and prognosis depending on pathologic features in patients with prostate cancer treated with radical external beam radiotherapy. The study included 139 patients with an initial Gleason score of 7 (3+4 or 4+3) i.e., Grade Group 2-3 (GG2-GG3) treated between 2008 and 2013. The clinical outcome was assessed with respect to biochemical control (BC) and biochemical disease-free survival (bDFS). After re-evaluation, the majority of patients (96 patients - 69%) were up-graded from GG2-3. Finally, there were 4 patients (3%) with grade GG1, 12 patients (9%) - GG2, 27 patients (19%) - GG3, 51 patients (37%) - GG4 and 45 patients (32%) - GG5. In 42 patients (30%) a cribriform pattern was observed. Among the analyzed factors only the GGs were important for BC (p = 0.011) and the cribriform pattern was of borderline significance (p = 0.06). The 5-year biochemical control was 100% in GG1-3 and 84% in GG4-5. The 5-year biochemical control was 81% and 93%, if cribriform or no cribriform pattern was detected, respectively. In conclusion, re-evaluation and verification of pathology specimens in accordance with contemporary rules upgraded the Gleason score in the majority of patients. The aggressive behavior of prostate cancer starts to occur from GG 4. Cribriform pattern almost tripled the biochemical failure rate.

Global challenges of radiotherapy for the treatment of locally advanced cervical cancer.

Cervical cancer represents a significant portion of the global cancer burden for women, with low- and middle-income countries carrying the bulk of this burden. Additionally, underserved populations in countries with sufficient resources may have a higher incidence of cervical cancer and poorer outcomes. Concurrent chemoradiotherapy is the standard-of-care treatment for locally advanced cervical cancer, which includes patients with stage IB3 to IVA disease, and it is effective for many patients; however, cervical cancer-related mortality remains high. The critical nature of cervical cancer treatment is underscored by the recent launch of the World Health Organization global initiative to accelerate the elimination of cervical cancer using a triple-intervention strategy of increased vaccination, screening, and treatment. The initiative calls for 90% of all patients diagnosed with cervical cancer to receive the appropriate treatment, but to reach this global goal there are significant barriers related to radiotherapy that must be addressed. We discuss and review evidence of the lack of adherence to guideline-recommended treatment, brachytherapy underutilization, limited access to radiotherapy in low- and middle-income countries, as well as regional limitations within high-income countries, as the major barriers to radiotherapy treatment for locally advanced cervical cancer. We further review ways these barriers are currently being addressed and, in some cases, make additional recommendations to address these issues. Finally, despite receiving recommended treatments, many patients with locally advanced cervical cancer have a poor prognosis. With effective administration of current standards of care, the global community will be able to shift focus to advancing treatment efficacy for these patients. We review several types of therapies under clinical investigation that are additions to concurrent chemoradiotherapy, including immune checkpoint inhibitors, antiangiogenic agents, DNA repair inhibitors, human papillomavirus vaccines, and radiosensitizing nanoparticles.

Volumetric staging in radiotherapy for oropharyngeal cancers.

INTRODUCTION: Despite routine use of 3D radiotherapy planning in radical radio(chemo)therapy for oropharyngeal cancers, volumetric data have not been implemented in initial staging. We analyzed 228 oropharyngeal cancer cases treated at one institution between 2004 and 2014 to compare the predictive value of volumetric staging and tumor nodal metastasis staging system (TNM) and determine whether they could be complementary for the estimation of survival. METHODS: This retrospective study analyzed 228 consecutive oropharyngeal cancer cases treated with radiotherapy (76.9%) or concurrent radiochemotherapy (23.1%) between 2004 and 2014. The volumetric parameters included primary gross tumor volume (pGTV), metastatic lymph nodes gross tumor volume (nGTV), and total gross tumor volume (tGTV), and were compared with the 7th edition of the TNM staging system. RESULTS: Median overall survival (OS) was 30.3 months. In the receiver operating characteristic analysis, tGTV had the highest area under the curve (AUC) of 0.66, followed by pGTV (AUC,0.64), nGTV (AUC 0.62), and TNM (AUC 0.6). The median OS for patients with tGTV ⩽32.2 mL was 40.5 months, compared to 15.4 months for >32.2 mL (p < 0.001). This threshold allowed for a statistically significant difference in survival between TNM stage IV cases with low and high tumor volume (p < 0.001). Despite both TNM and tGTV reaching statistical significance in univariate analysis, only the tGTV remained an independent prognostic factor in the multivariate analysis (hazard ratio 1.07, confidence interval 1.02-1.12, p = 0.008). CONCLUSIONS: tGTV is an independent prognostic factor, characterized by a higher discriminatory value than the TNM staging system, and can be used to further divide stage IV cases into subgroups with significantly different prognosis.

Positron Emission Tomography-Guided Bone Marrow-Sparing Radiation Therapy for Locoregionally Advanced Cervix Cancer: Final Results From the INTERTECC Phase II/III Trial.

PURPOSE: To test effects of positron emission tomography (PET)-based bone marrow-sparing (BMS) image-guided intensity modulated radiation therapy (IG-IMRT) on efficacy and toxicity for patients with locoregionally advanced cervical cancer. METHODS AND MATERIALS: In an international phase II/III trial, patients with stage IB-IVA cervical carcinoma were treated with either PET-based BMS-IG-IMRT (PET-BMS-IMRT group) or standard image-guided IMRT (IMRT group), with concurrent cisplatin (40 mg/m2 weekly), followed by brachytherapy. The phase II component nonrandomly assigned patients to PET-BMS-IMRT or standard IMRT. The phase III trial randomized patients to PET-BMS-IMRT versus IMRT, with a primary endpoint of progression-free survival (PFS) but was closed early for futility. Phase III patients were analyzed separately and in combination with phase II patients, comparing acute hematologic toxicity, cisplatin delivery, PFS, overall survival (OS), and patterns of failure. In a post-hoc exploratory analysis, we investigated the association between pretreatment absolute lymphocyte count (ALC) and OS. RESULTS: In total, 101 patients were enrolled on the phase II/III trial, including 29 enrolled in phase III (PET-BMS-IMRT group: 16; IMRT group: 13) before early closure. Median follow-up was 33 months for phase III patients and 39 months for all patients. PFS and OS at 5 years for all patients were 73.6% (95% confidence interval [CI], 64.9%-84.3%) and 84% (95% CI, 76%-92.9%]), respectively. There were no differences in number of cisplatin cycles, OS, PFS, or patterns of failure between groups for the combined cohort. The incidence of acute grade ≥ 3 neutropenia was significantly lower in the PET-BMS-IMRT group compared with IMRT for randomized patients (19% vs 54%, χ2P = .048) and in the combined cohort (13% vs 35%, χ2P = .01). Patients with pretreatment ALC ≤ 1.5 k/µL had nonsignificantly worse OS on multivariable analysis (HR 2.85; 95% CI, 0.94-8.62; adjusted P = .216), compared with patients with ALC > 1.5 k/µL. There was no difference in posttreatment ALC by treatment group. CONCLUSIONS: PET-BMS-IMRT significantly reduced acute grade ≥3 neutropenia, but not treatment-related lymphopenia, compared with standard IMRT. We found no evidence that PET-BMS-IMRT affected chemotherapy delivery or long-term outcomes, and weak evidence of an association between pretreatment ALC and OS.

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001.

BACKGROUND: Pembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy. PRIMARY OBJECTIVE: To compare the efficacy and safety of first-line pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease. STUDY HYPOTHESIS: Pembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression-free survival and overall survival in patients with mismatch repair-proficient tumors and all patients (all-comers). TRIAL DESIGN: Phase 3, randomized (1:1), open-label, active-controlled trial. Patients will receive pembrolizumab intravenously every 3 weeks plus lenvatinib orally daily or paclitaxel plus carboplatin intravenously every 3 weeks, stratified by mismatch repair status (proficient vs deficient). Patients with mismatch repair-proficient tumors will be further stratified by Eastern Cooperative Oncology Group performance status (0/1), measurable disease (yes/no), and prior chemotherapy and/or chemoradiation (yes/no). MAJOR INCLUSION/EXCLUSION CRITERIA: Adults with stage III/IV/recurrent histologically confirmed endometrial cancer that is measurable or radiographically apparent per blinded independent central review. Patients may have received previous chemotherapy only as neoadjuvant/adjuvant therapy and/or concurrently with radiation. Patients with carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, or other high grade sarcomas, or endometrial stromal sarcomas were excluded. PRIMARY ENDPOINTS: Progression-free and overall survival (dual primary endpoints). SAMPLE SIZE: About 875 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Enrollment is expected to take approximately 24 months, with presentation of results in 2022. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03884101.

The survival impact of significant delays between surgery and radiochemotherapy in glioblastoma patients: A retrospective analysis from a large tertiary center.

The optimal timing of adjuvant radiochemotherapy (RCT) in glioblastoma (GBM) patients remains unknown and the paradigm of 'the sooner, the better' has been challenged by many recent publications. In this study, we present unique data on the outcomes of patients with significant treatment delays. The study group consisted of 346 GBM patients (median age 56.8 years) who received surgical treatment (total or subtotal resection) and then underwent adjuvant concurrent RCT at one institution. The main endpoint was overall survival (OS). The Univariate and multivariate Cox Proportional-Hazard Model, log-rank test, and Kaplan-Meier method were used for the analysis. The median OS was 18.7 months and the 5-year overall survival was 8.5%. The median time interval from surgery to RCT was 9.8 weeks. The Cox regression showed that the time interval had no statistically significant impact on OS both in uni- and multivariate analysis. The explorative analysis suggested a positive trend for improved survival for patients in the 1st quartile of the time interval, especially for patients with residual disease or local recurrence prior to RCT, However, considering the 6.9 weeks median interval in the 1st quartile, this subgroup should still be regarded as 'moderate delay' compared with other literature data. The results indicate that the time interval is not a clear prognostic factor in the treatment of GBM. Prospective trials are highly warranted, as data suggest that moderate delays in the initiation of adjuvant treatment might be associated with survival benefit.

The prognostic value of red cell distribution width (RDW), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in radiotherapy for oropharyngeal cancer.

BACKGROUND: Red cell distribution width (RDW), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are known inflammatory indices. Elevated values are found in many cancers and may be associated with a poor prognosis. The article aimed to assess the impact of RDW, NLR, and PLR on overall survival (OS) of patients with oropharyngeal cancer treated with radiotherapy (RT). MATERIALS AND METHODS: This retrospective study includes 208 patients treated for oropharyngeal cancer with definitive RT or RT combined with neoadjuvant or concurrent systemic therapy, at one institution between 2004 and 2014. The receiver operating characteristic (ROC) method, log-rank testing, and Cox proportional hazards regression model were used for the analysis. RESULTS: The OS was significantly higher in RDW ≤ 13.8% (p = 0.001) and NLR ≤ 2.099 (p = 0.016) groups. The RDW index was characterized by the highest discriminatory ability [area under the curve (AUC) = 0.59, 95% confidence interval (CI): 0.51-0.67], closely followed by NLR (AUC = 0.58, 95% CI: 0.50-0.65). In the univariate Cox regression analysis, RDW [hazard ratio (HR): 1.28, 95% CI: 1.12-1.47, p < 0.001] and NLR (HR: 1.11, 95% CI: 1.06-1.18, p < 0.001) were associated with an increased risk of death. In the multivariate analysis, among the analyzed indices, only NLR was significantly associated with survival (HR: 1.16, 95% CI: 1.03-1.29, p = 0.012). CONCLUSIONS: In the study, only NLR proved to be an independent predictor of OS. However, its clinical value is limited due to the relatively low sensitivity and specificity.

Comparison of Hematologic Toxicity and Bone Marrow Compensatory Response in Head and Neck vs. Cervical Cancer Patients Undergoing Chemoradiotherapy.

Background: Hematologic toxicity is a critical problem limiting treatment delivery in cancer patients undergoing concurrent chemoradiotherapy. However, the extent to which anatomic variations in radiation dose limit chemotherapy delivery is poorly understood. A unique natural experiment arises in patients with head and neck and cervical cancer, who frequently undergo identical chemotherapy but receive radiation to different regions of the body. Comparing these cohorts can help elucidate to what extent hematologic toxicity is attributable to marrow radiation as opposed to chemotherapy. Methods: In this longitudinal cohort study, we compared hematologic toxicity and bone marrow compensatory response in 148 patients (90 cervix, 58 head/neck) undergoing chemoradiotherapy with concurrent weekly cisplatin 40 mg/m2. We used linear mixed effect models to compare baseline and time-varying peripheral cell counts and hemoglobin levels between cohorts. To assess bone marrow compensatory response, we measured the change in metabolically active bone marrow (ABM) volume on 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Results: We observed greater reductions in log-transformed lymphocyte, platelet, and absolute neutrophil counts (ANC) for cervix compared to head/neck cancer patients (fixed effects for time-cohort interaction [95% CI]: lymphocytes, -0.06 [-0.09, -0.031]; platelets,-0.028 [-0.051, -0.0047]; ANC, -0.043 [-0.075, -0.011]). Mean ANC nadirs were also lower for cervical vs. head/neck cancer cohorts (2.20 vs. 2.85 × 103 per µL, p < 0.01). Both cohorts exhibited reductions in ABM volume within the radiation field, and increases in ABM volume in out-of-field areas, indicating varying compensatory response to radiation injury. Conclusions: Cervical cancer patients had faster decreases in ANC, lymphocyte, and platelet counts, and lower ANC nadirs, indicating a significant effect of pelvic irradiation on acute peripheral blood cell counts. Both cohorts exhibited a compensatory response with increased out-of-field bone marrow activity.

Effectiveness and safety of CyberKnife radiosurgery in treatment of trigeminalgia - experiences of Polish neurological and oncological centres.

Trigeminal neuralgia (TN) is one of the most common cranial neuropathies. Pathologies located alongside the long nerve can also cause its mechanical compression or secondary involvement in the inflammatory process, and thus cause pain. TN is characterised by severe paroxysmal unilateral facial pain in the innervation area of branches I-III of the nerve V when provoked by light touch or slight movement. Multiple therapeutic methods are available, but most of them yield unsatisfactory results. According to guidelines (AAN and EFNS) the first-line therapy in trigeminalgia is carbamazepine/oxcarbazepine, and if there is a poor response - surgical treatment [1]. The array of surgical options includes percutaneous retrogasserian glycerol injection, radiofrequency thermocoagulation, balloon decompression, thermal rhizotomy, and stereotactic radiosurgery [2-4]. This paper presents our own experiences with CyberKnife (CK), a new type of radiosurgical (RS) treatment of 64 TN patients. CONCLUSIONS: CyberKnife radiotherapy is characterised by high efficacy in 80% of patients with trigeminalgia, minimal invasiveness, and subsiding mild side effects. Radioablation of nerve V root in patients with neuralgia allows us to entirely stop antiepileptic therapy or reduce its doses, which in turn reduces the risk of potential side effects. CyberKnife can be a therapeutic option in those patients who have been offered ineffective therapies, or treatments with limited efficacy, and/or in older patients with comorbidities.

Association of breast cancer grade with response to neoadjuvant chemotherapy assessed postoperatively.

Currently, breast cancer chemotherapy response can be predicted based on various parameters, with common reporting of tumour grade and Ki67 proliferation index. We analysed their association with pathological complete response (pCR) in a multivariate approach. The study was carried out in a group of 353 patients, treated by preoperative chemotherapy and prospectively observed. In selected patients, parallel to routing core needle biopsy assessment, gene expression profile of tumour was analysed by oligonucleotide microarrays. Tumour parameters associated with pCR in univariate analysis were: tumour grade, nuclear grade, mitotic index, Ki67, oestrogen and progesterone receptor (all p < 0.0001), and triple-negative status (p = 0.0032). The highest increase of pCR chance was observed in patients with high-grade tumours and with Ki67 ≥ 20%. In multivariate analysis, only tumour grade and oestrogen receptor status were predictive for pCR independently of other variables, with high grade increasing the odds of pCR 2.42 fold, and high ER decreasing the chance of pCR 0.41 fold. Tumour grading reflects important biological features of breast cancer and is not inferior to proliferation markers, including Ki67. It should be taken into account in decision-making for preoperative chemotherapy in parallel to breast cancer biologic subtypes, because grade 3 tumours exhibit a higher proportion of pCR.

Feasibility of atlas-based active bone marrow sparing intensity modulated radiation therapy for cervical cancer.

BACKGROUND: To test the hypothesis that atlas-based active bone marrow (ABM)-sparing intensity modulated radiation therapy (IMRT) yields similar dosimetric results compared to custom ABM-sparing IMRT for cervical cancer patients. METHODS: We sampled 62 cervical cancer patients with pre-treatment FDG-PET/CT in training (n=32) or test (n=30) sets. ABM was defined as the subvolume of the pelvic bone marrow (PBM) with standardized uptake value (SUV) above the mean on the average FDG-PET image (ABMAtlas) vs. the individual's PET (ABMCustom). Both were deformed to the planning CT. Overlap between the two subvolumes was measured using the Dice coefficient. Three IMRT plans designed to spare PBM, ABMAtlas, or ABMCustom were compared for 30 test patients. Dosimetric parameters were used to evaluate plan quality. RESULTS: ABMAtlas and ABMCustom volumes were not significantly different (p=0.90), with a mean Dice coefficient of 0.75, indicating good agreement. Compared to IMRT plans designed to spare PBM and ABMCustom, ABMAtlas-sparing IMRT plans achieved excellent target coverage and normal tissue sparing, without reducing dose to ABMCustom (mean ABMCustom dose 29.4Gy vs. 27.1Gyvs. 26.9Gy, respectively; p=0.10); however, PTV coverage and bowel sparing were slightly reduced. CONCLUSIONS: Atlas-based ABM sparing IMRT is clinically feasible and may obviate the need for customized ABM-sparing as a strategy to reduce hematologic toxicity.

Bone Marrow-sparing Intensity Modulated Radiation Therapy With Concurrent Cisplatin For Stage IB-IVA Cervical Cancer: An International Multicenter Phase II Clinical Trial (INTERTECC-2).

PURPOSE: To test the hypothesis that intensity modulated radiation therapy (IMRT) reduces acute hematologic and gastrointestinal (GI) toxicity for patients with locoregionally advanced cervical cancer. METHODS AND MATERIALS: We enrolled patients with stage IB-IVA cervical carcinoma in a single-arm phase II trial involving 8 centers internationally. All patients received weekly cisplatin concurrently with once-daily IMRT, followed by intracavitary brachytherapy, as indicated. The primary endpoint was the occurrence of either acute grade ≥3 neutropenia or clinically significant GI toxicity within 30 days of completing chemoradiation therapy. A preplanned subgroup analysis tested the hypothesis that positron emission tomography-based image-guided IMRT (IG-IMRT) would lower the risk of acute neutropenia. We also longitudinally assessed patients' changes in quality of life. RESULTS: From October 2011 to April 2015, 83 patients met the eligibility criteria and initiated protocol therapy. The median follow-up was 26.0 months. The incidence of any primary event was 26.5% (95% confidence interval [CI] 18.2%-36.9%), significantly lower than the 40% incidence hypothesized a priori from historical data (P=.012). The incidence of grade ≥3 neutropenia and clinically significant GI toxicity was 19.3% (95% CI 12.2%-29.0%) and 12.0% (95% CI 6.7%-20.8%), respectively. Compared with patients treated without IG-IMRT (n=48), those treated with IG-IMRT (n=35) had a significantly lower incidence of grade ≥3 neutropenia (8.6% vs 27.1%; 2-sided χ2P=.035) and nonsignificantly lower incidence of grade ≥3 leukopenia (25.7% vs 41.7%; P=.13) and any grade ≥3 hematologic toxicity (31.4% vs 43.8%; P=.25). CONCLUSIONS: IMRT reduces acute hematologic and GI toxicity compared with standard treatment, with promising therapeutic outcomes. Positron emission tomography IG-IMRT reduces the incidence of acute neutropenia.

Therapy-Related Changes in the Serum Proteome Patterns of Early Stage Breast Cancer Patients with Different Outcomes.

Adjuvant chemo- and/or radiotherapy is applied in a majority of patients treated for early stage breast cancer, although only a small percentage of these individuals are at high risk of metastasis or recurrence. Hence, knowledge of the biomarkers associated with the risk of disease progression might facilitate the planning of an optimal therapy and protect many patients from the toxicity of unnecessary treatment. In this study, we characterized the serum proteome of patients diagnosed with early-stage breast cancer, exhibiting either no evidence of disease five years after the end of therapy or suffering from metastasis, relapse or a second cancer during the corresponding follow-up. Samples collected before treatment and one year after the end of therapy, when no clinical symptoms of a treatment failure was evidenced, were analyzed using two classical proteomics approaches: LC-MS/MS and 2D-PAGE. A total of 42 proteins with relative quantities that were significantly different between pre- and post-treatment samples were identified in either group of patients; however, the observed changes were more frequent in the treatment-failure group. Among the posttreatment samples, 30 proteins were upregulated, and 10 proteins were downregulated, while 11 proteins were upregulated, and eight proteins were downregulated in the control group. Moreover, several proteins exhibited different patterns of changes in both groups of patients. For example, haptoglobin expression increased in the treatment-failure group but decreased in the control group (this pattern of changes was confirmed using an immunoassay). Notably, proteins affected in posttreatment samples in either group of patients could be associated with different molecular and cellular functions, including angiogenesis, blood coagulation and wound healing in the treatment-failure group and cell adhesion and cell death in the control group.

Early Detection of Malignant Transformation in Resected WHO II Low-Grade Glioma Using Diffusion Tensor-Derived Quantitative Measures.

OBJECTIVE: Here, we retrospectively investigate the value of voxel-wisely plotted diffusion tensor-derived (DTI) axial, radial and mean diffusivity for the early detection of malignant transformation (MT) in WHO II glioma compared to contrast-enhanced images. MATERIALS AND METHODS: Forty-seven patients underwent brain magnetic resonance imaging follow-up between 2006-2014 after gross-tumor resection of intra-axial WHO II glioma. Axial/Mean/Radial diffusivity maps (AD/MD/RD) were generated from DTI data. ADmin/MDmin/RDmin values were quantified within tumor regions-of-interest generated by two independent readers including tumor contrast-to-noise (CNR). Sensitivity/specificity and area-under-the-curve (AUC) were calculated using receiver-operating-characteristic analysis. Inter-reader agreement was assessed (Cohen's kappa). RESULTS: Eighteen patients demonstrated malignant transformation (MT) confirmed in 8/18 by histopathology and in 10/18 through imaging follow-up. Twelve of 18 patients (66.6%) with MT showed diffusion restriction timely coincidental with contrast-enhancement (CE). In the remaining six patients (33.3%), the diffusion restriction preceded the CE. The mean gain in detection time using DTI was (0.8±0.5 years, p = 0.028). Compared to MDmin and RDmin, ROC-analysis showed best diagnostic value for ADmin (sensitivity/specificity 94.94%/89.7%, AUC 0.96; p<0.0001) to detect MT. CNR was highest for AD (1.83±0.14), compared to MD (1.31±0.19; p<0.003) and RD (0.90±0.23; p<0.0001). Cohen's Kappa was 0.77 for ADmin, 0.71 for MDmin and 0.65 for RDmin (p<0.0001, respectively). CONCLUSION: MT is detectable at the same time point or earlier compared to T1w-CE by diffusion restriction in diffusion-tensor-derived maps. AD demonstrated highest sensitivity/specificity/tumor-contrast compared to radial or mean diffusivity (= apparent diffusion coefficient) to detect MT.